CN112341519A

CN112341519A - Immunomodulator

Info

Publication number: CN112341519A
Application number: CN202010781008.1A
Authority: CN
Inventors: 李进; 张登友; 洪新福; 黄昊岚; 白晓光; 尚巳耘; 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

Abstract

The invention discloses an immunomodulator, and particularly relates to a compound for inhibiting IL-17A and application thereof as an immunomodulator in preparation of a medicament. The invention discloses application of a compound shown as a formula I or a stereoisomer thereof in preparing IL-17A inhibiting medicines, and provides a new choice for clinically screening and/or preparing medicines for diseases related to IL-17A activity.

Description

Immunomodulator

Technical Field

The invention relates to an immunomodulator and application thereof in preparing 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 a major role in severe asthma and Chronic Obstructive Pulmonary Disease (COPD), and those patients generally 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 has been implicated in 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.

Targeting the binding of IL-17A to IL-17RA is an effective strategy for the treatment of IL-17A-mediated autoimmune inflammatory diseases. Treatment of animals with IL-17A neutralizing antibodies reduces disease incidence and severity in autoimmune encephalomyelitis (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.

Despite the existence of a variety of IL-17A antibodies, few small molecule specific inhibitors of IL-17 have been studied for oral bioavailability. In view of the cost consideration of antibody production and the limitation of administration route, the development of IL-17A small-molecule inhibitor drugs has good development prospect.

Disclosure of Invention

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 Wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6Alkyl, -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); wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaromatic ring may be further substituted by one, two or three R₃₁Substitution;

or R₃、R₄Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; whereinCycloalkyl, heterocycloalkyl may be 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 a 5-10-membered aromatic ring, a 5-10-membered aromatic heterocycle and a 3-10-membered cycloalkyl; wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by 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); wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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;

R₅selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl);

Y₁、Y₂、Y₃、Y₄each independently selected from N or CR_Y1；

Each R_Y1Independently selected from hydrogen, halogen, cyano, 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);

R₆、R₇are respectively and independently selected from hydrogen, halogen and C_1～10An alkyl group, a 3-to 10-membered cycloalkyl group, a 3-to 10-membered heterocycloalkyl group; wherein alkyl, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R₆₁Substitution;

or, R₆And R₇Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl, may be further substituted by one, two or three R₆₁Substitution;

each R₆₁Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-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);

l is selected from-C_0～4alkylene-C (O) NR_L21-、-C_0～4alkylene-NR_L21C(O)-、-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),

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; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted by one, two or three R_a1Substitution;

or R_a、R_a’Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be 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 oxideA group- (5-to 10-membered aromatic heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R_b1Substitution;

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 Wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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); wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaromatic ring may be further substituted by one, two or three R₃₁Substitution;

or R₃、R₄Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be 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 and a 3-6-membered cycloalkyl; wherein the aromatic ring, aromatic heterocycle, cycloalkyl may be further substituted by 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); wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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, -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;

R₅selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

Y₁、Y₂、Y₃、Y₄each independently selected from N or CR_Y1；

Each R_Y1Independently selected from hydrogen, halogen, cyano, 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);

R₆、R₇are respectively and independently selected from hydrogen, halogen and C_1～6Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; wherein the alkyl, cycloalkyl, heterocycloalkyl may be further substitutedStep by one, two or three R₆₁Substitution;

or, R₆And R₇Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl, may be further substituted by one, two or three R₆₁Substitution;

each R₆₁Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-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);

l is 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),

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; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle may be 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), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be 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);

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-memberedA heterocycloalkyl group.

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

wherein the content of the first and second substances,

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

R₅selected from hydrogen, -C_1～6An alkyl group;

R₆、R₇are respectively and independently selected from hydrogen, halogen and C_1～6Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; wherein alkyl, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R₆₁Substitution;

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); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted by one, two or three R_a1Substitution;

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

Further:

R₁is selected from-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 Wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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 specifically, R₁Is selected from

R₁₃Selected from hydrogen and methyl.

Further, in the present invention,

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, 5-to 6-membered arylheterocyclyl, -O (C)_1～6Alkyl), -O (3-6 membered cycloalkyl); wherein the alkyl, cycloalkyl, heterocycloalkyl, arylheterocyclyl may be further substituted by one, two or three R₃₁Substitution;

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 specifically, R₃、R₄At least one is hydrogen.

Further, in the present invention,

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; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by 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.

More specifically: ring A is selected from benzene ring and cyclohexane; wherein the benzene ring and the cyclohexane ring can be further substituted by one, two or three R_A1Substitution;

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

Further, in the present invention,

R₆、R₇are respectively and independently selected from hydrogen and C_1～6An alkyl group; wherein the alkyl group may be further substituted by one R₆₁Substitution;

R₆₁each independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups).

Further, R₆And R₇Are linked to form a 3-to 6-membered heterocycloalkyl group in which the heteroatom is an oxygen atom.

Further, in the present invention,

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); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle may be 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).

More specifically: r_aIs selected from 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein the 3-6 membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the hetero atoms of the heterocycloalkyl are O and/or N, wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_a1Substitution;

Further, in the present invention,

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); wherein alkyl, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_b1Substitution;

Further specifically, R_b、R_cAt least one is hydrogen.

In some embodiments of the invention, the compound of formula II is specifically:

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

wherein the content of the first and second substances,

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), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R₃₁Substitution;

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

R₅selected from hydrogen, -C_1～6An alkyl group;

or, R₆And R₇Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl, may be further substitutedOne, two or three R₆₁Substitution;

R_beach 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); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R_b1Substitution;

Further:

the R is₁Is selected from

R₁₃Selected from hydrogen, methyl;

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

the ring A is selected from benzene ring and cyclohexane; wherein the benzene ring and the cyclohexane ring can be further substituted by one, two or three R_A1Substitution;

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

R₆、R₇are respectively and independently selected from hydrogen and C_1～6An alkyl group; wherein the alkyl group may be further substituted by one R₆₁Substitution; r₆₁Each independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups);

R_aselected from hydrogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl.

In some embodiments of the invention, the compound of formula III is specifically:

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

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.

"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), 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.

