An immunomodulator

Abstract

The present invention discloses an immunomodulator, specifically a compound that inhibits IL-17A and its use as an immunomodulator in the preparation of a medicament. The present invention discloses the use of a compound represented by Formula I or a stereoisomer thereof in the preparation of a medicament that inhibits IL-17A, providing a new option for clinically screening and / or preparing medicaments for diseases associated with IL-17A activity.

Description

Technical Field

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

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

[0003] Targeting the binding of IL-17A to IL-17RA is an effective strategy for treating IL-17A-mediated autoimmune inflammatory diseases. Treatment of animals with autoimmune encephalomyelitis with IL-17A neutralizing antibodies reduced disease incidence and severity (Komiyama Y et al. J. Immunol., 2006, 177: 566-573). Clinical trials of existing 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 (Novartis's Cosentyx / secukinumab) was approved by the FDA for the treatment of psoriasis in January 2015.

[0004] Despite the existence of multiple IL-17A antibodies, few studies have investigated small molecule specific inhibitors of IL-17 with oral bioavailability. Given the cost of producing antibodies and the limitations of administration routes, the development of small molecule inhibitors of IL-17A has good research and development prospects. Summary of the Invention

[0005] The present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in,

[0008] R1 is selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(3-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle), -NR 11 R 12 、-OR 11 wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further replaced by one, two, or three independent R 13 replace;

[0009] R 11 、R 12 are independently selected from hydrogen, -C 1～6 Alkyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(3-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4Alkylene-(5-10 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three independent R 13 replace;

[0010] Each R 13 independently selected from halogen, cyano, carbonyl, nitro, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl);

[0011] R2 is selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl);

[0012] R3 and R4 are independently selected from hydrogen, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(3-10 membered heterocycloalkyl), -O(C 1～10 alkyl), -O(C 0～4 Alkylene) (3-10 membered cycloalkyl), -O(C 0～4 Alkylene) (3-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic heterocycle may be further replaced by one, two or three R 31 replace;

[0013] Or R3 and R4 are linked to form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl may be further separated by one, two or three R 31 replace;

[0014] Each R 31 independently selected from halogen, cyano, carbonyl, nitro, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -O(C 0～4 Alkylene) (3-10 membered cycloalkyl), -O(C 0～4 Alkylene) (3-10 membered heterocycloalkyl);

[0015] Ring A is selected from 5-10 membered aromatic rings, 5-10 membered aromatic heterocycles, and 3-10 membered cycloalkyl groups; wherein the aromatic rings and aromatic heterocycles may be further replaced by one, two or three R A1 replace;

[0016] Each R A1 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -C 0～4 Alkylene-OR A2 、-C 0～4 Alkylene-OC(O)R A2 、-C 0～4 Alkylene-C(O)R A2 、-C 0～4 Alkylene-C(O)OR A2 、-C 0～4 Alkylene-C(O)NR A2 R A3 、-C 0～4 Alkylene-NR A2 R A3 、-C 0～4 Alkylene-NR A2 C(O)R A3 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(3-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R A4 replace;

[0017] Each R A4 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -C 0～4 Alkylene-OR A2 、-C 0～4 Alkylene-OC(O)R A2 、-C 0～4 Alkylene-C(O)R A2 、-C 0～4 Alkylene-C(O)OR A2 、-C 0～4 Alkylene-C(O)NR A2 R A3 、-C 0～4 Alkylene-NR A2 R A3 、-C0～4 Alkylene-NR A2 C(O)R A3 ;

[0018] R A2 、R A3 are independently selected from hydrogen, -C 1～10 alkyl;

[0019] R5 is selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl);

[0020] Y1, Y2, Y3, and Y4 are independently selected from N or CR Y1 ;

[0021] Each R Y1 independently selected from hydrogen, halogen, cyano, nitro, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl);

[0022] R6, R7 are independently selected from hydrogen, halogen, C 1～10 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl; wherein alkyl, cycloalkyl, heterocycloalkyl may be further replaced by one, two or three R 61 replace;

[0023] Alternatively, R6 and R7 are linked to form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl may be further separated by one, two or three R 61 replace;

[0024] Each R 61 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C 1～10 alkyl), -NH2, -NH(C 1～10 Alkyl), -N(C 1～10 Alkyl)(C 1～10 alkyl);

[0025] L is selected from -C 0～4 Alkylene-C(O)NR L21 -、-C 0～4 Alkylene-NR L21 C(O)-、-C 0～4Alkylene-C(O)-, -C 0～4 Alkylene-NR L21 -;

[0026] R L21 Selected from hydrogen, -C 1～10 alkyl;

[0027] R is selected from -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(3-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle), 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, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R d replace;

[0028] R a 、R a’ are independently selected from hydrogen, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(3-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-12 membered spiro ring), -C 0～4 Alkylene-(5-12 membered spiroheterocycle), -C 0～4 Alkylene-(5-12 membered bridge ring), -C 0～4 Alkylene-(5-12 membered heterocyclic ring), -O(C 1～10 alkyl), -O(C 0～4 Alkylene) (3-10 membered cycloalkyl), -O(C 0～4 Alkylene) (3-10 membered heterocycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle may be further replaced by one, two or three R a1 replace;

[0029] or R a 、R a’ connected to form 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl may be further substituted by one, two or three R a1 replace;

[0030] Each R a1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～10 Alkyl, halogen-substituted -C1～10 Alkyl, -OH, -O(C 1～10 alkyl);

[0031] R b 、R c are independently selected from hydrogen, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(3-10 membered heterocycloalkyl), -C 0～4 Alkylene-(5-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further replaced by one, two or three R b1 replace;

[0032] Each R b1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -OH, -O(C 1～10 alkyl);

[0033] Each R d independently selected from halogen, cyano, carbonyl, nitro, -C 1～10 Alkyl, halogen-substituted -C 1～10 Alkyl, -C 0～4 Alkylene-OR d1 、-C 0～4 Alkylene-OC(O)R d1 、-C 0～4 Alkylene-C(O)R d1 、-C 0～4 Alkylene-C(O)OR d1 、-C 0～4 Alkylene-C(O)NR d1 R d2 、-C 0～4 Alkylene-NR d1 R d2 、-C 0～4 Alkylene-NR d1 C(O)R d2 ;

[0034] R d1 、R d2 are independently selected from hydrogen, -C 1～10 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl.

[0035] Further,

[0036] R1 is selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5- to 6-membered aromatic heterocycle), -NR 11 R 12 、-OR 11 wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further replaced by one, two, or three independent R 13 replace;

[0037] R 11 、R 12 are independently selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three independent R 13 replace;

[0038] Each R 13 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0039] R2 is selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 6-membered cycloalkyl);

[0040] R3 and R4 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl), -C 0～2Alkylene-(5-6 membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic heterocycle may be further replaced by one, two or three R 31 replace;

[0041] Or R3 and R4 are connected to form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl can be further replaced by one, two or three R 31 replace;

[0042] Each R 31 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl);

[0043] Ring A is selected from 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, 3-6 membered cycloalkyl; wherein aromatic ring, aromatic heterocycle, cycloalkyl can be further replaced by one, two or three R A1 replace;

[0044] Each R A1 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OR A2 、-C 0～2 Alkylene-OC(O)R A2 、-C 0～2 Alkylene-C(O)R A2 、-C 0～2 Alkylene-C(O)OR A2 、-C 0～2 Alkylene-C(O)NR A2 R A3 、-C 0～2 Alkylene-NR A2 R A3 、-C 0～2 Alkylene-NR A2 C(O)R A3 、-C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three RA4 replace;

[0045] Each R A4 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OR A2 、-C 0～2 Alkylene-OC(O)R A2 、-C 0～2 Alkylene-C(O)R A2 、-C 0～2 Alkylene-C(O)OR A2 、-C 0～2 Alkylene-C(O)NR A2 R A3 、-C 0～2 Alkylene-NR A2 R A3 、-C 0～2 Alkylene-NR A2 C(O)R A3 ;

[0046] R A2 、R A3 are independently selected from hydrogen, -C 1～6 alkyl;

[0047] R5 is selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 6-membered cycloalkyl);

[0048] Y1, Y2, Y3, and Y4 are independently selected from N or CR Y1 ;

[0049] Each R Y1 independently selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0050] R6, R7 are independently selected from hydrogen, halogen, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; wherein alkyl, cycloalkyl, heterocycloalkyl may be further replaced by one, two or three R 61 replace;

[0051] Alternatively, R6 and R7 are linked to form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl may be further separated by one, two or three R 61 replace;

[0052] Each R 61 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0053] L is selected from -C 0～2 Alkylene-C(O)NR L21 -、-C 0～2 Alkylene-NR L21 C(O)-、-C 0～2 Alkylene-C(O)-, -C 0～2 Alkylene-NR L21 -;

[0054] R L21 Selected from hydrogen, -C 1～6 alkyl;

[0055] R is selected from -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5- to 6-membered aromatic heterocycle),

[0056] Wherein the C ring is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further replaced by one, two or three R d replace;

[0057] R a 、R a’ are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(6-11 membered spiro ring), -C 0～2 Alkylene-(6-11 membered spiroheterocycle), -C 0～2Alkylene-(5-10 membered bridge ring), -C 0～2 Alkylene-(5-10 membered heterocyclic ring), -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro, spiro heterocycle, bridged ring, bridged heterocycle may be further replaced by one, two or three R a1 replace;

[0058] or R a 、R a’ connected to form 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl may be further substituted by one, two or three R a1 replace;

[0059] Each R a1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl);

[0060] R b 、R c are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R b1 replace;

[0061] Each R b1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl);

[0062] Each R d independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OR d1 、-C 0～2 Alkylene-OC(O)R d1 、-C0～2 Alkylene-C(O)R d1 、-C 0～2 Alkylene-C(O)OR d1 、-C 0～2 Alkylene-C(O)NR d1 R d2 、-C 0～2 Alkylene-NR d1 R d2 、-C 0～2 Alkylene-NR d1 C(O)R d2 ;

[0063] R d1 、R d2 are independently selected from hydrogen, -C 1～6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl.

