Cyclobutenedione compound, pharmaceutical composition thereof, and use thereof

Abstract

The present invention provides a compound of formula (I) or a racemate or stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate of the compound of formula (I). The compound has good CCR6 inhibitory activity and better selectivity than CXCR2, while possessing excellent pharmacokinetics and pharmacodynamics.

Description

Cyclobutenediones, their pharmaceutical compositions and uses

[0001] This application claims priority to the following Chinese patent applications: Chinese patent application 2024116684438, filed November 21, 2024; Chinese patent application 2025104971775, filed April 21, 2025; Chinese patent application 2025110810910, filed August 4, 2025; Chinese patent application 2025116255969, filed November 7, 2025; and Chinese patent application 2025116695210, filed November 14, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceuticals, and more particularly to cyclobutenediones, pharmaceutical compositions thereof, and uses. Background Technology

[0003] Chemokines are a class of cytokines that control the directed migration of cells, and their function is mediated by chemokine receptors. Through gene knockout, antibody blocking, and transgenic technologies, it has been demonstrated that the chemokine system plays a crucial role in pathogen clearance, inflammatory responses, pathogen infection, cell and organ development, wound repair, tumor formation and metastasis, and transplant rejection. Chemokines exert their biological effects by interacting with G protein-coupled transmembrane receptors (chemokine receptors). Chemokine receptors, as the natural ligands of chemokines, belong to a subfamily of seven transmembrane proteins on the cell surface. Based on the type of chemokine they bind, they are divided into four families: CCR (binding to CC chemokines), CXCR (binding to CXC chemokines), CX3CR1 (binding to the only CX3C chemokine (CX3CL1)), and XCR1 (binding to two XC chemokines (XCL1 and XCL2)).

[0004] CC chemokine receptor 6 (CCR6) is expressed on a variety of key immune cells, including immature dendritic cells, B cells, memory T cells (including all Th17 cells), neutrophils, and a subset of regulatory T cells (Tregs). CCR6 is the only known receptor for the chemokine CCL20, also known as macrophage inflammatory protein 3a (MIP-3a), liver and activated regulatory chemokine (LARC), which is produced by synovial cells, colonic epithelial cells, various skin cells (e.g., keratinocytes and dermal fibroblasts), and alveolar epithelial cells. The ligand-receptor pair CCL20-CCR6 is responsible for the migration of immature dendritic cells and effector / memory T cells to the skin and mucosal surfaces in homeostatic and inflammatory conditions, as well as in autoimmune diseases such as psoriasis and inflammatory bowel disease.

[0005] CCL20 is an inducible chemokine that is highly upregulated in the formation of inflammatory lesions in various inflammatory diseases, including allergic lung inflammation, psoriasis, contact hypersensitivity reactions, inflammatory bowel disease, Sjögren's syndrome, juvenile idiopathic arthritis, rheumatoid arthritis, and multiple sclerosis, among other autoimmune diseases. Studies have shown that CCL20 and CCR6 play important roles in regulating colonic mucosal physiology. In normal colonic mucosa, CCL20 is weakly expressed, but it is significantly upregulated upon inflammatory stimulation. Compared with normal mucosal tissue, the expression of CCL20 and CCR6 is significantly upregulated in colorectal cancer (CRC) liver metastases and is positively correlated with liver or lung metastases.

[0006] Inflammatory bowel disease (IBD) is an idiopathic, chronic, and relapsing inflammatory disease of the intestine. Its pathogenesis is highly complex, influenced by the interaction of genetic, environmental, and microbial factors. Clinical manifestations include diarrhea, abdominal pain, and even bloody stools, often accompanied by anemia, malnutrition, and fatigue, severely impacting patients' quality of life. Currently available drugs for IBD primarily include glucocorticoids and monoclonal antibodies such as Remicade, Humira, and Vedolizumab, as well as the small molecule inhibitor Imuran. CCL20 / CCR6 could serve as a novel therapeutic target for IBD patients.

[0007] Currently, there are no small molecule drugs on the market that serve as CCR6 inhibitors. Therefore, developing small molecule drugs with good bioactivity as CCR6 inhibitors is of positive significance for the treatment of the aforementioned diseases. Summary of the Invention

[0008] This invention provides compounds of formula (I), their racemates, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates of compounds of formula (I):

[0009] in,

[0010] R1 is H or C 1-6 alkyl;

[0011] R2 is C 4-12 Bridged ring group or 4-12 quinary bridged heterocyclic group, wherein the C 4-12 Bridged ring groups and 4-12 bridging heterocyclic groups are optionally coupled with one, two or more R groups. 2-1 replace;

[0012] Each R 2-1 Independently, H, halogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0013] R3 is a 5-membered heteroaryl, 7-12-membered heteroaryl, or C. 6-10 Aryl groups, wherein the 5-membered heteroaryl, 7-12-membered heteroaryl, and C 6-10 aryl groups are optionally coated with one, two or more R groups. 3-1 replace;

[0014] Each R 3-1 Independently, it can be H, -CN, -OH, -NH2, oxo (=O), halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-8-membered heterocycloalkyl groups may be optionally substituted with one, two or more substituents independently selected from halogens and deuterium;

[0015] Each R is independently H, -CN, halogen, C 1-6 Halogenated alkyl or C 1-6 alkyl;

[0016] n is 0, 1, or 2;

[0017] X is either N or CR5;

[0018] R5 represents H, -CN, halogen, or C. 1-6 Halogenated alkyl or C 1-6 alkyl;

[0019] R4 is -C(=O)NR m R n 5-7 membered heteroaryl, 3-7 membered heterocyclic, -NR x C(=O)R y -S(=O)(=NR) v )R wor -C(=O)R z The 5-7-membered heteroaryl and 3-7-membered heterocyclic groups are optionally surrounded by one, two or more R groups. 4-1 replace;

[0020] Each R 4-1 Independently, it is halogen, deuterium, oxo (=O), C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0021] R m and R n Each independently represents H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may optionally be substituted with one, two or more deuterium atoms;

[0022] R x For H or C 1-6 alkyl;

[0023] R y C 1-6 alkyl;

[0024] R z C 1-6 Alkyl, C 1-6 Halogenated alkyl or 4-10 membered heterocyclic alkyl, wherein the 4-10 membered heterocyclic alkyl is optionally surrounded by one, two or more R... z-1 replace;

[0025] Each R z-1 It can be halogen, oxo (=O) or C independently. 1-6 alkyl;

[0026] R v and R w Each independently is H or C 1-6 alkyl.

[0027] In certain preferred embodiments of the present invention, certain groups in the compound represented by formula (I), its racemate, stereoisomer, or pharmaceutically acceptable salt thereof, or in the solvate of the compound represented by formula (I) are defined as follows, and groups not mentioned are defined as in any embodiment of the present invention (hereinafter referred to as "in embodiments of the present invention").

[0028] According to an embodiment of the present invention, R1 is H or methyl, preferably H.

[0029] According to an embodiment of the present invention, R2 is C 4-12 Bridged cycloalkyl or 4-12-membered bridged heterocycloalkyl, wherein the C 4-12Bridged cycloalkyl groups and 4-12-membered bridged heterocycloalkyl groups are optionally bound by one, two or more R groups. 2-1 Instead, the respective R 2-1 It independently possesses the definition described in any of the schemes in this application.

[0030] According to an embodiment of the present invention, R2 is C 4-8 Bridged cycloalkyl or 4-8-membered bridged heterocycloalkyl, wherein the C 4-8 Bridged cycloalkyl groups and 4-8-membered bridged heterocycloalkyl groups are optionally bound by one, two or more R groups. 2-1 Instead, the respective R 2-1 It independently possesses the definition described in any of the schemes in this application.

[0031] According to an embodiment of the present invention, R2 is a C6 bridged cycloalkyl group, wherein the C6 bridged cycloalkyl group is bonded by one or two R... 2-1 Instead, the respective R 2-1 It independently possesses the definition described in any of the schemes in this application.

[0032] According to an embodiment of the present invention, R2 is bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.0]octyl, bicyclo[3.2.1]octyl, or 1-azabicyclo [2.1.1] Hexyl, 5-oxabicyclo[2.1.1] Hexyl, 3-oxabicyclo[3.1.0] Hexyl, 2-azabicyclo[2.2.1] Heptyl, 2-oxa-5-azabicyclo[2.2.1] Heptyl, 3,7-diazabicyclo[3.3.0] Octyl, 8-azabicyclo[3.2.1] Octyl, 3-oxa-8-azabicyclo[3.2.1] Octyl or 3-azabicyclo[3.2.1] Octyl, its The compounds described herein include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.0]octyl, bicyclo[3.2.1]octyl, 1-azabicyclo[2.1.1]hexyl, 5 -oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3,7-diazabicyclo[3.3.0]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl and 3-azabicyclo[3.2.1]octyl are optionally surrounded by one, two or more R2-1 Instead, the respective R 2-1 It independently possesses the definition described in any of the schemes in this application.

[0033] According to an embodiment of the present invention, R2 is a bicyclo[3.1.0]hexyl group, wherein the bicyclo[3.1.0]hexyl group is divided by one R 2-1 Instead, the R 2-1 It has the definition described in any of the schemes in this application.

[0034] According to an embodiment of the present invention, each R 2-1 It can be independently H, F, Cl, Br, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, -CH2F, -CHF2 or -CF3.

[0035] According to an embodiment of the present invention, each R 2-1 Independently methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0036] According to an embodiment of the present invention, R2 is Preferably, R2 is

[0037] According to an embodiment of the present invention, R2 is Preferably, R2 is More preferably, R2 is

[0038] According to an embodiment of the invention, R3 is a 5-membered heteroaryl or phenyl group, wherein the 5-membered heteroaryl or phenyl group is optionally surrounded by 1, 2, 3, or 4 R groups. 3-1 Instead, the respective R 3-1 It independently possesses the definition described in any of the schemes in this application.

[0039] According to an embodiment of the present invention, R3 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is surrounded by one, two, or three R groups. 3-1 Instead, the respective R 3-1 It independently possesses the definition described in any of the schemes in this application.

[0040] According to embodiments of the present invention, R3 is pyrazolyl, pyrroleyl, imidazoyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, or phenyl, wherein the pyrazolyl, pyrroleyl, imidazoyl, triazolyl, furanyl, thiazoyl, oxazolyl, isoxazolyl, thiazoyl, and phenyl are optionally represented by one, two, three, or four R3 groups. 3-1 Instead, the respective R 3-1It independently possesses the definition described in any of the schemes in this application.

[0041] According to an embodiment of the present invention, R3 is a pyrazolyl group, said pyrazolyl group being surrounded by one, two or three R groups. 3-1 Instead, the respective R 3-1 It independently possesses the definition described in any of the schemes in this application.

[0042] According to an embodiment of the present invention, each R 3-1 It can be H, -CN, -OH, -NH2, oxo (=O), F, Cl, Br, methyl, ethyl, cyclopropyl, -CH2F, -CHF2, -CF3 or -CD3 independently.

[0043] According to an embodiment of the present invention, each R 3-1 It is independently methyl or ethyl, preferably methyl.

