CN112341451A - Immunomodulator - Google Patents

Abstract

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

Description

Immunomodulator

Technical Field

The invention relates to an immunomodulator and application thereof in preparing a medicament.

Background

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

Targeting the binding of IL-17A to IL-17RA is an effective strategy for the treatment of IL-17A-mediated autoimmune inflammatory diseases. Treatment of animals with IL-17A neutralizing antibodies reduces disease incidence and severity in autoimmune encephalomyelitis (Komiyama Y et al J. Immunol.,2006,177: 566-573). Clinical trials with IL-17A antibodies have shown good results in IL-7A-mediated inflammatory diseases including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis. The IL-17A antibody (Cosentyx/secukinumab from Novartis) was approved by the FDA for the treatment of psoriasis 1 month 2015.

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

Disclosure of Invention

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

wherein the content of the first and second substances,

R₁selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromaticThe heterocyclic ring may be further substituted by one, two or three independent R₁₃Substitution;

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

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

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

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

each R_A1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_A2、-C_0～4alkylene-OC (O) R_A2、-C_0～4alkylene-C (O) R_A2、-C_0～4alkylene-C (O) OR_A2、-C_0～4alkylene-C (O) NR_A2R_A3、-C_0～4alkylene-S (O) NR_A2R_A3、-C_0～4alkylene-S (O)₂NR_A2R_A3、-C_0～4alkylene-P (O) (OH) NR_A2R_A3、-C_0～4alkylene-NR_A2R_A3、-C_0～4alkylene-NR_A2C(O)R_A3、-C_0～4alkylene-NR_A2S(O)R_A3、-C_0～4alkylene-NR_A2S(O)₂R_A3、-C_0～4alkylene-NR_A2P(O)(OH)R_A3、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle);

R_A2、R_A3each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

x is selected from O, S, NR_x1Or CR_x1R_x2；

R_x1、R_x2Each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

n is selected from 0, 1, 2 or 3;

R₃、R₄are respectively and independently selected from hydrogen, halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl); or, R₃、R₄Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～10Alkyl, halogen substituted-C_1～10An alkyl group;

Y₁、Y₂、Y₃each independently selected from N or CR_Y1；

Each R_Y1Independently selected from hydrogen, halogen, cyano, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl), -NH₂、-NH(C_1～10Alkyl), -N (C)_1～10Alkyl) (C_1～10Alkyl groups);

the B ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_B2、-C_0～4alkylene-OC (O) R_B2、-C_0～4alkylene-C (O) R_B2、-C_0～4alkylene-C (O) OR_B2、-C_0～4alkylene-C (O) NR_B2R_B3、-C_0～4alkylene-NR_B2R_B3、-C_0～4alkylene-NR_B2C(O)R_B3、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the cycloalkyl, alkylene, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R_B4Substitution;

R_B2、R_B3each independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl); or R_B2、R_B3Are linked to form a 3-to 10-membered heterocycloalkyl group; wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_B4Substitution;

each R_B4Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl), -NH₂、-NH(C_1～10Alkyl), -N (C)_1～10Alkyl) (C_1～10Alkyl groups).

Further, the air conditioner is provided with a fan,

R₁selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₁₃Substitution;

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

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

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

the ring A is selected from a 5-6-membered aromatic ring and a 5-6-membered aromatic heterocycle; wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R_A1Substitution;

each R_A1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_A2、-C_0～2alkylene-OC (O) R_A2、-C_0～2alkylene-C (O) R_A2、-C_0～2alkylene-C (O) OR_A2、-C_0～2alkylene-C (O) NR_A2R_A3、-C_0～2alkylene-NR_A2R_A3、-C_0～2alkylene-NR_A2C(O)R_A3、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle);

R_A2、R_A3each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

x is selected from O, S, NR_x1Or CR_x1R_x2；

R_x1、R_x2Each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

n is selected from 0, 1, 2 or 3;

R₃、R₄are respectively and independently selected from hydrogen, halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₃、R₄Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

Y₁、Y₂、Y₃each independently selected from N or CR_Y1；

Each R_Y1Independently selected from hydrogen, halogen, cyano, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups);

the B ring is selected from 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered aromatic ring,A 5-6 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_B2、-C_0～2alkylene-OC (O) R_B2、-C_0～2alkylene-C (O) R_B2、-C_0～2alkylene-C (O) OR_B2、-C_0～2alkylene-C (O) NR_B2R_B3、-C_0～2alkylene-NR_B2R_B3、-C_0～2alkylene-NR_B2C(O)R_B3、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the cycloalkyl, alkylene, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R_B4Substitution;

R_B2、R_B3each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or R_B2、R_B3Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_B4Substitution;

each R_B4Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

Further, the air conditioner is provided with a fan,

R₁selected from 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R₁₃Substitution;

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

Further, in the present invention,

R₁is selected from

R₁₃Independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group.

Further, the air conditioner is provided with a fan,

the ring A is selected from a 5-6-membered aromatic ring and a 5-6-membered aromatic heterocycle; wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R_A1Substitution;

each R_A1Independently selected from halogen, cyano, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_A2；

R_A2Selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

further, in the present invention,

ring A is

R_A1Selected from hydrogen, halogen, cyano, nitro, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

further, the air conditioner is provided with a fan,

R₃、R₄each independently selected from hydrogen, halogen, carbonyl and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycle)Alkyl groups); or, R₃、R₄Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group.

Further, in the present invention,

R₃、R₄to form cyclopropane.

Further, the air conditioner is provided with a fan,

ring B is selected from pyrimidine, morpholine and tetrahydrofuran; wherein the pyrimidine, morpholine, tetrahydrofuran may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-C (O) NR_B2R_B3；

R_B2、R_B3Each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or R_B2、R_B3Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_B4Substitution;

each R_B4Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

Further, in the present invention,

ring B is selected from

R_B11Independently selected from halogen, cyanoCarbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl or none;

R_B2、R_B3linked to form cyclobutylamine; wherein the cyclobutylamine may be further substituted by one, two or three R_B4Substitution;

each R_B4Independently selected from halogen, carbonyl, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

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

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

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

The invention also provides a pharmaceutical composition, which is a preparation prepared from the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.

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

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

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

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

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

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

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

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

The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix C_a～bAlkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C_1～4The alkyl group means an alkyl group having 1to 4 carbon atoms.

"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C₁～C₆Alkyl refers to an alkyl group having 1to 6 member atoms, for example 1to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C₁～C₆An alkoxy group.

"cycloalkyl" means having 3 to 14 carbon atoms and no ring heteroatomsAnd saturated or partially saturated cyclic groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:

dicyclohexyl and

a dicyclohexyl group.

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

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

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

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

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

"stereoisomers" includes enantiomers and diastereomers;

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

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

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

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

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

Detailed Description

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

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

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

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention. In the examples, the solution means an aqueous solution unless otherwise specified. In the examples, the reaction temperature is room temperature, unless otherwise specified. In the examples, M is mole per liter, unless otherwise specified.

The% in the text is not specifically indicated, and is a mass percentage.