[0064] Furthermore: the compound of formula I is shown in formula II:

[0065]

[0066] in,

[0067] R1 is selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5- to 6-membered aromatic heterocycle), -NR 11 R 12 、-OR 11 wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further replaced by one, two, or three independent R 13 replace;

[0068] R 11 、R 12 are independently selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three independent R 13 replace;

[0069] Each R 13independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0070] R2 is selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 6-membered cycloalkyl);

[0071] R3 and R4 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic heterocycle may be further replaced by one, two or three R 31 replace;

[0072] Or R3 and R4 are connected to form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl can be further replaced by one, two or three R 31 replace;

[0073] Each R 31 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl);

[0074] Ring A is selected from 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, 3-6 membered cycloalkyl; wherein aromatic ring, aromatic heterocycle, cycloalkyl can be further replaced by one, two or three R A1 replace;

[0075] Each R A1 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6Alkyl, -C 0～2 Alkylene-OR A2 、-C 0～2 Alkylene-OC(O)R A2 、-C 0～2 Alkylene-C(O)R A2 、-C 0～2 Alkylene-C(O)OR A2 、-C 0～2 Alkylene-C(O)NR A2 R A3 、-C 0～2 Alkylene-NR A2 R A3 、-C 0～2 Alkylene-NR A2 C(O)R A3 、-C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R A4 replace;

[0076] Each R A4 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OR A2 、-C 0～2 Alkylene-OC(O)R A2 、-C 0～2 Alkylene-C(O)R A2 、-C 0～2 Alkylene-C(O)OR A2 、-C 0～2 Alkylene-C(O)NR A2 R A3 、-C 0～2 Alkylene-NR A2 R A3 、-C 0～2 Alkylene-NR A2 C(O)R A3 ;

[0077] R A2 、R A3 are independently selected from hydrogen, -C 1～6 alkyl;

[0078] R5 is selected from hydrogen, -C1～6 alkyl;

[0079] R6, R7 are independently selected from hydrogen, halogen, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; wherein alkyl, cycloalkyl, heterocycloalkyl may be further replaced by one, two or three R 61 replace;

[0080] Alternatively, R6 and R7 are linked to form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl may be further separated by one, two or three R 61 replace;

[0081] Each R 61 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0082] R a Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(6-11 membered spiro ring), -C 0～2 Alkylene-(6-11 membered spiroheterocycle), -C 0～2 Alkylene-(5-10 membered bridge ring), -C 0～2 Alkylene-(5-10 membered heterocyclic ring), -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro, spiro heterocycle, bridged ring, bridged heterocycle may be further replaced by one, two or three R a1 replace;

[0083] Each R a1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl);

[0084] R b 、Rc are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R b1 replace;

[0085] Each R b1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl).

[0086] Further:

[0087] R1 is selected from -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5- to 6-membered aromatic heterocycle), -NR 11 R 12 、-OR 11 wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further replaced by one, two, or three independent R 13 replace;

[0088] R 11 、R 12 are independently selected from hydrogen, -C 1～6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl;

[0089] Each R 13 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl).

[0090] More specifically, R1 is selected from R 13Selected from hydrogen and methyl.

[0091] Furthermore,

[0092] R3 and R4 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic heterocyclic group, -O(C 1～6 alkyl), -O (3-6 membered cycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic heterocyclic group may be further replaced by one, two or three R 31 replace;

[0093] Each R 31 independently selected from halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -O(3- to 6-membered cycloalkyl).

[0094] More specifically, at least one of R3 and R4 is hydrogen.

[0095] Furthermore,

[0096] Ring A is selected from 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, 3-6 membered cycloalkyl; wherein aromatic ring, aromatic heterocycle, cycloalkyl can be further replaced by one, two or three R A1 replace;

[0097] Each R A1 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR A2 、-OC(O)R A2 、-C(O)R A2 、-C(O)OR A2 、-C(O)NR A2 R A3 、-NR A2 R A3 、-NR A2 C(O)R A3 , 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R A4 replace;

[0098] Each R A4 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR A2、-OC(O)R A2 、-C(O)R A2 、-C(O)OR A2 、-C(O)NR A2 R A3 、-NR A2 R A3 、-NR A2 C(O)R A3 ;

[0099] R A2 、R A3 are independently selected from hydrogen, -C 1～6 alkyl.

[0100] More specifically, the A ring is selected from a benzene ring and a cyclohexane ring; wherein the benzene ring and the cyclohexane ring can be further replaced by one, two or three R A1 replace;

[0101] Each R A1 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR A2 、-OC(O)R A2 、-C(O)R A2 、-C(O)OR A2 、-C(O)NR A2 R A3 、-NR A2 R A3 、-NR A2 C(O)R A3 , 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R A4 replace;

[0102] Each R A4 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR A2 、-OC(O)R A2 、-C(O)R A2 、-C(O)OR A2 、-C(O)NR A2 R A3 、-NR A2 R A3 、-NR A2 C(O)R A3 ;

[0103] RA2 、R A3 are independently selected from hydrogen, -C 1～6 alkyl.

[0104] Furthermore,

[0105] R6, R7 are independently selected from hydrogen, C 1～6 Alkyl; wherein the alkyl group may be further replaced by an R 61 replace;

[0106] R 61 are independently selected from halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl).

[0107] Furthermore, R6 and R7 are linked to form a 3- to 6-membered heterocycloalkyl group, wherein the heteroatom is an oxygen atom.

[0108] Furthermore,

[0109] R a Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-11 membered spiro ring, 6-11 membered spiro heterocycle, 5-10 membered bridged ring, 5-10 membered bridged heterocycle, -O(C 1～6 alkyl), -O (3- to 6-membered cycloalkyl), -O (3- to 6-membered heterocycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro, spiroheterocycle, bridged ring, bridged heterocycle may be further replaced by one, two or three R a1 replace;

[0110] Each R a1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl).

[0111] More specifically: R a is selected from 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein the 3-6 membered cycloalkyl is specifically cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the heteroatom of the heterocycloalkyl is O and / or N, wherein the cycloalkyl and heterocycloalkyl may be further replaced by one, two or three R a1 replace;

[0112] Each R a1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C1～6 alkyl).

[0113] Furthermore,

[0114] R b 、R c are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl may be further replaced by one, two or three R b1 replace;

[0115] Each R b1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl).

[0116] More specifically, R b 、R c At least one is hydrogen.