[0044] According to an embodiment of the present invention, R3 is

[0045] According to an embodiment of the present invention, R3 is

[0046] According to an embodiment of the present invention, R m and R n Each can be independently H, methyl, ethyl, -CD3, n-propyl, isopropyl, -CF3, -CH2CH2F, -CH2CHF2 or -CH2CF3.

[0047] According to an embodiment of the present invention, R m and R n Each can be independently methyl, ethyl, -CD3 or -CF3.

[0048] According to an embodiment of the present invention, R m and R n Each is independently methyl or ethyl, preferably methyl.

[0049] According to an embodiment of the present invention, R x H or methyl; R y It can be methyl or ethyl.

[0050] According to an embodiment of the present invention, R v H, methyl, or ethyl; R w It can be methyl or ethyl.

[0051] According to an embodiment of the present invention, R z C 1-3 Alkyl, C 1-3Halogenated alkyl or 5-8 membered heterocyclic alkyl, wherein the 5-8 membered heterocyclic alkyl is optionally surrounded by 1, 2, 3 or 4 R... z-1 Instead, wherein each of the R z-1 Independently having the definition described in any of the embodiments of this application; preferably, the 5-8 membered heterocyclic alkyl group contains 1, 2 or 3 N and 0, 1 or 2 O or S.

[0052] According to an embodiment of the present invention, each R z-1 It can be F, Cl, oxo (=O), methyl or ethyl.

[0053] According to an embodiment of the present invention, R z for

[0054] According to an embodiment of the present invention, in R4, the 5-7-membered heteroaryl group is pyrazolyl, pyrroleyl, imidazolyl, triazolyl, furanyl, thiopheneyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or pyridyl, wherein the pyrazolyl, pyrroleyl, imidazolyl, triazolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and pyridyl group is optionally represented by one, two, three, or four R groups. 4-1 Instead, the respective R 4-1 It independently possesses the definition described in any of the schemes in this application.

[0055] According to an embodiment of the present invention, in R4, the 3-7 membered heterocyclic group is oxetyl, aziretyl, pyrrolidinyl, or tetrahydrofuranyl, wherein the oxetyl, aziretyl, pyrrolidinyl, and tetrahydrofuranyl are optionally represented by one, two, or more R groups. 4-1 Instead, the respective R 4-1 It independently possesses the definition described in any of the schemes in this application.

[0056] According to an embodiment of the present invention, each R 4-1 It can be F, Cl, deuterium, oxo (=O), methyl, ethyl or -CF3 independently.

[0057] According to an embodiment of the present invention, R4 is

[0058] According to an embodiment of the present invention, R4 is -C(=O)NR m R n Preferred According to an embodiment of the present invention, n is 0 or 1, preferably 0.

[0059] According to an embodiment of the present invention, each R is independently H, -CN, F, Cl, -CH3 or -CH2F.

[0060] According to an embodiment of the present invention, R5 is H, -CN, F, Cl, -CH3 or -CH2F.

[0061] According to an embodiment of the present invention, X is N, CH, C(CN), CF, C(C1), C(CH3) or C(CH2F).

[0062] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown in formula (I-1):

[0063] Wherein, n, R, R1, R2, R3 and R4 each have the definition described in any of the schemes in this application.

[0064] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown in formula (I-1-a) or (I-1-b):

[0065] Wherein, n, R, R1, R2, R3 and R4 each have the definition described in any of the schemes in this application.

[0066] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown in formula (I-2):

[0067] Among them, R m R n Each of the following has its own definition as described in any of the schemes in this application: n, R, R2, and R3.

[0068] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown in formula (I-2-a) or (I-2-b):

[0069] Among them, R m R n Each of the following has its own definition as described in any of the schemes in this application: n, R, R2, and R3.

[0070] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown in any of the following structural formulas (I-3) to (I-7):

[0071] Among them, R m R n , n, R, R3 and R 2-1Each has an independent definition as described in any of the schemes in this application; m is 1, 2, or 3; q and p are each independently 1, 2, 3, or 4; x and z are each independently 0, 1, 2, 3, or 4; k and y are each independently 0, 1, 2, or 3; w and V are each independently C(R 2- 1) or N; U is -C(R) 2-1 )2-, -O-, -S- or -N(R) 2-1 )-.

[0072] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by any of the following structural formulas (I-3-a) to (I-7-b):

[0073] Among them, R m R n n, R, R3, R 2-1 Each of the following independently has the definition described in any of the schemes in this application: m, q, p, k, x, y, z, W, U, and V.

[0074] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown in formula (I-3-1):

[0075] Among them, R m and R n Each is independently methyl, ethyl, -CD3, or -CF3; R3 is optionally surrounded by 1, 2, or 3 Rs. 3-1 Substituted pyrazol groups; each R 3-1 Independently methyl, ethyl, cyclopropyl, -CH2F, -CHF2, -CF3 or -CD3; R 2-1 It can be independently H, F, Cl, Br, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, -CH2F, -CHF2 or -CF3.

[0076] According to embodiments of the present invention, the compound represented by formula (I) has a structure as shown in formula (I-3-1-m) or (I-3-1-n):

[0077] Among them, R m and R n Each is independently methyl, ethyl, -CD3, or -CF3; R3 is optionally surrounded by 1, 2, or 3 Rs. 3-1 Substituted pyrazol groups; each R 3-1 Independently methyl, ethyl, cyclopropyl, -CH2F, -CHF2, -CF3 or -CD3; R 2-1It can be independently H, F, Cl, Br, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, -CH2F, -CHF2 or -CF3.

[0078] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by any of the following structural formulas (I-3-a-1) to (I-3-b-2):

[0079] Among them, R m and R n Each is independently methyl, ethyl, -CD3, or -CF3; R3 is optionally surrounded by 1, 2, or 3 Rs. 3-1 Substituted pyrazol groups; each R 3-1 Independently methyl, ethyl, cyclopropyl, -CH2F, -CHF2, -CF3 or -CD3; R 2-1 It can be independently H, F, Cl, Br, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, -CH2F, -CHF2 or -CF3.

[0080] According to an embodiment of the present invention, the compound represented by formula (I) has the following structure:

[0081] According to an embodiment of the present invention, the compound represented by formula (I) has the following structure:

[0082] According to an embodiment of the present invention, the solvate of the compound represented by formula (I) has the structure shown in formula (I-3-1-S):

[0083] According to an embodiment of the present invention, the solvate of the compound represented by formula (I) has the structure shown in formula (I-3-1-S):

[0084] The solvate is in crystalline form, which has a tetragonal crystal system, space group P43, and unit cell parameters as follows:

[0085] The present invention also provides a method for preparing the compound shown in formula (I), comprising the following steps:

[0086] Compound Int-1 reacts with compound Int-2 to give the compound shown in formula (I);

[0087] Wherein, R1, R2, R3, R4, R, X, and n each independently have the definition described in any of the schemes in this application, and R0 is C 1-6 Alkyl group, preferably, R0 is methyl or ethyl.

[0088] According to an embodiment of the present invention, the preparation method comprises the following steps: in a solvent, under the action of an alkali, compound Int-1 and compound Int-2 undergo a substitution reaction to prepare the compound shown in formula (I);

[0089] Preferably, the solvent is an alcohol solvent, such as ethanol;

[0090] Preferably, the base is an organic base, such as N(R) s1 )3, each R s1 Independently for C 1-6 Alkyl group; more preferably, the base is N,N-diisopropylethylamine.

[0091] This invention also provides compounds represented by formula Int-2:

[0092] R1, R2, and R3 each independently have the definitions described in any of the schemes in this application.

[0093] According to an embodiment of the present invention, the compound represented by formula Int-2 is selected from the following compounds:

[0094] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) of the present invention, its racemate, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate of the compound of formula (I).

[0095] According to embodiments of the present invention, the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula (I) of the present invention, its racemate, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate of the compound of formula (I) and a pharmaceutically acceptable carrier.

[0096] The carrier in the pharmaceutical composition is pharmaceutically acceptable, compatible with (and preferably stabilizing) the active ingredient of the composition, and not harmful to the treated subject. One or more pharmaceutical excipients may be used to deliver the active compound.

[0097] The present invention further provides the use of the compound represented by formula (I), its racemate, stereoisomer or pharmaceutically acceptable salt thereof, or a solvate of the compound represented by formula (I), or the pharmaceutical composition thereof in the preparation of a medicament.

[0098] According to embodiments of the present invention, the drug is a drug for diagnosing, preventing and / or treating CCR6 receptor-mediated diseases or conditions.

[0099] According to an embodiment of the present invention, the disease or condition is an allergic disease, psoriasis, contact hypersensitivity reaction, Sjögren's syndrome, dry eye syndrome, or multiple sclerosis.

[0100] According to embodiments of the present invention, the disease or condition is rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic rheumatoid arthritis, oligoarticular rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis caused by inflammatory diseases.

[0101] According to an embodiment of the present invention, the disease or condition is inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis.

[0102] According to an embodiment of the present invention, the drug is a CCR6 inhibitor.

[0103] The present invention also provides a method for diagnosing, preventing and / or treating CCR6 receptor-mediated diseases or conditions, the method comprising administering, alone, a therapeutically effective amount of at least one compound of the present invention to a patient requiring such treatment, or optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0104] According to an embodiment of the present invention, the disease or condition is an allergic disease, psoriasis, contact hypersensitivity reaction, Sjögren's syndrome, dry eye syndrome, or multiple sclerosis.

[0105] According to embodiments of the present invention, the disease or condition is rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic rheumatoid arthritis, oligoarticular rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis caused by inflammatory diseases.

[0106] According to an embodiment of the present invention, the disease or condition is inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis.

[0107] The compounds of the present invention can be used in combination with other therapeutic agents. Beneficial effects

[0108] The present invention provides a cyclobutenedione compound of formula (I) which has good CCR6 inhibitory activity and good selectivity relative to CXCR2, and also has excellent pharmacokinetic and pharmacodynamic properties.

[0109] Terminology Definitions and Explanations

[0110] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0111] In the general formula definition of this application, the term "optional" (or "optionally", "optionally") means that it is substituted by 0, 1 or more substituents. For example, "optionally substituted by 1, 2 or more R" means that it may not be substituted by R (no substitution) or may be substituted by 1, 2 or more R.

[0112] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups. Alternatively, it can mean the replacement of the lone pair of electrons on an atom by another atom or group; for example, the lone pair of electrons on a sulfur atom can be replaced by an oxygen atom to form a hydrogen atom.

[0113] In this application Or "-" indicates the connection site between the group and other parts of the molecule.

[0114] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These three connection methods, even if an H atom is drawn on -N-, This also includes When the group is a bicyclic, tricyclic, or polycyclic ring system, one or more sites on any ring of the group can be connected to other groups through chemical bonds, for example... This indicates that any linkable site on the ring of the 1-azabicyclo

[0211] hexyl group can be connected to other groups by a single chemical bond, including at least... These are the four connection methods. For example... This indicates that the R group on the 1-azabicyclo[2.1.1]hexyl group can be located on the C of any ring of the group, including at least...

[0115] Term "C" n-m "and "C n -C m ", where n and m are integers, representing a group containing n to m carbon atoms. Examples include C 1-6 C 1-3 The term is intended to explicitly disclose each member within that scope, namely C. n C n+1 C n+2 ......C m-2 C m-1 C m For example, C 1-6 The intention is to disclose C1, C2, C3, C4, C5, and C6. "C" n-m The meaning of "C" is the same as "C". n -C m "same.