THF, tetrahydrofuran; NMP is N-methylpyrrolidone;

DCM is dichloromethane; TEA is triethylamine;

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;

DIBAL: diisobutylaluminum hydride;

NBS is N-bromosuccinimide; DMF is dimethylformamide;

HBTU is benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate;

DIPEA is N, N-diisopropylethylamine;

HOAt: n-hydroxy-7-azabenzotriazole.

EXAMPLE 1 preparation of intermediate 1

Step 1 preparation of intermediate 1-1

To a 250mL three-necked flask were added dimethyl carbonate (17g,189mmol) and THF (80mL), and added NaH (60% w/w,3.18g,79.4mmol) with nitrogen substitution at room temperature with stirring. A solution of 1-indanone (5g,37.8mmol) in THF (40mL) was added dropwise to the reaction solution via a dropping funnel, after completion of the addition, the reaction was heated to reflux for 2 hours, and TLC showed completion of the reaction. The reaction was poured into a mixture of 1M HCl and ice, extracted three times with ethyl acetate (100mL), the EA layers were combined and dried, spun dry to give 1-1 (crude, 7.11g, yield: 99%) as a black oil, which was used directly in the next reaction.

Step 2 preparation of intermediates 1-2

Intermediate 1-1(7.11g,37.8mmol) was added to a 250mL single neck flask, dissolved in MeOH (100mL), and NaBH added portionwise with ice cooling₄(1.58g,41.6mmol), after addition was complete the reaction was allowed to warm slowly to room temperature for 1 hour and TLC indicated completion. MeOH was removed under reduced pressure, the residue was taken up in water (100mL), extracted 3 times with ethyl acetate (100mL), the EA layers were combined, dried and spun dry to give a brown oil 1-2 (crude, 7.18g, yield: 99%) which was used directly in the next reaction, MS M/z:193(M +1)⁺。

Step 3 preparation of intermediates 1-3

Intermediate 1-2(7.18g,37.8mmol) was added to a 250mL single vial, DCM (100mL) was added to dissolve, TEA (15.7mL,113.4mmol) was added, methanesulfonyl chloride (4.4mL,56.7mmol) was added slowly dropwise with cooling in an ice bath, after addition was allowed to warm slowly to room temperature overnight, and TLC indicated completion of the reaction. The reaction mixture was washed with water (100mL), the DCM layer was separated, dried and spin-dried, and purified by column chromatography (silica gel 100-.

Step 4 preparation of intermediates 1-4

Intermediate 1-3(6.04g,35.1mmol) was added to a 250mL single-neck flask, dissolved by addition of anhydrous THF (60mL), cooled to-78 deg.C in a dry ice-ethanol bath, DIBAL (1M in toluene, 70.2mL,70.2mmol) was added slowly dropwise, and after the addition was complete, the reaction was allowed to warm to room temperature slowly overnight, as indicated by TLC. Pouring the reaction solution into 1M HCl, stirring for 30 minutes at room temperature, adding EA (100mL) for extraction for 3 times, combining EA layers, drying, spin-drying, and purifying by column chromatography (silica gel 100-200 mesh, PE: EA: 10:1to 5:1) to obtain yellow oil 1-4(2.3g, yield: 45.3%), MS M/z:147(M +1)⁺。

Step 5 preparation of intermediates 1-5

NBS (3.15g,17.7mmol) and DCM (50mL) were added to a 250mL three-necked flask, cooled to-30 ℃ under nitrogen, and Me was added dropwise₂S (1.23mL,16.9mmol), and after completion of the dropwise addition, the reaction was carried out at-30 ℃ for 30 minutes to obtain a pale yellow suspension. A solution of intermediate 1-4(2.35g,16.1mmol) in DCM (15mL) was added dropwise and the reaction was slowly warmed to room temperature for 2h, with the product formed by TLC. Transferring the reaction solution into a single-mouth bottle, and removing D by rotationCM, residue dissolved in water and ether (50mL), ether layer separated, aqueous layer extracted with ether (50mL) 2 times, combined ether layers dried and spun dry to give light brown liquid 1-5(3.36g, yield: 100%) for the next step.

Step 6 preparation of intermediates 1-6

A solution of (S) -ethyl 2- (tert-butylsulfinylimino) acetate (3.30g,16.1mmol) in DMF (50mL) and zinc powder (1.05g,16.1mmol) were charged into a 250mL one-neck flask and blanketed with nitrogen. A solution of intermediates 1-5(3.36g,16.1mmol) in DMF (10mL) was added at room temperature and reacted at room temperature overnight. LCMS showed reaction completion. The reaction solution was poured into water and EA (100mL), and insoluble matter was removed by filtration. Separating EA layer from the filtrate, extracting the water layer with EA (50mL) for 2 times, mixing the EA layers, drying, purifying by column chromatography (silica gel: 100 meshes, PE: EA ═ 5:1to 2:1, iodine color development) to obtain light yellow oil 1-6(1.53g, yield: 28.4%), MS M/z:336(M +1)⁺。

Step 7 preparation of intermediates 1-7

Intermediate 1-6(1.53g,4.57mmol) was added to a 100mL single neck flask and dissolved in MeOH (20mL), and a solution of hydrogen chloride in ethyl acetate (4M,2.3mL,9.13mmol) was added with stirring and allowed to react at room temperature for 2 hours, LCMS indicated completion. The reaction was used directly in the next step, MS M/z:232(M +1)⁺。

Step 8 preparation of intermediates 1-8

NaHCO is added to the reaction solution of the intermediates 1-7 in sequence₃(1.15g,13.7mmol) and benzyloxycarbonyl succinimide (1.37 g,5.48mmol), and stirred at room temperature overnight. LC (liquid Crystal)MS shows that the reaction is finished, the reaction liquid is dried in a rotating way, the residue is added with water and EA (30mL) to be dissolved, an EA layer is separated, an aqueous layer is extracted for 2 times by using EA (30mL), the EA layer is dried and dried in a rotating way, and the mixture is purified by column chromatography (silica gel: 100-200 meshes, PE: EA is 10:1to 5:1, potassium permanganate is developed) to obtain light yellow solid 1-8(1.67g, yield: 100%), MS M/z is 366(M +1)⁺。

Step 9 preparation of intermediates 1-9

Diethyl zinc (2M in toluene, 6.86mL,13.7mmol) and anhydrous DCM (50mL) were added to a 250mL single-neck flask, cooled to-10 deg.C, and chloroiodomethane (2mL,27.5mmol) was added dropwise and stirred at this temperature for 30 min to give a white suspension. Intermediate 1to 8(1.67g,4.58mmol) was dissolved in anhydrous DCM (10mL) and added dropwise to the reaction mixture. After the addition, the temperature was slowly raised to room temperature for overnight reaction. LCMS showed reaction completion. Saturated NH was poured into the reaction solution₄Cl solution (80mL), after stirring for 30 min, the DCM layer was separated, the aqueous layer was extracted 2 times with DCM (50mL), the DCM layers were combined, dried and spun dry to give yellow oil 1-9(1.73g, yield: 100%) which was used directly in the next step, MS M/z:380(M +1)⁺。