"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. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:

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.

"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.

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 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.

Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Enduragi chemistry, Chengdulong chemistry, Shaoshi chemistry technology, and Bailingwei technology.

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 or N is, unless otherwise specified, mol per liter.

The room temperature is the most suitable reaction temperature and is 20-30 ℃.

The% herein is expressed as a mass percentage unless otherwise specified.

THF: tetrahydrofuran; DCM: dichloromethane.

TEA is triethylamine; DMF: dimethylformamide (DMF).

DIPEA: n, N-diisopropylethylamine; TFA: trifluoroacetic acid.

HFIP: hexafluoroisopropanol.

EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

HOAt: n-hydroxy-7-azabenzotriazole.

HBTU: benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate.

EXAMPLE 1 preparation of intermediate amino acid 1

Step 1 preparation of intermediate 1-1

THF (3500mL) was added to a 10L three-necked flask equipped with mechanical stirring and nitrogen blanket, o-chlorobenzaldehyde (341g,2.43mol) and ethyl nitroacetate (323g,2.43mol) were added in this order, followed by cooling in an ice-salt bath to an internal temperature of-10 ℃ and TiCl was slowly added dropwise with mechanical stirring₄(920g,4.85mol), controlling the internal temperature not to exceed 0 ℃ when dropwise adding, keeping the temperature to continue reacting for 0.5h, then dropwise adding N-methylmorpholine (981.51g,9.70mol), controlling the internal temperature not to exceed 15 ℃ when dropwise adding, heating 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 solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating by silica gel column chromatography 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 is finished, 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 used for extraction, organic phases are combined and washed by water, saturated sodium chloride is washed by water, anhydrous sodium sulfate is dried, the filtration and the decompression are carried out on the organic phases, and the crude product is separated by silica gel column chromatography to obtain the intermediate 1-2(377g,1.26mol, 45.80% yield).

Step 3 preparation of intermediates 1-3

A10L three-necked flask equipped with mechanical stirring was charged with intermediates 1 to 2(730g,2.44mol) and glacial acetic acid (6L), cooled in an ice bath to 0 ℃ and zinc powder (796.24g,12.18mol) was added in portions with mechanical stirring while controlling the internal temperature at below 60 ℃. After the addition is finished, the reaction is continuously 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 (the volume ratio of petroleum ether to ethyl acetate is 50: 1-10: 1) to obtain an intermediate 1-3 (a mixture with the configuration of enantiomer (2S,3S) and (2R,3R), the point with lower polarity of Thin Layer Chromatography (TLC)), 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, adding 300mL of water, extracting with ethyl acetate (300mL multiplied by 2), combining organic phases, washing with saturated sodium chloride water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying a crude product by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 100: 1-50: 1) to obtain an intermediate 1-4(39.4g,106.52mmol, 47.89% yield), MS M/z:270[ M-99: 270%]⁺，314[M-55]⁺。

Step 5 preparation of intermediate 1

Adding NaOH (6.49g,162.21mmol) into a suspension of the intermediate 1-4(20.00g,54.07mmol) in methanol (100mL) and water (10mL), heating to 50 ℃ for reaction for 3 hours, concentrating the reaction solution after the reaction is finished, adding 100mL of water, extracting once with ethyl acetate (100mL), cooling the aqueous phase to 0-5 ℃, and using 1M of waterAdjusting pH to 3-4 with HCl, extracting with ethyl acetate (100mL), concentrating the organic phase under reduced pressure to obtain intermediate 1 in the form of one enantiomer (17.8g,52.07mmol, 96.30% yield) as yellow oil, separating the enantiomer by chiral separation with Supercritical Fluid Chromatography (SFC) to obtain (2S,3S) enantiomer 1, 6.5g, MS M/z:242[ M-99)]⁺，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 in methanol, wavelength 589nm), and the specific optical rotation of the (2R,3R) configuration was-72.60 ° (25 ℃,0.098g/100ml in methanol, wavelength 589 nm).

EXAMPLE 2 preparation of intermediate amino acid 2

Step 1 preparation of intermediate 2-2

Referring to example 1, the intermediate 1-2 was prepared from intermediate 1-1 by reacting it with isopropenylmagnesium bromide in 37% yield, MS M/z:298(M +1)⁺。

Step 2 preparation of intermediates 2-3

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

Step 3 preparation of intermediates 2-4

Reference example 1 preparation of intermediates 1-4 from Boc anhydride protected amino group, MS M/z 368[ M +1]⁺，312[M-55]⁺。

Step 4 preparation of intermediates 2-5

Ferric nitrate nonahydrate (439.29mg,1.09mmol) was dissolved in 10ml of water, ultrasonically degassed at 0 ℃ for 10min and protected with nitrogen, followed by the addition of 10ml of acetonitrile followed by 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo [ 2.2.2%]Octane bis (tetrafluoroborate) (384.92mg,1.09mmol) was prepared by dissolving intermediate 2-4(100mg,271.84umol) in 10ml of acetonitrile and NaBH, respectively, at 0 deg.C₄(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 after reaction, extracting with DCM, drying organic phase with sodium sulfate, concentrating under reduced pressure, spin drying, and separating and purifying crude product with silica gel column to obtain intermediate 2-5.

Step 5 preparation of intermediate 2

Reference example 1 preparation of intermediates 1 to 5, obtained by hydrolysis with sodium hydroxide, MS M/z:284[ M-55]]⁺. The four isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 2 can be respectively obtained by separation and preparation of a Supercritical Fluid Chromatography (SFC) chiral separation column.