[0117] In some specific embodiments of the present invention, the compound represented by formula II is specifically:

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] Furthermore, the compound of formula I is shown in formula III:

[0125]

[0126] in,

[0127] R1 is selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2Alkylene-(5- to 6-membered aromatic heterocycle), -NR 11 R 12 、-OR 11 wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further replaced by one, two, or three independent R 13 replace;

[0128] R 11 、R 12 are independently selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three independent R 13 replace;

[0129] Each R 13 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0130] R2 is selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 6-membered cycloalkyl);

[0131] R3 and R4 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl may be further replaced by one, two or three R 31 replace;

[0132] Or R3 and R4 are connected to form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl can be further replaced by one, two or three R31 replace;

[0133] Each R 31 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl);

[0134] Ring A is selected from 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, 3-6 membered cycloalkyl; wherein aromatic ring, aromatic heterocycle, cycloalkyl can be further replaced by one, two or three R A1 replace;

[0135] Each R A1 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OR A2 、-C 0～2 Alkylene-OC(O)R A2 、-C 0～2 Alkylene-C(O)R A2 、-C 0～2 Alkylene-C(O)OR A2 、-C 0～2 Alkylene-C(O)NR A2 R A3 、-C 0～2 Alkylene-NR A2 R A3 、-C 0～2 Alkylene-NR A2 C(O)R A3 、-C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R A4 replace;

[0136] Each R A4 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-OR A2、-C 0～2 Alkylene-OC(O)R A2 、-C 0～2 Alkylene-C(O)R A2 、-C 0～2 Alkylene-C(O)OR A2 、-C 0～2 Alkylene-C(O)NR A2 R A3 、-C 0～2 Alkylene-NR A2 R A3 、-C 0～2 Alkylene-NR A2 C(O)R A3 ;

[0137] R A2 、R A3 are independently selected from hydrogen, -C 1～6 alkyl;

[0138] R5 is selected from hydrogen, -C 1～6 alkyl;

[0139] R6, R7 are independently selected from hydrogen, halogen, C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; wherein alkyl, cycloalkyl, heterocycloalkyl may be further replaced by one, two or three R 61 replace;

[0140] Alternatively, R6 and R7 are linked to form a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl may be further separated by one, two or three R 61 replace;

[0141] Each R 61 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 alkyl);

[0142] R a Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl), -C 0～2 Alkylene-(6-11 membered spiro ring), -C 0～2Alkylene-(6-11 membered spiroheterocycle), -C 0～2 Alkylene-(5-10 membered bridge ring), -C 0～2 Alkylene-(5-10 membered heterocyclic ring), -O(C 1～6 alkyl), -O(C 0～2 Alkylene)(3-6 membered cycloalkyl), -O(C 0～2 Alkylene) (3-6 membered heterocycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, spiro, spiro heterocycle, bridged ring, bridged heterocycle may be further replaced by one, two or three R a1 replace;

[0143] Each R a1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl);

[0144] R b are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-6 membered cycloalkyl), -C 0～2 Alkylene-(3-6 membered heterocycloalkyl)-C 0～2 Alkylene-(5-6 membered aromatic ring), -C 0～2 Alkylene-(5-6 membered aromatic heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R b1 replace;

[0145] Each R b1 independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl).

[0146] Further:

[0147] The R1 is selected from R 13 is selected from hydrogen, methyl;

[0148] R3 and R4 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic heterocyclic group, -O(C 1～6 alkyl), -O (3-6 membered cycloalkyl); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic heterocyclic group may be further replaced by one, two or three R 31replace;

[0149] Each R 31 independently selected from halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl), -O(3- to 6-membered cycloalkyl);

[0150] The A ring is selected from a benzene ring and a cyclohexane ring; wherein the benzene ring and the cyclohexane ring can be further replaced by one, two or three R A1 replace;

[0151] Each R A1 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR A2 、-OC(O)R A2 、-C(O)R A2 、-C(O)OR A2 、-C(O)NR A2 R A3 、-NR A2 R A3 、-NR A2 C(O)R A3 , 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further replaced by one, two or three R A4 replace;

[0152] Each R A4 are independently selected from halogen, cyano, carbonyl, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR A2 、-OC(O)R A2 、-C(O)R A2 、-C(O)OR A2 、-C(O)NR A2 R A3 、-NR A2 R A3 、-NR A2 C(O)R A3 ;

[0153] R A2 、R A3 are independently selected from hydrogen, -C 1～6 alkyl;

[0154] R6, R7 are independently selected from hydrogen, C 1～6 Alkyl; wherein the alkyl group may be further replaced by an R61 Replacement; R 61 are independently selected from halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OH, -O(C 1～6 alkyl);

[0155] R a Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl.

[0156] In some specific embodiments of the present invention, the compound of formula III is specifically:

[0157]

[0158]

[0159] The present invention also provides the use of the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite in the preparation of a drug for treating IL-17A-mediated diseases.

[0160] IL-17A-mediated diseases, as defined herein, are diseases in which IL-17A plays a significant role in the pathogenesis of the disease. IL-17A's primary function is to coordinate local tissue inflammation, thereby playing a role in various diseases. IL-17A-mediated diseases include one or more of inflammation, autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.

[0161] "Cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other parts of the body (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. "Cancer cells" refer to cells in the early, intermediate, or late stages of a multi-step tumor progression. Cancers include sarcomas, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer. In some embodiments, the compound of Formula I is used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.

[0162] Autoimmune diseases are caused by the body's immune response to substances and tissues normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, Grave's disease, celiac disease, Crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barré syndrome, multiple sclerosis, and autoimmune retinopathy. Some embodiments of the present invention relate to treating autoimmune diseases such as psoriasis or multiple sclerosis.

[0163] Inflammatory diseases include a variety of conditions characterized by histopathological inflammation. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation caused by house dust mites, and interstitial cystitis. There is significant overlap between inflammatory diseases and autoimmune diseases. Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma. The immune system is often involved in inflammatory diseases, which are manifested in allergic reactions and some myopathies, and many immune system diseases lead to abnormal inflammation. IL-17A-mediated diseases also include autoimmune inflammatory diseases.

[0164] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0165] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0166] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0167] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0168] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may optionally be substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl groups can also be part of other groups, such as C1-C6 alkoxy.

[0169] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spirocyclic systems). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl) is used when the point of attachment is located 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, etc. Two such bicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and Biscyclohexyl.

[0170] "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms, and in some embodiments, 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least one site of vinyl unsaturation (>C=C<). For example, (C-C)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.

[0171] "Halogen" is fluorine, chlorine, bromine or iodine.

[0172] "Halogenalkyl" means that the hydrogen atoms in the alkyl group may be replaced by one or more halogen atoms. 1～4 The halogenalkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms.

[0173] "Heterocycle" and "heterocycloalkyl" refer to saturated or non-aromatic unsaturated rings containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0174] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0175] "Stereoisomers" include enantiomers and diastereomers;

[0176] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0177] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0178] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0179] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0180] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0181] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD), with tetramethylsilane (TMS) as the internal standard.

[0182] LC-MS analysis was performed using a Shimadzu LC-MS 2020 (ESI) mass spectrometer.

[0183] HPLC analysis was performed using a Shimadzu LC-20A high pressure liquid chromatograph.

[0184] MPLC (medium pressure preparative chromatography) was performed using a Gilson GX-281 reverse phase preparative chromatograph.

[0185] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0186] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0187] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0188] Unless otherwise specified in the examples, the reactions were carried out under a nitrogen atmosphere.

[0189] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0190] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0191] Unless otherwise specified in the examples, M or N refers to moles per liter.

[0192] Room temperature is the most suitable reaction temperature, which is 20℃~30℃.

[0193] Unless otherwise specified, the percentages in this document are expressed as mass percentages.

[0194] THF: tetrahydrofuran; DCM: dichloromethane.

[0195] TEA: triethylamine; DMF: dimethylformamide.

[0196] DIPEA: N,N-diisopropylethylamine; TFA: trifluoroacetic acid.

[0197] HFIP: hexafluoroisopropanol.

[0198] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0199] HOAt: N-hydroxy-7-azabenzotriazole.

[0200] HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0201] Example 1 Preparation of Intermediate Amino Acid 1

[0202] Step 1 Preparation of Intermediate 1-1

[0203]

[0204] THF (3500 mL) was added to a 10 L three-necked flask equipped with mechanical stirring and nitrogen protection, followed by o-chlorobenzaldehyde (341 g, 2.43 mol) and ethyl nitroacetate (323 g, 2.43 mol). The mixture was then cooled to an internal temperature of -10°C in an ice-salt bath. TiCl4 (920 g, 4.85 mol) was slowly added dropwise under mechanical stirring. The internal temperature was controlled not to exceed 0°C during the addition. After the addition was completed, the reaction was maintained at 0°C for 0.5 h. N-methylmorpholine (981.51 g, 9.70 mol) was then added dropwise. The internal temperature was controlled not to exceed 15°C during the addition. After the addition was completed, the mixture was warmed to room temperature and stirred for 1 h. Finally, 500 mL of saturated ammonium chloride was added to quench the mixture. The mixture was extracted with ethyl acetate (1000 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain intermediate 1-1 (580 g, 2.27 mol, 93.52% yield).

[0205] Step 2 Preparation of Intermediate 1-2

[0206]

[0207] To a 10L three-necked flask equipped with mechanical stirring and nitrogen protection, add 1M zinc chloride tetrahydrofuran solution (5.5mol, 5.5L), cool to 0°C in an ice bath, and slowly add 2M isopropylmagnesium chloride tetrahydrofuran solution (5.5mol, 2.75L) dropwise, controlling the internal temperature below 5°C. After completion of the addition, continue the reaction at 0-5°C for 30 minutes. Subsequently, slowly add a solution of intermediate 1-1 (702g, 2.75mol) in anhydrous THF (500mL), controlling the internal temperature below 5°C during the addition. After completion of the addition, continue the reaction at 0-5°C for 1 hour. After the reaction was completed, 500 g of ammonium chloride was prepared into a saturated aqueous solution and slowly added to the above reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (5 L × 2), and the organic phases were combined and washed with water, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain intermediate 1-2 (377 g, 1.26 mol, 45.80% yield).