[0116] The term "n-ary", where n is an integer, usually describes the number of ring atoms in a aryl atom.

[0117] The term "nm-aryl" refers to a cyclic ring in which n and m are integers, describing the number of ring-forming atoms in a range from n to m. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, and pyridinyl is an example of a 6-membered heteroaryl ring.

[0118] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0119] Unless otherwise stated, "more than" means three or more, such as 3, 4, 5, 6, 7, 8 or 9.

[0120] Term "C" 1-6 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The C 1-6 Alkyl groups include C 1-3 Alkyl, C 1-4 Alkyl, C 3-4 Alkyl, C 4-6 Alkyl groups, etc. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc., or their isomers.

[0121] Term "C" 1-6 "Alkyloxy" indicates a C-type carbon bonded by an oxygen bridge. 1-6 Alkyl; the C 1-6 The definition of alkyl is the same as above. Examples of alkoxy groups include, but are not limited to, methoxy and ethoxy groups.

[0122] Term "C" 3-6 "Cycloalkyl" refers to a monovalent or polyvalent cyclic alkane having 3-6 carbon atoms, including monocyclic, bicyclic, or tricyclic alkanes, wherein the bicyclic and tricyclic alkanes include bridged or spirocyclic rings. The C 3-6 Cycloalkyl groups include C 4-6 cycloalkyl, C 3-5 cycloalkyl, C 3-4 cycloalkyl, C 5-6 Cycloalkyl groups, etc. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0123] Term "C" 4-12A "bridged ring group" refers to a saturated or unsaturated cyclic group with 4-12 carbon atoms, formed by any two or more carbon ring structures sharing two or more carbon atoms. This cyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The C... 4- 12 Bridge ring base includes C 4-12 Bridged cycloalkyl and C 4-12 Bridged cyclic alkenyl groups. Based on the number of carbon atoms in the constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cyclic groups. Examples of such bridged cyclic groups include, but are not limited to: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.1.1]hex-2-enyl, bicyclo[4.1.0]hept-3-enyl, etc.

[0124] Term "C" 4-12 "Bridged cycloalkyl" refers to a saturated cyclic group with 4-12 carbon atoms formed by any two or more cycloalkane structures sharing two or more carbon atoms. The C 4-12 Bridged cycloalkyl groups include C 4-8 Bridged cycloalkyl, C 4-6 Bridged cycloalkyl, C 5-6 Bridged cycloalkyl groups, etc. Based on the number of carbon atoms in the constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups. Examples of such bridged cycloalkyl groups include, but are not limited to: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.0]octyl, bicyclo[3.2.1]octyl, etc.

[0125] The term "4-12-membered bridged heterocyclic group" refers to a saturated or unsaturated cyclic group with 4-12 atoms, formed by any two or more cyclic structures sharing two or more atoms. The ring atoms consist of a carbon atom and one, two, or more heteroatoms independently selected from O, S, and N, wherein N and S can optionally be oxidized to various oxidation states to form nitrides, -S(=O)-, or -S(=O)2- states. This cyclic group may contain one or more double bonds, but no ring has a fully conjugated π-electron system. The 4-12-membered bridged heterocyclic group includes 4-12-membered bridged heterocyclic alkyl groups and 4-12-membered bridged heterocyclic alkenyl groups. Based on the number of atoms constituting the ring, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups. Examples of the bridged heterocyclic groups include, but are not limited to: 1-azabicyclo[2.1.1]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3,7-diazabicyclo[3.3.0]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.2.1]oct-6-enyl, etc.

[0126] The term "4-12-membered bridged heterocyclic alkyl" refers to a saturated cyclic group with 4-12 atoms formed by any two or more cyclic structures sharing two or more atoms. The ring atoms consist of a carbon atom and one, two, or more heteroatoms independently selected from O, S, and N, wherein N and S can optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2- states. The 4-12-membered bridged heterocyclic alkyl includes 4-8-membered bridged heterocyclic alkyl, 4-6-membered bridged heterocyclic alkyl, 5-6-membered bridged heterocyclic alkyl, etc. Based on the number of atoms constituting the ring, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic alkyl. Examples of the bridged heterocyclic alkyl groups include, but are not limited to: 1-azabicyclo[2.1.1]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3,7-diazabicyclo[3.3.0]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl, etc.

[0127] Term "C" 6-10 "Aryl" refers to a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6, 7, 8, 9, or 10 carbon atoms, exhibiting monovalent or polyvalent aromaticity. Examples of aryl groups include, but are not limited to, phenyl, indenyl, and naphthyl groups.

[0128] The term "7-12-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 7-12 ring atoms, with the ring atoms comprising 1-5 heteroatoms independently selected from N, O, and S, and consisting of monovalent or polyvalent heteroatoms. Preferably, the 7-12-membered heteroaryl contains 1-3 heteroatoms. Additionally, in each case, the 7-12-membered heteroaryl may be benzofused. The 7-12-membered heteroaryl includes 7-10-membered heteroaryl, 7-9-membered heteroaryl, 9-membered heteroaryl, etc. Examples of the heteroaryl include, but are not limited to, indolyl, pyrazolopyridyl, quinolinyl, etc.

[0129] The term "5-7 membered heteroaryl" refers to a monocyclic aromatic ring system having 5-7 ring atoms, wherein the ring atoms include 1, 2, or 3 heteroatoms independently selected from N, O, and S, and is monovalent or polyvalent. The 5-7 membered heteroaryl includes 5-, 6-, or 7-membered heteroaryl groups. Examples of such heteroaryl groups include, but are not limited to, oxazolyl, isoxazolyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyridazinyl.

[0130] The term "3-10 membered heterocyclic alkyl" refers to a saturated ring or ring system having 3-10 ring atoms, wherein the ring atoms contain 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2- states. The 3-10 membered heterocyclic alkyl can be a 3, 4, 5, 6, or 7-membered monocyclic, a 7, 8, 9, or 10-membered bicyclic, or a 10-membered tricyclic ring system. The bicyclic and tricyclic ring systems include bridged rings or spirocyclic rings. The 3-10 membered heterocyclic alkyl groups include 4-10 membered heterocyclic alkyl groups, 3-8 membered heterocyclic alkyl groups, 5-8 membered heterocyclic alkyl groups, 4-6 membered heterocyclic alkyl groups, 4-5 membered heterocyclic alkyl groups, 5-6 membered heterocyclic alkyl groups, etc., wherein the 3-10 membered heterocyclic alkyl groups, 4-10 membered heterocyclic alkyl groups, 3-8 membered heterocyclic alkyl groups, and 5-8 membered heterocyclic alkyl groups preferably contain 1, 2, or 3 N atoms and 0, 1, or 2 O atoms or S atoms. Examples of heterocyclic alkyl groups include, but are not limited to: aziridine, oxaziridine, aziridine, oxaziridine, tetrahydrofuranyl, pyrrolyl, imidazoalkyl, pyrazolyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, 3,8-diazabicyclo

[0321] octyl, 2-oxa-5-azabicyclo

[0221] heptyl, 2,5-diazabicyclo

[0221] heptyl, etc.

[0131] The term "3-7 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system having 3-7 ring atoms, wherein the ring atoms contain one, two, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2- states. The 3-7 membered heterocyclic group can be a 3, 4, 5, 6, or 7-membered monocyclic ring, or a 6 or 7-membered bicyclic ring system. The bicyclic ring system includes bridged rings or spirocyclic rings. The 3-7 membered heterocyclic group includes 3-6 membered heterocyclic groups, 4-6 membered heterocyclic groups, 4-5 membered heterocyclic groups, etc. The heterocyclic group can be connected to the rest of the molecule through any one carbon or nitrogen atom (if present) on its ring. Examples of the heterocyclic group include, but are not limited to: 3-membered rings, such as azirropropyl and oxopropyl; 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, 2,3-dihydro-1H-imidazolyl, pyrrolyl, imidazoalkyl, pyrazolealkyl, pyrrolinyl; or 6-membered rings, such as dihydrofuranyl, dihydropyranyl, tetrahydropyranyl, dihydropyridyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, or trithiaalkyl.

[0132] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0133] The term "halogenation" refers to the substitution of one or more halogens.

[0134] Term "C" 1-6 "Halogenated alkyl" refers to an alkyl group as defined above, which is substituted with one or more halogens as defined above. Examples of halogenated alkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc.

[0135] The term "bridging ring" refers to a ring system in which two rings share two or more ring atoms.

[0136] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0137] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0138] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0139] The compounds described herein may include all stereoisomers of the compound. The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including enantiomers, diastereomers, cis-trans isomers, and conformational isomers.

[0140] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key Represents the absolute configuration of the center of a solid. Uses straight solid lines as keys. and straight dashed key Representing the relative configurations of a stereocenter, such as the cis-trans configurations of alicyclic compounds, for example... This indicates that R on the ring and the cyclopropyl group (a ring) in the bicyclic [3.1.0]hexyl group are cis-reciprocal (i.e., R and a ring are located on the same side of the face containing ring b: facing inwards or outwards). The configurations are the same; This indicates that R on the ring and the cyclopropyl group (a ring) in the bicyclic [3.1.0]hexyl group are inversely related (i.e., R and a ring are on opposite sides of the plane containing ring b), and... The configurations are the same.

[0141] Depending on their molecular structure, the compounds of the present invention can be chiral (having one or more stereocenters), and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention cover isomers of each chiral carbon in the R or S configuration, or mixtures thereof, or racemates. The compounds of the present invention or intermediates thereof can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0142] In some embodiments, the compounds of the present invention have an (R)-configuration. In other embodiments, the compounds have an (S)-configuration. In compounds having more than one chiral center, each chiral center in the compound may be independently (R) or (S), unless otherwise stated.

[0143] The compounds described herein may also include tautomer forms. The term "tautomer" refers to an isomer resulting from the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomer forms include proton-shift tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton-shift tautomers include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomer forms can be in equilibrium or spatially locked into one form through appropriate substitution.

[0144] The compounds described herein may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0145] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0146] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0147] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Attached Figure Description

[0148] Figure 1 is a thermo-ellipsoidal diagram of the molecular stereostructure of compound 1B-1 monohydrate. Detailed Implementation

[0149] The following detailed description, in conjunction with specific embodiments, illustrates the general formula compounds of the present invention, their preparation methods, and applications. The following embodiments are merely illustrative and explanatory of the invention and should not be construed as limiting the scope of protection of the invention. All technologies implemented based on the above description of the present invention are covered within the scope of protection intended by the present invention. The preparation methods included in the following specific embodiments are merely illustrative of the operational methods for that step; the raw materials used in the next step can be prepared in multiple batches using the same method.

[0150] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0151] Nouns and representative reagents

[0152] Unless otherwise stated, the terms used in the following specific experimental descriptions refer to the following reagents:

[0153] DMF: N,N-dimethylformamide; DCM: dichloromethane; DMSO: dimethyl sulfoxide; DMSO-d6: deuterated dimethyl sulfoxide; EtOH: ethanol; ACN: acetonitrile.

