WO2021027722A1

WO2021027722A1 - Immunomodulator

Info

Publication number: WO2021027722A1
Application number: PCT/CN2020/107788
Authority: WO
Inventors: 李进; 张登友; 白晓光; 尚巳耘; 洪新福; 钟猛; 刘利; 周贤思; 杨丹梅; 黄昊岚; 林燕萍; 陈欣
Original assignee: 成都先导药物开发股份有限公司
Priority date: 2019-08-09
Filing date: 2020-08-07
Publication date: 2021-02-18
Also published as: CN112341446B; CN112341446A

Abstract

Disclosed is an immunomodulator, and specifically disclosed are a compound that inhibits IL-17A and the use thereof as an immunomodulator in the preparation of a drug. Disclosed is the use of a compound as shown in formula I or a stereoisomer thereof in the preparation of a drug for inhibiting IL-17A, wherein same provides a new option for clinically screening and/or preparing a drug for treating diseases associated with IL-17A activity.

Description

An immunomodulator

Technical field

The invention relates to an immunomodulator and its use in preparing medicines.

Background technique

IL-17 (Interleukin-17) is a pro-inflammatory 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 inflammation, 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 and is 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 the cell via 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 through the up-regulation of pro-inflammatory and neutrophil migration cytokines and chemokines (including IL-6, G-CSF, TNF-α, IL-1, CXCL1, CCL2, CXCL2) Coordinate local tissue inflammation and 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). Those patients usually do not respond or respond poorly to currently available drugs (Al-Ramli et al. J Allergy Clin Immunol, 2009, 123:1185-1187). Up-regulation of IL-17A levels involves many diseases, including rheumatoid arthritis (RA), bone erosion, intraperitoneal abscess, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma, and multiple Sclerosis (Gaffen, SL et al. Arthritis Research & Therapy, 2004, 6: 240-247).

Targeting the combination of IL-17A and IL-17RA is an effective strategy to treat IL-17A-mediated autoimmune inflammatory diseases. Treating animals with IL-17A neutralizing antibodies reduces the incidence and severity of the disease in autoimmune encephalomyelitis (Komiyama Y et al. J. Immunol., 2006, 177: 566-573). The clinical trials of IL-17A antibody have shown good results on IL-7A-mediated inflammatory diseases (including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis). The IL-17A antibody (Cosentyx/secukinumab from Novartis) was approved by the FDA for the treatment of psoriasis in January 2015.

Although there are a variety of IL-17A antibodies, few studies have been conducted on small-molecule specific inhibitors of IL-17 with oral bioavailability. In view of the cost considerations of producing antibodies and the limitation of the route of administration, the development of IL-17A small molecule inhibitor drugs has a good research and development prospect.

Summary of the invention

The present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

among them,

R _{1 is} selected from hydrogen, -C _1-10 alkyl, -C _0-4 alkylene-(3-10 membered cycloalkyl), -C _0-4 alkylene-(3-10 membered heterocycloalkane Group), -C _0～4 alkylene-(5-10 membered aromatic ring), -C _0～4 alkylene-(5-10 membered aromatic heterocyclic ring), -NR ₁₁ R ₁₂ , -OR ₁₁ ; Wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring may be further substituted by one, two or three independent R ₁₃ ;

R ₁₁ and R ₁₂ are each independently selected from hydrogen, -C _1-6 alkyl, -C _0-4 alkylene-(3-10 membered cycloalkyl), -C _0-4 alkylene-(3～ 10-membered heterocycloalkyl), -C _0-4 alkylene-(5-10 membered aromatic ring), -C _0-4 alkylene-(5-10 membered aromatic heterocyclic ring); wherein cycloalkyl, The heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further substituted by one, two or three independent R ₁₃ ;

Each R _{13 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -OH, -O (C _1-10 alkyl), -NH ₂ , -NH (C _1-10 alkyl), -N (C _1-10 alkyl) (C _1-10 alkyl);

R _{2 is} selected from hydrogen, -C _1-10 alkyl, -C _0-4 alkylene-(3-10 membered cycloalkyl);

R ₃ and R ₄ are each independently selected from hydrogen, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -C _0-4 alkylene-(3-10 membered cycloalkyl),- C _0～4 alkylene group-(3～10 membered heterocycloalkyl group), -O(C _1～10 alkyl group), -O(C _0～4 alkylene group) (3～10 membered cycloalkyl group) , -O(C _0-4 alkylene) (3-10 membered heterocycloalkyl); wherein alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R ₃₁ ;

Or R ₃ and R _{4 are} connected to form a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three R ₃₁ ;

Each R _{31 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -OH, -O (C _1-10 alkyl), -O(C _0～4 alkylene) (3～10 membered cycloalkyl), -O(C _0～4 alkylene) (3～10 membered heterocycloalkyl);

Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; among them, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic The heterocycle may be further substituted by one, two or three R _A1 ;

Each R _{A1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -C _0-4 alkylene -OR _A2 ,- C _0～4 alkylene-OC(O)R _A2 , -C _0～4 alkylene-C(O)R _A2 , -C _0～4 alkylene-C(O)OR _A2 , -C _{0 ～4} alkylene-C(O)NR _A2 R _A3 , -C _0～4 alkylene-NR _A2 R _A3 , -C _0～4 alkylene-NR _A2 C(O)R _A3 , -C _{0 ～4} alkylene-(3～10 membered cycloalkyl), -C _0～4 alkylene-(3～10 member heterocycloalkyl), -C _0～4 alkylene-(5～10 member Aryl ring), -C _0～4 alkylene-(5～10 member aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further divided by one, two or three R _A4 replaced;

Each R _{A4 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -C _0-4 alkylene -OR _A2 ,- C _0～4 alkylene-OC(O)R _A2 , -C _0～4 alkylene-C(O)R _A2 , -C _0～4 alkylene-C(O)OR _A2 , -C _{0 ～4} alkylene-C(O)NR _A2 R _A3 , -C _0～4 alkylene-NR _A2 R _A3 , -C _0～4 alkylene-NR _A2 C(O)R _A3 ;

R _A2 and R _A3 are each independently selected from hydrogen and -C _1-10 alkyl;

X _{1 is} selected from CR _x1 or N;

X _{2 is} selected from NR _x2 , O, S or -(CR _x3 =CR _x4 )-;

R _x1 , R _x3 , and R _x4 are each independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -OH, -O(C _1-10 alkyl);

R _{x2 is} selected from hydrogen, -C _1-10 alkyl, -C(O) (C _1-10 alkyl);

Ring B is selected from 3-10 membered heterocycloalkyl; wherein heterocycloalkyl may be further substituted by one, two or three R _B1 ;

Each R _{B1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -OH, -O (C _1-10 alkyl), -NH ₂ , -NH (C _1-10 alkyl), -N (C _1-10 alkyl) (C _1-10 alkyl);

L _{2 is} selected from -C _0～4 alkylene-C(O)NR _L21 -, -C _0～4 alkylene-NR _L21 C(O)-, -C _0～4 alkylene-S(O )NR _L21 -, -C _0～4 alkylene-S(O) ₂ NR _L21 -, -C _0～4 alkylene-NR _L21 S(O)-, -C _0～4 alkylene-NR _L21 S(O) ₂ -, -C _0～4 alkylene-P(O)(OH)NR _L21 -, -C _0～4 alkylene-NR _L21 P(O)(OH)-, -C _0～4 alkylene-C(O)-, -C _0～4 alkylene-NR _L21 -;

R _{L21 is} selected from hydrogen, -C _1-10 alkyl;

R is selected from -C _0～4 alkylene-(3～10 membered cycloalkyl), -C _0～4 alkylene-(3～10 membered heterocycloalkyl), -C _0～4 alkylene -(5～10 membered aromatic ring), -C _0～4 alkylene-(5～10 membered aromatic heterocycle), -C _0～4 alkylene-(5～12 membered spiro ring), -C _{0 ～4} alkylene-(5～12 membered spiro heterocycle), -C _0～4 alkylene-(5～12 member bridged ring), -C _0～4 alkylene-(5～12 member bridge hetero ring),

Wherein C ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; wherein cycloalkyl, heterocycloalkyl, aromatic ring, The aromatic heterocyclic ring, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R _d ;

R _{_a,} R _a _'are each independently selected from hydrogen, -C _{1 ~ 10} alkyl, halogen-substituted -C _{1 ~ 10} alkyl, -C _{0 ~ 4} alkylene group - (3 to 10-membered cycloalkyl group), -C _0～4 alkylene-(3-10 membered heterocycloalkyl), -C _0～4 alkylene-(5-12 membered spiro ring), -C _0～4 alkylene-(5～ 12-membered spiro heterocycle), -C _0～4 alkylene-(5-12 membered bridged ring), -C _0～4 alkylene-(5-12 membered bridged heterocyclic ring), -O(C _{1～ 10} alkyl), -O (C _0-4 alkylene) (3-10 membered cycloalkyl), -O (C _0-4 alkylene) (3-10 membered heterocycloalkyl); wherein the alkane Group, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, bridged heterocyclic ring may be further substituted by one, two or three R _a1 ;

Each R _{a1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -OH, -O (C _1-10 alkyl);

R _b and R _c are each independently selected from hydrogen, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -C _0-4 alkylene-(3-10 membered cycloalkyl),- C _0～4 alkylene-(3～10 membered heterocycloalkyl), -C _0～4 alkylene-(5～10 member aromatic ring), -C _0～4 alkylene-(5～10 -Membered aromatic heterocycle), -C _0～4 alkylene-(5-12 membered spiro ring), -C _0～4 alkylene-(5-12 membered spiro heterocyclic ring), -C _0～4 Alkyl-(5-12 membered bridged ring), -C _0-4 alkylene-(5-12 membered bridged heterocyclic ring); among them alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring , Spiro ring, spiro heterocyclic ring, bridged ring, bridged heterocyclic ring may be further substituted by one, two or three R _b1 ;

Or R _a and R _{b are} connected to form a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered aromatic heterocycle, a 5- to 12-membered spiro heterocycle, and a 5- to 12-membered bridged heterocycle; among them, heterocycloalkyl and aromatic heterocycle , Spiro heterocycles and bridged heterocycles can be further substituted by one, two or three _Rd ;

Each R _{b1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -OH, -O (C _1-10 alkyl);

Each R _{d is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-10 alkyl, halogen-substituted -C _1-10 alkyl, -C _0-4 alkylene -OR _d1 , -C _0～4 alkylene-OC(O)R _d1 , -C _0～4 alkylene-C(O)R _d1 , -C _0～4 alkylene-C(O)OR _d1 , -C _{0～ 4} alkylene-C(O)NR _d1 R _d2 , -C _0～4 alkylene-NR _d1 R _d2 , -C _0～4 alkylene-NR _d1 C(O)R _d2 ;

R _d1 and R _d2 are each independently selected from hydrogen, -C _1-10 alkyl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl.

further,

R _{1 is} selected from hydrogen, -C _1-6 alkyl, -C _0-2 alkylene-(3-6 membered cycloalkyl), -C _0-2 alkylene-(3-6 membered heterocycloalkane) Group), -C _0～2 alkylene-(5-6 membered aromatic ring), -C _0～2 alkylene-(5-6 membered aromatic heterocyclic ring), -NR ₁₁ R ₁₂ , -OR ₁₁ ; Wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring may be further substituted by one, two or three independent R ₁₃ ;

R ₁₁ and R ₁₂ are each independently selected from hydrogen, -C _1-6 alkyl, -C _0-2 alkylene-(3-6 membered cycloalkyl), -C _0-2 alkylene-(3～ 6-membered heterocycloalkyl), -C _0-2 alkylene-(5-6 membered aromatic ring), -C _0-2 alkylene-(5-6 membered aromatic heterocyclic ring); wherein cycloalkyl, The heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further substituted by one, two or three independent R ₁₃ ;

Each R _{13 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl), -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl);

R _{2 is} selected from hydrogen, -C _1-6 alkyl, -C _0-2 alkylene-(3-6 membered cycloalkyl);

R ₃ and R ₄ are each independently selected from hydrogen, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -C _0-2 alkylene-(3-6 membered cycloalkyl),- C _0～2 alkylene-(3～6 membered heterocycloalkyl), -O(C _1～6 alkyl), -O(C _0～2 alkylene) (3～6 membered cycloalkyl) , -O(C _0-2 alkylene) (3-6 membered heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R ₃₁ ;

Or R ₃ and R _{4 are} connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three R ₃₁ ;

Each R _{31 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl), -O(C _0～2 alkylene) (3～6 membered cycloalkyl), -O(C _0～2 alkylene) (3～6 membered heterocycloalkyl);

Ring A is selected from a 5- to 6-membered aromatic ring and a 5- to 6-membered aromatic heterocyclic ring; wherein the aromatic ring and the aromatic heterocyclic ring may be further substituted by one, two or three R _A1 ;

Each R _{A1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -C _0-2 alkylene -OR _A2 ,- C _0～2 alkylene-OC(O)R _A2 , -C _0～2 alkylene-C(O)R _A2 , -C _0～2 alkylene-C(O)OR _A2 , -C _{0 ～2} alkylene-C(O)NR _A2 R _A3 , -C _0～2 alkylene-NR _A2 R _A3 , -C _0～2 alkylene-NR _A2 C(O)R _A3 , -C _{0 ～2} alkylene-(3～6 membered cycloalkyl), -C _0～2 alkylene-(3～6 membered heterocycloalkyl), -C _0～2 alkylene-(5～6 member Aromatic ring), -C _0～2 alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocycle can be further divided by one, two or three R _A4 replaced;

Each R _{A4 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -C _0-2 alkylene -OR _A2 ,- C _0～2 alkylene-OC(O)R _A2 , -C _0～2 alkylene-C(O)R _A2 , -C _0～2 alkylene-C(O)OR _A2 , -C _{0 ～2} alkylene-C(O)NR _A2 R _A3 , -C _0～2 alkylene-NR _A2 R _A3 , -C _0～2 alkylene-NR _A2 C(O)R _A3 ;

R _A2 and R _A3 are each independently selected from hydrogen and -C _1-6 alkyl;

X _{1 is} selected from CR _x1 or N;

X _{2 is} selected from NR _x2 , O, S or -(CR _x3 =CR _x4 )-;

R _x1 , R _x3 , and R _x4 are independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O(C _1-6 alkyl);

R _{x2 is} selected from hydrogen, -C _1-6 alkyl, -C(O) (C _1-6 alkyl);

Ring B is selected from 3-6 membered heterocycloalkyl groups; wherein heterocycloalkyl groups may be further substituted with one, two or three R _B1 ;

Each R _{B1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl), -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl);

L _{2 is} selected from -C _0～2 alkylene-C(O)NR _L21 -, -C _0～2 alkylene-NR _L21 C(O)-, -C _0～2 alkylene-C(O )-, -C _0～2 alkylene-NR _L21 -;

R _{L21 is} selected from hydrogen, -C _1-6 alkyl;

R is selected from -C _0～2 alkylene-(3～6 membered cycloalkyl), -C _0～2 alkylene-(3～6 membered heterocycloalkyl), -C _0～2 alkylene -(5～6 membered aromatic ring), -C _0～2 alkylene-(5～6 membered aromatic heterocyclic ring), -C _0～2 alkylene-(6～11 membered spiro ring), -C _{0 ～2} alkylene-(6～11 membered spiro heterocycle), -C _0～2 alkylene-(5～10 member bridged ring), -C _0～2 alkylene-(5～10 member bridge hetero ring),

Wherein C ring is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; wherein cycloalkyl, heterocycloalkyl, aromatic ring, The aromatic heterocyclic ring, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R _d ;

R _{_a,} R _a _'are each independently selected from hydrogen, -C _{1 ~ 6} alkyl, halogen-substituted -C _{1 ~ 6} alkyl, -C _{0 ~ 2} alkylene group - (3-6 membered cycloalkyl), -C _0～2 alkylene-(3-6 membered heterocycloalkyl), -C _0～2 alkylene-(6-11 membered spiro ring), -C _0～2 alkylene-(6～ 11-membered spiro heterocyclic ring), -C _0-2 alkylene-(5-10 membered bridged ring), -C _0-2 alkylene-(5-10 membered bridged heterocyclic ring), -O(C _{1～ 6} alkyl), -O (C _{0 ~ 2} alkylene) (3 ~ 6 membered cycloalkyl), -O (C _{0 ~ 2} alkylene) (3 ~ 6 membered heterocycloalkyl); Group, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, bridged heterocyclic ring may be further substituted by one, two or three R _a1 ;

Or R _a and R _a'are connected to form a 3-6 membered cycloalkyl group and a 3-6 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three _Ra1 ;

Each R _{a1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl);

R _b and R _c are each independently selected from hydrogen, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -C _0-2 alkylene-(3-6 membered cycloalkyl),- C _0～2 alkylene-(3～6 membered heterocycloalkyl), -C _0～2 alkylene-(5～6 member aromatic ring), -C _0～2 alkylene-(5～6 Membered aromatic heterocycle), -C _0～2 alkylene-(6-11 membered spiro ring), -C _0～2 alkylene-(6-11 membered spiro heterocyclic ring), -C _0～2 alkylene Group-(5-10 membered bridged ring), -C _0-2 alkylene-(5-10 membered bridged heterocyclic ring); among them alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring, The spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R _b1 ;

Or R _a and R _{b are} connected to form a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered aromatic heterocycle, a 5- to 12-membered spiro heterocycle, and a 5- to 12-membered bridged heterocycle; among them, heterocycloalkyl and aromatic heterocycle , Spiro heterocycle, bridge heterocycle may be further substituted by one, two or three R _d ; each R _{b1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl);

Each R _{d is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -C _0-2 alkylene -OR _d1 , -C _0～2 alkylene-OC(O)R _d1 , -C _0～2 alkylene-C(O)R _d1 , -C _0～2 alkylene-C(O)OR _d1 , -C _{0～ 2} alkylene-C(O)NR _d1 R _d2 , -C _0～2 alkylene-NR _d1 R _d2 , -C _0～2 alkylene-NR _d1 C(O)R _d2 ;

R _d1 and R _d2 are each independently selected from hydrogen, -C _1-6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl.

Further, the compound of formula I is represented by formula II:

among them,

Ring A is selected from 3 to 6 membered cycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; wherein the cycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further divided by one, two or three R _A1 replace;

Ring B is selected from 3-6 membered heterocycloalkyl groups;

R _a is selected from hydrogen, -C _{1 ~ 6} alkyl, halogen-substituted -C _{1 ~ 6} alkyl, -C _{0 ~ 2} alkylene group - (3-6 membered cycloalkyl), - C _{0 ~ 2} alkylene Alkyl-(3~6 membered heterocycloalkyl), -C _0~2 alkylene-(6~11 membered spiro ring), -C _0~2 alkylene-(6~11 membered spiro heterocyclic ring) , -C _0～2 alkylene group-(5～10 membered bridged ring), -C _0～2 alkylene group-(5～10 membered bridged heterocyclic ring), -O(C _1～6 alkyl group),- O(C _0～2 alkylene) (3～6 membered cycloalkyl), -O(C _0～2 alkylene) (3～6 membered heterocycloalkyl); of which alkyl, cycloalkyl, The heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R _a1 ;

R _b and R _c are each independently selected from hydrogen, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -C _0-2 alkylene-(3-6 membered cycloalkyl),- C _0～2 alkylene-(3～6 membered heterocycloalkyl)-C _0～2 alkylene-(5～6 member aromatic ring), -C _0～2 alkylene-(5～6 member Aromatic heterocycle), -C _0～2 alkylene-(6-11 membered spiro ring), -C _0～2 alkylene-(6-11 membered spiro heterocyclic ring), -C _0～2 alkylene -(5-10 membered bridged ring), -C _0-2 alkylene-(5-10 membered bridged heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spiro The ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R _b1 ;

Each R _{b1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl).

In some embodiments of the present invention, further,

R _{1 is} selected from -C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring, -NR ₁₁ R ₁₂ , -OR ₁₁ ; wherein cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocyclic ring may be further substituted by one, two or three independent R ₁₃ ;

R ₁₁ and R ₁₂ are each independently selected from hydrogen, -C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

Each R _{13 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl), -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl).

Furthermore, R _{1 is} selected from

-C _1-3 alkyl, -NR ₁₁ R ₁₂ or -OR ₁₁ ;

R ₁₁ and R ₁₂ are each independently selected from hydrogen, -C _1-2 alkyl, and 3-membered cycloalkyl;

R13 is selected from C _1-2 alkyl.

In some embodiments of the present invention, further,

R ₃ and R ₄ are each independently selected from hydrogen, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -O( C _1-6 alkyl), -O (3-6 membered cycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R ₃₁ ;

Each R _{31 is} independently selected from halogen, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl), -O (3--6 membered ring alkyl);

Preferably,

R _3, R ₄ are each independently selected from hydrogen, -C _{1 ~ 3} alkyl, -O (C ₁ alkyl), substituted with a R ₃₁ -C ₃ alkyl group, R ₃₁ a substituted 3-membered cycloalkyl group;

R _{31 is} selected from -C ₁ alkyl and halogen; halogen is preferably F.

Furthermore, at least one of R ₃ and R ₄ is hydrogen.

In some embodiments of the present invention, further,

Each R _{A1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OR _A2 , -OC(O)R _A2 ,- C(O)R _A2 , -C(O)OR _A2 , -C(O)NR _A2 R _A3 , -NR _A2 R _A3 , -NR _A2 C(O)R _A3 , 3-6 membered cycloalkyl, 3 ~ 6-membered heterocycloalkyl, 5 to 6-membered aromatic ring, 5 to 6-membered aromatic heterocyclic ring; wherein cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further divided by one, two or three R _A4 replaced;

Each R _{A4 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OR _A2 , -OC(O)R _A2 ,- C(O)R _A2 , -C(O)OR _A2 , -C(O)NR _A2 R _A3 , -NR _A2 R _A3 , -NR _A2 C(O)R _A3 ;

Preferably,

Ring A is selected from 6-membered cycloalkyl, one or two 6-membered aromatic rings substituted by R _A1 ;

Each R _{A1 is} independently selected from halogen;

The halogen is preferably Cl and F.

In some embodiments of the present invention, further, ring B is a 3-6 membered oxygen-containing heterocycloalkyl group.

Furthermore, L _{1 is} selected from the group consisting of methylene, ethylene, n-propylidene, and isopropylidene; ring B is oxetane, tetrahydropyran ring or tetrahydrofuran ring.

In some embodiments of the present invention, further,

R _{a is} selected from hydrogen, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-11 membered spiro ring, 6 ～11 membered spiro heterocyclic ring, 5-10 membered bridged ring, 5-10 membered bridged heterocyclic ring, -O(C _1-6 alkyl), -O(3-6 membered cycloalkyl), -O(3～ 6-membered heterocycloalkyl); wherein the alkyl, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted with one, two or three R _a1 ;

Preferably,

Ra is selected from hydrogen, -C _3-4 alkyl, 4-6 membered cycloalkyl, 5-6 membered oxacycloalkyl, 4-6 membered cycloalkyl substituted with one or two R _a1 ;

Each R _{a1 is} independently selected from -C ₁ alkyl, halogen;

The halogen is preferably F.

Furthermore, the spiro ring is

The bridge ring is

In some embodiments of the present invention, further,

R _b and R _c are each independently selected from hydrogen, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -C _0-2 alkylene-(3-6 membered cycloalkyl),- C _0～2 alkylene-(3～6 membered heterocycloalkyl), -C _0～2 alkylene-(6～11 membered spiro heterocycle); of which alkyl, cycloalkyl, heterocycloalkyl , Spiro heterocycle can be further substituted by one, two or three R _b1 ;

Each R _{b1 is} independently selected from halogen, cyano, carbonyl, nitro, -C _1-6 alkyl, halogen-substituted -C _1-6 alkyl, -OH, -O (C _1-6 alkyl);

Preferably,

R _b and R _c are each independently selected from hydrogen, -C _1-2 alkyl, one or two R _b1 substituted -C ₂ alkyl, -C _0-1 alkylene-(3 to 4-membered cycloalkyl ), a R _b1 substituted -C _0～1 alkylene-(3-membered cycloalkyl);

R _{b1 is} selected from -O (C ₁ alkyl), hydroxyl, halogen;

The halogen is preferably F.

Furthermore, at least one of R _b and R _c is hydrogen.

Further, R _a and R _{b are} connected to form a 5- to 12-membered spiro heterocyclic ring, and further, the spiro heterocyclic ring is

Furthermore, the compound of formula I is represented by formula III:

Where R _{1 is} selected from

-C _1-3 alkyl, -NR ₁₁ R ₁₂ or -OR ₁₁ ;

R _{13 is} selected from C _1-2 alkyl;

R _{31 is} selected from -C ₁ alkyl, halogen;

Each R _{A1 is} independently selected from halogen;

Halogen is preferably Cl and F;

R _{a is} selected from a 4-membered cycloalkyl group or a 4-membered cycloalkyl group substituted by a methyl group;

R _{d is} selected from hydrogen, -C ₁ alkylene-hydroxy or -C ₁ alkylene-amino.

In some specific embodiments of the present invention, the compound represented by formula I is specifically:

The present invention also provides the use of the aforementioned compounds, or stereoisomers, or pharmaceutically acceptable salts thereof in the preparation of drugs for treating IL-17A-mediated diseases.

Further, the IL-17A-mediated disease is one or more of diseases related to inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome.

The present invention also provides a pharmaceutical composition, which is a preparation prepared from the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, plus pharmaceutically acceptable excipients.

The present invention also provides the aforementioned compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrugs, or their metabolites in the preparation of therapeutic IL-17A-mediated Use in medicine for diseases.

The IL-17A-mediated diseases defined in the present invention are diseases in which IL-17A plays an important role in the pathogenesis of the disease. The main function of IL-17A is to coordinate local tissue inflammation, thereby playing a role in various diseases. IL-17A-mediated diseases include one or more of inflammation, autoimmune diseases, infectious diseases, cancer, and diseases related to precancerous syndrome. .

"Cancer" or "malignant tumor" refers to any of a variety of diseases characterized by uncontrolled abnormal cell proliferation, and the ability of affected cells to spread to other locations locally or through the bloodstream and lymphatic system The body (i.e. metastasis) and any of many characteristic structural and/or molecular characteristics. "Cancer cells" refer to cells that undergo multiple stages of tumor progression in the early, middle or late stages. Cancers include sarcoma, 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 being treated is a metastatic cancer.

Autoimmune diseases are caused by the body's immune response to substances and tissues that normally exist 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 type Arthritis, rheumatoid arthritis, fibromyalgia, Guillambali syndrome, multiple sclerosis and autoimmune retinopathy. Some embodiments of the invention relate to the treatment of autoimmune diseases such as psoriasis or multiple sclerosis.

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 and interstitial cystitis caused by house dust mites. There is a 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 usually involved in inflammatory diseases, which are manifested in allergic reactions and some myopathy. Many immune system diseases lead to abnormal inflammation. IL-17A-mediated diseases also include autoimmune inflammatory diseases.

The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.

Regarding the definitions of terms used in the present invention: Unless otherwise specified, the initial definitions of groups or terms provided herein are applicable to the groups or terms throughout the specification; for terms not specifically defined herein, it should be based on the disclosure and context , Give them the meaning that those skilled in the art can give them.

"Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

The minimum and maximum content of carbon atoms in a hydrocarbon group are indicated by prefixes. For example, the prefix _{Ca to b} alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C _1-4 alkyl" refers _to an alkyl group containing 1 to 4 carbon atoms.

"Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, a C ₁ to C ₆ alkyl group refers to an alkyl group having 1 to 6 member atoms, for example, 1 to 4 member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally 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) Base) and hexyl. The alkyl group may also be part of another group, such as a C ₁ to C ₆ alkoxy group.

"Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, when the point of attachment is at a non-aromatic carbon atom, the term "cycloalkyl" (e.g. 5,6,7,8,-tetra Hydronaphthalene-5-yl). The term "cycloalkyl" includes 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 multiple bicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, bicyclooctyl and the like. The following examples and names two such bicyclic alkyl polycyclic structures:

Dicyclohexyl and

Bicyclohexyl. "Alkenyl" means 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 1 site of ethylenic unsaturation (>C=C<) The straight or branched chain hydrocarbon group. For example, (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

"Alkynyl" refers to a straight chain monovalent hydrocarbon group or a branched chain monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups that have one triple bond and one double bond. For example, (C2-C6)alkynyl is meant to include ethynyl, propynyl, and the like.