[0208] Step 3 Preparation of Intermediate 1-3

[0209]

[0210] To a 10-L three-necked flask equipped with a mechanical stirrer, intermediate 1-2 (730 g, 2.44 mol) and glacial acetic acid (6 L) were added. The mixture was cooled to 0°C in an ice bath. Zinc powder (796.24 g, 12.18 mol) was added portionwise with mechanical stirring, maintaining the internal temperature below 60°C. The reaction was stirred and continued for 1 hour. After completion of the reaction, the mixture was filtered, and the filter cake was rinsed with 100 mL of ethyl acetate. The filtrate was concentrated under reduced pressure to remove the glacial acetic acid. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio of 50:1 to 10:1) to obtain intermediate 1-3 (a mixture of (2S,3S) and (2R,3R) enantiomers, with the less polar spot on thin-layer chromatography (TLC)). It was obtained as a yellow viscous liquid (280 g, 1.04 mol, 42.65% yield). MS m / z: 270 (M+1). + .

[0211] Step 4 Preparation of Intermediate 1-4

[0212]

[0213] To a suspension of intermediate 1-3 (60 g, 222.41 mmol) in tetrahydrofuran (200 mL) and water (100 mL) were added sodium bicarbonate (37.37 g, 444.83 mmol) and Boc-anhydride (53.34 g, 244.66 mmol) in sequence. The mixture was stirred at room temperature overnight. After completion of the reaction, 300 mL of water was added and the mixture was extracted with ethyl acetate (300 mL x 2). The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio of 100:1 to 50:1) to obtain intermediate 1-4 (39.4 g, 106.52 mmol, 47.89% yield). MS m / z: 270 [M-99]. + , 314[M-55] + .

[0214] Step 5 Preparation of Intermediate 1

[0215]

[0216] To a suspension of intermediate 1-4 (20.00 g, 54.07 mmol) in methanol (100 mL) and water (10 mL) was added NaOH (6.49 g, 162.21 mmol), and the temperature was raised to 50°C for 3 hours. After the reaction was complete, the reaction solution was concentrated, 100 mL of water was added, and the mixture was extracted once with ethyl acetate (100 mL). The aqueous phase was cooled to 0-5°C and the pH was adjusted to 3-4 with 1 M HCl. The mixture was then extracted with ethyl acetate (100 mL). The organic phase was concentrated under reduced pressure to obtain a pair of enantiomers of intermediate 1 (17.8 g, 52.07 mmol, 96.30% yield) as a yellow oil. The enantiomers were separated by chiral separation by supercritical fluid chromatography (SFC) to obtain (2S, 3S) enantiomer 1, 6.5 g, MS m / z: 242 [M-99]. + , 286[M-55] + . 1 H NMR (400 MHz, Chloroform-d) δ7.41–7.35 (m, 1H), 7.27–7.23 (m, 2H), 7.21–7.15 (m, 1H), 4.90–4.82 (m, 1H), 4.82–4.74 (m, 1H), 3.68–3.56 (m, 1H), 2.19–2.03 (m, 1H), 1.41 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H). The retention time of the (2S, 3S) configuration was 2.59 min, and the retention time of the (2R, 3R) configuration was 3.06 min ( AD-3 150*3mm, 5um, isocratic 5% ethanol 1mL / min). The specific rotation of the (2S,3S) configuration is 78.18° (25℃, 0.089g / 100ml methanol solution, wavelength 589nm), and the specific rotation of the (2R,3R) configuration is -72.60° (25℃, 0.098g / 100ml methanol solution, wavelength 589nm).

[0217] Example 2 Preparation of Intermediate Amino Acid 2

[0218] Step 1 Preparation of intermediate 2-2

[0219]

[0220] Referring to the preparation method of intermediate 1-2 in Example 1, intermediate 1-1 was reacted with isopropenyl magnesium bromide to obtain the product with a yield of 37%. MS m / z: 298 (M+1) + .

[0221] Step 2 Preparation of Intermediate 2-3

[0222]

[0223] Referring to the preparation method of intermediate 1-3 in Example 1, the nitro group was reduced by zinc powder-acetic acid system to obtain the product with a yield of 85%. MS m / z: 268 (M+1) + The four diastereomers were used in the next step without separation.

[0224] Step 3 Preparation of Intermediate 2-4

[0225]

[0226] Referring to the preparation method of intermediate 1-4 in Example 1, the amino group was protected by Boc anhydride to obtain the product. MS m / z: 368 [M+1] + , 312[M-55] + .

[0227] Step 4 Preparation of Intermediate 2-5

[0228]

[0229] Ferric nitrate nonahydrate (439.29 mg, 1.09 mmol) was dissolved in 10 ml of water and degassed by ultrasonication at 0°C for 10 min under nitrogen protection. Subsequently, 10 ml of acetonitrile and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (384.92 mg, 1.09 mmol) were added in sequence. A 10 ml acetonitrile solution of intermediate 2-4 (100 mg, 271.84 umol) and NaBH4 (66.84 mg, 1.77 mmol) were added to the reaction solution at 0°C. After 2 min, NaBH4 (66.84 mg, 1.77 mmol) was added and stirring was continued at 0°C for 30 min. After completion of the reaction, 1 ml of ammonia was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was dried over sodium sulfate, concentrated under reduced pressure and then purified by silica gel column chromatography to obtain intermediate 2-5.

[0230] Step 5 Preparation of Intermediate 2

[0231]

[0232] Referring to the preparation method of intermediate 1-5 in Example 1, it was obtained by hydrolysis with sodium hydroxide, MS m / z: 284 [M-55] + The four isomers of intermediate 2 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R) were obtained by separation on a supercritical fluid chromatography (SFC) chiral separation column.

[0233] Example 3 Preparation of Intermediate Chiral Cyclopropylmethyl Amino Acids 3a, 3b

[0234] Step 1 Preparation of Intermediate 3-1

[0235]

[0236] The diastereomeric mixture of intermediate 2-4 (a mixture of four chiral isomers) in Example 2 was separated and purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether volume ratio of 100:1) to obtain an enantiomer of intermediate 2-4, a mixture of (2S, 3S) and (2R, 3R) configurations. The enantiomer mixture was less polar on TLC plate chromatography. The enantiomer (1.7 g, 4.62 mmol) was taken and dissolved in 20 ml of dry DCM under nitrogen protection. The internal temperature was cooled to -30°C, and ZnEt2 (1 M solution in tetrahydrofuran, 2 7.73mL), after stirring at -30℃ for 1 hour, diiodomethane (9.90g, 36.97mmol) was added dropwise, and the internal temperature was maintained at no more than -20℃ during the addition. After the addition was completed, the internal temperature was allowed to slowly rise to room temperature and stirred overnight. LC-MS showed that there was about 30% of the by-product after de-Boc of the starting material 2-4. 5ml of water was added to quench the reaction, and the organic phase was concentrated to dryness under reduced pressure to obtain 1g of crude product. The crude product was now a mixture of the de-Boc form of 3-1 and the de-Boc form of the starting material 2-4. The mixture was dissolved in 10mL of THF and triethylamine was added in sequence. Amine (TEA) (897.78 mg, 8.87 mmol, 1.24 mL) and (Boc)2O (1.16 g, 5.32 mmol) were stirred at room temperature overnight and concentrated to dryness under reduced pressure. The crude product was separated and purified by silica gel column (volume ratio of petroleum ether / methyl tert-butyl ether 100:3) to obtain 0.5 g of a mixture of crude product of Boc-protected cyclopropylmethyl ethyl ester 3-1 and unreacted intermediate 2-4 in the previous step. The crude product was dissolved in a mixture of tetrahydrofuran (5 mL), acetonitrile (5 mL) and 5 mL of water, and potassium osmate dihydrate (44.3 The reaction mixture was stirred overnight at room temperature. LC-MS monitoring showed that no unreacted intermediate 2-4 was present. The reaction mixture was concentrated under reduced pressure to remove most of the organic solvent. The mixture was extracted with 15 ml of ethyl acetate. The organic phase was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1) to obtain intermediate 3-1 (0.5 g, 1.31 mmol, 28% yield, a mixture of 2S, 3S and 2R, 3R configurations). MS m / z: 382 [M+1] + .

[0237] Step 2 Preparation of intermediate 3-2

[0238]

[0239] Referring to the preparation method of intermediate 1-5 in Example 1, intermediate 3-2 was obtained by hydrolysis with sodium hydroxide. MS m / z: 298 [M-55] + .