Example 3 preparation of intermediate chiral cyclopropylmethyl amino acids 3a,3b

Step 1 preparation of intermediate 3-1

Diastereoisomer 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 volume ratio 100:1) to give an enantiomer of intermediate 2-4, a mixture of (2S,3S) and (2R,3R) configurations which was less polar on TLC plate chromatography, the enantiomer (1.7g,4.62mmol) was taken, dissolved in 20ml of dry DCM under nitrogen, cooled to an internal temperature of-30 ℃ and ZnEt was added₂(1M in tetrahydrofuran, 27.73mL), -stirring at 30 ℃ for 1 hour followed by the addition of diiodomethane (9.90g,36.97mmol) while maintaining the internal temperature at-20 ℃ and allowing the internal temperature to slowly rise to room temperature and stirring overnight, LC-MS showed about 30% of the Boc removed by-product of the starting material 2-4, adding 5mL of water to quench and concentrating the organic phase under reduced pressure to dryness to give crude 1g, which was then 3-1 in Boc removed form and 2-4 in Boc removed mixture, dissolving the mixture in 10mL of THF, and adding Triethylamine (TEA) (897.78mg,8.87mmol,1.24mL) and (Boc) in sequence₂O (1.16g,5.32mmol), stirred at room temperature overnight, concentrated to dryness under reduced pressure, purified by silica gel column separation (petroleum ether/methyl t-butyl ether volume ratio 100:3) to give a mixture of crude Boc-protected cyclopropylmethylethyl ester 3-1 and unreacted intermediate 2-4 from the previous step, 0.5g, dissolved in a mixture of tetrahydrofuran (5mL) and acetonitrile (5mL) and 5mL of water, added potassium osmate dihydrate (44.3mg,0.12mmol) and N-methyl-N-morpholine oxide (111mg,0.96mmol), removed unreacted 2-4 by double bond dihydroxylation, stirred at room temperature overnight, LC-MS monitoring shows that there is no unreacted intermediate 2-4, concentrated under reduced pressure to remove most of the organic solvent, extracted with ethyl acetate 15mL, concentrated organic phase, purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1) to give intermediate 3-1(0.5g,1.31mmol, 28% yield, mixture of 2S,3S and 2R,3R configurations), MS M/z:382[ M +1)]⁺。

Step 2 preparation of intermediate 3-2

Referring to example 1, intermediates 1 to 5 were prepared by hydrolysis with sodium hydroxide to give intermediates 3 to 2, MS M/z:298[ M-55]]⁺。

Step 3 preparation of intermediates 3a,3b

The intermediate 3-2 is in the form of a pair of enantiomers, and is separated by a Supercritical Fluid Chromatography (SFC) chiral column to respectively obtain a (2S,3S) enantiomer 3b and a (2R,3R) enantiomer 3a, and the MS M/z is 354[ M +1]]⁺. 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 methanol solution, wavelength 589nm), and the specific optical rotation of the (2R,3R) configuration was-40.695 ° (25 ℃,0.1g/100ml methanol solution, wavelength 589 nm).

Example 4 preparation of intermediate 4

Step 1 preparation of intermediate 4-1

At room temperature, intermediate 1-1(5g,19.56mmol) of example 1 was dissolved in methanol (50mL), sodium methoxide (4.23g,78.23mmol) was added, the reaction was stirred at room temperature for 2 hours, Thin Layer Chromatography (TLC) showed disappearance of the starting material, the solvent was removed by concentration under reduced pressure, saturated aqueous ammonium chloride solution (20 mL) was added, ethyl acetate (20mL × 2) was extracted, the organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was separated by silica gel column (petroleum ether/ethyl acetate volume ratio 4: 1) to give intermediate 4-1(3g,10.43mmol, 53.32% yield), pale yellow liquid, Rf 0.5 (hexane/EtOAc ═ 8: 1).

Step 2 preparation of intermediate 4-2

Dissolving intermediate 4-1(1.58g,5.48mmol) in 10mL glacial acetic acid, adding zinc powder (1.79g,27.41mmol), reacting at room temperature for 2 hours with stirring, filtering, washing with a small amount of ethyl acetate, concentrating the filtrate under reduced pressure to dryness, separating the crude product by silica gel column (the volume ratio of petroleum ether to ethyl acetate is 2:1) to obtain intermediate 4-2(0.83g,3.22mmol, 58.76% yield) as light yellow solid, MS M/z:258[ M +1 ].

Step 3 preparation of intermediates 4-3

Intermediate 4-2(0.83g,3.22mmol) was dissolved in a mixed solution of THF (3mL) and water (1mL), and NaHCO was added separately₃(541.11mg,6.44mmol) and Boc₂O (737.20mg,3.38mmol), stirring at room temperature for 12 hours, adding ethyl acetate (15mL) and water (15mL) for washing, washing the organic phase with water, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, separating the crude product with silica gel column (petroleum ether/ethyl acetate volume ratio of 4: 1) to obtain intermediate 4-3(1.1g,3.07mmol, 95.45% yield), light yellow liquid, MS M/z:302[ M-55 mmol: (M-X M X-M X)]。

Step 4 preparation of intermediate 4

Intermediate 4-3(1.23g,3.44mmol) was dissolved in a mixed solution of methanol (15mL) and water (15mL), and lithium hydroxide monohydrate (1.20g,28.53mmol) was added to stir the reaction at room temperature for 4 hours. The solvent is distilled off under reduced pressure, 0.5N HCl is dripped under ice bath to adjust the pH value to 4, ethyl acetate extraction-tetrahydrofuran 5:1 extraction is carried out, organic phase is concentrated under reduced pressure to obtain light yellow liquid (1.1g,3.34mmol,97.04 percent yield), and the crude product is separated by a Supercritical Fluid Chromatography (SFC) chiral separation column to prepare four isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 4. MS M/z 274[ M-55 ].