Step 10 preparation of intermediate 1

Intermediate 1-9(1.73g,4.56mmol) was added to a 100mL single-neck flask, ethanol (20mL) and water (2mL) were added, and the mixture was stirred to give a clear solution. Lithium hydroxide monohydrate (575mg,13.7mmol) was added, and the reaction was allowed to proceed overnight at 50 ℃. LCMS shows the reaction was complete, the reaction was spun dry, the residue made weakly acidic with 1M HCl, extracted 3 times with EA (20mL), the combined EA layers were dried and spun dry and purified on MPLC reverse phase column (MeCN/0.05% HCOOH in water, 55% MeCN peak) to give 1(540mg, yield: 33.8%) as a pale yellow solid, MS M/z:352(M +1)⁺。

Example 2 preparation of intermediate 2

Step 1 preparation of intermediate 2-1

Referring to the preparation method of example 1, dimethyl carbonate (13.5g,150mmol) and THF (80mL) were added to a 250mL three-necked flask, and NaH (60% w/w,1.68g,42mmol) was added under stirring at room temperature under nitrogen substitution. 6-fluoro-1-indanone (3g,20mmol) in THF (40mL) is added dropwise to the reaction solution via a dropping funnel, after the addition, the reaction solution is heated to reflux for 2 hours, and TLC shows that the reaction is complete. The reaction was poured into a mixture of 1M HCl and ice, extracted three times with EA (100mL), combined with the EA layer and dried, spun dry to give 2-1(4.12g, crude) as a black oil for the next reaction.

Step 2 preparation of intermediate 2-2

Intermediate 2-1(4.12g,20mmol) was added to a 250mL single neck flask, dissolved in MeOH (100mL), and NaBH added portionwise with ice-bath cooling₄(836mg,22mmol), after the addition was complete, the reaction was slowly warmed to room temperature for 1 hour and TLC indicated completion. MeOH was removed under reduced pressure and the residue was extracted with water (100mL) 3 times with EA (100mL), the EA layers were combined and dried and spun dry to give a brown oil 2-2(4.16g, crude) which was used directly in the next reaction, MS M/z:211(M +1)⁺。

Step 3 preparation of intermediates 2-3

Intermediate 2-2(4.16g,20mmol) was added to a 250mL single vial, DCM (80mL) was added to dissolve, TEA (8.3mL,60mmol) was added, methanesulfonyl chloride (2.32mL,30mmol) was added dropwise slowly with ice cooling, after addition was allowed to warm to room temperature slowly overnight, and TLC indicated completion of the reaction. Water (100mL) was added to the reaction solution to wash, a DCM layer was separated, dried and spin-dried, and purified by column chromatography (silica gel 100-.

Step 4 preparation of intermediates 2-4

Intermediate 2-3(2.7g,14.2mmol) was added to a 250mL single neck flask, dissolved by addition of anhydrous THF (40mL), cooled to-78 deg.C in a dry ice-ethanol bath, DIBAL (1M in toluene, 42.6mL,42.6mmol) was added slowly dropwise, and after the addition was complete, the reaction was allowed to warm to room temperature slowly overnight, as indicated by TLC. Pouring the reaction solution into 1M HCl, stirring for 30 min at room temperature, adding EA (100mL) for extraction for 3 times, combining EA layers, drying, and spin-drying to obtain yellow oil 2-4(2.3g, crude product), MS M/z:165(M +1)⁺。

Step 5 preparation of intermediates 2-5

NBS (2.39g,13.4mmol) and DCM (50mL) were added to a 250mL three-necked flask, cooled to-30 ℃ under nitrogen, and Me was added dropwise₂S (0.93mL,12.8mmol), and after dropping, the reaction was carried out at-30 ℃ for 30 minutes to obtain a pale yellow suspension. A solution of intermediate 2-4(2g,12.2mmol) in DCM (15mL) was added dropwise and the reaction was slowly warmed to room temperature for 2 hours, with the product being formed by TLC. The reaction was transferred to a one-necked flask, DCM was removed by vortexing, the residue was dissolved in water and diethyl ether (50mL), the diethyl ether layer was separated, the aqueous layer was extracted with diethyl ether (50mL) 2 times, the diethyl ether layers were combined and dried before vortexing to give light brown liquid 2-5(2.77g, crude) which was used directly in the next step.

Step 6 preparation of intermediates 2-6

A solution of (S) -ethyl 2- (tert-butylsulfinylimino) acetate (2.5g,12.2mmol) in DMF (30mL) and zinc powder (793mg,12.2mmol) were charged to a 250mL one-neck flask and purged with nitrogen. A solution of intermediate 2-5(2.77g,12.2mmol) in DMF (10mL) was added at room temperature and reacted at room temperature overnight. LCMS showed reaction completion. The reaction solution was poured into water and EA (100mL), and insoluble matter was removed by filtration. Separating EA layer from the filtrate, extracting the water layer with EA (50mL) for 2 times, mixing the EA layers, drying, purifying by column chromatography (silica gel: 100 meshes, PE: EA ═ 5:1to 2:1, iodine color development) to obtain light yellow oil 2-6(1.2g, yield: 27.8%), MS M/z:354(M +1)⁺。

Step 7 preparation of intermediates 2-7

Intermediate 2-6(1.2g,3.4mmol) was added to a 100mL single neck flask and dissolved in MeOH (10mL), a solution of hydrogen chloride in ethyl acetate (4M,1.7mL,6.8mmol) was added with stirring and the reaction was complete by LCMS after 2 hours at room temperature. The reaction was used directly in the next step, MS M/z:250(M +1)⁺。

Step 8 preparation of intermediates 2-8

NaHCO is added into the reaction liquid of the intermediates 2-7 in sequence₃(857mg,10.2mmol) and benzyloxycarbonyl succinimide (CbzOSu) (931mg,3.74mmol), and stirred at room temperature overnight. LCMS shows that the reaction is finished, the reaction liquid is dried in a rotating way, the residue is added with water and EA (30mL) to be dissolved, an EA layer is separated, an aqueous layer is extracted for 2 times by EA (30mL), the EA layer is combined and dried, dried in a rotating way and purified by column chromatography (silica gel: 100-⁺。

Step 9 preparation of intermediates 2-9

Diethyl zinc (2M toluene solution,4.62mL,9.24mmol) and anhydrous DCM (30mL) were added to a 250mL single-neck flask, cooled to-10 deg.C, and iodochloromethane (1.5mL,18.5mmol) was added dropwise and stirred at this temperature for 30 min to give a white suspension. Intermediate 2 to 8(1.18g,3.08mmol) was dissolved in anhydrous DCM (10mL) and added dropwise to the reaction mixture. After the addition, the temperature was slowly raised to room temperature for overnight reaction. LCMS showed reaction completion. Saturated NH was poured into the reaction solution₄Cl solution (80mL), after stirring for 30 min, the DCM layer was separated, the aqueous layer was extracted 2 times with DCM (50mL), the DCM layers were combined, dried and spun dry to give yellow oil 2-9(1.22g, crude) which was used directly in the next step, MS M/z:398(M +1)⁺。

