CN112341440A

CN112341440A - Immunomodulator

Info

Publication number: CN112341440A
Application number: CN202010789972.9A
Authority: CN
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: Hitgen Inc
Current assignee: Hitgen Inc
Priority date: 2019-08-09
Filing date: 2020-08-07
Publication date: 2021-02-09
Anticipated expiration: 2040-08-07
Also published as: WO2021027729A1; CN112341440B

Abstract

The invention discloses an immunomodulator, and particularly relates to a compound shown as a formula I, or a stereoisomer or a pharmaceutically acceptable salt thereofA salt thereof. Experiments prove that the compound has good IL-17A inhibitory activity, can be used for preparing IL-17A inhibitors and medicines for preventing and/or treating IL-17A mediated diseases (such as inflammation, autoimmune diseases, infectious diseases, cancer, precancerous syndrome and the like), and provides a new medicinal possibility for clinically treating diseases related to IL-17A activity abnormity.

Description

Immunomodulator

Technical Field

The invention belongs to the field of pharmacy, and particularly relates to an immunomodulator and application thereof in preparation of a medicament.

Background

IL-17 (interleukin-17) is a proinflammatory cytokine, playing a role in the induction of other inflammatory cytokines, chemokines and adhesion factors. The IL-17 family consists of cytokines involved in acute and chronic inflammatory responses, including IL-17A (CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F. IL-17A is expressed by TH17 cells, and is involved in the pathogenesis of inflammatory and autoimmune diseases. Human IL-17A is a glycoprotein having a molecular weight of about 17000 daltons. IL-17A signals intracellular through the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al. journal of immunology,2008,181: 2799-2805). The primary functions of IL-17A are to coordinate local tissue inflammation by upregulation of pro-and neutrophil migratory cytokines and chemokines (including IL-6, G-CSF, TNF- α, IL-1, CXCL1, CCL2, CXCL2), and matrix metalloproteases to allow activated T cells to penetrate the extracellular matrix. There are studies that have shown that IL-17A plays an important role in severe asthma and Chronic Obstructive Pulmonary Disease (COPD), but patients often do not respond or respond poorly to currently available drugs (Al-Ramli et Al J Allergy Clin Immunol,2009,123: 1185-1187). Upregulation of IL-17A levels can lead to a number of diseases including Rheumatoid Arthritis (RA), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma and multiple sclerosis (Gaffen, SL et al.

Studies have found that targeting the binding of IL-17A to IL-17RA is an effective strategy for treating IL-17A-mediated autoimmune inflammatory diseases. The incidence and severity of autoimmune encephalomyelitis can be reduced by IL-17A neutralizing antibody treatment (Komiyama Y et al J. Immunol.,2006,177: 566-573). Clinical trials with IL-17A antibodies have shown good results in 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 1 month 2015.

Although there are a number of IL-17A antibodies available, there are few reports of small molecule specific inhibitors of IL-17 with oral bioavailability. In view of the high cost of antibody production and the limitations of the route of administration, the development of new small molecule inhibitors of IL-17A is of great importance in the development of drugs for the treatment of IL-17A-mediated diseases.

Disclosure of Invention

The invention aims to provide a novel compound and application thereof in preparing an IL-17A inhibitor and a medicament for treating IL-17A mediated diseases.

The invention provides a compound shown as a formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof:

Wherein the content of the first and second substances,

R₁selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

each R₁₃Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl), -NH₂、-NH(C_1～10Alkyl), -N (C)_1～10Alkyl) (C_1～10Alkyl groups);

R₂selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl);

R₃、R₄each independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -O (C)_1～10Alkyl), -O (C)_0～4Alkylene) (3-to 10-membered cycloalkyl), -O (C)_0～4Alkylene) (3-to 10-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl are further substituted by one, two or three R ₃₁Substitution;

or R₃、R₄Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; or wherein cycloalkyl, heterocycloalkyl are further substituted by one, two or three R₃₁Substitution;

each R₃₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl), -O (C)_0～4Alkylene) (3-to 10-membered cycloalkyl), -O (C)_0～4Alkylene) (3-to 10-membered heterocycloalkyl);

the ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle; or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three R_A1Substitution;

each R_A1Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_A2、-C_0～4alkylene-OC (O) R_A2、-C_0～4alkylene-C (O) R_A2、-C_0～4alkylene-C (O) OR_A2、-C_0～4alkylene-C (O) NR_A2R_A3、-C_0～4alkylene-NR_A2R_A3、-C_0～4alkylene-NR_A2C(O)R_A3、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three R_A4Substitution;

each R _A4Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_A2、-C_0～4alkylene-OC (O) R_A2、-C_0～4alkylene-C (O) R_A2、-C_0～4alkylene-C (O) OR_A2、-C_0～4alkylene-C (O) NR_A2R_A3、-C_0～4alkylene-NR_A2R_A3、-C_0～4alkylene-NR_A2C(O)R_A3；

R_A2、R_A3Each independently selected from hydrogen and-C_1～10An alkyl group;

X₁selected from the group consisting of CR_x1Or N;

X₂selected from NR_x2O, S or- (CR)_x3＝CR_x4)-；

R_x1、R_x3、R_x4Are respectively and independently selected from hydrogen, halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl groups);

R_x2selected from hydrogen, -C_1～10Alkyl, -C (O) (C)_1～10Alkyl groups);

L₁is selected from-C_1～10Alkylene-;

R₅is selected from-C_1～10Alkyl, halogen substituted-C_1～10An alkyl group;

R₆selected from hydrogen, -C_1～10Alkyl, halogen substituted-C_1～10An alkyl group;

L₂is selected from-C_0～4alkylene-C (O) NR_L21-、-C_0～4alkylene-NR_L21C(O)-、-C_0～4alkylene-S (O) NR_L21-、-C_0～4alkylene-S (O)₂NR_L21-、-C_0～4alkylene-NR_L21S(O)-、-C_0～4alkylene-NR_L21S(O)₂-、-C_0～4alkylene-P (O) (OH) NR_L21-、-C_0～4alkylene-NR_L21P(O)(OH)-、-C_0～4alkylene-C (O) -, -C_0～4alkylene-NR_L21-；

R_L21Selected from hydrogen, -C_1～10An alkyl group;

r is selected from-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle), -C_0～4Alkylene- (5-to 12-membered spiro), -C_0～4Alkylene- (5-12 membered spiroheterocycle), -C_0～4Alkylene- (5-to 12-membered bridged ring), -C_0～4Alkylene- (5-to 12-membered bridged heterocycle),

Wherein the C ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle; or wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spiro heterocycle, bridged ring, bridged heterocycle is further substituted with one, two or three R_dSubstitution;

R_a、R_a’each independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 12-membered spiro), -C_0～4Alkylene- (5-12 membered spiroheterocycle), -C_0～4Alkylene- (5-to 12-membered bridged ring), -C_0～4Alkylene- (5-to 12-membered bridged heterocycle), -O (C)_1～10Alkyl), -O (C)_0～4Alkylene) (3-to 10-membered cycloalkyl), -O (C)_0～4Alkylene) (3-to 10-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle is further substituted with one, two or three R_a1Substitution;

or R_a、R_a’Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; or wherein cycloalkyl, heterocycloalkyl are further substituted by one, two or three R_a1Substitution;

each R_a1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C) _1～10Alkyl groups);

R_b、R_ceach independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); or wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is further substituted with one, two or three R_b1Substitution;

or R_a、R_bConnecting to form 3-10 membered heterocycloalkyl, 5-10 membered aromatic heterocycle, 5-12 membered spiroheterocycle and 5-12 membered bridged heterocycle; or wherein the heterocycloalkyl, heteroaromatic, spiroheterocycle, bridged heterocycle is further substituted with one, two or three R_dSubstitution;

each R_b1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl groups);

each R_dIndependently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_d1、-C_0～4alkylene-OC (O) R_d1、-C_0～4alkylene-C (O) R_d1、-C_0～4alkylene-C (O) OR_d1、-C_0～4alkylene-C (O) NR_d1R_d2、-C_0～4alkylene-NR_d1R_d2、-C_0～4alkylene-NR_d1C(O)R_d2；

R_d1、R_d2Each independently selected from hydrogen and-C_1～10Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl.

Further, the air conditioner is provided with a fan,

R₁selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C _0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

each R₁₃Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups);

R₂selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

R₃、R₄each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -O (C)_1～6Alkyl radical)、-O(C_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl are further substituted by one, two or three R ₃₁Substitution;

or R₃、R₄Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; or wherein cycloalkyl, heterocycloalkyl are further substituted by one, two or three R₃₁Substitution;

each R₃₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl);

the ring A is selected from a 5-6-membered aromatic ring, a 5-6-membered aromatic heterocycle, a 3-6-membered cycloalkyl group and a 3-6-membered heterocycloalkyl group; or wherein the aromatic ring, aromatic heterocycle, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl are further substituted with one, two or three R_A1Substitution;

each R_A1Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_A2、-C_0～2alkylene-OC (O) R_A2、-C_0～2alkylene-C (O) R_A2、-C_0～2alkylene-C (O) OR_A2、-C_0～2alkylene-C (O) NR_A2R_A3、-C_0～2alkylene-NR_A2R_A3、-C_0～2alkylene-NR_A2C(O)R_A3、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three R_A4Substitution;

each R _A4Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substitutionOf (a) to (C)_1～6Alkyl, -C_0～2alkylene-OR_A2、-C_0～2alkylene-OC (O) R_A2、-C_0～2alkylene-C (O) R_A2、-C_0～2alkylene-C (O) OR_A2、-C_0～2alkylene-C (O) NR_A2R_A3、-C_0～2alkylene-NR_A2R_A3、-C_0～2alkylene-NR_A2C(O)R_A3；

R_A2、R_A3Each independently selected from hydrogen and-C_1～6An alkyl group;

X₁selected from the group consisting of CR_x1Or N;

X₂selected from NR_x2O, S or- (CR)_x3＝CR_x4)-；

R_x1、R_x3、R_x4Are respectively and independently selected from hydrogen, halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups);

R_x2selected from hydrogen, -C_1～6Alkyl, -C (O) (C)_1～6Alkyl groups);

L₁is selected from-C_1～6Alkylene-;

R₅is selected from-C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

R₆selected from hydrogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

L₂is selected from-C_0～2alkylene-C (O) NR_L21-、-C_0～2alkylene-NR_L21C(O)-、-C_0～2alkylene-C (O) -, -C_0～2alkylene-NR_L21-；

R_L21Selected from hydrogen, -C_1～6An alkyl group;

r is selected from-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle), -C_0～2Alkylene- (6 &11-membered spiro ring), -C_0～2Alkylene- (6-to 11-membered spiroheterocycle), -C_0～2Alkylene- (5-to 10-membered bridged ring), -C_0～2Alkylene- (5-to 10-membered bridged heterocycle),

Wherein the C ring is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; or wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spiro heterocycle, bridged ring, bridged heterocycle is further substituted with one, two or three R _dSubstitution;

R_a、R_a’each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (6-to 11-membered spiro), -C_0～2Alkylene- (6-to 11-membered spiroheterocycle), -C_0～2Alkylene- (5-to 10-membered bridged ring), -C_0～2Alkylene- (5-to 10-membered bridged heterocycle), -O (C)_1～6Alkyl), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle is further substituted with one, two or three R_a1Substitution;

or R_a、R_a’Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; or wherein cycloalkyl, heterocycloalkyl are further substituted by one, two or three R_a1Substitution;

each R_a1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups);

R_b、R_ceach independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C₀～₂Alkylene oxideRadical- (5-6 membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is further substituted with one, two or three R _b1Substitution;

each R_b1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups);

each R_dIndependently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_d1、-C_0～2alkylene-OC (O) R_d1、-C_0～2alkylene-C (O) R_d1、-C_0～2alkylene-C (O) OR_d1、-C_0～2alkylene-C (O) NR_d1R_d2、-C_0～2alkylene-NR_d1R_d2、-C_0～2alkylene-NR_d1C(O)R_d2；

R_d1、R_d2Each independently selected from hydrogen and-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl.

Further, the air conditioner is provided with a fan,

the compound of formula I is represented by formula II:

wherein the content of the first and second substances,

R₁selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5 ℃)6-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C _0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

R₃、R₄each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -O (C)_1～6Alkyl), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl are further substituted by one, two or three R₃₁Substitution;

each R₃₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -O (C) _0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl);

each R_A4Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_A2、-C_0～2alkylene-OC (O) R_A2、-C_0～2alkylene-C (O) R_A2、-C_0～2alkylene-C (O) OR_A2、-C_0～2alkylene-C (O) NR_A2R_A3、-C_0～2alkylene-NR_A2R_A3、-C_0～2alkylene-NR_A2C(O)R_A3；

R_A2、R_A3Each independently selected from hydrogen and-C_1～6An alkyl group;

L₁is selected from-C_1～6Alkylene-;

R₅is selected from-C_1～6Alkyl, halogen substituted-C _1～6An alkyl group;

R_aselected from hydrogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (6-to 11-membered spiro), -C_0～2Alkylene- (6-to 11-membered spiroheterocycle), -C_0～2Alkylene- (5-to 10-membered bridged ring), -C_0～2Alkylene- (5-to 10-membered bridged heterocycle), -O (C)_1～6Alkyl), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle is further substituted with one, two or three R_a1Substitution;

R_b、R_ceach independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl) -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is further substituted with one, two or three R_b1Substitution;

or R_a、R_bConnecting to form 3-10 membered heterocycloalkyl, 5-10 membered aromatic heterocycle, 5-12 membered spiroheterocycle and 5-12 membered bridged heterocycle; or wherein the heterocycloalkyl, heteroaromatic, spiroheterocycle, bridged heterocycle is further substituted with one, two or three R _dSubstitution;

each R_b1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substitutionOf (a) to (C)_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups).

Further, the air conditioner is provided with a fan,

R₁is selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered aromatic ring, 5-to 6-membered aromatic heterocycle, -NR₁₁R₁₂、-OR₁₁(ii) a Or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6An alkyl group, a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group;

each R₁₃Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

Further, the air conditioner is provided with a fan,

R₁is selected from

Halogenated or non-halogenated C_1～3Alkyl, halogenated or non-halogenated C_1～3Alkoxy radical,

R₁₃Selected from methyl, ethyl, R_1a、R_1bAre respectively and independently selected from hydrogen and C_1～2Alkyl radical, C_1～2Alkoxy radical,

Preferably, said C_1～3The alkyl is selected from methyl, ethyl,

The halogen is selected from fluorine, chlorine and bromine.

Further, the air conditioner is provided with a fan,

R₃、R₄are each independently selected from hydrogen、-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, -O (C)_1～6Alkyl), -O (3-6 membered cycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl are further substituted by one, two or three R ₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -O (3-to 6-membered cycloalkyl).

Further, the air conditioner is provided with a fan,

R₃、R₄at least one is hydrogen; preferably, R₃、R₄One is hydrogen and the other is selected from the group consisting of halogen or methyl substituted: c_1～3Alkyl radical, C_1～3Alkoxy radical,

More preferably, said C_1～3The alkyl is selected from methyl, ethyl,

The halogen is selected from fluorine, chlorine and bromine.

Further, the air conditioner is provided with a fan,

the ring A is selected from a 5-6-membered aromatic ring, a 5-6-membered aromatic heterocycle and a 4-6-membered saturated cycloalkyl; or, wherein the aromatic ring, aromatic heterocycle, 4-6 membered saturated cycloalkyl is further substituted with one, two or three R_A1Substitution;

each R_A1Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OR_A2、-OC(O)R_A2、-C(O)R_A2、-C(O)OR_A2、-C(O)NR_A2R_A3、-NR_A2R_A3、-NR_A2C(O)R_A33-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three R_A4Substitution;

each R_A4Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OR_A2、-OC(O)R_A2、-C(O)R_A2、-C(O)OR_A2、-C(O)NR_A2R_A3、-NR_A2R_A3、-NR_A2C(O)R_A3；

R_A2、R_A3Each independently selected from hydrogen and-C_1～6An alkyl group;

preferably, ring A is selected from a benzene ring, a 4-6 membered saturated cycloalkyl group, or wherein the benzene ring, the 4-6 membered saturated cycloalkyl group are further substituted with one, two or three R _A1Substituted, each R_A1Each independently selected from halogens, preferably fluorine, chlorine, bromine.

Further, the air conditioner is provided with a fan,

L₁is selected from-C_1～4Alkylene-; r₅Is selected from-C_1～4An alkyl group; r₆Selected from hydrogen, -C_1～4An alkyl group.

Further, the air conditioner is provided with a fan,

L₁selected from methylene, ethylene, n-propylene, isopropylene; r₅Selected from methyl, ethyl, n-propyl, isopropyl; r₆Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl.

Further, the air conditioner is provided with a fan,

R_aselected from hydrogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 6-to 11-membered spirocyclic, 6-to 11-membered spiroheterocyclic, 5-to 10-membered bridged ring, 5-to 10-membered bridged heterocyclic, -O (C)_1～6Alkyl), -O (3-to 6-membered cycloalkyl), -O (3-to 6-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle is further substituted with one, two or three R_a1Substitution; preferably, the spiro ring is

The bridge ring is

Each R_a1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups).

Further, the air conditioner is provided with a fan,

R_ais selected from

Or, therein

Further substituted by one, two or three methyl, halogen, methoxy, said halogen being preferably fluorine, chlorine, bromine.

Further, the air conditioner is provided with a fan,

R_b、R_ceach independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl are further substituted by one, two or three R_b1Substitution;

each R_b1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups).

Further, the air conditioner is provided with a fan,

R_b、R_cat least one is hydrogen; preferably, R_b、R_cOne is hydrogen and the other is L_cR_c1；L_cIs selected from C_0～2Alkylene, preferably none, methylene, ethylene; r_c1Is selected from C_1～2Alkyl, aryl, heteroaryl, and heteroaryl,

Or, wherein C_1～2Alkyl, aryl, heteroaryl, and heteroaryl,

Further substituted by one, two or three R_b1Substituted, each R_b1Independently selected from halogen, hydroxy, C_1～2Alkyl radical, C_1～2An alkoxy group; the halogen is selected from fluorine, chlorine and bromine.

Further, the air conditioner is provided with a fan,

R_a、R_bare linked to form a 5-to 12-membered spiroheterocycle, further wherein said spiroheterocycle is

Further, the air conditioner is provided with a fan,

R₂is hydrogen.

Further, the air conditioner is provided with a fan,

the structure of the compound is shown as formula III:

wherein R is₁As described above;

R₂is hydrogen;

R₃、R₄as described above;

ring A is as described above;

R₅、R₆、L₁as described above;

n is an integer of 0 to 3, preferably 0 to 1;

R_fselected from hydrogen, L₀R_f1(ii) a Wherein L is ₀Is C_0～3Alkylene, preferably none or methylene; r_f1Selected from amino, hydroxy, C_1～3Alkyl radical, C_1～3Alkoxy, COOCH₃；

R_eSelected from substituted or unsubstituted 4-6 membered saturated cycloalkyl, preferably substituted or unsubstituted

The substituent is selected from halogen, hydroxyl and C_1～3Alkyl radical, C_1～3Alkoxy radical ofHalogen is preferably fluorine.

Further, the compound is selected from:

the invention also provides the application of the compound or the stereoisomer thereof or the pharmaceutically acceptable salt thereof in preparing medicines for treating IL-17A mediated diseases.

Further, the IL-17A mediated disease is one or more of diseases related to inflammation, autoimmune diseases, infectious diseases, cancer and precancerous syndrome; preferably rheumatoid arthritis, bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma or multiple sclerosis.

The invention also provides application of the compound or the stereoisomer or the pharmaceutically acceptable salt thereof in preparing the IL-17A inhibitor.

The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, or the stereoisomer or the pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.

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

"cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the body's ability of affected cells to spread to other sites either locally or through the bloodstream and lymphatic system (i.e., metastasis), and any of a number of characteristic structural and/or molecular features. "cancer cells" refers to cells that undergo multiple stages of early, intermediate or late stage tumor progression. The cancer includes 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 the group consisting of colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.

Autoimmune diseases are caused by the body's immune response to substances and tissues normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, graves 'disease, celiac disease, crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, gillyre 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 pathological inflammation of the tissue. 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, house dust mite-induced airway inflammation, and interstitial cystitis. There is a significant overlap between inflammatory and autoimmune diseases. Some embodiments of the invention relate to the treatment of the inflammatory disease asthma. The immune system is usually involved in inflammatory diseases, manifested in allergic reactions and in some myopathies, many of which cause abnormal inflammation. IL-17A mediated diseases also include autoimmune inflammatory diseases.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.

Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.

In the compound of the present invention,

to represent

Or a mixture of the two in any proportion.

In the group of the compounds of the invention "or" wherein cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted by one, two or three independent R₁₃Substituted means that the cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaromatic ring may be unsubstituted or substituted with one, two, or three independent R₁₃And (4) substitution.

"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix C_a～bAlkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C _1～4The alkyl group means an alkyl group having 1 to 4 carbon atoms.

"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C₁～C₆Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group may be linear 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)Alkyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. The alkyl group may also be part of another group, such as C₁～C₆An alkoxy group.

"alkylene" refers to a divalent saturated aliphatic hydrocarbon group having from 1 to 10 carbon atoms and in some embodiments from 1 to 6 carbon atoms. "(C)_a～C_b) Alkylene "refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, "(C)₁～C₆) Alkylene "is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" can be exemplified by the following structure:

Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

furthermore, the term "(C)₁～C₆) Alkylene "is intended to include such branched alkyl groups such as cyclopropylmethylene, which may be exemplified by the following structures:

"cycloalkyl" refers to a saturated or partially saturated cyclic group having from 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 having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. 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. Cycloalkyl radicals comprising polybicycloalkyl ring systemsExamples of (d) are dicyclohexyl, dicyclopentyl, dicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:

dicyclohexyl and

a dicyclohexyl group.

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

"alkenylene" refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated valencies. For example, (C)₃-C₆) Alkenylene radicals include>C＝CH-CH₂-、-CH-CH＝CH-CH₂-and the like.

"alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C)₂-C₆) Alkynyl is intended to include ethynyl, propynyl and the like.

"alkynylene" refers to a divalent hydrocarbon chain having 2 to 10 carbon atoms and at least one triple bond.

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

"haloalkyl" means an alkyl group in which the hydrogen atom may be replaced by one or more halogen atoms. E.g. C_1～4The haloalkyl group means an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom is substituted with one or more halogen atoms.

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

"heteroaromatic ring" refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom;

"stereoisomers" includes enantiomers and diastereomers;

The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.

The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.

Experiments prove that the compound provided by the invention has good IL-17A inhibitory activity, can be used for preparing IL-17A inhibitors and medicines for preventing and/or treating IL-17A mediated diseases (such as inflammation, autoimmune diseases, infectious diseases, cancer, precancerous syndrome and the like), and provides a new medicinal possibility for clinically treating diseases related to IL-17A activity abnormality.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed Description

The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.

The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using a (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic instrument using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl)₃) Deuterated methanol (CD3OD) with internal standard Tetramethylsilane (TMS).

LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (Medium pressure preparative chromatography) Gilson GX-281 reverse phase preparative chromatography was used. The thin layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier. Supercritical Fluid Chromatography (SFC).

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention. In the examples, the solution means an aqueous solution unless otherwise specified. In the examples, the reaction temperature is room temperature, unless otherwise specified. In the examples, M is mole per liter, unless otherwise specified. The room temperature is the most suitable reaction temperature and is 20-30 ℃.

EXAMPLE 1 preparation of intermediates 1-5a,1-5b

Step 1 preparation of intermediate 1-1

THF (3500mL) was added to a 10L three-necked flask equipped with mechanical stirring and nitrogen shielding, followed by o-chlorobenzaldehyde (341g,2.43mol) and ethyl nitroacetate (323g,2.43mol), followed by cooling in an ice-salt bath to-10 ℃ at internal temperature, and TiCl was slowly added dropwise with mechanical stirring₄(920g,4.85mol), keeping the internal temperature not more than 0 ℃ when dropwise adding, continuing to react for 0.5h while maintaining the internal temperature at 0 ℃, then dropwise adding N-methylmorpholine (981.51g,9.70mol), keeping the internal temperature not more than 15 ℃ when dropwise adding, allowing the temperature to rise to room temperature and stirring for 1h, finally adding 500mL of saturated ammonium chloride for quenching, extracting with ethyl acetate (1000mL multiplied by 3), washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating by silica gel column chromatography (petroleum ether/ethyl acetate 100:1) to obtain an intermediate 1-1(580g,2.27mol, 93.52% yield).

Step 2 preparation of intermediates 1-2

A10L three-necked flask equipped with mechanical stirring and nitrogen protection was charged with 1M zinc chloride tetrahydrofuran solution (5.5mol, 5.5L), cooled to 0 ℃ in an ice bath, and 2M isopropyl magnesium chloride tetrahydrofuran solution (5.5mol, 2.75L) was slowly added dropwise while controlling the internal temperature to be lower than 5 ℃ and the reaction was continued at 0-5 ℃ for 30 minutes after completion of the dropwise addition. Subsequently, a solution of intermediate 1-1(702g,2.75mol) in anhydrous THF (500mL) was slowly added dropwise while controlling the internal temperature to be lower than 5 ℃ and the reaction was continued at 0-5 ℃ for 1 hour after completion of the dropwise addition. After the reaction, 500g of ammonium chloride is prepared into a saturated aqueous solution, the saturated aqueous solution is slowly added into the reaction solution to quench the reaction, ethyl acetate (5L multiplied by 2) is extracted, organic phases are combined and washed by water, saturated sodium chloride is washed by water, anhydrous sodium sulfate is dried, the mixture is filtered and concentrated under reduced pressure, and a crude product is separated by silica gel column chromatography (petroleum ether/ethyl acetate 50:1) to obtain an intermediate 1-2(377g,1.26mol, 45.80% yield).

Step 3 preparation of intermediates 1-3

A10L three-neck flask equipped with mechanical stirring was charged with intermediates 1-2(730g,2.44mol) and glacial acetic acid (6L), cooled in an ice bath to 0 deg.C, and zinc powder (796.24g,12.18mol) was added in portions with mechanical stirring while controlling the internal temperature below 60 deg.C. After the addition, the reaction is continued to be stirred for 1 hour, the reaction is finished, the filtration is carried out, 100mL of ethyl acetate is used for leaching a filter cake, the filtrate is decompressed and concentrated 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) to obtain an intermediate 1-3 (a mixture of enantiomers (2S,3S) and (2R,3R) with a configuration, a point with a lower TLC polarity), a yellow viscous liquid (280g,1.04mol, 42.65% yield), MS M/z:270(M +1)⁺。

Step 4 preparation of intermediates 1-4

To a suspension of intermediates 1-3(60g,222.41mmol) in tetrahydrofuran (200mL) and water (100mL) were added sodium bicarbonate (37.37g,444.83mmol) and Boc-anhydride (53.34g,244.66mmol) in that order, and after the addition was completed, the mixture was stirred at room temperature overnight. After the reaction is finished, 300mL of water is added, ethyl acetate (300mL multiplied by 2) is extracted, organic phases are combined, saturated sodium chloride is washed by water, anhydrous sodium sulfate is dried, the mixture is filtered and concentrated under reduced pressure, and a crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 100: 1-50: 1) to obtain an intermediate 1-4(39.4g,106.52mmol, 47.89% yield), MS M/z is 270[ M-99: M/z [ ]⁺，314[M-55]⁺。

Step 5 preparation of intermediates 1-5a,1-5b

Adding NaOH (6.49g,162.21mmol) into a suspension of intermediates 1-4(20.00g,54.07mmol) in methanol (100mL) and water (10mL), heating to 50 ℃ for reaction for 3 hours, after the reaction is finished, concentrating the reaction solution, adding 100mL of water, extracting once with ethyl acetate (100mL), cooling the aqueous phase to 0-5 ℃, adjusting the pH to 3-4 with 1M HCl, extracting with ethyl acetate (100mL), concentrating the organic phase under reduced pressure to obtain a pair of enantiomeric forms of intermediates 1-5 (17.8g,52.07mmol, 96.30% yield) and yellow oily matter, and separating the enantiomers by chiral resolution with Supercritical Fluid Chromatography (SFC) to obtain single chiral isomers 1-5a (2R,3R),1-5b (2S,3S), 6.5g respectively, MS M/z:242[ M-99 ] (M-99S)]⁺，286[M-55]⁺。¹H NMR (400MHz, Chloroform-d) δ 7.41-7.35 (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). Wherein the retention time of the (2S,3S) configuration is 2.59min, the retention time of the (2R,3R) configuration is 3.06min (

AD-3150 × 3mm,5um, isocratic 5% ethanol 1 mL/min). The specific optical rotation of the (2S,3S) configuration was 78.18 ° (25 ℃,0.089g/100ml methanol solution, wavelength 589nm), and the specific optical rotation of the (2R,3R) configuration was-72.60 ° (25 ℃,0.098g/100ml methanol solution, wavelength 589 nm).

EXAMPLE 2 preparation of intermediates 2 to 6

Step 1 preparation of intermediate 2-2

Reference example 1 preparation of intermediate 1-2 from intermediate 1-1 with IsopropenePrepared by reaction of magnesium bromide, yield is 37%, MS M/z is 298(M +1)⁺。

Step 2 preparation of intermediates 2-3

Referring to example 1, the intermediates 1 to 3 were prepared by reducing the nitro group of 2-2 using zinc powder-acetic acid system in 85% yield, MS M/z:268(M +1)⁺. The four chiral isomers were used in the next step without resolution.

Step 3 preparation of intermediates 2-4

Referring to example 1, preparation of intermediates 1-4 from Boc anhydride protected amino groups 2-3, MS M/z 368[ M + 1%]⁺，312[M-55]⁺。

Step 4 preparation of intermediates 2-5

Iron nitrate nonahydrate (439.29mg,1.09mmol) was dissolved in 10ml water, sonicated at 0 ℃ for 10min and nitrogen blanketed, followed by the addition of 10ml acetonitrile and selectflur (384.92mg,1.09mmol) in that order, and intermediates 2-4(100mg, 271.84. mu. mol) in 10ml acetonitrile and NaBH, respectively, again at 0 ℃₄(66.84mg,1.77mmol) was added to the reaction mixture and after 2min, NaBH was added₄(66.84mg,1.77mmol), stirring at 0 deg.C for 30min, quenching reaction with 1ml ammonia water, DCM extracting, drying organic phase with sodium sulfate, concentrating under reduced pressure, spin-drying, separating and purifying crude product with silica gel column (petroleum ether/ethyl acetate 100: 1-50: 1) to obtain intermediate 2-5, (84.2mg, 217.6. mu. mol, 80.0% yield), MS M/z:388[ M +1 ] ]⁺。

Step 5 preparation of intermediates 2-6

Referring to example 1, intermediates 1 to 5 were prepared by hydrolysis of 2 to 5 sodium hydroxide, MS M/z:360[ M +1 ]]⁺。

EXAMPLE 3 preparation of the intermediate chiral Cyclopropylmethylamino acids 3-3a,3-3b

Step 1 preparation of intermediate 3-1

Diastereomer mixture of example 2 intermediate 2-4 (mixture of four chiral isomers) was purified by silica gel column chromatography (petroleum ether/methyl tert-butyl ether 100:1) to give an enantiomer of intermediate 2-4 (mixture of enantiomers 2-4a and 2-4b, (mixture of 2S,3S) and (2R,3R) configuration which was less polar on TLC plate chromatography), dissolved in 20ml of dry DCM under nitrogen, cooled to-40 deg.C, and ZnEt was added₂(1M tetrahydrofuran solution, 27.73 mL), stirring at 30 ℃ for 1 hour, adding diiodomethane (9.90g,36.97mmol) dropwise while maintaining the internal temperature at no higher than-20 ℃, allowing the internal temperature to slowly rise to room temperature and stirring overnight, LC-MS showing about 30% of the Boc-removed by-product of the starting material 2-4, adding 5mL of water to quench, concentrating the organic phase under reduced pressure to dryness to give a crude product 1g, which is in this case 3-1 Boc-removed form and a mixture of the starting materials 2-4 Boc-removed, dissolving the mixture in 10mL of THF, and adding TEA (897.78mg,8.87mmol,1.24mL) and (Boc) sequentially ₂O (1.16g,5.32mmol), stirred at room temperature overnight, concentrated to dryness under reduced pressure, purified by silica gel column separation (petroleum ether/methyl tert-butyl ether 100:3) to give a mixture of crude Boc-protected ethyl cyclopropylmethyl ester 3-1 and unreacted intermediate 2-4 from the previous step (0.5 g), dissolved in a mixture of tetrahydrofuran (5mL) and acetonitrile (5mL) and 5mL of waterTo this solution, potassium osmate dihydrate (44.3mg,0.12mmol) and N-methyl-N-morpholine oxide (111mg,0.96mmol) were added, unreacted 2-4 was removed by double bond dihydroxylation, stirring overnight at room temperature, LC-MS monitoring showed that no unreacted intermediate 2-4 had been present, the majority of the organic solvent was removed by concentration under reduced pressure, ethyl acetate 15ml was extracted, the organic phase was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1) to give intermediate 3-1(0.5g,1.31mmol, 28% yield), MS M/z:382[ M +1 ]: 382[ M +1]⁺.