EXAMPLE 5 preparation of intermediate 5

Referring to the method for preparing the intermediate 4 of example 4, the intermediate 1-1 reacts with sodium ethoxide, is subjected to nitro reduction, Boc protection of amino group, hydrolysis, and finally is separated by a Supercritical Fluid Chromatography (SFC) chiral separation column to prepare four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) capable of respectively obtaining the intermediate 5. MS M/z 288[ M-55]]⁺。

EXAMPLE 6 preparation of intermediate 6

Referring to the method for preparing the intermediate 4 of example 4, the intermediate 1-1 reacts with sodium isopropoxide, is subjected to nitro reduction, Boc protection of amino group, hydrolysis, and finally is separated by a Supercritical Fluid Chromatography (SFC) chiral separation column to prepare four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) capable of respectively obtaining the intermediate 6. MS M/z 302[ M-55]]⁺。

Example 7 preparation of intermediate 7

Referring to the method for preparing the intermediate 4 of example 4, the intermediate 1-1 reacts with the cyclopropanol in the presence of potassium tert-butoxide, and then four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 7 can be obtained by nitro reduction, Boc protection of amino group, hydrolysis and separation by a Supercritical Fluid Chromatography (SFC) chiral separation column. MS M/z 300[ M-55]]⁺。

EXAMPLE 8 preparation of intermediate 8

Referring to the method for preparing the intermediate 1 in example 1, four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 8 can be respectively obtained by condensing propionaldehyde serving as a starting material with ethyl nitroacetate, formatting with o-chlorophenyl magnesium bromide, reducing with nitrozinc powder, protecting amino with Boc, hydrolyzing with alkali, and finally separating by a Supercritical Fluid Chromatography (SFC) chiral separation column. MS M/z 228[ M-99 ]]⁺，272[M-55]⁺。

EXAMPLE 9 preparation of intermediate 9

Referring to the method for preparing the intermediate 1 in example 1, four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 9 can be respectively obtained by using cyclopropanecarboxaldehyde as a starting material, condensing with ethyl nitroacetate, formatting with o-chlorophenyl magnesium bromide, reducing with nitrozinc powder, protecting with Boc to obtain amino, hydrolyzing with alkali, and finally separating by a Supercritical Fluid Chromatography (SFC) chiral separation column. MS M/z 228[ M-99 ]]⁺，272[M-55]⁺。

EXAMPLE 10 preparation of intermediate 10

Referring to the method for preparing the intermediate 1 in example 1, the four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 10 can be respectively obtained by using cyclobutane as a starting material, condensing with ethyl nitroacetate, formatting with o-chlorophenyl magnesium bromide, reducing with nitrozinc powder, protecting with Boc to obtain amino, hydrolyzing with alkali, and finally separating with a Supercritical Fluid Chromatography (SFC) chiral separation column. MS M/z 254[ M-99 ]]⁺，298[M-55]⁺。

EXAMPLE 11 preparation of intermediate 11

Referring to the method for preparing the intermediate 1 in example 1, four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 11 can be respectively obtained by using cyclohexyl formaldehyde as a starting material, condensing with ethyl nitroacetate, formatting with o-chlorophenyl magnesium bromide, reducing with nitro zinc powder, protecting with Boc to obtain amino, hydrolyzing with alkali, and finally separating by a Supercritical Fluid Chromatography (SFC) chiral separation column. MS M/z 254[ M-99 ]]⁺，298[M-55]⁺。

EXAMPLE 12 preparation of intermediate 12

Adding dichloromethane activated resin to N-FMOC-3-cyclohexyl-D-alanine (FMOC-D-CHA-OH) (2.00g,5.08mmol) and DIPEA (1.97g,15.24mmol,2.66mL) in DMF (40.00mL), after 12 h shaking reaction, suction filtering, adding DCM/MeOH/DIPEA (85/10/5) to the resin, shaking for 30min, filtering, DCM (50X 10mL), DMF (50X 10mL), DCM (50X 10mL) sequentially washing, adding HFIP (20% in DCM) (913.89mg,5.08mmol,40.00mL) to the resin, shaking for a while, suction filtering, adding HFIP (20% in DCM) (913.89mg,5.08mmol,40.00mL) to the resin, shaking, combining filtrates, concentrating to obtain cyclohexyl-D-glycine (870.00mg,5.08mmol,100.00 mmol), suction filtering to obtain 2.92% yield), THF-water (v/v 1: 1, 20mL) was added, as well as sodium carbonate (618.98mg,5.84mmol) and Boc₂O (954.84mg,4.38mmol), stirred at rt overnight, most of the organic solvent was removed under reduced pressure, pH-4 adjusted with 0.5N HCl, extracted with ethyl acetate (3 × 10ml), the organic phases combined and concentrated under reduced pressure to give crude intermediate 12, 0.78 g.

EXAMPLE 13 preparation of intermediate 13

Reference example 4 preparationThe intermediate 4 is prepared by condensing cyclohexyl formaldehyde with ethyl nitroacetate, reacting with sodium methoxide, performing nitro reduction, protecting amino with Boc, hydrolyzing, and separating with Supercritical Fluid Chromatography (SFC) chiral separation column to obtain four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 13. MS M/z 302[ M +1]]⁺。

EXAMPLE 14 preparation of intermediate 14

Referring to the method for preparing the intermediate 4 of example 4, the intermediate 1-1 reacts with 4-methylpyrazole in a potassium carbonate-DMF system, and then the four chiral isomers (2S, 3S; 2R, 3R; 2R, 3S; 2S,3R) of the intermediate 14 can be obtained by reduction with nitrozinc powder, Boc protection of amino group, hydrolysis and separation with a Supercritical Fluid Chromatography (SFC) chiral separation column. MS M/z 324[ M-55]]⁺。

EXAMPLE 15 preparation of intermediate 15

Dissolving intermediate ethyl p-nitroacetoacetate (5g,23.90mmol) in EtOH (100mL), replacing with nitrogen, adding 10% Pd/C (2.9g), stirring under hydrogen atmosphere at normal pressure for reaction overnight, after the raw material disappears, filtering with diatomaceous earth, washing with ethanol, and concentrating the filtrate under reduced pressure to dryness to obtain intermediate 15(4.27g,23.83mmol, 99.69% yield), MS M/z:180[ M +1]]⁺The product was used directly in the next reaction without purification.

EXAMPLE 16 preparation of intermediate 16

Step 1 preparation of intermediate 16-1

To p-nitrophenylacetic acid ethyl ester (350g,1.67 mol/l) under nitrogen at 0 deg.CAdding Cs to the dried DMF (2L) solution₂CO₃(2.73kg,8.37mol), warmed to room temperature and stirred for 1 hour, then iodomethane (1.19kg,8.37mol) was slowly added dropwise, the reaction was carried out overnight at room temperature after dropwise addition, filtration was carried out, the filtrate was diluted with 10L of ethyl acetate, washed with saturated brine (3X 10L), dried over anhydrous sodium sulfate as the organic phase, filtered and concentrated to obtain intermediate 16-1(320g,1.24mol, 74.17% yield), MS M/z:238[ M +1]]⁺The crude product was used directly in the next step.