"Halogen" is fluorine, chlorine, bromine or iodine.

"Halogenalkyl" means that the hydrogen atom in the alkyl group can be replaced by one or more halogen atoms. For example, a C _1-4 halogen alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms.

"Heterocycle" and "heterocycloalkyl" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

"Aromatic heterocyclic ring" refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, and a sulfur atom;

"R _a and R _{b are} connected to form a heterocycloalkyl, aromatic heterocycle, spiro heterocycle or bridged heterocycle" means that when the structure of R is

When, R _a and R _b each have at least one atom through a chemical bond, so that the structural formula R "-CCN -", "- CCO- " or "-CCNS-" as part of the backbone chain of atoms with R _a ring structure Together with R _b constitute a heterocycloalkyl, aromatic heterocycle, spiro heterocycle or bridge heterocycle. "Stereoisomers" include enantiomers and diastereomers;

The term "pharmaceutically acceptable" refers to a certain carrier, carrier, diluent, excipient, and/or the salt formed is usually chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form, and physiologically Compatible with the receptor.

The terms "salts" and "pharmaceutically acceptable salts" refer to the above-mentioned compounds or their stereoisomers, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal Salt), also including quaternary ammonium salts, such as alkyl ammonium salts. These salts can be directly obtained in the final isolation and purification of the compound. It can also be obtained by mixing the above-mentioned compound or its stereoisomer with a certain amount of acid or base appropriately (for example, equivalent). These salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium. The salt in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.

In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compound of the present invention can be used in combination with any other active agent to prepare drugs or pharmaceutical compositions for regulating cell function or treating diseases. If a group of compounds are used, these compounds can be administered to the subject simultaneously, separately or sequentially.

The description "a may be further substituted by b" means that the compound or group may be selected from unsubstituted a or a substituted by b.

Obviously, according to the above content of the present invention, according to common technical knowledge and conventional means in the field, various other modifications, substitutions or changes can be made without departing from the above basic technical idea of the present invention.

Hereinafter, the above-mentioned content of the present invention will be further described in detail through specific implementations in the form of examples. However, it should not be understood that the scope of the above-mentioned subject of the present invention is limited to the following examples. All technologies implemented based on the foregoing content of the present invention belong to the scope of the present invention.

detailed description

The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR is measured by (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetometer, and the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), The internal standard is tetramethylsilane (TMS).

The LC-MS measurement uses Shimadzu LC-MS 2020 (ESI). Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A) was used for HPLC measurement. MPLC (Medium Pressure Preparative Chromatography) uses Gilson GX-281 reverse phase preparative chromatograph. The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications for thin layer chromatography separation and purification products are 0.4mm～0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier. Supercritical fluid chromatography (SFC)

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

There is no special description in the examples, and the reaction is carried out under a nitrogen atmosphere. There is no special description in the examples, and the solution refers to an aqueous solution. There are no special instructions in the examples, and the reaction temperature is room temperature. No special instructions in the examples, M is mole per liter. Room temperature is the most suitable reaction temperature, which is 20 to 30°C.

Example 1 Preparation of intermediate chiral isopropyl amino acids 1-5a, 1-5b

Step 1 Preparation of Intermediate 1-1

To a 10L three-necked flask equipped with mechanical stirring and nitrogen protection, THF (3500mL) was added, o-chlorobenzaldehyde (341g, 2.43mol) and nitroethyl acetate (323g, 2.43mol) were added successively, and then cooled to At an internal temperature of -10℃, slowly add TiCl ₄ (920g, 4.85mol) under mechanical stirring, and control the internal temperature to not exceed 0℃ during the dripping. After the dripping is completed, keep it at 0℃ to continue the reaction for 0.5h, and then add N-formaldehyde dropwise Glymorpholine (981.51g, 9.70mol), control the internal temperature not to exceed 15℃ during the dripping, after dripping, allow to rise to room temperature and stir for 1h, finally add 500mL saturated ammonium chloride to quench, ethyl acetate (1000mL×3 ) Extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 100:1) to obtain Intermediate 1-1 (580g, 2.27mol, 93.52% yield).

Step 2 Preparation of Intermediate 1-2

Add 1M zinc chloride tetrahydrofuran solution (5.5mol, 5.5L) to a 10L three-necked flask equipped with mechanical stirring and nitrogen protection, cool to 0℃ in an ice bath, and slowly add 2M isopropyl magnesium chloride tetrahydrofuran solution (5.5mol , 2.75L), control the internal temperature below 5°C, after dripping, continue the reaction at 0-5°C for 30 minutes. Subsequently, an anhydrous THF (500 mL) solution of Intermediate 1-1 (702g, 2.75mol) was slowly added dropwise, and the internal temperature was controlled to be lower than 5°C during the dropwise addition. After the dropping was completed, the reaction was continued at 0-5°C for 1 hour. After the reaction is complete, take 500g of ammonium chloride into a saturated aqueous solution, slowly add to the above reaction solution to quench the reaction, extract with ethyl acetate (5L×2), combine the organic phases and wash with water, wash with saturated sodium chloride, and dry with anhydrous sodium sulfate , Filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate 50:1) to obtain Intermediate 1-2 (377g, 1.26mol, 45.80% yield).

Step 3 Preparation of Intermediate 1-3

Add Intermediate 1-2 (730g, 2.44mol) and glacial acetic acid (6L) to a 10L three-necked flask equipped with mechanical stirring. Cool down to 0℃ in an ice bath. Add zinc powder (796.24g, 12.18mol) in batches under mechanical stirring. , When adding, control the internal temperature below 60℃. After the addition, continue to stir and react for 1 hour. After the reaction is complete, filter with suction, rinse the filter cake with 100 mL of ethyl acetate, and concentrate the filtrate under reduced pressure to remove glacial acetic acid. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 50:1 ~10:1) Intermediate 1-3 (a mixture of enantiomers (2S, 3S) and (2R, 3R) configuration) was obtained as a yellow viscous liquid (280g, 1.04mol, 42.65% yield), MS m/z: 270(M+1) ⁺ .

Step 4 Preparation of Intermediate 1-4

To a suspension of Intermediate 1-3 (60g, 222.41mmol) in tetrahydrofuran (200mL) and water (100mL), sodium bicarbonate (37.37g, 444.83mmol) and Boc-anhydride (53.34g, 244.66mmol) were added sequentially After the addition, stir overnight at room temperature. After the reaction is complete, add 300 mL of water, extract with ethyl acetate (300 mL×2), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ Ethyl acetate 100:1～50:1) to obtain Intermediate 1-4 (39.4g, 106.52mmol, 47.89% yield), MS m/z: 270[M-99] ⁺ , 314[M-55] ⁺ .

Step 5 Preparation of Intermediate 1-5

To the suspension of Intermediate 1-4 (20.00g, 54.07mmol) in methanol (100mL) and water (10mL), NaOH (6.49g, 162.21mmol) was added, and the temperature was raised to 50°C to react for 3 hours. After the reaction was completed, The reaction solution was concentrated, 100mL of water was added, and ethyl acetate (100mL) was added once. The temperature of the aqueous phase was cooled to 0～5°C, pH was adjusted to 3-4 with 1M HCl, and then extracted with ethyl acetate (100mL). The organic phase was concentrated under reduced pressure A pair of enantiomers of Intermediate 1-5 (17.8g, 52.07mmol, 96.30% yield) was obtained as a yellow oil. The enantiomers were chirally resolved by supercritical fluid chromatography (SFC). After separation and preparation, single chiral isomers 1-5a (2R, 3R) and 1-5b (2S, 3S) were obtained, respectively, 6.5g, MS m/z: 242[M-99] ⁺ , 286[M -55] ⁺ . ¹ H NMR(400MHz, Chloroform-d) δ7.41--7.35(m,1H), 7.27-7.23(m,2H), 7.21-7.15(m,1H), 4.90-4.82(m,1H), 4.82- 4.74(m,1H), 3.68–3.56(m,1H), 2.19–2.03(m,1H), 1.41(s,9H), 1.17(d,J=6.4Hz,3H),0.75(d,J= 6.7Hz, 3H). In supercritical fluid chromatography (SFC) chiral separation, the retention time of (2S,3S) configuration is 2.59min, and the retention time of (2R,3R) configuration is 3.06min(

150*3mm, 5um, isocratic 5% ethanol 1mL/min). The specific rotation of (2S, 3S) configuration is 78.18° (25°C, 0.089g/100ml in methanol, wavelength 589nm), and the specific rotation of (2R, 3R) configuration is -72.60° (25°C, 0.098) g/100ml in methanol, wavelength 589nm).

Example 2 Preparation of intermediate amino acids 2-6

Step 1 Preparation of Intermediate 2-2

Refer to the preparation method of Example 1 Intermediate 1-2, prepared by reacting Intermediate 1-1 with isopropenyl magnesium bromide, with a yield of 37%, MS m/z: 298(M+1) ⁺ .

Step 2 Preparation of Intermediate 2-3

Refer to the preparation method of Example 1 Intermediate 1-3, obtained by reducing the nitro group with zinc powder-acetic acid system, the yield is 85%, MS m/z: 268(M+1) ⁺ . The four diastereomers were used in the next step without resolution.

Step 3 Preparation of Intermediate 2-4

Refer to the preparation method of Example 1 Intermediate 1-4, obtained by protecting the amino group with Boc anhydride, MS m/z: 368[M+1] ⁺ , 312[M-55] ⁺ .

Step 4 Preparation of Intermediate 2-5

Dissolve ferric nitrate nonahydrate (439.29mg, 1.09mmol) in 10ml of water, degas ultrasonically at 0°C for 10min and protect with nitrogen, then add 10ml of acetonitrile and selectflour (384.92mg, 1.09mmol) successively, and then separate them at 0°C. Intermediate 2-4 (100mg, 271.84μmol) in 10ml of acetonitrile solution and NaBH ₄ (66.84mg, 1.77mmol) were added to the reaction solution, 2min later, added NaBH ₄ (66.84mg, 1.77mmol), at 0 ℃ Stirring was continued for 30 min. After the reaction was completed, the reaction was quenched by adding 1 ml of ammonia water, extracted with DCM, the organic phase was dried over sodium sulfate, concentrated under reduced pressure and spin-dried, the crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate gradient elution 100:1~ 50:1) Intermediate 2-5 was obtained, (84.2 mg, 217.6 μmol, 80.0% yield), MS m/z: 388[M+1] ⁺ .

Step 5 Preparation of Intermediate 2-6

Refer to the preparation method of Example 1 Intermediate 1-5, obtained by hydrolyzing Intermediate 2-5 with sodium hydroxide, MS m/z: 360[M+1] ⁺ .

Example 3 Preparation of intermediate chiral cyclopropyl methyl amino acid 3-3a, 3-3b

Step 1 Preparation of Intermediate 3-1

The diastereoisomer mixture intermediate 2-4 (a mixture of four chiral isomers) of Example 2 was separated and purified by silica gel column chromatography (petroleum ether/methyl tert-butyl ether 100:1) to obtain the intermediate Enantiomers of form 2-4 (a mixture of enantiomers of 2-4a and 2-4b, a mixture of (2S, 3S) and (2R, 3R) configurations), take the enantiomer (1.7 g, 4.62mmol), dissolved in 20ml of dry DCM under the protection of nitrogen, cool the internal temperature to -40℃, add ZnEt2 (1M tetrahydrofuran solution, 27.73mL), stir at -30℃ for 1 hour and add diiodine dropwise Methane (9.90g, 36.97mmol), keep the internal temperature not higher than -20°C during dripping. After dripping, allow the internal temperature to slowly rise to room temperature and stir overnight. LC-MS shows about 30% of the starting material 2- 4, add 5ml of water to quench the reaction. The organic phase was concentrated to dryness under reduced pressure to obtain 1g of crude product. The crude product is now the 3-1 de-Boc form and the starting material 2-4 after de-Boc The mixture was dissolved in 10 mL of THF, TEA (897.78 mg, 8.87 mmol, 1.24 mL) and (Boc) ₂ O (1.16 g, 5.32 mmol) were sequentially added, stirred at room temperature overnight, and concentrated under reduced pressure to dryness. The crude product was separated and purified by silica gel column (petroleum ether/methyl tert-butyl ether 100:3) to obtain 0.5 g of the mixture of Boc-protected cyclopropyl methyl ethyl 3-1 crude product and the unreacted intermediate 2-4 in the previous step , The crude product was dissolved in a mixture of tetrahydrofuran (5mL) and acetonitrile (5mL) and 5mL water, and potassium osmate dihydrate (44.3mg, 0.12mmol) and N-methyl-N-oxide morpholine (111mg, 0.96mmol), remove unreacted 2-4 by double bond double hydroxylation, stir overnight at room temperature, LC-MS monitoring shows that there is no unreacted intermediate 2-4, concentrate under reduced pressure to remove most of the organic solvent, ethyl acetate 15ml extraction, organic phase concentration, the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1) to obtain Intermediate 3-1 (0.5g, 1.31mmol, 28% yield), MS m/z: 382[M+1] ⁺ .

Step 2 Preparation of Intermediate 3-2

Refer to the preparation method of Example 1 Intermediate 1-5, obtained by hydrolysis of sodium hydroxide, MS m/z: 298[M-55] ⁺ .

Step 3 Preparation of intermediates 3-3a and 3-3b

Intermediate 3-2 (a mixture of enantiomers) can be separated and prepared by SFC chiral column to obtain single chiral isomers 3-3a (2R, 3R) and 3-3b (2S, 3S). In supercritical fluid chromatography (SFC) chiral resolution separation, the retention time of (2S, 3S) configuration is 5.904 min, and the retention time of (2R, 3R) configuration is 3.306 min (

150*3mm, 5um, isocratic 5% ethanol 1mL/min). The specific rotation of (2S, 3S) configuration is 48.755° (25℃, 0.1g/100ml in methanol, wavelength 589nm), and the specific rotation of (2R, 3R) configuration is -40.695° (25℃) , 0.1g/100ml in methanol, wavelength 589nm).

Example 4 Preparation of Intermediate Amino Acid 4-5

Step 1 Preparation of Intermediate 4-1

According to the preparation method of Example 1 Intermediate 1-1, it was prepared from 2-chloro-6-fluoro-benzaldehyde and ethyl nitroacetate.

Step 2 Preparation of Intermediate 4-2

Refer to the preparation method of Intermediate 1-2 in Example 1, which is prepared by reacting Intermediate 4-1 with isopropyl magnesium chloride.

Step 3 Preparation of Intermediate 4-3

According to the preparation method of Intermediate 1-3 in Example 1, it was prepared from Intermediate 4-2 through reduction of nitrozinc powder-acetic acid system, MS m/z: 288[M+1] ⁺ .

Step 4 Preparation of Intermediate 4-4

Refer to the preparation method of Intermediate 1-4 in Example 1, obtained by Boc protection on Intermediate 4-3, MS m/z: 388[M+1] ⁺ , 332[M-55] ⁺ .

Step 5 Preparation of Intermediate 4-5

Referring to the preparation method of Intermediate 1-5 in Example 1, Intermediate 4-4 was hydrolyzed to obtain 4-5, MS m/z: 360[M+1] ⁺ .

Example 5 Preparation of Intermediate Amino Acid 5-5

Step 1 Preparation of Intermediate 5-1

According to the preparation method of Example 1 Intermediate 1-1, it was prepared from 2-chloro-3-fluoro-benzaldehyde and ethyl nitroacetate.

Step 2 Preparation of Intermediate 5-2

Refer to the preparation method of Intermediate 1-2 in Example 1, which is prepared by reacting Intermediate 5-1 with isopropyl magnesium chloride.

Step 3 Preparation of Intermediate 5-3

With reference to the preparation method of Intermediate 1-3 in Example 1, it was prepared from Intermediate 5-2 through reduction of nitrozinc powder-acetic acid system, MS m/z: 288[M+1] ⁺ .

Step 4 Preparation of Intermediate 5-4

Refer to the preparation method of Example 1 Intermediate 1-4, obtained by Boc protection on Intermediate 5-3, MS m/z: 388[M+1] ⁺ , 332[M-55] ⁺ .

Step 5 Preparation of Intermediate 5-5

Referring to the preparation method of Intermediate 1-5 in Example 1, 5-5 is obtained from Intermediate 5-4 by hydrolysis, MS m/z: 360[M+1] ⁺ .

Example 6 Preparation of intermediate furan o-phenylenediamine 6-6a, 6-6b

Step 1 Preparation of Intermediate 6-1

At room temperature, add a catalytic amount of concentrated H2SO4 (1.66mol, 2mL) to the ethanol (1L) solution of p-nitrophenylacetic acid (300g, 1.66mol), raise the temperature to 80°C and stir for 16 hours. After the raw materials disappear, reduce pressure Concentrate to dryness, dissolve in 2L of ethyl acetate, wash with aqueous sodium bicarbonate solution, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain Intermediate 6-1 (330g, 1.58mol, 95.25% yield) ),MS m/z:210[M+1] ⁺ .

Step 2 Preparation of Intermediate 6-2

Under the protection of nitrogen, the intermediate 6-1 ethyl p-nitrophenylacetate (29.4g, 140.54mmol) was dissolved in dry 1.2L N,N-dimethylacetamide, and cooled to internal temperature in a dry ice-ethanol bath Add cesium carbonate (114.54g, 351.34mmol) at -40°C, stir for 15min at -40°C, slowly add 2-chloroethyl chloromethyl ether (19.94g, 154.59mmol) to the reaction solution dropwise, and allow the reaction to complete Return to room temperature and stir overnight. After the raw materials disappear, add 3L of ice water to quench the reaction, extract with ethyl acetate (2L×2), wash the organic phase with saturated brine (2L×2), and dry with anhydrous sodium sulfate , Filtered, concentrated to dryness under reduced pressure, the crude product was separated by silica gel column chromatography to obtain Intermediate 6-2 (6.5g, 24.50mmol, 17.44% yield), MS m/z: 266[M+1] ⁺ .

Step 3 Preparation of Intermediate 6-3

Intermediate 6-2 (15g, 56.55mmol) was dissolved in EtOH (100mL), after nitrogen replacement, 10% Pd/C (3g) was added, and the reaction was stirred overnight under normal pressure hydrogen atmosphere. After the raw materials disappeared, Soil suction filtration, ethanol washing, and the filtrate was concentrated to dryness under reduced pressure to obtain Intermediate 6-3 (12.7g, 53.98mmol, 95.46% yield), MS m/z: 236[M+1] ⁺ , the product was not purified Used directly in the next reaction.

Step 4 Preparation of Intermediate 6-4

Intermediate 6-3 (16g, 68.00mmol) was dissolved in acetic anhydride (136mL), cooled to 0°C, and stirred for 15min, HNO ₃ (9.45g, 102.01mmol, 68% mass fraction) was slowly added dropwise, and the solution was finished. After the reaction was stirred for 30 minutes, the raw materials disappeared. The reaction solution was poured into ice water, extracted with ethyl acetate (2×300mL), the organic phase was washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the middle Body 6-4 crude product (21 g, 65.15 mmol, 95.81% yield), MS m/z: 323[M+1] ⁺ , the product was directly used in the next reaction without purification.

Step 5 Preparation of Intermediate 6-5

Intermediate 6-4 (21g, 65.15mmol) was dissolved in 150ml of ethanol, SOCl ₂ (23.25g, 195.46mmol, 14.18mL) was added, heated to 50°C and stirred for 1 hour, LC-MS showed that the raw material disappeared, and the reaction solution decreased. Concentrate to dryness, add CH ₂ Cl ₂ (150 mL) and H ₂ O (150 mL), adjust the pH to ~8 with saturated NaHCO ₃ , extract the aqueous phase with CH ₂ Cl ₂ (2×150 mL), combine the organic phases, Dry with anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain the crude intermediate 6-5 (18 g, 64.22 mmol, 98.57% yield), MS m/z: 281[M+1] ⁺ , the product is not purified Used directly in the next reaction.

Step 6 Preparation of Intermediate 6-6a, 6-6b

Intermediate 6-5 (19g, 67.79mmol) was dissolved in methanol, Pd/C (5.7g) was added under nitrogen atmosphere, and hydrogenation was carried out at atmospheric pressure overnight. After the raw material disappeared, it was filtered through Celite and the filtrate was concentrated under reduced pressure. To dryness, MPLC C18 reversed-phase column purification to obtain the racemate, the SFC chiral column separation and separation, a single configuration 6-6a (7.5g, light brown semi-solid, 44% yield, chiral column retention time 2.554 min, CHIRALCEL OD-H (ODH0CD-TC013) 0.46cm ID*15cm L, mobile phase: 100% methanol, 35℃, flow rate: 1mL/min) and another single configuration 6-6b (7.5g, light brown half Solid, 44% yield, chiral column retention time 3.814min, CHIRALCEL OD-H (ODH0CD-TC013) 0.46cm ID*15cm L, mobile phase: 100% methanol, 35°C, flow rate: 1mL/min), MS m /z:251[M+1] ⁺ .

Example 7 Preparation of intermediate pyran o-phenylenediamine 7-5

Step 1 Preparation of Intermediate 7-1

Referring to the preparation method of Example 6 Intermediate 6-2, the starting material 6-1 was reacted with 2,2'-dibromodiethyl ether in anhydrous DMF using cesium carbonate as the acidic acid agent to obtain Intermediate 7-1. Rate 60%, MS m/z: 280[M+1] ⁺ .

Step 2 Preparation of Intermediate 7-2

Referring to the preparation method of Intermediate 6-3 in Example 6, Intermediate 7-1 was reduced by zinc powder-acetic acid system to obtain Intermediate 7-2 with a yield of 95%. MS m/z: 250[M+1] ⁺ .

Step 3 Preparation of Intermediate 7-3

Referring to the preparation method of Example 6 Intermediate 6-4, Intermediate 7-2 was nitrated in acetic anhydride to obtain Intermediate 7-3 with a yield of 74%. MS m/z: 337[M+1] ⁺ .

Step 4 Preparation of Intermediate 7-4

Referring to the preparation method of Example 6 Intermediate 6-5, Intermediate 7-3 was deacetylated to obtain Intermediate 7-4 with a yield of 96%. MS m/z: 295[M+1] ⁺ .

Step 5 Preparation of Intermediate 7-5

Referring to the preparation method of Example 6 Intermediate 6, Intermediate 7-4 was reduced by hydrogenation to obtain Intermediate 7-5 with a yield of 90%. MS m/z: 265[M+1] ⁺ .

Example 8 Preparation of intermediate R-cyclobutylglycinamide 8-2

Step 1 Preparation of Intermediate 8-1

Dissolve Boc-D-cyclobutylglycine (800mg, 3.49mmol) in DCM (8mL), cool to 0°C, add HBTU (1.06g, 4.19mmol), DIEA (2.25g, 17.45mmol) and ethylamine salt in turn Salt (284mg, 3.49mmol), after 15 minutes, turn to room temperature and react for 1.5 hours. LC-MS shows that the raw material disappeared. Washed with saturated ammonium chloride (10ml×3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to obtain Intermediate 8-1, a white solid (822mg, 3.21mmol, 92% yield), MS m/z: 257[M+ 1] ⁺ .

Step 2 Preparation of Intermediate 8-2

Dissolve 8-1 (822mg, 3.21mmol) in DCM (3mL), slowly add TFA (1.5mL) under ice bath, stir under ice bath for 1.5 hours, the raw material disappears, and concentrate under reduced pressure to dryness to give a colorless half TFA salt of 8-2 as a viscous solid (820 mg, 100%), MS m/z: 157[M+1] ⁺ , the crude product was used directly in the next step without purification.

Example 9 Preparation of Intermediate 9

Refer to the method of Example 8, which was obtained by condensing Boc-D-cyclobutylglycine and 1-aminomethyl-1-cyclopropanol, followed by Boc removal, MS m/z: 199[M+1] ⁺ .

Example 10 Preparation of Intermediate 10

Refer to the method in Example 8, obtained by condensation of Boc-D-cyclobutylglycine and methylamine, MS m/z: 143[M+1] ⁺ .

Example 11 Preparation of Intermediate 11

Refer to the method of Example 8, obtained by the condensation of Boc-D-cyclobutylglycine and cyclopropylamine, followed by de-Boc, MS m/z: 169[M+1] ⁺ .

Example 12 Preparation of Intermediate 12

Refer to the method of Example 8, obtained by the condensation of Boc-D-cyclobutylglycine and cyclopropylmethylamine, followed by de-Boc, MS m/z: 183[M+1] ⁺ .

Example 13 Preparation of Intermediate 13

Refer to the method in Example 8, which was obtained by condensing Boc-D-cyclobutylglycine and (1-fluorocyclopropyl)methylamine, followed by de-Boc, MS m/z: 201[M+1] ⁺ .

Example 14 Preparation of Intermediate 14

Refer to the method of Example 8, which was obtained by condensing Boc-D-cyclobutylglycine with (1-methoxycyclopropyl)methylamine, followed by de-Boc, MS m/z: 213[M+1] ⁺ .

Example 15 Preparation of Intermediate 15

Refer to the method of Example 8, which was obtained by condensing Boc-D-cyclobutylglycine with 2,2-difluoroethylamine and then removing Boc, MS m/z: 193[M+1] ⁺ .

Example 16 Preparation of Intermediate 16

Refer to the method of Example 8, obtained by the condensation of Boc-D-cyclobutylglycine and 2-fluoroethylamine, followed by de-Boc, MS m/z: 175[M+1] ⁺ .

Example 17 Preparation of Intermediate 17

Refer to the method in Example 8, which was obtained by condensing Boc-D-cyclopentylglycine with ethylamine hydrochloride and then removing Boc, MS m/z: 171[M+1] ⁺ .

Example 18 Preparation of Intermediate 18

Refer to the method of Example 8, obtained by condensing Boc-D-(tetrahydrofuran-2-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 173[M+1] ⁺ .

Example 19 Preparation of Intermediate 19

Refer to the method of Example 8, obtained by condensing Boc-D-(tetrahydropyran-4-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 187[M+1] ⁺ .

Example 20 Preparation of Intermediate 20

Refer to the method of Example 8, obtained by condensing Boc-D-cyclohexylglycine and ethylamine hydrochloride, followed by de-Boc, MS m/z: 285[M+1] ⁺ .

Example 21 Preparation of Intermediate 21

Refer to the method of Example 8, obtained by condensing Boc-D-(4,4-difluorocyclohexyl)glycine and ethylamine hydrochloride, followed by de-Boc, MS m/z: 321[M+1] ⁺ .

Example 22 Preparation of Intermediate 22

Refer to the method of Example 8, obtained by condensing Boc-D-cyclobutylglycine and cis-2-fluoro-cyclopropylamine, followed by de-Boc, MS m/z: 187[M+1] ⁺ .

Example 23 Preparation of Intermediate 23

Refer to the method of Example 8, obtained by condensation of Boc-D-cyclobutylglycine and trans-2-fluoro-cyclopropylamine, followed by de-Boc, MS m/z: 187[M+1] ⁺ .

Example 24 Preparation of Intermediate 24

Refer to the method of Example 8, obtained by condensation of the corresponding Boc-D-(3-fluorocyclobutyl)glycine and ethylamine hydrochloride, followed by de-Boc, MS m/z: 175[M+1] ⁺ .

Example 25 Preparation of Intermediate 25

Refer to the method of Example 8, obtained by condensing Boc-D-(3,3-difluorocyclobutyl)glycine with ethylamine hydrochloride, and then removing Boc, MS m/z: 193[M+1] ⁺ .

Example 26 Preparation of Intermediate 26

Refer to the method of Example 8, obtained by condensing Boc-D-(3-methylcyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 171[M+1] ⁺ .

Example 27 Preparation of Intermediate 27

Refer to the method of Example 8, obtained by condensing Boc-D-(3-methoxycyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 187[M+1] ⁺ .

Example 28 Preparation of Intermediate 28

Refer to the method of Example 8, obtained by condensing Boc-D-(1-methylcyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 171[M+1] ⁺ .

Example 29 Preparation of Intermediate 29

Refer to the method of Example 8, obtained by condensing Boc-(S)-(1-fluorocyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 175[M+1] ⁺ .

Example 30 Preparation of Intermediate 30

Refer to the method of Example 8, obtained by condensing Boc-D-(3-methyl-3-fluorocyclobutyl)glycine with ethylamine hydrochloride, and then removing Boc, MS m/z: 189[M+1] ⁺ .

Example 31 Preparation of Intermediate 31

Refer to the method in Example 8, obtained by condensing Boc-D-(spiro[2,3]hexane-5-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 183[M+1] ⁺ .