Step 2 preparation of intermediate 3-2

Reference example 1 preparation of intermediates 1-5 from 3-1 by hydrolysis with sodium hydroxide, MSm/z 298[ M-55 ]]⁺。

Step 3 preparation of intermediate 3-3a,3-3b

The intermediate 3-2 (an enantiomer mixture) can be respectively prepared into single chiral isomers 3-3a (2R,3R) and 3-3b (2S,3S) after being separated and separated by an SFC chiral column. Wherein the retention time of the (2S,3S) configuration is 5.904min, the retention time of the (2R,3R) configuration is 3.306min (

AD-3150 × 3mm,5um, isocratic 5% ethanol 1 mL/min). The specific optical rotation of the (2S,3S) configuration was 48.755 ° (25 ℃,0.1g/100ml in Methanol, wavelength 589nm), and the specific optical rotation of the (2R,3R) configuration was-40.695 ° (25 ℃,0.1g/100ml in Methanol, wavelength 589 nm).

EXAMPLE 4 preparation of intermediate amino acids 4-5

Step 1 preparation of intermediate 4-1

Prepared from 2-chloro-6-fluoro-benzaldehyde and ethyl nitroacetate according to the preparation method of intermediate 1-1 of example 1.

Step 2 preparation of intermediate 4-2

Prepared by reacting intermediate 4-1 with isopropyl magnesium chloride according to the method for preparing intermediate 1-2 of example 1.

Step 3 preparation of intermediates 4-3

Referring to example 1, the intermediate 1-3 was prepared by reducing nitro group of intermediate 4-2 with a nitrozinc powder-acetic acid system, MS M/z 288[ M +1 ]]⁺。

Step 4 preparation of intermediate 4-4

Reference example 1 preparation of intermediates 1-4 from intermediates 4-3 with Boc protection at amino group, MS M/z 388[ M +1 ]]⁺，332[M-55]⁺。

Step 5 preparation of intermediates 4-5

Reference example 1 preparation of intermediates 1 to 5 from intermediates 4 to 4 by NaOH hydrolysis, MS M/z 360[ M +1]⁺。

EXAMPLE 5 preparation of intermediate amino acids 5-5

Step 1 preparation of intermediate 5-1

Prepared from 2-chloro-3-fluoro-benzaldehyde and ethyl nitroacetate according to the preparation method of intermediate 1-1 of example 1.

Step 2 preparation of intermediate 5-2

Prepared by reacting intermediate 5-1 with isopropyl magnesium chloride according to the method for preparing intermediate 1-2 of example 1.

Step 3 preparation of intermediate 5-3

Referring to example 1, the intermediate 1-3 was prepared by reducing the intermediate 5-2 with a nitrozinc powder-acetic acid system, MS M/z 288[ M +1 ]]⁺。

Step 4 preparation of intermediates 5-4

Reference example 1 preparation of intermediates 1-4 from intermediates 5-3 with Boc protection at amino group, MS M/z 388[ M +1 ]]⁺，332[M-55]⁺。

Step 5 preparation of intermediates 5-5

Reference example 1 preparation of intermediates 1 to 5 from intermediates 5 to 4 by NaOH hydrolysis, MS M/z 360[ M +1]⁺。

EXAMPLE 6 preparation of intermediates 6-6a,6-6b

Step 1 preparation of intermediate 6-1

To a solution of ethyl p-nitrophenylacetate (156g,745.71mmol) in dry DMF (700mL) under nitrogen at 0 deg.C was added Cs₂CO₃(290.82g,894.85mmol), heating to room temperature and stirring for 1 hour, then cooling to 0 ℃ and slowly dropping methyl iodide (116.43g,820.28mmol), reacting overnight after dropping, filtering, diluting the filtrate with 2L ethyl acetate, washing with saturated brine (3X 1.5L), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain intermediate 6-1(165g,739.16mmol, 99.12% yield), MS M/z:224[ M +1 ] ]⁺The crude product was used directly in the next step.

Step 2 preparation of intermediate 6-2

Slowly adding a DMF (300mL) solution of the intermediate 6-1(11.48g,478.44mmol) into a dry 0.3L mixed solution of DMF and NaH (11.48g,478.44mmol) under the protection of nitrogen at-10 ℃, cooling to-50 ℃ after 30min, adding chloromethyl ether (48.15g,598.05mmol), stirring at-50 ℃ to-10 ℃ for 3 hours, quenching the reaction by cold saturated ammonium chloride, extracting by ethyl acetate (2 mL to 400mL), combining organic phases, washing by saturated saline water (400mL to 2), drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and performing silica gel chromatography on the crude productSeparating by gel column chromatography (petroleum ether/ethyl acetate 100: 1-50: 1) to obtain intermediate 6-2(45g,168.36mmol, 42.23% yield), MS M/z:268[ M +1 ]]⁺.

Step 3 preparation of intermediate 6-3

Dissolving intermediate 6-2(45g,168.36mmol) in EtOH (100mL), replacing with nitrogen, adding 10% Pd/C (8g), stirring under normal pressure hydrogen atmosphere for reaction overnight, filtering with diatomaceous earth, washing with ethanol, concentrating the filtrate under reduced pressure to dryness to obtain intermediate 6-3(34.6g,145.81mmol, 86.60% yield), MS M/z:260[ M +1+22 mmol%]⁺The product was used directly in the next reaction without purification.

Step 4 preparation of intermediate 6-4

Dissolving intermediate 6-3(15.9g,67.01mmol) in acetic anhydride (136mL), cooling to 0 deg.C, stirring for 15min, and slowly adding HNO dropwise₃(9.31g,100.51mmol, 68% mass fraction), after dropping, the reaction was stirred for another 30min, the starting material disappeared, the reaction solution was poured into ice water, extracted with ethyl acetate (2 x 100mL), the organic phases were combined, washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to give crude intermediate 6-4 (17g,52.42mmol, 78.23% yield), MS M/z:325[ M +1 ], (M + 1)]⁺。

Step 5 preparation of intermediates 6-5

Dissolving intermediate 6-4(21.73g,67.01mmol) in 100ml ethanol, adding NaOH (1.61g,40.20mmol), heating to 50 deg.C, stirring for 0.5 hr, TLC showing disappearance of raw material, concentrating the reaction solution under reduced pressure to dryness, adding H₂O (150mL), adjusting the pH to 7 with 6N HCl, passing the aqueous phase through CH₂Cl₂(2X 100mL), combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude intermediate 6-5 (8g,28.34mmol, 42.29% yield), MS M/z:283[ M +1 ]]⁺。

Step 6 preparation of intermediate 6-6a,6-6b

Dissolving intermediate 6-5(21g,74.2mmol) in methanol, adding 10% Pd/C (5g) under nitrogen atmosphere, hydrogenating overnight under normal pressure, filtering with diatomaceous earth after the raw material disappears, concentrating the filtrate under reduced pressure to dryness, purifying MPLCC18 reverse phase column to obtain racemate, separating with SFC chiral column to obtain single configuration 6-6a (7.5g, light brown semisolid, 40% yield, chiral column retention time 5.755min, CHIRALPAK AY-H (AYH0CE-VC001)0.46cm I.D. 25cm L, mobile phase n-hexane/ethanol 80/20(V/V),35 deg.C, flow rate 1mL/min) and another single configuration 6-6b (7.5g, light brown semisolid, 40% yield, chiral column retention time 6.805min, CHIRALPAKAY-H (AYH0 VC 64-0 CE) 0.46cm I.D. 25cm L, mobile phase n-hexane/5V 80/20V/ethanol), 35 ℃, flow rate: 1mL/min), MS M/z 253[ M +1 ] ]⁺.

EXAMPLE 7 preparation of intermediate 7-2

Step 1 preparation of intermediate 7-1

Boc-D-cyclobutylglycine (800mg,3.49mmol) was dissolved in DCM (8mL), cooled to 0 deg.C and HBTU (1.06g,4.19mmol), DIEA (2.25g,17.45mmol) and ethylamine hydrochloride (284mg,3.49mmol) were added in sequence, and after 15min turned to room temperature for 1.5 h, LC-MS showed disappearance of starting material, washed with saturated ammonium chloride (10 mL. times.3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressureDrying, separating and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to obtain intermediate 7-1, white solid (822mg,3.21mmol, 92% yield), MS M/z:257[ M +1 ]]⁺.

Step 2 preparation of intermediate 7-2

7-1(822mg,3.21mmol) was dissolved in DCM (3mL), TFA (1.5mL) was slowly added under ice-bath, stirring was carried out for 1.5 h under ice-bath, the starting material disappeared, and concentration under reduced pressure was carried out to dryness to give a TFA salt of 7-2 (820mg, 100%) as a colorless semi-viscous solid, MS M/z:157[ M + 1% ]]⁺The crude product was used in the next step without purification.

EXAMPLE 8 preparation of intermediate R-cyclobutyl glycinamide 8

Reference example 7 procedure from Boc-D- (3, 3-difluorocyclobutyl) glycine condensed with methylamine hydrochloride followed by Boc removal, MS M/z 179[ M +1 ]]⁺.

EXAMPLE 9 preparation of intermediate 9

Reference example 7 procedure from Boc-D-cyclobutylglycine condensed with methylamine hydrochloride followed by Boc removal, MS M/z 143[ M +1 ]]⁺.

EXAMPLE 10 preparation of intermediate 10

Reference example 7 procedure from Boc-D-cyclobutylglycine condensed with cyclopropylamine followed by Boc removal, MS M/z 169[ M +1 ]]⁺.

EXAMPLE 11 preparation of intermediate 11

Reference example 7 procedure from Boc-D-cyclobutylglycine condensed with cyclopropylmethylamine followed by removal of Boc, MS M/z 183[ M +1 ]]⁺.

EXAMPLE 12 preparation of intermediate 12

Reference example 7 procedure from Boc-D-cyclobutylglycine condensed with 1-aminomethyl-1-cyclopropanol followed by Boc removal, MS M/z 199[ M +1 ]]⁺.

EXAMPLE 13 preparation of intermediate 13

Reference example 7 procedure from Boc-D-cyclobutylglycine condensed with (1-methoxycyclopropyl) methylamine followed by Boc removal, MS M/z:213[ M +1 [)]⁺.

EXAMPLE 14 preparation of intermediate 14

Reference example 7 procedure from Boc-D-cyclobutylglycine condensed with (1-fluorocyclopropyl) methylamine followed by Boc removal, MS M/z:201[ M +1 ]]⁺.

EXAMPLE 15 preparation of intermediate 15

Reference example 7 method from Boc-D-cyclobutylglycine condensation with 2, 2-difluoroethylamineSynthesis and subsequent removal of Boc to yield, MS M/z:193[ M +1 ]]⁺.

EXAMPLE 16 preparation of intermediate 16

Reference example 7 procedure from Boc-D-cyclobutylglycine condensed with 2-fluoroethylamine followed by Boc removal, MS M/z 175[ M +1 ]]⁺.

EXAMPLE 17 preparation of intermediate 17

Reference example 7 procedure from Boc-D-cyclopentylglycine condensed with ethylamine hydrochloride followed by Boc removal, MS M/z:171[ M +1 [)]⁺.

EXAMPLE 18 preparation of intermediate 18

Reference example 7 procedure from Boc-D- (tetrahydrofuran-2-yl) glycine condensed with ethylamine hydrochloride followed by Boc removal, MS M/z 173[ M +1 ]]⁺.

EXAMPLE 19 preparation of intermediate 19

Reference example 7 from Boc-D- (tetrahydropyran-4-yl) glycine by condensation with ethylamine hydrochloride followed by Boc removal, MS M/z 187[ M +1 ]]⁺.

EXAMPLE 20 preparation of intermediate 20

Reference example 7 procedure from Boc-D-cyclohexylglycine condensed with ethylamine hydrochloride followed by removal of Boc, MS M/z 285[ M +1 ]]⁺.

EXAMPLE 21 preparation of intermediate 21

Reference example 7 procedure from Boc-D-cyclohexylglycine condensed with cis-2-fluoro-cyclopropylamine followed by Boc removal, MS M/z:187[ M +1]⁺.

EXAMPLE 22 preparation of intermediate 22

Reference example 7 procedure from Boc-D-cyclohexylglycine condensed with trans-2-fluoro-cyclopropylamine followed by Boc removal, MS M/z:187[ M +1 ]⁺.

EXAMPLE 23 preparation of intermediate 23

Reference example 7 from Boc-D- (3-fluorocyclobutyl) glycine condensed with ethylamine hydrochloride followed by Boc removal, MS M/z 175[ M +1 ]]⁺.

EXAMPLE 24 preparation of intermediate 24

Reference example 7 from Boc-D- (3, 3-difluorocyclobutyl) glycine by condensation with ethylamine hydrochloride followed by Boc removal, MS M/z:193[ M +1]⁺.

EXAMPLE 25 preparation of intermediate 25

Reference example 7 procedure from Boc-D- (3-methylcyclobutyl) glycine condensed with ethylamine hydrochloride followed by Boc removal, MS M/z 171[ M +1 ]]⁺.

EXAMPLE 26 preparation of intermediate 26

Reference example 7 from Boc-D- (3-methoxycyclobutyl) glycine condensed with ethylamine hydrochloride followed by Boc removal, MS M/z 187[ M +1 ]]⁺.

EXAMPLE 27 preparation of intermediate 27

Reference example 7 procedure from Boc-D- (1-methylcyclobutyl) glycine condensed with ethylamine hydrochloride followed by Boc removal, MS M/z 171[ M +1 ]]⁺.

EXAMPLE 28 preparation of intermediate 28

Reference example 7 procedure from Boc- (S) - (1-fluorocyclobutyl) glycine condensed with ethylamine hydrochloride followed by Boc removal, MS M/z 175[ M +1 ]]⁺.

EXAMPLE 29 preparation of intermediate 29

Reference example 7 from Boc-D- (3-methyl-3-fluorocyclobutyl) glycine condensed with ethylamine hydrochloride followed by Boc removal, MS M/z:189[ M +1 ] ]⁺.

EXAMPLE 30 preparation of intermediate 30

Reference example 7 procedure from Boc-D- (spiro [2,3 ]]Hexane-5-yl) glycine by condensation with ethylamine hydrochloride followed by removal of Boc, MS M/z 183[ M +1 ]]⁺.

EXAMPLE 31 preparation of intermediate 31

Reference example 7 procedure from Boc-D- (bicyclo [ 1.1.1)]Pentan-1-yl) glycine was condensed with ethylamine hydrochloride and subsequently Boc-removed, MS M/z:169[ M +1 ]]⁺.

EXAMPLE 32 preparation of intermediate 32

Reference example 7 procedure from Boc-D- (3- (methyl) bicyclo [1.1.1]Pentan-1-yl) glycine was condensed with ethylamine hydrochloride and subsequently Boc-removed, MS M/z 183[ M +1 ]]⁺.

EXAMPLE 33 preparation of intermediate 33

Reference example 7 procedure from Boc-D- (3- (fluoro) bicyclo [1.1.1]Pentan-1-yl) glycine was condensed with ethylamine hydrochloride and subsequently Boc-removed, MS M/z 187[ M +1 ]]⁺.

EXAMPLE 34 preparation of Compound 34-a, 34-b

Step 1 preparation of intermediate 34-1, 34-2 (in the form of a mixture of structural isomers)

Step 5, single configuration intermediates 1-5b (614.57mg,1.80mmol, SFC chiral resolution gives a single chiral isomer), EDCI (412.08mg,2.16mmol), DIPEA (697.08mg,5.39mmol,939.46uL), HOAt (293.42mg,2.16mmol) and step 6, single configuration intermediates 6-6b (0.45g,1.80mmol) in example 6 are sequentially added into DCM (10mL), reacted at room temperature for 3 hours, quenched with water, most of the organic solvent removed under reduced pressure, ethyl acetate (20mL x 3) extracted, the organic phases combined, saturated ammonium chloride and saturated common salt, respectively, dried over anhydrous sodium sulfate, dried under reduced pressure, purified and separated by silica gel column chromatography (petroleum ether/ethyl acetate 5:1) to give a mixture of structural isomers of intermediates 34-1 and 34-2 (0.4g, 696. mu. mol, 39% yield), MS M/z 576(M +1) ⁺And the two were not separated and used for the next step.

Step 2 preparation of intermediate 34-3

The intermediate 34-1, 34-2 mixture obtained in step 2 (0.4g, 696. mu. mol) was added to AcOH (2mL), reacted at 55 ℃ for 12h, concentrated under reduced pressure and spun dry, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 1:1) to give intermediate 34-3(330mg, 534.08. mu. mol, 76.66% yield), MS m/z: 558(M +1)⁺。

Step 3 preparation of intermediate 34-4

Intermediate 34-3(0.33g,593.43 μmol) from step 2 was dissolved in DCM (3mL), TFA (1mL) was added dropwise in ice bath, stirring was continued for 2h in ice bath and spin dried to give crude intermediate 34-4 (250mg,493.45 μmol, 83.15% yield), MS m/z: 458(M +1)⁺And directly used for the next reaction without purification.

Step 4 preparation of intermediate 34-5

HBTU (134.35mg, 353.56. mu. mol) and DIPEA (114.23mg, 883.89. mu. mol,153.95uL) are added to a DCM (5mL) solution of 1-methyl-1H-pyrazole-5-carboxylic acid (112.01mg, 888.21. mu. mol) in sequence, after 15min, intermediate 34-4(160mg, 294.63. mu. mol) obtained in step 3 is added, the mixture is reacted for 2H at room temperature, water is added for quenching, ethyl acetate (20 mL. about.3) is extracted, organic phases are combined, saturated ammonium chloride and saturated common salt are respectively washed, anhydrous sodium sulfate is dried and decompressed and dried, and the crude product is purified and separated by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to obtain intermediate 34-5(301mg, 480.26. mu. mol, 81.11% yield), MS m/z: 566(M +1) ⁺。

Step 5 preparation of intermediate 34-6

Adding NaOH (64.03mg,1.60mmol) into a mixture of intermediate 34-5(301mg,533.62 mu mol) in EtOH (3mL) and water (1mL), reacting at 75 ℃ for 12 hours, adjusting the pH to 4 with 1NHCl, extracting with EA (10 mL. times.3) after the raw materials are reacted, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product (202mg,376.85 mu mol, 70.62% yield) of intermediate 34-6, wherein MS M/z is 538[ M +1 ]: 538]⁺And directly used for the next reaction without purification.

Step 6 preparation of Compound 34-a, 34-b

Step 6-1 preparation of Compound 34-b:

HBTU (357.2mg, 942.5. mu. mol), DIPEA (146mg, 1131. mu. mol,187uL), were added sequentially to step5 intermediate 34-6(202mg,376.85 μmol) in DCM (5mL), after 15min addition of intermediate 7-2(71mg,452.4 μmol) from example 7, reaction at room temperature for 1h, quenching with 10mL water, removal of most of the organic solvent under reduced pressure, extraction with ethyl acetate (10mL x 3), combining the organic phases, washing with saturated ammonium chloride and saturated brine respectively, drying over anhydrous sodium sulfate, spin-drying under reduced pressure, purification and separation of the crude product by MPLC reverse phase C18 column chromatography (acetonitrile/0.05% water 0-60%) to give intermediate 34-b (204mg,309 μmol, 82% yield), MS m/z: 676(M +1) ⁺。¹HNMR(400MHz,MeOD):δ7.94(t,J＝5.6Hz,1H),7.60(d,J＝1.8Hz,1H),7.57–7.53(m,1H),7.53–7.49(m,1H),7.43(d,J＝8.0Hz,1H),7.40–7.32(m,3H),7.29(dd,J＝8.6,1.8Hz,1H),7.26–7.21(m,1H),6.51(d,J＝2.2Hz,1H),6.00(d,J＝9.3Hz,1H),4.37(t,J＝8.3Hz,1H),4.19(t,J＝7.8Hz,1H),4.01(d,J＝9.6Hz,1H),3.93(s,3H),3.74(d,J＝9.6Hz,1H),3.63(q,J＝7.0Hz,1H),3.44(s,3H),3.26–3.12(m,2H),2.64–2.52(m,1H),2.01–1.72(m,7H),1.59(s,3H),1.20(t,J＝7.0Hz,1H),1.10(t,J＝7.2Hz,3H),0.99(d,J＝6.7Hz,3H),0.86(d,J＝6.8Hz,3H).

Step 6-2 preparation of Compound 34-a:

referring to the method for preparing 34-b in step 1-6 of example 34, single configuration intermediates 1-5b in step 5 of example 1 and 6-6a in step 6 of example 6 are reacted, and subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with intermediate amide 7-2 of example 7, and the like to obtain 34-a, MS m/z: 676(M +1)⁺。

EXAMPLE 35 preparation of Compound 35-a,35-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 35-b was obtained by condensation with intermediate 9 of example 9. Class ISimilarly, starting from the intermediate of step 5 (another configuration of 34-6) which produces another configuration 34-a, condensation with intermediate 9 of example 9 affords compound 35-a. MS m/z: 662(M +1)⁺。

EXAMPLE 36 preparation of Compound 36-a,36-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 36-b was obtained by condensation with intermediate 10 of example 10. Similarly, compound 36-a can be obtained by condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a, intermediate 10 of example 10. MS m/z: 688(M +1)⁺。

EXAMPLE 37 preparation of Compounds 37-a,37-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 37-b was obtained by condensation with intermediate 11 of example 11. Similarly, starting from the step 5 intermediate (another configuration of 34-6) which produces another configuration 34-a, condensation with intermediate 11 of example 11 affords compound 37-a. MS m/z: 702(M +1)⁺. Nuclear magnetic hydrogen spectrum of 37-b:¹HNMR(400MHz,DMSO-d₆):δ12.52(s,1H),8.72(dd,J＝16.2,9.7Hz,1H),7.84–7.75(m,1H),7.62–7.54(m,1H),7.47–7.37(m,3H),7.35–7.27(m,2H),7.26–7.10(m,3H),6.49(s,1H),5.94–5.84(m,1H),4.38–4.30(m,1H),4.30–4.22(m,1H),3.91(d,J＝9.9Hz,1H),3.83(s,2H),3.64(d,J＝9.4Hz,1H),3.31–3.27(m,3H),3.00–2.93(m,1H),2.89–2.81(m,1H),2.69–2.66(m,1H),2.35–2.31(m,1H),1.87–1.64(m,6H),1.49(s,2H),0.81–0.73(m,4H),0.38–0.31(m,2H),0.11–0.05(m,2H).

EXAMPLE 38 preparation of Compound 38-a,38-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 38-b was obtained by condensation with intermediate 12 of example 12. Similarly, starting from the step 5 intermediate (another configuration of 34-6) for the preparation of another configuration 34-a, condensation with intermediate 12 of example 12 affords compound 38-a, MS m/z: 718(M +1)⁺。

EXAMPLE 39 preparation of Compounds 39-a,39-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 39-b was obtained by condensation with intermediate 13 of example 13. Similarly, starting from the step 5 intermediate (another configuration of 34-6) for the preparation of another configuration 34-a, condensation with intermediate 13 of example 13 affords the compound 39-a, MS m/z: 732(M +1)⁺. The nuclear magnetic hydrogen spectrum of compound 39-b is:¹HNMR(400MHz,DMSO-d₆):δ8.72(s,1H),7.92–7.82(m,1H),7.70–7.63(m,1H),7.63–7.58(m,1H),7.51–7.46(m,1H),7.42–7.23(m,7H),6.65(s,1H),6.01(s,1H),4.40–4.33(m,1H),4.23–4.16(m,1H),3.93–3.88(m,1H),3.86(s,3H),3.70–3.64(m,2H),3.29(s,3H),1.89–1.63(m,8H),1.50(s,3H),1.30–1.23(m,3H),0.91–0.84(m,3H),0.80–0.75(m,3H),0.50–0.44(m,2H),0.41–0.35(m,2H).

EXAMPLE 40 preparation of Compound 40-a,40-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 40-b was obtained by condensation with intermediate 14 of example 14. Similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 14 of example 14 affords compound 40-a, MS m/z: 720(M +1)⁺. 40-b nuclear magnetic hydrogen spectrum:¹HNMR(400MHz,DMSO-d₆):δ8.76(dd,J＝16.5,9.3Hz,2H),8.18(t,J＝5.9Hz,2H),7.63–7.52(m,2H),7.50–7.36(m,4H),7.31(dd,J＝6.8,4.9Hz,2H),7.22(dd,J＝15.0,7.5Hz,2H),7.18–7.07(m,2H),6.55(s,1H),6.49(s,2H),5.97–5.80(m,2H),4.40(t,J＝7.2Hz,2H),4.31–4.22(m,2H),3.91(dd,J＝9.4,3.4Hz,2H),3.82(s,3H),3.63(d,J＝9.5Hz,2H),1.94–1.61(m,9H),1.49(s,4H),1.24(s,2H),0.91(d,J＝18.7Hz,3H),0.77(t,J＝6.2Hz,6H),0.64(d,J＝7.9Hz,3H).

EXAMPLE 41 preparation of Compound 41-a,41-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 41-b was obtained by condensation with intermediate 15 of example 15. Similarly, starting from the step 5 intermediate (another configuration of 34-6) for the preparation of another configuration 34-a, condensation with intermediate 15 of example 15 affords the compound 41-a, MS m/z: 712(M +1)⁺. Nuclear magnetic hydrogen spectrum of 41-b:¹HNMR(400MHz,MeOD):δ7.63–7.49(m,4H),7.46(d,J＝8.0Hz,1H),7.38(dd,J＝9.3,4.0Hz,4H),7.32–7.21(m,3H),6.51(s,2H),6.00(d,J＝9.2Hz,2H),4.48(t,J＝4.9Hz,1H),4.46–4.39(m,2H),4.37(t,J＝4.9Hz,1H),4.19(s,2H),4.02(d,J＝9.6Hz,2H),3.94(s,3H),3.74(d,J＝9.5Hz,2H),3.44(s,3H),2.60(dd,J＝15.8,7.9Hz,3H),1.90(ddd,J＝21.8,11.1,5.6Hz,6H),1.79(d,J＝20.1Hz,3H),1.56(d,J＝23.0Hz,4H),1.44–1.35(m,2H),0.99(d,J＝6.1Hz,4H),0.86(d,J＝6.8Hz,4H).

EXAMPLE 42 preparation of Compound 42-a,42-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 42-b was obtained by condensation with intermediate 16 of example 16. Similarly, to prepare a step 5 intermediate of alternative configuration 34-a (alternative configuration of 34-6)) Condensation with intermediate 16 of example 16 gave compound 42-a, MS m/z: 694(M +1)⁺. 42-b nuclear magnetic hydrogen spectrum: ¹HNMR(400MHz,MeOD):δ7.63–7.49(m,4H),7.46(d,J＝8.0Hz,1H),7.38(dd,J＝9.3,4.0Hz,4H),7.32–7.21(m,3H),6.51(s,2H),6.00(d,J＝9.2Hz,2H),4.48(t,J＝4.9Hz,1H),4.46–4.39(m,2H),4.37(t,J＝4.9Hz,1H),4.19(s,2H),4.02(d,J＝9.6Hz,2H),3.94(s,3H),3.74(d,J＝9.5Hz,2H),3.44(s,3H),2.60(dd,J＝15.8,7.9Hz,3H),1.90(ddd,J＝21.8,11.1,5.6Hz,6H),1.79(d,J＝20.1Hz,3H),1.56(d,J＝23.0Hz,4H),1.44–1.35(m,2H),0.99(d,J＝6.1Hz,4H),0.86(d,J＝6.8Hz,4H).

EXAMPLE 43 preparation of Compounds 43-a,43-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 43-b was obtained by condensation with intermediate 17 of example 17. Similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 17 of example 17 affords compound 43-a, MS m/z: 690(M +1)⁺。

EXAMPLE 44 preparation of Compound 44-a,44-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 44-b was obtained by condensation with intermediate 18 of example 18; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 18 of example 18 affords compound 44-a, MS m/z: 692(M +1)⁺。

EXAMPLE 45 preparation of Compounds 45-a,45-b

By following the procedure for preparing 34-b in step 6 of example 34, starting from intermediate 34-6, compound 45-b was obtained by condensation with intermediate 19 of example 19; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 19 of example 19 affords compound 45-a, MS m/z: 706(M +1)⁺。

EXAMPLE 46 preparation of Compounds 46-a,46-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 46-b was obtained by condensation with intermediate 20 of example 20; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 20 of example 20 affords compound 46-a, MS m/z: 704(M +1)⁺。

EXAMPLE 47 preparation of Compounds 47-a,47-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 47-b was obtained by condensation with intermediate 21 of example 21; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 21 of example 21 affords compound 47-a, MS m/z: 706(M +1)⁺。

EXAMPLE 48 preparation of Compound 48-a,48-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 48-b was obtained by condensation with intermediate 22 of example 22; similarly, to prepare a step 5 intermediate of alternative configuration 34-a (alternative configuration of 34-6)) Condensation with intermediate 22 of example 22 gave compound 48-a, MS m/z: 706(M +1)⁺。

EXAMPLE 49 preparation of Compound 49-a,49-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 49-b was obtained by condensation with intermediate 23 of example 23; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 23 of example 23 affords compound 49-a, MS m/z: 694(M +1) ⁺。

EXAMPLE 50 preparation of Compounds 50-a,50-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 50-b was obtained by condensation with intermediate 24 of example 24; similarly, starting from the step 5 intermediate (another configuration of 34-6) for the preparation of another configuration 34-a, condensation with intermediate 24 of example 24 affords compound 50-a, MS m/z: 712(M +1)⁺。

EXAMPLE 51 preparation of Compounds 51-a,51-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 51-b was obtained by condensation with intermediate 25 of example 25; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 25 of example 25 affords compound 51-a, MS m/z: 690(M +1)⁺。

EXAMPLE 52 preparation of Compounds 52-a,52-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 52-b was obtained by condensation with intermediate 26 of example 26; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 26 of example 26 affords compound 52-a, MS m/z: 706(M +1)⁺。

EXAMPLE 53 preparation of Compounds 53a,53-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 53-b was obtained by condensation with intermediate 27 of example 27; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 27 of example 27 affords compound 53-a, MS m/z: 690(M +1)⁺. The nuclear magnetic hydrogen spectrum of compound 53-b is:¹H NMR(400MHz,MeOD)δ8.03(t,J＝4.2Hz,1H),7.64(d,J＝1.2Hz,1H),7.59(d,J＝8.8Hz,1H),7.55(d,J＝8.4Hz,2H),7.42–7.36(m,4H),7.28–7.24(m,1H),6.57(s,1H),6.04(d,J＝8.8Hz,1H),4.41(d,J＝8.8Hz,1H),4.17–4.11(m,1H),4.01(d,J＝10.0Hz,1H),3.96(s,3H),3.75(d,J＝10.0Hz,1H),3.46(s,3H),3.29–3.14(m,2H),2.27-2.20(m,1H),2.17-1.87(m,3H),1.78–1.66(m,1H),1.62–1.52(m,5H),1.13(d,J＝7.2Hz,2H),1.10(d,J＝3.6Hz,4H),1.05(d,J＝6.4Hz,3H),0.86(d,J＝6.8Hz,3H).