Step 2 preparation of intermediate 16

Referring to the procedure for the preparation of intermediate 15 in example 15, intermediate 16, MS M/z:208[ M +1] was obtained by hydrogenation reduction of intermediate 16-1]⁺。

EXAMPLE 17 preparation of intermediate 17

Step 1 preparation of intermediate 17-1

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), warming to room temperature and stirring for 1 hour, then cooling to 0 ℃ and slowly adding iodomethane (116.43g,820.28mmol) dropwise, reacting overnight after dropwise addition, 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 17-1(165g,739.16mmol, 99.12% yield), MS M/z:224[ M +1] (M +1)]⁺The crude product was used directly in the next step.

Step 2 preparation of intermediate 17

Reference example 15 method for preparing intermediate 15The intermediate 17 is obtained by hydrogenation reduction of the intermediate 17-1, MS M/z is 194[ M +1]]⁺。

EXAMPLE 18 preparation of intermediate 18

Step 1 preparation of intermediate 18-1

A solution of intermediate 17-1(11.48g,478.44mmol) in DMF (300mL) was slowly added dropwise to a dry 0.3L mixture of DMF and NaH (11.48g,478.44mmol) under nitrogen at-10 deg.C, after 30min, cooling to-50 ℃, dropwise adding chloromethyl methyl ether (48.15g,598.05mmol), stirring the reaction solution for 3 hours at the temperature of-50 ℃ to-10 ℃ after 30min of dropwise adding, after the reaction was completed, the reaction was quenched with cold saturated ammonium chloride, extracted with ethyl acetate (2 × 400ml), the organic phases were combined, washed with saturated brine (400ml × 2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio, 100:1 to 50:1) to give intermediate 18-1(45g,168.36mmol, 42.23% yield), MS m/z:268[ M + 1.]⁺。

Step 2 preparation of intermediate 18

Dissolving intermediate 18-1(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 18(34.6g,145.81mmol, 86.60% yield), MS M/z:260[ M +23 mmol%]⁺。

EXAMPLE 19 preparation of intermediate 19

Step 1 preparation of intermediate 19-1

Nitrogen protectionUnder the protection, dissolving ethyl p-nitrophenylacetate (29.4g,140.54mmol) in dry 1.2L of N, N-dimethylacetamide, cooling to an internal temperature of-40 ℃ with a dry ice-ethanol bath, adding cesium carbonate (114.54g,351.34mmol), stirring at 40 ℃ for 15min, slowly dropwise adding 2-chloroethyl chloromethyl ether (19.94g,154.59mmol) into the reaction solution, allowing the reaction to return to room temperature, stirring overnight, after the raw materials disappear, adding 3L of ice water to quench the reaction, extracting with ethyl acetate (2L 2), washing the organic phase with saturated saline (2L 2), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, separating the crude product by silica gel column chromatography to obtain intermediate 19-1(6.5g,24.50mmol, 17.44%) MS M/z 266[ M +1, M/z%]⁺。

Step 2 preparation of intermediate 19

Dissolving intermediate 19-1(15g,56.55mmol) in EtOH (100mL), replacing with nitrogen, adding 10% Pd/C (3g), stirring under normal pressure hydrogen atmosphere for reaction overnight, after the raw material disappeared, suction-filtering with diatomaceous earth, washing with ethanol, and concentrating the filtrate under reduced pressure to dryness to obtain intermediate 19(12.7g,53.98mmol, 95.46% yield), MS M/z:236[ M +1]]⁺。

EXAMPLE 20 preparation of intermediate 20

Step 1 preparation of intermediate 20-1

Referring to example 19, the preparation of intermediate 19-1 was carried out by reacting ethyl p-nitrophenylacetate with 2,2' -dibromodiethyl ether in anhydrous DMF and cesium carbonate as a deacidification agent to obtain intermediate 20-1 in 60% yield, MS M/z:280[ M +1]]⁺。

Step 2 preparation of intermediate 20

Referring to the procedure for the preparation of intermediate 15 in example 15, intermediate 20, MS M/z:250[ M +1], was obtained by hydrogenation reduction of intermediate 20-1]⁺。

EXAMPLE 21 preparation of Compound 21

Step 1 preparation of intermediate 21-1

Step 5, intermediate 1(614.57mg,1.80mmol) from example 1, EDCI (412.08mg,2.16mmol), DIPEA (697.08mg,5.39mmol,939.46uL), HOAt (293.42mg,2.16mmol) and intermediate 16(0.35g,1.80mmol) from example 16 were added sequentially to DCM (10mL) and reacted at room temperature for 3 hours, quenched with water, freed of most of the organic solvent under reduced pressure, extracted with ethyl acetate (20 mL. multidot.3), the combined organic phases washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, rotary dried under reduced pressure, and the crude product purified by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 5:1) to give intermediate 21-1(0.85g,1.6mmol, 89% yield), MS M/z:531(M +1)⁺。

Step 2 preparation of intermediate 21-2

Dissolving the intermediate 21-1(0.85g,1.6mmol) obtained in the step 1 in DCM (3mL), dropwise adding TFA (2mL) under ice bath, continuously stirring for reaction for 2h under ice bath, and spin-drying to obtain the trifluoroacetate (843mg,493.45umol, 100% yield) of the intermediate 21-2, wherein MS m/z: 431(M +1)⁺And directly used for the next reaction without purification.