[0240] Step 3 Preparation of intermediates 3a, 3b

[0241]

[0242] Intermediate 3-2 is a pair of enantiomers. After separation by supercritical fluid chromatography (SFC) chiral column, (2S, 3S) enantiomer 3b and (2R, 3R) enantiomer 3a were obtained, respectively. MS m / z: 354 [M+1] + The retention time of (2S,3S) configuration is 5.904min, and the retention time of (2R,3R) configuration is 3.306min. AD-3 150*3mm, 5um, isocratic 5% ethanol 1mL / min). The specific rotation of the (2S,3S) configuration is 48.755° (25℃, 0.1g / 100ml methanol solution, wavelength 589nm), and the specific rotation of the (2R,3R) configuration is -40.695° (25℃, 0.1g / 100ml methanol solution, wavelength 589nm).

[0243] Example 4 Preparation of Intermediate 4

[0244] Step 1 Preparation of Intermediate 4-1

[0245]

[0246] At room temperature, the intermediate 1-1 of Example 1 (5 g, 19.56 mmol) was dissolved in methanol (50 mL), and sodium methoxide (4.23 g, 78.23 mmol) was added. The reaction was stirred at room temperature for 2 hours. Thin layer chromatography (TLC) showed that the starting material disappeared. The solvent was removed by concentration under reduced pressure, and saturated aqueous ammonium chloride solution 20 mL was added. The mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was separated on a silica gel column (petroleum ether / ethyl acetate volume ratio of 4:1) to obtain intermediate 4-1 (3 g, 10.43 mmol, 53.32% yield) as a light yellow liquid with Rf=0.5 (hexane / EtOAc=8:1).

[0247] Step 2 Preparation of intermediate 4-2

[0248]

[0249] Intermediate 4-1 (1.58 g, 5.48 mmol) was dissolved in 10 mL of glacial acetic acid, and zinc powder (1.79 g, 27.41 mmol) was added. The reaction was stirred at room temperature for 2 hours, filtered, washed with a small amount of ethyl acetate, and the filtrate was concentrated to dryness under reduced pressure. The crude product was separated on a silica gel column (petroleum ether / ethyl acetate volume ratio of 2:1) to obtain intermediate 4-2 (0.83 g, 3.22 mmol, 58.76% yield) as a light yellow solid, MS m / z: 258 [M+1].

[0250] Step 3 Preparation of intermediate 4-3

[0251]

[0252] Intermediate 4-2 (0.83 g, 3.22 mmol) was dissolved in a mixed solution of THF (3 mL) and water (1 mL), and NaHCO3 (541.11 mg, 6.44 mmol) and Boc2O (737.20 mg, 3.38 mmol) were added respectively. The reaction was stirred at room temperature for 12 hours, and ethyl acetate (15 mL) and water (15 mL) were added for washing. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was separated on a silica gel column (petroleum ether / ethyl acetate volume ratio of 4:1) to obtain intermediate 4-3 (1.1 g, 3.07 mmol, 95.45% yield) as a light yellow liquid, MS m / z: 302 [M-55].

[0253] Step 4 Preparation of Intermediate 4

[0254]

[0255] Intermediate 4-3 (1.23 g, 3.44 mmol) was dissolved in a mixture of methanol (15 mL) and water (15 mL). Lithium hydroxide monohydrate (1.20 g, 28.53 mmol) was added and stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the pH was adjusted to ~4 by the addition of 0.5 N HCl dropwise under ice. The mixture was extracted with ethyl acetate and tetrahydrofuran (5:1). The organic phase was concentrated under reduced pressure to obtain a pale yellow liquid (1.1 g, 3.34 mmol, 97.04% yield). The crude product was separated by supercritical fluid chromatography (SFC) using a chiral separation column to obtain the four isomers of intermediate 4 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R). MS m / z 274 [M-55].

[0256] Example 5 Preparation of Intermediate 5

[0257]

[0258] Referring to the method for preparing intermediate 4 in Example 4, intermediate 1-1 was reacted with sodium ethoxide, followed by nitro group reduction, amino group protection with Boc, hydrolysis, and finally separation on a supercritical fluid chromatography (SFC) chiral separation column to obtain four chiral isomers of intermediate 5 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R). MS m / z: 288 [M-55] + .

[0259] Example 6 Preparation of Intermediate 6

[0260]

[0261] Referring to the method for preparing intermediate 4 in Example 4, intermediate 1-1 was reacted with sodium isopropoxide, followed by nitro group reduction, amino group protection with Boc, hydrolysis, and finally separation on a supercritical fluid chromatography (SFC) chiral separation column to obtain four chiral isomers of intermediate 6 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R). MS m / z: 302 [M-55] + .

[0262] Example 7 Preparation of Intermediate 7

[0263]

[0264] Referring to the method for preparing intermediate 4 in Example 4, intermediate 1-1 was reacted with cyclopropanol in the presence of potassium tert-butoxide, followed by nitro group reduction, amino group protection with Boc, and hydrolysis. Finally, four chiral isomers of intermediate 7 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R) were obtained by separation using a supercritical fluid chromatography (SFC) chiral separation column. MS m / z: 300 [M-55] + .

[0265] Example 8 Preparation of Intermediate 8

[0266]

[0267] Intermediate 1 was prepared by referring to the method of Example 1. Propionaldehyde was used as the starting material, condensed with ethyl nitroacetate, formatted with o-chlorophenylmagnesium bromide, reduced with nitrozinc powder, protected the amino group with Boc, and hydrolyzed with alkali. Finally, four chiral isomers of Intermediate 8 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R) were obtained. MS m / z: 228 [M-99] + , 272[M-55] + .

[0268] Example 9 Preparation of Intermediate 9

[0269]

[0270] Intermediate 1 was prepared by referring to the method of Example 1. Cyclopropanecarboxaldehyde was used as the starting material, and the product was condensed with ethyl nitroacetate, formatted with o-chlorophenylmagnesium bromide, reduced with nitrozinc powder, protected with Boc amino groups, and hydrolyzed with alkali. Finally, four chiral isomers of Intermediate 9 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R) were obtained. MS m / z: 228 [M-99] + , 272[M-55] + .

[0271] Example 10 Preparation of Intermediate 10

[0272]

[0273] Intermediate 1 was prepared by referring to the method of Example 1. Cyclobutanecarboxaldehyde was used as the starting material, and the product was condensed with ethyl nitroacetate, formatted with o-chlorophenylmagnesium bromide, reduced with nitrozinc powder, protected with Boc amino groups, and hydrolyzed with alkali. Finally, four chiral isomers of Intermediate 10 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R) were obtained by separation using a supercritical fluid chromatography (SFC) chiral separation column. MS m / z: 254 [M-99] + , 298[M-55] + .

[0274] Example 11 Preparation of Intermediate 11

[0275]

[0276] Intermediate 1 was prepared by referring to the method of Example 1. Cyclohexylcarboxaldehyde was used as the starting material, and the product was condensed with ethyl nitroacetate, formatted with o-chlorophenylmagnesium bromide, reduced with nitrozinc powder, protected with Boc amino groups, and hydrolyzed with alkali. Finally, four chiral isomers of Intermediate 11 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R) were obtained by separation using a supercritical fluid chromatography (SFC) chiral separation column. MS m / z: 254 [M-99] + , 298[M-55] + .

[0277] Example 12 Preparation of Intermediate 12

[0278]

[0279] The resin activated with dichloromethane was added to a solution of N-FMOC-3-cyclohexyl-D-alanine (FMOC-D-CHA-OH) (2.00 g, 5.08 mmol) and DIPEA (1.97 g, 15.24 mmol, 2.66 mL) in DMF (40.00 mL). After shaking for 12 hours, the mixture was filtered. DCM / MeOH / DIPEA (85 / 10 / 5) was added to the resin, shaken for 30 min, filtered, and washed with DCM (50*10 ml), DMF (50*10 ml), and DCM (50*10 ml) in sequence. HFIP (20% in DCM) (913.89 mg, 5.08 mmol, 40.00 mL) was added to the resin, shaken for a while, filtered, and HFIP (20% in DCM) (913.89 mg, 5.08 mmol, 40.00 mL) was added to the resin, shaken and filtered, the filtrates were combined and concentrated to give cyclohexyl-D-glycine (870.00 mg, 5.08 mmol, 100.00% yield). 500 mg (2.92 mmol) of this product was added to THF-water (v / v 1:1, 20 mL), sodium carbonate (618.98 mg, 5.84 mmol) and Boc2O (954.84 mg, 4.38 mmol), and the reaction was stirred at room temperature overnight. Most of the organic solvent was removed under reduced pressure, the pH was adjusted to 4 with 0.5N HCl, and the mixture was extracted with ethyl acetate (3*10 ml). The organic phases were combined and concentrated under reduced pressure to give 0.78 g of a crude product of intermediate 12.