Example 32 Preparation of Intermediate 32

Refer to the method of Example 8, obtained by condensing Boc-D-(bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 169[M+1] ⁺ .

Example 33 Preparation of Intermediate 33

Refer to the method of Example 8, obtained by condensing Boc-D-(3-(methyl)bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride and then removing Boc, MS m/z: 183[M+1] ⁺ .

Example 34 Preparation of Intermediate 34

Refer to the method of Example 8, obtained by condensing Boc-D-(3-(fluoro)bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 187 [M+1] ⁺ .

Example 35 Preparation of Compound 35-a, 35-b

Step 1 Preparation of Intermediate 35-1, 35-2 (mixture form)

Intermediate 1-5b (614.57 mg, 1.80 mmol, SFC chiral resolution to obtain a single chiral isomer) in step 5 of Example 1, EDCI (412.08 mg, 2.16 mmol), DIPEA (697.08 mg, 5.39 mmol) ,939.46uL), HOAt (293.42mg, 2.16mmol) and the single-configuration intermediate furan o-phenylenediamine 6-6b (0.45g, 1.80mmol) in step 6 of Example 6 were added to DCM (10mL) in turn at room temperature Reacted for 3 hours, quenched with water, removed most of the organic solvents under reduced pressure, extracted with ethyl acetate (20ml×3), combined the organic phases, washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and rotated under reduced pressure. Dry, the crude product is purified and separated by silica gel column chromatography (petroleum ether/ethyl acetate 5:1) to obtain the structural isomer mixture of intermediates 35-1 and 35-2 (0.4g, 696μmol, 34.88% yield) , MS m/z:574(M+1) ⁺ , the two do not need to be separated and used in the next step.

Step 2 Preparation of Intermediate 35-3

Add the mixture of intermediate 35-1 and 35-2 (0.4g, 696μmol) obtained in step 2 to AcOH (2mL), react at 55°C for 12h, concentrate under reduced pressure and spin dry, and separate and purify by silica gel column chromatography (petroleum ether/acetic acid) Ethyl ester 1:1) to obtain intermediate 35-3 (330 mg, 534.08 μmol, 76.66% yield), MS m/z: 557(M+1) ⁺ .

Step 3 Preparation of Intermediate 35-4

Intermediate 35-3 (0.33g, 593.43μmol) obtained in step 2 was dissolved in DCM (3mL), TFA (1mL) was added dropwise under an ice bath, the reaction was continued under ice bath for 2h, and the intermediate 35 was obtained by rotary drying. The crude product of -4 (250 mg, 493.45 μmol, 83.15% yield), MS m/z: 456 (M+1) ⁺ , was used directly in the next reaction without purification.

Step 4 Preparation of Intermediate 35-5

HBTU (134.35mg, 353.56μmol), DIPEA (114.23mg, 883.89μmol, 153.95uL) were added to 1-methyl-1H-pyrazole-5-carboxylic acid (112.01mg, 888.21μmol) in DCM (5mL ) In the solution, add the intermediate 35-4 (160mg, 294.63μmol) obtained in step 3 after 15min, react at room temperature for 2h, quench with water, extract with ethyl acetate (20ml×3), combine the organic phases, and then respectively saturate ammonium chloride Wash with saturated brine, dry with anhydrous sodium sulfate, and spin dry under reduced pressure. The crude product is purified and separated by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to obtain Intermediate 35-5 (301mg, 480.26μmol, 81.11) % Yield), MS m/z: 564(M+1) ⁺ .

Step 5 Preparation of Intermediate 35-6

NaOH (64.03mg, 1.60mmol) was added to the mixture of Intermediate 35-5 (301mg, 533.62μmol) in EtOH (3mL) and water (1mL) and reacted at 75℃ for 12 hours. LC-MS showed that the raw materials had reacted. After finishing, adjust the pH to 4 with 1N HCl, extract with EA (10ml*3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude intermediate 35-6 (202mg, 376.85) μmol, 70.62% yield), MS m/z: 536[M+1] ⁺ , used directly in the next reaction without purification.

Step 6 Preparation of compound 35-a, 35-b

Step 6-1 Preparation of compound 35-b:

HBTU (357.2mg, 942.5μmol), DIPEA (146mg, 1131μmol, 187uL) were added to step 5 Intermediate 35-6 (202mg, 376.85μmol) in DCM (5mL) solution, 15min later added to Example 10 Intermediate amide 10 (64.2mg, 452.4μmol), react at room temperature for 1h, add 10mL of water to quench, remove most of the organic solvents under reduced pressure, extract with ethyl acetate (10ml×3), combine the organic phases, and then respectively saturate ammonium chloride Wash with saturated brine, dry with anhydrous sodium sulfate, and spin dry under reduced pressure. The crude product is purified and separated by MPLC reverse-phase C18 column chromatography (acetonitrile/0.05% water 0-40%) to obtain intermediate 35-b (204mg, 309.14) μmol, 82% yield), MS m/z: 660(M+1) ⁺ . ¹ HNMR (400MHz, MeOD): δppm 7.35-7.54 (m, 3H), 7.22-7.27 (m, 3H), 7.06-7.16 (m, 2H), 6.39 (s, 1H), 5.87-5.90 (d, J =7.2Hz,1H),4.49-4.54(t,J=8.0Hz,1H),4.13-4.17(d,J=7.2Hz,1H),4.03-4.07(m,1H),3.85-3.90(m, 3H), 3.79-3.93(m, 3H), 2.74-2.80(m, 1H), 2.55(s, 3H), 2.36-2.43(m, 2H), 1.39-1.93(m, 7H), 0.87-0.91( d,J=6.4Hz,3H),0.72-0.73(d,J=6.8Hz,3H).

Step 6-2 Preparation of compound 35-a:

Refer to the method for preparing 35-b from steps 1 to 6 in Example 35, and use the intermediate 1-5b of step 5 in Example 1 (SFC chiral resolution to obtain a single chiral isomer) and the steps in Example 6 The single-configuration intermediate furan o-phenylenediamine 6-6a reacted with 6-6a, after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and the intermediate amide of Example 10 10 condensation and other steps to obtain 35-a, MS m/z: 660(M+1) ⁺ .

Example 36 Preparation of compound 36-a, 36-b

Refer to the method for preparing 35-b in step 6 of Example 35, using intermediate 35-6 as a raw material, and condensing with Example 8 intermediate 8-2 to obtain compound 36-b, MS m/z: 674(M+1) ⁺ . ¹ H NMR(400MHz,CD ₃ OD)δ7.90(s,1H), 7.68–7.55(m,2H), 7.51(d,J=7.7Hz,1H), 7.41–7.33(m,3H), 7.31 –7.21(m,2H),7.16(d,J=8.1Hz,1H),6.52(s,1H),6.01(d,J=9.2Hz,1H), 4.65(d,J=8.6Hz,1H) ,4.28(dd,J=9.1,8.1Hz,1H),4.21-4.13(m,1H),4.05-3.97(m,3H),3.94(s,3H),3.21-3.09(m,2H),2.95 –2.86(m,1H),2.56–2.45(m,2H),1.99–1.85(m,2H),1.84–1.73(m,3H),1.73–1.64(m,1H),1.62–1.53(m, 1H), 1.06 (d, J = 7.3 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H).

Similarly, using the intermediate of step 5 of the preparation of another configuration 35-a (another configuration of 35-6) as a raw material, and the condensation of the intermediate 8-2 of Example 8 to obtain compound 36-a, MS m/ z: 674(M+1) ⁺ . ¹ H NMR (400MHz, DMSO-d6+D ₂ O): δppm 7.51-7.53(m,2H),7.15-7.40(m,7H),6.45(s,1H),5.85-5.87(d,J=9.6 Hz,1H),4.50-4.53(d,J=8.4Hz,1H),4.09-4.24(m,2H),3.78-3.86(m,5H),2.83-3.03(m,3H),2.40-2.46( m, 1H), 2.25-2.33 (m, 1H), 1.64-1.71 (m, 5H), 1.43-1.56 (m, 2H), 0.84-0.87 (m, 3H), 0.65-0.79 (m, 6H).

Example 37 Preparation of Compound 37-a, 37-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 11 of Example 11 to obtain compound 37-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 37-a can be obtained by condensation with Example 11 Intermediate 11, MS m/z: 686(M+1) ⁺ .

Example 38 Preparation of Compound 38-a, 38-b

According to the method for preparing 35-b in step 6 of Example 35, the intermediate 35-6 was used as a raw material to condense with the intermediate 12 of Example 12 to obtain compound 38-b, MS m/z: 700(M+1) ⁺ . Similarly, using the intermediate in step 5 of the preparation of another configuration 35-a (another configuration of 35-6) as a raw material, and the condensation of the intermediate 12 in Example 12 to obtain compound 38-a, MS m/z: 700(M+1) ⁺ .

Example 39 Preparation of Compound 39-a, 39-b

According to the method for preparing 35-b in step 6 of Example 35, the intermediate 35-6 was used as a raw material to condense with the intermediate 13 of Example 13 to obtain compound 39-b, MS m/z: 718(M+1) ⁺ . Similarly, using the intermediate in step 5 of the preparation of another configuration 35-a (another configuration of 35-6) as the raw material, and the condensation of the intermediate 13 in Example 13 to obtain compound 39-a, MS m/z: 718(M+1) ⁺ .

Example 40 Preparation of compound 40-a, 40-b

According to the method for preparing 35-b in step 6 of Example 35, the intermediate 35-6 was used as a raw material, and the intermediate 14 of Example 14 was condensed to obtain compound 40-b, MS m/z: 730(M+1) ⁺ . Similarly, using the intermediate in step 5 of the preparation of another configuration 35-a (another configuration of 35-6) as a raw material, and the condensation of the intermediate 14 in Example 14 to obtain compound 40-a, MS m/z: 730(M+1) ⁺ .

Example 41 Preparation of compound 41-a, 41-b

According to the method for preparing 35-b in step 6 of Example 35, the intermediate 35-6 was used as a raw material, and the intermediate 15 of Example 15 was condensed to obtain compound 41-b, MS m/z: 710(M+1) ⁺ . Similarly, using the intermediate in step 5 of the preparation of another configuration 35-a (another configuration of 35-6) as a raw material, the compound 41-a can be obtained by condensation with the intermediate 15 of Example 15, MS m/z: 710(M+1) ⁺ .

Example 42 Preparation of Compound 42-a, 42-b

According to the method for preparing 35-b in step 6 of Example 35, the intermediate 35-6 was used as a raw material, and the intermediate 16 of Example 16 was condensed to obtain compound 42-b, MS m/z: 692(M+1) ⁺ . Similarly, using the intermediate in step 5 of the preparation of another configuration 35-a (another configuration of 35-6) as a raw material, the compound 42-a can be obtained by condensation with the intermediate 16 of Example 16, MS m/z: 692(M+1) ⁺ .

Example 43 Preparation of Compound 43-a, 43-b

Refer to the method for preparing 35-b in step 6 of Example 35. Using Intermediate 35-6 as a raw material, condense with Intermediate 17 of Example 17 to obtain compound 43-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 43-a can be obtained by condensation with Example 17 Intermediate 17, MS m/z: 688(M+1) ⁺ .

Example 44 Preparation of compound 44-a, 44-b

Refer to the method for preparing 35-b in Step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 18 of Example 18 to obtain compound 44-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 44-a can be obtained by condensation with Example 18 Intermediate 18, MS m/z: 690(M+1) ⁺ .

Example 45 Preparation of compound 45-a, 45-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 19 of Example 19 to obtain compound 45-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 45-a can be obtained by condensation with Example 19 Intermediate 19, MS m/z: 704(M+1) ⁺ .

Example 46 Preparation of compound 46-a, 46-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 20 of Example 20 to obtain compound 46-b; similarly, to prepare another configuration 35-a. 5 Intermediate (another configuration of 35-6) is a raw material, and compound 46-a can be obtained by condensation with Example 20 Intermediate 20, MS m/z: 702(M+1) ⁺ .

Example 47 Preparation of Compound 47-a, 47-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 21 in Example 21 to obtain compound 47-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 47-a can be obtained by condensation with the intermediate 21 of Example 21, MS m/z: 738(M+1) ⁺ .

Example 48 Preparation of compound 48-a, 48-b

Refer to the method for preparing 35-b in Step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 22 of Example 22 to obtain compound 48-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 48-a can be obtained by condensation with the intermediate 22 of Example 22, MS m/z: 704(M+1) ⁺ .

Example 49 Preparation of compound 49-a, 49-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 23 in Example 23 to obtain compound 49-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 49-a can be obtained by condensation with Example 23 Intermediate 23, MS m/z: 704(M+1) ⁺ .

Example 50 Preparation of compound 50-a, 50-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 24 of Example 24 to obtain compound 50-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 50-a can be obtained by condensation with the intermediate 24 of Example 24, MS m/z: 692(M+1) ⁺ .

Example 51 Preparation of compound 51-a, 51-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 25 of Example 25 to obtain compound 51-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 51-a can be obtained by condensation with the intermediate 25 of Example 25, MS m/z: 710(M+1) ⁺ .

Example 52 Preparation of Compound 52-a, 52-b

Refer to the method for preparing 35-b in Step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 26 of Example 26 to obtain compound 52-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 52-a can be obtained by condensing with Intermediate 26 of Example 26, MS m/z: 688(M+1) ⁺ .

Example 53 Preparation of Compound 53-a, 53-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 27 of Example 27 to obtain compound 53-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 53-a can be obtained by condensing with intermediate 27 of Example 27, MS m/z: 704(M+1) ⁺ .

Example 54 Preparation of Compound 54a, 54-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 28 in Example 28 to obtain compound 54-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 54-a can be obtained by condensation with Example 28 Intermediate 28, MS m/z: 688(M+1) ⁺ .

Example 55 Preparation of Compound 55-a, 55-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 29 in Example 29 to obtain compound 55-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 55-a can be obtained by condensation with Example 29 Intermediate 29, MS m/z: 692(M+1) ⁺ .

Example 56 Preparation of Compound 56-a, 56-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 30 in Example 30 to obtain compound 56-b; similarly, to prepare another configuration 35-a. 5 Intermediate (another configuration of 35-6) is a raw material, and compound 56-a can be obtained by condensing with intermediate 30 of Example 30, MS m/z: 706(M+1) ⁺ .

Example 57 Preparation of Compound 57-a, 57-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 31 in Example 31 to obtain compound 57-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 57-a can be obtained by condensation with the intermediate 31 of Example 31, MS m/z: 700(M+1) ⁺ .

Example 58 Preparation of Compound 58-a, 58-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 32 in Example 32 to obtain compound 58-b; similarly, to prepare another configuration 35-a. 5 Intermediate (another configuration of 35-6) is a raw material, and compound 58-a can be obtained by condensation with the intermediate 32 of Example 32, MS m/z: 686(M+1) ⁺ .

Example 59 Preparation of Compound 59-a, 59-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 33 in Example 33 to obtain compound 59-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 59-a can be obtained by condensation with the intermediate 33 of Example 33, MS m/z: 700(M+1) ⁺ .

Example 60 Preparation of compound 60-a, 60-b

Refer to the method for preparing 35-b in step 6 of Example 35, using Intermediate 35-6 as a raw material, and condensing with Intermediate 34 of Example 34 to obtain compound 60-b; similarly, to prepare another configuration 35-a 5 Intermediate (another configuration of 35-6) is a raw material, and compound 60-a can be obtained by condensing with intermediate 34 of Example 34, MS m/z: 704(M+1) ⁺ .

Example 61 Preparation of Compound 61

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with the intermediate amide 10 of Example 10 to obtain compound 61, MS m/z: 674(M+1) ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 7.64 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.51-7.46 (m, 2H), 7.34-7.31 (m, 2H), 7.24(d,J=7.2Hz,1H), 7.20-7.26(m,2H), 6.58(s,1H), 5.98(d,J=7.6Hz,1H), 4.20-4.16(m,1H),4.02 (t,J=7.2Hz,1H), 3.87(s,3H), 3.80-3.74(m,2H), 3.60-3.52(m,1H), 2.55(s,3H), 2.48-2.38(m,3H) ),2.05-1.94(m,3H),1.80-1.73(m,1H),1.71-1.62(m,1H),1.60-1.55(m,1H),1.46-1.41(m,1H),1.01(d ,J=6.4Hz,3H),0.74(d,J=6.4Hz,3H).

Example 62 Preparation of Compound 62

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 are condensed, ring closed, and deprotected. Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with the intermediate amide 8-2 of Example 8 to obtain compound 62, MS m/z: 688(M+1) ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ7.81 (s, 1H), 7.74 (d, J = 8.8Hz, 1H), 7.66-7.60 (m, 2H), 7.44 (s, 2H), 7.37- 7.27 (m, 2H), 6.75 (s, 1H), 6.16 (d, J = 7.6 Hz, 1H), 4.32-4.27 (m, 1H), 4.16 (t, J = 7.6 Hz, 1H), 3.99 (s ,3H),3.91-3.86(m,2H),3.69(t,J=10.8Hz 2H),3.20-3.07(m,2H),2.61-2.51(m,3H),2.15-2.05(m,3H) ,1.90-1.87(m,1H),1.81-1.80(m,3H),1.76-1.72(m,1H),1.59-1.55(m,1H),1.12(d,J=6.4Hz,3H),1.04 (t,J=7.2Hz,3H),0.85(d,J=6.4Hz,3H).

Example 63 Preparation of Compound 63

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with the intermediate amide 16 of Example 16 to obtain compound 63, MS m/z: 706(M+1) ⁺ . ¹ H NMR(400MHz, CD ₃ OD): δ7.79(s,1H), 7.72(d,J=8.4Hz,1H), 7.63(d,J=8.4Hz,2H), 7.25(s,2H) ,7.36(d,J=6.0Hz,2H),7.31(d,J=7.2Hz,1H), 6.72(s,1H), 6.13(d,J=7.6Hz,1H), 4.43(t,J= 4.8Hz, 1H), 4.37-4.29 (m, 2H), 4.15 (t, J = 6.8 Hz, 1H), 3.99 (s, 3H), 3.89-3.88 (m, 2H), 3.69 (t, J = 10.4 Hz 2H), 3.52-3.40 (m, 2H), 2.62-2.58 (m, 3H), 2.15-2.10 (m, 3H), 1.92-1.73 (m, 6H), 1.59-1.57 (m, 1H), 1.39 -1.27(m,1H), 1.12(d,J=5.6Hz,3H), 0.86(d,J=6.4Hz,3H).

Example 64 Preparation of Compound 64

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with the intermediate amide 15 of Example 15 to obtain compound 64, MS m/z: 724(M+1) ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ12.52 (d, J=14.6Hz, 1H), 8.70 (dt, J=30.9, 15.4Hz, 1H), 8.11 (q, J=5.9Hz, 1H) ,7.72–7.54(m,1H),7.53–7.36(m,3H),7.36–7.28(m,3H),7.27–7.19(m,2H),6.48(d,J=1.9Hz,1H),5.90 (dd,J=9.6,7.1Hz,1H),4.40–4.18(m,2H),3.90–3.68(m,5H),3.52(dd,J=24.3,12.3Hz,3H),2.04–1.84(m ,2H),1.67(ddd,J=29.0,19.3,6.8Hz,6H),1.55-1.35(m,1H),0.77(d,J=6.1Hz,6H).

Example 65 Preparation of Compound 65

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with the intermediate amide 13 of Example 13 to obtain compound 65, MS m/z: 732(M+1) ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ7.61 (s, 1H), 7.51 (d, J = 6.8Hz, 1H), 7.39-7.34 (m, 4H), 7.24 (t, J = 7.6Hz, 1H), 6.50 (s, 1H), 5.98 (d, J = 9.2 Hz, 1H), 4.37 (d, J = 9.2 Hz, 1H), 4.21-4.18 (m, 1H), 3.93 (s, 3H), 3.90-3.84(m,2H),3.75-3.69(m,2H),3.61-3.53(m,1H), 3.50-3.42(m,1H), 2.59(d,J=13.2Hz,2H), 2.20- 2.08(m,2H),1.96-1.85(m,2H),1.83-1.76(m,3H),1.68-1.66(m,1H),1.57-1.55(m,1H),0.98(d,J=5.6 Hz, 1H), 0.90 (d, J = 18.8 Hz, 2H), 0.85 (d, J = 6.8 Hz, 3H), 0.63-0.61 (m, 2H).

Example 66 Preparation of compound 66-a, 66-b, 66-c, 66-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Configuration) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 8-2 of Example 8, and then chiral resolution by SFC Compound 66-a, 66-b, 66-c, 66-d was obtained, MS m/z: 692(M+1) ⁺ .

Example 67 Preparation of compound 67-a, 67-b, 67-c, 67-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Configuration) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 16 of Example 16, and then chiral resolution by SFC to prepare the compound 67-a, 67-b, 67-c, 67-d, MS m/z: 710(M+1) ⁺ .

Example 68 Preparation of compound 68-a, 68-b, 68-c, 68-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Configuration) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 15 of Example 15, and then chiral resolution by SFC to prepare the compound 67-a, 67-b, 67-c, 67-d, MS m/z: 728(M+1) ⁺ .

Example 69 Preparation of Compound 69-a, 69-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 8-2 of Example 8 to obtain compound 69-b: ¹ H NMR (400MHz, CD ₃ OD): δ7.78–7.53(m,3H), 7.50–7.44(m,1H), 7.37–7.29(m,3H), 7.28–7.21(m,1H), 6.33(d,J=2.2Hz ,1H),6.02(d,J=11.9Hz,1H),5.51(s,2H),4.73-4.63(m,1H),4.29(d,J=9.2Hz,1H),4.08-3.96(m, 3H), 3.87 (s, 3H), 3.75 (d, J = 11.9 Hz, 1H), 3.22-3.08 (m, 2H), 2.98-2.87 (m, 1H), 2.60-2.46 (m, 2H), 1.94 –1.84(m,1H),1.81–1.49(m,5H),1.36–1.29(m,1H),1.12(s,3H),1.06(t,J=7.3Hz,3H),0.95–0.86(m ,2H),0.81–0.72(m,1H),0.06–0.04(m,1H),-0.09–0.21(m,2H); similarly, take the steps in Example 3 Intermediate 3-3a and Example 6 6 Furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration), after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, and finally Example 8 Intermediate amide 8-2 was condensed to obtain compound 69-a: ¹ H NMR (400MHz, CD3OD): δ 7.76-7.55 (m, 3H), 7.51-7.44 (m, 1H), 7.37-7.28 (m ,3H),7.28–7.22(m,1H),6.33(d,J=2.2Hz,1H),5.51(s,2H), 4.68(d,J=8.6Hz,1H), 4.60(s,0H) ,4.29(d,J=9.1Hz,1H),4.09–3.95(m,3H), 3.75(d,J=11.9Hz,1H), 3.25–3.04(m,2H), 2.97–2.85(m,1H ), 2.61–2.45(m,2H),1.94-1.84(m,1H),1.83-1.53(m,5H),1.34-1.29(m,1H),1.12(s,3H),1.05(t,J ＝7.2Hz,3H),0.95-0.86(m,2H),0.80 –0.71(m,1H),0.05–0.04(m,1H),-0.10–0.21(m,2H); MS m/z: 686(M+1) ⁺ .

Example 70 Preparation of compound 70-a, 70-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 10 of Example 10 to obtain compound 70-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed, and finally condensed with the intermediate amide 10 of Example 10 to obtain compound 70-a; MS m/z: 672(M+1) ⁺ .

Example 71 Preparation of compound 71-a, 71-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 11 of Example 11 to obtain compound 71-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 11 of Example 11 to obtain compound 71-a; MS m/z: 698(M+1) ⁺ .

Example 72 Preparation of Compound 72-a, 72-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 12 of Example 12 to obtain compound 72-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 12 of Example 12 to obtain compound 72-a; MS m/z: 712(M+1) ⁺ .

Example 73 Preparation of Compound 73-a, 73-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 13 of Example 13 to obtain compound 73-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 13 of Example 13 to obtain compound 73-a; MS m/z: 730(M+1) ⁺ .

Example 74 Preparation of compound 74-a, 74-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 14 of Example 14 to obtain compound 74-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed, and finally condensed with the intermediate amide 14 of Example 14 to obtain compound 74-a; MS m/z: 742(M+1) ⁺ .

Example 75 Preparation of compound 75-a, 75-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 15 of Example 15 to obtain compound 75-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 15 of Example 15 to obtain compound 75-a; MS m/z: 722(M+1) ⁺ .

Example 76 Preparation of Compound 76-a, 76-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 16 of Example 16 to obtain compound 76-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 16 of Example 16 to obtain compound 76-a; MS m/z: 704(M+1) ⁺ .

Example 77 Preparation of Compound 77-a, 77-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 17 of Example 17 to obtain compound 77-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 17 of Example 17 to obtain compound 77-a; MS m/z: 700(M+1) ⁺ .

Example 78 Preparation of Compound 78-a, 78-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 18 of Example 18 to obtain compound 78-b; similarly, the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 18 of Example 18 to obtain compound 78-a; MS m/z: 702(M+1) ⁺ .

Example 79 Preparation of Compound 79-a, 79-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 19 of Example 19 to obtain compound 79-b; similarly, the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed, and finally condensed with the intermediate amide 19 of Example 19 to obtain compound 79-a; MS m/z: 716(M+1) ⁺ .

Example 80 Preparation of Compound 80-a, 80-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 20 of Example 20 to obtain compound 80-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed, and finally condensed with the intermediate amide 20 of Example 20 to obtain compound 80-a; MS m/z: 714(M+1) ⁺ .

Example 81 Preparation of Compound 81-a, 81-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 21 of Example 21 to obtain compound 81-b; similarly, the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The oxazole-5-acyl group was hydrolyzed, and finally condensed with the amide 21 of Example 21 to obtain compound 81-a; MS m/z: 750(M+1) ⁺ .

Example 82 Preparation of Compound 82-a, 82-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 22 of Example 22 to obtain compound 82-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 22 of Example 22 to obtain compound 82-a; MS m/z: 716(M+1) ⁺ .

Example 83 Preparation of Compound 83-a, 83-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 23 of Example 23 to obtain compound 83-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 23 of Example 23 to obtain compound 83-a; MS m/z: 716(M+1) ⁺ .

Example 84 Preparation of Compound 84-a, 84-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 24 of Example 24 to obtain compound 84-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 24 of Example 24 to obtain compound 84-a; MS m/z: 704(M+1) ⁺ .

Example 85 Preparation of Compound 85-a, 85-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 25 of Example 25 to obtain compound 85-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 25 of Example 25 to obtain compound 85-a; MS m/z: 722(M+1) ⁺ .

Example 86 Preparation of Compound 86-a, 86-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 26 of Example 26 to obtain compound 86-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed, and finally condensed with the intermediate amide 26 of Example 26 to obtain compound 86-a; MS m/z: 700(M+1) ⁺ .

Example 87 Preparation of compound 87-a, 87-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 27 of Example 27 to obtain compound 87-b; similarly, the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 27 of Example 27 to obtain compound 87-a; MS m/z: 716(M+1) ⁺ .

Example 88 Preparation of Compound 88-a, 88-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 28 of Example 28 to obtain compound 88-b; similarly, the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The oxazole-5-acyl group was hydrolyzed, and finally condensed with the amide 28 of Example 28 to obtain compound 88-a; MS m/z: 700(M+1) ⁺ . 88-b NMR spectrum: ¹ H NMR(400MHz, Methanol-d ₄ )δ8.02(s,1H), 7.75–7.63(m,2H), 7.58(d,J=7.8Hz,1H), 7.48( d, J = 7.9 Hz, 1H), 7.34 (dd, J = 8.8, 3.5 Hz, 3H), 7.25 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.34 ( d, J = 2.1Hz, 1H), 6.03 (d, J = 11.9 Hz, 1H), 4.75 (d, J = 8.6 Hz, 1H), 4.36 (d, J = 8.9 Hz, 1H), 4.04 (dd, J = 8.0, 4.4 Hz, 3H), 3.88 (s, 3H), 3.76 (d, J = 12.0 Hz, 1H), 3.25–3.03 (m, 2H), 2.92–2.81 (m, 1H), 2.74–2.58 (m,1H),2.11–1.99(m,1H),1.99–1.88(m,1H),1.87–1.73(m,1H),1.63–1.50(m,1H),1.49–1.40(m,1H) ,1.40–1.29(m,2H),1.12(s,3H),1.07(t,J=7.3Hz,3H),0.98(s,3H),0.81–0.73(m,1H),0.05–-0.02( m,1H),-0.15(t,J=7.5Hz,2H).