[0154] Preparation Examples

[0155] Example 1a Preparation of compounds 1A, 1A-1, 1A-2, 1B, 1B-1 and 1B-2

[0156] 1a.1 Preparation of compound 1-1

[0157] Compound 1-a (10 g, 53.3 mmol) was weighed and added to dichloromethane (100 mL). Oxaloyl chloride (9 mL, 106.6 mmol) and two drops of N,N-dimethylformamide were added dropwise at 0 °C. The mixture was heated to ambient temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (150 mL). Triethylamine (22.3 mL, 160 mmol) was added at 0 °C, followed by a tetrahydrofuran solution of dimethylamine (32 mL, 64 mmol, 2N) added dropwise while maintaining the internal temperature below 5 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 12 hours. The reaction solution was quenched with water (200 mL) and extracted with dichloromethane (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 1-1 (11 g).

[0158] 1a.2 Preparation of compounds 1-2

[0159] Compound 1-1 (11 g, 51.25 mmol) was dissolved in 1,4-dioxane (300 mL), and tert-butyl carbamate (12 g, 102.5 mmol), cesium carbonate (33.4 g, 102.5 mmol), palladium acetate (1.15 g, 5.12 mmol), and 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (2.2 g, 5.12 mmol) were added. The mixture was stirred at 95 °C for 16 hours under nitrogen protection. The reaction mixture was cooled to 20 °C, filtered through a diatomaceous earth filter, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 1-2 (10 g).

[0160] 1a.3 Preparation of compounds 1-3

[0161] Dissolve compound 1-2 (10 g, 34 mmol) in dichloromethane (400 mL), add 52 mL (4 M) of 1,4-dioxane solution of hydrogen chloride, and stir at 20 °C for 4 hours. Concentrate the reaction solution directly under reduced pressure to obtain compound 1-3 (10 g, crude product), which can be used directly in the next step.

[0162] 1a.4 Preparation of compounds 1-4

[0163] Compounds 1-3 (10 g, 51.2 mmol) were dissolved in dichloromethane (50 mL), and tetrabutylammonium iodide (11.4 g, 30.7 mmol) was added. Under nitrogen protection, boron tribromide (154 mL, 154 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was quenched by slowly adding saturated sodium bicarbonate aqueous solution (200 mL). The resulting mixture was extracted with dichloromethane (200 mL × 2). The organic phase was discarded, and the aqueous phase was concentrated to obtain compounds 1-4 (35 g, crude product), which was used directly in the next step.

[0164] 1a.5 Preparation of compounds 1-5

[0165] 1-4 (35 g, 193.2 mmol) was weighed and dissolved in ethanol (150 mL). 1-b (6.78 g, 38.64 mmol) and N,N-diisopropylethylamine (21.6 g, 165.5 mmol) were added. The reaction solution was stirred overnight at 55 °C and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 1-5 (4.2 g).

[0166] 1a.6 Preparation of compounds 1-6

[0167] Diisopropylamine (25.2 mL, 180.0 mmol) was dissolved in tetrahydrofuran (70 mL), purged three times with nitrogen, and a hexane solution of n-butyllithium (80 mL, 200.0 mmol, 2.5 M) was added dropwise to the reaction solution at -78 °C. After the addition was complete, the reaction solution was allowed to react at this temperature for 0.5 hours, and then transferred to room temperature and stirred for 1 hour. Subsequently, the reaction solution was cooled to -30 °C, and compound 1-c (6.2 mL, 60.0 mmol) was added. After the addition was complete, the reaction solution was allowed to react at room temperature for 16 hours. The reaction system was cooled to -30 °C again, and iodomethane (5.6 mL, 90.0 mmol) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was allowed to react at room temperature for 16 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (80 mL × 3), the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compounds 1-6 (7.98 g, crude product), which were used directly in the next step.

[0168] 1a.7 Preparation of compounds 1-7

[0169] Compounds 1-6 (7.4 g, 58.30 mmol) were dissolved in a mixed solvent of dichloromethane (100 mL) and N,N-dimethylformamide (1 mL). Oxaloyl chloride (7.4 mL, 87.45 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). Triethylamine (28.4 mL, 200.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (8.5 g, 87.45 mmol) were added slowly sequentially at 0 °C. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compounds 1-7 (7.3 g, yield: 74%).

[0170] LCMS: [M+H] + =170.10.

[0171] 1a.8 Preparation of compounds 1-8

[0172] Compounds 1-7 (2.0 g, 11.8 mmol) were dissolved in dichloromethane (20 mL), purged three times with nitrogen, and a hexane solution of diethylzinc (59 mL, 59.0 mmol, 1 M) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then diiodomethane (31.6 g, 118.0 mmol) was added, and the mixture was stirred at 0 °C for 30 min, then heated to room temperature for 2 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (30 mL), and extracted with ethyl acetate (40 mL × 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give compounds 1-8 (1.1 g, yield: 50.79%). LCMS: [M+H] + =184.10.

[0173] Preparation of compounds 1-9, 1-9a and 1-9b

[0174] Compound 1-d (9.4 g, 42.32 mmol) was weighed into a three-necked flask, purged three times with nitrogen, and tetrahydrofuran (53 mL) was added. The system was cooled to -78 °C, and then a solution of n-butyllithium in n-hexane (19.4 mL, 48.5 mmol, 2.5 M) was slowly added dropwise. The reaction mixture was kept at -78 °C for 40 minutes. Then, compound 1-8 (3.9 g, 21.16 mmol) was added to the reaction system, and the reaction was kept at -78 °C for 1 hour. The reaction was quenched by slowly adding saturated ammonium chloride aqueous solution (80 mL), and then extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 1-9 (2.112 g). Compound 1-9 was further purified by high performance liquid chromatography to obtain compound 1-9a (1.464 g) and compound 1-9b (207 mg).

[0175] Compounds 1-9a:

[0176] LCMS: [M+H] + =219.10;

[0177] Chiral HPLC purity: 98.58%, retention time T R = 5.431 min (220 nm) (Chiral HPLC purity detection method: CHIRALPAK AD-H, 4.6*250 mm, particle size 5 μm, mobile phase: n-hexane containing 5% isopropanol, flow rate: 0.8 mL / min, column temperature: 30 ℃);

[0178] 1 H NMR (400MHz, CDCl3): δ7.10 (s, 1H), 3.87 (s, 3H), 2.76 (s, 1H), 2.72 (s, 1H), 2.22 (s, 3H), 1.87 (dd, J1=13.6 Hz, J2=4.0Hz, 2H), 1.53 (s, 3H), 1.26-1.22 (m, 2H), 0.42-0.36 (m, 1H), -0.10 (m, J1=8.8Hz, J2=4.0Hz, 1H).

[0179] Compounds 1-9b:

[0180] LCMS: [M+H] + =219.10;

[0181] Chiral HPLC purity: 99.26%, retention time T R= 5.564 min (220 nm) (Chiral HPLC purity detection method: CHIRALPAKAD-H, 4.6*250 mm, particle size 5 μm, mobile phase: n-hexane containing 5% isopropanol, flow rate: 0.8 mL / min, column temperature: 30 ℃);

[0182] 1 H NMR (400MHz, CDCl3): δ7.10 (s, 1H), 3.86 (s, 3H), 2.75 (dd, J1=14.4Hz, J2=4.4Hz, 2H), 2.24 (d, J=0.8Hz, 3H), 1. 72 (s, 1H), 1.68 (s, 1H), 1.40 (s, 3H), 1.35-1.31 (m, 2H), 0.59-0.53 (m, 1H), 0.30 (dd, J1=8.4Hz, J2=4.0Hz, 1H).

[0183] Preparation of compounds 1-10a, 1a.10

[0184] Compound 1-9a (218 mg, 1.0 mmol) was dissolved in ethanol (4 mL) at room temperature. Hydroxylamine hydrochloride (278 mg, 4.0 mmol) and sodium acetate (205 mg, 2.5 mmol) were added at 0 °C. The resulting reaction solution was heated to 90 °C and refluxed for 2 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and then extracted with dichloromethane (20 mL × 3). The organic phases were combined and washed with saturated brine (10 mL). After drying with anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 1-10a (270 mg, crude product).

[0185] LCMS: [M+H] + =234.10.

[0186] Preparation of compounds 1-11a.11

[0187] Compound 1-10a (270 mg, crude), zinc powder (654 mg, 10.0 mmol), and hydrochloric acid (5 mL, 2 M) were added sequentially to a reaction flask, and the reaction mixture was allowed to react at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 9 with saturated sodium carbonate aqueous solution, and then extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1-11a (212 mg, crude). LCMS: [M-NH2] + =203.10.

[0188] 1a.12 Preparation of compounds 1A, 1A-1 and 1A-2

[0189] Compound 1-11a (212 mg, crude), ethanol (3 mL), N,N-diisopropylethylamine (174 μL, 1.0 mmol), and compound 1-5 (200 mg, 0.7 mmol) were added sequentially to a reaction flask and stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) to obtain compound 1A (153 mg), which was then chirally resolved (resolution conditions: Daicel Chiralpak IG column, 250 × 30 mm ID, particle size 5 μm; mobile phase: A: 70% CO2, B: 30% (EtOH:ACN = 3:1 (0.1% NH3·H2O)); flow rate: 65 g / min) to obtain compound 1A-1 (56.3 mg) and compound 1A-2 (51.7 mg).

[0190] The characterization data of compound 1A-1 are as follows:

[0191] LCMS: [M+H] + =479.05;

[0192] Chiral purity: 98.38%, retention time T R = 13.101 min (254 nm) (Chirality detection method: CHIRALPAKAD-H, 4.6*250 mm, particle size 5 μm, mobile phase: hexane containing 10% ethanol, 10% isopropanol and 0.1% diethylamine, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0193] 1 H NMR (400MHz, DMSO-d6): δ9.06 (d, J=10.0Hz, 1H), 7.99 (d, J=5.6Hz, 1H), 7.9 0(d, J=4.4Hz, 1H), 7.40(s, 1H), 5.24(d, J=10.0Hz, 1H), 3.77(s, 3H), 3.13( s, 3H), 3.03 (s, 3H), 1.94 (s, 3H), 1.68-1.63 (m, 1H), 1.48 (d, J=11.2Hz, 3H) , 1.36-1.28 (m, 2H), 1.18 (s, 3H), 0.79-0.74 (m, 1H), 0.01 (d, J=4.0Hz, 1H).

[0194] The characterization data of compound 1A-2 are as follows:

[0195] LCMS: [M+H] + =479.05;

[0196] Chiral purity: 98.82%, retention time T R= 8.329 min (254 nm) (Chirality detection method: CHIRALPAKAD-H, 4.6*250 mm, particle size 5 μm, mobile phase: hexane containing 10% ethanol, 10% isopropanol and 0.1% diethylamine, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0197] 1 H NMR (400MHz, DMSO-d6) δ: 9.06 (d, J=10.0Hz, 1H), 8.00 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.40 (s, 1H), 5.24 (d, J=10.0Hz, 1H), 3.77 (s, 3H), 3.15 (s, 3H) ), 3.04 (s, 3H), 1.95 (s, 3H), 1.68-1.63 (m, 1H), 1.49 (d, J=11.2Hz, 3H), 1 .35-1.27 (m, 2H), 1.18 (s, 3H), 0.80-0.75 (m, 1H), 0.01 (d, J=3.6Hz, 1H).