[0280] Example 13 Preparation of Intermediate 13

[0281]

[0282] Intermediate 4 was prepared by referring to the method of Example 4. Cyclohexylcarboxaldehyde was used as the starting material, and the product was condensed with ethyl nitroacetate, reacted with sodium methoxide, reduced with the nitro group, protected with Boc amino groups, and hydrolyzed. Finally, four chiral isomers of Intermediate 13 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R) were obtained. MS m / z: 302 [M+1] + .

[0283] Example 14 Preparation of Intermediate 14

[0284]

[0285] Referring to the method for preparing intermediate 4 in Example 4, intermediate 1-1 was reacted with 4-methylpyrazole in a potassium carbonate-DMF system, reduced with nitrozinc powder, amino protected with Boc, hydrolyzed, and finally separated by supercritical fluid chromatography (SFC) chiral separation column to obtain four chiral isomers of intermediate 14 (2S, 3S; 2R, 3R; 2R, 3S; 2S, 3R). MS m / z: 324 [M-55] + .

[0286] Example 15 Preparation of Intermediate 15

[0287]

[0288] The intermediate ethyl p-nitrophenylacetate (5 g, 23.90 mmol) was dissolved in EtOH (100 mL). After nitrogen substitution, 10% Pd / C (2.9 g) was added and the mixture was stirred under normal pressure and hydrogen atmosphere overnight. After the starting material disappeared, the mixture was filtered through celite and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure to obtain intermediate 15 (4.27 g, 23.83 mmol, 99.69% yield). MS m / z: 180 [M+1] + The product was used directly in the next reaction without purification.

[0289] Example 16 Preparation of Intermediate 16

[0290] Step 1 Preparation of Intermediate 16-1

[0291]

[0292] To a solution of ethyl p-nitrophenylacetate (350 g, 1.67 mol l) in dry DMF (2 L) was added Cs2CO3 (2.73 kg, 8.37 mol) under nitrogen at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. Methyl iodide (1.19 kg, 8.37 mol) was then slowly added dropwise. The reaction was allowed to proceed overnight at room temperature and filtered. The filtrate was diluted with 10 L of ethyl acetate and washed with saturated brine (3*10 L). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 16-1 (320 g, 1.24 mol, 74.17% yield). MS m / z: 238 [M+1] + The crude product was used directly in the next step.

[0293] Step 2 Preparation of Intermediate 16

[0294]

[0295] Referring to the method for preparing intermediate 15 in Example 15, intermediate 16 can be obtained by hydrogenation reduction of intermediate 16-1. MS m / z: 208 [M+1] +.

[0296] Example 17 Preparation of Intermediate 17

[0297] Step 1 Preparation of Intermediate 17-1

[0298]

[0299] To a solution of ethyl p-nitrophenylacetate (156 g, 745.71 mmol) in dry DMF (700 mL) was added Cs2CO3 (290.82 g, 894.85 mmol) under nitrogen at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was then cooled to 0°C and iodomethane (116.43 g, 820.28 mmol) was slowly added dropwise. The reaction was allowed to proceed overnight and filtered. The filtrate was diluted with 2 L of ethyl acetate and washed with saturated brine (3*1.5 L). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 17-1 (165 g, 739.16 mmol, 99.12% yield). MS m / z: 224 [M+1] + The crude product was used directly in the next step.

[0300] Step 2 Preparation of Intermediate 17

[0301]

[0302] Referring to the method for preparing intermediate 15 in Example 15, intermediate 17 was obtained by hydrogenation reduction of intermediate 17-1. MS m / z: 194 [M+1] + .

[0303] Example 18 Preparation of Intermediate 18

[0304] Step 1 Preparation of Intermediate 18-1

[0305]

[0306] Under nitrogen protection and at -10 ° C, a solution of intermediate 17-1 (11.48 g, 478.44 mmol) in DMF (300 mL) was slowly added dropwise to a mixed solution of 0.3 L of dry DMF and NaH (11.48 g, 478.44 mmol). After 30 minutes, the temperature was lowered to -50 ° C, and chloromethyl methyl ether (48.15 g, 598.05 mmol) was added dropwise. The reaction solution was stirred at -50 ° C to -10 ° C for 30 minutes. The mixture was stirred for 3 hours. After the reaction was complete, the reaction was quenched with cold saturated ammonium chloride and extracted with ethyl acetate (2*400 ml). The organic phases were combined, washed with saturated brine (400 ml*2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, volume ratio, 100:1 to 50:1) to obtain intermediate 18-1 (45 g, 168.36 mmol, 42.23% yield), MS m / z: 268 [M+1] + .

[0307] Step 2 Preparation of Intermediate 18

[0308]

[0309] Intermediate 18-1 (45 g, 168.36 mmol) was dissolved in EtOH (100 mL). After nitrogen substitution, 10% Pd / C (8 g) was added and the mixture was stirred under normal pressure and hydrogen atmosphere overnight. After the starting material disappeared, the mixture was filtered through celite and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure to obtain intermediate 18 (34.6 g, 145.81 mmol, 86.60% yield). MS m / z: 260 [M+23] + .

[0310] Example 19 Preparation of Intermediate 19

[0311] Step 1 Preparation of Intermediate 19-1

[0312]

[0313] Under nitrogen, ethyl p-nitrophenylacetate (29.4 g, 140.54 mmol) was dissolved in 1.2 L of dry N,N-dimethylacetamide and cooled to -40°C in a dry ice-ethanol bath. Cesium carbonate (114.54 g, 351.34 mmol) was added and stirred at -40°C for 15 min. 2-Chloroethyl chloromethyl ether (19.94 g, 154.59 mmol) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction was allowed to return to room temperature and stirred overnight. After the starting material disappeared, 3 L of ice water was added to quench the reaction. The reaction was extracted with ethyl acetate (2 L*2). The organic phase was washed with saturated brine (2 L*2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was separated by silica gel column chromatography to obtain intermediate 19-1 (6.5 g, 24.50 mmol, 17.44% yield). MS m / z: 266 [M+1] + .

[0314] Step 2 Preparation of Intermediate 19

[0315]

[0316] Intermediate 19-1 (15 g, 56.55 mmol) was dissolved in EtOH (100 mL). After nitrogen substitution, 10% Pd / C (3 g) was added and the mixture was stirred under normal pressure and hydrogen atmosphere overnight. After the starting material disappeared, the mixture was filtered through celite and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure to obtain intermediate 19 (12.7 g, 53.98 mmol, 95.46% yield). MS m / z: 236 [M+1] + .

[0317] Example 20 Preparation of Intermediate 20

[0318] Step 1 Preparation of Intermediate 20-1

[0319]

[0320] Referring to the preparation method of intermediate 19-1 in Example 19, intermediate 20-1 was obtained by reacting ethyl p-nitrophenylacetate with 2,2'-dibromodiethyl ether in anhydrous DMF using cesium carbonate as an acidizing agent. The yield was 60%, MS m / z: 280 [M+1]. + .

[0321] Step 2 Preparation of Intermediate 20

[0322]

[0323] Referring to the method for preparing intermediate 15 in Example 15, intermediate 20 can be obtained by hydrogenation reduction of intermediate 20-1. MS m / z: 250 [M+1] + .

[0324] Example 21 Preparation of Compound 21

[0325] Step 1 Preparation of Intermediate 21-1

[0326]

[0327] Intermediate 1 (614.57 mg, 1.80 mmol) in step 5 of Example 1, EDCI (412.08 mg, 2.16 mmol), DIPEA (697.08 mg, 5.39 mmol, 939.46 uL), HOAt (293.42 mg, 2.16 mmol) and intermediate 16 (0.35 g, 1.80 mmol) in Example 16 were added to DCM (10 mL) in sequence and reacted at room temperature for 3 hours. The mixture was quenched with water and most of the organic solvent was removed under reduced pressure. The mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified and separated by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio of 5:1) to obtain intermediate 21-1 (0.85 g, 1.6 mmol, 89% yield). MS m / z: 531 (M+1) + .

[0328] Step 2 Preparation of Intermediate 21-2

[0329]

[0330] The intermediate 21-1 obtained in step 1 (0.85 g, 1.6 mmol) was dissolved in DCM (3 mL), and TFA (2 mL) was added dropwise under ice bath. The reaction was continued with stirring under ice bath for 2 h, and the mixture was dried to obtain the trifluoroacetate salt of the intermediate 21-2 (843 mg, 493.45 umol, 100% yield). MS m / z: 431 (M+1) + , and was used directly in the next reaction without purification.

[0331] Step 3 Preparation of Intermediate 21-3

[0332]

[0333] HBTU (134.35 mg, 353.56 μmol) and DIPEA (114.23 mg, 883.89 μmol, 153.95 μL) were added sequentially to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (112.01 mg, 888.21 μmol) in DCM (5 mL). After 15 min, the TFA salt of intermediate 21-2 obtained in step 2 (155 mg, 294.63 μmol) was added. The mixture was reacted at room temperature for 2 h, quenched with water, and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified and separated by silica gel column chromatography (petroleum ether / ethyl acetate 2:1) to obtain intermediate 21-3 (127 mg, 236 μmol, 80% yield). MS m / z: 539 (M+1) + .