Example 89 Preparation of Compound 89-a, 89-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 29 of Example 29 to obtain compound 89-b; similarly, use the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 29 of Example 29 to obtain compound 89-a; MS m/z: 704(M+1) ⁺ .

Example 90 Preparation of compound 90-a, 90-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 30 of Example 30 to obtain compound 90-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The oxazole-5-acyl group was hydrolyzed, and finally condensed with the amide 30 of Example 30 to obtain compound 90-a; MS m/z: 717(M+1) ⁺ .

Example 91 Preparation of compound 91-a, 91-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 31 of Example 31 to obtain compound 91-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The oxazole-5-acyl group was hydrolyzed, and finally condensed with the amide 31 of Example 31 to obtain compound 91-a; MS m/z: 712(M+1) ⁺ .

Example 92 Preparation of Compound 92-a, 92-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 32 of Example 32 to obtain compound 92-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed, and finally condensed with the amide 32 of Example 32 to obtain compound 92-a; MS m/z: 698(M+1) ⁺ . The proton nuclear magnetic spectrum of compound 92b is: ¹ H NMR (400MHz, MeOD) δ 7.69 (s, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.36 -7.32 (m, 3H), 7.25 (t, J = 7.6 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 6.03 (d, J = 12.0 Hz, 1H), 4.76 (d, J = 8.4Hz, 1H), 4.39 (s, 1H), 4.05-4.00 (m, 3H), 3.87 (s, 3H), 3.75 (d, J = 12.0Hz, 1H), 3.28-3.08 (m, 2H), 2.91–2.85(m,1H),2.66-2.59(m,1H),2.31(s,1H),1.51(s,6H),1.13-1.07(m,6H),0.79–0.74(m,1H), 0.03--0.02(m,1H), -0.15(t,J=7.6Hz,2H).

Example 93 Preparation of Compound 93-a, 93-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 33 of Example 33 to obtain compound 93-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 33 of Example 33 to obtain compound 93-a; MS m/z: 712(M+1) ⁺ .

Example 94 Preparation of compound 94-a, 94-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 34 of Example 34 to obtain compound 94-b; similarly, take the intermediate of Example 3 3-3b and Example 6 in step 6 furan o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) were condensed, closed, deprotected, and introduced 1-methyl-1H-pyridine The azole-5-acyl group was hydrolyzed and finally condensed with the intermediate amide 34 of Example 34 to obtain compound 94-a; MS m/z: 716(M+1) ⁺ .

Example 95 Preparation of Compound 95

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with the intermediate amide 8-2 of Example 8 to obtain compound 95, MS m/z: 700(M+1) ⁺ .

Example 96 Preparation of compound 96-a, 96-b, 96-c, 96-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 8-2 of Example 8, and then separated by SFC chiral column Purified and prepared compound 96-a, 96-b, 96-c, 96-d, MS m/z: 692(M+1) ⁺ ; 96-a: ¹ H NMR (400MHz, CD ₃ OD): δ7. 57-7.62(m,2H),7.33-7.40(m,3H),7.27-7.29(dd,J=2.0Hz,1H),7.13-7.18(m,1H),6.53(s,1H),6.00- 6.03(d,J=11.2Hz,1H),5.51(s,4H),4.64-4.66(d,J＝8..4Hz,1H),4.26-4.29(d,J＝9.2Hz,1H),4.18 -4.22(m,1H),3.96-4.02(m,3H),3.08-3.20(m,2H),2.86-2.93(m,1H),2.49-2.55(m,2H),1.53-2.00(m, 4H), 1.24-1.35 (m, 5H), 0.99-1.07 (m, 3H), 0.83-0.93 (m, 3H); 96-b: ¹ H NMR (400MHz, CD ₃ OD): δ7.53-7.66 (m,2H),7.27-7.39(m,4H),7.13-7.18(m 1H),6.53(s,1H),6.00-6.03(d,J=9.2Hz,1H),5.51(s,2H) ,4.64-4.66(d,J=8..4Hz,1H),4.26-4.29(d,J=9.2Hz,1H),4.18-4.22(m,1H),3.96-4.02(m,6H),3.01 -3.18(m,2H),2.86-2.93(m,1H),2.49-2.55(m,2H),1.85-1.95(m,2H),1.54-1.71(m,2H),1.00-1.06(m, 6H), 0.83-0.87 (m, 3H).

Example 97 Preparation of compound 97-a, 97-b, 97-c, 97-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 15 of Example 15, and then separation and purification by SFC chiral column Obtained compound 97-a, 97-b, 97-c, 97-d, MS m/z: 728(M+1) ⁺ ; 97-a: ¹ H NMR (400MHz, CD ₃ OD): δ7.57- 7.62(m,2H),7.33-7.40(m,3H),7.27-7.29(dd,J=1.6Hz,1H),7.13-7.18(m,1H),6.53(s,1H),6.00-6.03( d,J=9.2Hz,1H),5.51(s,4H),4.64-4.66(d,J=8..4Hz,1H),4.43-4.62(m,1H),4.31-4.34(m,2H) ,4.18-4.22(m,1H),3.96-4.02(m,3H),3.42-3.50(m,2H),2.86-2.93(m,1H),2.49-2.55(m,2H),1.86-1.97( m, 2H), 1.54-1.68 (m, 2H), 0.99-1.07 (m, 3H), 0.83-0.93 (d, J=6.4 Hz, 3H).

Example 98 Preparation of compound 98-a, 98-b, 98-c, 98-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 16 of Example 16, and then separation and purification by SFC chiral column Obtained compound 98-a, 98-b, 98-c, 98-d, MS m/z: 710(M+1) ⁺ ; 98-a: ¹ H NMR (400MHz, CD ₃ OD): δ7.50- 7.51 (m, 1H), 7.33-7.40 (m, 2H), 7.14-7.20 (m, 3H), 6.94-7.01 (m, 2H), 5.89-5.92 (m, 1H), 4.55-4.63 (m, 1H) ), 4.42-4.45 (m, 1H), 4.27-4.33 (m, 3H), 4.11 (s, 3H), 3.92-3.96 (m, 4H), 2.82 (s, 1H), 2.45-2.52 (m, 3H) ),1.47-1.86(m,3H),1.01-1.03(d,J=10.8Hz,1H),0.96-0.98(d,J=10.8Hz,2H),0.83-0.89(m,4H); 98- b: ¹ H NMR (400MHz, CD ₃ OD): δ7.42-7.51 (m, 3H), 7.15-7.23 (m, 4H), 6.94-7.01 (m, 2H), 5.89-5.92 (d, J= 10.8Hz,1H),4.55-4.63(d,J=8.4Hz,1H),4.42-4.45(m,1H),4.27-4.33(m,3H),4.11(s,3H),3.92-3.96(m ,4H),2.79-2.85(m,1H),2.45-2.52(m,3H),1.47-1.86(m,3H),1.01-1.03(d,J=10.8Hz,1H),0.96-0.98(d , J = 10.8Hz, 2H), 0.83-0.89 (m, 4H).

Example 99 Preparation of compound 99-a, 99-b, 99-c, 99-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 8-2 of Example 8, and then separated by SFC chiral column Purification and preparation of compound 99-a, 99-b, 99-c, 99-d, MS m/z: 692(M+1) ⁺ .

Example 100 Preparation of compound 100-a, 100-b, 100-c, 100-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 15 of Example 15, and then separated and purified by SFC chiral column Compound 100-a, 100-b, 100-c, 100-d, MS m/z: 728(M+1) ⁺ .

Example 101 Preparation of compound 101-a, 101-b, 101-c, 101-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 16 of Example 16, and then separation and purification by SFC chiral column Obtain compound 101-a, 101-b, 101-c, 101-d, MS m/z: 710(M+1) ⁺ .

Example 102 Preparation of compound 102-a, 102-b, 102-c, 102-d

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 9 of Example 9, and then separated and purified by SFC chiral column Compound 102-a, 102-b, 102-c, 102-d was obtained, MS m/z: 734(M+1) ⁺ .

Example 103 Preparation of Compound 103-a, 103-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 103-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis and condensation to obtain compound 103-a. MS m/z: 700(M+1) ⁺ .

Example 104 Preparation of compound 104-a, 104-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with Example 8 intermediate 8-2 to obtain compound 104-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of propionyl group, hydrolysis and condensation to obtain compound 104-a. MS m/z: 634 (M+1) ⁺ .

Example 105 Preparation of Compound 105-a, 105-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 105-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of isobutyryl group, hydrolysis and condensation to obtain compound 105-a. MS m/z: 648 (M+1) ⁺ .

Example 106 Preparation of Compound 106-a, 106-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 106-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of pyrrolidinyl carbonyl, hydrolysis and condensation to obtain compound 106-a. MS m/z: 675(M+1) ⁺ .

Example 107 Preparation of Compound 107-a, 107-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 107-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis and condensation to obtain compound 107-a. MS m/z: 649 (M+1) ⁺ .

Example 108 Preparation of Compound 108-a, 108-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 108-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methylamine carbonyl, hydrolysis and condensation to obtain compound 108-a. MS m/z: 635(M+1) ⁺ .

Example 109 Preparation of Compound 109-a, 109-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure. Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 109-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis and condensation to obtain compound 109-a. MS m/z: 662 (M+1) ⁺ .

Example 110 Preparation of compound 110-a, 110-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of ethylaminocarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 110-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of ethylamine carbonyl, hydrolysis and condensation to obtain compound 110-a. MS m/z: 649 (M+1) ⁺ .

Example 111 Preparation of compound 111-a, 111-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with Example 8 intermediate 8-2 to obtain compound 111-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and condensation to obtain compound 111-a. MS m/z: 677 (M+1) ⁺ .

Example 112 Preparation of Compound 112-a, 112-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 112-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce N-methyl-N'-cyclopropylcarbonyl, hydrolyze, and condense to obtain compound 112-a. MS m/z: 675(M+1) ⁺ .

Example 113 Preparation of compound 113-a, 113-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 8 intermediate 8-2 to obtain compound 113-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis and condensation to obtain compound 113-a. MS m/z: 688 (M+1) ⁺ .

Example 114 Preparation of compound 114-a, 114-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 114-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis and condensation give compound 114-a. MS m/z: 622 (M+1) ⁺ .

Example 115 Preparation of Compound 115-a, 115-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of isopropyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 115-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of isopropyl acyl group, hydrolysis and condensation to obtain compound 115-a. MS m/z: 636 (M+1) ⁺ .

Example 116 Preparation of compound 116-a, 116-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of pyrrolidinyl carbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 116-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of pyrrolidinyl carbonyl group, hydrolysis and condensation to obtain compound 116-a. MS m/z: 663 (M+1) ⁺ .

Example 117 Preparation of Compound 117-a, 117-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with Example 8 intermediate 8-2 to obtain compound 117-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis and condensation to obtain compound 117-a. MS m/z: 637 (M+1) ⁺ .

Example 118 Preparation of Compound 118-a, 118-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 118-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis and condensation to obtain compound 118-a. MS m/z: 623 (M+1) ⁺ .

Example 119 Preparation of compound 119-a, 119-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 119-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a of step 6 in Example 6 (prepared by SFC chiral resolution to obtain another single configuration) were reacted, Condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and condensation to obtain compound 119-a. MS m/z: 651 (M+1) ⁺ .

Example 120 Preparation of compound 120-a, 120-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of ethylaminocarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 120-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of ethylaminocarbonyl, hydrolysis, and condensation to obtain compound 120-a. MS m/z: 637 (M+1) ⁺ .

Example 121 Preparation of compound 121-a, 121-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of N'N-diethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 121-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of N'N-diethylcarbonyl, hydrolysis, and condensation to obtain compound 121-a. MS m/z: 665 (M+1) ⁺ .

Example 122 Preparation of Compound 122-a, 122-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, after condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with Example 8 intermediate 8-2 to obtain compound 122-b. Similarly, the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl group, hydrolysis and condensation to obtain compound 122-a. MS m/z: 663 (M+1) ⁺ .

Example 123 Preparation of compound 123-a, 123-b, 123-c, 123-d, 123-e, 123-f, 123-g, 123-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare the compound 123-a, 123-b, 123-c, 123-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, 1-ethyl-1H-pyrazole- The 5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 123-e, 123-f, 123-g, 123-h. MS m/z: 706 (M+1) ⁺ .

Example 124 Preparation of compound 124-a, 124-b, 124-c, 124-d, 124-e, 124-f, 124-g, 124-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 124-a, 124-b, 124-c ,124-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of propionyl groups, hydrolysis, condensation, and then SFC Chiral resolution prepared compound 124-e, 124-f, 124-g, 124-h. MS m/z: 640(M+1) ⁺ .

Example 125 Preparation of compound 125-a, 125-b, 125-c, 125-d, 125-e, 125-f, 125-g, 125-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) after condensation, ring closure, deprotection, introduction of isopropionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 125-a, 125-b, 125- c, 125-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of isopropyl acyl group, hydrolysis, condensation, and then SFC chiral resolution prepared compound 125-e, 125-f, 125-g, 125-h. MS m/z: 654(M+1) ⁺ .

Example 126 Preparation of compound 126-a, 126-b, 126-c, 126-d, 126-e, 126-f, 126-g, 126-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 8 intermediate 8-2, and then chiral resolution by SFC to prepare compound 126-a, 126-b ,126-c,126-d. Similarly, take the step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and condensation , And then chiral resolution by SFC to prepare compound 126-e, 126-f, 126-g, 126-h. MS m/z: 681 (M+1) ⁺ .

Example 127 Preparation of compound 127-a, 127-b, 127-c, 127-d, 127-e, 127-f, 127-g, 127-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 127-a,127 -b,127-c,127-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, introduced N,N-dimethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 127-e, 127-f, 127-g, 127-h. MS m/z: 655(M+1) ⁺ .

Example 128 Preparation of compound 128-a, 128-b, 128-c, 128-d, 128-e, 128-f, 128-g, 128-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) After condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 128-a, 128-b, 128- c,128-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, condensation, and then SFC chiral resolution to prepare compound 128-e, 128-f, 128-g, 128-h. MS m/z: 641 (M+1) ⁺ .

Example 129 Preparation of compound 129-a, 129-b, 129-c, 129-d, 129-e, 129-f, 129-g, 129-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 129- a,129-b,129-c,129-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, and N-methyl-N'-ethyl was introduced. The carbonyl group is hydrolyzed, condensed, and then chiralized by SFC to prepare compound 129-e, 129-f, 129-g, 129-h. MS m/z: 669 (M+1) ⁺ .

Example 130 Preparation of compound 130-a, 130-b, 130-c, 130-d, 130-e, 130-f, 130-g, 130-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compounds 130-a, 130-b, 130-c, 130-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and condensation, After chiral resolution by SFC, compound 130-e, 130-f, 130-g, 130-h was obtained. MS m/z: 655(M+1) ⁺ .

Example 131 Preparation of compound 131-a, 131-b, 131-c, 131-d, 131-e, 131-f, 131-g, 131-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) After condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 131-a,131 -b,131-c,131-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, deprotected, introduced N,N-diethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 131-e, 131-f, 131-g, 131-h. MS m/z: 683 (M+1) ⁺ .

Example 132 Preparation of compound 132-a, 132-b, 132-c, 132-d, 132-e, 132-f, 132-g, 132-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 132 -a,132-b,132-c,132-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, N-methyl-N'-cyclopropyl was introduced The compound 132-e, 132-f, 132-g, 132-h was prepared by hydrolysis, condensation, and chiral resolution by SFC. MS m/z: 681 (M+1) ⁺ .

Example 133 Preparation of compound 133-a, 133-b, 133-c, 133-d, 133-e, 133-f, 133-g, 133-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare the compound 133-a, 133-b, 133-c, 133-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, 1-ethyl-1H-pyrazole- The 5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 133-e,133-f,133-g,133-h. MS m/z: 706 (M+1) ⁺ .

Example 134 Preparation of compound 134-a, 134-b, 134-c, 134-d, 134-e, 134-f, 134-g, 134-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 134-a, 134-b, 134-c ,134-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of propionyl groups, hydrolysis, condensation, and then SFC Chiral resolution prepared compound 134-e, 134-f, 134-g, 134-h. MS m/z: 640(M+1) ⁺ .

Example 135 Preparation of compound 135-a, 135-b, 135-c, 135-d, 135-e, 135-f, 135-g, 135-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, introduction of isopropionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 135-a, 135-b, 135- c,135-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of isopropyl acyl group, hydrolysis, condensation, and then SFC chiral resolution to prepare compound 135-e, 135-f, 135-g, 135-h. MS m/z: 654(M+1) ⁺ .

Example 136 Preparation of compound 136-a, 136-b, 136-c, 136-d, 136-e, 136-f, 136-g, 136-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2, and then chiral resolution by SFC to prepare compound 136-a, 136-b ,136-c,136-d. Similarly, take the step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and condensation , And then chiral resolution by SFC to prepare compound 136-e, 136-f, 136-g, 136-h. MS m/z: 681 (M+1) ⁺ .

Example 137 Preparation of compound 137-a, 137-b, 137-c, 137-d, 137-e, 137-f, 137-g, 137-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 137-a,137 -b,137-c,137-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, introduced N,N-dimethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 137-e, 137-f, 137-g, 137-h. MS m/z: 655(M+1) ⁺ .

Example 138 Preparation of compound 138-a, 138-b, 138-c, 138-d, 138-e, 138-f, 138-g, 138-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 138-a,138-b,138- c,138-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, condensation, and then SFC chiral resolution to prepare compound 138-e, 138-f, 138-g, 138-h. MS m/z: 641 (M+1) ⁺ .

Example 139 Preparation of compound 139-a, 139-b, 139-c, 139-d, 139-e, 139-f, 139-g, 139-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 139- a,139-b,139-c,139-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, and N-methyl-N'-ethyl was introduced. The carbonyl group is hydrolyzed, condensed, and then chiralized by SFC to prepare compound 139-e,139-f,139-g,139-h. MS m/z: 669 (M+1) ⁺ .

Example 140 Preparation of compound 140-a, 140-b, 140-c, 140-d, 140-e, 140-f, 140-g, 140-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2, and then chiral resolution by SFC to prepare compounds 140-a, 140-b, 140-c, 140-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and condensation, After chiral resolution by SFC, compounds 140-e, 140-f, 140-g, 140-h were obtained. MS m/z: 655(M+1) ⁺ .

Example 141 Preparation of compound 141-a, 141-b, 141-c, 141-d, 141-e, 141-f, 141-g, 141-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 141-a,141 -b,141-c,141-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, deprotected, introduced N,N-diethylcarbonyl, and hydrolyzed , Condensation, and chiral resolution by SFC to prepare compound 141-e,141-f,141-g,141-h. MS m/z: 683 (M+1) ⁺ .

Example 142 Preparation of compound 142-a, 142-b, 142-c, 142-d, 142-e, 142-f, 142-g, 142-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 142 -a,142-b,142-c,142-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, N-methyl-N'-cyclopropyl was introduced The compound 142-e, 142-f, 142-g, 142-h was prepared by hydrolysis, condensation, and SFC chiral resolution. MS m/z: 681 (M+1) ⁺ .

Example 143 Preparation of compound 143-a, 143-b, 143-c, 143-d, 143-e, 143-f, 143-g, 143-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare the compound 143-a,143-b,143-c,143-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, 1-ethyl-1H-pyrazole- The 5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 143-e,143-f,143-g,143-h. MS m/z: 706 (M+1) ⁺ .

Example 144 Preparation of compound 144-a, 144-b, 144-c, 144-d, 144-e, 144-f, 144-g, 144-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 144-a, 144-b, 144-c ,144-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of propionyl groups, hydrolysis, condensation, and then SFC Compound 144-e, 144-f, 144-g, 144-h were prepared by chiral resolution. MS m/z: 640(M+1) ⁺ .

Example 145 Preparation of compound 145-a, 145-b, 145-c, 145-d, 145-e, 145-f, 145-g, 145-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, introduction of isopropanoyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 145-a,145-b,145- c,145-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of isopropyl acyl group, hydrolysis, condensation, and then SFC chiral resolution prepared compound 145-e, 145-f, 145-g, 145-h. MS m/z: 654(M+1) ⁺ .

Example 146 Preparation of compound 146-a, 146-b, 146-c, 146-d, 146-e, 146-f, 146-g, 146-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 8 intermediate 8-2, and then chiral resolution by SFC to prepare compound 146-a, 146-b ,146-c,146-d. Similarly, take the step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and condensation , And then chiral resolution by SFC to prepare compound 146-a, 146-b, 146-c, 146-d. MS m/z: 681 (M+1) ⁺ .

Example 147 Preparation of compound 147-a, 147-b, 147-c, 147-d, 147-e, 147-f, 147-g, 147-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2, and then chiral resolution by SFC to prepare compound 147-a,147 -b,147-c,147-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, introduced N,N-dimethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 147-e,147-f,147-g,147-h. MS m/z: 655(M+1) ⁺ .

Example 148 Preparation of compound 148-a, 148-b, 148-c, 148-d, 148-e, 148-f, 148-g, 148-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 148-a, 148-b, 148- c,148-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, condensation, and then SFC chiral resolution prepared compound 148-e, 148-f, 148-g, 148-h. MS m/z: 641 (M+1) ⁺ .

Example 149 Preparation of compound 149-a, 149-b, 149-c, 149-d, 149-e, 149-f, 149-g, 149-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 149- a, 149-b, 149-c, 149-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, and N-methyl-N'-ethyl was introduced. The carbonyl group is hydrolyzed, condensed, and then chiralized by SFC to prepare compound 149-e, 149-f, 149-g, 149-h. MS m/z: 669 (M+1) ⁺ .

Example 150 Preparation of compound 150-a, 150-b, 150-c, 150-d, 150-e, 150-f, 150-g, 150-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compounds 150-a, 150-b, 150-c, 150-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and condensation, After chiral resolution by SFC, compounds 150-e, 150-f, 150-g, 150-h were obtained. MS m/z: 655(M+1) ⁺ .

Example 151 Preparation of compound 151-a, 151-b, 151-c, 151-d, 151-e, 151-f, 151-g, 151-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 151-1,151 -b,151-c,151-d. Similarly, in step 6, o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, deprotected, introduced N,N-diethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 151-1e,151-f,151-g,151-h. MS m/z: 683 (M+1) ⁺ .

Example 152 Preparation of compound 152-a, 152-b, 152-c, 152-d, 152-e, 152-f, 152-g, 152-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2, and then SFC chiral resolution to prepare compound 152 -a,152-b,152-c,152-d. Similarly, using step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, N-methyl-N'-cyclopropyl was introduced The carbonyl carbonyl group is hydrolyzed, condensed, and then chiralized by SFC to prepare compound 152-e, 152-f, 152-g, 152-h. MS m/z: 681 (M+1) ⁺ .

Example 153 Preparation of Compound 153-a, 153-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with L-cyclobutyl-N-ethylglycamine amide to obtain compound 153-b; Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally L-cyclobutyl-N-ethylglycamine amide condensation to obtain compound 153-a. MS m/z: 686 (M+1) ⁺ . ¹ H NMR(400MHz,Methanol-d ₄ )δ7.76–7.55(m,3H), 7.51–7.44(m,1H), 7.37–7.28(m,3H), 7.28–7.22(m,1H), 6.33 (d,J=2.2Hz,1H),5.51(s,2H), 4.68(d,J=8.6Hz,1H), 4.60(s,0H), 4.29(d,J=9.1Hz,1H),4.09 –3.95(m,3H), 3.75(d,J=11.9Hz,1H), 3.25–3.04(m,2H), 2.97–2.85(m,1H), 2.61–2.45(m,2H), 1.94–1.84 (m,1H),1.83-1.53(m,5H),1.34-1.29(m,1H),1.12(s,3H),1.05(t,J=7.2Hz,3H),0.95-0.86(m,2H ), 0.80--0.71(m,1H), 0.05---0.04(m,1H), -0.10---0.21(m,2H).

Example 154 Preparation of Compound 154-a, 154-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 154-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally D-isopropyl-N-ethylglycamine amide condensation to obtain compound 154-a. MS m/z: 674 (M+1) ⁺ .

Example 155 Preparation of Compound 155-a, 155-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 155-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally D-tert-butyl-N-ethylglycamine amide condensation to obtain compound 155-a. MS m/z: 688 (M+1) ⁺ . ¹ HNMR (400MHz, MeOD): δ = 8.14-8.16 (t, J = 5.24, 1H), 7.64-7.66 (m, 2H), 7.55-7.57 (m, 1H), 7.44-7.46 (m, 1H), 7.28-7.33(m,3H),7.21-7.25(m,1H), 6.60-6.62(d,J=9.3,1H),6.319-6.324(d,J=2.1,1H),5.99-6.02(d, J = 11.9, 1H), 4.73-4.75 (d, J = 8.5, 1H), 4.18-4.20 (d, J = 9.4, 1H), 3.98-4.04 (m, 3H), 3.85 (s, 3H), 3.71 -3.74(d,J=11.9,6H),3.06-3.22(m,2H),2.80-2.86(m,1H),2.57-2.64(m,1H),1.10(s,3H),1.05-1.08( t,J=7.3,3H),0.76(s,10H),-0.03-0.01(m,1H),-0.20--0.17(m,1H).

Example 156 Preparation of Compound 156-a, 156-b

According to the method for preparing 35-b in step 6 of Example 35, the intermediate 36-6 was used as a raw material to condense with D-isopropyl-N-ethylglycineamide to obtain compound 156-b. Similarly, using the intermediate in step 5 of the preparation of another configuration 35-a (another configuration of 35-6) as a raw material, compound 156- can be obtained by condensation with D-isopropyl-N-ethylglycamine amide a. MS m/z: 662 (M+1) ⁺ .

Example 157 Preparation of Compound 157-a, 157-b

According to the method for preparing 35-b in step 6 of Example 35, the intermediate 36-6 was used as a raw material to condense with D-tert-butyl-N-ethylglycineamide to obtain compound 157-b. Similarly, using the intermediate in step 5 of the preparation of another configuration 35-a (another configuration of 35-6) as a raw material, compound 157- can be obtained by condensation with D-tert-butyl-N-ethylglycamine amide a. MS m/z: 676 (M+1) ⁺ .

Example 158 Preparation of compound 158-a, 158-b, 158-c, 158-d, 158-e, 158-f, 158-g, 158-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 158-a, 158-b, 158-c, 158-d. Similarly, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 158-e, 158-f, 158-g, 158-h. MS m/z: 680 (M+1) ⁺ .

Example 159 Preparation of compound 159-a, 159-b, 159-c, 159-d, 159-e, 159-f, 159-g, 159-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 159-a, 159-b, 159-c, 159-d. Similarly, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 159-e, 159-f, 159-g, 159-h. MS m/z: 694 (M+1) ⁺ .

Example 160 Preparation of compound 160-a, 160-b, 160-c, 160-d, 160-e, 160-f, 160-g, 160-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral SFC The compound 160-a, 160-b, 160-c, and 160-d were obtained by resolution. Similarly, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) are condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 160-e, 160-f, 160-g, 160-h. MS m/z: 680 (M+1) ⁺ .

Example 161 Preparation of compound 161-a, 161-b, 161-c, 161-d, 161-e, 161-f, 161-g, 161-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 161-a, 161-b, 161-c, and 161-d. Similarly, using the intermediate 4-5 of step 5 in Example 4 in step 6, o-phenylenediamine 6-6a in step 6 (prepared by SFC chiral resolution to obtain a single configuration) was subjected to condensation, ring closure, and deprotection. , Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycineamide, and then undergo chiral resolution by SFC to prepare compound 161-e,161 -f,161-g,161-h. MS m/z: 694 (M+1) ⁺ .

Example 162 Preparation of compound 162-a, 162-b, 162-c, 162-d, 162-e, 162-f, 162-g, 162-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 162-a, 162-b, 162-c, 162-d. Similarly, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) are condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 162-e, 162-f, 162-g, 162-h. MS m/z: 680 (M+1) ⁺ .

Example 163 Preparation of compound 163-a, 163-b, 163-c, 163-d, 163-e, 163-f, 163-g, 163-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 163-a, 163-b, 163-c, 163-d. Similarly, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) are condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 163-e, 163-f,163-g,163-h. MS m/z: 694 (M+1) ⁺ .