Step 10 preparation of intermediate 2

Intermediate 2-9(1.22g,3.07mmol) was added to a 100mL single-neck flask, ethanol (20mL) and water (2mL) were added, and the mixture was stirred to give a clear solution. Lithium hydroxide monohydrate (387mg,9.22mmol) was added, and the reaction was allowed to proceed at 50 ℃ for 3 hours. LCMS shows the reaction is complete, the reaction is spun dry, the residue is made weakly acidic with 1M HCl, extracted 3 times with EA (20mL), the combined EA layers are dried and spun dry and purified with MPLC (MeCN/0.05% aqueous HCOOH, 55% MeCN peak) to give 2 as a pale yellow solid (450 mg. yield: 39.8%), MS M/z:370(M +1)⁺。¹H NMR(400MHz,Chloroform-d)δ7.38–7.28(m,5H),7.19–7.11(m,1H),6.99–6.90(m,1H),6.87–6.80(m,1H),5.18–5.01(m,2H),4.85–4.64(m,2H),3.35(s,1H),3.23–3.01(m,1H),2.41(s,1H),1.05–0.88(m,1H),0.81–0.58(m,3H).

EXAMPLE 3 preparation of intermediate 3

Step 1 preparation of intermediate 3-1

Referring to the preparation of example 1, benzofuran-2-carboxylic acid ethyl ester (5.63g,29.6mmol) was added to a 250mL single-neck flask, dissolved by adding anhydrous THF (60mL), cooled to-78 ℃ in a dry ice-ethanol bath, DIBAL (1M toluene solution, 74mL,74mmol) was added dropwise slowly and allowed to warm to room temperature overnight after the addition, and TLC indicated completion of the reaction. The reaction was poured into 1M HCl, stirred at room temperature for 30 minutes, extracted 3 times with EA (100mL), combined EA layers dried and spun dry to give light yellow oil 3-1(4.5g, yield: 102.6%), MS M/z:149(M +1)⁺。

Step 2 preparation of intermediate 3-2

NBS (5.95g,33.4mmol) and DCM (80mL) were added to a 250mL three-necked flask, cooled to-30 ℃ under nitrogen, and Me was added dropwise₂S (2.33mL,31.9mmol), and after dropping, the reaction was carried out at-30 ℃ for 30 minutes to obtain a pale yellow suspension. A solution of intermediate 3-1(4.5g,30.4mmol) in DCM (20mL) was added dropwise and the reaction was slowly warmed to room temperature for 2 hours, with the product formed by TLC. The reaction was transferred to a one-necked flask, DCM was removed by rotation, the residue was dissolved in water and diethyl ether (50mL), the diethyl ether layer was separated, the aqueous layer was extracted with diethyl ether (50mL) 2 times, the diethyl ether layers were combined, dried and then dried by rotation to give light brown liquid 3-2(6.41g, yield: 100%) which was used in the next step.

Step 3 preparation of chiral intermediate 3-3

A solution of (S) -ethyl 2- (tert-butylsulfinylimino) acetate (6.23g,30.4mmol) in DMF (50mL) and zinc powder (1.97g,30.4mmol) were charged into a 250mL one-neck flask and blanketed with nitrogen. Intermediate 3-2 (6) was added at room temperature41g,30.4mmol) of DMF (20mL) and reacted at room temperature overnight. LCMS showed reaction completion. The reaction solution was poured into water and EA (100mL), and insoluble matter was removed by filtration. Separating EA layer from the filtrate, extracting the water layer with EA (50mL) for 2 times, mixing the EA layers, drying, purifying by column chromatography (silica gel: 100 meshes, PE: EA ═ 5:1to 2:1, iodine color development) to obtain light yellow oil 3-3(3.25g, yield: 31%), MS M/z:338(M +1)⁺。

Step 4 preparation of intermediates 3-4

Intermediate 3-3(1.48g,4.39mmol) was added to a 100mL single-neck flask, dissolved in MeOH (30mL), and PtO was added₂(750mg) and replace the protection with hydrogen and stir overnight at room temperature, LCMS showed reaction complete. The catalyst was removed by filtration through celite and the filtrate was spin dried to give intermediate 3-4(1.48g, crude) which was used directly in the next step. MS M/z 340(M +1)⁺。

Step 5 preparation of intermediates 3-5

Intermediate 3-4(1.15g,3.4mmol) was added to a 100mL single neck flask and dissolved in MeOH (10mL), a solution of hydrogen chloride in ethyl acetate (4M,1.7mL,6.8mmol) was added with stirring and the reaction was complete by LCMS after 2 hours at room temperature. The reaction was used directly in the next step, MS M/z:236(M +1)⁺。

Step 6 preparation of intermediates 3-6

NaHCO is added into the reaction liquid of the intermediate 3-5 in sequence₃(857mg,10.2mmol) and benzyloxycarbonyl succinimide (CbzOSu) (931mg,3.74mmol), and stirred at room temperature overnight. LCMS shows reaction complete, spin dry reaction and add residueDissolving water and EA (30mL), separating an EA layer, extracting an aqueous layer for 2 times by using EA (30mL), combining the EA layers, drying, performing spin-drying, and performing column chromatography purification (silica gel: 100-200 meshes, PE: EA: 10:1to 5:1, potassium permanganate for color development) to obtain 3-6(1.05g, yield: 65%) light yellow solid. MS M/z 370(M +1)⁺。

Step 7 preparation of intermediate 3

Intermediate 3-6(1.0g,2.71mmol) was added to a 100mL single-neck flask, ethanol (20mL) and water (2mL) were added, and the mixture was stirred to give a clear solution. Lithium hydroxide monohydrate (387mg,9.22mmol) was added, and the reaction was allowed to proceed at 50 ℃ for 3 hours. LCMS showed the reaction was complete, the reaction was spun dry, the residue was made weakly acidic with 1M HCl, extracted 3 times with EA (20mL), the combined EA layers were dried and spun dry and purified with MPLC (MeCN/0.05% aqueous HCOOH, 55% MeCN peak) to give 3 as a pale yellow solid (714 mg. yield: 77.0%). MS M/z:342(M +1)⁺。

Example 4 preparation of intermediate 4

Step 1 preparation of intermediate 4-1

A250 mL single vial was charged with o-hydroxybenzaldehyde (10g,82.0mmol) and t-butyl acrylate (15.7g,122.6mmol), dissolved by addition of NMP (80mL), and reacted for 4 hours by addition of potassium carbonate (11.3g,81.9mmol) and TLC indicated completion of the reaction. The reaction solution was poured into water, extracted 3 times with EA (100mL), combined with the EA layer, dried and spin-dried, and purified by column chromatography (silica gel: 100-200 mesh, PE: EA: 20:1to 10:1) to give 4-1(12g, yield: 63%) as a yellow oil.