[0334] Step 4 Preparation of Intermediate 21-4

[0335]

[0336] To a mixture of intermediate 21-3 (127 mg, 236 umol) in EtOH (1 mL) and water (0.2 mL) was added NaOH (64.03 mg, 1.60 mmol) and reacted at 75°C for 12 hours. LC-MS showed that the reaction of the starting material was complete. The pH was adjusted to 4 with 1N HCl and extracted with EA (10 ml*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product of intermediate 21-4 (87 mg, 170 umol, 72% yield). MS m / z: 511 [M+1] + , and was used directly in the next reaction without purification.

[0337] Step 5 Preparation of Intermediate 21-5

[0338]

[0339] HBTU (97 mg, 255 μmol) and DIPEA (110 mg, 850 μmol, 140 μL) were added sequentially to a DCM (5 mL) solution of the intermediate 21-4 (87 mg, 170 μmol) in step 4. After 15 min, D-leucine methyl ester hydrochloride (31 mg, 170 μmol) was added and reacted at room temperature for 1 h. The mixture was quenched with 10 mL of water and most of the organic solvent was removed under reduced pressure. The mixture was extracted with ethyl acetate (10 ml*3). The organic phases were combined, washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified and separated by MPLC reverse phase C18 column chromatography (acetonitrile / 0.05% water 0-40%) to obtain intermediate 21-5 (89 mg, 139 μmol, 82% yield). MS m / z: 638 (M+1) + .

[0340] Step 6 Preparation of Compound 21

[0341]

[0342] To a mixture of intermediate 21-5 (89 mg, 139 umol) in THF (0.2 mL), MeOH (0.2 mL) and water (0.2 mL) was added NaOH (11 mg, 0.28 mmol) and reacted at 55°C for 12 hours. LC-MS showed that the reaction of the starting material was complete. The pH was adjusted to 4 with 1N HCl and extracted with EA (10 ml*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by MPLC C18 reverse phase column to give compound 21 (56 mg, 90 umol, 65% yield), MS m / z: 624 [M+1]. + .

[0343] Example 22 Preparation of Compound 22

[0344]

[0345] Referring to the method of Example 21, intermediate 21-2 was reacted with phenylacetyl chloride, the ethyl ester was hydrolyzed with alkaline, and the methyl ester was hydrolyzed with alkaline to obtain compound 22. MS m / z: 634 (M+1) + .

[0346] Example 23 Preparation of Compound 23

[0347]

[0348] Intermediate 1-1 was reduced by hydrogenation with Pd / C, and the amino group was protected by Boc. Then, according to the method of Example 21, it was condensed with Intermediate 16 of Example 16. The Boc protecting group was removed and the compound was reacted with phenylacetyl chloride. The ethyl ester was hydrolyzed with alkaline, and the methyl ester was hydrolyzed with D-leucine methyl ester. Finally, the methyl ester was hydrolyzed with alkaline to obtain compound 23. MS m / z: 592 (M+1) + .

[0349] Example 24 Preparation of Compound 24

[0350]

[0351] Referring to the method of Example 21, intermediate 21-4 was condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 24. MS m / z: 649 (M+1) + .

[0352] Example 25 Preparation of Compound 25

[0353]

[0354] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 2 was used as the starting material, and condensed with intermediate 16, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 25. MS m / z: 667 (M+1) + .

[0355] Example 26 Preparation of Compound 26

[0356]

[0357] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 16, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 26. MS m / z: 661 (M+1) + .

[0358] Example 27 Preparation of Compound 27

[0359]

[0360] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 4 was used as the starting material, and condensed with intermediate 16, deBocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 27. MS m / z: 637 (M+1) + .

[0361] Example 28 Preparation of Compound 28

[0362]

[0363] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 5 was used as the starting material, and condensed with intermediate 16, deBocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 28. MS m / z: 651 (M+1) + .

[0364] Example 29 Preparation of Compound 28

[0365]

[0366] Referring to the method of Example 21, the (2S,3S) configuration of intermediate 6 was used as the starting material, and condensed with intermediate 16, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 29. MS m / z: 665 (M+1) + .

[0367] Example 30 Preparation of Compound 30

[0368]

[0369] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 7 was used as the starting material, and condensed with intermediate 16, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 30. MS m / z: 663 (M+1) + .

[0370] Example 31 Preparation of Compound 31

[0371]

[0372] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 8 was used as the starting material, and the product was condensed with intermediate 16, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 31. MS m / z: 635 (M+1) + .

[0373] Example 32 Preparation of Compound 32

[0374]

[0375] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 9 was used as the starting material, and condensed with intermediate 16, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 32. MS m / z: 647 (M+1) + .

[0376] Example 33 Preparation of Compound 33

[0377]

[0378] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 10 was used as the starting material, and condensed with intermediate 16, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 33. MS m / z: 661 (M+1) + .

[0379] Example 34 Preparation of Compound 34

[0380]

[0381] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 11 was used as the starting material, and condensed with intermediate 16, deBocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 34. MS m / z: 689 (M+1) + .

[0382] Example 35 Preparation of Compound 35

[0383]

[0384] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 12 was used as the starting material, and condensed with intermediate 16, deBocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 35. MS m / z: 579 (M+1) + .

[0385] Example 36 Preparation of Compound 36

[0386]

[0387] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 13 was used as the starting material, and condensed with intermediate 16, deBocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 36. MS m / z: 609 (M+1) + .

[0388] Example 37 Preparation of Compound 37

[0389]

[0390] Referring to the method of Example 21, the (2S, 3S) configuration of intermediate 14 was used as the starting material, and condensed with intermediate 16, deBocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 37. MS m / z: 687 (M+1) + .

[0391] Example 38 Preparation of Compound 38

[0392]

[0393] Referring to the method of Example 21, intermediate 1 was used as the starting material, condensed with intermediate 15, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 38, MS m / z: 621 (M+1) + .

[0394] Example 39 Preparation of Compound 39

[0395]

[0396] Referring to the method of Example 21, intermediate 1 was used as the starting material, condensed with intermediate 17, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 39, MS m / z: 635 (M+1) + .

[0397] Example 40 Preparation of Compound 40

[0398]

[0399] Referring to the method of Example 21, intermediate 1 was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 40, MS m / z: 679 (M+1) + .

[0400] Example 41 Preparation of Compound 41

[0401]

[0402] Referring to the method of Example 21, intermediate 1 was used as the starting material, condensed with intermediate 19, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 41. MS m / z: 677 (M+1) + .

[0403] Example 42 Preparation of Compound 42

[0404]

[0405] Referring to the method of Example 21, intermediate 1 was used as the starting material, condensed with intermediate 20, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 42, MS m / z: 691 (M+1) + .

[0406] Example 43 Preparation of Compound 43

[0407]

[0408] Referring to the method of Example 21, intermediate 2 was used as the starting material, condensed with intermediate 15, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 43, MS m / z: 639 (M+1) + .

[0409] Example 44 Preparation of Compound 44

[0410]

[0411] Referring to the method of Example 21, intermediate 2 was used as the starting material, condensed with intermediate 17, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 44, MS m / z: 653 (M+1) + .

[0412] Example 45 Preparation of Compound 45

[0413]

[0414] Referring to the method of Example 21, intermediate 2 was used as the starting material, condensed with intermediate 17, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 45, MS m / z: 667 (M+1) + .

[0415] Example 46 Preparation of Compound 46

[0416]

[0417] Referring to the method of Example 21, intermediate 2 was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 46, MS m / z: 697 (M+1) + .

[0418] Example 46 Preparation of Compound 46

[0419]

[0420] Referring to the method of Example 21, intermediate 2 was used as the starting material, condensed with intermediate 19, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 46, MS m / z: 695 (M+1) + .

[0421] Example 47 Preparation of Compound 47

[0422]

[0423] Referring to the method of Example 21, intermediate 2 was used as the starting material, condensed with intermediate 20, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain 47. MS m / z: 709 (M+1) + .

[0424] Example 48 Preparation of Compound 48

[0425]

[0426] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 15, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 48. MS m / z: 633 (M+1) + .

[0427] Example 49 Preparation of Compound 49

[0428]

[0429] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 15, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 49. MS m / z: 661 (M+1) + .

[0430] Example 50 Preparation of Compound 50

[0431]

[0432] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 17, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 50. MS m / z: 647 (M+1) + .

[0433] Example 51 Preparation of Compound 51

[0434]

[0435] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 51. MS m / z: 691 (M+1) + .

[0436] Example 52 Preparation of Compound 52

[0437]

[0438] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 19, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 52. MS m / z: 689 (M+1)+ .