Example 164 Preparation of compound 164-a, 164-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 164-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introducing 1-ethyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with D-isopropyl-N-ethylglycamine amide to obtain compound 164-a. MS m/z: 688 (M+1) ⁺ .

Example 165 Preparation of compound 165-a, 165-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 165-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of propionyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 165-a. MS m/z: 622 (M+1) ⁺ .

Example 166 Preparation of Compound 166-a, 166-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 166-b. Similarly, the intermediate 3-3b of step 3 in Example 3 and the intermediate 3-3b of step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 of Example 6 (SFC chiral resolution preparation The obtained another single configuration) is subjected to condensation, ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 166-a. MS m/z: 636 (M+1) ⁺ .

Example 167 Preparation of Compound 167-a, 167-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 167-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 167-a. MS m/z: 663 (M+1) ⁺ .

Example 168 Preparation of Compound 168-a, 168-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 168-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 168-a. MS m/z: 637 (M+1) ⁺ .

Example 169 Preparation of Compound 169-a, 169-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 169-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 169-a. MS m/z: 623 (M+1) ⁺ .

Example 170 Preparation of Compound 170-a, 170-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 170-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introducing N-methyl-N'-ethylcarbonyl, hydrolyzing, and finally condensing with D-isopropyl-N-ethylglycamine amide to obtain compound 170-a. MS m/z: 651 (M+1) ⁺ .

Example 171 Preparation of Compound 171-a, 171-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 171-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 171-a. MS m/z: 637 (M+1) ⁺ .

Example 172 Preparation of Compound 172-a, 172-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 172-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 172-a. MS m/z: 665 (M+1) ⁺ .

Example 173 Preparation of compound 173-a, 173-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 173-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introducing N-methyl-N'-cyclopropylcarbonyl, hydrolyzing, and finally condensing with D-isopropyl-N-ethylglycamine amide to obtain compound 173-a. MS m/z: 663 (M+1) ⁺ .

Example 174 Preparation of compound 174-a, 174-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure. Type) After condensation, ring closure, deprotection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7 to obtain compound 174-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7 to obtain compound 174-a. MS m/z: 636 (M+1) ⁺ .

Example 175 Preparation of compound 175-a, 175-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide to obtain compound 175-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 175-a. MS m/z: 624 (M+1) ⁺ .

Example 176 Preparation of Compound 176-a, 176-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 176-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 176-a. MS m/z: 638 (M+1) ⁺ .

Example 177 Preparation of Compound 177-a, 177-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 177-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce 1-ethyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycamine amide to obtain compound 177-a. MS m/z: 702 (M+1) ⁺ .

Example 178 Preparation of Compound 178-a, 178-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 178-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce propionyl group, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycineamide to obtain compound 178-a. MS m/z: 636 (M+1) ⁺ .

Example 179 Preparation of compound 179-a, 179-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure. Type) through condensation, ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 179-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 179-a. MS m/z: 650 (M+1) ⁺ .

Example 180 Preparation of compound 180-a, 180-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 180-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 180-a. MS m/z: 677 (M+1) ⁺ .

Example 181 Preparation of compound 181-a, 181-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 181-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 181-a. MS m/z: 651 (M+1) ⁺ .

Example 182 Preparation of Compound 182-a, 182-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 182-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methylamine carbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycamine amide to obtain compound 182-a. MS m/z: 637 (M+1) ⁺ .

Example 183 Preparation of compound 183-a, 183-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 183-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce N-methyl-N'-ethylcarbonyl, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycamine amide to obtain compound 183-a. MS m/z: 666 (M+1) ⁺ .

Example 184 Preparation of compound 184-a, 184-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure. Type) After condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 184-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 184-a. MS m/z: 651 (M+1) ⁺ .

Example 185 Preparation of Compound 185-a, 185-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 185-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 185-a. MS m/z: 679 (M+1) ⁺ .

Example 186 Preparation of compound 186-a, 186-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycamine amide to obtain compound 186-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce N-methyl-N'-cyclopropylcarbonyl, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycineamide to obtain compound 186-a. MS m/z: 677 (M+1) ⁺ .

Example 187 Preparation of Compound 187-a, 187-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) after condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycineamide to obtain compound 187-b. Similarly, the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 187-a. MS m/z: 612 (M+1) ⁺ .

Example 188 Preparation of compound 188-a, 188-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycamine amide to obtain compound 188-b. Similarly, the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 188-a. MS m/z: 626 (M+1) ⁺ .

Example 189 Preparation of compound 189-a, 189-b, 189-c, 189-d, 189-e, 189-f, 189-g, 189-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 189-a,189 -b,189-c,189-d. Similarly, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 189-e,189-f,189-g,189- h. MS m/z: 630 (M+1) ⁺ .

Example 190 Preparation of compound 190-a, 190-b, 190-c, 190-d, 190-e, 190-f, 190-g, 190-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 190-a,190 -b,190-c,190-d. Similarly, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 190-e,190-f,190-g,190- h. MS m/z: 644 (M+1) ⁺ .

Example 191 Preparation of compound 191-a, 191-b, 191-c, 191-d, 191-e, 191-f, 191-g, 191-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 191-a,191 -b,191-c,191-d. Similarly, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) are condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 191-e,191-f,191-g,191- h. MS m/z: 630 (M+1) ⁺ .

Example 192 Preparation of compound 192-a, 192-b, 192-c, 192-d, 192-e, 192-f, 192-g, 192-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 192-a,192 -b,192-c,192-d. Similarly, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) are condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 192-e,192-f,192-g,192- h. MS m/z: 644 (M+1) ⁺ .

Example 193 Preparation of compound 193-a, 193-b, 193-c, 193-d, 193-e, 193-f, 193-g, 193-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 193-a,193 -b,193-c,193-d. Similarly, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) are condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 193-e,193-f,193-g,193- h. MS m/z: 630 (M+1) ⁺ .

Example 194 Preparation of compound 194-a, 194-b, 194-c, 194-d, 194-e, 194-f, 194-g, 194-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 194-a,194 -b,194-c,194-d. Similarly, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) are condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 194-e,194-f,194-g,194- h. MS m/z: 644 (M+1) ⁺ .

Example 195 Preparation of Compound 195

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the intermediate 7-5 of Example 7 were condensed, ring closed, deprotected, and 1-methyl-1H was introduced. -Pyrazol-5-acyl group, hydrolyzed, and finally condensed with L-cyclobutyl-N-ethylglycamine amide to obtain compound 195, MS m/z: 700(M+1) ⁺ .

Example 196 Preparation of Compound 196

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the intermediate 7-5 of Example 7 were condensed, ring closed, deprotected, and 1-methyl-1H was introduced. -Pyrazol-5-acyl group, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide to obtain compound 196. MS m/z: 688 (M+1) ⁺ .

Example 197 Preparation of Compound 197

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the intermediate 7-5 of Example 7 were condensed, ring closed, deprotected, and 1-methyl-1H was introduced. -Pyrazol-5-acyl group, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide to obtain compound 197. MS m/z: 702 (M+1) ⁺ .

Example 198 Preparation of Compound 198

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-isopropyl-N-ethylglycamine amide to obtain compound 198. MS m/z: 676 (M+1) ⁺ .

Example 199 Preparation of Compound 199

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with D-tert-butyl-N-ethylglycineamide to obtain compound 199. MS m/z: 690(M+1)+.

Example 200 Preparation of compound 200-a, 200-b, 200-c, 200-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the pyran o-phenylenediamine 7-5 in step 5 in Example 7 are condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-isopropyl-N-ethylglycamine amide, and then undergo chiral resolution by SFC to prepare compound 200-a,200- b,200-c,200-d. MS m/z: 694 (M+1) ⁺ .

Example 201 Preparation of compound 201-a, 201-b, 201-c, 201-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 2-6 of step 5 in Example 2 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. , Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycamine amide, and then undergo chiral resolution by SFC to prepare compound 201-1,201 -b,201-c,201-d. MS m/z: 708 (M+1) ⁺ .

Example 202 Preparation of compound 202-a, 202-b, 202-c, 202-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 4-5 of step 5 in Example 4 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-isopropyl-N-ethylglycamine amide, and then undergo chiral resolution by SFC to prepare compound 202-a, 202- b, 202-c, 202-d. MS m/z: 694 (M+1) ⁺ .

Example 203 Preparation of compound 203-a, 203-b, 203-c, 203-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 4-5 of step 5 in Example 4 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-tert-butyl-N-ethylglycamine amide, and then undergo chiral resolution by SFC to prepare compound 203-a,203- b, 203-c, 203-d. MS m/z: 708 (M+1) ⁺ .

Example 204 Preparation of compound 204-a, 204-b, 204-c, 204-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 of step 5 in Example 5 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 are condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 204-a,204- b,204-c,204-d. MS m/z: 694 (M+1) ⁺ .

Example 205 Preparation of compound 205-a, 205-b, 205-c, 205-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 of step 5 in Example 5 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 are condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-tert-butyl-N-ethylglycineamide, and then undergo chiral resolution by SFC to prepare compound 205-a,205- b,205-c,205-d. MS m/z: 708 (M+1) ⁺ .

Example 206 Preparation of Compound 206

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce 1-ethyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-isopropyl-N-ethylglycamine amide to obtain compound 206. MS m/z: 702 (M+1) ⁺ .

Example 207 Preparation of Compound 207

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The propionyl group is introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide to obtain compound 207. MS m/z: 636 (M+1) ⁺ .

Example 208 Preparation of Compound 208

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The isobutyryl group is introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide to obtain compound 208. MS m/z: 650 (M+1) ⁺ .

Example 209 Preparation of Compound 209

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce N-pyrrolidinylcarbonyl, hydrolyze, and finally condense with D-isopropyl-N-ethylglycamine amide to obtain compound 209. MS m/z: 677 (M+1) ⁺ .

Example 210 Preparation of Compound 210

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce N,N-dimethylcarbonyl, hydrolyze, and finally condense with D-isopropyl-N-ethylglycamine amide to obtain compound 210. MS m/z: 651 (M+1) ⁺ .

Example 211 Preparation of Compound 211

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methylamine carbonyl group is introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide to obtain compound 211. MS m/z: 637 (M+1) ⁺ .

Example 212 Preparation of Compound 212

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce N-methyl-N'-ethylcarbonyl, hydrolyze, and finally condense with D-isopropyl-N-ethylglycamine amide to obtain compound 212. MS m/z: 665 (M+1) ⁺ .

Example 213 Preparation of Compound 213

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The N-ethylcarbonyl group is introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide to obtain compound 213. MS m/z: 651 (M+1) ⁺ .

Example 214 Preparation of Compound 214

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing N,N-diethylcarbonyl, hydrolyzing, and finally condensing with D-isopropyl-N-ethylglycamine amide to obtain compound 214. MS m/z: 679 (M+1) ⁺ .

Example 215 Preparation of Compound 215

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce N-methyl-N'-cyclopropylcarbonyl, hydrolyze, and finally condense with D-isopropyl-N-ethylglycamine amide to obtain compound 215. MS m/z: 677 (M+1) ⁺ .

Example 216 Preparation of Compound 216

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methoxycarbonyl group is introduced, hydrolyzed, and finally condensed with the intermediate 7-2 of Example 7 to obtain compound 216. MS m/z: 650 (M+1) ⁺ .

Example 217 Preparation of Compound 217

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methoxycarbonyl group is introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide to obtain compound 217. MS m/z: 638 (M+1) ⁺ .

Example 218 Preparation of Compound 218

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methoxycarbonyl group is introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide to obtain compound 218. MS m/z: 652 (M+1) ⁺ .

Example 219 Preparation of Compound 219

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce 1-ethyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycineamide to obtain compound 219. MS m/z: 716 (M+1) ⁺ .

Example 220 Preparation of Compound 220

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The propionyl group is introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide to obtain compound 220. MS m/z: 650 (M+1) ⁺ .

Example 221 Preparation of Compound 221

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The isobutyryl group is introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide to obtain compound 221. MS m/z: 664 (M+1) ⁺ .

Example 222 Preparation of Compound 222

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing N-pyrrolidinylcarbonyl, hydrolyzing, and finally condensing with D-tert-butyl-N-ethylglycamine amide to obtain compound 222. MS m/z: 691 (M+1) ⁺ .

Example 223 Preparation of Compound 223

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce N,N-dimethylcarbonyl, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycamine amide to obtain compound 223. MS m/z: 665 (M+1) ⁺ .

Example 224 Preparation of Compound 224

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methylamine carbonyl group is introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide to obtain compound 224. MS m/z: 651 (M+1) ⁺ .

Example 225 Preparation of Compound 225

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. N-methyl-N'-ethylcarbonyl is introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide to obtain compound 225. MS m/z: 679 (M+1) ⁺ .

Example 226 Preparation of Compound 226

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The N-ethylcarbonyl group is introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide to obtain compound 226. MS m/z: 665 (M+1) ⁺ .

Example 227 Preparation of Compound 227

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. , Introducing N,N-diethylcarbonyl, hydrolyzing, and finally condensing with D-tert-butyl-N-ethylglycamine amide to obtain compound 227. MS m/z: 693 (M+1) ⁺ .

Example 228 Preparation of Compound 228

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycamine amide to obtain compound 228. MS m/z: 691 (M+1) ⁺ .

Example 229 Preparation of Compound 229

With reference to the method of steps 1 to 6 in Example 35, the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycamine amide to obtain compound 229. MS m/z: 626 (M+1) ⁺ .

Example 230 Preparation of Compound 230

Referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methoxycarbonyl group is introduced, hydrolyzed, and finally compound 230 is obtained with D-tert-butyl-N-ethylglycamine amide. MS m/z: 626 (M+1) ⁺ .

Example 231 Preparation of compound 231-a, 231-b, 231-c, 231-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the pyran o-phenylenediamine 7-5 in step 5 in Example 7 are condensed, ring closed, and deprotected. The methoxycarbonyl group was introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC was used to prepare compound 231-1a, 231-b, 231-c, and 231-d. MS m/z: 644 (M+1) ⁺ .

Example 232 Preparation of compound 232-a, 232-b, 232-c, 232-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the pyran o-phenylenediamine 7-5 in step 5 in Example 7 are condensed, ring closed, and deprotected. The methoxycarbonyl group was introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC was used to prepare compound 232-a, 232-b, 232-c, 232-d. MS m/z: 658 (M+1) ⁺ .

Example 233 Preparation of compound 233-a, 233-b, 233-c, 233-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 4-5 of step 5 in Example 4 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methoxycarbonyl group is introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 233-a,233-b,233-c,233-d. MS m/z: 644 (M+1) ⁺ .

Example 234 Preparation of compound 234-a, 234-b, 234-c, 234-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 4-5 of step 5 in Example 4 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methoxycarbonyl group is introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC is used to prepare compound 234-a, 234-b, 234-c, 234-d. MS m/z: 658 (M+1) ⁺ .

Example 235 Preparation of compound 235-a, 235-b, 235-c, 235-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 of step 5 in Example 5 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 are condensed, ring closed, and deprotected. The methoxycarbonyl group is introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 235-a, 235-b, 235-c, 235-d. MS m/z: 644 (M+1) ⁺ .

Example 236 Preparation of compound 236-a, 236-b, 236-c, 236-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 of step 5 in Example 5 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 are condensed, ring closed, and deprotected. The methoxycarbonyl group was introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC was used to prepare compound 236-a, 236-b, 236-c, 236-d. MS m/z: 658 (M+1) ⁺ .

Example 237 Preparation of Compound 237-a, 237-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally with (R)-8-amino-6-azaspiro[3.4]octane-7 -Ketone condensation gives compound 237-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce 1-ethyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 237- a. MS m/z: 670 (M+1) ⁺ . The proton nuclear magnetic spectrum of 237-b: ¹ HNMR (400MHz, MeOD): δ7.75 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 7.9, 1.6 Hz, 1H) ,7.47(dd,J=8.0,1.3Hz,1H),7.41(dd,J=8.5,1.8Hz,1H),7.37–7.29(m,2H),7.25(t,1H),6.33(d,J ＝2.1Hz,1H), 6.02(d,J＝11.9Hz,1H), 4.82(d,J＝8.5Hz,1H), 4.67–4.58(m,1H), 4.43(d,J＝21.4Hz,1H ), 4.11–3.97(m,3H), 3.87(s,3H), 3.74(d,J=11.9Hz,1H),3.41(d,J=9.9Hz,1H),3.06–2.96(m,1H) ,2.72–2.61(m,1H),2.22–2.04(m,1H),1.95–1.83(m,1H),1.79–1.61(m,2H),1.53–1.26(m,3H),1.12(s, 3H), 0.81–0.71(m,1H), 0.02–0.04(m,1H), -0.09–0.23(m,2H).

Example 238 Preparation of Compound 238-a, 238-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally with (R)-8-amino-6-azaspiro[3.4]octane-7 -Ketone condensation gives compound 238-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce 1-ethyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 238- a. MS m/z: 684 (M+1) ⁺ .

Example 239 Preparation of Compound 239-a, 239-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally (R)-8-amino-6-azaspiro[3.4]octane-7-one condensation to obtain compound 239-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of propionyl group, hydrolysis, and finally condensation with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 239-a. MS m/z: 618 (M+1) ⁺ .

Example 240 Preparation of compound 240-a, 240-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of isobutyryl, hydrolysis, and finally (R)-8-amino-6-azaspiro[3.4]octane-7-one condensation to obtain compound 240-b. Similarly, the intermediate 3-3b of step 3 in Example 3 and the intermediate 3-3b of step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 of Example 6 (SFC chiral resolution preparation The other single configuration obtained) is obtained by condensation, ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with (R)-8-amino-6-azaspiro[3.4]octane-7-one Compound 240-a. MS m/z: 632 (M+1) ⁺ .

Example 241 Preparation of compound 241-a, 241-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 241-4 b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 241-a. MS m/z: 659 (M+1) ⁺ .

Example 242 Preparation of compound 242-a, 242-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally (R)-8-amino-6-azaspiro[3.4]octane-7-one condensation to obtain the compound 242-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introducing N,N-dimethylcarbonyl, hydrolyzing, and finally condensing with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 242-a. MS m/z: 633 (M+1) ⁺ .

Example 243 Preparation of compound 243-a, 243-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally (R)-8-amino-6-azaspiro[3.4]octane-7-one condensation to obtain compound 243-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methylamine carbonyl, hydrolysis, and finally with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 243-a. MS m/z: 619 (M+1) ⁺ .

Example 244 Preparation of Compound 244-a, 244-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally with (R)-8-amino-6-azaspiro[3.4]octane-7-one Condensation gives compound 244-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introducing N-methyl-N'-ethylcarbonyl, hydrolyzing, and finally condensing with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 244-a. MS m/z: 647 (M+1) ⁺ .

Example 245 Preparation of compound 245-a, 245-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 245-b . Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 245-a. MS m/z: 633 (M+1) ⁺ .

Example 246 Preparation of Compound 246-a, 246-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally (R)-8-amino-6-azaspiro[3.4]octane-7-one condensation to obtain the compound 246-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce N,N-diethylcarbonyl, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 246-a. MS m/z: 661 (M+1) ⁺ .

Example 247 Preparation of Compound 247-a, 247-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure. Type) after condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally with (R)-8-amino-6-azaspiro[3.4]octane-7- The condensation of the ketone yields compound 247-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce N-methyl-N'-cyclopropylcarbonyl, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 247-a . MS m/z: 659 (M+1) ⁺ .

Example 248 Preparation of Compound 248-a, 248-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 248-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 248-a. MS m/z: 620 (M+1) ⁺ .

Example 249 Preparation of Compound 249

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 249. MS m/z: 684 (M+1) ⁺ .

Example 250 Preparation of Compound 250

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce 1-ethyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 250. MS m/z: 698 (M+1) ⁺ .

Example 251 Preparation of Compound 251

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The propionyl group is introduced, hydrolyzed, and finally condensed with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 251. MS m/z: 632 (M+1) ⁺ .

Example 252 Preparation of Compound 252

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The isobutyryl group is introduced, hydrolyzed, and finally condensed with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 252. MS m/z: 646 (M+1) ⁺ .

Example 253 Preparation of Compound 253

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing N-pyrrolidinylcarbonyl, hydrolyzing, and finally condensing with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 253. MS m/z: 673 (M+1) ⁺ .

Example 254 Preparation of Compound 254

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce N,N-dimethylcarbonyl, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 254. MS m/z: 647 (M+1) ⁺ .

Example 255 Preparation of Compound 255

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methylamine carbonyl group is introduced, hydrolyzed, and finally condensed with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 255. MS m/z: 633 (M+1) ⁺ .

Example 256 Preparation of Compound 256

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce N-methyl-N'-ethylcarbonyl, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 256. MS m/z: 661 (M+1) ⁺ .

Example 257 Preparation of Compound 257

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The N-ethylcarbonyl group is introduced, hydrolyzed, and finally condensed with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 257. MS m/z: 647 (M+1) ⁺ .

Example 258 Preparation of Compound 258

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introducing N,N-diethylcarbonyl, hydrolyzing, and finally condensing with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 258. MS m/z: 675(M+1) ⁺ .

Example 259 Preparation of Compound 259

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce N-methyl-N'-cyclopropylcarbonyl, hydrolyze, and finally condense with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 259. MS m/z: 673 (M+1) ⁺ .

Example 260 Preparation of Compound 260

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. The methoxycarbonyl group is introduced, hydrolyzed, and finally condensed with (R)-8-amino-6-azaspiro[3.4]octane-7-one to obtain compound 260. MS m/z: 634 (M+1) ⁺ .

Example 261 Preparation of compound 261-a, 261-b, 261-c, 261-d, 261-e, 261-f, 261-g, 261-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 261-a, 261-b, 261-c, and 261-d. Similarly, the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 261-e, 261-f, 261-g, 261-h. MS m/z: 676 (M+1) ⁺ .

Example 262 Preparation of compound 262-a, 262-b, 262-c, 262-d, 262-e, 262-f, 262-g, 262-h

With reference to the method of steps 1 to 6 in Example 35, the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral SFC The compound 262-a, 262-b, 262-c, and 262-d were obtained by resolution. Similarly, using the intermediate 4-5 of step 5 in Example 4 in step 6, o-phenylenediamine 6-6a in step 6 (prepared by SFC chiral resolution to obtain a single configuration) was subjected to condensation, ring closure, and deprotection. , Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycineamide, and then undergo chiral resolution by SFC to prepare compound 262-e,262 -f,262-g,262-h. MS m/z: 676 (M+1) ⁺ .

Example 263 Preparation of compound 263-a, 263-b, 263-c, 263-d, 263-e, 263-f, 263-g, 263-h

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 263-a, 263-b, 263-c, 263-d. Similarly, the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) are condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 263-e, 263-f, 263-g, 263-h. MS m/z: 676 (M+1) ⁺ .

Example 264 Preparation of compound 264-a, 264-b, 264-c, 264-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 2-6 in step 5 in Example 2 and the pyran o-phenylenediamine 7-5 in step 5 in Example 7 are condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-tert-butyl-N-ethylglycineamide, and then undergo chiral resolution by SFC to prepare compound 264-a,264- b,264-c,264-d. MS m/z: 690 (M+1) ⁺ .

Example 265 Preparation of compound 265-a, 265-b, 265-c, 265-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 4-5 of step 5 in Example 4 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-tert-butyl-N-ethylglycineamide, and then undergo chiral resolution by SFC to prepare compound 265-a,265- b,265-c,265-d. MS m/z: 690 (M+1) ⁺ .

Example 266 Preparation of compound 266-a, 266-b, 266-c, 266-d

Referring to the method of steps 1 to 6 in Example 35, the intermediate 5-5 of step 5 in Example 5 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 are condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-isopropyl-N-ethylglycamine amide, and then undergo chiral resolution by SFC to prepare compound 266-a,266- b, 266-c, 266-d. MS m/z: 690 (M+1) ⁺ .

Example 267 Preparation of Compound 267-a, 267-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally with (R)-8-amino-6-azaspiro[3.4]octane-7 -Ketone condensation gives compound 267-b. Similarly, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally with (8R)-8-amino-5-ethyl-6-azaspiro[3.4]octane-7-one Condensation gives compound 267-a. MS m/z: 698M+1) ⁺ . Among them, compound 267-b was resolved by SFC to obtain two component peaks (from the ethyl racemate of 5-ethyl-6-azaspiro[3.4]octane), one of the components, 267-b1; Component two 267-b2. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.81-7.71(m,2H), 7.65(d,J=8.5Hz,1H), 7.57(d,J=7.8Hz,1H), 7.51-7.40( m, 2H), 7.39–7.29 (m, 2H), 7.26 (t, 1H), 6.33 (d, J = 2.1 Hz, 1H), 6.02 (d, J = 11.9 Hz, 1H), 4.64 (d, J =8.7Hz,1H),4.14–4.05(m,2H),4.01(d,J=8.5Hz,1H), 3.87(s,3H), 3.75(d,J=11.9Hz,1H), 3.16(dd ,1H),3.10–2.99(m,1H), 2.75–2.60(m,1H), 2.16–2.02(m,1H), 2.02–1.90(m,1H), 1.82–1.66(m,2H), 1.61 –1.19(m,6H),1.11(s,3H),1.04(t,J=7.5Hz,3H),0.81–0.72(m,1H),0.05–-0.03(m,1H),-0.17(t ,J=7.6Hz,2H).

Example 268 Preparation of Compound 268-a, 268-b

Using compounds 69-b and 69-a in Example 69 as raw materials, 268-b and 268-a can be obtained by hydrodechlorination with Pd(OH) ₂ in ethanol. MS m/z: 652 (M+1) ⁺ . 268-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.71–7.58(m,2H), 7.37(d,J=4.4Hz,4H), 7.33–7.24(m,3H), 6.28(d,J＝2.1Hz,1H), 6.01(d,J＝12.1Hz,1H), 4.68(d,J＝8.6Hz,1H), 4.29(d,J＝9.1Hz,1H), 4.08- 3.96(m,3H), 3.87(s,3H), 3.23–3.02(m,2H), 2.95–2.87(m,1H), 2.84(d,J=12.1Hz,1H), 2.60–2.45(m, 2H),1.94–1.50(m,6H),1.11(s,3H),1.05(t,J=7.3Hz,3H),0.48–0.40(m,1H),0.02–0.03(m,1H), -0.11---0.21(m,2H).

Example 269 Preparation of Compound 269

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 8 Intermediate 8 to obtain compound 269. MS m/z: 672 (M+1) ⁺ .

Example 270 Preparation of Compound 270

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 8 of Example 8 to obtain compound 270. MS m/z: 686 (M+1) ⁺ .

Example 271 Preparation of Compound 271

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with Example 8 Intermediate 8 to obtain compound 271. MS m/z: 620 (M+1) ⁺ .

Example 272 Preparation of Compound 272

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of methoxyformyl group, hydrolysis, and finally condensation with Example 8 Intermediate 8 to obtain compound 272. MS m/z: 622 (M+1) ⁺ .

Example 273 Preparation of Compound 273

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8 to obtain compound 273. MS m/z: 661 (M+1) ⁺ .

Example 274 Preparation of Compound 274

Similarly, referring to the method of steps 1 to 6 in Example 35, the intermediate 1-5b and 3-(3,4-diaminophenyl)oxetane-3-carboxy of step 3 in Example 3 After condensation, ring closure, deprotection of the ethyl ester, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 8 of Example 8 to obtain compound 274. MS m/z: 646 (M+1) ⁺ .

Example 275 Preparation of Compound 275

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 8 Intermediate 8 to obtain compound 275. MS m/z: 674 (M+1) ⁺ .

Example 276 Preparation of Compound 276

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with the intermediate 8 of Example 8 to obtain compound 276. MS m/z: 608 (M+1) ⁺ .

Example 277 Preparation of Compound 277

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of methoxyformyl group, hydrolysis, and finally condensation with Example 8 Intermediate 8 to obtain compound 277. MS m/z: 610 (M+1) ⁺ .

Example 278 Preparation of Compound 278

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with the intermediate 8 of Example 8 to obtain compound 278. MS m/z: 649 (M+1) ⁺ .

Example 279 Preparation of Compound 279

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and ethyl 2-(3,4-diaminophenyl)tetrahydrofuran-2-carboxylate were condensed to close Ring, deprotection, introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with Example 8 Intermediate 8 to obtain compound 279. MS m/z: 686 (M+1) ⁺ .