[0198] Preparation of compounds 1-10b (1a.13)

[0199] Compound 1-9b (180 mg, 0.83 mmol) was dissolved in ethanol (4 mL) at room temperature. Hydroxylamine hydrochloride (229 mg, 3.30 mmol) and sodium acetate (169 mg, 2.06 mmol) were added at 0 °C. The reaction mixture was heated to 90 °C and refluxed for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined and washed with saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1-10b (210 mg, crude product).

[0200] Preparation of compounds 1-11b (1a.14)

[0201] Compound 1-10b (210 mg, crude), zinc powder (540 mg, 8.25 mmol), and hydrochloric acid (4 mL, 2 M) were added sequentially to a reaction flask, and the reaction mixture was allowed to react at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 9 with saturated sodium carbonate aqueous solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-11b (229 mg, crude). LCMS: [M-NH2] + =203.10.

[0202] Preparation of compounds 1a.15, 1B, 1B-1, and 1B-2

[0203] Compound 1-11b (229 mg, crude), ethanol (3 mL), N,N-diisopropylethylamine (145 μL, 0.83 mmol), and compound 1-5 (200 mg, 0.66 mmol) were added sequentially to a reaction flask. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain compound 1B (191 mg), which was then chirally resolved (resolution conditions: Daicel Chiralpak IG column, 250 × 30 mm ID, particle size 5 μm; mobile phase: A: 70% CO2, B: 30% (EtOH:ACN = 3:1 (0.1% NH3·H2O)); flow rate: 65 g / min) to obtain compound 1B-1 (74.8 mg) and compound 1B-2 (72.8 mg).

[0204] The characterization data of compound 1B-1 are as follows:

[0205] LCMS: [M+H] + =479.05;

[0206] Chiral purity: 100%, retention time T R = 12.183 min (254 nm) (Chirality detection method: CHIRALPAK AD-H, 4.6*250 mm, particle size 5 μm, mobile phase: hexane containing 10% ethanol, 10% isopropanol and 0.1% diethylamine, flow rate: 0.8 mL / min, column temperature: 30 °C).

[0207] 1 H NMR (400MHz, DMSO-d6): δ9.11 (d, J=10.0Hz, 1H), 7.97 (d, J=5.6Hz, 1H), 7.87 ( d, J=5.2Hz, 1H), 7.40 (s, 1H), 5.36 (d, J=10.0Hz, 1H), 3.76 (s, 3H), 3.09 (s, 3H) , 3.01(s, 3H), 2.20(dd, J1=13.6Hz, J2=6.0Hz, 1H), 1.99(s, 3H), 1.33-1.24(m, 3H), 1.14-1.11 (m, 2H), 1.07 (s, 3H), 0.68-0.63 (m, 1H), 0.18 (q, J=4.0Hz, 1H).

[0208] The single-crystal diffraction pattern of compound IB-1 monohydrate is shown in Figure 1 (i.e., the thermal ellipsoid diagram of the molecular stereostructure of compound IB-1 monohydrate). Its configuration was confirmed by the single-crystal diffraction pattern of its monohydrate.

[0209] The characterization data of compound 1B-2 are as follows:

[0210] LCMS: [M+H] + =479.05;

[0211] Chiral purity: 100%, retention time T R = 8.797 min (254 nm) (Chirality detection method: CHIRALPAKAD-H, 4.6*250 mm, particle size 5 μm, mobile phase: hexane containing 10% ethanol, 10% isopropanol and 0.1% diethylamine, flow rate: 0.8 mL / min, column temperature: 30 ℃);

[0212] 1 H NMR (400MHz, DMSO-d6): δ9.12 (d, J=10.4Hz, 1H), 7.98 (d, J=5.2Hz, 1H), 7.89 (d , J=5.2Hz, 1H), 7.40 (s, 1H), 5.37 (d, J=10.4Hz, 1H), 3.77 (s, 3H), 3.11 (s, 3H), 3 .02(s, 3H), 2.20(dd, J1=13.6Hz, J2=6.0Hz, 1H), 1.99(s, 3H), 1.38-1.22(m, 4H) , 1.13 (d, J=13.6Hz, 1H), 1.07 (s, 3H), 0.69-0.63 (m, 1H), 0.18 (q, J=3.6Hz, 1H).

[0213] Preparation of Compound 1 in Example 1b

[0214] 1b.1 Preparation of compounds 1-10

[0215] Compounds 1-9 (400 mg, 1.83 mmol) were dissolved in ethanol (4 mL) at room temperature. Hydroxylamine hydrochloride (510 mg, 7.33 mmol) and sodium acetate (300 mg, 3.66 mmol) were added at 0 °C, and the reaction mixture was heated to 85 °C and reacted for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1-10 (500 mg, crude product). LC-MS: [M+H] + =234.10.

[0216] 1b.2 Preparation of compounds 1-11

[0217] Compound 1-10 (500 mg, 2.14 mmol) and zinc powder (1.4 g, 21.43 mmol) were dissolved in hydrochloric acid (5 mL, 2N) at room temperature and reacted for 2 hours. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1-11 (300 mg, crude product).

[0218] 1b.3 Preparation of Compound 1

[0219] Compounds 1-11 (70 mg, 0.32 mmol), 1-5 (97 mg, 0.32 mmol), and N,N-diisopropylethylamine (83 mg, 0.64 mmol) were dissolved in ethanol (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was purified by high-performance liquid chromatography (under alkaline conditions) and then freeze-dried to give compound 1 (23.0 mg). LC-MS: [M+H] + =479.05.

[0220] 1 H NMR (400MHz, DMSO-d6): δ11.66 (s, 1H), 9.88 (s, 1H), 9.15-8.95 (m, 1H), 8.09-7.94 (m, 2H), 7.42 (s, 1H), 5.30 (d, J=10.0Hz, 1H), 3.78 (s, 3H), 3. 19 (s, 3H), 3.05 (s, 3H), 1.97 (s, 3H), 1.66 (dd, J=12.8, 5.2Hz, 1H), 1.49 (s, 3H), 1.35-1.28 (m, 2H), 1.23 (s, 1H), 1.18 (s, 3H), 0.82-0.72 (m, 1H).

[0221] Example 2 Preparation of Compound 2

[0222] 2.1 Preparation of Compound 2-1

[0223] Compound 2-a (3 g, 26.75 mmol) was dissolved in ultradry dichloromethane (40 mL), cooled to 0 °C, and purged with nitrogen three times. Oxaloyl chloride (6.79 g, 53.5 mmol) was then added, followed by the slow addition of N,N-dimethylformamide (0.2 g, 2.68 mmol). The mixture was stirred at room temperature for 1 hour. The temperature was lowered again to 0 °C, and N,N-diisopropylethylamine (8.9 g, 68.94 mmol) and dimethylhydroxylamine hydrochloride (2.6 g, 27.58 mmol) were added. The mixture was allowed to return to room temperature and reacted overnight. The reaction solution was concentrated, and the residue was dissolved in dichloromethane (100 mL) and water (20 mL). The aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-1 (2.76 g, yield: 77%). LC-MS: [M+H] + =156.05.

[0224] 2.2 Preparation of Compound 2-2

[0225] Compound 1-d (284.2 mg, 1.28 mmol) was dissolved in ultra-dry tetrahydrofuran (3 mL), purged with nitrogen three times, cooled to 0 °C, and isopropyl magnesium chloride-lithium chloride (316.04 mg, 2.18 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour, then cooled to 0 °C again, and compound 2-1 (100 mg, 0.64 mmol) was added. The mixture was allowed to react overnight at room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, and then extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 2-2 (50 mg, yield: 40%). LC-MS: [M+H] + =191.10.

[0226] 2.3 Preparation of compounds 2-3

[0227] Compound 2-2 (42 mg, 0.22 mmol) was dissolved in anhydrous ethanol (1 mL), and sodium acetate (36.09 mg, 0.44 mmol) and hydroxylamine hydrochloride (61.15 mg, 0.88 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was diluted with water (15 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3), and the organic phase was collected. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-3 (45 mg, yield: 99%). LC-MS: [M+H] + =206.05.

[0228] 2.4 Preparation of compounds 2-4

[0229] Compound 2-3 (41 mg, 0.20 mmol) was added to a reaction flask, followed by acetic acid (12.01 mg, 0.20 mmol) and zinc powder (78.49 mg, 1.20 mmol). The mixture was stirred at room temperature for 4 hours. The pH of the reaction solution was adjusted to 14 with saturated sodium hydroxide aqueous solution, and then extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (30 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 2-4 (35 mg, yield: 91%). LC-MS: [M+H] + =175.10.

[0230] 2.5 Preparation of Compound 2

[0231] Compounds 2-4 (30 mg, 0.16 mmol) were dissolved in anhydrous ethanol (0.2 mL), and N,N-diisopropylethylamine (41.36 mg, 0.32 mmol) and compounds 1-5 (58.62 mg, 0.19 mmol) were added. The mixture was stirred at 55 °C for 2 hours. The reaction solution was purified by high-performance liquid chromatography (under alkaline conditions) to give compound 2 (24.3 mg). LC-MS: [M+H] + =449.00;

[0232] 1 H NMR (400MHz, DMSO-d6): δ9.19 (s, 1H), 8.02 (t, 2H), 7.44 (s, 1H), 5.41 (d, 1H), 3.7 9(s, 3H), 3.18(s, 3H), 3.05(s, 3H), 2.53(s, 1H), 1.95(s, 3H), 1.64-1.70(m, 6H).

[0233] Example 3 Preparation of Compound 3

[0234] Compound 3 was prepared using the same method as Compound 2 in Example 2, except that the starting material was replaced with 3-a, yielding Compound 3 (30.2 mg). LC-MS: [M+H] + =469.15;

[0235] 1H NMR (400MHz, DMSO-d6): δ9.22 (d, J=9.2Hz, 1H), 8.01 (d, J=5.2Hz, 1H), 7.94 (s, 1H), 7.45 (s, 1H), 5.71 (d, J=8. 8Hz, 1H), 3.79 (s, 3H), 3.09 (d, J=44.4Hz, 6H), 2.50 (d, J=1.6Hz, 3H), 2.01 (d, J=9.2Hz, 3H), 1.96-1.92 (m, 6H).

[0236] Example 4: Preparation of Compound 4

[0237] 4.1 Preparation of compound 4-1

[0238] Compound 4-a (5.0 g, 29.4 mmol) was mixed in DCM (60 mL), and oxalyl chloride (7.46 g, 58.8 mmol) and DMF (42.9 mg, 0.59 mmol) were added at room temperature. The resulting reaction solution was stirred at room temperature for 2 hours, and then the reaction solution was concentrated under reduced pressure to obtain compound 4-1 (4.7 g, crude product), which was used directly in the next step.