Step 3 preparation of intermediate 21-3

HBTU (134.35mg,353.56umol), DIPEA (114.23mg,883.89umol,153.95uL) were added to 1-methyl-1H-pyrazole-5-carboxylic acid in this order(112.01mg,888.21umol) in DCM (5mL), after 15min add TFA salt (155mg,294.63umol) of intermediate 21-2 from step 2, react at room temperature for 2h, quench with water, extract with ethyl acetate (20mL x 3), combine the organic phases, wash with saturated ammonium chloride and saturated brine, dry over anhydrous sodium sulfate, spin-dry under reduced pressure, purify the crude product by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give intermediate 21-3(127mg,236umol, 80% yield), MS m/z: 539(M +1)⁺。

Step 4 preparation of intermediates 21-4

To a mixture of intermediate 21-3(127mg, 236. mu. mol) in EtOH (1mL) and water (0.2mL) was added NaOH (64.03mg,1.60mmol) and reacted at 75 ℃ for 12 hours, LC-MS showed the starting material had reacted, pH was adjusted to 4 with 1N HCl, EA (10 mL. sup.3) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude intermediate 21-4(87mg, 170. mu. mol, 72% yield), MS M/z:511[ M +1], [ M + [ 1], ]]⁺And directly used for the next reaction without purification.

Step 5 preparation of intermediates 21-5

Adding HBTU (97mg,255umol) and DIPEA (110mg,850umol and 140uL) into DCM (5mL) solution of intermediate 21-4(87mg,170umol) in step 4 in sequence, adding D-leucine methyl ester hydrochloride (31mg,170umol) after 15min, reacting for 1h at room temperature, adding 10mL of water for quenching, removing most of organic solvent under reduced pressure, extracting with ethyl acetate (10mL of 3), combining organic phases, washing with saturated ammonium chloride and saturated common salt water respectively, drying with anhydrous sodium sulfate, drying under reduced pressure, purifying and separating the crude product by MPLC reverse phase 18 column chromatography (acetonitrile/0.05% water is 0-40%), thus obtaining intermediate 21-5(89mg,139umol and 82% yield), MS m/z: 638(M +1)⁺。

Step 6 preparation of Compound 21

To a mixture of intermediate 21-5(89mg, 139. mu. mol) in THF (0.2mL), MeOH (0.2mL) and water (0.2mL) was added NaOH (11mg,0.28mmol) and reacted at 55 ℃ for 12 h, LC-MS showed the starting material had reacted, pH was adjusted to 4 with 1N HCl, EA (10 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by MPLC 18 reverse phase column to give compound 21(56mg, 90. mu. mol, 65% yield), MS M/z:624[ M +1, 65% yield)]⁺。

EXAMPLE 22 preparation of Compound 22

Referring to example 21, compound 22 was obtained by reacting intermediate 21-2 with phenylacetyl chloride, alkali hydrolyzing the ethyl ester, and D-leucine methyl ester, and finally alkali hydrolyzing the methyl ester, MS m/z: 634(M +1)⁺。

EXAMPLE 23 preparation of Compound 23

The intermediate 1-1 is subjected to Pd/C hydrogenation reduction, Boc protection of amino, then the method of the example 21 is referred to, the intermediate 16 of the example 16 is condensed, Boc protection group is removed, the intermediate reacts with phenylacetyl chloride, ethyl ester is hydrolyzed with alkali, D-leucine methyl ester is hydrolyzed with alkali, and finally methyl ester is hydrolyzed with alkali, so that the compound 23 can be obtained, wherein MS m/z: 592(M +1)⁺。

EXAMPLE 24 preparation of Compound 24

By following the procedure of example 21, via intermediate 21-4 and (R) -N-ethylcyclobutyl glycerolCondensation of the aminoacyl to give the compound 24, MS m/z: 649(M +1)⁺。

EXAMPLE 25 preparation of Compound 25

Referring to example 21, starting with the (2S,3S) configuration of intermediate 2, compound 25, MS m/z: 667(M +1)⁺。

EXAMPLE 26 preparation of Compound 26

Referring to example 21, starting from intermediate 3b, compound 26, MS m/z: 661(M +1)⁺。

EXAMPLE 27 preparation of Compound 27

Referring to example 21, starting with the (2S,3S) configuration of intermediate 4, compound 27 was obtained by condensation with intermediate 16, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis, and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 637(M +1)⁺。

EXAMPLE 28 preparation of Compound 28

Reference is made to example 21, in whichThe (2S,3S) configuration of intermediate 5 is the starting material, which is condensed with intermediate 16, de-Boc, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R) -N-ethylcyclobutyl glycinamide to obtain compound 28, MS m/z: 651(M +1)⁺。

EXAMPLE 29 preparation of Compound 28

Referring to example 21, starting with the (2S,3S) configuration of intermediate 6, compound 29, MS m/z: 665(M +1)⁺。

EXAMPLE 30 preparation of Compound 30

Referring to example 21, starting with the (2S,3S) configuration of intermediate 7, compound 30, MS m/z: 663(M +1)⁺。

EXAMPLE 31 preparation of Compound 31

Referring to example 21, starting with the (2S,3S) configuration of intermediate 8, compound 31 was obtained by condensation with intermediate 16, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis, and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 635(M +1)⁺。

EXAMPLE 32 preparation of Compound 32

Referring to example 21, starting with the (2S,3S) configuration of intermediate 9, compound 32, MS m/z: 647(M +1)⁺。

EXAMPLE 33 preparation of Compound 33

Referring to example 21, starting with the (2S,3S) configuration of intermediate 10, compound 33, MS m/z: 661(M +1)⁺。

EXAMPLE 34 preparation of Compound 34

Referring to example 21, starting with the (2S,3S) configuration of intermediate 11, compound 34, MS m/z: 689(M +1)⁺。

EXAMPLE 35 preparation of Compound 35

Referring to example 21, starting with the (2S,3S) configuration of intermediate 12, compound 35 was obtained by condensation with intermediate 16, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis, and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z:579(M+1)⁺。

EXAMPLE 36 preparation of Compound 36

Referring to example 21, starting with the (2S,3S) configuration of intermediate 13, compound 36, MS m/z: 609(M +1)⁺。

EXAMPLE 37 preparation of Compound 37

Referring to example 21, starting with the (2S,3S) configuration of intermediate 14, compound 37, MS m/z: 687(M +1)⁺。

EXAMPLE 38 preparation of Compound 38

Referring to example 21, starting from intermediate 1, compound 38 was obtained by condensation with intermediate 15, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 621(M +1)⁺。