Example 280 Preparation of Compound 280

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)tetrahydro-2H-pyran-3-carboxylic acid of step 3 in Example 3 The ethyl ester was condensed, closed the ring, deprotected, introduced 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with the intermediate 8 of Example 8 to obtain compound 280. MS m/z: 700(M+1) ⁺ .

Example 281 Preparation of Compound 281

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and 3-(3,4-diaminophenyl)oxetane-3-carboxylic acid ethyl ester of step 3 in Example 3 After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 32 of Example 32 to obtain compound 281. MS m/z: 684.0 [M+1] ⁺ .

Example 282 Preparation of Compounds 282-a and 282-b

With reference to the method of Example 8, Boc-D-(1-methylcyclobutyl)glycine was condensed with methylamine hydrochloride, followed by de-Boc to obtain 282-1 intermediate, MS m/z: 157.0[M+1] ⁺ .

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the intermediate 6-6b of Example 6 were condensed, ring closed, deprotected, and 1-methyl-1H was introduced. -Pyrazol-5-acyl group, hydrolyzed, and finally condensed with intermediate 282-1 to obtain compound 282-b. MS m/z: 686.0 (M+1) ⁺ . Similarly, using Intermediate 3-3b as a raw material, the compound 282-a can be obtained by condensation with another configuration 6-6a of the Intermediate of Example 6. MS m/z: 686.0 (M+1) ⁺ . 282-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.69(s,2H),7.58(dd,J=7.9,1.6Hz,1H),7.48(dd,J=8.0,1.4 Hz,1H),7.38–7.29(m,3H),7.26(td,J=7.7,1.6Hz,1H),6.34(d,J=2.2Hz,1H),6.02(d,J=12.0Hz,1H ), 4.75(d,J=8.5Hz,1H), 4.36(s,1H), 4.08–4.00(m,3H), 3.87(s,3H), 3.75(d,J=11.9Hz,1H), 2.86 (ddd,J=12.3,6.9,5.0Hz,1H),2.68(s,3H),2.67–2.60(m,1H),2.08–1.98(m,1H),1.96–1.73(m,2H),1.62 --1.28(m,4H),1.13(s,3H),0.96(s,3H),0.82--0.73(m,1H),0.02---0.02(m,1H),-0.11---0.19(m,2H) ).

Example 283 Preparation of Compound 283-a and 283-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the intermediate 6-6b of Example 6 were condensed, ring closed, deprotected, and 1-methyl-1H was introduced. -Pyrazol-5-acyl group, hydrolyzed, and finally condensed with cyclobutylmethylamine to obtain compound 283-b. Similarly, using Intermediate 3-3b as a raw material and condensing with another configuration 6-6a of Example 6 Intermediate, compound 283-a can be obtained, MS m/z: 615.0(M+1) ⁺ . 283-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.64(d,J＝1.7Hz,1H), 7.63–7.55(m,3H),7.47(dd,J＝8.0,1.4 Hz, 1H), 7.34 (dd, J = 7.5, 1.4 Hz, 1H), 7.31 (d, J = 2.1 Hz, 2H), 7.30-7.22 (m, 2H), 6.32 (d, J = 2.2 Hz, 1H ), 6.02 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 8.6 Hz, 1H), 4.07 (d, J = 8.6 Hz, 1H), 4.03-3.95 (m, 2H), 3.86 (s ,3H), 3.75(d,J=11.9Hz,1H), 3.23–3.13(m,2H), 2.99–2.91(m,1H), 2.49–2.37(m,2H),1.90–1.65(m,5H) ), 1.63-1.53(m, 2H), 1.12(s, 3H), 0.81-0.73(m, 1H), 0.02---0.02(m, 1H), -0.09---0.20(m, 2H).

Example 284 Preparation of Compound 284-a and 284-b

Using the compounds 88-b and 88-a in Example 88 as raw materials, 284-b and 284-a can be obtained by hydrodechlorination with Pd(OH) ₂ in ethanol. MS m/z: 666.0 (M+1) ⁺ . 284-b NMR spectrum: ¹ H NMR (400MHz, Methanol-d ₄ ) δ7.67 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 4.3Hz, 4H), 7.32-7.24 (m, 3H), 6.28 (d, J = 2.1 Hz, 1H), 6.02 (d, J = 12.0 Hz, 1H), 4.74 (d, J = 8.5 Hz, 1H) , 4.35 (s, 1H), 4.07-3.98 (m, 3H), 3.86 (s, 3H), 3.25-3.06 (m, 2H), 2.91-2.80 (m, 2H), 2.68-2.57 (m, 1H) ,2.04(q,J=9.5Hz,1H),1.93(q,J=9.6Hz,1H),1.86–1.74(m,1H),1.61–1.30(m,6H),1.11(s,3H), 1.07(t,J=7.3Hz,3H),0.97(s,3H),0.49–0.41(m,1H),0.02–-0.03(m,1H),-0.16(t,J=7.6Hz,2H) .

Example 285 Preparation of Compounds 285-a and 285-b

Using the compounds 282-b and 282-a in Example 282 as raw materials, 285-b and 285-a can be obtained by hydrodechlorination with Pd(OH) ₂ in ethanol. MS m/z: 652.0 (M+1) ⁺ . 285-b NMR spectrum: ¹ H NMR (400MHz, Methanol-d ₄ ) δ7.66 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 4.3Hz, 4H), 7.33 -7.24 (m, 3H), 6.27 (d, J = 2.2 Hz, 1H), 6.03 (d, J = 12.1 Hz, 1H), 4.74 (d, J = 8.5 Hz, 1H) , 4.39–4.35(m,1H), 4.06–3.98(m,3H), 3.85(s,3H), 2.89–2.80(m,2H), 2.68(s,3H), 2.65–2.57(m,1H) ,2.07–1.97(m,1H),1.95–1.85(m,1H),1.83–1.73(m,1H),1.58–1.27(m,5H),1.11(s,3H),0.96(s,3H) ,0.48–0.41(m,1H),0.02–0.03(m,1H),-0.16(t,J=7.5Hz,2H).

Example 286 Preparation of Compound 286-a and 286-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) After condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with intermediate 8-2 to obtain compound 286-b. Similarly, using Intermediate 1-5b as a raw material and condensing with another configuration of Example 6 Intermediate 6-6a, compound 286-a can be obtained after the same steps, MS m/z: 624.0(M+1) ⁺ . 286-b NMR spectrum: ¹ H NMR (400MHz, Methanol-d ₄ )δ7.61–7.45(m,3H), 7.36(t,J=7.5Hz,1H), 7.34–7.27(m,2H), 7.28–7.19(m,2H), 5.58(d,J=7.9Hz,1H), 4.65(d,J=8.6Hz,1H), 4.28(d,J=9.2Hz,1H), 4.05-3.96(m ,3H),3.97-3.88(m,1H),3.58(s,3H),3.23-3.07(m,2H),2.94-2.83(m,2H),2.58-2.45(m,2H),2.02-1.92 (m,0H),1.94–1.84(m,1H),1.84–1.73(m,3H),1.71–1.64(m,1H),1.63–1.50(m,1H),1.05(t,J=7.2Hz ,6H),0.79(d,J=6.7Hz,3H).

Example 287 Preparation of Compound 287-a and 287-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 (SFC chiral resolution) were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with intermediate 282-1 to obtain compound 287-b. , MS m/z: 636.0(M+1) ⁺ . . Similarly, using Intermediate 1-5b and the other configuration 6-6a of Example 6 as raw materials for condensation, compound 287-a can be obtained after the same procedure, MS m/z: 636.0(M+1) ⁺ . 287-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.69–7.67(m,1H), 7.65(d,J=8.4Hz,1H), 7.54(dd,J=7.9,1.7 Hz,1H),7.49(dd,J=8.0,1.4Hz,1H),7.40–7.26(m,3H),6.72(d,J=8.9Hz,1H), 5.58(d,J=11.8Hz,1H ), 4.75 (d, J = 8.5 Hz, 1H), 4.37 (d, J = 8.9 Hz, 1H), 4.08–3.98 (m, 3H), 3.55 (d, J = 11.9 Hz, 1H), 3.47 (s ,3H), 2.86(ddd,J=12.3,7.0,5.0Hz,1H), 2.72–2.67(m,3H), 2.67–2.60(m,1H),2.07–2.02(m,1H),1.97–1.72 (m,3H),1.63-1.50(m,2H),1.07(s,3H),0.97(s,3H),0.79-0.72(m,1H),-0.17---0.27(m,2H).

Example 288 Preparation of Compound 288-a and 288-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) After condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with intermediate 10 to obtain compound 288-b. Similarly, using Intermediate 1-5b as a raw material, and condensing with another configuration of Example 6 Intermediate 6-6a, after the same step, compound 288-a can be obtained, MS m/z: 610.0(M+1) ⁺ . 288-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.60–7.48(m,3H),7.42–7.18(m,5H), 5.59(dd,J=56.7,7.5Hz,1H ), 4.64(d,J=8.6Hz,1H),4.31–4.24(m,1H),4.04–3.95(m,3H),3.97–3.87(m,2H), 3.60(s,3H), 2.93– 2.84(m,1H), 2.70–2.68(m,3H), 2.57–2.46(m,2H), 2.10–1.94(m,1H), 1.93–1.84(m,1H), 1.82–1.72(m,4H) ), 1.71–1.64(m,1H), 1.55(t,J=8.4Hz,1H),1.08(s,3H),0.79(d,J=6.7Hz,3H).

Example 289 is used for the preparation of intermediates for the preparation of compounds 289-a and 289-b

Preparation of Intermediate 289-4

Step 1 Preparation of Intermediate 289-1

Under ice bath, sodium methoxide (27.88g, 531.32mmol) was added to the methanol solution of compound 1-1 (33g, 129.08mmol). The reaction solution was gradually warmed to room temperature and stirred for 3h. TLC detection showed that the raw material reaction was complete. The reaction solution was diluted with water under ice bath, the mixture was extracted with ethyl acetate, the organic phases were combined and concentrated, and the crude product obtained was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1, v/v) to obtain compound 289-1 (13g, 45.19mmol, yield 35%) yellow oil. MS m/z:288[M+1] ⁺

Step 2 Preparation of Intermediate 289-2

At room temperature, Zn powder (14.69g, 226mmol) was slowly added in batches to the acetic acid (50mL) solution of Intermediate 281-1 (13g, 45.2mmol). The reaction solution was stirred at room temperature for 4h. After the reaction was completed, the reaction was filtered. The filtrate was concentrated, the resulting crude product was diluted with sodium carbonate aqueous solution, extracted with ethyl acetate, the combined organic phase was concentrated, and then separated and purified by silica gel column (petroleum ether/ethyl acetate=1/1, v/v) as the target intermediate 289 -2 (9g, 34.9mmol, yield 77.3%), yellow oil. MS m/z:258.0[M+1] ⁺

Step 3 Preparation of Intermediate 289-3

With reference to the preparation method of Intermediate 1-4 in Example 1, Intermediate 289-2 was obtained by adding sodium bicarbonate to a mixed solution of tetrahydrofuran and water and stirring with Boc ₂ O. The reaction mixture was extracted and purified by column chromatography. Intermediate 289-3, colorless oil. The yield is 30%. MS m/z:358.0[M+1] ⁺

Step 4 Preparation of Intermediate 289-4

Referring to the preparation method of Intermediate 1-5 in Example 1, Intermediate 289-3 was hydrolyzed by lithium hydroxide to obtain 289-4, MS m/z: 330.0 [M+1] ⁺ . The yield was 76%.

Example 289 Preparation of Compound 289-a and 289-b

With reference to the method of steps 1 to 6 in Example 35, the above intermediate 289-4 and the step 6 o-phenylenediamine 6-6a in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were used as raw materials. Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with intermediate 28 to obtain compound 289-a. Similarly, using Intermediate 289-4 as a raw material and condensing with another configuration 6-6b of the Intermediate of Example 6, after the same steps, compound 289-b can be obtained, MS m/z: 676.0(M+1) ⁺ . 289-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.67–7.55(m,2H),7.49(q,J＝4.3,3.6Hz,2H),7.41(dt,J＝8.1 ,3.0Hz,1H),7.35-7.22(m,3H),6.95(d,J=2.1Hz,1H),5.92(d,J=3.5Hz,1H),5.54(d,J=3.5Hz,1H ), 4.71(d,J=8.5Hz,1H), 4.36(s,1H),4.06–3.95(m,3H),3.91(s,3H), 3.46(t,J=7.1Hz,2H),3.31 (s, 3H), 3.16 (ddt, J = 31.9, 13.5, 6.9 Hz, 2H), 2.94-2.80 (m, 1H), 2.84 (s, 3H), 2.59 (dt, J = 12.7, 8.0 Hz, 1H ), 2.37(t,J=8.1Hz,2H),2.11–1.99(m,3H),2.00–1.68(m,3H),1.67–1.52(m,1H),1.57–1.23(m,5H), 1.31(s,5H),1.08(t,J=7.2Hz,3H),1.00(s,3H),1.07-0.83(m,3H).

Example 290 Preparation of Compound 290-a and 290-b

Preparation of Intermediate 290-2

Step 1: Preparation of Intermediate 290-1

Isobutyl chloroformate (206mg, 0.51mmol) was slowly dropped into Fmoc-D-methylcyclobutylglycine (500mg, 1.37mmol) and N-methylmorpholine (153mg, 151mmol) in anhydrous THF (7mL) , At minus five degrees, the reaction solution was stirred at -5°C for 30 min, and then filtered. After cooling to -5°C, a mixture of NaBH ₄ (103 mg, 2.7 mmol) and ice water (3 mL) was dropped into the above filtrate dropwise , The dripping is complete, the mixed solution continues to stir at -5°C for 1h. Then, the reaction was quenched with water, extracted with ethyl acetate, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. The crude product was separated and purified by silica gel column to obtain Intermediate 290-1 (450 mg, 93% yield). rate). MS m/z: 352.0 (M+1) ⁺ .

Step 2: Preparation of Intermediate 290-2

Under an ice bath, an aqueous solution (1 mL) of LiOHH ₂ O (72 mg, 1.7 mmol) was dropped into a mixed solution of 290-1 (500 mg, 1.4 mmol) in THF (5 mL) and H ₂ O (5 mL). The reaction solution was stirred at room temperature for 1 hour, the mixed solution was spin-dried to dry the solvent, the crude product was dissolved in water, adjusted to pH 5 with 6N HCl, extracted with a mixture of petroleum ether/ethyl acetate (1/1), and the liquid phase was sodium bicarbonate aqueous solution Adjust the pH to 7-8, then spin dry the liquid phase to obtain 290-2 (180 mg), which is used directly in the next step without purification. MS m/z: 130.0(M+1) ⁺

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and the intermediate 6-6a of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were subjected to condensation, ring closure, hydrolysis, and Intermediate 290-2 is condensed, deprotected, and finally reacted with methyl chloroformate to obtain compound 290-a. Similarly, using intermediate 3-3b and another configuration intermediate 6-6b as raw materials, after the same steps such as condensation, compound 290-b can be obtained, MS m/z: 609.0(M+1) ⁺ . 290-b NMR spectrum: ¹ H NMR(400MHz, Methanol-d ₄ )δ7.59(s,2H), 7.51(d,J=7.7Hz,1H),7.46(d,1H),7.37–7.29( m, 2H), 7.25 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 9.4 Hz, 1H), 5.54 (d, J = 11.9 Hz, 1H), 4.73 (d, J = 8.5 Hz, 1H), 4.06–3.94(m, 4H), 3.55–3.49(m, 2H), 3.45(s, 3H), 3.43–3.36(m, 1H), 2.93–2.84(m, 1H), 2.67–2.55( m,1H),1.92-1.82(m,2H),1.63-1.42(m,2H),1.31-1.17(m,2H),1.04(s,3H),0.90(s,3H),0.76-0.67( m,1H),-0.04---0.11(m,1H),-0.21---0.29(m,2H).

Example 291 Preparation of Compound 291-a and 291-b

With reference to the method of step 1-6 in Example 35, cyclohexyl-L-alanine hydrochloride and step 6 o-phenylenediamine 6-6a (SFC in Example 6) were prepared by chiral resolution to obtain a single configuration ) Is the starting material after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with intermediate 28 to obtain compound 291-a.

Similarly, using cyclohexyl-L-alanine hydrochloride and the o-phenylenediamine 6-6b in step 6 of Example 6 as raw materials, after condensation, ring closure, and deprotection, 1-methyl-1H-pyridine was introduced The azole-5-acyl group is hydrolyzed and finally condensed with intermediate 28 to obtain compound 291-b, MS m/z: 618.0(M+1) ⁺ , MS m/z: 618.0(M+1) ⁺ , ¹ H NMR (400MHz,Methanol-d ₄ )δ7.81–7.72(m,2H), 7.60–7.50(m,2H), 7.00(dd,2H), 5.62(dd,J=10.2,5.4Hz,1H), 4.68 (dd,J=22.1,8.7Hz,1H), 4.43–4.34(m,1H), 4.10(s,3H), 4.08–3.92(m,3H), 3.29–3.05(m,2H), 2.99–2.85 (m,1H), 2.59–2.45(m,1H), 2.27–1.95(m,4H), 1.93–1.74(m,5H), 1.73–1.60(m,2H), 1.57–1.41(m,3H) ,1.37–1.17(m,5H),1.09(d,J=7.2Hz,3H),1.06(d,J=2.5Hz,3H)

Preparation of Example Compounds 292-a and 292-b

Preparation of intermediate 292-6

Step 1, Preparation of 292-1

(Trans)-3-Cyclohexyl-2-Methyl Bing-2-en-1-ol (6g, 38.9mmol) was dissolved in dichloromethane (60mL), cooled to 0°C, and CBr ₄ (15g , 45 mmol), and slowly dropwise add PPh ₃ (11.2 g, 43 mmol) in 20 mL of dichloromethane solution. After the dripping is completed, the temperature is kept for 1 hour, and the reaction is completed and diluted with water, extracted with ethyl acetate, and the separated organic phase is concentrated. The crude product is separated and purified by a silica gel column to obtain 292-1 (7.5g, 34.5mmol, yield 88%).

Step 2, Preparation of 292-2

Under ice bath, Zn (1.19g, 18.13mmol) and I ₂ (31mg, 0.12mmol) were added to 292-2 (3.29g, 15.14mmol) and (E)-[(S)-2-methylpropane- 2-sulfinamide] ethyl acetate (3.1 g, 15.10 mmol) in DMF (32 mL) and water (81 μL). Maintain the ice bath and stir the reaction for 1 h, then slowly rise to room temperature and stir overnight. The reaction solution was filtered with celite, diluted with water, extracted with ethyl acetate, the separated organic phase was washed with saturated brine, and concentrated to obtain crude product 292-2, which was directly used in the next reaction. MS m/z: 344.0 (M+1) ⁺ .

Step 3. Preparation of 292-3

Dissolve 292-2 (5.5g, 16.08mmol) in ethyl acetate, add HCl/EtOAC (64mmol, 16mL) dropwise at room temperature, and stir overnight. The reaction solution was concentrated and diluted with water and petroleum ether. The separated aqueous phase was adjusted to weakly alkaline with sodium carbonate, and then extracted with ethyl acetate. The separated organic phase was concentrated to obtain intermediate 292-3 (2.0g, 8.36mmol) . MS m/z: 240.0 (M+1) ⁺ .

Step 4. Preparation of 292-4

Referring to the preparation of Intermediate 3-1 in Example 3, Intermediate 292-3 was used as raw materials, and diethylzinc and methyl chloroiodomethane were used as cyclization reagents to obtain Intermediate 292-4 (808 mg, 2.09 mmol). MS m/z: 254.0 (M+1) ⁺ .

Step 5, preparation of 292-5

Refer to the preparation of Intermediate 1-4 in Example 1, using THF and water as the solvent, NaHCO ₃ as the base, and Intermediate 292-4 as the raw material to obtain from Boc, MS m/z: 354.0[M+1] ⁺ .

Step 5, preparation of 292-6

Referring to the preparation method of Intermediate 1-5 in Example 1, 292-6 was obtained by hydrolysis of Intermediate 292-5, MS m/z: 326.0 [M+1] ⁺ .

Step 6. Preparation of compound 292-a and 292-b

Referring to the method of preparing 35-b in steps 1 to 6 in Example 35, the above-mentioned intermediate 292-6 and the single-configuration intermediate furan o-phenylenediamine 6-6a in step 6 in Example 6 were reacted with each other. Cycling, hydrolysis, condensation with the intermediate amide 28 of Example 28, deprotection, and reaction with ethyl chloroformate to obtain 292-a, MS m/z: 636.0 (M+1) ⁺ .

Similarly, the above-mentioned intermediate 292-6 and the single-configuration intermediate furan o-phenylenediamine 6-6b in step 6 of Example 6 were reacted to obtain compound 292-b through the same procedure, MS m/z: 636.0 ( M+1) ⁺ . ¹ H NMR(400MHz,Methanol-d ₄ )δ7.58(m,2H),7.27-7.23(m,1H),5.37-5.32(m,2H),4.73(dd,J=8.5,5.3Hz,1H ), 4.34-4.32(m,1H), 4.27-3.99(m,5H), 3.26-3.04(m,2H), 2.84-2.80(m,1H), 2.63-2.59(m,1H), 2.11-2.01 (m,2H),1.90–1.74(m,5H),1.64-1.42(m,6H),1.34–1.23(m,6H),1.12–1.02(m,7H),0.96(s,3H),0.58 --0.56(m,1H),0.37--0.33(m,1H),0.29--0.17(m,1H),-0.18---0.26(m,1H).

Example 293 Preparation of compounds 293-a and 293-b

Referring to the method for preparing 35-b in steps 1 to 6 in Example 35, the intermediate 292-6 and the single configuration intermediate furan o-phenylenediamine 6-6a in step 6 in Example 6 were reacted, and the ring was closed after condensation. , Deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, condensation with the intermediate amide 28 of Example 28 and other steps to obtain 293-a, MS m/z: 672.0(M+1) ⁺ .

Similarly, by reacting 292-6 with 6-6b in Example 6, the compound 293-b was obtained through the same steps, MS m/z: 672.0(M+1) ⁺ . ¹ H NMR(400MHz,Methanol-d ₄ )δ7.62(brs,2H), 7.52(d,J=2.0Hz,1H), 7.28(d,J=7.8Hz,1H), 6.86(d,J= 2.0Hz, 1H), 5.75 (d, J = 8.6 Hz, 1H), 4.73 (d, J = 8.4 Hz, 1H), 4.37-4.30 (m, 1H), 4.10 (s, 3H), 4.02-3.90 ( m,4H),3.76-3.73(m,5H),3.26-3.07(m,7H),2.85-2.81(m,1H),2.65-2.61(m,1H),2.03-1.86(m,4H), 1.76–1.71(m,5H), 1.54–1.49(m,5H), 1.06-1.15(m,1H), 0.64–0.47(m,2H), 0.36–0.34(m,1H), 0.25–0.23(m ,1H),0.17-0.14(m,1H).

Example 294 Preparation of Compounds 294-a and 294-b

Referring to the method of steps 1 to 6 of Example 35, the intermediate 3-3b of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) Condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 28 of Example 28 to obtain compound 294-b, MS m/z: 688.0 (M+ 1) ⁺ . ¹ H NMR(400MHz,Methanol-d ₄ )δ7.76–7.60(m,2H),7.56–7.42(m,2H),7.39–7.24(m,3H),5.92(d,J=12.1Hz,1H ), 4.75(d,J=8.5Hz,1H), 4.36(s,1H), 4.13–3.94(m,3H), 3.78(d,J=12.1Hz,1H), 3.26–3.06(m,2H) ,2.94–2.82(m,1H), 2.72–2.57(m,1H), 2.09–2.00(m,1H), 1.98–1.88(m,1H), 1.85–1.75(m,1H), 1.60–1.51( m,1H),1.46--1.40(m,1H),1.12-1.03(m,6H),0.98(s,3H),0.95-0.86(m,2H),0.83-0.76(m,1H),0.01- -0.03(m,1H),-0.09---0.24(m,2H).

Similarly, the intermediate 3-3a of Example 3 and the step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with the intermediate amide 28 of Example 28 to obtain compound 294-a, MS m/z: 688.0(M+1) ⁺ .

Example 295 Preparation of Compounds 295-a and 295-b

Preparation of Intermediate 295-5

Referring to the method of preparing intermediate 289-4 in Example 289, starting with cyclohexylformaldehyde, it was condensed with ethyl nitroacetate, reacted with sodium methoxide, reduced by nitro, protected by Boc, and hydrolyzed. Four single chiral isomers 295-5a, 295-5b, 295-5c, and 295-5d of intermediate 295-5 can be obtained by SFC chiral separation column. MS m/z:302.0[M+1] ⁺

Preparation of compound 295-a and 295-b

With reference to the method of steps 1 to 6 in Example 35, the above intermediate 295-5a and the step 6 furan o-phenylenediamine 6-6a in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 28 of Example 28 to obtain compound 295-a, MS m/z: 648.0 (M+1) ⁺ .

Similarly, intermediate 295-5a and step 6 of Example 6 furan o-phenylenediamine 6-6b (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring closed, deprotected, and 1-methyl was introduced. Group-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with the intermediate amide 28 of Example 28 to obtain compound 295-b, MS m/z: 648.0(M+1) ⁺ .

Example 296 Preparation of Compounds 296-a and 296-b

Referring to the method of steps 1 to 6 in Example 35, the above-mentioned intermediate 289-4 and the o-phenylenediamine 6-6a in step 6 of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed and closed. Ring, hydrolysis, condensation with intermediate 28, deprotection, and finally reaction with methyl chloroformate to obtain compound 296-a. Similarly, using Intermediate 289-4 and the other configuration 6-6b of Intermediate of Example 6 as raw materials, after the same steps such as condensation, compound 296-b can be obtained, MS m/z: 626.0(M+1) ⁺ . The proton nuclear magnetic spectrum of 296-b: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.71–7.57(m,3H),7.58–7.50(m,1H),7.42(dd,J=7.3,1.8Hz, 1H),7.41–7.29(m,2H),7.27(dd,J＝8.5,1.9Hz,1H), 5.40(dd,J＝19.2,3.2Hz,2H),4.71(d,J＝8.5Hz,1H ), 4.36(s,1H),4.02(td,J=7.6,6.7,2.0Hz,3H),3.55(s,3H), 3.24(s,3H), 3.29-3.04(m,2H), 2.86( dt,J＝12.5,6.2Hz,1H), 2.59(dt,J＝12.8,8.0Hz,1H),2.05(q,J＝9.2Hz,1H),1.94(dt,J＝11.1,9.0Hz,1H ), 1.82 (dp, J = 11.4, 8.6 Hz, 1H), 1.57 (dtt, J = 11.2, 9.3, 3.8 Hz, 1H), 1.51–1.26 (m, 2H), 1.31 (s, 3H), 1.08 ( t,J=7.3Hz,3H),1.00(s,3H),0.97-0.87(m,2H).

Example 297 Preparation of Compounds 297-a and 297-b

Preparation of Intermediate 297-2

Step 1, Preparation of 297-1

Under a dry ice acetone bath, LiHMDS (396 mmol, 1M in THF) was added dropwise to a solution of Boc-glycine methyl ester (15 g, 79.28 mmol) in anhydrous THF (180 mL). After stirring for 1 hour, 2-chloroacetophenone (13.5 g, 87.21 mmol) was added. The reaction mixture was stirred for about 2 hours, then quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the combined organic phase was washed with water and saturated brine, and the crude product 297-1 (12.25g, 44%) was spin-dried. , Directly used in the next reaction.

Step 2, Preparation of 297-2

Add iodomethane (37g, 262mmol) and Ag ₂ O (16.2g, 69.81mmol, 2.27mL) to a 297-1 (3g, 8.73mmol) solution in acetonitrile (50mL). The mixture is heated to 60°C and stirred for reaction After 50 hours, after the reaction, Ag ₂ O was filtered off, the filtrate was spin-dried, and the crude product was purified by reverse phase HPLC to obtain 297-2 (3.12 g, 26%). MS m/z: 344.0 (M+1) ⁺ .