[0239] 4.2 Preparation of compound 4-2

[0240] Sodium pyrithione (4.12 g, 32.4 mmol), azobisisobutyronitrile (204.6 mg, 1.25 mmol), and DMAP (30.4 mg, 0.25 mmol) were mixed in carbon tetrachloride (75 mL). The reaction mixture was stirred at 80 °C for 30 minutes. Then, a carbon tetrachloride solution of compound 4-1 (4.7 g, 24.9 mmol) in carbon tetrachloride (12.5 mL) was added dropwise, and the reaction mixture was continued at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, and hydrochloric acid (1 M, 50 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 4-2 (4.7 g, crude product).

[0241] 4.3 Preparation of compound 4-3

[0242] Compound 4-2 (500 mg, 3.11 mmol) and concentrated sulfuric acid (2.80 g, 27.9 mmol, 98% purity) were mixed in THF (8 mL) and water (8 mL), and the resulting reaction solution was stirred at 50 °C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 4-3 (220 mg, yield: 48.21%).

[0243] 4.4 Preparation of Compound 4

[0244] Compound 4 was prepared using the same method as Compound 2 in Example 2, except that the starting material was replaced with 4-3, yielding Compound 4 (51.6 mg, yield: 49.80%). LCMS: [M+H] + =485.10;

[0245] 1 H NMR (400MHz, DMSO-d6): δ9.17 (s, 2H), 7.91 (d, J=4.8Hz, 1H), 7.74 (d, J=4.4Hz, 1H), 7.42 (s, 1H), 5. 58 (s, 1H), 3.75 (s, 3H), 2.99 (d, J=11.2Hz, 6H), 2.50-2.47 (m, 2H), 2.11-2.02 (m, 5H), 1.92 (s, 2H).

[0246] Example 5: Preparation of Compound 5

[0247] Compound 5 was prepared using the same method as Compound 2 in Example 2, except that the starting material was replaced with 5-a, yielding Compound 5 (56.8 mg, yield: 47.47%). LC-MS: [M+H] + =519.10;

[0248] 1 H NMR (400MHz, DMSO-d6): δ9.21-9.19 (d, J=8.0Hz, 1H), 8.03-8.02 (d, J=4.0Hz, 1H), 7.95 (s, 1H), 7.47 (s, 1H), 5.53-5. 51 (d, J=8.0Hz, 1H), 3.80 (s, 3H), 3.16 (s, 3H), 3.04 (s, 3H), 1.95-1.93 (d, J=8.0Hz, 3H), 1.88-1.86 (d, J=8.0Hz, 3H).

[0249] Example 6: Preparation of single crystals of compound 1B-1 monohydrate

[0250] Take about 20 mg of compound 1B-1 in a 10 mL clean sample vial, add 2 mL of dichloromethane and sonicate to dissolve. After filtering with a 0.45 μm organic PTFE filter membrane, add 6 mL of acetonitrile and shake to mix. Seal with aluminum foil and then make two vent holes with a 1 mL syringe needle for solvent evaporation. After placing in a dark and stable place at room temperature for 10 days, seal and send for testing.

[0251] Example 7 Single-crystal diffraction analysis of compound 1B-1 monohydrate

[0252] Testing instrument and model: D8 Venture

[0253] Instrument parameters:

[0254] Light source: Cu target X-ray Cu-Kα

[0255] Detector: CMOS surface detector; Resolution:

[0256] Current and voltage: 50kV, 1.2mA; Exposure time: 1s

[0257] Distance from surface detector to sample: 40 mm; Test temperature: 173(2) K

[0258] Figure 1 shows the thermo-ellipsoidal diagram of the molecular stereostructure of compound 1B-1 monohydrate. The crystal structure data are summarized in Table 1.

[0259] Table 1 Crystal structure data of compound 1B-1 monohydrate

[0260] Structural analysis and refinement process:

[0261] After integrating and restoring the diffraction data using the SAINT program, empirical absorption correction was performed on the data using the SADABS program. The single crystal structure was analyzed by direct method using SHELXT2014, and the structure was refined using least squares method. The hydrogen atom refinement process was obtained by isotropic calculation, and the hydrogen atoms on CH were obtained by calculated hydrogen addition, and the structure was refined using a riding model. The Flack constant is -0.08(12). In Figure 1, C1 and C4 are S configurations, and C3 and C8 are R configurations.

[0262] Biological activity test

[0263] 1. Screening experiment on calcium flux activity of the compounds of this invention

[0264] 1.1 Screening for human CCR6 calcium flux activity

[0265] Compound activity was evaluated using HEK293 cells stably expressing human CCR6 via the FLIPR platform. Cells were seeded at a density of 20,000 cells / well in 384-well black cell culture plates (Greiner, 781946) and incubated overnight at 37°C with 5% CO2. The culture medium was removed from the wells, and 20 μL of Fluo-4 Direct was added to each well. TM Calcium content assay buffer (Invitrogen, F10471, component C), 20 μL 2×Fluo-4 Direct TM Calcium content assay reagent (Invitrogen, F10471, component A) working solution and 10 μL of 6× analyte working solution were prepared. The cell plate was incubated at 37°C with 5% CO2 for 50 min, followed by incubation at room temperature for 10 min. Additionally, 6× EC was prepared. 80 After incubation, transfer 10 μL / well of human MIP-3 alpha / CCL20 (MCE, HY-P7262) working solution to 6×EC via FLIPR instrument. 80 Human MIP-3 alpha / CCL20 working solution was applied to cell plates, and the changes in fluorescence signals at excitation wavelength of 494 nm and emission wavelength of 516 nm were recorded within 90 seconds. The maximum fluorescence signal (RFU) was used as the criterion. Max ) and minimum fluorescence signal (RFU) Min The difference between the values ​​is taken as the output signal. The log values ​​of the compound inhibition rate and compound concentration are calculated. Four-parameter fitting analysis is performed using GraphPad Prism 8 software to obtain the IC50 of the test compound. 50 value.

[0266] 1.2 Screening for calcium flux activity in human CXCR2

[0267] Compound activity was evaluated using HEK293 cells stably expressing human CXCR2 via the FLIPR platform. Cells were seeded at a density of 20,000 cells / well in 384-well black cell culture plates (Greiner, 781946) and incubated overnight at 37°C with 5% CO2. The culture medium was removed from the wells, and 20 μL of Fluo-4 Direct was added to each well. TM Calcium content assay buffer (Invitrogen, F10471, component C), 20 μL 2×Fluo-4 Direct TMCalcium content assay reagent (Invitrogen, F10471, component A) working solution and 10 μL of 6× analyte working solution were prepared. The cell plate was incubated at 37°C with 5% CO2 for 50 min, followed by incubation at room temperature for 10 min. Additionally, 6× EC was prepared. 80 After incubation, transfer 10 μL / well of human IL-8 (Sigma, SRP3311) working solution to 6×EC using a FLIPR instrument. 80 Human IL-8 working solution was applied to corresponding cell wells, and the changes in fluorescence signals at excitation wavelengths of 494 nm and emission wavelengths of 516 nm were recorded over 130 seconds. The maximum fluorescence signal (RFU) was used as the criterion. Max ) and minimum fluorescence signal (RFU) Min The difference between the values ​​is taken as the output signal. The log values ​​of the compound inhibition rate and compound concentration are calculated. Four-parameter fitting analysis is performed using GraphPad Prism 8 software to obtain the IC50 of the test compound. 50 value.

[0268] The test results for 1.1 and 1.2 above are shown in Table 2.

[0269] Table 2. Inhibitory activity data of the compounds of the present invention against CCR6 and CXCR2.

[0270] Experimental conclusion: The compound of this invention has a good inhibitory effect on CCR6 and good selectivity relative to CXCR2.

[0271] 2. In vivo pharmacokinetic studies of the compounds of this invention

[0272] 2.1 Experimental Apparatus

[0273] The specifics are shown in Table 3.

[0274] Table 3 Experimental Instruments

[0275] 2.2 Experimental Preparation

[0276] 2.2.1 Laboratory Animals

[0277] Rats: SD rats, SPF grade, 3 males per group;

[0278] Beagles: 3 per group, males.

[0279] 2.2.2 Rearing conditions:

[0280] SD rats: housed in a standard animal facility with free access to food and water, 3 rats per cage, with a 12 / 12-hour light / dark cycle (7:00 am / 7:00 pm), and a temperature of 23±1℃.

[0281] Beagle: Standard animal housing, single cage, free access to water, 150g of food in the morning and 100g in the afternoon, fed twice a day, 12 hours of light (7 am to 7 pm), temperature 23±5℃.

[0282] 2.2.3 Medication preparation steps:

[0283] Rat PO experimental group: After accurately weighing the compound, add the required volume of DMSO, vortex for 10s to mix, then add the required volume of Solutol HS15, vortex for 10s, then add the required volume of pure water, stir magnetically for 1min, and prepare a homogeneous drug solution of 0.1mg / mL. Take the middle layer of the drug solution for administration.

[0284] In rat IV experimental group: After accurately weighing the compound, add the required volume of DMSO, vortex for 10s to mix, then add the required volume of Solutol HS15, vortex for 10s, then add the required volume of pure water, stir magnetically for 1min, and prepare a homogeneous drug solution of 0.4mg / mL. Take the middle layer of the drug solution for administration.

[0285] Canine PO experimental group: After accurately weighing the compound, add 5% of the required volume of DMSO, vortex until dissolved, then add 10% of the required volume of Solutol HS15, vortex mix, then add 85% of the required volume of purified water, stir magnetically to clarify, and prepare a homogeneous drug solution of 0.6 mg / mL. Take the middle layer of the drug solution for administration.

[0286] Canine IV experimental group: After accurately weighing the compound, add 5% of the required volume of DMSO, vortex until dissolved, then add 10% of the required volume of Solutol HS15 and vortex to mix, then add 85% of the required volume of physiological saline, stir magnetically to clarify, and prepare a homogeneous drug solution of 1 mg / mL. Take the middle layer of the drug solution for administration.

[0287] 2.3 Dosing regimen:

[0288] Rats were randomly divided into groups of three based on body weight, with each compound administered via either a PO (potentially purgative) route (fasting overnight but allowing free water, followed by food return 4 hours after administration) or an IV (potentially purgative) route (fasting and allowing free water throughout administration). Blood samples were collected at 0.167 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h for the PO group of compound 1; and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h for the PO group of compound 1B-1. Similarly, blood samples were collected at 0.033 h, 0.167 h, 1 h, 2 h, 4 h, 6 h, and 8 h for the IV group of compound 1; and at 0.033 h, 0.167 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h for the IV group of compound 1.

[0289] Dogs were randomly divided into groups of 3 based on their body weight. Each compound was administered via single gavage (PO, fasting before administration but water allowed) or single intravenous administration (IV, fasting and water allowed throughout administration). Blood samples were collected at 0.083h, 0.167h, 0.5h, 1h, 2h, 3h, 4h, 6h, 9h, and 24h in the PO and IV administration groups.

[0290] 2.4 Sample Collection and Preparation

[0291] After administration to rats, blood was collected from the orbital venous plexus at sampling time points. Approximately 0.2-0.3 mL of blood was collected at each time point into an anticoagulant EP tube (containing 4 μL of EDTA-K2, 375 mg / mL). The tube was slowly inverted three times and stored in an ice box (for no more than 30 minutes). The tube was centrifuged at 3500 × g for 10 minutes at 4°C. The supernatant was transferred to a labeled EP tube for bioanalytical analysis. If the sample could not be tested on the same day, it should be stored at -80°C until testing (note that repeated freezing / thawing should be avoided).