EXAMPLE 54 preparation of Compounds 54-a,54-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 54-b was obtained by condensation with intermediate 28 of example 28; similarly, in step 5 to prepare another configuration 34-aIntermediate (34-6, another configuration) was used as a starting material, and condensed with intermediate 28 of example 28 to give compound 54-a, MS m/z: 694(M +1)⁺。

EXAMPLE 55 preparation of Compounds 55-a,55-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 55-b was obtained by condensation with intermediate 29 of example 29; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 29 of example 29 affords compound 55-a, MS m/z: 708(M +1)⁺。

EXAMPLE 56 preparation of Compounds 56-a,56-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 56-b was obtained by condensation with intermediate 30 of example 30; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 30 of example 30 affords compound 56-a, MS m/z: 702(M +1)⁺。

EXAMPLE 57 preparation of Compounds 57-a,57-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 57-b was obtained by condensation with intermediate 31 of example 31; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 31 of example 31 affords compound 57-a, MS m/z: 688(M +1)⁺. Nuclear magnetism of compound 57-b:¹H NMR(400MHz,Methanol-d₄)δ7.68(s,2H),7.58(d,J＝7.2Hz,1H),7.48(d,J＝7.2Hz,1H),7.35-7.32(m,3H),7.27-7.23(m,1H),6.33(d,J＝2.0Hz,1H),6.03(d,J＝12.0Hz,1H),4.76(d,J＝8.8Hz,1H),4.69(s,1H),4.07–3.97(m,3H),3.87(s,3H),3.76(d,J＝12.0Hz,1H),3.26–3.08(m,2H),2.93–2.87(m,1H),2.64-2.57(m,1H),1.77–1.72(m,6H),1.12–1.07(m,6H),0.79-0.74(m,1H),0.02–-0.02(m,1H),-0.14(t,J＝7.6Hz,2H).

EXAMPLE 58 preparation of Compound 58-a,58-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 58-b was obtained by condensation with intermediate 32 of example 32; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 32 of example 32 affords compound 58-a, MS m/z: 702(M +1)⁺。

EXAMPLE 59 preparation of Compounds 59a,59-b

By following the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, compound 59-b was obtained by condensation with intermediate 33 of example 33; similarly, condensation of step 5 intermediate (another configuration of 34-6) starting from another configuration 34-a with intermediate 33 of example 33 affords compound 59-a, MS m/z: 706(M +1) ⁺。

EXAMPLE 60 preparation of the Compound 60-a,60-b,60-c,60-d,60-e,60-f,60-g,60-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected,1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, finally condensed with the intermediate 9 of the embodiment 9, and then the compound 60-a,60-b,60-c,60-d is prepared by SFC chiral resolution. Similarly, the intermediate 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 60-e,60-f,60-g and 60-H. MS m/z: 680(M +1)⁺。

EXAMPLE 61 preparation of the compound 61-a,61-b,61-c,61-d,61-e,61-f,61-g,61-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 61-a,61-b,61-c, 61-d. Similarly, the intermediate 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compound 61-e,61-f,61-g and 61-H. MS m/z: 694(M +1) ⁺。

EXAMPLE 62 preparation of compound 62-a,62-b,62-c,62-d,62-e,62-f,62-g,62-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) were subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 10 of example 10, and SFC chiral resolutionTo prepare the compound 62-a,62-b,62-c, 62-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 62-e,62-f,62-g and 62-H. MS m/z: 706(M +1)⁺。

EXAMPLE 63 preparation of the Compounds 63-a,63-b,63-c,63-d,63-e,63-f,63-g,63-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 11 of example 11, and SFC chiral resolution to obtain compounds 63-a,63-b,63-c, 63-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 63-e,63-f,63-g and 63-H. MS m/z: 720(M +1) ⁺。

EXAMPLE 64 preparation of Compounds 64-a,64-b,64-c,64-d,64-e,64-f,64-g,64-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 12 of example 12, and SFC chiral resolution to obtain compounds 64-a,64-b,64-c, 64-d. Similarly, intermediates 2 to 6 of step 5 in example 2 and examples6, condensing, closing a ring, deprotecting, introducing 1-methyl-1H-pyrazole-5-acyl, hydrolyzing, condensing, and then carrying out SFC chiral resolution to prepare a compound 64-e,64-f,64-g and 64-H, wherein the compound has a single configuration, and the single configuration is prepared by SFC chiral resolution. MS m/z: 736(M +1)⁺。

EXAMPLE 65 preparation of the Compounds 65-a,65-b,65-c,65-d,65-e,65-f,65-g,65-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 13 of example 13, and SFC chiral resolution to obtain compounds 65-a,65-b,65-c and 65-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 65-e,65-f,65-g and 65-H. MS m/z: 750(M +1) ⁺。

EXAMPLE 66 preparation of Compounds 66-a,66-b,66-c,66-d,66-e,66-f,66-g,66-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 14 of example 14, and SFC chiral resolution to obtain compounds 66-a,66-b,66-c, 66-d. Similarly, intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, and introduced into 1-methylHydrolyzing and condensing the 1H-pyrazole-5-acyl group, and then carrying out SFC chiral resolution to prepare the compounds 66-e,66-f,66-g and 66-H. MS m/z: 738(M +1)⁺。

EXAMPLE 67 preparation of the Compounds 67-a,67-b,67-c,67-d,67-e,67-f,67-g,67-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 15 of example 15, and SFC chiral resolution to obtain compounds 67-a,67-b,67-c, 67-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 67-e,67-f,67-g and 67-H. MS m/z: 730(M +1) ⁺。

EXAMPLE 68 preparation of Compounds 68-a,68-b,68-c,68-d,68-e,68-f,68-g,68-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 16 of example 16, and SFC chiral resolution to obtain compounds 68-a,68-b,68-c, 68-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 68-e,68-f,68-g and 68-H。MS m/z：712(M+1)⁺。

EXAMPLE 69 preparation of the Compounds 69-a,69-b,69-c,69-d,69-e,69-f,69-g,69-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 17 of example 17, and SFC chiral resolution to obtain compounds 69-a,69-b,69-c, 69-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 69-e,69-f,69-g and 69-H. MS m/z: 708(M +1) ⁺。

EXAMPLE 70 preparation of Compound 70-a,70-b,70c,70-d,70-e,70-f,70-g,70-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 18 of example 18, and SFC chiral resolution to obtain compounds 70-a,70-b,70c, 70-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 70-e,70-f,70-g and 70-H. MS m/z: 710(M +1)⁺。

EXAMPLE 71 preparation of the Compounds 71-a,71-b,71-c,71-d,71-e,71-f,71-g,71-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, finally condensed with intermediate 19 of example 19, and then subjected to SFC chiral resolution to obtain compounds 71-a,71-b,71-c, 71-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 71-e,71-f,71-g and 71-H. MS m/z: 724(M +1) ⁺。

EXAMPLE 72 preparation of the Compounds 72-a,72-b,72-c,72-d,72-e,72-f,72-g,72-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 20 of example 20, and SFC chiral resolution to obtain compounds 72-a,72-b,72-c and 72-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 72-e,72-f,72-g and 72-H. MS m/z: 722(M +1)⁺。

EXAMPLE 73 preparation of the Compounds 73-a,73-b,73-c,73-d,73-e,73-f,73-g,73-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 21 of example 21, and SFC chiral resolution to obtain compounds 73-a,73-b,73-c, 73-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 73-e,73-f,73-g and 73-H. MS m/z: 724(M +1) ⁺。

EXAMPLE 74 preparation of Compounds 74-a,74-b,74-c,74-d,74-e,74-f,74-g,74-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 22 of example 22, and SFC chiral resolution to obtain compounds 74-a,74-b,74-c and 74-d. Similarly, compounds 74-e,74-f,74-g,74-H were prepared from intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 724(M +1)⁺。

EXAMPLE 75 preparation of the Compounds 75-a,75b,75-c,75-d,75-e,75-f,75-g,75-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 23 of example 23, and SFC chiral resolution to obtain compounds 75-a,75b,75-c, 75-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 75-e,75-f,75-g and 75-H. MS m/z: 712(M +1) ⁺。

EXAMPLE 76 preparation of the Compound 76-a,76b,76-c,76-d,76-e,76-f,76-g,76-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 24 of example 24, and SFC chiral resolution to obtain compounds 76-a,76b,76-c, 76-d. Similarly, compounds 76-e,76-f,76-g and 76-H were prepared from intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution. MS m/z: 730(M +1)⁺。

EXAMPLE 77 preparation of Compounds 77-a,77b,77-c,77-d,77-e,77-f,77-g,77-h

Reference is made to the procedures of steps 1 to 6 of example 34, as in example 2The intermediates 2 to 6 in the step 5 and the intermediates 66 to 6b (prepared by SFC chiral resolution to obtain a single configuration) in the step 6 are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with the intermediate 25 in the example 25, and then SFC chiral resolution to obtain the compounds 77-a,77b,77-c and 77-d. Similarly, intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare compounds 77-e,77-f,77-g and 77-H. MS m/z: 708(M +1) ⁺。

EXAMPLE 78 preparation of Compounds 78-a,78b,78-c,78-d,78-e,78-f,78-g,78-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 26 of example 26, and SFC chiral resolution to obtain compounds 78-a,78b,78-c, 78-d. Similarly, compounds 78-e,78-f,78-g,78-H were prepared from intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 724(M +1)⁺。

EXAMPLE 79 preparation of Compounds 79-a,79-b,79-c,79-d,79-e,79-f,79-g,79-h

With reference to the procedures of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and 66-6b of example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed and isolatedRing deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 27 from example 27, and SFC chiral resolution to obtain compounds 79-a,79b,79-c, 79-d. Similarly, the intermediate 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 79-e,79-f,79-g and 79-H. MS m/z: 708(M +1) ⁺。

EXAMPLE 80 preparation of Compounds 80-a,80-b,80-c,80-d,80-e,80-f,80-g,80-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, finally condensed with intermediate 28 of example 28, and then subjected to SFC chiral resolution to obtain compounds 80-a,80-b,80-c, 80-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 80-e,80-f,80-g and 80-H. MS m/z: 712(M +1)⁺。

EXAMPLE 81 preparation of the Compounds 81-a,81-b,81-c,81-d,81-e,81-f,81-g,81-h

Referring to the procedures of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) were subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, final condensation with intermediate 29 of example 29, and further condensation The compound 81-a,81-b,81-c,81-d is prepared by SFC chiral resolution. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 81-e,81-f,81-g and 81-H. MS m/z: 726(M +1)⁺。

EXAMPLE 82 preparation of Compounds 82-a,82-b,82-c,82-d,82-e,82-f,82-g,82-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 30 of example 30, and SFC chiral resolution to obtain compounds 82-a,82-b,82-c, 82-d. Similarly, compounds 82-e,82-f,82-g,82-H were prepared from intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 720(M +1) ⁺。

EXAMPLE 83 preparation of 83-a,83-b,83-c,83-d,83-e,83-f,83-g,83-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 31 of example 31, and SFC chiral resolution to obtain compounds 83-a,83-b,83-c and 83-d. Similarly, in the middle of step 5 in example 2Bodies 2-6 and 6-6a (a single configuration is obtained by SFC chiral resolution preparation) of step 6 in example 6 are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution to prepare compounds 83-e,83-f,83-g and 83-H. MS m/z: 706(M +1)⁺。

EXAMPLE 84 preparation of Compounds 84-a,84-b,84-c,84-d,84-e,84-f,84-g,84-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 32 of example 32, and SFC chiral resolution to obtain compounds 84-a,84-b,84-c and 84-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 84-e,84-f,84-g and 84-H. MS m/z: 720(M +1) ⁺。

EXAMPLE 85 preparation of the Compounds 85-a,85-b,85-c,85-d,85-e,85-f,85-g,85-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 33 of example 33, and SFC chiral resolution to obtain compounds 85-a,85-b,85-c and 85-d. Similarly, intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed, ring-closed, and ring-removedProtection, namely introducing 1-methyl-1H-pyrazole-5-acyl, hydrolyzing, condensing, and carrying out SFC chiral resolution to obtain compounds 85-e,85-f,85-g and 85-H. MS m/z: 724(M +1)⁺。

EXAMPLE 86 preparation of Compounds 86-a,86-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 9 of example 9 to give compound 86-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 86-a. MS m/z: 674(M +1) ⁺. Nuclear magnetic spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.66(s,1H),7.59(dd,J＝12.6,8.2Hz,2H),7.47(d,J＝8.0Hz,2H),7.37–7.28(m,3H),7.24(t,J＝7.6Hz,1H),6.32(s,1H),6.03(d,J＝11.9Hz,1H),4.38(t,J＝8.2Hz,1H),4.04(d,J＝9.5Hz,1H),3.85(s,3H),3.76(d,J＝10.5Hz,2H),3.45(s,3H),2.73(d,J＝3.8Hz,3H),2.66–2.53(m,1H),2.02–1.81(m,4H),1.81–1.67(m,2H),1.60(s,3H),1.12(s,3H),0.82–0.74(m,1H),0.06–-0.01(m,1H),-0.12(t,J＝7.5Hz,2H).

EXAMPLE 87 preparation of Compounds 87-a,87-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 87-b. Class ISimilarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally condensed with intermediate 7-2 from example 7 to give compound 87-a. MS m/z: 688(M +1)⁺(ii) a 87b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄) δ 7.99-7.91 (m,1H), 7.69-7.64 (m,1H), 7.64-7.54 (m,2H), 7.51-7.44 (m,2H), 7.37-7.31 (m,3H), 7.29-7.21 (m,1H),6.34(d, J-2.1 Hz,1H),6.01(d, J-11.9 Hz,1H),4.38(t, J-8.3 Hz,1H),4.04(d, J-9.6 Hz,1H),3.87(s,3H),3.77(d, J-1.5 Hz,1H),3.74(d, J-3.8 Hz,1H),3.45(s,3H), 3.24-3.12 (m,2H),2.66 (m,2H), 1H), 1.15-0.15H, 1H), 0.15-6H, 1H, 15, 1: ¹H NMR(400MHz,Methanol-d₄)δ8.01(s,1H),7.66(s,1H),7.61-7.56(m,2H),7.48(dd,J＝8.0,1.2Hz,1H),7.41(d,J＝7.6Hz,1H),7.35–7.31(m,3H),7.25(td,J＝8.0,1.6Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.37(t,J＝8.0Hz,1H),4.00(d,J＝9.6Hz,1H),3.87(s,3H),3.74(t,J＝10.2Hz,2H),3.43(s,3H),3.24–3.14(m,2H),2.64-2.58(m,1H),1.97–1.83(m,7H),1.64(s,3H),1.13-1.08(m,6H),0.79–0.74(m,1H),-0.04--0.01(m,1H),-0.09–-0.15(m,2H).

EXAMPLE 88 preparation of Compounds 88-a,88-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 10 of example 10 to give compound 88-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazol-5-yl, hydrolysis, condensation and condensationCompound 88-a is obtained. MS m/z: 688(M +1)⁺Nuclear magnetic hydrogen spectrum of 88 b:¹H NMR(400MHz,Methanol-d₄)δ8.08(s,1H),7.70–7.53(m,3H),7.51–7.42(m,2H),7.37–7.29(m,3H),7.25(td,J＝7.7,1.6Hz,1H),6.34(d,J＝2.1Hz,1H),6.01(d,J＝11.9Hz,1H),4.34(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.76(d,J＝1.8Hz,1H),3.74(s,1H),3.46(s,3H),2.66–2.51(m,2H),1.98–1.70(m,6H),1.61(s,3H),1.13(s,3H),0.81–0.67(m,3H),0.46(dd,J＝8.6,3.8Hz,2H),0.02(dt,J＝10.4,5.1Hz,1H),-0.08–-0.18(m,2H).

EXAMPLE 89 preparation of Compounds 89-a,89-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 11 of example 11 to give compound 89-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 89-a. MS m/z: 714(M +1) ⁺.

EXAMPLE 90 preparation of Compound 90-a,90-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 12 of example 12 to give compound 90-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution)Prepared into another single configuration) is condensed, closed, deprotected, and then 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed and condensed to obtain a compound 90-a. MS m/z: 730(M +1)⁺.

EXAMPLE 91 preparation of Compounds 91-a,91-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 13 of example 13 to give compound 91-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 91-a. MS m/z: 744(M +1) ⁺.

EXAMPLE 92 preparation of Compounds 92-a,92-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 14 of example 14 to give compound 92-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 92-a. MS m/z: 732(M +1)⁺.

EXAMPLE 93 preparation of Compounds 93-a,93-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yielded a single configuration) of example 6 were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl introduced, hydrolyzed, and finally condensed with intermediate 15 of example 15 to yield compound 93-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 93-a. MS m/z: 724(M +1) ⁺.

EXAMPLE 94 preparation of Compounds 94-a,94-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 16 of example 16 to give compound 94-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 94-a. MS m/z: 706(M +1)⁺Nuclear magnetism of compound 94-b:¹H NMR(400MHz,Methanol-d₄)δ7.71–7.53(m,3H),7.52–7.42(m,2H),7.38–7.30(m,3H),7.29–7.20(m,1H),6.33(d,J＝2.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.52–4.34(m,3H),4.08–4.01(m,1H),3.87(s,3H),3.81–3.68(m,2H),3.59–3.37(m,5H),2.73–2.49(m,1H),2.01–1.73(m,6H),1.61(s,3H),1.13(s,3H),0.85–0.67(m,1H),0.01(dt,J＝10.1,5.2Hz,1H),-0.13(tt,J＝7.6,4.8Hz,2H).

EXAMPLE 95 preparation of Compounds 95-a,95-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 17 of example 17 to give compound 95-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 95-a. MS m/z: 702(M +1) ⁺Nuclear magnetization of compound 95-b:¹H NMR(400MHz,Methanol-d₄)δ8.03(t,J＝5.2,Hz,1H),7.65-7.57(m,3H),7.48(d,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.37-7.29(m,3H),7.27-7.23(m,1H),6.33(d,J＝1.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.27(t,J＝8.0Hz,1H),4.03(d,J＝9.2Hz,1H),3.87(s,3H),3.80-3.70(m,2H),3.45(s,3H),3.29-3.06(m,2H),2.27-2.03(m,1H),1.76-1.44(m,9H),1.42-1.16(m,3H),1.13-1.10(m,,6H),0.79-0.74(m,1H),0.04-0.0(m,1H),-0.11--0.14(m,2H).

EXAMPLE 96 preparation of Compound 96-a,96-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 18 of example 18 to give compound 96-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 96-a. MS m/z: 704(M +1)⁺The compound 96-b is then resolved by SFC to give two component peaks, one of which, 96-b1, has a nuclear magnetism:¹H NMR(400MHz,Methanol-d₄) δ 7.65(s,1H), 7.63-7.55 (m,2H),7.48(dd,1H), 7.36-7.29 (m,3H), 7.28-7.21 (m,1H),6.33(d, J ═ 2.1Hz,1H),6.02(d, J ═ 12.0Hz,1H),4.47(d, J ═ 7.3Hz,1H),4.03(q, J ═ 9.5Hz,2H),3.87(s,3H), 3.86-3.81 (m,1H), 3.79-3.67 (m,3H),3.45(s,3H),3.22(q, J ═ 7.3Hz,2H), 1.95-1.71 (m,4H),1.60(s,3H), 1.81 (m, 13.81H), 0.0.05-0H), 0.05-0H, 0H), -1H; the nuclear magnetism of one of the components 96-b2 is: ¹H NMR(400MHz,Methanol-d₄)δ7.77–7.05(m,10H),6.33(d,J＝2.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.47–4.42(m,1H),4.28–4.23(m,1H),4.11(d,J＝9.6Hz,1H),3.92–3.71(m,5H),3.53(s,3H),3.28–3.19(m,2H),1.81–1.65(m,1H),1.60(s,3H),1.58–1.49(m,2H),1.41(d,J＝11.0Hz,1H),1.37–1.24(m,4H),1.16–1.08(m,6H),0.81–0.75(m,1H),-0.08–-0.17(m,2H).

EXAMPLE 97 preparation of Compounds 97-a,97-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 19 of example 19 to give compound 97-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 97-a. MS m/z: 718(M +1)⁺The nuclear magnetization of 97-b is:¹H NMR(400MHz,Methanol-d₄)δ7.73–7.62(m,1H),7.62–7.52(m,2H),7.51–7.45(m,1H),7.37–7.28(m,3H),7.28–7.22(m,1H),6.34(s,1H),6.01(d,J＝11.9Hz,1H),4.32–4.26(m,1H),4.05(d,J＝9.6Hz,1H),3.87(s,5H),3.74(d,J＝9.5Hz,2H),3.45(s,3H),3.21(s,2H),1.92(dt,J＝7.8,3.9Hz,1H),1.65–1.56(m,3H),1.54–1.19(m,6H),1.16–1.07(m,6H),0.83–0.72(m,1H),0.02(m,1H),-0.13(m,2H).

EXAMPLE 98 preparation of Compounds 98-a,98-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 20 of example 20 to give compound 98-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 98-a. MS m/z: 716(M +1) ⁺Nuclear magnetic hydrogen spectrum of 98 b:¹H NMR(400MHz,Methanol-d₄)δ8.07–7.99(m,1H),7.70–7.54(m,3H),7.51–7.45(m,1H),7.38–7.20(m,5H),6.37–6.27(m,1H),6.01(d,J＝11.9Hz,1H),4.28–4.22(m,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.79–3.72(m,2H),3.46(s,3H),3.26–3.17(m,2H),1.82–1.51(m,10H),1.36–1.27(m,1H),1.15–1.11(m,6H),1.10(s,1H),0.06–-0.02(m,1H),-0.06–-0.22(m,2H).

EXAMPLE 99 preparation of Compounds 99-a,99-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 21 of example 21 to give compound 99-b. Similarly, another single configuration was prepared as intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution)) The compound 99-a is obtained by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation. MS m/z: 718(M +1)⁺99b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.72–7.55(m,3H),7.53(d,J＝7.9Hz,1H),7.48(dd,J＝8.0,1.4Hz,1H),7.33(dt,J＝7.3,1.7Hz,3H),7.25(td,J＝7.7,1.6Hz,1H),6.34(d,J＝2.1Hz,1H),6.01(d,J＝11.9Hz,1H),4.69(td,J＝5.7,3.1Hz,0H),4.53(td,J＝5.7,3.1Hz,0H),4.45(t,J＝8.2Hz,1H),4.03(d,J＝9.6Hz,1H),3.87(s,3H),3.76(s,1H),3.74(d,J＝2.3Hz,1H),3.46(s,3H),2.73–2.65(m,1H),2.64–2.53(m,1H),2.00–1.69(m,6H),1.61(s,3H),1.13(s,3H),0.92(dddd,J＝24.6,8.4,5.9,3.1Hz,1H),0.81–0.72(m,1H),0.05–-0.03(m,1H),-0.13(ddd,J＝9.0,6.0,2.2Hz,2H).

EXAMPLE 100 preparation of Compounds 100-a,100-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yielded a single configuration) of example 6 were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 22 of example 22 to yield compound 100-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 100-a. MS m/z: 718(M +1) ⁺The compound 100-b is then separated by SFC to obtain two component peaks (fluorotricyclic cis-trans isomerism), wherein the nuclear magnetism of one component 100-b1 is as follows:¹H NMR(400MHz,Methanol-d₄)δ7.69–7.54(m,3H),7.52–7.44(m,2H),7.37–7.29(m,3H),7.25(td,J＝7.6,1.6Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12Hz,1H),4.60-4.57(m,0.5H),4.48-4.40(m,0.5H),4.31(t,J＝8.2Hz,1H),4.17–4.08(m,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.79–3.71(m,2H),3.46(s,3H),3.04–2.91(m,1H),2.60-2.55(m,1H),1.99–1.71(m,6H),1.60(s,3H),1.41–1.29(m,1H),1.13(s,3H), 0.97-0.85 (m,1H),0.79-0.74(m,1H), 0.06-0.04 (m,1H), -0.10-0.14 (m, 2H); the nuclear magnetism of the second 100-b2 component is:¹H NMR(400MHz,Methanol-d₄)δ7.73–7.51(m,3H),7.48(dd,J＝8.0,1.2Hz,1H),7.37–7.29(m,3H),7.25(td,J＝7.6,1.6Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.62-4.60(m,0.5H),4.45-4.44(m,0.5H),4.33-4.29(m,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.79–3.70(m,2H),3.46(s,3H),2.99-2.92(m,1H),2.62–2.50(m,1H),1.99–1.69(m,6H),1.36–1.20(m,1H),1.12(s,3H),0.93-0.85(m,1H),0.78-0.74(m,1H),0.07–-0.04(m,1H),-0.11--0.14(m,1H).

EXAMPLE 101 preparation of Compounds 101-a,101-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 23 of example 23 to give compound 101-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 101-a. MS m/z: 706(M +1)⁺Nuclear magnetism of compound 101-b is:¹H NMR(400MHz,Methanol-d₄)δ7.65(s,1H),7.63–7.55(m,2H),7.50–7.45(m,1H),7.37–7.30(m,3H),7.28–7.21(m,1H),6.37–6.28(m,1H),6.02(d,J＝11.9Hz,1H),4.79–4.67(m,1H),4.61(s,0H),4.48–4.40(m,1H),4.05(d,J＝9.6Hz,1H),3.86(s,3H),3.80–3.70(m,2H),3.46(s,3H),3.26–3.13(m,2H),2.34(ddq,J＝23.3,11.8,6.0Hz,2H),2.13–1.99(m,2H),1.99–1.84(m,1H),1.62(s,3H),1.15–1.07(m,6H),0.82–0.71(m,1H),0.06–-0.03(m,1H),-0.07–-0.17(m,2H).

EXAMPLE 102 preparation of Compounds 102-a,102-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 24 of example 24 to give compound 102-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 102-a. MS m/z: 724(M +1) ⁺The nuclear magnetization of compound 102-b is:¹H NMR(400MHz,Methanol-d₄)δ7.67–7.53(m,4H),7.45(dd,J＝8.0,1.2Hz,1H),7.33–7.26(m,3H),7.23(td,J＝7.6,1.6Hz,1H),6.31(d,J＝2.0Hz,1H),5.99(d,J＝12.0Hz,1H),4.48(t,J＝7.6Hz,1H),4.06(d,J＝9.6Hz,1H),3.84(s,3H),3.76-3.71(m,2H),3.44(s,3H),3.24–3.11(m,2H),2.64–2.25(m,6H),1.61(s,3H),1.11-1.06(m,6H),0.81–0.71(m,1H),0.02--0.03(m,1H),-0.09–-0.21(m,2H).

EXAMPLE 103 preparation of Compounds 103-a,103-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 25 of example 25 to give compound 103-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 103-a. MS m/z: 702(M +1)⁺The compound 103-b is then separated by SFC to give two groupsPeak separation (cis-trans structure of 3-methylcyclobutyl), nuclear magnetism of one of components 103-b 1:¹H NMR(400MHz,Methanol-d₄) δ 7.74-7.52(m,3H),7.46(d, J ═ 8.0Hz,1H),7.37-7.28(m,3H),7.25(t, J ═ 7.6Hz,1H),6.33(d, J ═ 2.0Hz,1H),6.01(d, J ═ 12.0Hz,1H),4.31(d,5.6Hz,1H),4.05(d, J ═ 9.6Hz,1H),3.76(dd, J ═ 12.0Hz,4.0Hz,2H),3.46(s,3H),3.28-3.09(m,2H),2.41-2.34(m, 1H),2.24-1.95(m,3H),1.60(s3H),1.47-1.39(m, 1.81H), 1.31 (m,1H), 1.3H, 1H, 15- (m-3.0H), 15, 3.3.3H, 1H, 15- (d, 3H), 3H, 1H, 3H, 1, 3H, 3; the nuclear magnetism of the second component 103-b2 is: ¹H NMR(400MHz,Methanol-d₄)δ7.72-7.52(m,3H),7.51-7.45(m,1H),7.36-7.29(m,3H),7.28-7.21(m,1H),6.34(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.44-4.40(m,1H),4.05(d,J＝9.6Hz,1H),3.87(s,3H),3.77-3.73(m,2H),3.45(s,3H),3.25-3.11(m,2H),2.65-2.52(m,1H),2.34-2.21(m,1H),2.10-2.04(m,1H),1.96-1.89(m,1H),1.68-1.52(m,5H),1.15-1.04(m,9H),0.83-0.70(m,1H),0.06--0.03(m,1H),-0.08--0.18(m,2H).

EXAMPLE 104 preparation of Compounds 104-a,104-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 26 of example 26 to give compound 104-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 104-a. MS m/z: 718(M +1)⁺The compound 104-b is then separated by SFC to obtain two component peaks (which are cis-trans structures of 3-methoxycyclobutyl), one of the components 104-b 1; component two 104-b 2.

EXAMPLE 105 preparation of Compounds 105-a,105-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 27 of example 27 to give compound 105-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 105-a. MS m/z: 702(M +1) ⁺The nuclear magnetization of 105-b is:¹H NMR(400MHz,Methanol-d₄)δ7.72(s,1H),7.69–7.60(m,2H),7.60–7.52(m,3H),7.52–7.43(m,3H),7.33(dd,J＝8.8,4.2Hz,8H),7.29–7.16(m,2H),6.34(s,3H),6.01(d,J＝11.9Hz,3H),4.48–4.32(m,3H),4.04(d,J＝9.7Hz,3H),3.87(s,8H),3.82–3.68(m,5H),3.54–3.49(m,1H),3.17–3.13(m,1H),2.28–2.17(m,3H),2.14–2.02(m,3H),1.97–1.86(m,2H),1.82–1.67(m,3H),1.55(s,4H),1.17–1.02(m,25H),0.81–0.69(m,2H),0.06–-0.04(m,3H),-0.07–-0.22(m,6H).

EXAMPLE 106 preparation of Compound 106-a,106-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 28 of example 28 to give compound 106-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 106-a.MS m/z：706(M+1)⁺.

EXAMPLE 107 preparation of compound 107-a,107-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 29 of example 29 to give compound 107-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 107-a. MS m/z: 720(M +1) ⁺.

EXAMPLE 108 preparation of Compounds 108-a,108-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 30 of example 30 to give compound 108-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 108-a. MS m/z: 714(M +1)⁺.

EXAMPLE 109 preparation of Compounds 109-a,109-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 31 of example 31 to give compound 109-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 109-a. MS m/z: 700(M +1) ⁺The nuclear magnetization of compound 109-b is: 1H NMR (400MHz, Methanol-d4) δ 7.68(s,1H), 7.65-7.54 (m,2H),7.48(dd, J ═ 7.9,1.4Hz,1H), 7.39-7.29 (m,3H),7.25(td, J ═ 7.6,1.6Hz,1H),6.34(d, J ═ 2.2Hz,1H),6.02(d, J ═ 11.9Hz,1H),4.42(t, J ═ 2.6Hz,1H),4.01(d, J ═ 9.7Hz,1H),3.87(s,3H),3.76(t,2H),3.47(s,3H), 3.29-3.11 (m,2H),2.44(s,1H), 1.63-1H, 1.81 (s,1H), 0.06 (m, 0.08), 0.7H, 1H, 0.06 (m), 0.06 (m, 0.08), 0.7H, 1H, 0, 1H, 0H, 0, 1H, 0, 1.