Step 2-8 preparation of intermediate 4

Referring to the steps 1-7 of example 3, intermediate 4-1 was used as a starting material and prepared by seven steps of reactions to give 4.MS M/z 356(M +1)⁺。

EXAMPLE 5 preparation of intermediate 5

Reference example 3, steps 1-7, starting from ethyl 5-fluoro-benzofuran-2-carboxylate, intermediate 5 was prepared. MS M/z 360(M +1)⁺。

EXAMPLE 6 preparation of intermediate 6

Referring to the method of example 4, step 1 and example 3, steps 1-7, intermediate 6 was prepared from 5-fluorosalicylaldehyde. MS M/z 374(M +1)⁺。

EXAMPLE 7 preparation of intermediates 7-3

Step 1 preparation of intermediate 7-1

Adding intermediate 1(10.27g,29.25mmol), EDCI (6.73g,35.11mmol), DIPEA (11.31g,87.43mmol), HOAt (4.78g,35.12mmol) and 4-bromo-o-phenylenediamine (5.47g,1.80mmol) into DCM (100mL) in sequence, reacting at room temperature for 3 hours, adding water for quenching, removing most of the organic solvent under reduced pressure, extracting with ethyl acetate (100 mL. about.3), combining the organic phases, washing with saturated ammonium chloride and saturated common salt water, drying with anhydrous sodium sulfate, spin-drying under reduced pressure, purifying and separating the crude product by silica gel column chromatography to obtain intermediate 7-1(12.93g,24.86mmol, 85% yield), MS M/z:520(M +1)⁺。

Step 2 preparation of intermediate 7-2

Intermediate 7-1(10.69g,20.6mmol) was added to AcOH (100mL), reacted at 55 ℃ for 12h, concentrated under reduced pressure and dried, and purified by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 1:1) to give intermediate 7-2(7.24g,14.42mol, 70% yield), MS m/z: 502(M +1)⁺。

Step 3 preparation of intermediate 7-3

Adding pinacol diboron (3.78g,14.91mmol), potassium acetate (4.18,42.59mmol) and 1,4 dioxane (70ml) into intermediate 7-2(7.11g,14.20mmol), vacuumizing and protecting with nitrogen, adding Pd (dppf) Cl2(0.52g,0.71mmol), vacuumizing and protecting with nitrogen, heating to 105 ℃, reacting for 12h, filtering, concentrating under reduced pressure and spin-drying, separating and purifying by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio is 1:1) to obtain intermediate 7-3(5.62g,10.22mol, 72% yield), MS m/z: 550(M +1)⁺。

EXAMPLE 8 preparation of intermediates 8-3

The intermediate 2 was used as a starting material in accordance with the method of example 7, and obtained via the same synthetic route, MS m/z: 568(M +1)⁺。

EXAMPLE 9 preparation of intermediates 9-3

The intermediate 3 was used as a starting material in accordance with the method of example 7, and obtained through the same synthetic route, MS m/z:540(M+1)⁺。

EXAMPLE 10 preparation of intermediate 10-3

The intermediate 4 was used as a starting material in accordance with the method of example 7, and obtained through the same synthetic route, MS m/z: 554(M +1)⁺。

EXAMPLE 11 preparation of intermediate 11-3

The intermediate 5 was used as a starting material in accordance with the method of example 7, and obtained through the same synthetic route, MS m/z: 558(M +1)⁺。

EXAMPLE 12 preparation of intermediates 12-3

The intermediate 6 was used as a starting material in accordance with the method of example 7, and obtained through the same synthetic route, MS m/z: 572(M +1)⁺。

EXAMPLE 13 preparation of intermediates 13-8

Step 1 preparation of intermediate 13-1

THF (100ml) was added to tert-butyl 3-oxomorpholine-4-carboxylate (10g, 49.70mmol) under nitrogen, the temperature was reduced to-30 ℃ and lithium bistrimethylsilyl amide (LiHMDS) (54.6ml, 54.60mmol) was added dropwise and stirred for 1 hour with incubation. Adding diphenyl chlorophosphate dropwise into the reaction solutionThe ester (14.02g, 52.19mmol) was added dropwise and allowed to slowly warm to room temperature for 6 hours. The reaction mixture was added to 100ml of a saturated ammonium chloride solution, 100ml of ethyl acetate was added for extraction, the organic layer was washed with brine, concentrated under reduced pressure to dryness and purified by a silica gel column to give intermediate 13-1(14.60g, 33.69mmol, 67.79% yield) MS m/z: 434(M +1)⁺。

Step 2 preparation of intermediate 13-2

Adding pinacol diboron (7.13g,28.07mmol), potassium acetate (7.87,80.19mmol) and 1, 4-dioxane (50ml) into a raw material of 4-bromo-o-phenylenediamine (5g, 26.73mmol), vacuumizing and adding nitrogen for protection

Pd(dppf)Cl₂(0.98g,1.34mmol), vacuumizing under nitrogen, heating to 105 ℃ for 12h, filtering, concentrating under reduced pressure, drying by spinning, and separating and purifying by silica gel column chromatography (petroleum ether/ethyl acetate 1:1) to obtain intermediate 13-2(5.26g,22.47mol, 84.06% yield), MS m/z: 235(M +1)⁺。

Step 3 preparation of intermediate 13-3

Intermediate 13-1(10.18g,23.50mmol), potassium acetate (6.29,64.08mmol) and 1,4 dioxane (50ml) were added to intermediate 13-2(5g, 21.36mmol), evacuated under nitrogen and Pd (dppf) Cl was added₂(0.78g, 1.07mmol), vacuumizing and protecting with nitrogen, heating to 105 ℃ for reaction for 12h, filtering, concentrating under reduced pressure and drying, separating and purifying by silica gel column chromatography to obtain intermediate 13-3(4.68g,16.08mol, 75.28% yield), MS m/z: 292(M +1)⁺。

Step 4 preparation of intermediate 13-4

To intermediate 13-3(4.68g,16.08 mmol) was added ethanol (50ml), 10% palladium on carbon (1.0g) was hydrogenated, filtered, concentrated under reduced pressure and spun dry to give intermediate 13-4(4.05g,13.81mol, 85.88% yield), MS m/z: 294(M +1) +.