[0439] Example 53 Preparation of Compound 53

[0440]

[0441] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 20, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with (R)-N-ethylcyclobutylglycinamide to obtain compound 53. MS m / z: 703 (M+1) + .

[0442] Example 54 Preparation of Compound 54

[0443]

[0444] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 54. MS m / z: 677 (M+1) + .

[0445] Example 55 Preparation of Compound 55

[0446]

[0447] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 55. MS m / z: 703 (M+1) + .

[0448] Example 56 Preparation of Compound 56

[0449]

[0450] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 56. MS m / z: 691 (M+1) + .

[0451] Example 57 Preparation of Compound 57

[0452]

[0453] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 57. MS m / z: 707 (M+1) + .

[0454] Example 58 Preparation of Compound 58

[0455]

[0456] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 58. MS m / z: 695 (M+1) + .

[0457] Example 59 Preparation of Compound 59

[0458]

[0459] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 59. MS m / z: 713 (M+1) + .

[0460] Example 60 Preparation of Compound 60

[0461]

[0462] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 60. MS m / z: 691 (M+1) + .

[0463] Example 61 Preparation of Compound 61

[0464]

[0465] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 61. MS m / z: 693 (M+1) + .

[0466] Example 62 Preparation of Compound 62

[0467]

[0468] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 62 (MS m / z: 705M+1). + .

[0469] Example 63 Preparation of Compound 63

[0470] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-methyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 63. MS m / z: 707 (M+1) + .

[0471] Example 64 Preparation of Compound 64

[0472]

[0473] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 64. MS m / z: 691 (M+1) + .

[0474] Example 65 Preparation of Compound 65

[0475]

[0476] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 65. MS m / z: 717 (M+1) + .

[0477] Example 66 Preparation of Compound 66

[0478]

[0479] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 66. MS m / z: 705 (M+1) + .

[0480] Example 67 Preparation of Compound 67

[0481]

[0482] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 67. MS m / z: 721 (M+1) + .

[0483] Example 68 Preparation of Compound 68

[0484]

[0485] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 68. MS m / z: 709 (M+1) + .

[0486] Example 69 Preparation of Compound 69

[0487]

[0488] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 69. MS m / z: 727 (M+1) + .

[0489] Example 70 Preparation of Compound 70

[0490]

[0491] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 70. MS m / z: 705 (M+1) + .

[0492] Example 71 Preparation of Compound 71

[0493]

[0494] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 71. MS m / z: 707 (M+1) + .

[0495] Example 72 Preparation of Compound 72

[0496]

[0497] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 72. MS m / z: 719 (M+1) + .

[0498] Example 73 Preparation of Compound 73

[0499]

[0500] Referring to the method of Example 21, intermediate 3b was used as the starting material, condensed with intermediate 18, de-Bocated, condensed with 1-ethyl-1H-pyrazole-5-carboxylic acid, hydrolyzed, and finally condensed with the corresponding substituted glycinamide to obtain compound 73. MS m / z: 721 (M+1) + .

[0501] Example 74 Preparation of Compound 74

[0502]

[0503] Referring to the method of Example 21, intermediate 3b was used as the starting material, and condensed with intermediate 3-(4-aminophenyl)oxetane-3-carboxylic acid ethyl ester, Boc removal, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, ethyl ester hydrolysis, and finally condensation with (R)-N-ethylcyclobutylglycinamide to obtain compound 74. MS m / z: 675 (M+1) + .

[0504] Example 75 Preparation of Compound 75

[0505]

[0506] Referring to the method of Example 21, intermediate 1 was used as the starting material, and condensed with intermediate 3-(4-aminophenyl)oxetane-3-carboxylic acid ethyl ester, Boc removal, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, ethyl ester hydrolysis, and finally condensation with (R)-N-ethylcyclobutylglycinamide to obtain compound 75. MS m / z: 663 (M+1) + .

[0507] In order to illustrate the beneficial effects of the present invention, the present invention provides the following test examples.

[0508] Test Example 1 IL-17 enzyme-linked immunosorbent assay (ELISA) experiment

[0509] Competitive ELISA was used to quantify the inhibition of receptor-ligand binding by IL-17A inhibitors. 0.2 μg / mL IL-17A (Sino Biological Inc. Cat#12047-H07B) was added to 100 μL of 50 mM phosphate buffer, pH 7.4, per well in a 96-well plate and incubated at 37°C for 30 minutes. The plate was washed four times with PBST (PBS, 0.05% Tween-20), 200 μL of 5% skim milk was added, and the plate was incubated on a shaker at 25°C for 30 minutes. Test compounds were prepared at 100X concentrations, with final concentrations ranging from 0.0002 μM to 30 μM. After washing the plate four times with PBST (PBS, 0.05% Tween-20), 89 μL of PBST and 1 μL of the 100X test compound were added, mixed, and pre-incubated at 25°C for 10 minutes. Add 10 μL of 16 nM IL-17R (Sino Biological Inc., Cat. #10895-H03H) and incubate at 25°C on a shaker for 30 minutes. Wash the plate four times, then add 100 μL of anti-Fc tag HRP-conjugated antibody (Sino Biological Inc., Cat. #10702-T16-H-50) and incubate at 25°C on a shaker for 30 minutes. Wash the plate four times, then add 100 μL of TMB substrate solution and incubate at 25°C in the dark. Add 100 μL of 2.5 M HCl, and measure absorbance at 450 nm using a microplate reader.

[0510] The compounds prepared in the examples were tested for their IL-17A inhibitory activity according to the above method. The test results are shown in Table 1. The IC values ​​of each compound were determined. 50 According to the description, in Table 1:

[0511] “+” indicates IC 50 The measured value is less than 100 μM and greater than 1 μM;

[0512] Table 1. Inhibitory activity of compounds against IL-17A

[0513] Example <![CDATA[IC 50 ]]> 21 + 22 + 23 + 24 + 27 + 34 + 35 + 43 + 44 + 63 + 75 +

[0514] The experiments show that the compounds of the examples of the present invention have good IL-17A inhibitory activity and can be effectively used to treat diseases with abnormal IL-17A activity.

[0515] In summary, the new compound represented by Formula I disclosed in the present invention exhibits good IL-17A inhibitory activity, providing a new medicinal possibility for the clinical treatment of diseases related to abnormal IL-17A activity.

Claims

1. A compound represented by formula I, or a pharmaceutically acceptable salt thereof: in, R1 is selected from Each R 13 Independently selected from methyl and ethyl; R2 is selected from hydrogen; R3 and R4 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 alkyl), -3 to 6-membered cycloalkyl; wherein the cycloalkyl may be further replaced by an R 31 and at least one of R3 and R4 is hydrogen; Each R 31 Independently selected from -C 1～6 alkyl; Ring A is selected from R5 is selected from hydrogen; Y1, Y2, Y3, and Y4 are independently selected from CR Y1 ; Each R Y1 independently selected from hydrogen; R6, R7 are independently selected from hydrogen, -CH3, -CH2OCH3; Alternatively, R6 and R7 are connected to form L is selected from -C(O)NR L21 -; R L21 selected from hydrogen; R is selected from R a 、R a’ are independently selected from hydrogen, -C 1～6 alkyl, R b 、R c are independently selected from hydrogen, -C 1～6 alkyl; and R b 、R c At least one is hydrogen.

2. The compound according to claim 1, characterized in that: The compound of formula I is shown in formula II: in, R1 is selected from Each R 13 Independently selected from methyl and ethyl; R2 is selected from hydrogen; R3 and R4 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -3 to 6-membered cycloalkyl, -O(C 1～6 Alkyl); wherein the cycloalkyl group may be further replaced by an R 31 replace; Each R 31 Independently selected from -C 1～6 alkyl; Ring A is selected from R5 is selected from hydrogen; R6, R7 are independently selected from hydrogen, -CH3, -CH2OCH3; Alternatively, R6 and R7 are connected to form R a Selected from cyclobutyl, R b 、R c are independently selected from hydrogen, -C 1～6 alkyl.

3. The compound according to claim 2, characterized in that: R1 is selected from R 13 Selected from methyl.

4. The compound according to claim 2, characterized in that: The compound shown in formula II is specifically:

5. The compound according to claim 1, characterized in that: The compound of formula I is shown in formula III: in, R1 is selected from Each R 13 Independently selected from methyl and ethyl; R2 is selected from hydrogen; R3 and R4 are independently selected from hydrogen, -C 1～6 alkyl; Ring A is selected from R5 is selected from hydrogen; R6 and R7 are independently selected from hydrogen and -CH3; R a Selected from -C 1～6 alkyl; R b are each independently selected from hydrogen.

6. The compound according to claim 5, characterized in that: The compound of formula III is specifically:

7. Use of the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating IL-17A-mediated diseases.

8. The use according to claim 7, characterized in that: The IL-17A-mediated disease is one or more diseases related to inflammation, autoimmune diseases, and infectious diseases.

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