EXAMPLE 110 preparation of Compounds 110-a,110-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl group, hydrolyzed, and finally condensed with intermediate 32 of example 32 to give compound 110-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 110-a. MS m/z: 714(M +1)⁺The nuclear magnetization of compound 110-b is:¹H NMR(400MHz,Methanol-d₄)δ7.78–7.51(m,3H),7.48(dd,J＝8.0,1.4Hz,1H),7.41(d,J＝7.7Hz,1H),7.38–7.29(m,3H),7.25(td,J＝7.7,1.6Hz,1H),6.34(d,J＝2.1Hz,1H),6.02(d,J＝12.0Hz,1H),4.43(d,1H),4.01(d,J＝9.7Hz,1H),3.87(s,3H),3.76(t,2H),3.47(s,3H),3.30–3.10(m,2H),1.59(s,3H),1.55–1.45(m,6H),1.17–1.07(m,9H),0.81–0.72(m,1H),0.05–-0.03(m,1H),-0.13(ddd,J＝8.8,6.1,2.1Hz,2H).

EXAMPLE 111 preparation of Compound 111-a,111-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 33 of example 33 to give compound 111-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation to obtain compound 111-a. MS m/z: 718(M +1) +. nuclear magnetism of compound 111-b:¹H NMR(400MHz,Methanol-d₄)δ8.16(s,1H),7.68(s,1H),7.65–7.60(m,1H),7.60–7.55(m,2H),7.50–7.45(m,1H),7.38–7.30(m,3H),7.29–7.22(m,1H),6.40–6.26(m,1H),6.02(d,J＝11.6Hz,1H),4.74(d,J＝7.7Hz,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.81–3.71(m,2H),3.47(s,3H),3.29–3.10(m,2H),1.97–1.85(m,6H),1.60(s,3H),1.17–1.09(m,6H),0.82–0.73(m,1H),0.07–-0.03(m,1H),-0.12(t,J＝7.5Hz,2H).

EXAMPLE 112 preparation of the Compounds 112-a,112-b,112-c,112-d,112-e,112-f,112-g,112-h

Referring to the method of steps 1-6 of example 34, the intermediates 4-5 of step 5 of example 4 and the step 66-6b of example 6 (SFC chiral resolution preparation yields a single configuration) are condensed, ring-closed, deprotected, and 1-methyl-1H-substitutedPyrazole-5-acyl, hydrolysis, final condensation with intermediate 9 of example 9, and SFC chiral resolution to obtain compounds 112-a,112-b,112-c, 112-d. Similarly, compounds 112-e,112-f,112-g,112-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 680(M +1) ⁺。

EXAMPLE 113 preparation of the compounds 113-a,113-b,113-c,113-d,113-e,113-f,113-g,113-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 113-a,113-b,113-c and 113-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 113-e,113-f,113-g and 113-H. MS m/z: 694(M +1)⁺. 113-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,MeOD):δ＝7.97(t,J＝4.4Hz,1H),7.58(s,1H),7.53(d,J＝8.4Hz,1H),7.46(d,J＝8.0Hz,1H),7.41(d,J＝2.0Hz,1H),7.30-7.24(m,2H),7.21(d,J＝7.2Hz,1H),7.16-7.11(m,1H),6.56(d,J＝2.4Hz,1H),6.11(d,J＝8.8Hz,1H),4.36(t,J＝8.8Hz,1H),4.17(t,J＝8.4Hz,1H),4.00(t,J＝9.6Hz,1H),3.97(s,3H),3.73(d,J＝9.6Hz,1H),3.43(s,3H),3.25-3.13(m,2H),2.61-2.55(m,1H),2.30-2.25(m,1H),1.96-1.74(m,6H),1.58(s,3H),1.10(t,J＝7.2Hz,3H),0.94(d,J＝6.4Hz,3H),0.84(dd,d1＝1.6Hz,d2＝6.8Hz,1H).

EXAMPLE 114 preparation of compounds 114-a,114-b,114-c,114-d,114-e,114-f,114-g,114-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 10 of example 10, and SFC chiral resolution to obtain compounds 114-a,114-b,114-c and 114-d. Similarly, compounds 114-e,114-f,114-g,114-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 706(M +1) ⁺。

EXAMPLE 115 preparation of the Compounds 115-a,115-b,115-c,115-d,115-e,115-f,115-g,115-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 11 of example 11, and SFC chiral resolution to obtain compounds 115-a,115-b,115-c, 115-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 115-e,115-f,115-g and 115-H. MS m/z: 720(M +1)⁺。

EXAMPLE 116 preparation of the Compounds 116-a,116-b,116-c,116-d,116-e,116-f,116-g,116-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 12 of example 12, and SFC chiral resolution to obtain compounds 116-a,116-b,116-c, 116-d. Similarly, compounds 116-e,116-f,116-g,116-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 736(M +1) ⁺。

EXAMPLE 117 preparation of the Compounds 117-a,117-b,117-c,117-d,117-e,117-f,117-g,117-h

Referring to the methods of example 34, steps 1-6, intermediate 4-5 of step 5 in example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl group was introduced, hydrolyzed, finally condensed with intermediate 13 of example 13, and then SFC chiral resolution was performed to obtain compounds 117-a,117-b,117-c, 117-d. Similarly, compounds 117-e,117-f,117-g,117-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 750(M +1)⁺。

EXAMPLE 118 preparation of the Compounds 118-a,118-b,118-c,118-d,118-e,118-f,118-g,118-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 14 of example 14, and SFC chiral resolution to obtain compounds 118-a,118-b,118-c, 118-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 118-e,118-f,118-g and 118-H. MS m/z: 738(M +1) ⁺。

EXAMPLE 119 preparation of the Compounds 119-a,119-b,119-c,119-d,119-e,119-f,119-g,119-h

Referring to the methods of example 34, steps 1-6, intermediate 4-5 of step 5 in example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, finally condensed with intermediate 15 of example 15, and then SFC chiral resolution was performed to obtain compounds 119-a,119-b,119-c, 119-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 119-e,119-f,119-g and 119-H. MS m/z: 730(M +1)⁺。

EXAMPLE 120 preparation of the Compounds 120-a,120-b,120-c,120-d,120-e,120-f,120-g,120-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 16 of example 16, and SFC chiral resolution to obtain compounds 120-a,120-b,120-c, 120-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 120-e,120-f,120-g and 120-H. MS m/z: 712(M +1) ⁺。

EXAMPLE 121 preparation of Compounds 121-a,121-b,121-c,121-d,121-e,121-f,121-g,121-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 17 of example 17, and SFC chiral resolution to obtain compounds 121-a,121-b,121-c, 121-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 121-e,121-f,121-g and 121-H. MS m/z: 708(M +1)⁺。

EXAMPLE 122 preparation of compound 122-a,122-b,122-c,122-d,122-e,122-f,122-g,122-h

Reference is made to the process of example 34, Steps 1 to 64, the intermediate 4-5 of step 5 and 66-6b (a single configuration is obtained by SFC chiral resolution preparation) of example 6 are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with the intermediate 18 of example 18, and then SFC chiral resolution to prepare the compounds 122-a,122-b,122-c and 122-d. Similarly, compounds 122-e,122-f,122-g, and 122-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 710(M +1) ⁺。

EXAMPLE 123 preparation of the Compounds 123-a,123-b,123-c,123-d,123-e,123-f,123-g,123-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 19 of example 19, and SFC chiral resolution to obtain compounds 123-a,123-b,123-c, 123-d. Similarly, compounds 123-e,123-f,123-g and 123-H are prepared by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution of intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is prepared by SFC chiral resolution). MS m/z: 724(M +1)⁺。

EXAMPLE 124 preparation of compounds 124-a,124-b,124-c,124-d,124-e,124-f,124-g,124-h

With reference to the procedures of steps 1 to 6 of example 34, intermediates 4 to 5 of step 5 of example 4 and steps 66 to 6b of example 6 (preparation by SFC chiral resolution) were usedTo obtain a single configuration), condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with the intermediate 20 of example 20, and SFC chiral resolution to obtain the compounds 124-a,124-b,124-c, 124-d. Similarly, compounds 124-e,124-f,124-g,124-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 722(M +1) ⁺。

EXAMPLE 125 preparation of Compounds 125-a,125-b,125-c,125-d,125-e,125-f,125-g,125-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 21 of example 21, and SFC chiral resolution to obtain compounds 125-a,125-b,125-c and 125-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 125-e,125-f,125-g and 125-H. MS m/z: 724(M +1)⁺。

EXAMPLE 126 preparation of the Compounds 126-a,126-b,126-c,126-d,126-e,126-f,126-g,126-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, and 1-methyl group was introduced-1H-pyrazole-5-acyl, hydrolyzed, finally condensed with intermediate 22 of example 22, and then subjected to SFC chiral resolution to obtain compounds 126-a,126-b,126-c, 126-d. Similarly, compounds 126-e,126-f,126-g,126-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 724(M +1) ⁺。

EXAMPLE 127 preparation of the compounds 127-a,127-b,127-c,127-d,127-e,127-f,127-g,127-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 23 of example 23, and SFC chiral resolution to obtain compounds 127-a,127-b,127-c and 127-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to obtain the compounds 127-e,127-f,127-g and 127-H. MS m/z: 712(M +1)⁺。

EXAMPLE 128 preparation of the Compounds 128-a,128-b,128-c,128-d,128-e,128-f,128-g,128-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 24 of example 24, Then the compounds 128-a,128-b,128-c and 128-d are prepared by SFC chiral resolution. Similarly, compounds 128-e,128-f,128-g and 128-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution. MS m/z: 730(M +1)⁺。

EXAMPLE 129 preparation of the Compounds 129-a,129-b,129-c,129-d,129-e,129-f,129-g,129-h

Referring to the procedures of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl group was introduced, hydrolyzed, finally condensed with intermediate 25 of example 25, and then subjected to SFC chiral resolution to obtain compounds 129-a,129-b,129-c, 129-d. Similarly, compounds 129-e,129-f,129-g,129-H were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 708(M +1) ⁺。

EXAMPLE 130 preparation of Compounds 130-a,130-b,130-c,130-d,130-e,130-f,130-g,130-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 26 of example 26, and SFC chiral resolution to obtain compounds 130-a,130-b,130-c, 130-d. Class ISimilarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 130-e,130-f,130-g and 130-H. MS m/z: 724(M +1)⁺。

EXAMPLE 131 preparation of Compounds 131-a,131-b,131-c,131-d,131-e,131-f,131-g,131-h

Referring to the procedures of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl group was introduced, hydrolyzed, finally condensed with intermediate 27 of example 27, and then subjected to SFC chiral resolution to obtain compounds 131-a,131-b,131-c, 131-d. Similarly, compounds 131-e,131-f,131-g and 131-H can be prepared by condensing, ring-closing, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution of intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution). MS m/z: 708(M +1) ⁺。

EXAMPLE 132 preparation of the compound 132-a,132-b,132-c,132-d,132-e,132-f,132-g,132-h

Referring to the methods of example 34, steps 1-6, intermediate 4-5 of step 5 in example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, finally condensed with intermediate 28 of example 28, and then SFC chiral resolution was performed to obtain compounds 132-a,132-b,132-c, 132-d. Similarly, intermediates 4 to 5 of step 5 in example 4 and step 6 in example 6 were usedCondensing 6-6a (a single configuration is obtained by SFC chiral resolution preparation), closing a ring, deprotecting, introducing 1-methyl-1H-pyrazole-5-acyl, hydrolyzing, condensing, and then preparing the compounds 132-e,132-f,132-g and 132-H by SFC chiral resolution. MS m/z: 712(M +1)⁺。

EXAMPLE 133 preparation of Compounds 133-a,133-b,133-c,133-d,133-e,133-f,133-g,133-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 29 of example 29, and SFC chiral resolution to obtain compounds 133-a,133-b,133-c, 133-d. Similarly, intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare compounds 133-e,133-f,133-g and 133-H. MS m/z: 726(M +1) ⁺。

EXAMPLE 134 preparation of the Compounds 134-a,134-b,134-c,134-d,134-e,134-f,134-g,134-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 30 of example 30, and SFC chiral resolution to obtain compounds 134-a,134-b,134-c and 134-d. Similarly, intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed, ring-closed,deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution to obtain compounds 134-e,134-f,134-g and 134-H. MS m/z: 720(M +1)⁺。

EXAMPLE 135 preparation of the Compounds 135-a,135-b,135-c,135-d,135-e,135-f,135-g,135-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 31 of example 31, and SFC chiral resolution to obtain compounds 135-a,135-b,135-c, 135-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 135-e,135-f,135-g and 135-H. MS m/z: 706(M +1) ⁺。

EXAMPLE 136 preparation of compounds 136-a,136-b,136-c,136-d,136-e,136-f,136-g,136-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 32 of example 32, and SFC chiral resolution to obtain compounds 136-a,136-b,136-c and 136-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then subjected to condensationThe compound 136-e,136-f,136-g and 136-h is prepared by SFC chiral resolution. MS m/z: 720(M +1)⁺。

EXAMPLE 137 preparation of compounds 137-a,137-b,137-c,137-d,137-e,137-f,137-g,137-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 33 of example 33, and SFC chiral resolution to obtain compounds 137-a,137-b,137-c and 137-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 137-e,137-f,137-g and 137-H. MS m/z: 724(M +1) ⁺。

EXAMPLE 138 preparation of the Compounds 138-a,138-b,138-c,138-d,138-e,138-f,138-g,138-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with intermediate 9 of example 9, and SFC chiral resolution to obtain compounds 138-a,138-b,138-c, 138-d. Similarly, the intermediate 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 138-e,138-f,138-g and 138-H. MS m/z: 680(M+1)⁺。

EXAMPLE 139 preparation of Compounds 139-a,139-b,139-c,139-d,139-e,139-f,139-g,139-h

Referring to the methods of steps 1-6 of example 34, the intermediates 5-5 of step 5 of example 5 and the intermediates 66-6b of step 66-6b of example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl introduced, hydrolyzed, finally condensed with the intermediate 7-2 of example 7, and then subjected to SFC chiral resolution to obtain the compounds 139-a,139-b,139-c, 139-d. Similarly, compounds 139-e,139-f,139-g,139-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 680(M +1) ⁺。

EXAMPLE 140 preparation of Compounds 140-a,140-b,140-c,140-d,140-e,140-f,140-g,140-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 10 of example 10, and SFC chiral resolution to obtain compounds 140-a,140-b,140-c and 140-d. Similarly, compounds 140-e,140-f,140-g and 140-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution. MS m/z: 706(M +1)⁺。

EXAMPLE 141 preparation of the Compound 141-a,141-b,141-c,141-d,141-e,141-f,141-g,141-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 11 of example 11, and SFC chiral resolution to obtain compounds 141-a,141-b,141-c, 141-d. Similarly, the intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 141-e,141-f,141-g and 141-H. MS m/z: 720(M +1) ⁺。

EXAMPLE 142 preparation of the Compounds 142-a,142-b,142-c,142-d,142-e,142-f,142-g,142-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 12 of example 12, and SFC chiral resolution to obtain compounds 142-a,142-b,142-c and 142-d. Similarly, the intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 142-e,142-f,142-g and 142-H. MS m/z: 736(M +1)⁺。

EXAMPLE 143 preparation of the compound 143-a,143-b,143-c,143-d,143-e,143-f,143-g,143-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 13 of example 13, and SFC chiral resolution to obtain compounds 143-a,143-b,143-c, 143-d. Similarly, the intermediate 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 143-e,143-f,143-g and 143-H. MS m/z: 750(M +1) ⁺。

EXAMPLE 144 preparation of compounds 144-a,144-b,144-c,144-d,144-e,144-f,144-g,144-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 14 of example 14, and SFC chiral resolution to obtain compounds 144-a,144-b,144-c and 144-d. Similarly, compounds 144-e,144-f,144-g,144-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 738(M +1)⁺。

EXAMPLE 145 preparation of Compounds 145-a,145-b,145-c,145-d,145-e,145-f,145-g,145-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with intermediate 15 of example 15, and SFC chiral resolution to obtain compounds 145-a,145-b,145-c and 145-d. Similarly, the intermediate 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 145-e,145-f,145-g and 145-H. MS m/z: 730(M +1) ⁺。

EXAMPLE 146 preparation of Compounds 146-a,146-b,146-c,146-d,146-e,146-f,146-g,146-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 16 of example 16, and SFC chiral resolution to obtain compounds 146-a,146-b,146-c and 146-d. Similarly, the intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 146-e,146-f,146-g and 146-H. MS m/z: 712(M +1)⁺。

EXAMPLE 147 preparation of Compounds 147-a,147-b,147-c,147-d,147-e,147-f,147-g,147-h

Referring to the method of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with intermediate 17 of example 17, and SFC chiral resolution to obtain compounds 147-a,147-b,147-c and 147-d. Similarly, the intermediate 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 147-e,147-f,147-g and 147-H. MS m/z: 708(M +1) ⁺。

EXAMPLE 148 preparation of Compounds 148-a,148-b,148-c,148-d,148-e,148-f,148-g,148-h

Referring to the procedures of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl group was introduced, hydrolyzed, finally condensed with intermediate 18 of example 18, and then subjected to SFC chiral resolution to obtain compounds 148-a,148-b,148-c, 148-d. Similarly, compounds 148-e,148-f,148-g,148-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 710(M +1)⁺。

EXAMPLE 149 preparation of Compounds 149-a,149-b,149-c,149-d,149-e,149-f,149-g,149-h

Referring to the procedures of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl introduced, hydrolyzed, finally condensed with intermediate 19 of example 19, and then subjected to SFC chiral resolution to obtain compounds 149-a,149-b,149-c, 149-d. Similarly, compounds 149-e,149-f,149-g,149-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 724(M +1) ⁺。

EXAMPLE 150 preparation of Compounds 150-a,150-b,150-c,150-d,150-e,150-f,150-g,150-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 20 of example 20, and SFC chiral resolution to obtain compounds 150-a,150-b,150-c, 150-d. Similarly, the intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 150-e,150-f,150-g and 150-H. MS m/z: 722(M +1)⁺。

EXAMPLE 151 preparation of Compounds 151-a,151-b,151-c,151-d,151-e,151-f,151-g,151-h

Reference is made to the process of example 34, Steps 1 to 6The intermediate 5-5 of step 5 in example 5 and step 66-6b (a single configuration is obtained by SFC chiral resolution preparation) in example 6 are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with the intermediate 21 of example 21, and SFC chiral resolution to prepare compounds 151-a,151-b,151-c, 151-d. Similarly, compounds 151-e,151-f,151-g,151-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 724(M +1) ⁺。

EXAMPLE 152 preparation of Compounds 152-a,152-b,152-c,152-d,152-e,152-f,152-g,152-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 22 of example 22, and SFC chiral resolution to obtain compounds 152-a,152-b,152-c, 152-d. Similarly, compounds 152-e,152-f,152-g and 152-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution. MS m/z: 724(M +1)⁺。

EXAMPLE 153 preparation of Compounds 153-a,153-b,153-c,153-d,153-e,153-f,153-g,153-h

With reference to the procedures of steps 1 to 6 of example 34, intermediates 5 to 5 of step 5 of example 5 and steps 66 to 6b of example 6 (preparation by SFC chiral resolution) were usedTo obtain a single configuration), condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with the intermediate 23 of example 23, and SFC chiral resolution to obtain the compounds 153-a,153-b,153-c, 153-d. Similarly, compounds 153-e,153-f,153-g,153-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 712(M +1) ⁺。

EXAMPLE 154 preparation of Compounds 154-a,154-b,154-c,154-d,154-e,154-f,154-g,154-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, finally condensed with intermediate 24 of example 24, and then subjected to SFC chiral resolution to obtain compounds 154-a,154-b,154-c, 154-d. Similarly, compounds 154-e,154-f,154-g,154-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 730(M +1)⁺。

EXAMPLE 155 preparation of Compounds 155-a,155-b,155-c,155-d,155-e,155-f,155-g,155-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, and 1-methyl group was introduced-1H-pyrazole-5-acyl, hydrolyzed, finally condensed with the intermediate 25 of example 25, and then subjected to SFC chiral resolution to prepare the compound 155-a,155-b,155-c, 155-d. Similarly, compounds 155-e,155-f,155-g,155-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 708(M +1) ⁺。

EXAMPLE 156 preparation of the Compound 156-a,156-b,156-c,156-d,156-e,156-f,156-g,156-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, finally condensed with intermediate 26 of example 26, and then subjected to SFC chiral resolution to obtain compounds 156-a,156-b,156-c, 156-d. Similarly, compounds 156-e,156-f,156-g,156-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 724(M +1)⁺。

EXAMPLE 157 preparation of the compound 157-a,157-b,157-c,157-d,157-e,157-f,157-g,157-h

Referring to the procedures of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 27 of example 27, Then compounds 157-a,157-b,157-c and 157-d are prepared by SFC chiral resolution. Similarly, compounds 157-e,157-f,157-g,157-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 708(M +1)⁺。

EXAMPLE 158 preparation of Compounds 158-a,158-b,158-c,158-d,158-e,158-f,158-g,158-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 28 of example 28, and SFC chiral resolution to obtain compounds 158-a,158-b,158-c, 158-d. Similarly, compounds 158-e,158-f,158-g and 158-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution. MS m/z: 712(M +1) ⁺。

EXAMPLE 159 preparation of Compounds 159-a,159-b,159-c,159-d,159-e,159-f,159-g,159-h

Referring to the procedures of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl introduced, hydrolyzed, finally condensed with intermediate 29 of example 29, and then subjected to SFC chiral resolution to give compounds 159-a,159-b,159-c, 159-d. Class ISimilarly, compounds 159-e,159-f,159-g,159-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation and SFC chiral resolution. MS m/z: 726(M +1)⁺。

EXAMPLE 160 preparation of Compounds 160-a,160-b,160-c,160-d,160-e,160-f,160-g,160-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 30 of example 30, and SFC chiral resolution to obtain compounds 160-a,160-b,160-c, 160-d. Similarly, compounds 160-e,160-f,160-g,160-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 720(M +1) ⁺。

EXAMPLE 161 preparation of Compounds 161-a,161-b,161-c,161-d,161-e,161-f,161-g,161-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 31 of example 31, and SFC chiral resolution to obtain compounds 161-a,161-b,161-c, 161-d. Similarly, intermediates 5 to 5 of step 5 in example 5 and step 6 in example 6 were usedCondensing 6-6a (a single configuration is obtained by SFC chiral resolution preparation), closing a ring, deprotecting, introducing 1-methyl-1H-pyrazole-5-acyl, hydrolyzing, condensing, and then preparing the compounds 161-e,161-f,161-g and 161-H by SFC chiral resolution. MS m/z: 706(M +1)⁺。

EXAMPLE 162 preparation of the Compound 162-a,162-b,162-c,162-d,162-e,162-f,162-g,162-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 32 of example 32, and SFC chiral resolution to obtain compounds 162-a,162-b,162-c, 162-d. Similarly, compounds 162-e,162-f,162-g,162-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 720(M +1) ⁺。

EXAMPLE 163 preparation of compounds 163-a,163-b,163-c,163-d,163-e,163-f,163-g,163-h

Referring to the procedures of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl introduced, hydrolyzed, finally condensed with intermediate 33 of example 33, and then subjected to SFC chiral resolution to obtain compounds 163-a,163-b,163-c, 163-d. Similarly, intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed, ring-closed,deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution to obtain compounds 163-e,163-f,163-g, and 163-H. MS m/z: 724(M +1)⁺。

EXAMPLE 164 preparation of Compounds 164-a,164-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-ethyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 164-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, 1-ethyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, and condensed to obtain compound 164-a. MS m/z: 702(M +1) ⁺. 164b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.66(s,1H),7.61–7.58(m,2H),7.48–7.45(m,2H),7.35–7.31(m,3H),7.24(td,J＝8.0,1.6Hz,1H),6.34(d,J＝2.0Hz,1H),6.02(d,J＝12.0Hz,1H),4.40–4.24(m,3H),4.04(d,J＝9.6Hz,1H),3.78-3.74(m,2H),3.45(s,3H),3.25-3.15(m,2H),2.61–2.56(m,1H),1.99–1.75(m,7H),1.61(s,3H),1.34–1.27(m,2H),1.18(t,J＝7.2Hz,3H),1.13-1.08(m,7H),0.78-0.74(m,1H),-0.01--0.02(m,1H),-0.11--0.16(m,2H).

EXAMPLE 165 preparation of Compounds 165-a,165-b

Referring to the procedures of steps 1-6 of example 34, intermediate 3-3b of step 3 of example 3 and step 66-6b of example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed, ring-closed, deprotected, propionyl group introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 165-b.Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, propionyl group introduced, hydrolyzed, and condensed to give compound 165-a. MS m/z: 636(M +1)⁺. 165b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ8.01–7.91(m,1H),7.67–7.24(m,8H),5.86(d,J＝12.0Hz,1H),4.38(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.66(d,J＝12.0Hz,1H),3.46(s,3H),3.26–3.14(m,2H),2.66–2.53(m,1H),2.01–1.72(m,8H),1.61(s,3H),1.47–1.19(m,3H),1.16–1.02(m,6H),0.99–0.84(m,1H),0.78(t,J＝7.6Hz,4H),0.01–-0.04(m,1H),-0.13–-0.20(m,2H).

EXAMPLE 166 preparation of Compounds 166-a,166-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) in example 6 were condensed, ring-closed, deprotected, isobutyryl group introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to yield compound 166-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, isobutyryl group introduced, hydrolyzed, and condensed to give compound 166-a. MS m/z: 650(M +1) ⁺. 166-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.95(s,0H),7.69–7.22(m,8H),5.87(d,J＝12.0Hz,1H),4.43–4.33(m,1H),4.04(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.64(d,J＝12.0Hz,1H),3.46(s,3H),3.26–3.14(m,2H),2.69–2.50(m,1H),2.23–2.13(m,1H),2.00–1.71(m,6H),1.61(s,3H),1.18–1.03(m,6H),0.83(d,J＝6.8Hz,3H),0.79–0.71(m,1H),0.66(d,J＝6.9Hz,3H),0.01–-0.06(m,1H),-0.12–-0.22(m,2H).

EXAMPLE 167 preparation of Compounds 167-a,167-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation gave a single configuration) in example 6 were condensed, ring-closed, deprotected, N-pyrrolidinylcarbonyl introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 167-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis and condensation to obtain compound 167-a. MS m/z: 677(M +1)⁺. 167-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.99(s,1H),7.71–7.61(m,2H),7.61–7.47(m,3H),7.45–7.26(m,3H),5.68(d,J＝11.6Hz,1H),4.38(t,J＝8.3Hz,1H),4.03(d,J＝9.6Hz,1H),3.77(d,J＝9.6Hz,1H),3.60(d,J＝11.6Hz,1H),3.46(s,3H),3.29–3.15(m,1H),2.96(s,2H),2.65–2.55(m,1H),1.98–1.82(m,3H),1.78(d,J＝6.6Hz,8H),1.61(s,3H),1.31(s,1H),1.16–1.07(m,6H),0.77–0.68(m,1H),0.12(s,2H),-0.06–-0.24(m,2H).

EXAMPLE 168 preparation of Compounds 168-a,168-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-dimethylcarbonyl was introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 168-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N, N-dimethyl carbonyl, hydrolysis and condensation to obtain compound 168-a. MS m/z: 651(M +1) ⁺. 168-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.95(s,1H),7.72–7.17(m,8H),5.66(d,J＝11.7Hz,1H),4.38(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.65–3.54(m,1H),3.52–3.49(m,0H),3.46(s,3H),3.27–3.13(m,2H),2.66(s,6H),2.60(q,J＝7.9Hz,1H),2.01–1.73(m,6H),1.61(s,3H),1.31(s,1H),1.16–1.05(m,6H),0.91(d,J＝7.8Hz,1H),0.70(d,J＝7.0Hz,1H),0.00–-0.05(m,1H),-0.13–-0.22(m,2H).

EXAMPLE 169 preparation of Compounds 169-a,169-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) in example 6 were condensed, ring-closed, deprotected, methylamine carbonyl was introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to yield compound 169-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution preparation) were condensed, ring-closed, deprotected, methylamine carbonyl introduced, hydrolyzed, and condensed to give compound 169-a. MS m/z: 637(M +1)⁺. 169-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.62(d,J＝1.7Hz,1H),7.59–7.52(m,2H),7.50–7.42(m,2H),7.36(td,J＝7.6,1.4Hz,1H),7.31–7.22(m,2H),5.62(d,J＝11.7Hz,1H),4.37(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.75(d,J＝9.6Hz,1H),3.55–3.48(m,1H),3.46(s,3H),3.25–3.13(m,2H),2.59(q,J＝7.9Hz,1H),2.51(s,3H),2.00–1.72(m,6H),1.60(s,3H),1.14–1.04(m,7H),0.75(dt,J＝10.0,5.3Hz,1H),-0.01–-0.08(m,1H),-0.16–-0.25(m,2H).

EXAMPLE 170 preparation of Compounds 170-a,170-b

Referring to the procedures of steps 1 to 6 of example 34, intermediates 3 to 3b of step 3 of example 3 and the procedure of example 6 were usedStep 66-6b (SFC chiral resolution preparation gave a single configuration) was condensed, ring closed, deprotected, N-methyl-N' -ethylcarbonyl introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 170-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, N-methyl-N' -ethylcarbonyl is introduced, hydrolyzed, and condensed to obtain compound 170-a. MS m/z: 665(M +1) ⁺，¹H NMR(400MHz,Methanol-d₄)δ7.63(s,1H),7.56(t,2H),7.47(t,2H),7.39–7.22(m,3H),5.68(d,J＝11.8Hz,1H),4.38(t,J＝8.3Hz,1H),4.05(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.57(d,J＝11.7Hz,1H),3.46(s,3H),3.27–2.98(m,6H),2.63(s,3H),1.99–1.73(m,6H),1.61(s,3H),1.12(t,6H),1.09(s,1H),0.78(t,J＝7.1Hz,3H),0.73–0.65(m,1H),0.01–-0.06(m,1H),-0.14–-0.26(m,2H).

EXAMPLE 171 preparation of Compounds 171-a,171-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) in example 6 were condensed, ring-closed, deprotected, N-ethylcarbonyl was introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to yield compound 171-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-ethylcarbonyl introduced, hydrolyzed, and condensed to give compound 171-a. MS m/z: 651(M +1)⁺. 171-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.62(s,1H),7.57–7.54(m,2H),7.48-7.43(m,2H),7.36(t,J＝7.2Hz,1H),7.27(t,J＝8.4Hz,2H),5.63(d,J＝11.6Hz,1H),4.38(t,J＝7.6Hz,1H),4.04(d,J＝9.6Hz,1H),3.75(d,J＝9.6Hz,1H),3.52(d,J＝11.6Hz,1H),3.45(s,3H),3.24-3.15(m,2H),2.95(dd,J＝6.8,4.0Hz,2H),2.59(d,J＝7.6Hz,1H),2.95–1.76(m,6H),1.60(s,3H),1.13–1.08(m,6H),0.91(t,J＝7.2Hz,3H),0.73–0.68(m,1H),0.01--0.06(m,1H),-0.17–-0.26(m,2H).

EXAMPLE 172 preparation of Compound 172-a,172-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b of example 6 (a single configuration was obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-diethylcarbonyl was introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 172-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, N-diethylcarbonyl is introduced, hydrolyzed and condensed to obtain compound 172-a. MS m/z: 679(M +1) ⁺. 172-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.63(s,1H),7.57(t,J＝8.4Hz,2H),7.49-7.45(m,2H),7.37-7.24(m,3H),5.71(d,J＝12.0Hz,1H),4.38(t,J＝8.4Hz,1H),4.05(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.57(d,J＝11.6Hz,1H),3.46(s,3H),3.23–3.13(m,4H),3.02-2.93(m,2H),2.63-2.55(m,1H),1.98–1.75(m,6H),1.61(s,3H),1.39(d,J＝5.2Hz,1H),1.12–1.09(m,6H),0.80(t,J＝7.2Hz,6H),0.73–0.68(m,1H),0.01–-0.06(m,1H),-0.17–-0.26(m,2H).