Step 5 preparation of intermediates 13-5

Referring to example 7, the preparation of intermediate 7-1, intermediate 1 was condensed with 13-4 to give a mixture MS M/z 627[ M +1 ]]⁺。

Step 6 preparation of intermediate 13-6

Referring to example 7, the intermediate 7-2 was prepared by cyclization in acetic acid of intermediate 13-5, MS M/z 645[ M +1 ]]⁺。

Step 7 preparation of intermediates 13-7

To intermediate 13-6(2.83g, 4.66mmol) was added THF (10ml) and triphosgene (1.11g, 3.73mmol) reacted at 0 ℃ for 30 minutes. To 3, 3-difluorotrimethylene imine hydrochloride (0.53g, 4.10mmol) was added THF (5ml) and DIPEA (0.53g, 4.10mmol), stirred at room temperature for 1 hour, filtered, added dropwise to the previous reaction solution, allowed to warm to room temperature after completion of the addition to react for 12 hours, concentrated to dryness after completion of the reaction, and purified by a silica gel column to give intermediate 13-7(1.90g,3.03mol, 65.02% yield), MS m/z: 628(M +1)⁺。

Step 8 preparation of intermediates 13-8

To intermediate 13-7(1.90g,3.03mol) in dichloromethane (50ml)Adding PdCl into the solution₂(70mg) and triethylamine (0.4ml), then cooled to 0 ℃, triethylsilane was slowly added dropwise, stirring was continued for 2 hours after completion of the addition, water was added to quench, filtration was carried out, concentration under reduced pressure and spin-drying, and the resulting product was passed through a silica gel short column to give intermediate 13-8(1.48g,3.0mol, 99% yield, crude product), MS m/z: 494(M +1)⁺。

EXAMPLE 14 preparation of intermediate 14-4

Referring to the preparation method of example 13, intermediate 14-4.MS m/z can be obtained by using intermediate 13-4 and intermediate 2 as raw materials, condensing, closing imidazole ring, condensing, and finally removing Cbz: 512(M +1)⁺。

EXAMPLE 15 preparation of intermediate 15-4

Referring to the preparation method of example 13, intermediate 13-4 and intermediate 3 were used as raw materials, and subjected to condensation, imidazole ring closure, condensation, and finally Cbz removal to obtain intermediate 15-4.MS m/z: 484(M +1)⁺。

EXAMPLE 16 preparation of intermediate 16-4

Referring to the preparation method of example 13, intermediate 13-4 and intermediate 4 were used as raw materials to undergo condensation, imidazole ring closure, condensation, and Cbz removal to obtain intermediate 16-4.MS m/z: 498(M +1)⁺。

EXAMPLE 17 preparation of intermediates 17-4

Reference example 13 preparation method, intermediate 13-4 andthe intermediate 5 is a raw material, and is subjected to condensation, imidazole ring closing, condensation and Cbz removal to obtain an intermediate 17-4.MS m/z: 502(M +1)⁺。

EXAMPLE 18 preparation of intermediate 18-4

Referring to the preparation method of example 13, intermediate 13-4 and intermediate 6 were used as raw materials, and after condensation, imidazole ring closing, condensation, and finally Cbz removal, intermediate 18-4.MS m/z was obtained: 516(M +1)⁺。

EXAMPLE 19 preparation of intermediates 19-8

Step 1 preparation of intermediate 19-1:

to the starting 4-oxo-3-carboxylic acid ethyl ester furan (10g, 63.23mmol) was added DCM (100ml), DIPEA (9.81g, 75.88mmol), cooled to-78 deg.C, added trifluoromethanesulfonic anhydride (21.41g,75.88mmol), slowly warmed to room temperature after the addition for 2 hours, and after the completion of the reaction, concentrated to dryness followed by column purification to give intermediate 19-1(14.75g,50.84mmol, yield: 80.4%).

Step 2 preparation of intermediate 19-2

Intermediate 19-1(14.75g,50.84 mmol) was added with intermediate 5-4(13.09g,55.92mmol), potassium acetate (14.97g,152.52mmol) and 1,4 dioxane (50ml), evacuated under nitrogen and Pd (dppf) Cl was added₂(1.86g, 2.54mmol), vacuumizing and protecting with nitrogen, heating to 105 deg.C for 12h, filtering, concentrating under reduced pressure, spin-drying, separating and purifying by silica gel column chromatographyIntermediate 19-2(9.63g,38.79mmol, 76.30% yield), MS m/z: 249(M +1)⁺。

Step 3 preparation of intermediate 19-3

To intermediate 19-2(9.63g,38.79mmol) was added ethanol (100ml), hydrogenated with 10% palladium on carbon (2.0g), filtered, concentrated under reduced pressure and dried to give intermediate 19-3(8.57g, 34.42mmol, 88.73 yield), MS m/z:250(M +1).

Step 4 preparation of intermediate 19-4

Referring to the preparation method of example 13, intermediate 19-4.MS m/z can be obtained by using intermediate 19-3 and intermediate 1 as raw materials, condensing, closing imidazole ring, condensing, and finally removing Cbz: 584(M +1)⁺。

Step 5 preparation of intermediates 19-5

Referring to example 7, the intermediate 7-1 was prepared by cyclization in acetic acid of intermediate 19-4, MS M/z:566[ M +1 ]]⁺。

Step 6 preparation of intermediate 19-6

Reference example 7 preparation of intermediate 7-2 from intermediate 19-5 by hydrolysis with sodium hydroxide, MS M/z:538[ M +1 ]]⁺。

Step 7 preparation of intermediates 19-7

Reference example 13 preparation of intermediates 13 to 7 from intermediate 19 to 6 by condensation with 3-difluorotrimethyleneimine, MS M/z 613[ M +1]⁺。

Step 7 preparation of intermediates 19-8

Reference example 13 preparation of intermediates 13 to 8 from intermediates 19 to 7 by Tri-removal of Cbz, MS M/z:479[ M +1 ]]⁺。

EXAMPLE 20 preparation of intermediates 20-5

Referring to the method of example 19, intermediate 19-3 and intermediate 2 were used as raw materials to undergo condensation, imidazole ring closure, condensation, and finally Cbz removal to obtain intermediate 20-5.MS m/z: 497(M +1)⁺。

EXAMPLE 21 preparation of intermediates 21-5

Referring to the method of example 19, intermediate 19-3 and intermediate 3 were used as raw materials to undergo condensation, imidazole ring closure, condensation, and finally Cbz removal to obtain intermediate 21-5.MS m/z: 469(M +1)⁺。

EXAMPLE 22 preparation of intermediates 22-5

Referring to the method of example 19, intermediate 22-5.MS m/z was obtained by using intermediate 19-3 and intermediate 4 as raw materials, followed by condensation, imidazole ring closure, condensation, and finally Cbz removal: 483(M +1)⁺。

EXAMPLE 23 preparation of intermediates 23-5

Referring to the method of example 19, intermediate 19-3 and intermediate 5 were used as raw materials to undergo condensation, imidazole ring closure, condensation, and finally Cbz removal to obtain intermediate 23-5.MS m/z: 487(M +1)⁺。

EXAMPLE 24 preparation of intermediates 24-5

Referring to the method of example 19, intermediate 19-5. MS m/z was obtained by condensation, imidazole ring closure, condensation, and finally Cbz removal using intermediate 19-3 and intermediate 6 as raw materials: 501(M +1)⁺。

EXAMPLE 25 preparation of intermediate 25

Step 1 preparation of intermediate 25-1

Reference example 13 preparation of intermediate 13-7 by condensation of 2-methyl-5-bromopyrimidine-4-carboxylic acid with 3, 3-difluorotrimethylene imine (MS M/z:291[ M +1)]⁺。

Step 2-3 preparation of intermediate 25-3

Reference example 13 preparation of intermediate 13-8 coupling of intermediate 25-1 and intermediate 7-3 followed by Cbz deprotection gives an intermediateBody 25-3, MS M/z 501[ M +1 ]]⁺。