Step 3. Preparation of compound 297-a and 297-b

With reference to the method of steps 1 to 6 in Example 35, the above-mentioned intermediate 297-2 and the step 6 o-phenylenediamine 6-6a in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed and closed. Ring, hydrolysis, condensation with intermediate 28, deprotection, and finally reaction with methyl chloroformate to obtain compound 297-a. Similarly, using intermediate 297-2 and another configuration 6-6b of the intermediate of Example 6 as raw materials, compound 297-b can be obtained after the same steps such as condensation, MS m/z: 690.0(M+1) ⁺ . 297-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.60–7.49(m,2H),7.45(d,J=2.2Hz,1H),7.42–7.38(m,1H), 7.37–7.25(m,2H), 7.24–7.15(m,2H), 7.10(t,J=7.6Hz,1H), 6.84(d,J=2.0Hz,1H), 6.41(s,1H), 4.66 (dd,J=8.5,2.2Hz,1H), 4.34–4.28(m,1H), 4.02–3.95(m,3H), 3.92(s,3H), 3.36–3.31(m,4H), 3.23–3.13 (m,1H), 3.13-3.04(m,1H), 2.86-2.76(m,1H), 2.62-2.49(m,1H), 2.05--1.96(m,1H), 1.95-1.86(m,1H) ,1.83(s,3H),1.80–1.75(m,1H),1.58–1.48(m,1H),1.45–1.39(m,1H),1.31–1.27(m,1H),1.08–1.01(m, 3H), 0.97(s, 3H).

Example 298 Preparation of Compounds 298-a and 298-b

Preparation of Intermediate 298-7

Step 1. Preparation of Intermediate 298-1

Add 4-bromo-3fluoro-2nitroaniline (10g, 42.55mmol) in dioxane (200mL) and water (20mL) into the reaction flask, and add 3,6-dihydro-2H-pyridine in turn Pinacol 4-boric acid pinacol ester (8.94g, 42.55mmol), Pd(dppf)Cl ₂ (1.55g, 2.12mmol) and K ₂ CO ₃ (17.60g, 127.54mmol), after mixing uniformly, vacuum nitrogen Protect, warm to 100°C and react for 3 hours. After the reaction, cool to room temperature, filter, add ethyl acetate and brine to separate the filtrate, concentrate to dryness to obtain crude product 298-1 (9.69g, 40.68mmol, 95.60% yield), MS m/z: 239.0(M+1) ⁺ .

Step 2. Preparation of Intermediate 298-2

Ac2O (484mg, 4.74mmol) was added to the solution of 298-1 (700mg, 2.94mmol) in acetic acid (7mL), the mixture was heated to 90℃ and reacted for 2 hours. After the reaction, it was added dropwise to 35ml of water, filtered and concentrated to dryness. 298-2 (618 mg, 2.21 mmol, 75.04% yield). MS m/z: 281.0(M+1) ⁺

Step 3. Preparation of Intermediate 298-3

M-CPBA (246.31mg, 1.43mmol) was added to the dichloromethane solution of 298-2 (200mg, 713.65umol), the mixture was stirred overnight at room temperature, 1/3 of the raw material remained, the reaction solution was heated to 40°C and the reaction continued for 4 hours , Adding sodium carbonate aqueous solution and ethyl acetate extraction, the organic layer was washed with sodium sulfite aqueous solution, the separated organic layer was concentrated to obtain intermediate 298-3 (205mg, 691.98umol, 96.96% yield), MS m/z: 297.0( M+1) ⁺

Step 4. Preparation of Intermediate 298-4

Under ice bath, add BF ₃ .OEt (2.74g, 19.28mmol) to the dichloromethane (50mL) solution of 298-3 (1.9g, 6.41mmol), gradually warm to room temperature and stir for 2 hours. Use after reaction It was quenched with sodium carbonate, extracted with ethyl acetate, and the organic phase was spin-dried to obtain a crude product, which was separated and purified by a forward silica gel column (eluent, dichloromethane/ethyl acetate=10:1～5:1) to obtain 298- 4 (1.37g, 4.62mmol, 72.11% yield) product. MS m/z: 297.0(M+1) ⁺

Step 5. Preparation of Intermediate 298-5

Add NaClO ₂ (1.31g, 12.95mmol) and NaH ₂ PO ₄ (1.59g, 10.17mmol) into the reaction flask, mix well and cool to 0℃, add 298-4 (1.37g, 4.62mmol) of tert-butyl The mixed solution of alcohol (12mL) and water (9mL) was kept and stirred for 1 hour. After the reaction, the acid was adjusted to pH=5-6. After ethyl acetate extraction, the organic phase was concentrated to obtain 298-5 (1.38g, 4.42mmol, 95.57) % Yield). MS m/z: 297.0(M+1) ⁺

Step 6. Preparation of Intermediate 298-6

SOCl ₂ (685.82 mg, 5.76 mmol, 418.18 uL) was added dropwise to a solution of 298-5 (600 mg, 1.92 mmol) in EtOH (12 mL), and after the addition, the temperature was raised to 60° C. to react for 12 hours. After cooling to room temperature, the reaction solution was poured into sodium bicarbonate solution, then extracted with ethyl acetate and concentrated to obtain crude product 298-6 (434mg, 1.46mmol, 75.72% yield), MS m/z: 299.0(M+1) ⁺

Step 7. Preparation of intermediates 298-7a and 298-7b

Palladium-carbon was added to a solution of 298-6 (434mg, 1.61mmol) in ethanol (8mL), replaced by a hydrogen balloon and stirred at room temperature for 12 hours. After the reaction, the palladium-carbon was filtered off, the filtrate was concentrated, and a forward silica gel column (two Chloroform/methanol=50/1, v/v) was purified to obtain 298-7 (187mg, 697.02umol, 43.40% yield), MS m/z: 269.0(M+1) ⁺ , resolved by SFC chiral column After separation, a single configuration 298-7a (82 mg, 44% yield) and another single configuration 298-7b (82 mg, 44% yield) were obtained,

Step 8. Preparation of compound 298-a and 298-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and the above-mentioned intermediate 298-7a (prepared by SFC chiral resolution to obtain a single configuration) were condensed, closed, and hydrolyzed with intermediate 28. Condensation, deprotection, and finally reaction with methyl chloroformate, and finally chiral resolution by SFC to obtain compounds 298-a and 298-b, MS m/z: 668.0(M+1) ⁺ .

Example 299 Preparation of Compound 299-a and 299-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the intermediate 6-6a of Example 6 were condensed, ring closed, deprotected, and 1-methyl-1H was introduced. -Pyrazol-5-acyl group, hydrolyzed, and finally condensed with intermediate 290-2 to obtain compound 299-a. MS m/z: 659.0 (M+1) ⁺ . Similarly, using Intermediate 3-3b as a raw material, and condensing with another configuration of Example 6 Intermediate 6-6b, compound 299-b can be obtained. MS m/z: 659.0 (M+1) ⁺ . 299-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.93-7.86(m,1H), 7.82(d,J=8.4Hz,1H), 7.62(d,J=8.9Hz, 1H), 7.52(t,J=6.7Hz,2H),7.42–7.26(m,3H),7.11(d,J=7.8Hz,1H),6.49–6.38(m,1H),6.20–6.05(m ,1H), 4.70(d,J＝8.7Hz,1H), 4.15–4.01(m,4H), 3.92(s,3H), 3.88(d,J＝12.2Hz,1H),3.57(dd,J＝ 11.4, 3.8Hz, 1H), 3.47–3.38(m,1H), 3.01–2.90(m,1H), 2.65–2.52(m,1H), 2.01–1.89(m,2H), 1.88–1.77(m, 1H), 1.71-1.61(m, 1H), 1.60-1.51(m, 1H), 1.38-1.28(m, 2H), 1.11(s, 3H), 0.98(s, 3H), 0.92-0.85(m, 1H), 0.16--0.06(m,1H), -0.01---0.16(m,2H).

Example 300 Preparation of Compound 300

Preparation of Intermediate 300-2

Refer to the method of Intermediate 292-2 of Example 292, using Fmoc-D-cyclobutylglycine as raw materials, adding isobutyl chloroformate and N-methylmorpholine, and then reducing with NaBH ₄ to obtain Intermediate 300-1 . Then, Fmoc was removed to obtain intermediate 300-2. MS m/z: 116.0 (M+1) ⁺ .

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and the intermediate 6-6a of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were subjected to condensation, ring closure, hydrolysis, and Intermediate 290-2 is condensed, deprotected, and finally reacted with acetic anhydride to obtain compound 300-a. Similarly, using intermediate 3-3b and another configuration intermediate 6-6b as raw materials, after the same steps such as condensation, compound 300-b can be obtained, MS m/z: 579.0(M+1) ⁺ .

Example 301 Preparation of Compounds 301-a and 301-b

Referring to the method of steps 1 to 6 in Example 35, the above-mentioned intermediate 3-3b and the step 6 o-phenylenediamine 6-6a in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed and closed. Ring, hydrolyze, condensation with intermediate 28, deprotection, and finally react with acetic anhydride to obtain compound 301-a. Similarly, using intermediate 3-3b and the other configuration 6-6b of the intermediate of Example 6 as raw materials, after the same steps such as condensation, compound 301-b can be obtained, MS m/z: 634.0(M+1) ⁺ . 301-b NMR spectrum: ¹ H NMR (400MHz, Methanol-d ₄ )δ7.66(s,1H), 7.62(d,J=8.5Hz,1H), 7.48(td,J=7.9,1.6Hz, 2H), 7.38–7.25(m,3H), 5.87(d,J=12.0Hz,1H), 4.75(d,J=8.5Hz,1H), 4.35(s,1H),4.08–3.97(m,3H ), 3.68–3.61(m, 1H), 3.28–3.05(m, 2H), 2.85(ddd, J = 12.3, 7.0, 5.0Hz, 1H), 2.70–2.57(m, 1H), 2.09–2.00(m ,1H),1.92(q,J=9.3Hz,1H),1.86-1.73(m,1H),1.68(s,3H),1.61-1.50(m,1H),1.49-1.40(m,1H), 1.39–1.32(m,2H),1.08(t,J=7.3Hz,3H),1.04(s,3H),0.97(s,3H),0.94–0.86(m,2H),0.84–0.74(m, 1H),0.12(d,J=2.9Hz,1H),0.00---0.07(m,1H), -0.18---0.24(m,2H).

Example 302 Preparation of Compounds 302-a and 302-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and the intermediate 6-6a of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were subjected to condensation, ring closure, hydrolysis, and Intermediate 300-2 is condensed, deprotected, and finally reacted with methyl chloroformate to obtain compound 302-a. Similarly, using intermediate 3-3b and another configuration intermediate 6-6b as raw materials, after the same steps such as condensation, compound 302-b can be obtained, MS m/z: 595.0(M+1) ⁺ . 302-b NMR spectrum: ¹ H NMR (400MHz, Methanol-d ₄ )δ7.88(s,1H), 7.82(d,J=8.5Hz,1H), 7.75(d,J=7.8Hz,1H) ,7.70(d,J=7.9Hz,1H),7.62–7.44(m,3H), 7.27(d,J=9.0Hz,1H), 5.78(d,J=11.8Hz,1H), 4.92(d, J = 8.5Hz, 1H), 4.30–4.18 (m, 3H), 4.18–4.06 (m, 1H), 3.76 (d, J = 11.9 Hz, 1H), 3.72–3.59 (m, 5H), 3.20–3.05 (m,1H), 2.86–2.72(m,1H), 2.61(h,J=8.1Hz,1H), 2.23–2.07(m,1H), 2.03–1.71(m,5H), 1.28(s,3H) ),1.02-0.88(m,1H),0.21-0.12(m,1H).

Example 303 Preparation of Compounds 303-a and 303-b

Preparation of Intermediate 303-3

Step 1. Preparation of Intermediate 303-1

Under ice bath, to Fmoc-D-(1-methylcyclobutyl)glycine (10g, 27.37mmol) in dichloromethane (137mL) was added HBTU (8.34g, 32.84mmol) and triethylamine (8.31g , 82.10 mmol), and then ammonium chloride (2.96, 54.73 mmol) was added. The reaction solution was gradually raised to room temperature and stirred for 1 hour. The reaction solution was diluted with water and extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, and the crude product obtained by rotary drying was separated and purified by a silica gel column to obtain intermediate 303-1. (9 g, 24.7 mmol, 90% yield), MS m/z: 365.0 (M+1) ⁺ .

Step 2. Preparation of Intermediate 303-2

Under ice bath, add 301-1 (500mg, 1.38mmol) to a 50mL three-necked flask. Under nitrogen protection, add THF (6mL) and BH ₃ THF (2.76mL) successively. Heat to 65℃ under nitrogen protection, then stir to react. 5 hours. The reaction system was cooled to room temperature, methanol (1 mL), Boc ₂ O (451 mg, 2.1 mmol) and water (1 mL) were added, and stirring was continued at room temperature for 1 hour. After the system was spin-dried, diluted with water, extracted with ethyl acetate, the organic phase was washed with water, saturated brine, and dried over anhydrous sodium sulfate. After spin-drying, the crude product was purified by normal phase silica gel column to obtain Intermediate 303-2 (161 mg, 0.36 mmol) , 26% yield), MS m/z: 451.0 (M+1) ⁺ .

Step 3. Preparation of Intermediate 303-3

LiOHH ₂ O (20mg, 0.5mmol) was added to the mixed solution of 303-2 (161mg, 0.36mmol) in THF (6mL), H ₂ O (2mL) and MeOH (1mL), and stirred overnight at room temperature. After the reaction was completed , The reaction solution was directly spin-dried, and the crude product was washed with petroleum ether to obtain Intermediate 303-3 (66 mg, 0.31 mmol, 85% yield). MS m/z: 229.0 (M+1) ⁺ .

Step 4. Preparation of compound 303

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b and the intermediate 6-6a of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were subjected to condensation, ring closure, hydrolysis, and Intermediate 303-3 is condensed, deprotected, reacted with methyl chloroformate, and finally Boc is removed to obtain compound 303-a. Similarly, using intermediate 3-3b and another configuration intermediate 6-6b as raw materials, after the same steps such as condensation, compound 303-b can be obtained, MS m/z: 608.0(M+1) ⁺ . 303-b NMR spectrum: ¹ H NMR (400MHz, Methanol-d ₄ )δ8.53(s,1H), 7.64(s,1H), 7.59(t,J=8.2Hz,1H), 7.53–7.49( m,1H),7.48–7.44(m,1H),7.38–7.19(m,4H),5.54(d,J=11.8Hz,1H), 4.80(d,J=8.5Hz,2H), 4.14–4.09 (m, 1H), 4.04 (q, J = 6.5, 5.6 Hz, 2H), 3.94 (d, J = 8.5 Hz, 1H), 3.68 (s, 1H), 3.52 (d, J = 12.3 Hz, 1H) , 3.45 (s, 3H), 2.93-2.85 (m, 2H), 2.80 (s, 0H), 2.77 (d, J = 2.7 Hz, 1H), 2.76-2.64 (m, 2H), 1.88-1.69 (m ,4H),1.67–1.47(m,3H),1.29(d,J=3.0Hz,1H),1.04(s,3H),0.85(s,3H),0.78(s,1H),0.73(d, J=8.2Hz, 1H).

Example 304 Preparation of Compounds 304-a and 304-b

Referring to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of Example 3 and the intermediate 6-6a of Example 6 were condensed, ring closed, deprotected, and 1-methyl-1H-pyrazole was introduced. The -5-acyl group is hydrolyzed and condensed with intermediate 303-3, and finally Boc is removed to obtain compound 304-a. MS m/z: 659.0 (M+1) ⁺ . Similarly, using Intermediate 3-3b as a raw material and condensing with another configuration 6-6b of Example 6 Intermediate, compound 304-b can be obtained. MS m/z: 659.0 (M+1) ⁺ . 304-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d4)δ8.53(s,1H), 7.66(d,J=1.7Hz,1H), 7.62(d,J=8.4Hz,1H), 7.55(dd,J=7.9,1.7Hz,1H),7.47–7.43(m,1H),7.35–7.29(m,3H),7.28–7.19(m,1H),6.32(d,J=2.2Hz, 1H), 6.01(d,J=12.0Hz,1H), 4.82(d,J=8.5Hz,1H), 4.19–4.09(m,1H),4.09–3.97(m,2H), 3.92(d,J =8.5Hz, 1H), 3.85 (s, 3H), 3.73 (d, J = 11.9 Hz, 1H), 2.96-2.77 (m, 4H), 2.70 (d, J = 12.8, 7.7 Hz, 1H), 1.89 –1.68(m,3H),1.70–1.46(m,2H),1.22–1.14(m,1H),1.10(s,3H),0.84(s,3H),0.81–0.71(m,1H),- 0.03(d,J=4.9Hz,1H),-0.15---0.24(m,2H).

Example 305 Preparation of Compounds 305-a and 305-b

Referring to the method of steps 1 to 6 in Example 35, the above-mentioned intermediate 3-3b and the step 6 o-phenylenediamine 6-6a in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed and closed. The ring is reacted with acetic anhydride, hydrolyzed, condensed with intermediate 303-3, deprotected, and finally compound 305-a is obtained. Similarly, using intermediate 3-3b and the other configuration 6-6b of the intermediate of Example 6 as raw materials, after the same steps such as condensation, compound 305-b can be obtained, MS m/z: 592.0(M+1) ⁺ . 305-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.63(d,J=1.7Hz,1H), 7.55(d,J=8.4Hz,1H), 7.49–7.39(m, 2H), 7.35–7.19(m,3H), 5.85(d,J=12.0Hz,1H), 4.19–4.12(m,1H), 4.10–3.98(m,2H), 3.90(d,J=8.5Hz) ,1H),3.63(d,J=12.0Hz,1H),2.98–2.79(m,3H), 2.76–2.64(m,1H),1.87–1.69(m,3H),1.64(s,3H), 1.62–1.48(m,2H),1.21–1.08(m,1H),1.02(s,3H),0.83(s,3H),0.80–0.74(m,1H),-0.18---0.30(m,2H) ).

Example 306 Preparation of Compounds 306-a and 306-b

With reference to the method of steps 1 to 6 in Example 35, the intermediate 3-3b of step 3 in Example 3 and the intermediate diamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. Type) After condensation, ring closure, deprotection, reaction with methyl chloroformate to introduce methoxycarbonyl, then ester hydrolysis, and finally condensation with intermediate 28 to obtain compound 306-b. , MS m/z: 636.0(M+1) ⁺ . Similarly, using intermediate 3-3b and the other configuration 6-6a of Example 6 as raw materials for condensation, compound 306-a can be obtained after the same steps, MS m/z: 650(M+1) ⁺ . 306-b NMR spectrum: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.75–7.54(m,2H),7.54–7.49(m,1H),7.48–7.42(m,1H),7.39– 7.30(m,1H),7.30–7.20(m,2H),5.55(d,J=11.9Hz,1H), 4.72(d,J=8.5Hz,1H),4.33(s,1H),4.06–3.92 (m,3H),3.51(d,J=12.0Hz,1H),3.44(s,3H),3.12(ddq,J=27.9,14.3,7.2Hz,2H),2.88–2.77(m,1H), 2.61 (dt, J = 12.7, 8.1 Hz, 1H), 2.01 (q, J = 9.2 Hz, 1H), 1.89 (q, J = 9.1 Hz, 1H), 1.84-1.71 (m, 1H), 1.60-1.47 (m,1H),1.46–1.36(m,1H),1.35–1.25(m,1H),1.08–1.01(m,6H),0.94(s,3H),0.72(q,J=7.4Hz,1H ),-0.04---0.12(m,1H),-0.25(t,J=7.5Hz,2H).

To illustrate the beneficial effects of the present invention, the present invention provides the following test examples.

Test Example 1 IL-17 enzyme-linked immunosorbent assay (ELISA) experiment

The inhibition of receptor-ligand binding by IL-17A inhibitors was quantitatively detected by competitive ELISA. Incubate 0.2μg/mL IL-17A (Sino Biologicallnc.Cat#12047-H07B) with 100μL (50mM phosphate buffer, pH 7.4) per well in a 96-well plate at 37°C for 30 minutes. Wash the plate with PBST (PBS, 0.05% Tween-20) 4 times, 200 μL each time per well, add 200 μL 5% non-fat milk and incubate on a shaker at 25 degrees for 30 minutes. Prepare 100X concentration of the test compound, the final concentration is from 0.0002μM to 30μM. Wash the plate with PBST (PBS, 0.05% Tween-20) 4 times, add 89 μL PBST and 1 μL 100X concentration test compound, mix well, and pre-incubate at 25°C for 10 minutes. Add 10μL 16nM IL-17R (Sino Biological lnc.Cat#10895-H03H) and incubate on a shaker at 25 degrees for 30 minutes. After washing the plate 4 times, add 100 μL of anti-Fc tag HRP conjugate antibody (Sino Biological lnc.Cat#10702-T16-H-50) and incubate on a shaker at 25 degrees for 30 minutes. After washing the plate 4 times, add 100 μL of TMB substrate solution and incubate at 25 degrees in the dark. After adding 100μL 2.5M HCl, use a microplate reader to detect the light absorption value at 450nm wavelength.

The compounds prepared in the examples were tested for their IL-17A inhibitory activity according to the above method. The test results are shown in Table 1. The IC ₅₀ of each compound was determined according to the instructions. In Table 1:

"+" means that the IC ₅₀ measured value is less than 100μM and greater than 1μM;

"++" means that the IC ₅₀ measured value is less than 1μM and greater than 100nM;

"+++" means that the IC ₅₀ measured value is less than 100 nM.

Table 1. Inhibitory activity of compounds on IL-17A

化合物Compound	IC ₅₀ IC ₅₀	化合物Compound	IC ₅₀ IC ₅₀	化合物Compound	IC ₅₀ IC ₅₀	化合物Compound	IC ₅₀ IC ₅₀	化合物Compound	IC ₅₀ IC ₅₀	化合物Compound	IC ₅₀ IC ₅₀
35-a35-a	++++++	88-b88-b	++++++	133-a133-a	++++++	163-e163-e	++++++	238-b238-b	++++++	298-b298-b	++++++
35-b35-b	++++++	89-a89-a	++++++	133-b133-b	++++++	163-f163-f	++++++	239-a239-a	++++++	299-b299-b	++++
36-a36-a	++++++	89-b89-b	++++++	133-c133-c	++	163-g163-g	++	239-b239-b	++++++	300-b300-b	++++
36-b36-b	++++++	90-a90-a	++++++	133-d133-d	++	163-h163-h	++	240-a240-a	++++++	301-b301-b	++++++
41-a41-a	++++++	90-b90-b	++++++	133-e133-e	++++++	164-a164-a	++++++	240-b240-b	++++++	302-b302-b	++++++
41-b41-b	++++++	91-a91-a	++++++	133-f133-f	++++++	164-b164-b	++++++	241-a241-a	++++++	303-b303-b	++++++
42-a42-a	++++++	91-b91-b	++++++	133-g133-g	++	165-a165-a	++++++	241-b241-b	++++++	304-b304-b	++++++
42-b42-b	++++++	92-a92-a	++++++	133-h133-h	++	165-b165-b	++++++	242-a242-a	++++++	305-b305-b	++++
43-a43-a	++++++	92-b92-b	++++++	134-a134-a	++++++	166-a166-a	++++++	242-b242-b	++++++	306-b306-b	++++++
43-b43-b	++++++	93-a93-a	++++++	134-b134-b	++++++	166-b166-b	++++++	243-a243-a	++++++	To	To
44-a44-a	++++++	93-b93-b	++++++	134-c134-c	++	167-a167-a	++++++	243-b243-b	++++++	To	To
44-b44-b	++++++	94-a94-a	++++++	134-d134-d	++	167-b167-b	++++++	244-a244-a	++++++	To	To
45-a45-a	++++++	94-b94-b	++++++	134-e134-e	++++++	168-a168-a	++++++	244-b244-b	++++++	To	To
45-b45-b	++++++	9595	++++++	134-f134-f	++++++	168-b168-b	++++++	245-a245-a	++++++	To	To
46-a46-a	++++++	96-a96-a	++++++	134-g134-g	++	169-a169-a	++++++	245-b245-b	++++++	To	To
46-b46-b	++++++	96-b96-b	++++++	134-h134-h	++	169-b169-b	++++++	246-a246-a	++++++	To	To
47-a47-a	++++++	96-c96-c	++	135-a135-a	++++++	170-a170-a	++++++	246-b246-b	++++++	To	To
47-b47-b	++++++	96-d96-d	++++	135-b135-b	++++++	170-b170-b	++++++	247-a247-a	++++++	To	To
48-a48-a	++++++	97-a97-a	++++++	135-c135-c	++	171-a171-a	++++++	247-b247-b	++++++	To	To

48-b48-b	++++++	97-b97-b	++++++	135-d135-d	++	171-b171-b	++++++	248-a248-a	++++++	To	To
49-a49-a	++++++	97-c97-c	++	135-e135-e	++++++	172-a172-a	++++++	248-b248-b	++++++	To	To
49-b49-b	++++++	97-d97-d	++	135-f135-f	++++++	172-b172-b	++++++	249249	++++++	To	To
50-a50-a	++++++	98-a98-a	++++++	135-g135-g	++	173-a173-a	++++++	250250	++++++	To	To
50-b50-b	++++++	98-b98-b	++++++	135-h135-h	++	173-b173-b	++++++	251251	++++++	To	To
51-a51-a	++++++	98-c98-c	++++	143-a143-a	++++++	174-a174-a	++++++	252252	++++++	To	To
51-b51-b	++++++	98-d98-d	++	143-b143-b	++++++	174-b174-b	++++++	253253	++++++	To	To
52-a52-a	++++++	99-a99-a	++++++	143-c143-c	++	175-a175-a	++++++	254254	++++++	To	To
52-b52-b	++++++	99-b99-b	++++++	143-d143-d	++	175-b175-b	++++++	255255	++++++	To	To
53-a53-a	++++++	99-c99-c	++	143-e143-e	++++++	176-a176-a	++++++	256256	++++++	To	To
53-b53-b	++++++	99-d99-d	++	143-f143-f	++++++	176-b176-b	++++++	257257	++++++	To	To
54-a54-a	++++++	100-a100-a	++++++	143-g143-g	++	177-a177-a	++++++	258258	++++++	To	To
54-b54-b	++++++	100-b100-b	++++++	143-h143-h	++	177-b177-b	++++++	259259	++++++	To	To
55-a55-a	++++++	100-c100-c	++	144-a144-a	++++++	178-a178-a	++++++	260260	++++++	To	To
55-b55-b	++++++	100-d100-d	++	144-b144-b	++++++	178-b178-b	++++++	261-a261-a	++++++	To	To
56-a56-a	++++++	101-a101-a	++++++	144-c144-c	++	179-a179-a	++++++	261-b261-b	++++++	To	To
56-b56-b	++++++	101-b101-b	++++++	144-d144-d	++	179-b179-b	++++++	261-c261-c	++	To	To
57-a57-a	++++++	101-c101-c	++	144-e144-e	++++++	180-a180-a	++++++	261-d261-d	++	To	To
57-b57-b	++++++	101-d101-d	++	144-f144-f	++++++	180-b180-b	++++++	261-e261-e	++++++	To	To
58-a58-a	++++++	102-a102-a	++++++	144-g144-g	++	181-a181-a	++++++	261-f261-f	++++++	To	To
58-b58-b	++++++	102-b102-b	++++++	144-h144-h	++	181-b181-b	++++++	261-g261-g	++	To	To
59-a59-a	++++++	102-c102-c	++	153-a153-a	++++++	182-a182-a	++++++	261-h261-h	++	To	To
59-b59-b	++++++	102-d102-d	++	153-b153-b	++++++	182-b182-b	++++++	262-a262-a	++++++	To	To
60-a60-a	++++++	103-a103-a	++++++	154-a154-a	++++++	183-a183-a	++++++	262-b262-b	++++++	To	To
60-b60-b	++++++	103-b103-b	++++++	154-b154-b	++++++	183-b183-b	++++++	262-c262-c	++	To	To
6161	++++++	104-a104-a	++++++	155-a155-a	++++++	184-a184-a	++++++	262-d262-d	++	To	To
6262	++++++	104-b104-b	++++++	155-b155-b	++++++	184-b184-b	++++++	262-e262-e	++++++	To	To
6363	++++++	105-a105-a	++++++	156-a156-a	++++++	185-a185-a	++++++	262-f262-f	++++++	To	To
6464	++++++	105-b105-b	++++++	156-b156-b	++++++	185-b185-b	++++++	262-g262-g	++	To	To
6565	++++++	106-a106-a	++++++	157-a157-a	++++++	186-a186-a	++++++	262-h262-h	++	To	To
66-a66-a	++++++	106-b106-b	++++++	157-b157-b	++++++	186-b186-b	++++++	263-a263-a	++++++	To	To
66-b66-b	++++++	107-a107-a	++++++	158-a158-a	++++++	187-a187-a	++++++	263-b263-b	++++++	To	To
67-a67-a	++++++	107-b107-b	++++++	158-b158-b	++++++	187-b187-b	++++++	263-c263-c	++	To	To
67-b67-b	++++++	108-a108-a	++++++	158-c158-c	++	188-a188-a	++++++	263-d263-d	++	To	To
68-a68-a	++++++	108-b108-b	++++++	158-d158-d	++	188-b188-b	++++++	263-e263-e	++++++	To	To
68-b68-b	++++++	109-a109-a	++++++	158-e158-e	++++++	189-a189-a	++++++	263-f263-f	++++++	To	To
69-a69-a	++++++	109-b109-b	++++++	158-f158-f	++++++	189-b189-b	++++++	263-g263-g	++	To	To
69-b69-b	++++++	110-a110-a	++++++	158-g158-g	++	189-c189-c	++	263-h263-h	++	To	To
70-a70-a	++++++	110-b110-b	++++++	158-h158-h	++	189-d189-d	++	264-a264-a	++++++	To	To
70-b70-b	++++++	111-a111-a	++++++	159-a159-a	++++++	189-e189-e	++++++	264-b264-b	++++++	To	To
71-a71-a	++++++	111-b111-b	++++++	159-b159-b	++++++	189-f189-f	++++++	264-c264-c	++	To	To
71-b71-b	++++++	112-a112-a	++++++	159-c159-c	++	189-g189-g	++	264-d264-d	++	To	To
72-a72-a	++++++	112-b112-b	++++++	159-d159-d	++	189-h189-h	++	265-a265-a	++++++	To	To