[0292] After administration to dogs, at each time point, approximately 1.0 mL of whole blood was collected from the peripheral blood vessels of the non-administered limb of each animal and injected into EP tubes containing EDTA-K2 anticoagulant. The EP tubes containing whole blood were immediately shaken twice to mix thoroughly and then placed on a tube rack on wet ice or an ice pack. The tubes were centrifuged at 3000×g at 4℃ for 10 minutes within 1 hour. The supernatant was collected and placed in an environment of -75±15℃ until analysis was performed (note that multiple freezing / thawing processes should not be performed).

[0293] 2.5 Sample Analysis and Data Analysis

[0294] The data will be analyzed using WinNonlin via a non-compartmental model to obtain PK parameters (Cp selected based on different routes of administration). max AUC 0-last T 1 / 2(Parameters such as oral bioavailability F). Please see Tables 4 and 5 for specific data.

[0295] Table 4. PK test results of the compounds of this invention on SD rats.

[0296] Table 5. PK test results of the compounds of this invention compared with those of a dog.

[0297] N / A: The fitted data is inaccurate; the mean was not calculated.

[0298] Experimental conclusion: The compounds of this invention can achieve high in vivo exposure and high oral bioavailability at low doses, and have superior overall pharmacokinetic properties.

[0299] 3. In vitro hepatic microsomal metabolic stability experiment of the compounds of this invention.

[0300] Experimental methods:

[0301] 3.1 Preparations before the experiment

[0302] 3.1.1 Preparation of standard solutions:

[0303] Preparation of working solution for test compound: Accurately weigh an appropriate amount of the compound, add the corresponding volume of DMSO to dissolve it, and prepare a 1mM stock solution of the test compound. Then dissolve it in methanol to a 100μM working solution of the test compound. Note that the DMSO content in the working solution should be below 10%.

[0304] 3.1.2 Preparation of internal standard working solution:

[0305] The internal standard compound, testosterone (or tolbutamide), and its corresponding solvent and internal standard concentration (200 ng / mL) are selected based on the properties of the test compound.

[0306] 3.1.3 Preparation of 0.1 mol / L potassium phosphate buffer solution (pH 7.4)

[0307] Solution A: 0.1 mol / L K2HPO4 (2.28 g K2HPO4·3H2O dissolved in 100 mL double-distilled water);

[0308] Solution B: 0.1 mol / L KH2PO4 (1.36 g KH2PO4 dissolved in 100 mL double-distilled water);

[0309] Take 80.2 mL of solution A and 19.8 mL of solution B, mix them thoroughly, and adjust the pH value to 7.4 to obtain the final solution.

[0310] 3.1.4 Preparation of 5 mmol / L glycine buffer

[0311] Weigh 37.5 mg of glycine, dissolve it in 100 mL of ultrapure water, and adjust the pH to 8.0 with NaOH.

[0312] 3.1.5 Preparation of 500 U / mL glucose-6-phosphate dehydrogenase

[0313] Weigh 1.25 mg of glucose-6-phosphate dehydrogenase (400 U / mg) (the exact amount to be weighed depends on the activity of the glucose-6-phosphate dehydrogenase purchased), dissolve it in 1 mL of glycine buffer to a concentration of 500 U / mL, aliquot into 20 μL tubes, and store at -20℃ for later use.

[0314] 3.1.6 Preparation of cofactor solution

[0315] Accurately weigh NADP (7.83 mg), D-6-phosphate glucose (260 mg / mL, 0.06 mL), and MgCl2·6H2O (10.17 mg) and dissolve them in 1 mL of pure water. Cofactor composition: NADP (10 mM), D-6-phosphate glucose (60 mM), MgCl2·6H2O (50 mM).

[0316] 3.2 Experimental Section

[0317] 3.2.1 Incubation Experiment

[0318] The reaction system (taking a 500 μL system as an example) consists of the following solution ratios: 416.5 μL phosphate buffer, 5 μL compound working solution, 25 μL liver microsomes, 3.5 μL glucose-6-phosphate dehydrogenase, and 50 μL cofactor solution. The total incubation volume can be adjusted according to experimental requirements.

[0319] Add 25 μL of liver microsomes, 3.5 μL of glucose-6-phosphate dehydrogenase, and 50 μL of cofactor solution to 416.5 μL of phosphate buffer. Vortex twice to mix and incubate in a 37°C water bath for 5 min. Then add 5 μL of the working solution of the test compound and vortex twice for 2-3 seconds each time. Incubate in a 37°C water bath to start the reaction. Set up two parallel samples. At 0 min, 2 min, 5 min, 15 min, 30 min, 60 min, 90 min, and 120 min after the reaction, add 50 μL of the solution to a centrifuge tube containing 200 μL of pre-cooled internal standard working solution at 0°C. Terminate the reaction, vortex to mix for 1 min, and centrifuge at 13000 rpm for 10 min in a high-speed centrifuge pre-cooled at 4°C. Collect the supernatant for analysis. After adding the compound and shaking to mix, quickly add 50 μL to a centrifuge tube containing 200 μL of pre-cooled internal standard working solution at 0℃ to terminate the reaction. Vortex to mix for 1 min, and use this as the relative zero-point sample (relative standard group). Then place the sample in a 37℃ water bath to start the reaction and begin timing.

[0320] 3.3 Sample Analysis

[0321] Sample analysis of the test compounds was performed using liquid chromatography-tandem mass spectrometry (LCMS / MS). Semi-quantitative determination was performed using the ratio of analyte peak area to internal standard peak area. Retention times of the analyte and internal standard, chromatographic acquisition, and chromatographic integration were processed using Analyst software.

[0322] 3.4 Data Analysis

[0323] The in vitro elimination rate constant k of the test compound is obtained by converting the ratio of the peak area of ​​the test compound to that of the internal standard into a residual rate. Then, T is calculated according to the following formula. 1 / 2 .

[0324] See Table 6 for specific data.

[0325] Table 6. Results of hepatic microsomal metabolic stability experiments of the compounds of this invention.

[0326] Experimental conclusion: The compounds of this invention exhibit good metabolic stability in human liver microsomes.

[0327] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. A compound represented by formula (I), a racemate, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate of the compound represented by formula (I): ###00001### (I) ​ wherein, R1is H or C 1-6 alkyl; R2is C 4-12 bridged cycloalkyl or 4-12 membered bridged heterocycloalkyl, wherein the C 4-12 bridged cycloalkyl and 4-12 membered bridged heterocycloalkyl are optionally substituted with 1, 2, or more R 2-1 substituents; each R is independently H, halogen, deuterium, C 2-1 is independently H, halogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 haloalkyl; R3is 5-membered heteroaryl, 7-12-membered heteroaryl, or C 6-10 aryl, wherein the 5-membered heteroaryl, 7-12-membered heteroaryl, and C 6-10 aryl are optionally substituted with 1, 2, or more R 3-1 substituents; each R is independently H, -CN, -OH, -NH2, oxo (=0), halogen, C 3-1 is independently H, -CN, -OH, -NH2, oxo (=0), halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-8 membered heterocycloalkyl are optionally substituted with 1, 2, or more substituents independently selected from halogen and deuterium; each R is independently H, -CN, halogen, C 1-6 haloalkyl or C 1-6 alkyl; n is 0, 1 or 2; X is N or CR5; R5is H, -CN, halogen, C 1-6 haloalkyl or C 1-6 alkyl; R4is -C(=O)NR m R n , 5-7 membered heteroaryl, 3-7 membered heterocyclyl, -NR x C(=O)R y , -S(=O)(=NR v )R w or -C(=O)R z wherein said 5-7 membered heteroaryl and 3-7 membered heterocyclyl are optionally substituted with 1, 2, or more R 4-1 ; Each R 4-1 Independently, it is halogen, deuterium, oxo (=O), C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m and R n each independently H, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or more deuterium; R x is H or C 1-6 alkyl; R y is C 1-6 alkyl; R z is C 1-6 alkyl, C 1-6 haloalkyl or 4-10 membered heterocycloalkyl, wherein said 4-10 membered heterocycloalkyl is optionally substituted with 1, 2 or more R z-1 substituents; each R is independently halogen, oxo (=0) or C z-1 independently halogen, oxo (=0) or C 1-6 alkyl; R v and R w each independently H or C 1-6 alkyl.

2. The compound according to claim 1, its racemate, stereoisomer or their pharmaceutically acceptable salts, or solvate of the compound according to claim 1, characterized in that, which satisfies one or more of the following conditions: (1) R1is H or methyl; (2) R2is the following Scheme 1 or Scheme 2: Scheme 1: R2is C 4-12 cycloalkyl or 4-12 membered bridged heterocycloalkyl, wherein the C 4-12 cycloalkyl and 4-12 membered bridged heterocycloalkyl are optionally substituted with 1, 2, or more R 2-1 substituents; Scheme 2: R2is a C6bridged alkyl group, which is substituted by 1 or 2 R 2-1 substituents; (3) each R 2-1 is independently Scheme 1 or Scheme 2: Scheme 1: each R 2-1 independently H, F, Cl, Br, deuterium, methyl, ethyl, n-propyl, i-propyl, methoxy, -CH2F, -CHF2, or -CF3; Scheme 2: each R 2-1 independently methyl, ethyl, n-propyl or i-propyl; (4) R3is the following Scheme 1 or Scheme 2: Scheme 1: R3is a 5-membered heteroaryl or phenyl, wherein the 5-membered heteroaryl and phenyl are optionally substituted with 1, 2, 3, or 4 R 3-1 substituents; Scheme 2: R3is a 5-membered heteroaryl, which is substituted by 1, 2, or 3 R 3-1 substituents; (5) each R 3-1 is independently Scheme 1 or Scheme 2: Scheme 1: each R 3-1 independently H, -CN, -OH, -NH2, oxo (=0), F, Cl, Br, methyl, ethyl, cyclopropyl, -CH2F, -CHF2, -CF3, or -CD3; Scheme 2: each R 3-1 independently methyl or ethyl; (6) R m and R n each independently H, methyl, ethyl, -CD3, n-propyl, i-propyl, -CF3, -CH2CH2F, -CH2CHF2, or -CH2CF3; (7) R x is H or methyl; R y is methyl or ethyl; (8) R v is H, methyl or ethyl; R w is methyl or ethyl; (9) R z is C 1-3 alkyl, C 1-3 haloalkyl or 5-8 membered heterocycloalkyl, wherein said 5-8 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R z-1 substituents; (10) each R z-1 independently F, CI, oxo (=0), methyl or ethyl; (11) in R4, the 5-7 membered heteroaryl is pyrazolyl, pyrrolyl, imidazolyl, triazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or pyridyl, wherein the pyrazolyl, pyrrolyl, imidazolyl, triazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and pyridyl are optionally substituted with 1, 2, 3, or 4 R 4-1 substituents; (12) in R4, the 3-7 membered heterocyclyl is oxetanyl, azetidinyl, pyrrolidinyl, or tetrahydrofuranyl, wherein the oxetanyl, azetidinyl, pyrrolidinyl, and tetrahydrofuranyl are optionally substituted with 1, 2, or more R 4-1 substituents; (13) each R 4-1 independently F, CI, deuterium, oxo (=0), methyl, ethyl, or -CF3; (14) each R is independently H, -CN, F, Cl, -CH3or -CH2F; (15) R5is H, -CN, F, Cl, -CH3or -CH2F; (16) X is N, CH, C(CN), CF, C(Cl), C(CH3) or C(CH2F); (17) n is 0 or 1.