EXAMPLE 173 preparation of Compounds 173-a,173-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (a single configuration was obtained by SFC chiral resolution) in example 6 were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl was introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 173-b. Similarly, as intermediates 3-3b of step 3 in example 3 and in example 66-6a (another single configuration obtained by SFC chiral resolution preparation) in the step 6 is subjected to condensation, ring closing and deprotection, N-methyl-N' -cyclopropyl carbonyl is introduced, and the compound 173-a is obtained through hydrolysis and condensation. MS m/z: 679(M +1)⁺. 173-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.66–7.49(m,2H),7.46(d,J＝8.0Hz,1H),7.41–7.26(m,3H),7.20–7.05(m,1H),6.06–6.04(m,0.2H),5.73–5.62(m,0.8H),4.43–4.28(m,1H),4.05(d,J＝9.6Hz,0.6H),3.94(d,J＝9.6Hz,0.4H),3.76(d,J＝9.6Hz,0.6H),3.70–3.61(m,0.4H),3.56(d,J＝12.0Hz,1H),3.46(s,2H),3.40(s,1H),3.27–3.10(m,2H),2.89(s,1H),2.69(s,2H),2.37–2.22(m,1H),2.01–1.68(m,6H),1.61(s,2H),1.51(s,1H),1.24(s,1H),1.18–1.05(m,5H),1.03-0.80(m,3H),0.73–0.56(m,2H),0.50-0.45(m,0.5H),-0.06--0.05(m,0.5H),-0.15--0.31(m,2H)。

EXAMPLE 174 preparation of Compounds 174-a,174-b

Referring to the procedures of steps 1 to 6 of example 34, intermediates 1 to 5 of step 5 of example 1 (S, S enantiomer obtained by SFC chiral resolution) and 6 to 6b of step 6 of example 6 (prepared by SFC chiral resolution to obtain a single configuration) were reacted, followed by condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 174-b. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediate 6 to 6a of step 6 in example 6 (prepared by SFC chiral resolution to obtain another single configuration) were reacted, subjected to condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and condensation to obtain compound 174-a. MS m/z: 690(M +1) ⁺. 173b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.66(s,1H),7.61–7.58(m,2H),7.48–7.45(m,2H),7.35–7.31(m,3H),7.24(td,J＝8.0,1.6Hz,1H),6.34(d,J＝2.0Hz,1H),6.02(d,J＝12.0Hz,1H),4.40–4.24(m,3H),4.04(d,J＝9.6Hz,1H),3.78-3.74(m,2H),3.45(s,3H),3.25-3.15(m,2H),2.61–2.56(m,1H),1.99–1.75(m,7H),1.61(s,3H),1.34–1.27(m,2H),1.18(t,J＝7.2Hz,3H),1.13-1.08(m,7H),0.78-0.74(m,1H),-0.01--0.02(m,1H),-0.11--0.16(m,2H).

EXAMPLE 175 preparation of Compounds 175-a,175-b

Referring to the procedures of steps 1-6 of example 34, intermediates 1-5 of step 5 of example 1 (S, S enantiomer obtained by SFC chiral resolution) and 6-6b of step 6 of example 6 (prepared by SFC chiral resolution to obtain a single configuration) were reacted, followed by condensation, ring closure, deprotection, introduction of propionyl, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 175-b. Similarly, intermediates 1-5 of step 5 in example 1 (S, S enantiomer from SFC chiral resolution) and intermediates 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give another single configuration) were reacted, condensed, ring-closed, deprotected, propionyl was introduced, hydrolyzed, and condensed to give compound 175-a. MS m/z: 624(M +1)⁺。

EXAMPLE 176 preparation of Compounds 176-a,176-b

Referring to the procedures of steps 1-6 of example 34, intermediates 1-5 of step 5 of example 1 (S, S enantiomer obtained by SFC chiral resolution) and 6-6b of step 6 of example 6 (prepared by SFC chiral resolution to obtain a single configuration) were reacted, followed by condensation, ring closure, deprotection, introduction of isopropionyl, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 176-b. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediates 6 to 6a of step 6 in example 6 (prepared by SFC chiral resolution to obtain another single configuration) were reacted, condensed, ring-closed, deprotected, isopropionyl introduced, hydrolyzed, and condensed to obtain compound 176-a. MS m/z: 638(M +1) ⁺。

EXAMPLE 177 preparation of Compounds 177-a,177-b

Referring to the methods of steps 1-6 of example 34, intermediates 1-5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and 6-6b of step 6 in example 6 (a single configuration obtained by SFC chiral resolution) were reacted, followed by condensation, ring closure, deprotection, introduction of pyrrolidinylcarbonyl, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 177-b. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediate 6 to 6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were reacted, condensed, ring-closed, deprotected, pyrrolidinylcarbonyl group introduced, hydrolyzed, and condensed to obtain compound 177-a. MS m/z: 665(M +1)⁺。

EXAMPLE 178 preparation of Compounds 178-a,178-b

Referring to the methods of steps 1-6 of example 34, intermediates 1-5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and 6-6b of step 6 in example 6 (a single configuration obtained by SFC chiral resolution) were reacted, followed by condensation, ring closure, deprotection, introduction of N, N-dimethylcarbonyl, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 178-b. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediates 6 to 6a of step 6 in example 6 (prepared by SFC chiral resolution to obtain another single configuration) were reacted, condensed, ring-closed, deprotected, introduced with N, N-dimethylcarbonyl group, hydrolyzed, and condensed to obtain compound 178-a. MS m/z: 639(M +1) ⁺。

EXAMPLE 179 preparation of Compound 179-a,179-b

Referring to the methods of steps 1-6 of example 34, intermediates 1-5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and 6-6b of step 6 in example 6 (a single configuration obtained by SFC chiral resolution) were reacted, followed by condensation, ring closure, deprotection, introduction of a methylamine carbonyl group, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 179-b. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediate 6 to 6a of step 6 in example 6 (prepared by SFC chiral resolution to obtain another single configuration) were reacted, condensed, ring-closed, deprotected, and methylamine carbonyl was introduced, hydrolyzed, and condensed to obtain compound 179-a. MS m/z: 625(M +1) +.

EXAMPLE 180 preparation of Compound 180-a,180-b

Referring to the methods of steps 1-6 of example 34, intermediates 1-5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and 6-6b of step 6 in example 6 (a single configuration obtained by SFC chiral resolution) were reacted, followed by condensation, ring closure, deprotection, introduction of N-methyl-N' -ethylcarbonyl, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 180-b. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediate 6 to 6a of step 6 in example 6 (prepared by SFC chiral resolution to obtain another single configuration) were reacted, condensed, ring-closed, deprotected, introduced with N-methyl-N' -ethylcarbonyl, hydrolyzed, and condensed to obtain compound 180-a. MS m/z: 653(M +1) ⁺。

EXAMPLE 181 preparation of Compounds 181-a,181-b

Reference toThe method of example 34, steps 1-6, reacts with intermediate 1-5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediate 6-6b of step 6 in example 6 (a single configuration obtained by SFC chiral resolution preparation), and compounds 181-b are obtained by condensation, ring closure, deprotection, introduction of an ethylamine carbonyl group, hydrolysis, and finally condensation with intermediate 7-2 of example 7. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediate 6 to 6a of step 6 in example 6 (prepared by SFC chiral resolution to obtain another single configuration) were reacted, condensed, ring-closed, deprotected, introduced with ethylamine carbonyl group, hydrolyzed, and condensed to obtain compound 181-a. MS m/z: 639(M +1)⁺。

EXAMPLE 182 preparation of Compound 182-a,182-b

Referring to the methods of steps 1-6 of example 34, intermediates 1-5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and 6-6b of step 6 in example 6 (a single configuration obtained by SFC chiral resolution) were reacted, followed by condensation, ring closure, deprotection, introduction of N' N-diethylcarbonyl, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 182-b. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediates 6 to 6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were reacted, followed by condensation, ring closure, deprotection, introduction of N' N-diethylcarbonyl group, hydrolysis, and condensation to obtain compound 182-a. MS m/z: 667(M +1) ⁺。

EXAMPLE 183 preparation of Compounds 183-a,183-b

With reference to the procedures of steps 1 to 6 of example 34, intermediates 1 to 5 of step 5 of example 1 (S, S enantiomer obtained by SFC chiral resolution) and the intermediate of step 6 of example 6 were usedIntermediate 6-6b (a single configuration is obtained by SFC chiral resolution preparation) is reacted, and after condensation, ring closing and deprotection, N-methyl-N' -cyclopropyl carbonyl is introduced, and hydrolysis is carried out, and finally, the intermediate 7-2 is condensed with the intermediate 7-2 in the embodiment 7, so that compound 183-b is obtained. Similarly, intermediates 1 to 5 of step 5 in example 1 (S, S enantiomer obtained by SFC chiral resolution) and intermediate 6 to 6a of step 6 in example 6 (prepared by SFC chiral resolution to obtain another single configuration) were reacted, condensed, ring-closed, deprotected, introduced with N-methyl-N' -cyclopropylcarbonyl, hydrolyzed, and condensed to obtain compound 183-a. MS m/z: 665(M +1)⁺。

EXAMPLE 184 preparation of 184-a,184-b,184-c,184-d,184-e,184-f,184-g,184-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 184-a,184-b,184-c and 184-d. Similarly, compound 184-e,184-f,184-g,184-H was prepared by condensing 6-6a (a single configuration was prepared by SFC chiral resolution) of step 6 in example 6, closing the ring, deprotecting, introducing 1-ethyl-1H-pyrazole-5-acyl, hydrolyzing, condensing, and SFC chiral resolution. MS m/z: 708(M +1) ⁺。

EXAMPLE 185 preparation of compounds 185-a,185-b,185-c,185-d,185-e,185-f,185-g,185-h

Referring to the procedures of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, cyclized, deprotected, propionyl group introduced, hydrolyzed, and finally reacted with the intermediates of example 2 and 66-6b of example 6 to obtain a single configuration7, condensing the intermediate 7-2, and then carrying out SFC chiral resolution to prepare the compounds 185-a,185-b,185-c and 185-d. Similarly, compounds 185-e,185-f,185-g,185-h were prepared from intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give a single configuration) by condensation, ring closure, deprotection, introduction of propionyl, hydrolysis, condensation, and then SFC chiral resolution. MS m/z: 642(M +1)⁺。

EXAMPLE 186 preparation of compounds 186-a,186-b,186-c,186-d,186-e,186-f,186-g,186-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, isopropionyl introduction, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 186-a,186-b,186-c, 186-d. Similarly, intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (prepared by chiral resolution of SFC to give a single configuration) were condensed, ring-closed, deprotected, isopropionyl introduced, hydrolyzed, condensed, and then subjected to chiral resolution of SFC to give compounds 186-e,186-f,186-g, 186-h. MS m/z: 656(M +1) ⁺。

EXAMPLE 187 Compounds 187-a,187-b,187-c,187-d,187-e,187-f,187-g,187-h preparation

Referring to the method of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, N-pyrrolidinylcarbonyl is introduced, hydrolyzed, finally condensed with intermediate 7-2 of example 7, and then subjected to SFC chiral resolution to obtain compounds 187-a,187-b,187-c, 187-d. Similarly, step 5 of example 2The intermediates 2 to 6 of (a) and 6 to 6a (a single configuration is obtained by SFC chiral resolution preparation) of the step 6 in the example 6 are subjected to condensation, ring closing, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 187-e,187-f,187-g and 187-h. MS m/z: 683(M +1)⁺。

EXAMPLE 188 preparation of Compounds 188-a,188-b,188-c,188-d,188-e,188-f,188-g,188-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N, N-dimethylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to prepare compounds 188-a,188-b,188-c, 188-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N, N-dimethyl carbonyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 188-e,188-f,188-g and 188-h. MS m/z: 657(M +1) ⁺。

EXAMPLE 189 preparation of the Compounds 189-a,189-b,189-c,189-d,189-e,189-f,189-g,189-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of a methylamine carbonyl group, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to prepare compounds 189-a,189-b,189-c and 189-d. Similarly, intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed, ring-closed,deprotection, introduction of methylamine carbonyl, hydrolysis, condensation, and SFC chiral resolution to obtain 189-e,189-f,189-g, and 189-h compounds. MS m/z: 643(M +1)⁺。

EXAMPLE 190 preparation of the Compound 190-a,190-b,190-c,190-d,190-e,190-f,190-g,190-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N-methyl-N' -ethylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 190-a,190-b,190-c and 190-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N-methyl-N' -ethylcarbonyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 190-e,190-f,190-g and 190-h. MS m/z: 671(M +1) ⁺。

EXAMPLE 191 preparation of Compounds 191-a,191-b,191-c,191-d,191-e,191-f,191-g,191-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 191-a,191-b,191-c and 191-d. Similarly, intermediate 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, condensation and SFC chiral resolution to prepare compound 191-e,191-f,191-g,191-h。MS m/z：657(M+1)⁺。

EXAMPLE 192 preparation of Compounds 192-a,192-b,192-c,192-d,192-e,192-f,192-g,192-h

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N, N-diethylcarbonyl, hydrolysis, final condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 192-a,192-b,192-c and 192-d. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N, N-diethylcarbonyl, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 192-e,192-f,192-g and 192-h. MS m/z: 685(M +1) ⁺。

EXAMPLE 193 preparation of the Compounds 193-a,193-b,193-c,193-d,193-e,193-f,193-g,193-h

Referring to the methods of example 34, steps 1-6, intermediate 2-6 of step 5 in example 2 and 66-6b (a single configuration is obtained by SFC chiral resolution) in example 6 were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl was introduced, hydrolyzed, finally condensed with intermediate 7-2 of example 7, and then subjected to SFC chiral resolution to obtain compounds 193-a,193-b,193-c, 193-d. Similarly, compounds 193-e,193-f,193-g,193-h were prepared from intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (prepared by chiral resolution of SFC to give a single configuration) by condensation, ring closure, deprotection, introduction of N-methyl-N' -cyclopropylcarbonyl, hydrolysis, condensation, and then chiral resolution of SFC. MS m/z: 683(M +1)⁺。

EXAMPLE 194 preparation of Compounds 194-a,194-b,194-c,194-d,194-e,194-f,194-g,194-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 194-a,194-b,194-c and 194-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, and 1-ethyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, condensed, and then subjected to SFC chiral resolution to obtain the compounds 194-e,194-f,194-g and 194-H. MS m/z: 708(M +1) ⁺。

EXAMPLE 195 Compounds 195-a,195-b,195-c,195-d,195-e,195-f,195-g,195-h preparation

Referring to the procedures of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were subjected to condensation, cyclization, deprotection, propionyl introduction, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 195-a,195-b,195-c and 195-d. Similarly, compounds 195-e,195-f,195-g,195-h were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (prepared by chiral resolution of SFC to give a single configuration) by condensation, ring closure, deprotection, introduction of propionyl, hydrolysis, condensation, and chiral resolution of SFC. MS m/z: 642(M +1)⁺。

EXAMPLE 196-a,196-b,196-c,196-d,196-e,196-f,196-g,196-h preparation of the Compound

Referring to the procedures of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, cyclized, deprotected, isopropionylated, hydrolyzed, and finally condensed with intermediate 7-2 of example 7, followed by SFC chiral resolution to obtain compounds 196-a,196-b,196-c, and 196-d. Similarly, compounds 196-e,196-f,196-g,196-h were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give a single configuration) by condensation, ring closure, deprotection, introduction of isopropionyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 656(M +1) ⁺。

EXAMPLE 197 preparation of Compounds 197-a,197-b,197-c,197-d,197-e,197-f,197-g,197-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 197-a,197-b,197-c and 197-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, N-pyrrolidinylcarbonyl introduction, hydrolysis, condensation and SFC chiral resolution to obtain the compounds 197-e,197-f,197-g and 197-h. MS m/z: 683(M +1)⁺。

EXAMPLE 198 preparation of Compounds 198-a,198-b,198-c,198-d,198-e,198-f,198-g,198-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-dimethylcarbonyl was introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7, followed by SFC chiral resolution to obtain compounds 198-a,198-b,198-c, 198-d. Similarly, compounds 198-e,198-f,198-g,198-h were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of N, N-dimethylcarbonyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 657(M +1) ⁺。

EXAMPLE 199 preparation of Compounds 199-a,199-b,199-c,199-d,199-e,199-f,199-g,199-h

Referring to the methods of example 34, steps 1-6, intermediate 4-5 of step 5 in example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, methylamine carbonyl was introduced, hydrolyzed, finally condensed with intermediate 7-2 of example 7, and then subjected to SFC chiral resolution to obtain compounds 199-a,199-b,199-c, 199-d. Similarly, intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed, ring-closed, deprotected, and methylamine carbonyl was introduced, hydrolyzed, condensed, and then subjected to SFC chiral resolution to give compounds 199-e,199-f,199-g, and 199-h. MS m/z: 643(M +1)⁺。

EXAMPLE 200 preparation of Compounds 200-a,200-b,200-c,200-d,200-e,200-f,200-g,200-h

Procedure of reference example 341-6, condensing, ring closing, deprotection, introduction of N-methyl-N' -ethylcarbonyl, hydrolysis, condensation with the intermediate 7-2 of example 7, and SFC chiral resolution to obtain the compounds 200-a,200-b,200-c,200-d, using the intermediate 4-5 of step 5 of example 4 and the intermediate 66-6b (SFC chiral resolution preparation to obtain a single configuration) of example 6. Similarly, compounds 200-e,200-f,200-g,200-h were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of N-methyl-N' -ethylcarbonyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 671(M +1) ⁺。

EXAMPLE 201 preparation of Compounds 201-a,201-b,201-c,201-d,201-e,201-f,201-g,201-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 201-a,201-b,201-c, 201-d. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, N-ethylcarbonyl introduction, hydrolysis, condensation and SFC chiral resolution to prepare the compounds 201-e,201-f,201-g and 201-h. MS m/z: 657(M +1)⁺。

EXAMPLE 202 preparation of Compounds 202-a,202-b,202-c,202-d,202-e,202-f,202-g,202-h

With reference to the procedures of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (SFC chiral resolution)Preparation to obtain a single configuration) through condensation, ring closure, deprotection, introduction of N, N-diethylcarbonyl, hydrolysis, final condensation with the intermediate 7-2 of example 7, and SFC chiral resolution to obtain the compounds 202-a,202-b,202-c, 202-d. Similarly, compounds 202-e,202-f,202-g,202-h were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of N, N-diethylcarbonyl, hydrolysis, condensation, and then SFC chiral resolution. MS m/z: 685(M +1) ⁺。

EXAMPLE 203 preparation of the Compounds 203-a,203-b,203-c,203-d,203-e,203-f,203-g,203-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N-methyl-N' -cyclopropylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 203-a,203-b,203-c, 203-d. Similarly, compounds 203-e,203-f,203-g,203-h were prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of N-methyl-N' -cyclopropylcarbonyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 683(M +1)⁺。

EXAMPLE 204 preparation of the Compounds 204-a,204-b,204-c,204-d,204-e,204-f,204-g,204-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, and 1-ethyl-1H-pyrazine is introducedOxazole-5-acyl, hydrolyzed, finally condensed with the intermediate 7-2 of example 7, and then subjected to SFC chiral resolution to prepare compounds 204-a,204-b,204-c, 204-d. Similarly, compounds 204-e,204-f,204-g,204-H were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 708(M +1) ⁺。

EXAMPLE 205 preparation of Compounds 205-a,205-b,205-c,205-d,205-e,205-f,205-g,205-h

Referring to the methods of example 34, steps 1-6, intermediate 5-5 of step 5 in example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were subjected to condensation, ring closure, deprotection, propionyl introduction, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 205-a,205-b,205-c, 205-d. Similarly, compounds 205-e,205-f,205-g,205-h were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (prepared by chiral resolution of SFC to give a single configuration) by condensation, ring closure, deprotection, introduction of propionyl, hydrolysis, condensation, and then chiral resolution of SFC. MS m/z: 642(M +1)⁺。

EXAMPLE 206 preparation of Compounds 206-a,206-b,206-c,206-d,206-e,206-f,206-g,206-h

Referring to the procedures of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were subjected to condensation, cyclization, deprotection, isopropionyl introduction, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 206-a,206-b, 206-206 C, 206-d. Similarly, compounds 206-e,206-f,206-g,206-h were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of isopropionyl, hydrolysis, condensation, and then SFC chiral resolution. MS m/z: 656(M +1)⁺。

EXAMPLE 207 preparation of the Compound 207-a,207-b,207-c,207-d,207-e,207-f,207-g,207-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 207-a,207-b,207-c, 207-d. Similarly, the intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, condensation and SFC chiral resolution to obtain the compounds 207-a,207-b,207-c and 207-d. MS m/z: 683(M +1)⁺。

EXAMPLE 208 preparation of compounds 208-a,208-b,208-c,208-d,208-e,208-f,208-g,208-h

Referring to the methods of example 34, steps 1-6, intermediate 5-5 of step 5 in example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-dimethylcarbonyl was introduced, hydrolyzed, finally condensed with intermediate 7-2 of example 7, and then subjected to SFC chiral resolution to obtain compounds 208-a,208-b,208-c, 208-d. Similarly, intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (SFC chiral resolution)Preparation to obtain a single configuration) through condensation, ring closure, deprotection, introduction of N, N-dimethyl carbonyl, hydrolysis, condensation and SFC chiral resolution to obtain the compounds 208-e,208-f,208-g and 208-h. MS m/z: 657(M +1)⁺。

EXAMPLE 209 preparation of the Compounds 209-a,209-b,209-c,209-d,209-e,209-f,209-g,209-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 in example 5 and steps 66-6b (a single configuration is obtained by SFC chiral resolution preparation) in example 6 are subjected to condensation, ring closure, deprotection, introduction of a methylamine carbonyl group, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to prepare compounds 209-a,209-b,209-c and 209-d. Similarly, compounds 209-e,209-f,209-g,209-h were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was prepared by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of a methylaminocarbonyl group, hydrolysis, condensation, and then SFC chiral resolution. MS m/z: 643(M +1) ⁺。

EXAMPLE 210 preparation of Compounds 210-a,210-b,210-c,210-d,210-e,210-f,210-g,210-h

Referring to the methods of example 34, steps 1-6, intermediate 5-5 of step 5 in example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -ethylcarbonyl was introduced, hydrolyzed, finally condensed with intermediate 7-2 of example 7, and then subjected to SFC chiral resolution to obtain compounds 210-a,210-b,210-c, 210-d. Similarly, intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, N-methyl-N' -ethylcarbonyl is introduced, hydrolyzed, condensed and condensedAnd then the compounds 210-e,210-f,210-g and 210-h are prepared by SFC chiral resolution. MS m/z: 671(M +1)⁺。

EXAMPLE 211 preparation of the Compounds 211-a,211-b,211-c,211-d,211-e,211-f,211-g,211-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 211-a,211-b,211-c and 211-d. Similarly, compounds 211-e,211-f,211-g,211-h were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, condensation, and then SFC chiral resolution. MS m/z: 657(M +1) ⁺。

EXAMPLE 212 preparation of Compounds 212-a,212-b,212-c,212-d,212-e,212-f,212-g,212-h

Referring to the methods of example 34, steps 1-6, intermediate 5-5 of step 5 in example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-diethylcarbonyl was introduced, hydrolyzed, finally condensed with intermediate 7-2 of example 7, and then subjected to SFC chiral resolution to obtain compounds 212-a,212-b,212-c, 212-d. Similarly, compounds 212-e,212-f,212-g,212-h were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of N, N-diethylcarbonyl, hydrolysis, condensation, and then SFC chiral resolution. MS m/z: 685(M +1)⁺。

EXAMPLE 213 preparation of the Compounds 213-a,213-b,213-c,213-d,213-e,213-f,213-g,213-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of N-methyl-N' -cyclopropylcarbonyl, hydrolysis, condensation with intermediate 7-2 of example 7, and SFC chiral resolution to obtain compounds 213-a,213-b,213-c, 213-d. Similarly, compounds 213-e,213-f,213-g,213-h were prepared from intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration was obtained by SFC chiral resolution) by condensation, ring closure, deprotection, introduction of N-methyl-N' -cyclopropylcarbonyl, hydrolysis, condensation, and SFC chiral resolution. MS m/z: 683(M +1) ⁺。

EXAMPLE 214 preparation of Compounds 214-a,214-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (a single configuration is obtained by SFC chiral resolution preparation) in example 6 were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, and finally condensed with L-cyclobutyl-N-ethylglycinamide to give compound 214-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration from the preparation of the SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally condensed with L-cyclobutyl-N-ethylglycinamide to give compound 214-a. MS m/z: 688(M +1)⁺(ii) a 214-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.66(s,1H),7.61-7.56(m,2H),7.47(dd,J＝8.0,1.2Hz,1H),7.42(d,J＝8.0Hz,1H),7.38–7.28(m,3H),7.24(td,J＝7.8,1.6Hz,1H),6.91(d,J＝2.0Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.40–4.33(m,1H),4.14(s,1H),4.00(d,J＝9.6Hz,1H),3.87(s,3H),3.74(t,J＝11.2Hz,2H),3.42(s,3H),3.28–3.12(m,2H),2.61(dd,J＝15.2,7.6Hz,1H),2.01–1.74(m,7H),1.63(s,3H),1.16–1.07(m,6H),0.81–0.73(m,1H),0.01(dt,J＝10.0,5.2Hz,1H),-0.08–-0.17(m,2H).

EXAMPLE 215 preparation of Compounds 215-a,215-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (a single configuration is obtained by SFC chiral resolution preparation) in example 6 were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 215-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration from the preparation of the SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 215-a. MS m/z: 676(M +1) ⁺215-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ8.17–7.90(m,1H),7.66(s,1H),7.64–7.54(m,2H),7.52–7.43(m,1H),7.41–7.30(m,4H),7.29–7.16(m,1H),6.33(d,J＝2.2Hz,1H),6.01(d,J＝11.9Hz,1H),4.30–4.19(m,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.80–3.69(m,2H),3.46(s,3H),3.29–3.13(m,2H),2.11–1.93(m,1H),1.61(s,3H),1.18–1.06(m,6H),0.92(d,J＝6.8Hz,3H),0.83(d,J＝6.8Hz,3H),0.80–0.73(m,1H),0.06–-0.04(m,1H),-0.07–-0.19(m,2H).

EXAMPLE 216 preparation of Compounds 216-a,216-b

Procedure of reference example 34The method of steps 1-6 comprises the steps of condensing, ring closing, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis and condensation with D-tert-butyl-N-ethylglycinamide to obtain a compound 216-b by using an intermediate 3-3b of step 3 in example 3 and a single configuration obtained by SFC chiral resolution in example 6. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration from the preparation of the SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 216-a. MS m/z: 690(M +1)⁺215-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,MeOD)δ8.16(t,J＝5.6Hz,1H),7.68(s,1H),7.82-7.57(m,2H),7.51–7.46(m,2H),7.35–7.32(m,3H),7.26(dd,J＝7.6,1.2Hz,1H),6.34(d,J＝1.6Hz,1H),6.02(d,J＝12.0Hz,1H),4.24(d,J＝8.8Hz,1H),4.02(d,J＝9.6Hz,1H),3.87(s,3H),3.76-3.72(m,2H),3.46(s,3H),3.29–3.15(m,2H),1.60(s,3H),1.15–1.11(m,6H),0.92(s,9H),0.79-0.74(m,1H),0.04–-0.02(m,1H),-0.14(t,J＝7.6Hz,2H).

EXAMPLE 217 preparation of Compounds 217-a,217-b

Referring to the procedure for preparation of 34-b in step 6 of example 34, starting from intermediate 34-6, condensation with D-isopropyl-N-ethylglycinamide affords compound 217-b. Similarly, starting from the step 5 intermediate (alternative configuration of 34-6) in the preparation of alternative configuration 34-a, condensation with D-isopropyl-N-ethylglycinamide affords compound 217-a. MS m/z: 664(M +1) ⁺。

EXAMPLE 218 preparation of Compounds 218-a,218-b

By the method of preparing 34-b according to step 6 of example 34, starting from intermediate 34-6, a compound was obtained by condensation with D-tert-butyl-N-ethylglycinamide218-b. Similarly, the compound 218-a can be obtained by condensation of the step 5 intermediate (another configuration of 34-6) starting from the preparation of another configuration 34-a with D-tert-butyl-N-ethylglycinamide. MS m/z: 678(M +1)⁺. 218-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,MeOD)δ8.15(t,J＝5.6Hz,1H),7.62(s,1H),7.56-7.49(m,3H),7.39–7.33(m,3H),7.30(dd,J＝8.8,1.6Hz,1H),7.24(td,J＝7.6,1.6Hz,1H),6.51(s,1H),6.00(d,J＝9.2Hz,1H),4.23(d,J＝8.8Hz,1H),4.21-4.16(m,1H),4.00(d,J＝9.6Hz,1H),3.94(s,3H),3.71(d,J＝9.6Hz,1H),3.45(s,3H),3.29–3.13(m,2H),1.96-1.91(m,1H),1.58(s,3H),1.13(t,J＝7.2Hz,3H),1.01(d,J＝5.6Hz,3H),0.93(s,9H),0.86(d,J＝6.8Hz,3H).

EXAMPLE 219 preparation of Compounds 219-a,219-b,219-c,219-d,219-e,219-f,219-g,219-h

Referring to the methods of steps 1-6 of example 34, the intermediates 2-6 of step 5 of example 2 and the intermediates 66-6b of step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide, and SFC chiral resolution to obtain the compounds 219-a,219-b,219-c, 219-D. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, finally condensed with D-isopropyl-N-ethylglycinamide, and then subjected to SFC chiral resolution to obtain the compounds 219-e,219-f,219-g and 219-H. MS m/z: 682(M +1) ⁺。

EXAMPLE 220 preparation of the Compounds 220-a,220-b,220-c,220-d,220-e,220-f,220-g,220-h

With reference to the procedures of steps 1 to 6 of example 34 to practiceThe intermediates 2-6 of step 5 in example 2 and 66-6b (single configuration obtained by SFC chiral resolution preparation) in example 6 were subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, final condensation with D-tert-butyl-N-ethylglycinamide, and SFC chiral resolution to obtain compounds 220-a,220-b,220-c, 220-D. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with D-tert-butyl-N-ethylglycinamide, and SFC chiral resolution to prepare compounds 220-e,220-f,220-g and 220-H. MS m/z: 696(M +1)⁺。

EXAMPLE 221 preparation of Compounds 221-a,221-b,221-c,221-d,221-e,221-f,221-g,221-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide, and SFC chiral resolution to obtain compounds 221-a,221-b,221-c and 221-D. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, finally condensed with D-isopropyl-N-ethylglycinamide, and then subjected to SFC chiral resolution to obtain the compounds 221-e,221-f,221-g and 221-H. MS m/z: 682(M +1) +.