72-b72-b	++++++	113-a113-a	++++++	159-e159-e	++++++	191-a191-a	++++++	265-b265-b	++++++	To	To
73-a73-a	++++++	113-b113-b	++++++	159-f159-f	++++++	191-b191-b	++++++	265-c265-c	++	To	To
73-b73-b	++++++	114-a114-a	++++++	159-g159-g	++	191-c191-c	++	265-d265-d	++	To	To
74-a74-a	++++++	114-b114-b	++++++	159-h159-h	++	191-d191-d	++	266-a266-a	++++++	To	To
74-b74-b	++++++	115-a115-a	++++++	160-a160-a	++++++	191-e191-e	++++++	266-b266-b	++++++	To	To
75-a75-a	++++++	115-b115-b	++++++	160-b160-b	++++++	191-f191-f	++++++	266-c266-c	++	To	To
75-b75-b	++++++	116-a116-a	++++++	160-c160-c	++	191-g191-g	++	266-d266-d	++	To	To
76-a76-a	++++++	116-b116-b	++++++	160-d160-d	++	191-h191-h	++	267-a267-a	++++++	To	To
76-b76-b	++++++	117-a117-a	++++++	160-e160-e	++++++	192-a192-a	++++++	267-b1267-b1	++++++	To	To
77-a77-a	++++++	117-b117-b	++++++	160-f160-f	++++++	192-b192-b	++++++	267-b2267-b2	++++++	To	To
77-b77-b	++++++	118-a118-a	++++++	160-g160-g	++	192-c192-c	++	268-a268-a	++++++	To	To
78-a78-a	++++++	118-b118-b	++++++	160-h160-h	++	192-d192-d	++	268-b268-b	++++++	To	To
78-b78-b	++++++	119-a119-a	++++++	161-a161-a	++++++	192-e192-e	++++++	281281	++++++	To	To
79-a79-a	++++++	119-b119-b	++++++	161-b161-b	++++++	192-f192-f	++++++	282-b282-b	++++++	To	To
79-b79-b	++++++	120-a120-a	++++++	161-c161-c	++	192-g192-g	++	283-b283-b	++++++	To	To
80-a80-a	++++++	120-b120-b	++++++	161-d161-d	++	192-h192-h	++	284-b284-b	++++++	To	To
80-b80-b	++++++	121-a121-a	++++++	161-e161-e	++++++	195195	++++++	285-b285-b	++++++	To	To
81-a81-a	++++++	121-b121-b	++++++	161-f161-f	++++++	215215	++++++	286-b286-b	++++++	To	To
81-b81-b	++++++	122-a122-a	++++++	161-g161-g	++	216216	++++++	287-b287-b	++++++	To	To
82-a82-a	++++++	122-b122-b	++++++	161-h161-h	++	217217	++++++	288-b288-b	++++++	To	To
82-b82-b	++++++	123-a123-a	++++++	162-a162-a	++++++	218218	++++++	289-b289-b	++	To	To
83-a83-a	++++++	123-b123-b	++++++	162-b162-b	++++++	219219	++++++	290-b290-b	++++++	To	To
83-b83-b	++++++	123-c123-c	++	162-c162-c	++	220220	++++++	291-a291-a	++++++	To	To
84-a84-a	++++++	123-d123-d	++	162-d162-d	++	221221	++++++	291-b291-b	++++++	To	To
84-b84-b	++++++	123-e123-e	++++++	162-e162-e	++++++	226226	++++++	292-b292-b	++++	To	To
85-a85-a	++++++	123-f123-f	++++++	162-f162-f	++++++	227227	++++++	293-b293-b	++++++	To	To
85-b85-b	++++++	123-g123-g	++	162-g162-g	++	228228	++++++	294-b294-b	++++++	To	To
86-a86-a	++++++	123-h123-h	++	162-h162-h	++	229229	++++++	295-b295-b	++	To	To
86-b86-b	++++++	124-a124-a	++++++	163-a163-a	++++++	230230	++++++	296-a296-a	++	To	To
87-a87-a	++++++	124-b124-b	++++++	163-b163-b	++++++	237-a237-a	++++++	296-b296-b	++++	To	To
87-b87-b	++++++	124-c124-c	++	163-c163-c	++	237-b237-b	++++++	297-a297-a	++	To	To
88-a88-a	++++++	124-d124-d	++	163-d163-d	++	238-a238-a	++++++	297-b297-b	++	To	To

Tests have shown that the compounds of the examples of the present invention have good IL-17A inhibitory activity and can be effectively used in the treatment of diseases with abnormal IL-17A activity.

In summary, the new compound represented by formula I disclosed in the present invention exhibits good IL-17A inhibitory activity and provides a new medicinal possibility for the clinical treatment of diseases related to abnormal IL-17A activity.

Claims

The compound represented by formula I, or its stereoisomer, or its pharmaceutically acceptable salt:

among them,

R 1 is selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkane Group), -C 0～4 alkylene-(5-10 membered aromatic ring), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic ring), -NR 11 R 12 , -OR 11 ; Wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;

R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3～ 10-membered heterocycloalkyl), -C 0-4 alkylene-(5-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic ring); wherein cycloalkyl, The heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;

Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl), -NH 2 , -NH (C 1-10 alkyl), -N (C 1-10 alkyl) (C 1-10 alkyl);

R 2 is selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl);

R 3 and R 4 are each independently selected from hydrogen, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl),- C 0～4 alkylene group-(3～10 membered heterocycloalkyl group), -O(C 1～10 alkyl group), -O(C 0～4 alkylene group) (3～10 membered cycloalkyl group) , -O(C 0-4 alkylene) (3-10 membered heterocycloalkyl); wherein alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R 31 ;

Or R 3 and R 4 are connected to form a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three R 31 ;

Each R 31 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl), -O(C 0～4 alkylene) (3～10 membered cycloalkyl), -O(C 0～4 alkylene) (3～10 membered heterocycloalkyl);

Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; among them, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic The heterocycle may be further substituted by one, two or three R A1 ;

Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene -OR A2 ,- C 0～4 alkylene-OC(O)R A2 , -C 0～4 alkylene-C(O)R A2 , -C 0～4 alkylene-C(O)OR A2 , -C 0 ～4 alkylene-C(O)NR A2 R A3 , -C 0～4 alkylene-NR A2 R A3 , -C 0～4 alkylene-NR A2 C(O)R A3 , -C 0 ～4 alkylene-(3～10 membered cycloalkyl), -C 0～4 alkylene-(3～10 member heterocycloalkyl), -C 0～4 alkylene-(5～10 member Aryl ring), -C 0～4 alkylene-(5～10 member aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further divided by one, two or three R A4 replaced;

Each R A4 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene -OR A2 ,- C 0～4 alkylene-OC(O)R A2 , -C 0～4 alkylene-C(O)R A2 , -C 0～4 alkylene-C(O)OR A2 , -C 0 ～4 alkylene-C(O)NR A2 R A3 , -C 0～4 alkylene-NR A2 R A3 , -C 0～4 alkylene-NR A2 C(O)R A3 ;

R A2 and R A3 are each independently selected from hydrogen and -C 1-10 alkyl;

X 1 is selected from CR x1 or N;

X 2 is selected from NR x2 , O, S or -(CR x3 =CR x4 )-;

R x1 , R x3 , and R x4 are each independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O(C 1-10 alkyl);

R x2 is selected from hydrogen, -C 1-10 alkyl, -C(O) (C 1-10 alkyl);

Ring B is selected from 3-10 membered heterocycloalkyl; wherein heterocycloalkyl may be further substituted by one, two or three R B1 ;

Each R B1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl), -NH 2 , -NH (C 1-10 alkyl), -N (C 1-10 alkyl) (C 1-10 alkyl);

L 2 is selected from -C 0～4 alkylene-C(O)NR L21 -, -C 0～4 alkylene-NR L21 C(O)-, -C 0～4 alkylene-S(O )NR L21 -, -C 0～4 alkylene-S(O) 2 NR L21 -, -C 0～4 alkylene-NR L21 S(O)-, -C 0～4 alkylene-NR L21 S(O) 2 -, -C 0～4 alkylene-P(O)(OH)NR L21 -, -C 0～4 alkylene-NR L21 P(O)(OH)-, -C 0～4 alkylene-C(O)-, -C 0～4 alkylene-NR L21 -;

R L21 is selected from hydrogen, -C 1-10 alkyl;

R is selected from -C 0～4 alkylene-(3～10 membered cycloalkyl), -C 0～4 alkylene-(3～10 membered heterocycloalkyl), -C 0～4 alkylene -(5～10 membered aromatic ring), -C 0～4 alkylene-(5～10 membered aromatic heterocycle), -C 0～4 alkylene-(5～12 membered spiro ring), -C 0 ～4 alkylene-(5～12 membered spiro heterocycle), -C 0～4 alkylene-(5～12 member bridged ring), -C 0～4 alkylene-(5～12 member bridge hetero ring),

Wherein C ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; wherein alkylene, cycloalkyl, heterocycloalkyl , Aromatic ring, aromatic heterocyclic ring, spiro ring, spiro heterocyclic ring, bridged ring, bridged heterocyclic ring may be further substituted by one, two or three Rd ;

R a, R a 'are each independently selected from hydrogen, -C 1 ~ 10 alkyl, halogen-substituted -C 1 ~ 10 alkyl, -C 0 ~ 4 alkylene group - (3 to 10-membered cycloalkyl group), -C 0～4 alkylene-(3-10 membered heterocycloalkyl), -C 0～4 alkylene-(5-12 membered spiro ring), -C 0～4 alkylene-(5～ 12-membered spiro heterocycle), -C 0～4 alkylene-(5-12 membered bridged ring), -C 0～4 alkylene-(5-12 membered bridged heterocyclic ring), -O(C 1～ 10 alkyl), -O (C 0-4 alkylene) (3-10 membered cycloalkyl), -O (C 0-4 alkylene) (3-10 membered heterocycloalkyl); wherein the alkane Group, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, bridged heterocyclic ring may be further substituted by one, two or three R a1 ;

Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl);

R b and R c are each independently selected from hydrogen, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl),- C 0～4 alkylene-(3～10 membered heterocycloalkyl), -C 0～4 alkylene-(5～10 member aromatic ring), -C 0～4 alkylene-(5～10 Membered aromatic heterocycle), -C 0～4 alkylene-(5-12 membered spiro ring), -C 0～4 alkylene-(5-12 membered spiro heterocyclic ring), -C 0～4 alkylene Group-(5-12 membered bridged ring), -C 0-4 alkylene- (5-12 membered bridged heterocycle); among them alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring, The spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R b1 ;

Or R a and R b are connected to form a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered aromatic heterocycle, a 5- to 12-membered spiro heterocycle, and a 5- to 12-membered bridged heterocycle; among them, heterocycloalkyl and aromatic heterocycle , Spiro heterocycles and bridged heterocycles can be further substituted by one, two or three Rd ;

Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl);

Each R d is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene -OR d1 , -C 0～4 alkylene-OC(O)R d1 , -C 0～4 alkylene-C(O)R d1 , -C 0～4 alkylene-C(O)OR d1 , -C 0～ 4 alkylene-C(O)NR d1 R d2 , -C 0～4 alkylene-NR d1 R d2 , -C 0～4 alkylene-NR d1 C(O)R d2 ;

R d1 and R d2 are each independently selected from hydrogen, -C 1-10 alkyl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl.
The compound of claim 1, wherein:

R 1 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3-6 membered heterocycloalkane) Group), -C 0～2 alkylene-(5-6 membered aromatic ring), -C 0～2 alkylene-(5-6 membered aromatic heterocyclic ring), -NR 11 R 12 , -OR 11 ; Wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;

R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3～ 6-membered heterocycloalkyl), -C 0-2 alkylene-(5-6 membered aromatic ring), -C 0-2 alkylene-(5-6 membered aromatic heterocyclic ring); wherein cycloalkyl, The heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;

Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl);

R 2 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl);

R 3 and R 4 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0～2 alkylene-(3～6 membered heterocycloalkyl), -O(C 1～6 alkyl), -O(C 0～2 alkylene) (3～6 membered cycloalkyl) , -O(C 0-2 alkylene) (3-6 membered heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R 31 ;

Or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three R 31 ;

Each R 31 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O(C 0～2 alkylene) (3～6 membered cycloalkyl), -O(C 0～2 alkylene) (3～6 membered heterocycloalkyl);

Ring A is selected from a 5- to 6-membered aromatic ring and a 5- to 6-membered aromatic heterocyclic ring; wherein the aromatic ring and the aromatic heterocyclic ring may be further substituted by one, two or three R A1 ;

Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 ,- C 0～2 alkylene-OC(O)R A2 , -C 0～2 alkylene-C(O)R A2 , -C 0～2 alkylene-C(O)OR A2 , -C 0 ～2 alkylene-C(O)NR A2 R A3 , -C 0～2 alkylene-NR A2 R A3 , -C 0～2 alkylene-NR A2 C(O)R A3 , -C 0 ～2 alkylene-(3～6 membered cycloalkyl), -C 0～2 alkylene-(3～6 membered heterocycloalkyl), -C 0～2 alkylene-(5～6 member Aromatic ring), -C 0～2 alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocycle can be further divided by one, two or three R A4 replaced;

Each R A4 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 ,- C 0～2 alkylene-OC(O)R A2 , -C 0～2 alkylene-C(O)R A2 , -C 0～2 alkylene-C(O)OR A2 , -C 0 ～2 alkylene-C(O)NR A2 R A3 , -C 0～2 alkylene-NR A2 R A3 , -C 0～2 alkylene-NR A2 C(O)R A3 ;

R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl;

X 1 is selected from CR x1 or N;

X 2 is selected from NR x2 , O, S or -(CR x3 =CR x4 )-;

R x1 , R x3 , and R x4 are independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O(C 1-6 alkyl);

R x2 is selected from hydrogen, -C 1-6 alkyl, -C(O) (C 1-6 alkyl);

Ring B is selected from 3-6 membered heterocycloalkyl groups; wherein heterocycloalkyl groups may be further substituted with one, two or three R B1 ;

Each R B1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl);

L 2 is selected from -C 0～2 alkylene-C(O)NR L21 -, -C 0～2 alkylene-NR L21 C(O)-, -C 0～2 alkylene-C(O )-, -C 0～2 alkylene-NR L21 -;

R L21 is selected from hydrogen, -C 1-6 alkyl;

R is selected from -C 0～2 alkylene-(3～6 membered cycloalkyl), -C 0～2 alkylene-(3～6 membered heterocycloalkyl), -C 0～2 alkylene -(5～6 membered aromatic ring), -C 0～2 alkylene-(5～6 membered aromatic heterocyclic ring), -C 0～2 alkylene-(6～11 membered spiro ring), -C 0 ～2 alkylene-(6～11 membered spiro heterocycle), -C 0～2 alkylene-(5～10 member bridged ring), -C 0～2 alkylene-(5～10 member bridge hetero ring),

Wherein C ring is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; wherein cycloalkyl, heterocycloalkyl, aromatic ring, The aromatic heterocyclic ring, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R d ;

R a, R a 'are each independently selected from hydrogen, -C 1 ~ 6 alkyl, halogen-substituted -C 1 ~ 6 alkyl, -C 0 ~ 2 alkylene group - (3-6 membered cycloalkyl), -C 0～2 alkylene-(3-6 membered heterocycloalkyl), -C 0～2 alkylene-(6-11 membered spiro ring), -C 0～2 alkylene-(6～ 11-membered spiro heterocyclic ring), -C 0-2 alkylene-(5-10 membered bridged ring), -C 0-2 alkylene-(5-10 membered bridged heterocyclic ring), -O(C 1～ 6 alkyl), -O (C 0 ~ 2 alkylene) (3 ~ 6 membered cycloalkyl), -O (C 0 ~ 2 alkylene) (3 ~ 6 membered heterocycloalkyl); Group, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, bridged heterocyclic ring may be further substituted by one, two or three R a1 ;

Or R a and R a'are connected to form a 3-6 membered cycloalkyl group and a 3-6 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three Ra1 ;

Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);

R b and R c are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0～2 alkylene-(3～6 membered heterocycloalkyl), -C 0～2 alkylene-(5～6 member aromatic ring), -C 0～2 alkylene-(5～6 Membered aromatic heterocycle), -C 0～2 alkylene-(6-11 membered spiro ring), -C 0～2 alkylene-(6-11 membered spiro heterocyclic ring), -C 0～2 alkylene Group-(5-10 membered bridged ring), -C 0-2 alkylene-(5-10 membered bridged heterocyclic ring); among them alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring, The spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R b1 ;

Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);

Or R a and R b are connected to form a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered aromatic heterocycle, a 5- to 12-membered spiro heterocycle, and a 5- to 12-membered bridged heterocycle; among them, heterocycloalkyl and aromatic heterocycle , Spiro heterocycles, bridged heterocycles can be further substituted by one, two or three Rd ; each Rd is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen substituted -C 1～6 alkyl, -C 0～2 alkylene-OR d1 , -C 0～2 alkylene-OC(O)R d1 , -C 0～2 alkylene-C(O)R d1 , -C 0～2 alkylene-C(O)OR d1 , -C 0～2 alkylene-C(O)NR d1 R d2 , -C 0～2 alkylene-NR d1 R d2 , -C 0～2 alkylene-NR d1 C(O)R d2 ;

R d1 and R d2 are each independently selected from hydrogen, -C 1-6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl.
The compound of claim 1, wherein the compound of formula I is represented by formula II:

among them,

R 1 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3-6 membered heterocycloalkane) Group), -C 0～2 alkylene-(5-6 membered aromatic ring), -C 0～2 alkylene-(5-6 membered aromatic heterocyclic ring), -NR 11 R 12 , -OR 11 ; Wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;

R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3～ 6-membered heterocycloalkyl), -C 0-2 alkylene-(5-6 membered aromatic ring), -C 0-2 alkylene-(5-6 membered aromatic heterocyclic ring); wherein cycloalkyl, The heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;

Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl);

R 2 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl);

R 3 and R 4 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0～2 alkylene-(3～6 membered heterocycloalkyl), -O(C 1～6 alkyl), -O(C 0～2 alkylene) (3～6 membered cycloalkyl) , -O(C 0-2 alkylene) (3-6 membered heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R 31 ;

Or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three R 31 ;

Each R 31 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O(C 0～2 alkylene) (3～6 membered cycloalkyl), -O(C 0～2 alkylene) (3～6 membered heterocycloalkyl);

Ring A is selected from 3 to 6 membered cycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; wherein the cycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further divided by one, two or three R A1 replace;

Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 ,- C 0～2 alkylene-OC(O)R A2 , -C 0～2 alkylene-C(O)R A2 , -C 0～2 alkylene-C(O)OR A2 , -C 0 ～2 alkylene-C(O)NR A2 R A3 , -C 0～2 alkylene-NR A2 R A3 , -C 0～2 alkylene-NR A2 C(O)R A3 , -C 0 ～2 alkylene-(3～6 membered cycloalkyl), -C 0～2 alkylene-(3～6 membered heterocycloalkyl), -C 0～2 alkylene-(5～6 member Aromatic ring), -C 0～2 alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocycle can be further divided by one, two or three R A4 replaced;

Each R A4 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 ,- C 0～2 alkylene-OC(O)R A2 , -C 0～2 alkylene-C(O)R A2 , -C 0～2 alkylene-C(O)OR A2 , -C 0 ～2 alkylene-C(O)NR A2 R A3 , -C 0～2 alkylene-NR A2 R A3 , -C 0～2 alkylene-NR A2 C(O)R A3 ;

R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl;

Ring B is selected from 3-6 membered heterocycloalkyl groups;

R a is selected from hydrogen, -C 1 ~ 6 alkyl, halogen-substituted -C 1 ~ 6 alkyl, -C 0 ~ 2 alkylene group - (3-6 membered cycloalkyl), - C 0 ~ 2 alkylene Alkyl-(3~6 membered heterocycloalkyl), -C 0~2 alkylene-(6~11 membered spiro ring), -C 0~2 alkylene-(6~11 membered spiro heterocyclic ring) , -C 0～2 alkylene group-(5～10 membered bridged ring), -C 0～2 alkylene group-(5～10 membered bridged heterocyclic ring), -O(C 1～6 alkyl group),- O(C 0～2 alkylene) (3～6 membered cycloalkyl), -O(C 0～2 alkylene) (3～6 membered heterocycloalkyl); of which alkyl, cycloalkyl, The heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R a1 ;

Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);

R b and R c are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0～2 alkylene-(3～6 membered heterocycloalkyl)-C 0～2 alkylene-(5～6 member aromatic ring), -C 0～2 alkylene-(5～6 member Aromatic heterocycle), -C 0～2 alkylene-(6-11 membered spiro ring), -C 0～2 alkylene-(6-11 membered spiro heterocyclic ring), -C 0～2 alkylene -(5-10 membered bridged ring), -C 0-2 alkylene-(5-10 membered bridged heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spiro The ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted by one, two or three R b1 ;

Or R a and R b are connected to form a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered aromatic heterocycle, a 5- to 12-membered spiro heterocycle, and a 5- to 12-membered bridged heterocycle; among them, heterocycloalkyl and aromatic heterocycle , Spiro heterocycles and bridged heterocycles can be further substituted by one, two or three Rd ;

Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl).
The compound of claim 3, wherein:

R 1 is selected from -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring, -NR 11 R 12 , -OR 11 ; wherein cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;

R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl).
The compound of claim 4, wherein R 1 is selected from
-C 1-3 alkyl, -NR 11 R 12 or -OR 11 ;

R 11 and R 12 are each independently selected from hydrogen, -C 1-2 alkyl, and 3-membered cycloalkyl;

R 13 is selected from C 1-2 alkyl.
The compound of claim 3, wherein:

R 3 and R 4 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -O( C 1-6 alkyl), -O (3-6 membered cycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R 31 ;

Each R 31 is independently selected from halogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O (3--6 membered ring alkyl);

Preferably,

R 3, R 4 are each independently selected from hydrogen, -C 1 ~ 3 alkyl, -O (C 1 alkyl), substituted with a R 31 -C 3 alkyl group, R 31 a substituted 3-membered cycloalkyl group;

R 31 is selected from -C 1 alkyl and halogen; halogen is preferably F.
The compound of claim 6, wherein at least one of R 3 and R 4 is hydrogen.
The compound of claim 3, wherein:

Ring A is selected from 3 to 6 membered cycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; wherein the cycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further divided by one, two or three R A1 replace;

Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR A2 , -OC(O)R A2 ,- C(O)R A2 , -C(O)OR A2 , -C(O)NR A2 R A3 , -NR A2 R A3 , -NR A2 C(O)R A3 , 3-6 membered cycloalkyl, 3 ~ 6-membered heterocycloalkyl, 5 to 6-membered aromatic ring, 5 to 6-membered aromatic heterocyclic ring; wherein cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further divided by one, two or three R A4 replaced;

Each R A4 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR A2 , -OC(O)R A2 ,- C(O)R A2 , -C(O)OR A2 , -C(O)NR A2 R A3 , -NR A2 R A3 , -NR A2 C(O)R A3 ;

R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl;

Preferably,

Ring A is selected from 6-membered cycloalkyl, one or two 6-membered aromatic rings substituted by R A1 ;

Each R A1 is independently selected from halogen;

The halogen is preferably Cl and F.
The compound according to claim 3, wherein the ring B is a 3- to 6-membered oxygen-containing heterocycloalkyl group.
The compound of claim 9, wherein the B ring is an oxetane, a tetrahydrofuran ring, or a tetrahydropyran ring.
The compound of claim 3, wherein:

R a is selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-11 membered spiro ring, 6 ～11 membered spiro heterocyclic ring, 5-10 membered bridged ring, 5-10 membered bridged heterocyclic ring, -O(C 1-6 alkyl), -O(3-6 membered cycloalkyl), -O(3～ 6-membered heterocycloalkyl); wherein the alkyl, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted with one, two or three R a1 ;

Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);

Preferably,

R a is selected from hydrogen, -C 3-4 alkyl, 4-6 membered cycloalkyl, 5-6 membered oxacycloalkyl, 4-6 membered cycloalkyl substituted with one or two R a1 ;

Each R a1 is independently selected from -C 1 alkyl, halogen;

The halogen is preferably F.
The compound of claim 11, wherein the spiro ring is
The bridge ring is
The compound of claim 3, wherein:

R b and R c are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0～2 alkylene-(3～6 membered heterocycloalkyl), -C 0～2 alkylene-(6～11 membered spiro heterocycle); of which alkyl, cycloalkyl, heterocycloalkyl , Spiro heterocycle can be further substituted by one, two or three R b1 ;

Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);

Preferably,

R b and R c are each independently selected from hydrogen, -C 1-2 alkyl, one or two R b1 substituted -C 2 alkyl, -C 0-1 alkylene-(3 to 4-membered cycloalkyl ), a R b1 substituted -C 0～1 alkylene-(3-membered cycloalkyl);

R b1 is selected from -O (C 1 alkyl), hydroxyl, halogen;

The halogen is preferably F.
The compound of claim 13, wherein at least one of R b and R c is hydrogen.
The compound according to claim 3, characterized in that: R a and R b are connected to form a 5-12 membered spiro heterocyclic ring, and further, the spiro heterocyclic ring is
The compound of claim 1, wherein the compound of formula I is represented by formula III:

Where R 1 is selected from
-C 1-3 alkyl, -NR 11 R 12 or -OR 11 ;

R 11 and R 12 are each independently selected from hydrogen, -C 1-2 alkyl, and 3-membered cycloalkyl;

R 13 is selected from C 1-2 alkyl;

R 3, R 4 are each independently selected from hydrogen, -C 1 ~ 3 alkyl, -O (C 1 alkyl), substituted with a R 31 -C 3 alkyl group, R 31 a substituted 3-membered cycloalkyl group;

R 31 is selected from -C 1 alkyl, halogen;

Ring A is selected from 6-membered cycloalkyl, one or two 6-membered aromatic rings substituted by R A1 ;

Each R A1 is independently selected from halogen;

Halogen is preferably Cl and F;

R a is selected from a 4-membered cycloalkyl group or a 4-membered cycloalkyl group substituted by a methyl group;

R d is selected from hydrogen, -C 1 alkylene-hydroxy or -C 1 alkylene-amino.
The compound according to claim 1, wherein the compound represented by formula I is specifically:
Use of the compound of any one of claims 1-17, or a stereoisomer, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating IL-17A-mediated diseases.
The use of claim 18, wherein the IL-17A-mediated disease is one or more of diseases related to inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome .
A pharmaceutical composition, characterized in that it is a compound according to any one of claims 1-16, or a stereoisomer, or a pharmaceutically acceptable salt thereof, plus pharmaceutically acceptable excipients The prepared preparation.