EXAMPLE 26 preparation of intermediate 26-2

Reference example 13 preparation of intermediate 13-8 coupling of intermediate 25-1 with intermediate 8-3 followed by Cbz deprotection gave intermediate 26-2, MS M/z 519[ M +1 ]]⁺。

EXAMPLE 27 preparation of intermediate 27-2

Reference example 13 preparation of intermediate 13-8 coupling of intermediate 25-1 and intermediate 9-3 followed by Cbz deprotection gave intermediate 27-2, MS M/z 491[ M +1 ]]⁺。

EXAMPLE 28 preparation of intermediate 28-2

Reference example 13 preparation of intermediate 13-8 coupling of intermediate 25-1 and intermediate 10-3 followed by Cbz deprotection gave intermediate 28-2, MS M/z:505[ M +1 ]]⁺。

EXAMPLE 29 preparation of intermediate 29-2

Reference example 13 preparation of intermediate 13-8 coupling of intermediate 25-1 and intermediate 11-3 followed by Cbz deprotection gave intermediate 29-2, MS M/z 509[ M +1]⁺。

EXAMPLE 30 preparation of intermediate 30-2

Reference example 13 preparation of intermediate 13-8 coupling of intermediate 25-1 and intermediate 12-3 followed by Cbz deprotection gave intermediate 30-2, MS M/z 523[ M +1 ]]⁺。

EXAMPLE 31 preparation of Compound 31

HBTU (357.2mg,942.5umol) and DIPEA (146mg,1131umol,187uL) were added to a DCM (5mL) solution of 1-methyl-1H-pyrazole-5-carboxylic acid (57mg,452.4umol) in sequence, after 15min, intermediate 13-8(186mg,376.85umol) of example 5 was added, the reaction was carried out at room temperature for 1H, 10mL of water was added to quench, most of the organic solvent was removed under reduced pressure, ethyl acetate (10mL of 3) was extracted, the organic phases were combined, then saturated ammonium chloride and saturated common salt were washed with water, anhydrous sodium sulfate was dried, spin-dried under reduced pressure, and the crude product was purified by MPLC reverse phase 18 column chromatography (acetonitrile/0.05% water 0-40%) to obtain compound 31(181mg, yield 80%) and MS M/z:602[ M + 1. mu.1%]⁺。

EXAMPLE 32 preparation of Compound 32

Referring to example 31, intermediate 14-4 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 32, MS M/z:620[ M +1 ]]⁺。

EXAMPLE 33 preparation of Compound 33

Referring to example 31, intermediate 15-4 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 33, MS M/z 592[ M +1 ]]⁺。

EXAMPLE 34 preparation of Compound 34

Referring to example 31, intermediate 16-4 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 34, MS M/z:606[ M +1 ]]⁺。

EXAMPLE 35 preparation of Compound 35

Referring to example 31, intermediate 17-4 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 35, MS M/z:610[ M +1 ]]⁺。

EXAMPLE 36 preparation of Compound 36

Referring to example 31, intermediate 18-4 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 36, MS M/z:624[ M +1 ]]⁺。

EXAMPLE 37 preparation of Compound 37

Referring to example 31, intermediate 19-4 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 37, MS M/z 587[ M +1 ]]⁺。

EXAMPLE 38 preparation of Compound 38

Reference example 31 condensation of intermediate 20-5 with 1-methyl-1H-pyrazole-5-carboxylic acid gave compound 38, MS M/z 605[ M +1 ]]⁺。

EXAMPLE 39 preparation of Compound 39

Referring to example 31, intermediate 21-5 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 39, MS M/z 577[ M +1 ]]⁺。

EXAMPLE 40 preparation of Compound 40

Reference example 31 condensation of intermediate 22-5 with 1-methyl-1H-pyrazole-5-carboxylic acid gave compound 40, MS M/z:591[ M +1 ]]⁺。

EXAMPLE 41 preparation of Compound 41

Referring to example 31, intermediate 23-5 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 41, MS M/z 595[ M +1 ]]⁺。

EXAMPLE 42 preparation of Compound 42

Referring to example 31, intermediate 24-5 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 42, MS M/z 609[ M +1 ]]⁺。

EXAMPLE 43 preparation of Compound 43

Reference example 31 condensation of intermediate 25-3 with 1-methyl-1H-pyrazole-5-carboxylic acidTo compound 43, MS M/z 609[ M +1]⁺。

EXAMPLE 44 preparation of Compound 44

Referring to example 31, intermediate 26-2 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 44, MS M/z 627[ M +1 ]]⁺。¹H NMR(400MHz,Methanol-d4)δ8.94(s,1H),7.90(d,J＝8.5Hz,2H),7.66(d,J＝8.5Hz,1H),7.51(s,1H),7.31(t,J＝6.7Hz,1H),7.04(t,J＝8.9Hz,1H),6.93–6.82(m,2H),5.77(d,J＝6.6Hz,1H),4.73(t,J＝11.8Hz,2H),4.46(t,J＝12.0Hz,2H),4.05(s,3H),3.61(d,J＝6.7Hz,1H),3.33(s,2H),3.22(d,J＝15.8Hz,1H),2.82(s,3H),2.42(d,J＝16.1Hz,1H),0.74–0.67(m,2H),0.62(d,J＝8.4Hz,1H),0.47(t,J＝9.8Hz,1H).

EXAMPLE 45 preparation of Compound 45

Referring to example 31, intermediate 27-2 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 45, MS M/z:599[ M +1 ]]⁺。

EXAMPLE 46 preparation of Compound 46

With reference to the procedure of example 31, intermediate 28-2 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 46, MS M/z:613[ M +1 ]]⁺。

EXAMPLE 47 preparation of Compound 47

Reference example 31 Process, intermediate 27-2 and 1-methylCondensation of-1H-pyrazole-5-carboxylic acid to give compound 47, MS M/z 617[ M +1 ]]⁺。

EXAMPLE 48 preparation of Compound 48

Referring to example 31, intermediate 30-2 was condensed with 1-methyl-1H-pyrazole-5-carboxylic acid to give compound 48, MS M/z 631[ M +1 ]]⁺。