EXAMPLE 222 preparation of Compounds 222-a,222-b,222-c,222-d,222-e,222-f,222-g,222-h

Step 1E to E of reference example 346, the intermediate 4-5 of step 5 in example 4 and the intermediate 66-6b (single configuration obtained by SFC chiral resolution preparation) in example 6 are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, finally condensed with D-tert-butyl-N-ethylglycinamide, and then subjected to SFC chiral resolution to prepare the compounds 222-a,222-b,222-c and 222-D. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, finally condensed with D-tert-butyl-N-ethylglycinamide, and then subjected to SFC chiral resolution to obtain the compounds 222-e,222-f,222-g and 222-H. MS m/z: 696(M +1)⁺。

EXAMPLE 223 preparation of the Compounds 223-a,223-b,223-c,223-d,223-e,223-f,223-g,223-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide, and SFC chiral resolution to obtain compounds 223-a,223-b,223-c and 223-D. Similarly, the intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide, and SFC chiral resolution to prepare the compounds 223-e,223-f,223-g and 223-H. MS m/z: 682(M +1) ⁺。

EXAMPLE 224 preparation of the Compound 224-a,224-b,224-c,224-d,224-e,224-f,224-g,224-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, condensation with D-tert-butyl-N-ethylglycinamide, and SFC chiral resolution to obtain compounds 224-a,224-b,224-c, 224-D. Similarly, the intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, finally condensed with D-tert-butyl-N-ethylglycinamide, and then subjected to SFC chiral resolution to obtain the compounds 224-e,224-f,224-g and 224-H. MS m/z: 696(M +1)⁺。

EXAMPLE 225 preparation of Compounds 225-a,225-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (a single configuration is obtained by SFC chiral resolution preparation) in example 6 were condensed, ring-closed, deprotected, 1-ethyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 225-b. Similarly, intermediate 3-3b of step 3 in example 3, and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-ethyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 225-a. MSm/z: 690(M +1) ⁺。

EXAMPLE 226 preparation of Compounds 226-a,226-b

Referring to the procedures of steps 1 to 6 of example 34, intermediates 3 to 3b and examples of step 3 of example 3Example 6, step 66-6b (SFC chiral resolution preparation gave a single configuration) was condensed, ring closed, deprotected, propionyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 226-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, propionyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 226-a. MS m/z: 624(M +1)⁺。

EXAMPLE 227 preparation of Compound 227-a,227-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) in example 6 were condensed, ring-closed, deprotected, isobutyryl group introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 227-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration prepared by SFC chiral resolution) were condensed, ring-closed, deprotected, isobutyryl group introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 227-a. MS m/z: 638(M +1) ⁺。

EXAMPLE 228 preparation of Compounds 228-a,228-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, N-pyrrolidinylcarbonyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 228-b. Similarly, as intermediates 3-3b of step 3 in example 3 and of step 6 in example 66-6a (another single configuration obtained by SFC chiral resolution) is condensed, subjected to ring closure and deprotection, introduced with N-pyrrolidinylcarbonyl, hydrolyzed and condensed with D-isopropyl-N-ethylglycinamide to obtain a compound 228-a. MS m/z: 665(M +1)⁺。

EXAMPLE 229 preparation of Compounds 229-a,229-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yielded a single configuration) of example 6 were condensed, ring-closed, deprotected, N-dimethylcarbonyl was introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to yield compound 229-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-dimethylcarbonyl was introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 229-a. MS m/z: 639(M +1) ⁺。

EXAMPLE 230 preparation of Compounds 230-a,230-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) in example 6 were condensed, ring-closed, deprotected, methylamine carbonyl was introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 230-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, methylamine carbonyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 230-a. MS m/z: 625(M +1)⁺。

EXAMPLE 231 preparation of Compounds 231-a,231-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, N-methyl-N' -ethylcarbonyl was introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 231-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -ethylcarbonyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 231-a. MS m/z: 653(M +1) ⁺。

EXAMPLE 232 preparation of Compounds 232-a,232-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, N-ethylcarbonyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to yield compound 232-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-ethylcarbonyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 232-a. MS m/z: 639(M +1)⁺。

EXAMPLE 233 preparation of Compounds 233-a,233-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation gave a single configuration) in example 6 were condensed, ring-closed, deprotected, N-diethylcarbonyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 233-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-diethylcarbonyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 233-a. MS m/z: 667(M +1) ⁺。

EXAMPLE 234 preparation of Compounds 234-a,234-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (a single configuration is obtained by SFC chiral resolution preparation) in example 6 were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl was introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 234-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 234-a. MS m/z: 665(M +1)⁺。

EXAMPLE 235 preparation of Compounds 235-a,235-b

With reference to the procedures of steps 1 to 6 of example 34, intermediates 3-3b of step 3 of example 3 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, and methoxycarbonyl group was introducedHydrolysis and final condensation with intermediate 7-2 of example 7 gave compound 235-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, methoxycarbonyl group introduced, hydrolyzed, and finally condensed with intermediate 7-2 from example 7 to give compound 235-a. MS m/z: 638(M +1) ⁺. 235-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.72–7.57(m,1H),7.56–7.49(m,2H),7.48–7.42(m,1H),7.38–7.31(m,1H),7.31–7.21(m,2H),5.53(d,J＝11.8Hz,1H),4.35(d,J＝8.6Hz,1H),4.02(d,J＝9.6Hz,1H),3.73(d,J＝9.6Hz,1H),3.58–3.39(m,7H),3.24–3.10(m,2H),2.57(q,J＝8.0Hz,1H),1.97–1.80(m,4H),1.80–1.69(m,2H),1.59(s,3H),1.08(t,J＝7.3Hz,3H),1.05(s,3H),0.76–0.68(m,1H),-0.04–-0.10(m,1H),-0.17–-0.26(m,2H).

EXAMPLE 236 preparation of Compounds 236-a,236-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation gave a single configuration) in example 6 were condensed, ring-closed, deprotected, methoxycarbonyl group introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 236-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, methoxycarbonyl group introduced, hydrolyzed, and finally condensed with D-isopropyl-N-ethylglycinamide to give compound 236-a. MS m/z: 626(M +1)⁺。

EXAMPLE 237 preparation of Compounds 237-a,237-b

With reference to the procedures of steps 1 to 6 of example 34, the procedure of example 3 was followedThe intermediate 3-3b of step 3 and step 66-6b (SFC chiral resolution preparation gives a single configuration) in example 6 are condensed, ring-closed, deprotected, methoxycarbonyl group is introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 237-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, methoxycarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 237-a. MS m/z: 640(M +1) ⁺。

EXAMPLE 238 preparation of Compounds 238-a,238-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (a single configuration is obtained by SFC chiral resolution preparation) in example 6 were condensed, ring-closed, deprotected, 1-ethyl-1H-pyrazole-5-acyl was introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 238-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-ethyl-1H-pyrazole-5-acyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 238-a. MS m/z: 704(M +1)⁺。

Preparation of the Compound 239-a,239-b of example 239

Referring to the methods of example 34, steps 1-6, intermediate 3-3b of step 3 in example 3 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, propionyl introduction, hydrolysis, and condensation with D-tert-butyl-N-ethylglycinamide to obtain compound 239-b. Similarly, in example 3The intermediate 3-3b of step 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, propionyl introduction, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycinamide to obtain compound 239-a. MS m/z: 638(M +1) ⁺。

EXAMPLE 240 preparation of Compounds 240-a,240-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, isobutyryl group introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 240-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, isobutyryl group introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 240-a. MS m/z: 652(M +1)⁺。

EXAMPLE 241 preparation of Compounds 241-a,241-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, N-pyrrolidinylcarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to yield compound 241-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration from the preparation of the SFC chiral resolution) were condensed, ring-closed, deprotected, N-pyrrolidinylcarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 241-a. MS m/z: 679(M +1) ⁺。

EXAMPLE 242 preparation of Compounds 242-a,242-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, N-dimethylcarbonyl was introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 242-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-dimethylcarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 242-a. MS m/z: 653(M +1)⁺。

Example 243 preparation of Compounds 243-a,243-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) in example 6 were condensed, ring-closed, deprotected, methylamine carbonyl was introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 243-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration from the preparation of the SFC chiral resolution) were condensed, ring-closed, deprotected, methylamine carbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 243-a. MS m/z: 639(M +1) ⁺。

EXAMPLE 244 preparation of Compounds 244-a,244-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, N-methyl-N' -ethylcarbonyl was introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 244-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -ethylcarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 244-a. MS m/z: 667(M +1)⁺。

EXAMPLE 245 preparation of Compounds 245-a,245-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, N-ethylcarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 245-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-ethylcarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 245-a. MS m/z: 653(M +1) ⁺。

EXAMPLE 246 preparation of Compounds 246-a,246-b

Referring to the methods of steps 1-6 of example 34, intermediates 3-3b of step 3 in example 3 and steps 66-6b (SFC chiral resolution preparation yields a single configuration) of example 6 were condensed, ring-closed, deprotected, N was introduced,n-diethylcarbonyl, hydrolysis, and condensation with D-tert-butyl-N-ethylglycinamide to give 246-b. Similarly, intermediate 3-3b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-diethylcarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 246-a. MS m/z: 681(M +1)⁺。

EXAMPLE 247 preparation of Compounds 247-a,247-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (a single configuration is obtained by SFC chiral resolution preparation) in example 6 were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl was introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 247-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 247-a. MS m/z: 679(M +1) ⁺。

EXAMPLE 248 preparation of Compounds 248-a,248-b

Referring to the methods of steps 1-6 of example 34, intermediates 1-5b of step 5 of example 1 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, methoxycarbonyl group is introduced, hydrolyzed, and finally reacted with D-tert-butyl-N-ethylglycinamide to obtain compound 248-b. Similarly, intermediates 1-5b of step 5 in example 1 and 6-6a of step 6 in example 6 (another single configuration prepared by SFC chiral resolution) were condensed and relatedRing deprotection, introducing methoxycarbonyl, hydrolysis and condensation with D-tert-butyl-N-ethylglycinamide to obtain the compound 248-a. MS m/z: 614(M +1)⁺。

EXAMPLE 249 preparation of Compounds 249-a,249-b

With reference to the methods of steps 1-6 of example 34, intermediates 1-5b of step 5 of example 1 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, methoxycarbonyl group is introduced, hydrolyzed, and finally reacted with D-tert-butyl-N-ethylglycinamide to obtain compound 249-b. Similarly, intermediates 1-5b from step 5 in example 1 and 6-6a from step 6 in example 6 (another single configuration from the preparation of the SFC chiral resolution) were condensed, ring-closed, deprotected, methoxycarbonyl introduced, hydrolyzed, and finally condensed with D-tert-butyl-N-ethylglycinamide to give compound 249-a. MS m/z: 628(M +1) ⁺。

EXAMPLE 250 preparation of Compounds 250-a,250-b,250-c,250-d,250-e,250-f,250-g,250-h

Referring to the methods of steps 1-6 of example 34, the intermediates 2-6 of step 5 of example 2 and the intermediates 66-6b of step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide, and SFC chiral resolution to obtain the compounds 250-a,250-b,250-c and 250-D. Similarly, the intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide and SFC chiral resolution to prepare the compounds 250-e,250-f,250-g and 250-h. MS m/z: 632(M +1)⁺。

EXAMPLE 251 preparation of the Compounds 251-a,251-b,251-c,251-d,251-e,251-f,251-g,251-h

Referring to the methods of steps 1-6 of example 34, the intermediates 2-6 of step 5 of example 2 and the intermediates 66-6b of step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-tert-butyl-N-ethylglycinamide, and SFC chiral resolution to obtain the compounds 251-a,251-b,251-c, 251-D. Similarly, the intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, methoxycarbonyl is introduced, hydrolyzed, finally condensed with D-tert-butyl-N-ethylglycinamide, and then subjected to SFC chiral resolution to obtain the compounds 251-e,251-f,251-g and 251-h. MS m/z: 646(M +1) ⁺。

EXAMPLE 252 preparation of compounds 252-a,252-b,252-c,252-d,252-e,252-f,252-g,252-h

Referring to the methods of steps 1-6 of example 34, the intermediates 4-5 of step 5 of example 4 and the intermediates 66-6b of step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide, and SFC chiral resolution to obtain the compounds 252-a,252-b,252-c and 252-D. Similarly, intermediate 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide and SFC chiral resolution to prepare the compounds 252-e,252-f,252-g and 252-h. MS m/z: 632(M +1)⁺。

EXAMPLE 253 preparation of compounds 253-a,253-b,253-c,253-d,253-e,253-f,253-g,253-h

Referring to the methods of steps 1-6 of example 34, the intermediates 4-5 of step 5 of example 4 and the intermediates 66-6b of step 6 (a single configuration is obtained by SFC chiral resolution) of example 6 are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-tert-butyl-N-ethylglycinamide, and SFC chiral resolution to obtain the compounds 253-a,253-b,253-c and 253-D. Similarly, compounds 253-e,253-f,253-g and 253-h are prepared from intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) through condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-tert-butyl-N-ethylglycinamide and SFC chiral resolution. MS m/z: 646(M +1) ⁺。

EXAMPLE 254 preparation of the Compounds 254-a,254-b,254-c,254-d,254-e,254-f,254-g,254-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide, and SFC chiral resolution to obtain compounds 254-a,254-b,254-c and 254-D. Similarly, intermediate 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-isopropyl-N-ethylglycinamide and SFC chiral resolution to prepare compounds 254-e,254-f,254-g and 254-h. MS m/z: 632(M +1)⁺。

EXAMPLE 255 preparation of Compounds 255-a,255-b,255-c,255-d,255-e,255-f,255-g,255-h

Referring to the methods of steps 1-6 of example 34, the intermediates 5-5 of step 5 of example 5 and the intermediates 66-6b of step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-tert-butyl-N-ethylglycinamide, and SFC chiral resolution to obtain the compounds 255-a,255-b,255-c and 255-D. Similarly, the intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis, condensation with D-tert-butyl-N-ethylglycinamide and SFC chiral resolution to prepare the compounds 255-e,255-f,255-g and 255-h. MS m/z: 646(M +1) ⁺。

EXAMPLE 256 preparation of Compounds 256-a,256-b

Referring to the methods of steps 1-6 of example 34, intermediates 3-3b of step 3 of example 3 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]Condensing octane-7-ketone to obtain 256-b compound. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]Condensing octane-7-ketone to obtain 256-a compound. MS m/z: 672(M +1)⁺256-b nuclear magnetic hydrogen spectrum:¹HNMR(400MHz，MeOD):δ7.82–7.72(m,1H),7.65–7.55(m,2H),7.51–7.45(m,1H),7.42(dd,J＝8.6,1.8Hz,1H),7.36–7.29(m,2H),7.28–7.21(m,1H),6.33(d,J＝2.2Hz,1H),6.02(d,J＝11.9Hz,1H),4.09(d,J＝9.5Hz,1H),3.87(s,4H),3.74(d,J＝12.0Hz,1H),3.52–3.37(m,5H),2.32(q,J＝9.1Hz,1H),2.03–1.93(m,2H),1.90–1.81(m,1H),1.67(s,5H),1.13(s,3H),0.81–0.71(m,1H),0.02–-0.03(m,1H),-0.09–-0.18(m,2H).

EXAMPLE 257 preparation of Compound 257-a,257-b

Referring to the methods of steps 1-6 of example 34, intermediates 3-3b of step 3 of example 3 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, introduced with 1-ethyl-1H-pyrazole-5-acyl, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]The octane-7-one is condensed to obtain a compound 257-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-ethyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ] ]The octane-7-one is condensed to obtain a compound 257-a. MS m/z: 686(M +1)⁺。

EXAMPLE 258 preparation of Compound 258-a,258-b

Referring to the procedures of steps 1-6 of example 34, intermediates 3-3b of step 3 of example 3 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, propionyl group introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]Condensing octane-7-ketone to obtain compound 258-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, propionyl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]Condensing octane-7-ketone to obtain compound 258-a.MS m/z：620(M+1)⁺。

Preparation of the Compound 259-a,259-b of example 259

Referring to the methods of steps 1-6 of example 34, intermediates 3-3b of step 3 of example 3 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, isobutyryl group introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]The condensation of octane-7-one gives the compound 259-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, isobutyryl group introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ] azaspiro [ sic ] ]The condensation of octane-7-one gives the compound 259-a. MS m/z: 634(M +1)⁺。

EXAMPLE 260 preparation of Compound 260-a,260-b

With reference to the procedures of steps 1 to 6 of example 34, intermediates 3-3b of step 3 of example 3 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were subjected to condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally reaction with (R) -8-amino-6-azaspiro [3.4 ]]The condensation of octane-7-one gives the compound 260-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-pyrrolidinylcarbonyl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]The condensation of octane-7-one gives compound 260-a. MS m/z: 661(M +1)⁺。

EXAMPLE 261 preparation of Compounds 261-a,261-b

With reference to the procedures of steps 1 to 6 of example 34, intermediates 3-3b of step 3 of example 3 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were subjected to condensation, ring closure, deprotection, introduction of N, N-dimethylcarbonyl, hydrolysis, and finally reaction with (R) -8-amino-6-azaspiro [3.4 ]]The octane-7-one is condensed to obtain the compound 261-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-dimethylcarbonyl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ] ]The octane-7-one is condensed to obtain the compound 261-a. MS m/z: 635(M +1)⁺。

EXAMPLE 262 preparation of Compounds 262-a,262-b

Referring to the methods of steps 1-6 of example 34, intermediates 3-3b of step 3 of example 3 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of a methylaminocarbonyl group, hydrolysis, and finally reaction with (R) -8-amino-6-azaspiro [3.4 ]]The octane-7-one is condensed to obtain the compound 262-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, methylamine carbonyl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ] azaspiro [ sic ]]The octane-7-one is condensed to obtain the compound 262-a. MS m/z: 621(M +1)⁺。

EXAMPLE 263 preparation of Compounds 263-a,263-b

With reference to the procedures of steps 1 to 6 of example 34, intermediates 3-3b of step 3 of example 3 and steps 66-6b of example 6 (SFC hands)Preparing a single configuration by sexual resolution), condensing, closing ring, removing protection, introducing N-methyl-N' -ethylcarbonyl, hydrolyzing, and finally reacting with (R) -8-amino-6-azaspiro [3.4 ]]The octane-7-one is condensed to obtain a compound 263-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -ethylcarbonyl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ] ]The octane-7-one is condensed to obtain a compound 263-a. MS m/z: 649(M +1)⁺。

EXAMPLE 264 preparation of Compounds 264-a,264-b

Referring to the methods of steps 1-6 of example 34, intermediates 3-3b of step 3 of example 3 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-ethylcarbonyl was introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]Condensing octane-7-ketone to obtain the compound 264-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-ethylcarbonyl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]Condensing octane-7-ketone to obtain the compound 264-a. MS m/z: 635(M +1)⁺。

EXAMPLE 265 preparation of Compounds 265-a,265-b

Referring to the methods of example 34, steps 1-6, the intermediates 3-3b of step 3 in example 3 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-diethylcarbonyl was introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]The octane-7-one is condensed to obtain the compound 265-b. Similarly, in the examples The intermediate 3-3b of step 3 in 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of N, N-diethylcarbonyl, hydrolysis and final reaction with (R) -8-amino-6-azaspiro [3.4 ]]The condensation of octane-7-one gives compound 265-a. MS m/z: 663(M +1)⁺。

EXAMPLE 266 preparation of Compounds 266-a,266-b

Referring to the methods of steps 1-6 of example 34, intermediates 3-3b of step 3 of example 3 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl was introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]Octane-7-one affords compound 266-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ]]The condensation of octane-7-one gives compound 266-a. MS m/z: 661(M +1)⁺。

EXAMPLE 267 preparation of Compound 267-a,267-b

Referring to the methods of steps 1-6 of example 34, intermediates 3-3b of step 3 of example 3 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl was introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ] ]The condensation of octane-7-one affords compound 267-b. Similarly, intermediates 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration produced by SFC chiral resolution) were condensed, ring-closed, deprotected, N-methyl-N' -cyclopropylcarbonyl introduced, hydrolyzed, and finallyPost-and (R) -8-amino-6-azaspiro [3.4 ]]The condensation of octane-7-one affords compound 267-a. MS m/z: 622(M +1)⁺。

EXAMPLE 268 preparation of Compounds 268-a,268-b

Preparation of 34-b starting from intermediate 34-6 with reference to step 6 of example 34, (R) -8-amino-6-azaspiro [ 3.4)]The condensation of octane-7-one gives compound 268-b. Similarly, starting from the step 5 intermediate (another configuration of 34-6) for the preparation of another configuration 34-a, is reacted with (R) -8-amino-6-azaspiro [3.4 ]]Condensation of octane-7-one affords compound 268-a. MS m/z: 660(M +1)⁺. 268-b nuclear magnetic hydrogen spectrum:¹HNMR(400MHz,MeOD):δ7.75(d,J＝8.0Hz,1H),7.68(s,1H),7.57-7.50(m,2H),7.42-7.32(m,4H),7.24(t,J＝7.2Hz,1H),6.50(s,1H),6.00(d,J＝8.8Hz,1H),4.47(d,J＝8.0Hz,1H),4.19(s,1H),4.07(d,J＝9.6Hz,1H),3.93(s,3H),3.85(d,J＝9.6Hz,1H),3.49(d,J＝10.0Hz,1H),3.45(s,3H),3.41-3.37(m,1H),2.35–2.28(m,1H),1.99-1.82(m,5H),1.74-1.59(m,5H),0.98(d,J＝4.4Hz,3H),0.86(d,J＝6.4Hz,3H).

EXAMPLE 269-a,269-b,269-c,269-d,269-e,269-f,269-g,269-h preparation of the compound

Referring to the methods of steps 1-6 of example 34, intermediates 2-6 of step 5 of example 2 and steps 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ] ]Octane-7-ketone, and then obtaining compounds 269-a,269-b,269-c and 269-d through SFC chiral resolution. Similarly, intermediates 2-6 of step 5 in example 2 and 6-6a of step 6 in example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed and hydrolyzedFinally with (R) -8-amino-6-azaspiro [3.4 ]]Octane-7-ketone, and then obtaining compounds 269-e,269-f,269-g and 269-h through SFC chiral resolution. MS m/z: 678(M +1)⁺。

EXAMPLE 270 preparation of the Compounds 270-a,270-b,270-c,270-d,270-e,270-f,270-g,270-h

Referring to the methods of steps 1-6 of example 34, intermediates 4-5 of step 5 of example 4 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, and final reaction with (R) -8-amino-6-azaspiro [3.4 ]]Octane-7-ketone, and then SFC chiral resolution is carried out to prepare compounds 270-a,270-b,270-c and 270-d. Similarly, intermediates 4-5 of step 5 in example 4 and 6-6a of step 6 in example 6 (a single configuration is prepared by SFC chiral resolution) are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, and finally reacted with (R) -8-amino-6-azaspiro [3.4 ] ]Octane-7-ketone, and then SFC chiral resolution is carried out to prepare compounds 270-e,270-f,270-g and 270-h. MS m/z: 678(M +1)⁺。

EXAMPLE 271 preparation of compounds 271-a,271-b,271-c,271-d,271-e,271-f,271-g,271-h

Referring to the methods of steps 1-6 of example 34, intermediates 5-5 of step 5 of example 5 and 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, methoxycarbonyl introduction, hydrolysis and (R) -8-amino-6-azaspiro [3.4 ]]Condensing octane-7-ketone, and carrying out SFC chiral resolution to obtain compounds 271-a,271-b,271-c and 271-d. Similarly, intermediates 5-5 of step 5 in example 5 and 6-6a of step 6 in example 6 (prepared by SFC chiral resolution to give a single configuration) were condensed, ring-closed, and ring-removedProtection, introducing methoxycarbonyl, hydrolysis, and reaction with (R) -8-amino-6-azaspiro [3.4]Condensing octane-7-ketone, and carrying out SFC chiral resolution to obtain compounds 271-e,271-f,271-g and 271-h. MS m/z: 628(M +1)⁺。

EXAMPLE 272 preparation of Compound 272-a,272-b

Referring to the methods of steps 1-6 of example 34, intermediate 3-3b of step 3 in example 3 and step 66-6b (SFC chiral resolution preparation gave a single configuration) in example 6 were condensed, ring-closed, deprotected, methoxyformyl group introduced, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 272-b. Similarly, intermediate 3-3b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration obtained by SFC chiral resolution) were condensed, ring-closed, deprotected, methoxyformyl group introduced, hydrolyzed, and condensed to give compound 272-a. MS m/z: 638(M +1) ⁺. 272-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,MeOD)δ7.67–7.51(m,3H),7.49-7.44(m,2H),7.36(t,J＝7.2Hz,1H),7.33–7.24(m,2H),5.56(d,J＝12.0Hz,1H),4.40-4.36(m,1H),4.04(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.59–3.42(m,7H),3.27–3.11(m,2H),2.62-2.54(m,1H),2.03–1.68(m,6H),1.61(s,3H),1.11(t,J＝7.2Hz,3H),1.07(s,3H),0.79–0.70(m,1H),-0.01–-0.08(m,1H),-0.14–-0.24(m,2H).

EXAMPLE 273 preparation of Compounds 273-a,273-b

Step 1 preparation of intermediates 273-1a, 273-1b

Referring to the similar method in example 1, example 2 and example 3, m-chlorobenzaldehyde is used as a starting material to prepare the compound, wherein one diastereomer is prepared by separation and separation through an SFC chiral column to respectively obtain single chiral isomers 273-1a (2R,3R) and 273-1b (2S, 3S). MS m/z: 354(M+1)⁺。

Step 2 preparation of Compounds 273-a,273-b

Referring to the methods of steps 1-6 of example 34, intermediate 273-1b of step 1 and step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are subjected to condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, and finally condensation with intermediate 7-2 of example 7 to obtain compound 273-b. Similarly, intermediate 273-1b from step 3 in example 3 and 6-6a from step 6 in example 6 (another single configuration from the preparation of the SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally condensed with intermediate 7-2 from example 7 to give compound 273-a. MS m/z: 688(M +1)⁺. 273-b nuclear magnetic hydrogen spectrum 1HNMR (400MHz, MeOD): δ 7.72-7.76(m,2H),7.51-7.56(m,2H),7.29-7.40(m,5H),6.43-6.44(d, J ═ 2.2,1H),6.03-6.06(d, J ═ 12.2,1H),4.33-4.37(t, J ═ 8.3,1H),3.98-4.00(d, J ═ 9.6,1H),3.93(s,3H),3.75-3.77(d, J ═ 9.7,1H),3.43(s,3H),3.11-3.24(m,2H),2.94-2.97(d, J ═ 12.1,1H), 2.52-2H (m, 60, 1H), 1.50 (m,1H), 1.1.1H), 1.6-4.1H (t, 1H), 3.1, 1H (d, 1H), -0.06-0.01 (m,1H), -0.14-0.09 (m,1H).

EXAMPLE 274 preparation of Compounds 274-a,274-b

Referring to the methods of steps 1-6 of example 34, intermediate 273-1b of step 1 and step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution preparation) are condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl is introduced, hydrolyzed, and finally condensed with intermediate 11 of example 11 to obtain compound 274-b. Similarly, intermediate 273-1b of step 3 in example 3 and 6-6a of step 6 in example 6 (another single configuration prepared by SFC chiral resolution) were condensedClosing the ring, deprotecting, introducing 1-methyl-1H-pyrazole-5-acyl, hydrolyzing, and finally condensing with intermediate 11 of example 11 to obtain compound 274-a. MS m/z: 714(M +1)⁺. Nuclear magnetic hydrogen spectrum of compound 274-b:¹HNMR(400MHz，MeOD):δ7.78-7.83(m,2H),7.59-7.63(m,2H),7.29-7.41(m,5H),6.470-6.475(d,J＝2.1,1H),6.07-6.10(d,J＝12.4,1H),4.37-4.41(t,J＝8.4,1H),3.97-3.99(d,J＝9.6,1H),3.94(s,3H),3.75-3.78(d,J＝9.6,1H),3.42(s,3H),3.06-3.13(m,1H),2.97-3.00(m,2H),2.56-2.61(m,1H),1.78-1.96(m,6H),1.61(s,3H),1.08(s,3H),0.90-0.96(m,1H),0.53-0.58(m,1H),0.44-0.48(m,2H),0.12-0.19(m,3H),-0.02-0.01(m,1H),-0.14--0.09(m,1H).

EXAMPLE 275 preparation of Compounds 275-a,275-b

Starting from the compounds 272-b and 272-a from example 272, respectively, in ethanol over Pd (OH)₂Hydrogenation dechlorination can respectively obtain 275-b and 275-a. MS m/z: 604(M +1)⁺. Nuclear magnetic hydrogen spectrum of compound 275-b:¹H NMR(400MHz,MeOD)δ7.62(s,1H),7.57(d,J＝8.4Hz,1H),7.39-7.28(m,6H),5.56(d,J＝11.6Hz,1H),4.61(s,2H),4.37(d,J＝8.8Hz,1H),4.04(d,J＝9.6Hz,1H),3.75(d,J＝9.6Hz,1H),3.47(s,3H),3.45(s,3H),3.25-3.13(m,2H),2.62-2.56(m,2H),2.03–1.70(m,6H),1.61(s,3H),1.11(t,J＝7.6Hz,3H),1.06(s,3H),0.44–0.35(m,1H),-0.01--0.06(m,1H),-0.15–-0.25(m,2H).

EXAMPLE 276 preparation of Compound 276-a,276-b

Starting from the compounds 87-b and 87-a from example 87, respectively, in ethanol over Pd (OH)₂Hydrogenation dechlorination can respectively obtain 276-b and 276-a. MS m/z: 654(M +1) ⁺。¹H NMR(400MHz,Methanol-d₄)δ7.64(s,1H),7.59(d,J＝8.3Hz,1H),7.37(d,J＝4.3Hz,4H),7.33–7.25(m,3H),6.28(d,J＝1.8Hz,1H),6.00(d,J＝12.1Hz,1H),4.37(d,J＝8.6Hz,1H),4.04(d,J＝9.6Hz,1H),3.86(s,3H),3.75(d,J＝9.6Hz,1H),3.45(s,3H),3.26–3.11(m,2H),2.83(d,J＝12.0Hz,1H),2.63–2.54(m,1H),1.99–1.73(m,7H),1.61(s,3H),1.13–1.07(m,6H),0.48–0.40(m,1H),0.02–-0.03(m,1H),-0.08–-0.17(m,2H).

EXAMPLE 277 preparation of Compound 277-a,277-b

Starting from compounds 165-b and 165-a from example 165, respectively, in ethanol over Pd (OH)₂Hydrodechlorination to obtain 277-b and 277-a respectively. MS m/z: 602(M +1)⁺。

EXAMPLE 278 preparation of Compound 278-a,278-b

Step 1 preparation of intermediates 278-1a, 278-1b

By referring to the similar methods in example 1, example 2 and example 3, 3-chlorothiophene-2-carbaldehyde can be prepared as a starting material, wherein one diastereomer can be prepared by separation and separation through an SFC chiral column to obtain single chiral isomers 278-1a (2R,3S) and 278-1b (2S,3R) respectively. MS m/z: 260(M +1)⁺。

Step 2 preparation of Compounds 278-a,278-b

Referring to the methods of steps 1-6 of example 34, intermediate 278-1b of step 1 and step 66-6b of example 6 (a single configuration was prepared by SFC chiral resolution) were condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl introduced, hydrolyzed, and finally condensed with intermediate 27 of example 27 to give compound 278-b. Similarly, intermediate 278-1b from step 3 of example 3And 6-6a (another single configuration obtained by SFC chiral resolution preparation) of step 6 in example 6, by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl, hydrolysis, and finally condensation with intermediate 27 of example 27 to give compound 278-a. MS m/z: 708(M +1) ⁺. Compound 278-b nuclear magnetic data:¹HNMR(400M,MeOD),δ7.28-7.51(m,5H),7.17-7.19(d,J＝7.68,1H),6.875-6.880(d,J＝2,1H),6.66-6.67(d,J＝5.36,1H),5.77-5.80(d,J＝11.76,1H),4.58(s,1H),4.35-4.38(m,1H),4.11(s,3H),3.92-3.93(m,2H),3.66-3.68(d,J＝9.68,1H),3.59-3.62(d,J＝11.72,1H),3.41(s,3H),3.10-3.24(m,2H),2.17-2.21(m,1H),2.01-2.04(m,2H),1.85-1.92(m,1H),1.53-1.57(m,2H),1.49(s,3H),1.07-1.10(t,J＝7.2,3H),1.03(s,3H),0.88-0.92(m,1H),0.55-0.59(m,2H),0.18-0.21(m,1H).

preparation of the Compound 279-a,279-b of example 279

Step 1 preparation of intermediates 279-1a, 279-1b

By referring to the similar methods in example 1, example 2 and example 3, 3-fluoro-2-chloroformaldehyde can be prepared as a starting material, wherein one diastereomer can be prepared by separation and separation through an SFC chiral column to obtain single chiral isomers 279-1a (2S,3S) and 279-1b (2R,3R) respectively. MS m/z: 272(M +1)⁺。

Step 2 preparation of Compounds 279-a,279-b

Referring to the methods of steps 1-6 of example 34, intermediate 279-1b of step 1 and step 66-6b of example 6 (a single configuration is obtained by SFC chiral resolution) are condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to obtain compound 278-b. Similarly, intermediate 279-1b of step 3 in example 3 and 6-6a of step 6 in example 6 (SFC chiral resolution system)Prepared with another single configuration) was condensed, ring-closed, deprotected, introduced with 1-methyl-1H-pyrazole-5-acyl, hydrolyzed, and finally condensed with intermediate 7-2 of example 7 to give compound 279-a. MS m/z: 706(M +1)⁺. 279-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,MeOD)δ7.96(t,J＝5.7Hz,1H),7.68–7.57(m,2H),7.47(d,J＝7.9Hz,1H),7.44–7.24(m,4H),7.18-7.14(m,1H),6.36(d,J＝2.1Hz,1H),6.01(d,J＝11.9Hz,1H),4.38(t,J＝8.3Hz,1H),4.03(d,J＝9.6Hz,1H),3.89(s,3H),3.77(dd,J＝13.3,10.7Hz,2H),3.45(s,3H),3.20(dddd,J＝18.9,17.3,9.5,4.3Hz,2H),2.59(h,J＝8.4,8.0Hz,1H),2.00–1.70(m,6H),1.61(s,3H),,1.21–1.04(m,6H),0.74(dt,J＝9.9,5.3Hz,1H),0.03-0.02(m,1H),-0.11(dp,J＝14.0,4.9Hz,2H)。

EXAMPLE 280 preparation of Compound 280-a, 280-b

Referring to the procedure of steps 1-6 of example 34, starting from cyclohexyl-L-alanine hydrochloride and 6-6a of step 6 of example 6 (a single configuration is obtained by SFC chiral resolution), the process proceeds by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazol-5-yl, hydrolysis and finally condensation with intermediate 7-2 of example 7 to give compound 280-a, MS m/z: 606.0(M +1)⁺。

Similarly, cyclohexyl-L-alanine hydrochloride and example 6 in 66-6b (SFC chiral resolution preparation of another single configuration) as raw materials, through the same steps, compounds 280-b. ,¹H NMR(400MHz,Methanol-d₄)δ7.94(s,1H),7.63–7.48(m,3H),7.41(d,J＝8.1Hz,1H),7.27(d,J＝8.6Hz,1H),6.94(d,J＝2.1Hz,1H),5.48(dd,J＝9.4,6.1Hz,1H),4.36(t,J＝8.3Hz,1H),4.12(s,3H),3.99(d,J＝9.6Hz,1H),3.73(d,J＝9.6Hz,1H),3.43(s,3H),3.24–3.14(m,2H),2.57(q,J＝7.9Hz,1H),2.11–1.98(m,2H),1.98–1.72(m,11H),1.58(s,3H),1.42(s,1H),1.27(dd,J＝20.3,10.1Hz,3H),1.18–0.96(m,5H).

example 281 preparation of Compounds 281-a, 281-b

Referring to the procedure of steps 1-6 of example 34, cyclohexyl-L-alanine hydrochloride was condensed with 6-6a of step 6 of example 6 (a single configuration was obtained by SFC chiral resolution), ring closure, ester hydrolysis, condensation with intermediate 7-2 of example 7, deprotection, and finally reaction with methyl chloroformate to give compound 281-a.