3. The compound according to claim 1, its racemate, stereoisomer or pharmaceutically acceptable salt thereof, or solvate of the compound according to claim 1, characterized in that, which satisfies one or more of the following conditions: (1) R1is H; (2) R2is the following Scheme 1 or Scheme 2: Scheme 1: R2is C 4-8 cycloalkyl or 4-8 membered bridged heterocycloalkyl, wherein the C 4-8 cycloalkyl and 4-8 membered bridged heterocycloalkyl are optionally substituted with 1, 2, or more R 2-1 substituents; Scheme 2: R2is bicyclo[3.1.0]hexyl, which bicyclo[3.1.0]hexyl is substituted with 1 R 2-1 substituents; (3) R 2-1 is methyl; (4) R3is the following Scheme 1 or Scheme 2: Scheme 1 : R3is pyrazolyl, pyrrolyl, imidazolyl, triazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or phenyl, wherein the pyrazolyl, pyrrolyl, imidazolyl, triazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and phenyl are optionally substituted with 1, 2, 3, or 4 R 3-1 substituents; Scheme 2: R3is a pyrazolyl group, which is substituted by 1, 2, or 3 R 3-1 substituents; (5) R 3-1 is methyl; (6) R m and R n each independently is methyl, ethyl, -CD3, or -CF3; (7) R z To (8) R4is the following Scheme 1 or Scheme 2: Scheme 1: R4is Scheme 2: R4is -C(=O)NR m R n ; (9) n is 0.

4. The compound according to claim 1, its racemate, stereoisomer or pharmaceutically acceptable salt thereof, or solvate of the compound according to claim 1, characterized in that, which satisfies one or more of the following conditions: (1) R2is bicyclo[l. l.0]butyl, bicyclo[2. l.0]pentyl, bicyclo[l. l. l]pentyl, bicyclo[3. l.0]hexyl, bicyclo[2. l. l]hexyl, bicyclo[4. l.0]heptyl, bicyclo[2.

2. l]heptyl, bicyclo[3. l. l]heptyl, bicyclo[3.

2. l]octyl, bicyclo[3.3.0]octyl, bicyclo[3.

2. l]octyl, l -azabicyclo[2. l. l]hexyl, 5-oxabicyclo[2. l. l]hexyl, 3-oxabicyclo[3. l.0]hexyl, 2-azabicyclo[2.

2. l]heptyl, 2-oxa-5-azabicyclo[2.

2. l]heptyl, 3,7-diazabicyclo[3.3.0]octyl, 8-azabicyclo[3.

2. l]octyl, 3-oxa-8-azabicyclo[3.

2. l]octyl, or 3-azabicyclo[3.

2. l]octyl, wherein the bicyclo[l. l.0]butyl, bicyclo[2. l.0]pentyl, bicyclo[l. l. l]pentyl, bicyclo[3. l.0]hexyl, bicyclo[2. l. l]hexyl, bicyclo[4. l.0]heptyl, bicyclo[2.

2. l]heptyl, bicyclo[3. l. l]heptyl, bicyclo[3.

2. l]octyl, bicyclo[3.3.0]octyl, bicyclo[3.

2. l]octyl, l -azabicyclo[2. l. l]hexyl, 5-oxabicyclo[2. l. l]hexyl, 3-oxabicyclo[3.1.0]hexyl, 2-azabicyclo[2.

2. l] heptyl, 2-oxa-5-azabicyclo[2.2.l]heptyl, 3,7-diazabicyclo[3.

3. 0]octyl, 8-azabicyclo[3.

2. l] octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, and 3-azabicyclo[3.

2. l]octyl are optionally substituted with 1, 2, or more R 2-1 substituents; (2) R3is the following Scheme 1 or Scheme 2: Scheme 1: R3is Scheme 2: R3is (3) R m and R n each independently is methyl or ethyl.

5. The compound according to claim 1, its racemate, stereoisomer or pharmaceutically acceptable salt thereof, or solvate of the compound according to claim 1, characterized in that, which satisfies one or more of the following conditions: (1) R2is the following Scheme 1 or Scheme 2: Scheme 1: Scheme 2: R2is (2) R m and R n each independently methyl; (3) R4 is 6. The compound according to claim 1, racemate, stereoisomer or pharmaceutically acceptable salt thereof, or solvate of the compound according to claim 1, characterized in that, R2satisfies any of the following Schemes: Scheme 1: R2is Scheme 2: R2is Scheme 3: R2is 7. The compound according to at least one of claims 1 to 6, its racemate, its stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate of the compound according to at least one of claims 1 to 6, characterized in that The compound represented by formula (I) satisfies any of the following Schemes: Scheme 1: Compounds of formula (I) have the following structure of formula (I-1): wherein n, R, R1, R2, R3and R4each independently have the definition described in at least one of claims 1-6; Scheme 2: Compounds of formula (I) have the following structure of formula (I-2) wherein R m , R n , n, R, R2and R3each independently have the definitions described in at least one of claims 1 to 6; Scheme 3: Compounds of formula (I) have the structure according to any one of formulae (I-3) to (I-7): wherein m is 1, 2 or 3, q and p are each independently 1, 2, 3 or 4, x and z are each independently 0, 1, 2, 3 or 4, k and y are each independently 0, 1, 2 or 3; W and V are each independently C(R 2-1 ) or N; U is -C(R 2-1 )2-, -0-, -S- or -N(R 2-1 )-; R m , R n , n, R, R3and R 2- 1 each independently have the definitions described in at least one of claims 1 to 6. Scheme 4: Compounds of formula (I) have the structure according to formula (I-3-1) wherein R m and R n each independently is methyl, ethyl, -CD3, or -CF3; R3is pyrazolyl optionally substituted with 1, 2, or 3 R 3-1 each independently is methyl, ethyl, -CD3, or -CF3; R3is pyrazolyl optionally substituted with 1, 2, or 3 R 3-1 each independently is methyl, ethyl, -CD3, or -CF3; R3is pyrazolyl optionally substituted with 1, 2, or 3 R 2-1 each independently is H, F, Cl, Br, deuterium, methyl, ethyl, n-propyl, i-propyl, methoxy, -CH2F, -CHF2, or -CF3; Scheme 5: Compounds of formula (I) having the following formula (I-1-a) or (I-1-h): wherein n, R, R1, R2, R3and R4each independently has the definition described in at least one of claims 1-6; Scheme 6: Compounds of formula (I) have the following formula (I-2-a) or (I-2-b): wherein R m , R n , n, R, R2and R3each independently have the definitions described in at least one of claims 1 to 6; Scheme 7: Compounds of formula (I) have the structure according to any one of the following formulae (I-3-a) to (I-7-b): wherein m is 1, 2 or 3, q and p are each independently 1, 2, 3 or 4, x and z are each independently 0, 1, 2, 3 or 4, k and y are each independently 0, 1, 2 or 3; W and V are each independently C(R 2-1 ) or N; U is -C(R 2-1 )2-, -0-, -S- or -N(R 2-1 )-; R m , R n , n, R, R3and R 2- 1 each independently have the definitions described in at least one of claims 1 to 6. Scheme 8: Compounds of formula (I) have the structure according to formula (I-3-1-m) or (I-3-1-n) wherein R m and R n are each independently methyl, ethyl, -CD3, or -CF3; R3is pyrazolyl optionally substituted with 1, 2, or 3 R 3-1 groups; each R 3-1 is independently methyl, ethyl, cyclopropyl, -CH2F, -CHF2, -CF3, or -CD3; R 2-1 is independently H, F, Cl, Br, deuterium, methyl, ethyl, n-propyl, i-propyl, methoxy, -CH2F, -CHF2, or -CF3; Scheme 9: Compounds of formula (I) have the structure according to any one of the following formulae (I-3-a-1) to (I-3-b-2): wherein R m and R n each independently is methyl, ethyl, -CD3, or -CF3; R3is pyrazolyl optionally substituted with 1, 2, or 3 R 3-1 each independently is methyl, ethyl, -CD3, or -CF3; R3is pyrazolyl optionally substituted with 1, 2, or 3 R 3-1 each independently is methyl, ethyl, -CD3, or -CF3; R3is pyrazolyl optionally substituted with 1, 2, or 3 R 2-1 each independently is H, F, Cl, Br, deuterium, methyl, ethyl, n-propyl, i-propyl, methoxy, -CH2F, -CHF2, or -CF3.

8. The compound according to at least one of claims 1 to 7, its racemate, its stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate of the compound according to at least one of claims 1 to 7, characterized in that, The compound represented by formula (I) satisfies the following Scheme 1 or Scheme 2: Scheme 1 : Compounds of formula (I) have the structure shown below: Scheme 2: Compounds of formula (I) have the structure shown below:

9. The compound according to claim 1, racemate, stereoisomer or pharmaceutically acceptable salt thereof, or solvate of the compound according to claim 1, characterized in that, The solvate of the compound has a structure represented by the following formula (I-3-1-S):

10. The compound according to claim 9, its racemate, stereoisomer or pharmaceutically acceptable salt thereof, or solvate of the compound according to claim 9, characterized in that, The solvate is in a crystalline form, the crystal system of the crystalline form is tetragonal, the space group is P43, and the unit cell parameters are:

11. A process for the preparation of a compound according to at least one of claims 1 to 8, a racemate, a stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate of a compound according to at least one of claims 1 to 8, comprising the following steps: The compound Int-1 is reacted with the compound Int-2 to obtain the compound represented by formula (I); wherein R1, R2, R3, R4, R, X and n each independently have the definition described in at least one of claims 1 to 8, R0is C 1-6 alkyl; preferably, R0is methyl or ethyl.

12. A compound of formula Int-2: wherein R1, R2and R3each independently has the definition described in at least one of claims 1-8.

13. The compound of claim 12, represented by Formula Int-2, wherein The compound of Formula Int-2 is selected from the following compounds:

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound, a racemate, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a solvate of the compound described in at least one of claims 1-10, and a pharmaceutically acceptable carrier.

15. Use of a compound, a racemate, a stereoisomer thereof or a pharmaceutically-acceptable salt thereof, or a solvate of the compound described in at least one of claims 10, or a pharmaceutical composition of claim 14, in the manufacture of a medicament for the diagnosis, prevention and / or treatment of a disease or a condition, which satisfies any of the following Schemes: Scheme 1: the disease or the condition is a CCR6 receptor-mediated disease or condition; Scheme 2: the disease or the condition is a CCR6 receptor-mediated allergic disease, psoriasis, contact hypersensitivity, Sjogren's syndrome, dry eye or multiple sclerosis; Scheme 3: The disease or condition is CCR6 receptor mediated rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, oligoarticular rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis, psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis, juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis resulting from an inflammatory disease; Scheme 4: The disease or condition is CCR6 receptor mediated inflammatory bowel disease, Crohn's disease, or ulcerative colitis.

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