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

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

The inhibition of receptor-ligand binding by IL-17A inhibitors was quantitatively determined by competitive ELISA. IL-17A (Nano Biological incc. Cat #12047-H07B) at 0.2. mu.g/mL was incubated at 37 degrees for 30 minutes in 96-well plates at 100. mu.L (50mM phosphate buffer, pH 7.4) per well. The plate was washed 4 times with PBST (PBS, 0.05% Tween-20), 200. mu.L of each well was added 200. mu.L of 5% skim milk and incubated for 30 minutes on a 25 degree shaker. 100X concentrations of test compound were prepared, with final concentrations ranging from 0.0002. mu.M to 30. mu.M. The plates were washed 4 times with PBST (PBS, 0.05% Tween-20), mixed with 89. mu.L of PBST and 1. mu.L of 100 Xconcentration test compound, and preincubated at 25 ℃ for 10 minutes. Add 10. mu.L of 16nM IL-17R (Nano Biological lnc. Cat #10895-H03H) and incubate for 30 min on a 25 degree shaker. After washing the plate 4 times, 100. mu.L of anti-Fc-tag HRP-conjugated antibody (Nano Biological lnc. Cat #10702-T16-H-50) was added and incubated for 30 minutes on a 25 degree shaker. After washing the plate 4 times, 100. mu.L of TMB substrate solution was added and incubated at 25 ℃ in the dark. After addition of 100. mu.L of 2.5M HCl, the absorbance was measured at a wavelength of 450nm using a microplate reader. The compounds prepared in the examples were tested for IL-17A inhibitory activity according to the methods described above, and the results are shown in Table 1, in which the IC of each compound was determined₅₀Sorted by description, in table 1:

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

"+ +" denotes IC₅₀Measured at less than 1 μ M and greater than 100 nM;

"+ + + +" denotes IC₅₀The assay value is less than 100 nM;

TABLE 1 inhibitory Activity of Compounds on IL-17A

Examples	IC50
		31	++
32	++
		37	++
38	++
		43	++
44	++

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

In conclusion, the novel compound shown in the formula I shows good IL-17A inhibitory activity, and provides a new medicinal possibility for clinically treating diseases related to IL-17A activity abnormity.

Claims (14)

1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R₁selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₁₃Substitution;

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

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

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

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

each R_A1Independently selected from halogen,Cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_A2、-C_0～4alkylene-OC (O) R_A2、-C_0～4alkylene-C (O) R_A2、-C_0～4alkylene-C (O) OR_A2、-C_0～4alkylene-C (O) NR_A2R_A3、-C_0～4alkylene-S (O) NR_A2R_A3、-C_0～4alkylene-S (O)₂NR_A2R_A3、-C_0～4alkylene-P (O) (OH) NR_A2R_A3、-C_0～4alkylene-NR_A2R_A3、-C_0～4alkylene-NR_A2C(O)R_A3、-C_0～4alkylene-NR_A2S(O)R_A3、-C_0～4alkylene-NR_A2S(O)₂R_A3、-C_0～4alkylene-NR_A2P(O)(OH)R_A3、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle);

R_A2、R_A3each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

x is selected from O, S, NR_x1Or CR_x1R_x2；

R_x1、R_x2Each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

n is selected from 0, 1, 2 or 3;

R₃、R₄are respectively and independently selected from hydrogen, halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl); or, R₃、R₄Are connected to form3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl; wherein alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～10Alkyl, halogen substituted-C_1～10An alkyl group;

Y₁、Y₂、Y₃each independently selected from N or CR_Y1；

Each R_Y1Independently selected from hydrogen, halogen, cyano, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl), -NH₂、-NH(C_1～10Alkyl), -N (C)_1～10Alkyl) (C_1～10Alkyl groups);

the B ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_B2、-C_0～4alkylene-OC (O) R_B2、-C_0～4alkylene-C (O) R_B2、-C_0～4alkylene-C (O) OR_B2、-C_0～4alkylene-C (O) NR_B2R_B3、-C_0～4alkylene-NR_B2R_B3、-C_0～4alkylene-NR_B2C(O)R_B3、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the cycloalkyl, alkylene, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R_B4Substitution;

R_B2、R_B3each independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl); or R_B2、R_B3Are linked to form a 3-to 10-membered heterocycloalkyl group; wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_B4Substitution;

each R_B4Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl), -NH₂、-NH(C_1～10Alkyl), -N (C)_1～10Alkyl) (C_1～10Alkyl groups).

2. The compound of claim 1, wherein:

R₁selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₁₃Substitution;

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

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

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

the ring A is selected from a 5-6-membered aromatic ring and a 5-6-membered aromatic heterocycle; wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R_A1Substitution;

each R_A1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_A2、-C_0～2alkylene-OC (O) R_A2、-C_0～2alkylene-C (O) R_A2、-C_0～2alkylene-C (O) OR_A2、-C_0～2alkylene-C (O) NR_A2R_A3、-C_0～2alkylene-NR_A2R_A3、-C_0～2alkylene-NR_A2C(O)R_A3、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle);

R_A2、R_A3each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

x is selected from O, S, NR_x1Or CR_x1R_x2；

R_x1、R_x2Each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

n is selected from 0, 1, 2 or 3;

R₃、R₄are respectively and independently selected from hydrogen, halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₃、R₄Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; whereinAlkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

Y₁、Y₂、Y₃each independently selected from N or CR_Y1；

Each R_Y1Independently selected from hydrogen, halogen, cyano, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups);

the B ring is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_B2、-C_0～2alkylene-OC (O) R_B2、-C_0～2alkylene-C (O) R_B2、-C_0～2alkylene-C (O) OR_B2、-C_0～2alkylene-C (O) NR_B2R_B3、-C_0～2alkylene-NR_B2R_B3、-C_0～2alkylene-NR_B2C(O)R_B3、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the cycloalkyl, alkylene, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R_B4Substitution;

R_B2、R_B3each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene-(3-to 6-membered heterocycloalkyl); or R_B2、R_B3Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_B4Substitution;

each R_B4Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

3. The compound of claim 1, wherein:

R₁selected from 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R₁₃Substitution;

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

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

R₁is selected from

R₁₃Independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group.

5. The compound of claim 1, wherein:

the ring A is selected from a 5-6-membered aromatic ring and a 5-6-membered aromatic heterocycle; wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R_A1Substitution;

each R_A1Independently selected from halogen, cyano, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_A2；

R_A2Selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl).

6. The compound of claim 5, wherein:

ring A is

R_A1Selected from hydrogen, halogen, cyano, nitro, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group.

7. The compound of claim 1, wherein:

R₃、R₄each independently selected from hydrogen, halogen, carbonyl and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₃、R₄Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group.

8. The compound of claim 7, wherein:

R₃、R₄to form cyclopropane.

9. The compound of claim 1, wherein:

ring B is selected from pyrimidine and morpholineTetrahydrofuran; wherein the pyrimidine, morpholine, tetrahydrofuran may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-C (O) NR_B2R_B3；

R_B2、R_B3Each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or R_B2、R_B3Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three R_B4Substitution;

each R_B4Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

10. The compound of claim 9, wherein:

ring B is selected from

R_B11Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl or none;

R_B2、R_B3linked to form cyclobutylamine; wherein the cyclobutylamine may be further substituted by one, two or three R_B4Substitution;

each R_B4Independently selected from halogen, carbonyl, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

11. The compound of claim 1, wherein: the compound shown in the formula I is specifically:

12. use of a compound of any one of claims 1-11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an IL-17A mediated disease.

13. Use according to claim 12, characterized in that: the IL-17A mediated disease is one or more of diseases related to inflammation, autoimmune diseases, infectious diseases, cancer and precancerous syndrome.

14. A pharmaceutical composition characterized by: the compound, the stereoisomer or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1to 11, and pharmaceutically acceptable auxiliary materials.