Similarly, starting from cyclohexyl-L-alanine hydrochloride and step 66-6b of example 6 (another single configuration prepared by SFC chiral resolution), the same procedure was followed to give compound 281-b, MS m/z: 556.0(M +1) ⁺，¹H NMR(400MHz,Methanol-d₄)δ7.56(s,1H),7.50(d,J＝8.5Hz,1H),7.28–7.20(m,1H),5.01(t,J＝7.8Hz,1H),4.41–4.31(m,1H),4.00(d,J＝9.5Hz,1H),3.72(d,J＝9.6Hz,1H),3.68(s,3H),3.43(s,3H),3.24–3.12(m,2H),2.63–2.51(m,1H),1.99–1.71(m,12H),1.69(s,1H),1.58(s,3H),1.45–1.18(m,4H),1.10(t,J＝7.3Hz,3H),1.07–0.96(m,2H)。

EXAMPLE 282 preparation of Compounds 282-a, 282-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediates 3-3b of example 3 and 6-6a of step 6 of example 6 (prepared by SFC chiral resolution to give a single configuration), the reaction mixture is condensed, ring-closed, deprotected, 1-methyl-1H-pyrazole-5-acyl introduced, ester hydrolyzed, and finally condensed with cyclobutylmethylamine to give compound 282-a, MS m/z: 617.0(M +1)⁺.

Similarly, the intermediate 3-3b of example 3 and step 66-6b of example 6 (another single configuration obtained by SFC chiral resolution) are used as raw materials, and compound 282-b is obtained by the same steps,¹H NMR(400MHz,Methanol-d₄)δ7.62(s,1H),7.58(d,J＝8.3Hz,2H),7.46(d,J＝8.0Hz,1H),7.39(t,J＝5.6Hz,1H),7.36–7.28(m,3H),7.24(t,J＝7.6Hz,1H),6.31(s,1H),6.02(d,J＝12.0Hz,1H),3.96(d,J＝9.4Hz,1H),3.84(s,3H),3.76(d,J＝11.9Hz,1H),3.71(d,J＝9.4Hz,1H),3.38(s,3H),3.33(d,3H),3.27–3.17(m,2H),2.56–2.46(m,1H),2.02–1.91(m,2H),1.91–1.76(m,2H),1.69(q,J＝8.8Hz,2H),1.63(s,3H),1.12(s,3H),0.81–0.74(m,1H),0.06–-0.01(m,1H),-0.13(t,J＝7.6Hz,2H)。

EXAMPLE 283 preparation of Compounds 283-a, 283-b

The compounds 283-a and 283-b can be obtained by the Pd/C hydrodechlorination of the raw materials of the examples 86-a and 86-b in ethanol. MS m/z: 640.0(M +1)⁺283-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,Methanol-d₄)δ7.63(s,1H),7.58(d,J＝8.5Hz,1H),7.45(d,J＝7.9Hz,1H),7.36(d,J＝4.2Hz,4H),7.33–7.24(m,3H),6.27(s,1H),6.01(d,J＝12.0Hz,1H),4.38(t,J＝8.1Hz,1H),4.04(d,J＝9.5Hz,1H),3.86(s,3H),3.76(d,J＝9.5Hz,1H),3.45(s,3H),2.84(d,J＝12.0Hz,1H),2.72(s,3H),2.63–2.54(m,1H),2.00–1.85(m,4H),1.76(d,2H),1.60(s,3H),1.12(s,3H),0.50–0.40(m,2H),0.03–-0.02(m,2H),-0.09–-0.16(m,2H).

EXAMPLE 284 preparation of Compound 284-a, 284-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 3-3b of example 3 and 6-6a of step 6 of example 6 (preparation of a single configuration by SFC chiral resolution), the intermediate is condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl is introduced, ester hydrolyzed, and finally condensed with D-cyclobutyl glycinamide to give compound 284-a, MS m/z: 660.0(M +1) ⁺.

Similarly, starting from intermediate 3-3b of example 3 and step 66-6b of example 6 (another single configuration prepared by SFC chiral resolution), compound 284-b was obtained by the same procedure，¹H NMR(400MHz,Methanol-d₄)δ7.66(s,1H),7.59(t,J＝9.3Hz,2H),7.46(t,J＝7.1Hz,2H),7.36–7.30(m,3H),7.28–7.21(m,1H),6.33(s,1H),6.02(d,J＝11.9Hz,1H),4.46–4.40(m,1H),4.06(d,J＝9.5Hz,1H),3.86(d,J＝1.1Hz,3H),3.76(dd,J＝10.7,8.1Hz,2H),3.45(d,J＝1.2Hz,3H),2.70–2.58(m,1H),2.05–1.73(m,7H),1.61(s,3H),1.13(s,3H),0.82–0.72(m,2H),0.02–-0.02(m,1H),-0.08–-0.17(m,2H)。

EXAMPLE 285 preparation of Compounds 285-a, 285-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 3-3b of example 3 and 6-6a of step 6 of example 6 (a single configuration is prepared by SFC chiral resolution), the reaction mixture is condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl is introduced, ester hydrolyzed, and finally condensed with D-cyclobutylglycine methyl ester to give compound 285-a, MS m/z: 675.0(M +1)⁺.

Similarly, starting from intermediate 3-3b of example 3 and step 66-6b of example 6 (another single configuration obtained by SFC chiral resolution), compound 285-b was obtained by the same procedure,¹H NMR(400MHz,Methanol-d₄)δ7.71(d,J＝7.9Hz,1H),7.65(d,J＝1.7Hz,1H),7.61–7.56(m,2H),7.47(dd,J＝7.9,1.4Hz,1H),7.36–7.29(m,3H),7.24(td,J＝7.6,1.6Hz,1H),6.32(d,J＝2.1Hz,1H),6.02(d,J＝11.9Hz,1H),4.45(t,J＝8.2Hz,1H),4.01(d,J＝9.6Hz,1H),3.85(s,3H),3.74(t,J＝11.0Hz,2H),3.69(s,3H),3.42(s,3H),2.74–2.62(m,1H),2.07–1.71(m,7H),1.61(s,3H),1.12(s,3H),0.81–0.73(m,1H),0.02–-0.03(m,1H),-0.09–-0.16(m,2H)。

EXAMPLE 286 preparation of Compounds 286-a, 286-b

Preparation of intermediate 286-10

Step 1, preparation of intermediate 286-1

To a solution of di-tert-butyl malonate (22.72g,105.05mmol) in DMF (250mL) under ice-bath was added NaH (7.56g,315.14mmol), the mixture was stirred under ice-bath for 30 minutes, and then a solution of 1-bromo-4, 5-difluoro-2-nitrobenzene (25g,105.05mmol) in DMF (50mL) was added dropwise. The reaction solution was stirred at room temperature for 3 hours.

The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 286-1(41g, crude) which was used in the next reaction without purification.

Step 2, preparation of intermediate 286-2

HCl (120mL) was added slowly to a solution of 286-1(94.0g,216.46mmol) in acetic acid (320mL) at room temperature, and the reaction mixture was warmed to 110 ℃ and stirred for 2 hours.

The reaction was directly concentrated to give 286-2(60g, crude) which was used in the next reaction without purification. MS m/z:

step 3, preparation of intermediate 286-3

Concentrated sulfuric acid (5mL) was slowly added dropwise to a solution of 286-2(60g, 215.80mmol) in ethanol (300mL) at room temperature, and the reaction was warmed to 85 ℃ and stirred for 2 hours.

The reaction was concentrated, diluted with water, extracted with ethyl acetate, and the combined organic phases were washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 286-3(66g) of a yellow oil.

Step 4, preparation of intermediate 286-4

Cs2CO3(36.19g,111.08mmol) was added to a solution of 286-3(34.0g,111.08mmol) in DMF (300mL) at room temperature, stirred for 30 minutes, cooled to zero, MeI (12.61g,88.86mmol) was added, and the reaction was stirred overnight at room temperature. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (0% to 60% ethyl acetate/petroleum ether) to give intermediate 286-4(25g, 71%) as a yellow oil.

Step 5, preparation of intermediate 286-5

To a solution of intermediate 286-4(11.0g,34.36mmol) in DMF (125mL) under ice bath was added NaH (907.18mg,37.80mmol) in portions and the mixture was stirred for 30 min under ice bath. Then, a solution of MOMBr (5.58g,44.67mmol) in DMF (25mL) was added and the reaction was stirred at room temperature overnight. After the reaction was complete, the combined drug was concentrated and the crude product was purified by silica gel column separation (ethyl acetate/petroleum ether 0-100%) to give intermediate 286-5(5g, 40% yield) as a yellow solid.

Step 6, preparation of intermediate 286-6

To an ethanol solution of intermediate 286-5(9.4g,25.81mmol) was added acetic acid (15mL) and water (50mL), the mixture was warmed to 50 degrees, iron powder (10.81g,193.59mmol) was added in portions and slowly, and after the addition, the reaction solution was warmed to 85 degrees and stirred for 3 hours. After the reaction was complete, the iron powder was filtered and the filter cake was washed with ethanol and the filtrate was concentrated to give intermediate 286-6(8.4g, 97% yield, crude), MS m/z: 334.0(M +1)⁺

Used in the next reaction without purification.

Step 7, preparation of intermediate 286-7

To a solution of intermediate 286-6(8.4g,25.14mmol) in dichloromethane (120mL) was added acetic anhydride (2.57g,25.14mmol), stirred at room temperature for 3 hours, and after completion of the reaction, the reaction was concentrated to give intermediate 286-7(9.4g, 99% yield, crude). MS (ESI) 378.0(M +2) M/z ⁺.

Step 8, preparation of intermediate 286-8

To a solution of 286-7(1g,2.66mmol) in HNO3 (68%) (3.0mL) under ice-bath was added H2SO4 (98%) (3.0mL) dropwise and the reaction was stirred under ice-bath for 1 hour. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate and the organic phase concentrated to give crude intermediate 286-8(0.9g, 80% yield). MS (ESI) 422.0(M +1)⁺.

Step 9, preparation of intermediate 286-9

To a solution of 286-8(3.13g,7.43mmol) in ethanol was added SOCl under ice-cooling₂(5.30g,44.59mmol,3.23mL), the reaction was warmed to 60 ℃ and stirred overnight. After the reaction is finishedThe reaction was concentrated and the crude product was purified by silica gel column separation to give intermediate 286-9(575mg, 20% yield). MS (ESI) 379.0(M +1) M/z⁺.

Step 10, preparation of intermediate 286-10

To a solution of intermediate 286-9(0.570g,1.50mmol) in ethanol (50mL) was added Pd/C (0.057g), and after replacement with H2, H2 was stirred overnight at room temperature under protection. After completion of the reaction, Pd/C was removed by filtration, the filtrate was concentrated, and purified by MPLC 18 reverse phase column to give racemate 286-10(420mg, 90% purity, 93% yield). MS m/z: 271.0(M +1)⁺

Preparation of Compounds 286-a, 286-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 3-3b of example 3 and intermediate 286-10 above, the reaction mixture is condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally condensed with intermediate 7-2 to give compound 286, MS m/z: 706.0(M +1) ⁺Compound 286 is prepared by SFC chiral resolution to obtain two isomers at the chiral carbon position, labeled 286-a and 286-b, respectively.¹H NMR(400MHz,Methanol-d₄)δ7.56(d,J＝7.5Hz,1H),7.47(dd,J＝8.0,1.3Hz,1H),7.40(s,1H),7.37–7.29(m,3H),7.27–7.21(m,1H),6.36(s,1H),6.01(d,J＝11.8Hz,1H),4.37(d,J＝8.4Hz,1H),4.07(d,J＝9.5Hz,1H),3.87(s,3H),3.71(dd,J＝17.9,10.7Hz,2H),3.46(s,3H),3.24–3.11(m,3H),2.66–2.52(m,1H),2.02–1.79(m,6H),1.63(s,3H),1.14–1.09(m,6H),0.02–-0.03(m,2H),-0.13(t,J＝7.4Hz,2H).

EXAMPLE 287 preparation of Compound 287-a, 287-b

Using examples 105-a and 105-b, respectively, as starting materials, compounds 287-a and 287-b were obtained by Pd/C hydrodechlorination in ethanol, MS m/z: 668.0(M +1)⁺287-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,MeOD)δ8.01(s,1H),7.67(d,J＝1.2Hz,1H),7.60(d,J＝8.6Hz,1H),7.49(d,J＝8.5Hz,1H),7.37-7.35(m,5H),7.32–7.26(m,2H),6.28(d,J＝2.1Hz,1H),6.01(d,J＝12.1Hz,1H),4.41(d,J＝8.5Hz,1H),4.03(d,J＝9.7Hz,1H),3.87(s,3H),3.76(d,J＝9.7Hz,1H),3.47(s,3H),3.29–3.12(m,2H),2.83(d,J＝12.1Hz,1H),2.23(dd,J＝19.6,9.5Hz,1H),2.09(dd,J＝19.7,9.3Hz,1H),1.97–1.84(m,1H),1.80–1.67(m,1H),1.59-1.57(m,5H),1.15–1.06(m,9H),0.45(dd,J＝11.8,7.8Hz,1H),0.01–-0.01(m,1H),-0.13(d,J＝7.5Hz,2H).

EXAMPLE 288 preparation of Compounds 288-a, 288-b

By the method described above with reference to example 287, compounds 288-a and 288-b are hydrodechlorinated from the corresponding compounds. MS m/z: 654.0(M +1)⁺288-b nuclear magnetic hydrogen spectrum:¹H NMR(400MHz,MeOD)δ7.94(d,J＝4.4Hz,1H),7.67(d,J＝1.2Hz,1H),7.61(d,J＝8.6Hz,1H),7.50(d,J＝8.4Hz,1H),7.41–7.33(m,5H),7.31–7.25(m,2H),6.29(d,J＝2.1Hz,1H),6.01(d,J＝12.1Hz,1H),4.42(d,J＝8.4Hz,1H),4.04(d,J＝9.7Hz,1H),3.87(s,3H),3.77(d,J＝9.7Hz,1H),3.48(s,3H),2.83(d,J＝12.1Hz,1H),2.73(d,J＝3.8Hz,3H),2.22(dd,J＝19.8,9.1Hz,1H),2.07(dd,J＝19.8,9.2Hz,1H),1.91(ddd,J＝19.8,13.0,5.6Hz,1H),1.73(tdd,J＝13.5,9.4,4.1Hz,1H),1.65–1.49(m,5H),1.11(s,3H),1.07(s,3H),0.45(dd,J＝12.6,7.0Hz,1H),0.02–-0.01(m,1H),-0.10–-0.19(m,2H).

EXAMPLE 289 preparation of Compounds 289-a, 289-b

Preparation of intermediate 289-3

Referring to the relevant synthesis method of the patent, Fmoc-D- (cyclobutyl) glycine is used as a raw material and subjected to condensation borane reduction, Boc adding and Fmoc removing steps to obtain an intermediate 289-3。MS m/z：215.0(M+1)⁺

Preparation of Compounds 289-a, 289-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 3-3b of example 3 and 6-6a of step 6 of example 6 (SFC chiral resolution preparation gives a single configuration), the process proceeds by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazol-5-yl, ester hydrolysis, condensation with intermediate 289-3, and finally Boc removal to give compound 289-a, MS m/z: 646.0(M +1) ⁺.

Similarly, the intermediate 3-3b in example 3 and the step 66-6b in example 6 (another single configuration obtained by SFC chiral resolution) are used as raw materials to obtain a compound 289-b through the same steps, and a nuclear magnetic spectrum¹H NMR(400MHz,Methanol-d₄)δ7.83(d,J＝1.3Hz,1H),7.80(d,1H),7.58(dd,J＝8.7,1.7Hz,1H),7.52(ddd,J＝7.9,3.8,1.5Hz,2H),7.39–7.36(m,1H),7.34(d,J＝2.2Hz,1H),7.29(td,J＝7.7,1.6Hz,1H),6.46(d,J＝2.2Hz,1H),6.16(d,J＝12.2Hz,1H),4.08(d,J＝9.5Hz,1H),3.93(s,3H),3.89(q,2H),3.48(s,3H),3.02(dd,J＝13.1,3.4Hz,1H),2.81(dd,J＝13.0,9.8Hz,1H),2.49–2.38(m,1H),2.11–2.01(m,1H),1.94–1.69(m,6H),1.65(s,3H),1.11(s,3H),0.93–0.86(m,1H),0.14–0.08(m,1H),-0.02–-0.14(m,2H)。

EXAMPLE 290 preparation of Compounds 290-a, 290-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 3-3b of example 3 and 6-6a of step 6 of example 6 (SFC chiral resolution preparation gives a single configuration), the reaction mixture is condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl is introduced, ester hydrolyzed, and finally condensed with (1-fluorocyclobutyl) methylamine hydrochloride to give compound 290-a, MS m/z: 635.0(M +1)⁺。

Similarly, the nuclear magnetic spectrum of the compound 290-b is obtained by using the intermediate 3-3b in example 3 and the step 66-6b (another single configuration obtained by SFC chiral resolution preparation) in example 6 as raw materials through the same steps¹H NMR(400MHz,Methanol-d₄)δ7.68–7.63(m,1H),7.62–7.56(m,2H),7.53(t,J＝6.0Hz,1H),7.50–7.45(m,1H),7.38–7.30(m,3H),7.29–7.21(m,1H),6.33(d,J＝2.1Hz,1H),6.01(d,J＝12.0Hz,1H),4.13(s,0H),4.00(d,J＝9.5Hz,1H),3.86(s,3H),3.74(t,J＝11.0Hz,2H),3.64–3.52(m,2H),3.40(s,3H),2.27–2.11(m,4H),1.86–1.75(m,1H),1.65(s,3H),1.60–1.50(m,1H),1.31(s,2H),1.13(s,3H),0.96–0.85(m,1H),0.77(dt,J＝10.4,5.8Hz,1H),-0.08–-0.17(m,2H)。

EXAMPLE 291 preparation of Compounds 291-a, 291-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 3-3b of example 3 and 6-6a of step 6 of example 6 (preparation of a single configuration by SFC chiral resolution), the reaction mixture is condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl is introduced, ester hydrolyzed, and finally condensed with 1- (aminomethyl) cyclobutanol to give compound 291-a, MS m/z: 633.0(M +1) ⁺

Similarly, starting from intermediate 3-3b of example 3 and step 66-6b of example 6 (another single configuration prepared by SFC chiral resolution), compound 291-b is obtained via the same procedure,¹H NMR(400MHz,Methanol-d4)δ7.70–7.63(m,1H),7.62–7.54(m,2H),7.46(dd,J＝8.0,1.3Hz,1H),7.39(t,J＝5.7Hz,1H),7.36–7.29(m,3H),7.30–7.19(m,2H),6.32(d,J＝2.2Hz,1H),6.00(d,J＝11.9Hz,1H),3.98(d,J＝9.5Hz,1H),3.85(s,3H),3.73(dd,J＝13.7,10.7Hz,2H),3.45–3.37(m,5H),2.08–1.91(m,4H),1.78–1.66(m,2H),1.63(s,3H),1.60–1.48(m,1H),1.12(s,3H),0.00(m,2H),-0.13(td,J＝6.9,6.4,3.4Hz,2H).。

EXAMPLE 292 preparation of Compounds 292-a, 292-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 3-3b of example 3 and 6-6a of step 6 of example 6 (SFC chiral resolution preparation gave a single configuration), the reaction mixture was condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, ester hydrolyzed, and finally condensed with (R) -1-cyclobutyl-2 methoxyethylamine to give compound 292-a, MS m/z: 661.0(M +1)⁺。

Similarly, the intermediate 3-3b of example 3 and step 66-6b of example 6 (another single configuration obtained by SFC chiral resolution) are used as raw materials, and the compound 292-b is obtained through the same steps,¹H NMR(400MHz,Methanol-d₄)δ7.67–7.63(m,1H),7.62–7.50(m,3H),7.48(dd,J＝7.9,1.4Hz,1H),7.37–7.30(m,3H),7.29–7.21(m,1H),6.33(d,J＝2.1Hz,1H),6.01(d,J＝12.0Hz,1H),4.00(d,J＝9.5Hz,1H),3.86(s,3H),3.74(t,J＝11.0Hz,2H),3.65–3.52(m,2H),3.40(s,3H),2.17(m,4H),1.80(m,1H),1.65(s,3H),1.56(m,1H),1.13(s,3H),0.95–0.86(m,1H),0.81–0.72(m,1H),-0.08–-0.17(m,2H)。

EXAMPLE 293 preparation of Compounds 293-a, 293-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 3-3b of example 3 and 6-6a of step 6 of example 6 (SFC chiral resolution preparation gives a single configuration), the reaction mixture is condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl is introduced, ester hydrolyzed, and finally condensed with (R) -2-amino-2-cyclobutylethanol to give compound 293-a, MS m/z: 647.0(M +1) ⁺.

Similarly, compound 293-b was obtained by the same procedure starting from intermediate 3-3b of example 3 and step 66-6b of example 6 (another single configuration prepared by SFC chiral resolution). ,¹H NMR(400MHz,Methanol-d₄)δ7.65(s,1H),7.58(td,J＝5.8,3.1Hz,2H),7.47(dd,J＝8.0,1.4Hz,1H),7.37–7.29(m,3H),7.25(td,J＝7.7,1.6Hz,1H),7.16(d,J＝8.9Hz,1H),6.33(d,J＝2.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.02–3.92(m,2H),3.86(s,3H),3.80–3.72(m,2H),3.47(d,2H),3.42(s,3H),2.57–2.44(m,1H),2.08–1.75(m,6H),1.62(s,3H),1.13(s,3H),0.82–0.72(m,1H),0.03–-0.03(m,1H),-0.08–-0.18(m,2H)

EXAMPLE 294 preparation of Compounds 294-a, 294-b

To a solution of compound 288-a (40mg, 0.05mmol) of example 288 in dichloromethane (1mL) were added HBTU (25.92mg,68.40umol), DIPEA (20.40mg,157.84umol,27.49uL) and acetic acid (3.48mg,57.88umol), and the reaction was stirred at room temperature under nitrogen for 1 hour. After the reaction, the crude product was obtained by concentration under reduced pressure, and the crude product was isolated and purified by reverse phase column (ACN/0.05% FA) to obtain 294-a (20mg, 26.08umol) with a yield of 50%. MS m/z: 688.0(M +1)⁺.

Similarly, compound 294-b was obtained by condensation of compound 288-b of example 288 with acetic acid. ,¹H NMR(400MHz,Methanol-d₄)δ7.64(d,J＝1.7Hz,1H),7.58(t,J＝7.7Hz,2H),7.47(dd,J＝7.9,1.3Hz,1H),7.36–7.30(m,3H),7.25(td,J＝7.7,1.6Hz,1H),7.11(d,J＝9.0Hz,1H),6.33(d,J＝2.1Hz,1H),6.02(d,J＝12.0Hz,1H),4.09–4.01(m,1H),3.99(d,J＝9.3Hz,1H),3.86(s,3H),3.77(d,J＝3.0Hz,1H),3.74(s,1H),3.42(s,3H),3.21–3.10(m,2H),2.44–2.32(m,1H),2.06–1.94(m,1H),1.93–1.86(m,2H),1.85–1.74(m,4H),1.63(s,3H),1.12(s,3H),0.82–0.72(m,1H),0.02–-0.01(m,1H),-0.08–-0.19(m,2H)

EXAMPLE 295 preparation of Compounds 295-a, 295-b

Using compound 288-a as a starting material, the resulting product was condensed with cyclopropylformic acid according to the method described in example 293 to give compound 295-a, MS m/z: 714.0(M +1)⁺

The compound 295-b is obtained by similar condensation using 288-b as the starting material. ,¹H NMR(400MHz,Methanol-d₄)δ7.63(d,J＝1.7Hz,1H),7.62–7.54(m,2H),7.47(dq,J＝7.9,1.3Hz,1H),7.32(m,3H),7.29–7.20(m,1H),7.15(d,J＝8.9Hz,1H),6.33(q,J＝1.8Hz,1H),6.01(dd,J＝11.9,1.8Hz,1H),4.06(td,J＝8.6,4.8Hz,1H),3.97(d,J＝9.3Hz,1H),3.89–3.83(m,3H),3.77(s,1H),3.78–3.72(m,1H),3.41(d,J＝1.2Hz,3H),3.26–3.10(m,2H),2.45–2.32(m,1H),2.07–1.95(m,1H),1.85(m,6H),1.63(s,3H),1.48(tt,J＝7.9,4.7Hz,1H),1.12(s,3H),0.84–0.70(m,3H),0.73–0.62(m,2H),0.02(s,1H),-0.07–-0.18(m,2H).

EXAMPLE 296 preparation of Compounds 296-a, 296-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediates 1-5b of example 1 and 6-6a of step 6 of example 6 (a single configuration was prepared by SFC chiral resolution), condensation, ring closure, ester hydrolysis, condensation with intermediate 7-2 of example 7, deprotection, and finally reaction with methyl chloroformate gave compound 296-a, MS m/z: 626.0(M +1) ⁺

Similarly, starting from intermediates 1-5b of example 1 and steps 66-6b of example 6 (another single configuration prepared by SFC chiral resolution), compound 296-b is obtained by the same procedure. ,¹H NMR(400MHz,Methanol-d₄)δ7.55(s,1H),7.52–7.46(m,2H),7.43(d,J＝7.7Hz,1H),7.39–7.19(m,5H),5.58(d,J＝7.9Hz,1H),4.36(t,J＝8.3Hz,1H),4.01(d,J＝9.6Hz,1H),3.96–3.89(m,1H),3.73(d,J＝9.6Hz,1H),3.58(s,3H),3.43(s,3H),3.24–3.12(m,2H),2.63–2.52(m,1H),2.01–1.82(m,6H),1.79–1.72(m,2H),1.58(s,3H),1.10(t,J＝7.3Hz,3H),1.04(d,J＝5.3Hz,3H),0.80(d,J＝6.7Hz,3H).

EXAMPLE 297 preparation of Compounds 297-a, 297-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediates 1-5b of example 1 and 6-6a of step 6 of example 6 (a single configuration was prepared by SFC chiral resolution), the reaction mixture was condensed, ring-closed, ester hydrolyzed, condensed with intermediate 9 of example 9, deprotected, and finally reacted with methyl chloroformate to give compound 297-a, MS m/z: 612.0(M +1)⁺

Similarly, starting from intermediates 1-5b of example 1 and step 66-6b of example 6 (another single configuration prepared by SFC chiral resolution), compound 297-b is obtained via the same procedure. ,¹H NMR(400MHz,Methanol-d₄)δ7.79(d,J＝1.6Hz,1H),7.76(d,J＝8.7Hz,1H),7.60–7.51(m,3H),7.44–7.27(m,4H),6.37(d,J＝2.2Hz,1H),6.06(d,J＝12.1Hz,1H),3.98(d,J＝9.7Hz,1H),3.92(s,3H),3.88(d,J＝12.1Hz,1H),3.75(d,J＝9.7Hz,1H),3.55–3.52(m,2H),3.42(s,3H),3.17(s,3H),2.18–2.07(m,2H),1.92–1.83(m,2H),1.82–1.67(m,2H),1.64(s,3H),1.31(s,6H),1.12(s,3H).

EXAMPLE 298 preparation of Compound 298-a, 298-b

Preparation of intermediate 298-7

Step 1, preparation of intermediate 298-1

Triethyl 2-phosphonopropyl ester (2.04g,10.49mmol) was added dropwise to a THF (25mL) dispersion of NaH (251.65mg,10.49mmol) under ice-bath conditions, stirred for 20min under ice-bath conditions, then cyclobutylformaldehyde (840mg,9.99mmol) was added dropwise, and after the addition was complete, the mixture was gradually warmed to room temperature and stirred overnight. After the reaction was complete, it was quenched with saturated ammonium chloride, extracted with ethyl acetate, the combined organic phases were dried by spinning, and the crude product was isolated and purified by silica gel column to give intermediate 298-1(1.6g,9.51mmol, 95.24% yield).

Step 2, preparation of intermediate 298-2

-78 ℃ conditions. DIBAL (15.11g,107.00mmol,18.93mL) was added dropwise to a solution of intermediate 298-1(9.0g,53.50mmol) in DCM (60mL), after the addition was completed, the reaction was allowed to proceed for 2 hours with incubation, TLC checked for completion of the reaction, quenched by dropwise addition of water, the reaction solution was filtered, the filtrate was separated into layers, the crude product obtained was spin-dried on the organic phase, and purified by silica gel column separation to give intermediate 298-2(5.6g,44.38mmol, 82.95% yield).

Step 3, preparation of intermediate 298-3

To a solution of intermediate 298-2(1.5g,12.12mmol) in DCM (60mL) under an ice bath was added CBr₄(4.57g,13.94mmol), then PPh was added dropwise₃(3.33g,127.30mmol) in DCM (5 mL). The reaction was stirred at 0 ℃ for 1 h, then the reaction mixture was filtered and the crude product obtained after concentration of the filtrate was purified on silica gel column (eluent petroleum ether) to give intermediate 298-3(2.2g,11.6mmol, 95.96% yield).