EXAMPLE 39 preparation of Compound 39

Referring to the method of example 21, intermediate 1, starting from intermediate 17, was condensed,removing Boc, condensing with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzing, and finally condensing with (R) -N-ethylcyclobutyl glycinamide to obtain a compound 39, MS m/z: 635(M +1)⁺。

EXAMPLE 40 preparation of Compound 40

Referring to example 21, starting from intermediate 1, compound 40 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 679(M +1)⁺。

EXAMPLE 41 preparation of Compound 41

Referring to example 21, starting from intermediate 1, compound 41 was obtained by condensation with intermediate 19, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 677(M +1)⁺。

EXAMPLE 42 preparation of Compound 42

Referring to example 21, starting from intermediate 1, compound 42 was obtained by condensation with intermediate 20, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 691(M +1)⁺。

EXAMPLE 43 preparation of Compound 43

Referring to example 21, starting from intermediate 2, compound 43 was obtained by condensation with intermediate 15, debobbing, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 639(M +1)⁺。

EXAMPLE 44 preparation of Compound 44

Referring to example 21, starting from intermediate 2, compound 44 was obtained by condensation with intermediate 17, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 653(M +1)⁺。

EXAMPLE 45 preparation of Compound 45

Referring to example 21, starting from intermediate 2, compound 45 was obtained by condensation with intermediate 17, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 667(M +1)⁺。

EXAMPLE 46 preparation of Compound 46

Referring to example 21, starting from intermediate 2, compound 46 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 697(M +1)⁺。

EXAMPLE 46 preparation of Compound 46

Referring to example 21, starting from intermediate 2, compound 46 was obtained by condensation with intermediate 19, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 695(M +1)⁺。

EXAMPLE 47 preparation of Compound 47

Referring to example 21, starting from intermediate 2, 47, MS m/z: 709(M +1)⁺。

EXAMPLE 48 preparation of Compound 48

Referring to example 21, starting from intermediate 3b, compound 48, MS m/z: 633(M +1)⁺。

EXAMPLE 49 preparation of Compound 49

Referring to example 21, starting from intermediate 3b, compound 49 was obtained by condensation with intermediate 15, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 661(M +1)⁺。

EXAMPLE 50 preparation of Compound 50

Referring to example 21, starting from intermediate 3b, compound 50, MS m/z: 647(M +1)⁺。

EXAMPLE 51 preparation of Compound 51

Referring to example 21, starting from intermediate 3b, compound 51 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 691(M +1)⁺。

EXAMPLE 52 preparation of Compound 52

Referring to example 21, starting from intermediate 3b, compound 52 was obtained by condensation with intermediate 19, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 689(M +1)⁺。

EXAMPLE 53 preparation of Compound 53

Referring to example 21, starting from intermediate 3b, the intermediate was condensed with intermediate 20, debiboc, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R) -N-ethylcyclobutyl glycinamideTo give compound 53, MS m/z: 703(M +1)⁺。

EXAMPLE 54 preparation of Compound 54

Referring to example 21, starting from intermediate 3b, compound 54 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 677(M +1)⁺。

EXAMPLE 55 preparation of Compound 55

Referring to example 21, starting from intermediate 3b, compound 55 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 703(M +1)⁺。

EXAMPLE 56 preparation of Compound 56

Referring to example 21, starting from intermediate 3b, compound 56 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 691(M +1)⁺。

EXAMPLE 57 preparation of Compound 57

Referring to example 21, starting from intermediate 3b, condensation with intermediate 18, Boc removal, and 1-methylAnd (2) condensing the base-1H-pyrazole-5-carboxylic acid, hydrolyzing, and finally condensing with corresponding substituted glycinamide to obtain a compound 57, wherein MS m/z: 707(M +1)⁺。

EXAMPLE 58 preparation of Compound 58

Referring to example 21, starting from intermediate 3b, compound 58, MS m/z: 695(M +1)⁺。

EXAMPLE 59 preparation of Compound 59

Referring to example 21, starting from intermediate 3b, compound 59, MS m/z: 713(M +1)⁺。

EXAMPLE 60 preparation of Compound 60

Referring to example 21, starting from intermediate 3b, compound 60 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 691(M +1)⁺。

EXAMPLE 61 preparation of Compound 61

Reference example21, taking the intermediate 3b as a starting material, condensing with the intermediate 18, removing Boc, condensing with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzing, and finally condensing with corresponding substituted glycinamide to obtain a compound 61, wherein the molar ratio of MS m/z: 693(M +1)⁺。

EXAMPLE 62 preparation of Compound 62

Referring to example 21, starting from intermediate 3b, compound 62 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 705M +1)⁺。

EXAMPLE 63 preparation of Compound 63

Referring to example 21, starting from intermediate 3b, compound 63 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 707(M +1)⁺。

EXAMPLE 64 preparation of Compound 64

Referring to example 21, starting from intermediate 3b, compound 64, MS m/z: 691(M +1)⁺。

EXAMPLE 65 preparation of Compound 65

Referring to example 21, starting from intermediate 3b, compound 65, MS m/z: 717(M +1)⁺。

EXAMPLE 66 preparation of Compound 66

Referring to example 21, starting from intermediate 3b, compound 66 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 705(M +1)⁺。

EXAMPLE 67 preparation of Compound 67

Referring to example 21, starting from intermediate 3b, compound 67, MS m/z: 721(M +1)⁺。

EXAMPLE 68 preparation of Compound 68

Referring to example 21, starting from intermediate 3b, compound 68 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 709(M +1)⁺。

EXAMPLE 69 preparation of Compound 69

Referring to example 21, starting from intermediate 3b, compound 69 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 727(M +1)⁺。

EXAMPLE 70 preparation of Compound 70

Referring to example 21, starting from intermediate 3b, compound 70 was obtained by condensation with intermediate 18, de-Boc, condensation with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolysis and final condensation with the corresponding substituted glycinamide, MS m/z: 705(M +1)⁺。

EXAMPLE 71 preparation of Compound 71

Referring to example 21, starting from intermediate 3b, compound 71, MS m/z: 707(M +1)⁺。

EXAMPLE 72 preparation of Compound 72

Referring to example 21, starting from intermediate 3b, compound 72, MS m/z: 719(M +1)⁺。