Step 4, preparation of intermediate 298-4

To 298-3(1.4g,7.40mmol) and (2Z) -2- [ ((S) -tert-butylsulfinyl group) at room temperature]Ethyliminoacetate) (507mg, 2.47mmol) in THF (15mL) was added Sat. NaBr. H₂O (679.68mg,2.59mmol,30mL), followed by addition of Indium (1.13g,9.87 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen. The mixture was filtered, the filtrate diluted with water, extracted with ethyl acetate, and the combined organic phases washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude intermediate 298-4(770mg,2.44mmol) which was used in the next reaction without purification. MS m/z: 316.0(M +1) ⁺

Step 5, preparation of intermediate 298-5

And (5) performing ice-bath treatment. HCl/EA (4M, 0.5mL) was added dropwise to 298-4(150mg,475.48umol) in methanol (1.6mL), the reaction solution was stirred at room temperature for 1 hour, and then concentrated, the crude product was dissolved in a mixture of THF (2mL) and water (2mL), and NaHCO was added in ice bath₃(79.88mg,950.96umol) and CbzOSU (118.50mg,475.48umol) were sequentially added to the reaction mixture, the reaction mixture was stirred at room temperature for 30 minutes, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was then separated and purified by silica gel column to give intermediate 298-5(20mg,57.90umol, 12.18% yield). MS m/z: 346.0(M +1)⁺

Step 6, preparation of intermediate 298-6

To 298-5(500mg,1.45mmol) of dry dichloromethane (10mL) at room temperature under nitrogen was added CH₂ICl (1.1mL), cooling to subzero 20 ℃ to subzero 25 ℃, and slowly dropwise adding ZnEt₂(8.7mL), after the addition was complete, the reaction was stirred overnight at room temperature.

Quenching the reaction solution with saturated ammonium chloride, extracting with ethyl acetate, concentrating the combined organic phases to obtain a crude product containing about 10% of 298-5 unreacted, and dissolving the crude product in MeOH/THF/H₂O (1/1/1, 150mL total) solution, K was added₂OsO₄(70mg, 0.19mmol), the mixture was stirred at room temperature overnight, after completion of the reaction, the reaction mixture was concentrated, diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, and concentrated to give a crude product, which was isolated and purified by silica gel column to give intermediate 298-6(313mg, yield 59%). MS m/z: 360.0(M +1) ⁺

Step 7, preparation of intermediate 298-7 to 298-6(420mg,1.17mmol) in THF (2mL)/MeOH (2mL)/H₂Adding LiOH, H2O (147.22mg,3.51mmol) into a mixed solution of O (2mL), stirring the reaction solution at room temperature overnight, concentrating the reaction solution under reduced pressure after the reaction is finished, diluting a crude product with water, adjusting the pH value of the crude product to 4-6 with 6N diluted hydrochloric acid, extracting with dichloromethane, drying a combined organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain an intermediate 298-7(340mg,1.03mmol, 87.80% yield), MS m/z: 332.0(M +1)⁺

Preparation of Compound 298

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 298-7 above and 6-6a of step 6 of example 6 (prepared by chiral resolution of SFC to give a single configuration), the reaction proceeds by condensation, ring closure, ester hydrolysis, condensation with intermediate 9 of example 9, deprotection, and finally reaction with methyl chloroformate to give compound 298-a, MS m/z: 582.0(M +1)⁺

Similarly, 298-7 was compared with example 6, steps 66-6b (prepared by SFC chiral resolution)Another single configuration) as a starting material, through the same procedure, to give compound 298-b,¹H NMR(400MHz,Methanol-d₄)δ7.68–7.40(m,2H),7.26(dd,J＝8.6,1.8Hz,1H),4.96(d,J＝9.4Hz,1H),4.35(d,J＝8.6Hz,1H),4.02(d,J＝9.5Hz,1H),3.73(d,J＝9.6Hz,1H),3.66(s,3H),3.44(s,3H),3.26–3.11(m,2H),2.63–2.45(m,2H),2.09–1.81(m,6H),1.79–1.70(m,2H),1.58(s,3H),1.53–1.15(m,4H),1.10(t,J＝7.3Hz,3H),1.01(s,3H),0.51–0.35(m,2H),0.30–0.18(m,2H).。

EXAMPLE 299 preparation of Compounds 299-a, 299-b

Preparation of intermediate 299-1

To a solution of 1-methoxycyclobutylamide (100mg,774.25umol) in dry THF (5mL) was added dropwise BH at room temperature ₃THF (3.87mmol,3.8mL) was then the reaction stirred at 65 ℃ overnight. The mixture was slowly cooled to 0 ℃ and the reaction was quenched with 4mL of methanol. The mixture was distilled under reduced pressure to give 299-1(85mg,738.02umol, 95.32% yield) as crude product which was used in the next step without purification, MS m/z: 116.0(M +1)⁺

Preparation of Compounds 299-a, 299-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediates 3-3b of example 3 and 6-6a of step 6 of example 6 (a single configuration was prepared by SFC chiral resolution), the reaction mixture was condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl was introduced, ester hydrolyzed, and finally condensed with intermediate 299-1 to give compound 298-a, MS m/z: 647.0(M +1)⁺

Similarly, starting from 3-3b in example 3 and step 66-6b in example 6 (another single configuration obtained by SFC chiral resolution), compound 299-b is obtained by the same procedure,¹HNMR(400MHz,Methanol-d₄)δ7.56–7.46(m,3H),7.42(d,J＝8.0Hz,1H),7.38–7.29(m,2H),7.28–7.20(m,2H),5.57(d,J＝8.2Hz,1H),4.41–4.33(m,1H),4.02(d,J＝9.5Hz,1H),3.94(s,1H),3.74(d,J＝9.6Hz,1H),3.58(s,3H),3.44(s,3H),2.72(s,3H),2.59(q,J＝7.6Hz,1H),2.02–1.82(m,6H),1.82–1.70(m,3H),1.57(s,3H),1.31(s,7H),1.07–1.00(m,3H),0.94–0.87(m,3H).。

EXAMPLE 300 preparation of Compounds 300-a, 300-b

Preparation of intermediate 300-7

Preparation of step 1, 300-1

Potassium tert-butoxide (16.91g,150.72mmol) was dissolved in THF (300mL) under nitrogen protection, triethylphosphonoacetate (33.6g,149.87mmol) was added dropwise with stirring, after completion of the addition, the reaction was carried out at room temperature for 30 minutes, a solution of p-bromoacetophenone (10g,50.24mmol) in THF (100mL) was added dropwise, and the solution was added dropwise over 20 minutes. The reaction was then refluxed for 3 hours. The reaction was concentrated and purified by column on silica gel (ethyl acetate/petroleum ether as eluent) to give intermediate 300-1(13.5g,50.16mmol, 99.84% yield) as a pale yellow oily liquid. MS m/z: 269.0(M +1) ⁺

Preparation of step 2, 300-2

DIBAL-H (14.17g,100.32mmol,100mL) was added dropwise to a solution of 300-1(13.5g,50.16mmol) in DCM (300mL) under nitrogen atmosphere while using a dry ice ethanol bath, and the incubation was continued for 1 hour. Then gradually warmed to room temperature, quenched with water, filtered, the filter cake washed with DCM, the combined organic phases in the filtrate dried and the crude isolated by silica gel column purification to give 300-2(8.4g,36.99mmol, 73.74% yield), MS m/z: 211.0(M +1)⁺

Preparation of step 3, 300-3

HBr (5.42g,66.93mmol,13.6mL) is added dropwise to a mixed solution of 300-2(7.6g,33.47mmol) of DCM (30mL) and PE (60mL) at normal temperature, the mixture is stirred at normal temperature for 2 hours after dropping, the reaction liquid is separated after standing, the lower aqueous phase is extracted with petroleum ether, the combined organic phases are dried by spinning, the crude product is separated and purified by a silica gel column, and 300-3(9.3g,32.07mmol, 95.83% yield) is obtained.

Preparation of step 4, 300-4

To a suspension of Zn (2.44g,37.24mmol) in DMF (100mL) was added sequentially the reaction mixture of E-ethyl-2- ((tert-butylsulfinamide) hexamethyleneimine) ester, 300-3(9g,31.04mmol), and elemental iodine (100mg, 0.4mmol) at room temperature overnight, diluted with water, extracted with ethyl acetate, and the combined organic phases were concentrated to give the crude 300-4 product (12.92g,31.03mmol, 100.00% yield) which was used in the next step without purification. MS m/z: 416.0,418.0(M +1) ⁺

Step 5, preparation of 300-5

Adding HCl/EA (2.19g,60.04mmol) dropwise into 300-4(12.5g,30.02mmol) methanol (50mL), stirring at room temperature for 1 hr after dropping, diluting the reaction solution with water, extracting with ethyl acetate, and extracting with Na₂CO₃Adjusting the pH to 8-9, extracting with ethyl acetate again, concentrating the organic phase to dryness, adding H into the oily solution in THF (70mL) in turn₂O(70mL)，K₂CO₃(8.30g,60.04mmol) and (Boc)₂O (13.10g,60.04mmol), stirring for 2 hours, refining to separate layers, extracting the aqueous layer with ethyl acetate, combining the organic phases, spin drying, and separating and purifying the crude product with silica gel column to obtain 300-5(1g,2.43mmol, 8.08% yield). MS m/z: 412.0,414.0(M +1)⁺

Preparation of step 6, 300-6

Pd/C (147.28mg,1.21mmol) and triethylamine (490.88mg,4.85mmol) were added to a solution of 300-5(1g,2.43mmol) in methanol, and the mixture was substituted for H₂Then, at H₂Stirring was carried out overnight at room temperature under protection. After the reaction was completed, filtration was carried out, the filtrate was dried by spinning, extraction was carried out with ethyl acetate, and the organic phase was dried by spinning to obtain 300-6(813.54mg,2.43mmol, 100.00% yield) as a pale yellow oil. Used in the next step without purification. MS m/z: 336.0(M +1)⁺

Preparation of Steps 7, 300-7

Adding NaOH (291.56mg,7.29mmol) and water (1mL) into 300-6(815mg,2.43mmol) ethanol (10mL), heating to 60 deg.C, reacting for 3 hr, concentrating the reaction solution, adding water, extracting with ethyl acetate, adding dilute hydrochloric acid into the water phase to adjust pH to 4-5, separating layers, collecting the organic layer The organic layer was spin dried to give 300-7(558mg,1.82mmol, 74.71% yield) as a pale yellow oil. MS m/z: 308.0(M +1)⁺

Preparation of Compounds 300-a, 300-b

Referring to the procedure of steps 1-6 of example 34, starting from the above intermediates 300-7 and 6-6a of step 6 of example 6 (a single configuration was prepared by SFC chiral resolution), the following steps were performed by condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazol-5-yl, ester hydrolysis, and finally condensation with intermediate 7-2 to give compound 300-a, MS m/z: 642.0(M +1)⁺

Similarly, starting from 300-7 and step 66-6b of example 6 (another single configuration obtained by SFC chiral resolution), compound 300-b is obtained by the same procedure,¹H NMR(400MHz,MeOD)δ8.02(s,0.3H),7.79–7.45(m,4H),7.38-7.26(m,3H),6.71(d,J＝8.8Hz,0.3H),5.57(d,J＝12.0Hz,1H),4.75(d,J＝8.4Hz,1H),4.37-4.34(m,1H),4.10–3.96(m,3H),3.60–3.41(m,4H),3.25–3.05(m,2H),2.90–2.79(m,1H),2.67-2.60(m,1H),2.07-2.00(m,1H),1.93-1.88(m,1H),1.87–1.73(m,1H),1.59-1.51(m,1H),1.49–1.31(m,2H),1.09-1.06(m,6H),0.97(s,3H),0.77-0.72(m,1H),-0.01–-0.08(m,1H),-0.22(t,J＝7.6Hz,2H).。

EXAMPLE 301 preparation of Compounds 301-a, 301-b

Referring to the method of example 34, steps 1-6, using intermediate 298-7 of example 298 and 6-6a of step 6 of example 6 (SFC chiral resolution preparation yields a single configuration) as starting materials, condensing, ring closing, ester hydrolyzing, introducing a trifluoroacetyl group, deprotecting, and finally condensing with intermediate 7-2 to obtain compound 301-a, MS m/z: 620.0(M +1)⁺。

Similarly, starting from 298-7 and step 66-6b of example 6 (another single configuration produced by SFC chiral resolution), compound 301-b is obtained via the same procedure.

EXAMPLE 302 preparation of Compounds 302-a, 302-b

Referring to the procedure of steps 1-6 of example 34, starting from 2-Boc-ammonia-3- (2-chlorophenyl) -3-methoxypropionic acid and 6-6a of step 6 of example 6 (prepared by SFC chiral resolution to give a single configuration), condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazol-5-yl, ester hydrolysis, and final condensation with intermediate 7-2 gave compound 302-a, MS m/z: 664.0(M +1)⁺

Similarly, starting from 2-Boc-ammonia-3- (2-chlorophenyl) -3-methoxypropionic acid and step 66-6b in example 6 (another single configuration prepared by SFC chiral resolution), compound 302-b was obtained via the same procedure. ,¹HNMR(400MHz,CD3OD)δ7.61-7.24(m,8H),6.94(d,J＝2.1Hz,1H),5.91(d,J＝3.4Hz,1H),5.52(d,J＝3.4Hz,1H),4.37(d,J＝8.7Hz,1H),4.02(d,J＝9.6Hz,1H),3.91(s,3H),3.74(d,J＝9.6Hz,1H),3.44(s,3H),3.31(s,3H),3.19(m,2H),2.58(m,1H),2.00-1.73(m,6H),1.59(s,3H),1.32-1.06(m,2H),0.93(s,3H),0.94-0.85(m,1H).

EXAMPLE 304 preparation of Compounds 304-a, 304-b

Preparation of intermediate 304-5

Step 1, preparation of intermediate 304-1

Ethyl nitroacetate (118.66g,891.50mmol) was added to a solution of cyclohexylacetaldehyde (100g,891.50mmol) in THF (1.5L) under ice-bath, the reaction was replaced with nitrogen, and TiCl was slowly added₄(169.10g,891.50mmol), and the reaction mixture was stirred for 30 minutes. 4-methylmorpholine (90.18g,891.50mmol) was added slowly and carefully under ice-cooling followed by stirring for 4 hours. Slowly pouring the reaction solution into ice water, and extracting with ethyl acetateThe organic phase was concentrated to give intermediate 304-1(60g,264.02mmol, 98.72% yield) as a crude yellow oil which was used directly in the next reaction.

Step 2, preparation of intermediate 304-2

To 304-1(60g,264.02mmol) of CH under ice-bath₃OH (500mL) was slowly added CH₃ONa (57.03g,1.06mol), the reaction was slowly warmed to room temperature and stirred for 3 h, the mixture was diluted with water, extracted with ethyl acetate and the organic phase was dried by spinning to give intermediate 304-2(68g,262.25mmol, 99.33% yield) as a yellow oil.

Step 3, preparation of intermediate 304-3

Zn (3.2g, 50.14mmol) was added slowly in portions to 304-2(13g,50.14mmol) in acetic acid (180mL) under ice bath. The reaction was stirred at room temperature for 4 hours, filtered, the filtrate was spin-dried, the crude product was diluted with saturated sodium carbonate, extracted with ethyl acetate, and the organic phase was concentrated to give the crude product which was separated and purified by reverse phase HPLC to give intermediate 304-3(10g,43.6mmol, 87% yield) as a yellow oil.

Step 4, preparation of intermediate 304-4

To 304-3(7g,30.53mmol) in DCM (100mL) was added Cbz-Osu (8.36g,33.58mmol) and TEA (6.18g,61.05mmol,8.52 mL). The reaction was stirred overnight at room temperature. The mixture was concentrated and purified by silica gel column separation (PE/EA 4:1) to give intermediate 304-4(5g,13.76mmol, 45.07% yield) as a yellow oil.

Step 5, preparation of intermediate 304-5

To a mixture of 304-4(2g,5.50mmol) in methanol (8mL) and water (6mL) was added NaOH (330.17mg,8.25mmol), the reaction was stirred at room temperature for 1 hour, the organic phase was spun dry, the crude product was extracted with dichloromethane, the aqueous phase was adjusted to acidic pH with 1M HCl <3, re-extraction with ethyl acetate and spin-drying of the organic phase gave 304-5(1.5g, 4.5mmol, 81% yield). MS m/z: 336.0(M +1)⁺

Preparation of Compounds 304-a, 304-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 304-5 and 6-6a of step 6 of example 6 (prepared by SFC chiral resolution to give a single configuration), condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazol-5-yl, ester hydrolysis and final condensation with intermediate 7-2 gave compound 304-a, MS m/z: 664.0(M +1)⁺.

Similarly, starting from 304-5 and step 66-6b of example 6 (another single configuration produced by SFC chiral resolution), compound 304-b is obtained via the same procedure. ,¹H NMR(400MHz,Methanol-d₄)δ7.55(d,J＝2.1Hz,1H),7.33–7.21(m,1H),6.99(d,J＝2.2Hz,1H),5.65(d,J＝2.6Hz,1H),4.40–4.28(m,1H),4.12(s,3H),4.01(d,J＝9.5Hz,1H),3.73(d,J＝9.5Hz,1H),3.63–3.56(m,1H),3.43(s,3H),3.27–3.09(m,5H),2.64–2.51(m,1H),2.05–1.67(m,12H),1.58(s,3H),1.36–1.15(m,8H),1.14–1.06(m,3H)

EXAMPLE 305 preparation of Compounds 305-a, 305-b

Referring to the procedure of steps 1-6 of example 34, 2-Boc-ammonia-3- (2-chlorophenyl) -3-methoxypropionic acid was condensed, ring-closed, ester-hydrolyzed, condensed with intermediate 7-2 of example 7, deprotected, and finally reacted with methyl chloroformate to give compound 305-a, MS m/z: 614.0(M +1)⁺

Similarly, starting from 2-Boc-ammonia-3- (2-chlorophenyl) -3-methoxypropionic acid and step 66-6b in example 6 (another single configuration prepared by SFC chiral resolution), compound 305-b was obtained via the same procedure. , ¹H NMR(400MHz,Methanol-d₄)δ7.61-7.53(m,3H),743–7.33(m,3H),7.26(dd,J＝8.5,1.8Hz,1H),5.41-4.37(m,2H),4.42–4.32(m,1H),4.02(d,J＝9.6Hz,1H),3.74(d,J＝9.6Hz,1H),3.54(s,2H),3.44(s,3H),3.24(s,3H),3.28–3.11(m,1H),2.60-2.56(m,1H),1.95-1.77(m,3H),1.59(s,3H),1.31(s,3H),1.11(t,J＝7.3Hz,3H),0.96–0.85(m,2H).

EXAMPLE 306 preparation of Compounds 306-a, 306-b

Preparation of intermediate 306-7

Referring to the preparation method of intermediate 298-7 in example 298, cyclohexane formaldehyde was used as a raw material, and the raw material was sequentially subjected to Horner-Wittig reaction, DIBAL oxidation, CBr₄Bromo, (2Z) -2- [ ((S) -tert-butylsulfinyl group]Ethyl iminoacetate) to obtain compound 306-4, removing Cbz protected amino group from tert-butylsulfinyl group, chloroiodomethane and diethyl zinc to close cyclopropane, separating and purifying to obtain the invented product. Finally, the ester is hydrolyzed to obtain an intermediate 306-7.

Preparation of Compounds 306-a, 306-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediate 306-7 above and 6-6a of step 6 of example 6 (prepared by SFC chiral resolution to give a single configuration), the reaction mixture is condensed, ring-closed, deprotected, 1-methyl-1H-pyrazol-5-yl introduced, hydrolyzed, and finally condensed with intermediate 7-2 to give compound 306-a, MS m/z: 660.0(M +1)⁺。

Similarly, using 306-7 and step 66-6b (another single configuration obtained by SFC chiral resolution preparation) in example 6 as raw materials, compound 306-b is obtained through the same steps,¹H NMR(400MHz,Methanol-d₄)δ7.93(t,J＝4.9Hz,1H),7.58(t,J＝2.4Hz,1H),7.55–7.49(m,2H),7.43(t,J＝7.6Hz,1H),7.27(ddd,J＝8.6,5.7,1.8Hz,1H),6.89(dd,J＝21.8,2.1Hz,1H),5.72(dd,J＝11.2,8.6Hz,1H),4.40–4.27(m,1H),4.10(s,3H),4.01(d,J＝9.6Hz,1H),3.73(d,J＝9.5Hz,1H),3.44(s,3H),3.26–3.10(m,2H),2.58(q,J＝7.8Hz,1H),2.04–1.66(m,12H),1.59(s,3H),1.49(dd,J＝8.7,6.2Hz,1H),1.15(s,2H),1.13–1.06(m,6H),0.53–0.44(m,1H),0.39–0.30(m,1H),0.30–0.22(m,1H),0.19–0.12(m,1H)。

EXAMPLE 307 preparation of Compounds 307-a, 307-b

Referring to the procedure of steps 1-6 of example 34, starting from 305-7 and 6-6a of step 6 of example 6 (a single configuration was obtained by SFC chiral resolution), condensation, ring closure, ester hydrolysis, condensation with intermediate 7-2 of example 7, deprotection, and finally reaction with methyl chloroformate gave compound 307-a, MS m/z: 624.0(M +1)⁺。

Similarly, starting from 305-7 and step 66-6b of example 6 (another single configuration prepared by SFC chiral resolution), compound 307-b is obtained via the same procedure.

EXAMPLE 308 preparation of Compounds 308-a, 308-b

Referring to the procedure of steps 1-6 of example 34, starting from intermediates 3-3b of example 3 and 6-6a of step 6 of example 6 (a single configuration was prepared by SFC chiral resolution), condensation, ring closure, ester hydrolysis, condensation with intermediate 7-2 of example 7, deprotection, and finally introduction of trifluoroacetyl group gave compound 308-a, MS m/z: 676.0(M +1)⁺。

Analogously, starting from 3-3b and example 6, step 66-6b (another single configuration prepared by SFC chiral resolution), the same procedure gave compound 308-b, 1H NMR (400MHz, Methanol-d4), δ 7.73-7.55 (m,2H), 7.55-7.42 (m,3H), 7.38-7.25 (m,3H),5.91(d, J ═ 12.1Hz,1H), 4.42-4.34 (m,1H),4.04(d, J ═ 9.5Hz,1H), 3.82-3.73 (m,2H),3.46(s,3H), 3.26-3.13 (m,2H), 2.64-2.55 (m,1H), 2.00-1.72 (m,6H),1.61(s,3H), 1.26-3.13 (m,2H), 2.64-2.55 (m,1H), 2.00-1.72 (m,6H),1.61(s,3H), 1.03-0.08 (m, 0.07-0.07 (m, 3H).

In order to illustrate the advantageous effects of the present invention, the present invention provides the following test examples.

Test example 1: IL-17 enzyme-linked immunosorbent assay (ELISA) assay

1. Experimental methods

The inhibitory effect of the test compound on receptor-ligand binding is quantitatively determined by a competitive ELISA assay. The specific steps are as follows: IL-17A (Nano Biological incc. Cat #12047-H07B) at 0.2. mu.g/mL (100. mu.L, 50mM phosphate buffer, pH7.4) was incubated in 96-well plates at 37 ℃ for 30 minutes. The plate was washed 4 times with PBST (PBS, 0.05% Tween-20), 200. mu.L of each well was added 200. mu.L of 5% skim milk and incubated for 30 minutes on a 25 degree shaker. 100X concentrations of test compound (compound prepared in the examples) were prepared, with final concentrations ranging from 0.0002. mu.M to 30. mu.M. The plates were washed 4 times with PBST (PBS, 0.05% Tween-20), mixed with 89. mu.L of PBST and 1. mu.L of 100 Xconcentration test compound, and preincubated at 25 ℃ for 10 minutes. Add 10. mu.L of 16nM IL-17R (Nano Biological lnc. Cat #10895-H03H) and incubate for 30 min on a 25 degree shaker. After washing the plate 4 times, 100. mu.L of anti-Fc-tag HRP-conjugated antibody (Nano Biological lnc. Cat #10702-T16-H-50) was added and incubated for 30 minutes on a 25 degree shaker. After washing the plate 4 times, 100. mu.L of TMB substrate solution was added and incubated at 25 ℃ in the dark. After addition of 100. mu.L of 2.5M HCl, the absorbance was measured at a wavelength of 450nm using a microplate reader.

2. Results of the experiment

The inhibitory activity of the compounds prepared in examples against IL-17A was measured according to the above-mentioned method, and the results are shown in Table 1, in which IC of each compound₅₀Classified according to the following description, table 1:

"+" denotes IC₅₀Measuring less than 100. mu.M and greater than 1. mu.M;

"+ +" denotes IC₅₀Measured at less than 1 μ M and greater than 100 nM;

"+ + + +" denotes IC₅₀The assay was less than 100 nM.

TABLE 1 inhibitory Activity of Compounds on IL-17A

Test results show that the compound provided by the invention has good IL-17A inhibitory activity, can be used as an IL-17A inhibitor and is used for preparing medicines for treating diseases related to IL-17A activity abnormity.

In conclusion, the compound shown in the formula I disclosed by the invention shows good IL-17A inhibitory activity, can be used for preparing IL-17A inhibitors and medicines for preventing and/or treating IL-17A mediated diseases (such as inflammation, autoimmune diseases, infectious diseases, cancer, precancerous syndrome and the like), and provides a new medicinal possibility for clinically treating diseases related to IL-17A activity abnormity.

Claims

1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R₁selected from hydrogen, -C_1～10Alkyl, -C _0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

X₁selected from the group consisting of CR_x1Or N;

X₂selected from NR_x2O, S or- (CR)_x3＝CR_x4)-；

R_x2selected from hydrogen, -C_1～10Alkyl, -C (O) (C)_1～10Alkyl groups);

L₁is selected from-C_1～10Alkylene-;

R₅is selected from-C_1～10Alkyl, halogen substituted-C_1～10An alkyl group;

R_L21Selected from hydrogen, -C_1～10An alkyl group;

R_a、R_a’each independently selected from hydrogen and-C_1～10Alkyl radicalHalogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 12-membered spiro), -C_0～4Alkylene- (5-12 membered spiroheterocycle), -C_0～4Alkylene- (5-to 12-membered bridged ring), -C_0～4Alkylene- (5-to 12-membered bridged heterocycle), -O (C)_1～10Alkyl), -O (C)_0～4Alkylene) (3-to 10-membered cycloalkyl), -O (C)_0～4Alkylene) (3-to 10-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle is further substituted with one, two or three R_a1Substitution;

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R₁Selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R₁₃Substitution;

each R₁₃Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl radical)、-NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups);

R₃、R₄each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -O (C)_1～6Alkyl), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl are further substituted by one, two or three R ₃₁Substitution;

each R _A4Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_A2、-C_0～2alkylene-OC (O) R_A2、-C_0～2alkylene-C (O) R_A2、-C_0～2alkylene-C (O) OR_A2、-C_0～2alkylene-C (O) NR_A2R_A3、-C_0～2alkylene-NR_A2R_A3、-C_0～2alkylene-NR_A2C(O)R_A3；

R_A2、R_A3Each independently selected from hydrogen and-C_1～6An alkyl group;

X₁selected from the group consisting of CR_x1Or N;

X₂selected from NR_x2O, S or- (CR)_x3＝CR_x4)-；

R_x2selected from hydrogen, -C_1～6Alkyl, -C (O) (C)_1～6Alkyl groups);

L₁is selected from-C_1～6Alkylene-;

R₅is selected from-C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

R_L21Selected from hydrogen, -C_1～6An alkyl group;

r is selected from-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle), -C_0～2Alkylene- (6-to 11-membered spiro), -C_0～2Alkylene- (6-to 11-membered spiroheterocycle), -C_0～2Alkylene- (5-to 10-membered bridged ring), -C_0～2Alkylene- (5-to 10-membered bridged heterocycle),

R_b、R_ceach independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is further substituted with one, two or three R _b1Substitution;

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: the compound of formula I is represented by formula II:

wherein the content of the first and second substances,

R₁selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Or wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl is further substituted with one, two or three independent R ₁₃Substitution;

each R₃₁Independently selected from halogen, cyano, carbonyl, nitro, -C _1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl);

R_A2、R_A3Each independently selected from hydrogen and-C _1～6An alkyl group;

L₁is selected from-C_1～6Alkylene-;

R₅is selected from-C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

R_b、R_ceach independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl) -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene-, (ii) alkylene5-6 membered aromatic heterocycle); or wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is further substituted with one, two or three R _b1Substitution;

4. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

5. The compound of claim 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: r ₁Is selected from

Preferably, said C_1～3The alkyl is selected from methyl, ethyl,

The halogen is selected from fluorine, chlorine and bromine.

6. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R₃、R₄each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, -O (C)_1～6Alkyl), -O (3-6 membered cycloalkyl); or wherein alkyl, cycloalkyl, heterocycloalkyl are further substituted by one, two or three R₃₁Substitution;

7. The compound of claim 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: r₃、R₄At least one is hydrogen; preferably, R₃、R₄One is hydrogen and the other is selected from the group consisting of halogen or methyl substituted: c_1～3Alkyl radical, C_1～3Alkoxy radical,

More preferably, said C_1～3The alkyl is selected from methyl, ethyl,

The halogen is selected from fluorine, chlorine and bromine.

8. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R_A2、R_A3Each independently selected from hydrogen and-C_1～6An alkyl group;

preferably, ring A is selected from a benzene ring, a 4-6 membered saturated cycloalkyl group, or wherein the benzene ring, the 4-6 membered saturated cycloalkyl group are further substituted with one, two or three R_A1Substituted, each R_A1Each independently selected from halogen, preferably halogenFluorine, chlorine and bromine.

9. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: l is ₁Is selected from-C_1～4Alkylene-; r₅Is selected from-C_1～4An alkyl group; r₆Selected from hydrogen, -C_1～4An alkyl group.

10. The compound according to claim 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: l is₁Selected from methylene, ethylene, n-propylene, isopropylene; r₅Selected from methyl, ethyl, n-propyl, isopropyl; r₆Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl.

11. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

The bridge ring is

12. The compound according to claim 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: r _aIs selected from

Or, therein

13. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

14. The compound according to claim 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: r_b、R_cAt least one is hydrogen; preferably, R_b、R_cOne is hydrogen and the other is L_cR_c1；L_cIs selected from C_0～2Alkylene, preferably none, methylene, ethylene; r_c1Is selected from C_1～2Alkyl, aryl, heteroaryl, and heteroaryl,

Or, wherein C_1～2Alkyl, aryl, heteroaryl, and heteroaryl,

15. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: r_a、R_bAre linked to form a 5-to 12-membered spiroheterocycle, further wherein said spiroheterocycle is

16. A compound according to any one of claims 3 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that:

R₂is hydrogen.

17. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: the structure of the compound is shown as formula III:

wherein R is₁As claimed in claim 4 or 5;

R₂is hydrogen;

R₃、R₄as claimed in claim 6 or 7;

ring a is as defined in claim 8;

R₅、R₆、L₁as claimed in claim 9 or 10;

n is an integer of 0 to 3, preferably 0 to 1;

R_fselected from hydrogen, L₀R_f1(ii) a Wherein L is₀Is C_0～3Alkylene, preferably none or methylene; r_f1Selected from amino, hydroxy, C_1～3Alkyl radical, C_1～3Alkoxy, COOCH₃；

The substituent is selected from halogen, hydroxyl and C_1～3Alkyl radical, C_1～3Alkoxy, said halogen being preferably fluorine.

18. A compound according to any one of claims 1 to 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: the compound is selected from:

19. Use of a compound of any one of claims 1-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an IL-17A-mediated disease.

20. The use according to claim 19, characterized in that: the IL-17A mediated disease is one or more of inflammation, autoimmune disease, infectious disease, cancer, precancerous syndrome related diseases, preferably rheumatoid arthritis, bone erosion, intraperitoneal abscess, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma or multiple sclerosis.

21. Use of a compound of any one of claims 1-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of an inhibitor of IL-17A.

22. A pharmaceutical composition characterized by: the compound or the stereoisomer or the pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable auxiliary materials.