EXAMPLE 73 preparation of Compound 73

Referring to example 21, starting from intermediate 3b, compound 73, MS m/z: 721(M +1)⁺。

EXAMPLE 74 preparation of Compound 74

Referring to example 21, starting from intermediate 3b, compound 74 was obtained by condensation with intermediate 3- (4-aminophenyl) oxetane-3-carboxylic acid ethyl ester, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis of the ethyl ester, and finally condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 675(M +1)⁺。

EXAMPLE 75 preparation of Compound 75

Referring to example 21, starting from intermediate 1, compound 75 was obtained by condensation with intermediate 3- (4-aminophenyl) oxetane-3-carboxylic acid ethyl ester, de-Boc, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolysis of the ethyl ester, and finally condensation with (R) -N-ethylcyclobutyl glycinamide, MS m/z: 663(M +1)⁺。

In order to illustrate the advantageous effects of the present invention, the present invention provides the following test examples.

Test example 1IL-17 enzyme-linked immunosorbent assay (ELISA) test

The inhibition of receptor-ligand binding by IL-17A inhibitors was quantitatively determined by competitive ELISA. IL-17A (Nano Biological incc. Cat #12047-H07B) at 0.2. mu.g/mL was incubated at 37 degrees for 30 minutes in 96-well plates at 100. mu.L (50mM phosphate buffer, pH 7.4) per well. 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 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 30min 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. LTMB 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.

The compounds prepared in the examples were tested for IL-17A inhibitory activity according to the methods described above, and the results are shown in Table 1, in which the IC of each compound was determined₅₀Sorted by description, in table 1:

"+" denotes IC₅₀Measuring less than 100. mu.M and greater than 1. mu.M;

TABLE 1 inhibitory Activity of Compounds on IL-17A

Examples	IC₅₀
		21	+
22	+
		23	+
24	+
		27	+
34	+
		35	+
43	+
		44	+
63	+
		75	+

Experiments show that the compounds of the embodiment of the invention have good IL-17A inhibitory activity and can be effectively used for treating diseases with abnormal IL-17A activity.

In conclusion, the novel compound shown in the formula I shows good IL-17A inhibitory activity, 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,

or R₃、R₄Are linked to form a 3-to 10-membered cycloalkyl group3-to 10-membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R₃₁Substitution;

the ring A is selected from a 5-10-membered aromatic ring, a 5-10-membered aromatic heterocycle and a 3-10-membered cycloalkyl; wherein the aromatic ring, aromatic heterocycle, cycloalkyl may be further substituted by one, two or three R_A1Substitution;

Y₁、Y₂、Y₃、Y₄each independently selected from N or CR_Y1；

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 radical- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle),

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)Aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R_b1Substitution;

2. The compound of claim 1, wherein:

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); wherein the cycloalkyl radicalThe heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R₁₃Substitution;

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

Y₁、Y₂、Y₃、Y₄each independently selected from N or CR_Y1；

R₆、R₇are respectively and independently selected from hydrogen, halogen and C_1～6Alkyl, 3 &A 6-membered cycloalkyl group, a 3-6-membered heterocycloalkyl group; wherein alkyl, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R₆₁Substitution;

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

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 hetero)Ring), -O (C)_1～6Alkyl), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted by one, two or three R_a1Substitution;

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

3. The compound of claim 1, wherein: the compound of formula I is represented by formula II:

wherein the content of the first and second substances,

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), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaromatic ring may be further substituted by one, two or three R₃₁Substitution;

each R_A4Each independently selected from halogen, cyano, carbonylRadical, nitro radical, -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;

R₅selected from hydrogen, -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); it is composed ofThe middle alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R_a1Substitution;

4. A compound according to claim 3, characterized in that:

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) and-N(C_1～6Alkyl) (C_1～6Alkyl groups).

5. The compound of claim 4, wherein: r₁Is selected from

R₁₃Selected from hydrogen and methyl.

6. A compound according to claim 3, characterized in that:

7. The compound of claim 6, wherein: r₃、R₄At least one is hydrogen.

8. A compound according to claim 3, characterized in that:

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

9. The compound of claim 8, wherein: ring A is selected from benzene ring and cyclohexane; wherein the benzene ring and the cyclohexane ring can be further substituted by one, two or three R_A1Substitution;

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

10. A compound according to claim 3, characterized in that:

11. A compound according to claim 3, characterized in that: r₆And R₇Are linked to form a 3-to 6-membered heterocycloalkyl group in which the heteroatom is an oxygen atom.

12. A compound according to claim 3, characterized in that:

13. The compound of claim 12, wherein: r_aIs selected from 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein the 3-6 membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the hetero atoms of the heterocycloalkyl are O and/or N, wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_a1Substitution;

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

14. A compound according to claim 3, characterized in that:

15. The compound of claim 14, wherein: r_b、R_cAt least one is hydrogen.

16. A compound according to claim 3, characterized in that: the compound shown in the formula II is specifically:

17. the compound of claim 1, wherein: the compound of formula I is represented by formula III:

wherein the content of the first and second substances,

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); wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three R_A4Substitution;

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

R₅selected from hydrogen, -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)-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), -O (C)_1～6Alkyl), -O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), -O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted by one, two or three R_a1Substitution;

R_beach 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); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R_b1Substitution;

18. The compound of claim 17, wherein:

the R is₁Is selected from

R₁₃Selected from hydrogen, methyl;

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, 5-to 6-membered arylheterocyclyl, -O (C)_1～6Alkyl), -O (3-6 membered cycloalkyl); wherein the alkyl, cycloalkyl, heterocycloalkyl, arylheterocyclyl may be further substitutedStep by one, two or three R₃₁Substitution;

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

19. The compound of claim 18, wherein: the compound of formula III is specifically:

20. use of a compound of any one of claims 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an IL-17A-mediated disease.

21. The use according to claim 20, characterized in that: the IL-17A mediated disease is one or more of diseases related to inflammation, autoimmune diseases, infectious diseases, cancer and precancerous syndrome.

22. A pharmaceutical composition characterized by: the compound of any one of claims 1 to 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient.