AT2R agonists

Abstract

The present disclosure relates to the field of medicine, specifically, the present disclosure provides a compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs, which can be used as agonists of the AT2 receptor. JPEG2025511239000238.jpg59170I

Description

[Technical field]

[0001] The present disclosure relates to the field of medicine, specifically, the present disclosure relates to angiotensin II (AngII) type 2 receptor (AT2R) agonists. [Background technology]

[0002] Idiopathic pulmonary fibrosis (IPF) refers to the abnormal repair of damaged alveolar epithelial cells, the proliferation and transformation of pulmonary fibroblasts into myofibroblasts, the excessive secretion of extracellular matrix, the deposition of collagen, the change in alveolar structure, and finally the formation of fibrosis. The pathogenesis of IPF has not yet been fully elucidated, and current research suggests that it is closely related to oxidative stress, inflammatory response, and the regulation of the renin-angiotensin-aldosterone system (RAAS) by body fluids. At present, the RAAS system plays an important role in the process of pulmonary fibrosis, and angiotensin converting enzyme (ACE) can hydrolyze angiotensin I (AngI) to angiotensin II (AngII), and AngII is thought to play an important role in the occurrence and development of various inflammations.

[0003] In humans, two major Ang II receptors have been identified, named Ang II type 1 receptor (AT1 receptor) and Ang II type 2 receptor (AT2 receptor). Ang II exerts these physiological actions of regulating blood pressure, fluid and electrolyte balance in many organs, such as the kidney, adrenal gland, heart, blood vessels, brain, gastrointestinal and reproductive organs. The effects of Ang II are regulated and controlled by the balance of expression of two G protein-coupled receptors (GPCRs), AT1R and AT2R. AT1R is expressed throughout the life cycle and is mainly responsible for blood pressure regulation, and its blockers are widely used as antihypertensive drugs in clinical practice, while AT1R controls many of the physiological actions of Ang II. AT2R is mainly expressed in embryonic tissues and is related to blood pressure regulation control, nerve growth, pain control and myocardial regeneration, and drugs targeting AT2R can contribute to improving cardiovascular function, relieving neuropathic pain, etc. However, in pathological situations such as vascular injury, wound healing and heart failure, the expression of AT2R is obviously increased.

[0004] Several studies in adult individuals appear to demonstrate that AT2 receptor activation has the opposite effect to that of AT1 receptors in modulating responses following AngII stimulation.

[0005] It has been shown that the AT2 receptor is involved in the inhibition of apoptosis and cell proliferation. Recently, AT2 receptor agonists may be used for the treatment and / or prevention of gastrointestinal disorders, such as dyspepsia and irritable bowel syndrome, and multiple organ failure (see International Patent Application WO99 / 43339).

[0006] There remains a need for effective and / or selective AT2 receptor agonists, which are expected to be useful in the above-mentioned diseases. Summary of the Invention [Problem to be solved by the invention]

[0007] The present disclosure aims to solve one of the technical problems in the related art to a certain extent.Therefore, an object of the present disclosure is to provide a heterocyclic compound as an AT2 receptor agonist and its use, the heterocyclic compound having the structure shown in the first aspect of the present disclosure, the heterocyclic compound can be used to prepare a drug, pharmaceutical composition or preparation for treating and / or preventing a disease or pathology associated with AT2R, or to treat and / or prevent a disease or pathology associated with AT2R. [Means for solving the problem]

[0008] Thus, a first aspect of the disclosure provides a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt, or prodrug thereof,

[0009] [ka] I Ring B is selected from a benzene ring or a 5- or 6-membered heteroaromatic ring; Ring B is a benzene ring; R6 is hydrogen; m is selected from 1, 2, 3, or 4; L is a C1-C6 alkyl group unsubstituted or substituted with one or more substituents, each substituent being independently selected from halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, and oxo (=O); when there are multiple substituents, the substituents are the same or different; Alternatively, ring B is a benzene ring, R6 is hydrogen, and m is selected from 0; L is a C1-C6 alkyl group substituted with one or more substituents, each substituent being independently selected from halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, and oxo (=O); and when there are multiple substituents, the substituents are the same or different; Alternatively, ring B is a benzene ring, R6 is selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, -O-C3-C7 cycloalkyl, m is selected from 0, 1, 2, 3, or 4, L is a C1-C6 alkyl group unsubstituted or substituted with one or more substituents, each substituent is independently selected from halogen, C1-C6 alkyl, C1-C6 halogenated alkyl, and oxo (=O), R6 is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C3-C7 cycloalkyl, and when there are multiple substituents, the substituents are the same or different; Alternatively, when ring B is a 5-6 membered heteroaromatic ring, m is selected from 0, 1, 2, 3 or 4; L is a C1-C6 alkyl group unsubstituted or substituted with one or more substituents, each substituent being independently selected from halogen, C1-C6 alkyl group, C1-C6 halogenated alkyl group, and oxo (=O); R6 is hydrogen or selected from halogen, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, C3-C7 cycloalkyl group, C1-C6 alkoxy group, and -O-C3-C7 cycloalkyl group, each of which is independently substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, and C3-C7 cycloalkyl group, and when there are multiple substituents, the substituents are the same or different; R1 and R3 are each independently selected from a hydroxyl group, a cyano group, an amino group, an oxo (=O), a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, and a -O-C3-C7 cycloalkyl group; R1 and R3 are each independently substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C3-C7 cycloalkyl; when the substituents are multiple, the substituents may be the same or different; R2 represents a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, or a C1-C6 alkyl group; R2 is substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl; when R2 has a plurality of substituents, R2 may be the same or different; Z is selected from -O- or -NR4-; R4 is a C1-C3 alkyl group or H; Ring A is a 5-6 membered heteroaryl group; n is selected from 1, 2, 3, 4 or 5, and when there are multiple substituents R5, said substituents may be the same or different; R5 is selected from H, halogen, -CN, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, -O-C3-C7 cycloalkyl group; The C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, and -O-C3-C7 cycloalkyl group in R5 are independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, and C3-C7 cycloalkyl groups, and when there are multiple substituents, the substituents are the same or different.

[0010] In a preferred embodiment of the present disclosure, the compound is selected from the following structures:

[0011] [ka] II where L is a C1-C6 alkyl group that is unsubstituted or substituted with one or more substituents, each substituent being independently selected from halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, and oxo (=O); Ring B is selected from a benzene ring or a 6-membered heteroaromatic ring; When ring B is a benzene ring, m is selected from 1, 2, 3, or 4; Ring B is a 6-membered heteroaromatic ring and m is selected from 0, 1, 2, 3, or 4; R1 and R3 are each independently selected from a hydroxyl group, a cyano group, an amino group, an oxo (=O), a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, and a -O-C3-C7 cycloalkyl group; R1 and R3 are each independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C3-C7 cycloalkyl, and when there are multiple substituents, the substituents are the same or different; R2 is selected from a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, and a C1-C6 alkyl group; R2 is substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl; when R2 has a plurality of substituents, R2 may be the same or different; Z is selected from -O- or -NR4-; R4 is a C1-C3 alkyl group or H; Ring A is a 5-6 membered heteroaryl group; n is selected from 1, 2, 3, 4 or 5, and when there are multiple substituents R5, said substituents may be the same or different; R5 is selected from H, halogen, -CN, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, -O-C3-C7 cycloalkyl group; The C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, and -O-C3-C7 cycloalkyl group in R5 are independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxyl group, C1-C6 alkyl group, and C3-C7 cycloalkyl group, and when there are multiple substituents, the substituents are the same or different.

[0012] In a preferred embodiment of the present disclosure, the compound is selected from the following structures:

[0013] [ka] III where L is a C1-C6 alkyl group substituted with one or more substituents, each substituent being independently selected from halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, and oxo (=O); m is selected from 0, 1, 2, 3 or 4, preferably m is 0; The definitions of R1, R2, R3, R5, Z and n are as described in the first aspect of the present disclosure; The definition of Ring A is as described in the first aspect of the present disclosure.

[0014] In a preferred embodiment of the present disclosure, the compound is selected from the following structures:

[0015] [ka] IV wherein R6 is selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, and -O-C3-C7 cycloalkyl; R6 is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C3-C7 cycloalkyl; when R6 is substituted with a plurality of substituents, R6 may be the same or different; m is selected from 0, 1, 2, 3 or 4; L is a C1-C6 alkyl group that is unsubstituted or substituted with one or more substituents, each substituent being independently selected from halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, and oxo (=O); R1, R2, R3 and R5 are as defined in the first aspect of the present disclosure; Z and n are as defined in the first aspect of the present disclosure; The definition of Ring A is as described in the first aspect of the present disclosure.

[0016] In a preferred embodiment of the present disclosure, the compound is selected from the following structures:

[0017] [ka] V wherein Ring B is selected from a 5-6 membered heteroaryl group; R5 is selected from H; R6 is hydrogen or selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, and -O-C3-C7 cycloalkyl; when R6 is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C3-C7 cycloalkyl, when R6 is a plurality of substituents, R6 is the same or different; m is selected from 0, 1, 2, 3 or 4; L is a C1-C6 alkyl group that is unsubstituted or substituted with one or more substituents, each substituent being independently selected from halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, and oxo (=O); R1, R2 and R3 are as defined in the first aspect of the present disclosure; Z and n are as defined in the first aspect of the present disclosure; The definition of Ring A is as described in the first aspect of the present disclosure.

[0018] In a preferred embodiment of the present disclosure, L is a C1-C6 alkyl group; The L is optionally substituted with the following substituents: halogen, C1-C6 alkyl group, C1-C6 halogenated alkyl group, and oxo (=O).

[0019] In one preferred embodiment of the present disclosure, L is a C1-C3 alkyl group, a C1-C3 alkyl group substituted with a C1-C6 alkyl group.

[0020] In one preferred embodiment of the present disclosure, L is -CH2- or -CH(CH3)-.

[0021] In a preferred embodiment of the present disclosure, R3 is selected from a cyano group, an amino group, a C1-C3 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, and an -O-C3-C7 cycloalkyl group; R3 is independently substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C3-C7 cycloalkyl, and when R3 has multiple substituents, R3 is the same or different.

[0022] In a preferred embodiment of the present disclosure, R3 is selected from a cyano group, a methyl group, a methoxy group, a halomethyl group, and a cyclopropyl group.

[0023] In one preferred embodiment of the present disclosure, ring B is a 5-6 membered heteroaromatic ring, said heteroaromatic ring having 1 or 2 heteroatoms which are N.

[0024] In a preferred embodiment of the present disclosure, the ring B is selected from a pyridine ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring; R3 is selected from a hydroxyl group, a cyano group, an amino group, an oxo (=O), a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, and an -O-C3-C7 cycloalkyl group; R3 is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C3-C7 cycloalkyl, and when R3 has multiple substituents, R3 may be the same or different.

[0025] In a preferred embodiment of the present disclosure, R3 is selected from a cyano group, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 halogenated alkyl group, and a C1-C3 alkoxy group.

[0026] In a preferred embodiment of the present disclosure, R3 is selected from a cyano group, a methyl group, a methoxy group, a halomethyl group, and a cyclopropyl group.

[0027] In one preferred embodiment of the present disclosure, ring B is a benzene ring, and the benzene ring is substituted with 1, 2, 3 or 4 R3, where R3 is selected from hydroxyl, cyano, amino, oxo (=O), C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, -O-C3-C7 cycloalkyl; R3 is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C3-C7 cycloalkyl, and when R3 has multiple substituents, R3 may be the same or different.

[0028] In a preferred embodiment of the present disclosure, R3 is selected from a cyano group, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 halogenated alkyl group, and a C1-C3 alkoxy group.

[0029] In a preferred embodiment of the present disclosure, R3 is selected from a cyano group, a methyl group, a methoxy group, a halomethyl group, and a cyclopropyl group.

[0030] In one preferred embodiment of the present disclosure, R1 is selected from a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkyl group, and a C1-C6 alkyl group.

[0031] In one preferred embodiment of the present disclosure, R1 is selected from C1-C6 alkyl groups.

[0032] In one preferred embodiment of the present disclosure, R1 is an isobutyl group.

[0033] In a preferred embodiment of the present disclosure, R2 is selected from the group consisting of a C1-C6 alkyl group and a C1-C6 halogenated alkyl group; R2 is substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C3-C7 cycloalkyl group, 5-6 membered aryl group, and 5-6 membered heteroaryl group, and when there are multiple substituents, the substituents are the same or different.

[0034] In a preferred embodiment of the present disclosure, R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, trifluoropropyl, butyl, isobutyl, C1-C3 alkyl group-6-membered heteroaryl group.

[0035] In a preferred embodiment of the present disclosure, R2 is selected from the group consisting of a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group.

[0036] In a preferred embodiment of the present disclosure, R2 is a methyl group, a trifluoropropyl group, a butyl group, or a pyridylmethyl group.

[0037] In one preferred embodiment of the present disclosure, R2 is a butyl group.

[0038] In one preferred embodiment of the present disclosure, Z is selected from -O-, -NH- or -NC1-C3 alkyl group-.

[0039] In one preferred embodiment of the present disclosure, Z is -O- or -NH-.

[0040] In one preferred embodiment of the present disclosure, Z is -NH-.

[0041] In a preferred embodiment of the present disclosure, ring A is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms; n is 1, 2, 3, 4 or 5.

[0042] In one preferred embodiment of the present disclosure, the heteroatoms are selected from N, O, and S.

[0043] In one preferred embodiment of the present disclosure, the heteroatom is N.

[0044] In one preferred embodiment of the present disclosure, Ring A is selected from pyrrole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0045] In one preferred embodiment of the present disclosure,

[0046] [ka] teeth,

[0047] [ka] The structure is R5 is selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, -O-C3-C7 cycloalkyl, and when R5 is more than one, said substituents are the same or different.

[0048] In a preferred embodiment of the present disclosure, R5 is selected from H, halogen, methyl, ethyl, t-butyl, cyclopropyl, and halomethyl.

[0049] In one preferred embodiment of the present disclosure,

[0050] [ka] teeth,

[0051] [ka] It has the structure:

[0052] In a preferred embodiment of the present disclosure, R6 is selected from H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl, and -O-C3-C7 cycloalkyl; The R6 is independently substituted with 0, 1, 2, 3 or 4 substituents selected from a halogen, a hydroxyl group, an amino group, a cyano group, a C1-C6 alkyl group, and a C3-C7 cycloalkyl group, and when there are multiple substituents, the substituents are the same or different.

[0053] In one preferred embodiment of the present disclosure, R6 is selected from H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, or C3-C7 cycloalkyl.

[0054] In one preferred embodiment of the present disclosure, R6 is selected from H, halogen, or a C1-C3 alkyl group.

[0055] In one preferred embodiment of the present disclosure, R6 is selected from H, fluorine or a methyl group.

[0056] In one preferred embodiment of the present disclosure, ring B is a benzene ring, R6 is H, and m is selected from 1, 2, 3, or 4; L is a C1-C3 alkyl group, a C1-C3 alkyl group substituted with a C1-C6 alkyl group;

[0057] [ka] teeth,

[0058] [ka] The structure is R1 is selected from isobutyl groups; R3 is selected from a cyano group and a methyl group; Z is selected from -O- or -NH-; R2 is selected from C1-C6 alkyl groups; The R2 is substituted with 0, 1, 2, or 3 substituents selected from a halogen, a hydroxyl group, and a 5- or 6-membered heteroaryl group.

[0059] In one preferred embodiment of the present disclosure, L is -CH2- or -CH(CH3)-.

[0060] In one preferred embodiment of the present disclosure, when ring B is a benzene ring, R6 is H, and m is 0, L is a C1-C3 alkyl group or a C1-C3 alkyl group substituted with a C1-C6 alkyl group;

[0061] [ka] teeth,

[0062] [ka] The structure is R1 is selected from isobutyl groups; R3 is selected from a cyano group and a methyl group; Z is selected from -O-; R2 is selected from C1-C6 alkyl groups.

[0063] In one preferred embodiment of the present disclosure, L is -CH2- or -CH(CH3)-.

[0064] In a preferred embodiment of the present disclosure, ring B is a benzene ring, R6 is not hydrogen and is selected from halogen or a C1-C3 alkyl group; When m is 0 or 1, L is a C1-C3 alkyl group, a C1-C3 alkyl group substituted with a C1-C6 alkyl group;

[0065] [ka] teeth,

[0066] [ka] The structure is R1 is selected from isobutyl groups; R3 is selected from the group consisting of methyl groups; Z is selected from -O-; R2 is selected from C1-C6 alkyl groups.

[0067] In a preferred embodiment of the present disclosure, R6 is selected from fluorine or a methyl group.

[0068] In one preferred embodiment of the present disclosure, Ring B is a 5-6 membered heteroaryl group, R5 and R6 are both hydrogen; m is 0,

[0069] [ka] teeth,

[0070] [ka] The structure is R1 is selected from isobutyl groups; Z is selected from -O-; R2 is selected from C1-C6 alkyl groups.

[0071] In one preferred embodiment of the present disclosure, the 5-6 membered heteroaryl group is selected from a pyridine ring, a pyrimidine ring, a pyrazine ring, and a pyridazine ring.

[0072] In one preferred embodiment of the present disclosure, the compounds of formula I, their tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs include the following:

[0073] [ka] [ka] [ka]

[0074] A second aspect of the disclosure provides a pharmaceutical composition comprising a compound of Formula I as described in the first aspect, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0075] A third aspect of the present disclosure is the use of a compound of formula I as described in the first aspect, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as described in the second aspect, said use comprising: Use as an AT2 receptor agonist; and / or the prevention and / or treatment of diseases in which there is an endogenous deficiency of AngII; and / or prevention and / or treatment of diseases in which increased Ang II activity is expected or required; and / or the preparation of drugs, pharmaceutical compositions or formulations as AT2 receptor agonists and / or for preventing and / or treating disorders in which the AT2 receptor is expressed and which expect or require stimulation.

[0076] It is provided that the compounds of formula I according to the first aspect, their tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs, or the pharmaceutical compositions according to the second aspect, can be used to treat diseases of the gastrointestinal, cardiovascular, respiratory tract, kidneys, eyes, female reproductive system or central nervous system (CNS).

[0077] Gastrointestinal diseases to be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease (e.g. hepatitis), gallbladder disease, multiple organ failure, sepsis, etc. Other gastrointestinal diseases to be mentioned include xerostomia, gastritis, gastric fistula, hyperacidity, biliary tract disease, abdominal disease, segmental ileitis, ulcerative colitis, diarrhea, constipation, colic, dysphagia, nausea, vomiting and Sjogren's syndrome.

[0078] Airway diseases to be mentioned include inflammatory diseases such as asthma, obstructive pulmonary disease (eg chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, adult respiratory distress syndrome and idiopathic pulmonary fibrosis.

[0079] Renal diseases to be mentioned include renal failure, nephritis and renal hypertension.

[0080] Eye diseases to be mentioned include diabetic retinopathy, retinopathy of prematurity and retinal microvascularization.

[0081] Disorders of the female reproductive system which should be mentioned include disorders of the ovulation mechanism.

[0082] Cardiovascular diseases to be mentioned include hypertension, myocardial hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, post-balloon dilatation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmias, intermittent claudication, pre-eclampsia, myocardial infarction, reinfarction, ischemic disorders, erectile dysfunction and neointimal hyperplasia.

[0083] CNS disorders to be mentioned include cognitive dysfunction, feeding dysfunction, dry mouth, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction.

[0084] The compounds of formula I according to the first aspect, their tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs, or the pharmaceutical compositions according to the second aspect may also be used to regulate growth metabolism and proliferation, for example to treat hypertrophy, prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, nerve regeneration, ulceration, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer (e.g. gastrointestinal cancer, lung cancer, etc.), apoptosis, tumors (general), proliferation diabetes, neurological disorders and organ rejection.

[0085] The compounds of formula I according to the first aspect of the present disclosure, their tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs, or the pharmaceutical compositions according to the second aspect, are suitable for the therapeutic and / or prophylactic treatment of the above mentioned diseases.

[0086] A fourth aspect of the present disclosure provides a method for treating a disease, wherein there is an endogenous deficiency of AngII and / or an increase in ngII action is desired or required and / or an AT2 receptor is expressed and stimulation is desired or required, the method comprising administering to a person suffering from or susceptible to the disease a therapeutically effective amount of a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmacologic acceptable salt or prodrug thereof as described in the first aspect of the present disclosure, or a pharmaceutical composition as described in the second aspect.

[0087] Additional aspects and advantages of the disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] Hereinafter, the embodiments of the present disclosure will be described in detail. The embodiments described below are illustrative and are intended only to explain the present disclosure, and should not be understood as limiting the present disclosure.

[0089] It should be noted that the terms "first" and "second" are used for descriptive purposes only and cannot be understood as expressing or implying a relative importance or a number of technical features to be shown. Thus, a feature defined by "first" or "second" can explicitly or implicitly include at least one of the feature. In the description of this disclosure, "plurality" means at least two, e.g., two, three, etc., unless otherwise limited.

[0090] Terms and Definitions

[0091] Unless otherwise stated, the definitions of groups and terms described in the specification and claims of this application, including illustrative definitions, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., can be combined with each other in any combination. The group definitions and compound structures combined in such a manner should fall within the scope described in the specification of this application.

[0092] Unless otherwise defined, all technical terms herein have the same meaning as would be commonly understood by one skilled in the art of the subject matter of the claims. Unless otherwise stated, all patents, patent applications, and publications cited throughout this specification are hereby incorporated by reference in their entirety. In the event that there are multiple definitions for terms in this specification, the definitions in this section shall prevail.

[0093] It should be understood that the above brief description and the following details are exemplary and explanatory only, and do not limit the subject matter of the present disclosure in any way. In this application, the use of the singular includes the plural unless otherwise specified. It should be noted that the singular form used in this specification and the claims includes the plural of what it refers to, unless otherwise specified herein. The use of "or" and "alternative" indicates "and / or" unless otherwise specified. It should be noted that the use of the term "comprises" and other forms such as "includes", "includes" and "containing" is not limiting.

[0094] Definitions of standard chemical terms can be found in references, including Carey and Sundberg, "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A(2000) and B(2001), Plenum Press, New York. Unless otherwise specified, routine methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are employed. Unless specific definitions are provided, the terms used in this specification to describe analytical chemistry, organic synthetic chemistry, and drugs and drug chemistry are known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. For example, the manufacturer's instructions for use of reagent kits can be used, or reactions can be carried out and purified in a manner known in the art or as described in this disclosure. Generally, the techniques and methods described above are carried out according to routine methods well known in the art, based on the descriptions in several general and more specific literature cited and discussed herein. Groups and their substituents are selected herein by those of skill in the art to provide stable structural moieties and compounds.

[0095] When a substituent is written in a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that would result if the structural formula were written in a similarly right to left manner. For example, CH2O is equivalent to OCH2. As used herein,

[0096] [ka] indicates the attachment site of the group. As used herein, "R", "R1" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, the meaning of similar definitions is the same.

[0097] The chapter titles used herein should not be construed as limitations on the subject matter, but are used for organizing purposes only. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and papers, are incorporated herein by reference in their entirety.

[0098] Except as noted above, when used in the specification and claims of this application, the following terms have the following meanings unless otherwise specified.

[0099] With respect to the numerical ranges described in the specification and claims of this application, when the numerical range is understood as being "integers", it should be understood that the two endpoints of the range and each integer within the range are described. For example, "an integer from 1 to 6" should be understood to describe the integers 1, 2, 3, 4, 5, and 6.

[0100] In this application, "AT2 receptor" and "AT2R" have the same definition.

[0101] In this application, the term "halogen" used alone or as part of another substituent refers to fluorine, chlorine, bromine, and iodine.

[0102] In this application, the term "amino group" when used alone or as part of another substituent refers to -NH2.

[0103] As used herein, the term "hydroxyl" when used alone or as part of another substituent refers to --OH.

[0104] As used herein, the term "cyano" as used alone or as part of another substituent refers to -CN.

[0105] As used herein, the term "alkyl group" when used alone or as part of another substituent refers to a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturated bonds, e.g., 1-6 carbon atoms, and connected to the remainder of the molecule by a single bond. Illustrative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl groups. Alkyl groups are unsubstituted or substituted with one or more suitable substituents. Alkyl groups may be isotopic isomers of natural abundance alkyl groups of carbon and / or hydrogen-rich isotopes (i.e., deuterium or tritium). As used herein, the term "alkenyl group" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl group" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0106] The term "C1-C6 alkyl group", when used alone or as part of another substituent, should be understood to denote a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-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, and the like, or isomers thereof. In particular, the group has 1, 2 or 3 carbon atoms (a "C1-C3 alkyl group"), such as a methyl group, a methylene group, an ethyl group, a n-propyl group or an isopropyl group.

[0107] The term "C1-C6 alkoxy group", when used alone or as part of another substituent, refers to a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or a C1-C6 alkyl group -O-C1-C6 alkyl group, as defined herein, which indicates that the oxygen atom can be attached to any carbon atom of the C1-C6 alkyl group, either linear or non-linear, including, but not limited to, methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-), and butoxy (C4H9-O-).

[0108] The term "oxo" used alone or as part of another substituent refers to =O where two hydrogens on a methylene group are replaced with oxygen; ie, the methylene group is replaced with a carbonyl group.

[0109] The terms "cycloalkyl group" or "carbocyclic group" used alone or as part of another substituent refer to a cyclic alkyl group. m -C n The term "cycloalkyl group" should be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-15 membered cycloalkyl group" or "C3-C 15"Cycloalkyl group" refers to a cyclic alkyl group having 3 to 15, 3 to 9, 3 to 6, or 3 to 5 carbon atoms, and may contain 1 to 4 rings. "5-8 membered cycloalkyl group" contains 5 to 8 carbon atoms. It includes monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings. Illustrative examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl groups, or bicyclohydrocarbyl groups such as decalin rings. The cycloalkyl group is substituted with one or more substituents. In some implementations, the cycloalkyl group may be a cycloalkyl group fused with an aryl or heteroaryl group. The term "C3-C6 cycloalkyl group" should be understood to refer to a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. For example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0110] The term "halogenated cycloalkyl group" used alone or as part of another substituent refers to a cycloalkyl group as described above, where any number (at least one) of the hydrogen atoms attached to the cycloalkyl group are replaced with fluorine, chlorine, bromine, or iodine.

[0111] The term "halogenated alkyl group" used alone or as part of another substituent refers to branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens (e.g., -CvFw, where v=1-3, w=1-(2v+1)). Examples of halogenated alkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl groups.

[0112] The term "aryl group" when used alone or as part of another substituent refers to a monocyclic or polycyclic carbocyclic ring having 6 to 20 carbon atoms, at least one ring being aromatic. When one of the rings is non-aromatic, the group may be connected by aromatic rings and non-aromatic rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthranyl, and acenaphthylene.

[0113] When used alone or as part of another substituent, the term "heteroaromatic ring" may be used interchangeably with "heteroaryl group" and refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is independently selected from oxygen, sulfur, and nitrogen heteroatoms, the remaining ring atoms are C, and at least one ring is aromatic. The group may be a carbon or heteroatom group (i.e., C-connected or N-connected, where possible). When one of the rings is non-aromatic, the group may be connected by an aromatic ring and connected by a non-aromatic ring. Illustrative examples of heteroaryl groups include, but are not limited to, imidazole, acridinyl, carbazolyl, cinnolinyl, quinoxalyl, pyrazole, indole, benzotriazole, furyl, thienyl, benzothienyl, benzofuryl, quinoline, isoquinolyl, oxazolyl, isoxazolyl, indole, pyrazine, pyridazine, pyridine, pyrimidine, pyrrole, N-methylpyrrolidone, and tetrahydroquinoline. The term "heteroaromatic ring" can be used interchangeably with the terms "heteroaromatic ring", "heteroaryl group" or "heteroaromatic ring group".

[0114] When used alone or as part of another substituent, the term "5-6 membered heteroaromatic ring" may be used interchangeably with "5-6 membered heteroaryl group" and should be understood as an aromatic ring group having 5 or 6 ring atoms and containing 1-3 heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaromatic ring" should be understood as an aromatic ring group having 5 or 6 ring atoms and containing 1-3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrole, oxazolyl, thiazolyl, imidazole, pyrazole, or pyridine, pyridazine, pyrimidine and pyrazine groups.

[0115] As used herein, "any" or "optionally" indicates that the subsequently described event or circumstance may or may not occur, and the description includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, an "optionally substituted aryl group" indicates that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

[0116] As used herein, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable alkali addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0117] "Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable alkali addition salt" refers to a salt formed with an inorganic or organic base that retains the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated in the present disclosure. These can be used in the purification of the compounds or as intermediates in the preparation of other pharmaceutically acceptable salts, or to identify, characterize, or purify the compounds of the present disclosure.

[0118] The term "amine salt" refers to the product of neutralizing an alkyl group primary amine, secondary amine, or tertiary amine with an acid, including inorganic or organic acids as described herein.

[0119] The term "stereoisomer" refers to isomers resulting from different arrangements of atoms in molecules in space, and includes cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0120] Depending on the choice of raw materials and methods, the compounds of the present disclosure may exist as one of the possible isomers or as a mixture thereof, e.g., pure optical isomers, or mixtures of isomers, e.g., racemates and diastereomeric mixtures, as determined by the number of asymmetric carbon atoms. When describing a compound having optical activity, the prefixes D and L or R and S indicate the absolute configuration of the molecule with respect to the chiral center (or centers) within the molecule. The prefixes D and L or (+) and (-) are symbols to designate the rotation of plane polarized light by the compound, with (-) or L indicating that the compound is levorotatory. Compounds with a prefix of (+) or D are dextrorotatory.

[0121] When the bonds to the chiral carbons in the formulae of this disclosure are drawn as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures generated therefrom are included within the scope of this general formula. In this specification, the method of illustrating racemic or enantiomerically pure compounds is taken from Maehr, J.Chem.Ed.1985, 62:114-120. Unless otherwise indicated, the wedge keys and dashed keys indicate the absolute configuration of a single stereocenter.

[0122] The term "tautomer" refers to an isomer of a functional group resulting from the rapid migration of an atom in a molecule at two positions. Compounds of the present disclosure may exhibit the phenomenon of tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-shift tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium forms, and attempts to isolate a single tautomer usually produce a mixture whose physical and chemical properties match the mixture of compounds. The position of the equilibrium is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone type predominates, while in phenols, the enol type predominates. The present disclosure includes all tautomeric forms of the compounds.

[0123] In this application, "pharmaceutical composition" refers to a formulation of a vehicle for delivering a compound of the present disclosure and a biologically active compound to a mammal (e.g., a human) that is generally accepted in the art. The vehicle includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and facilitate absorption of the active ingredient to exert its biological activity.

[0124] As used herein, "pharmaceutical acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending aid, stabilizer, isotonicity agent, solvent, or emulsifier approved by the relevant governmental department as an acceptable adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending aid, stabilizer, isotonicity agent, solvent, or emulsifier for human or veterinary use.

[0125] The term "solvate" means that a compound of the present disclosure or a salt thereof contains a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces, and when the solvent is water, is a hydrate.

[0126] The term "prodrug" refers to a compound of the present disclosure that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present disclosure is produced by modifying a functional group in the compound, and the modification can be removed by conventional manipulation or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting one hydroxyl group or amino group in the compound of the present disclosure to any group, and when the prodrug of the compound of the present disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, a free amino group.

[0127] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0128] The term "additive" refers to a medicamentous inactive ingredient. Illustrative examples of types of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, diluents, etc. Excipients can enhance the handling properties of a drug formulation, i.e., by increasing flow and / or cohesiveness, making the formulation suitable for direct compression.

[0129] As used herein, the term "treatment" and other similar synonyms include the following meanings: (i) preventing a disease or condition from occurring in a mammal, particularly where such a mammal is susceptible to the disease or condition but has not been diagnosed with the disease or condition; (ii) inhibiting the disease or condition, i.e. inhibiting its development; (iii) alleviating the disease or condition, i.e., causing the disease or condition to recede; or (iv) alleviating symptoms caused by the disease or condition.

[0130] The present disclosure will be further described below by combining specific examples. It should be understood that the following description is only the preferred embodiment of the present disclosure, and should not be considered as limiting the scope of protection of the present disclosure. After fully understanding the present disclosure, the experimental methods in the following examples without specific conditions are usually according to conventional conditions or conditions proposed by manufacturers, and those skilled in the art can make non-essential changes to the technical solutions of the present disclosure, and such changes are considered to be within the scope of protection of the present disclosure.

[0131] This application has the following definitions: Sign or unit: I C 50 : Median inhibitory concentration, the concentration at which half of the maximum inhibitory effect is achieved M: mol / L. For example, n-butyllithium (14.56mL, 29.1mmol, 2.5M n-hexane solution) indicates a n-butyllithium solution with a molar concentration of 2.5mol / L. N: equivalent concentration, for example, 2N hydrochloric acid indicates a 2 mol / L hydrochloric acid solution. RT: hold time

[0132] reagent: DCM: dichloromethane DMF: N,N-dimethylformamide DIPEA: N,N-diisopropylethylamine EA: Ethyl acetate HATU: 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethylurea hexafluorophosphate MeOH: Methanol PE: Petroleum ether Toluene: Toluene THF: tetrahydrofuran XPhos Pd G4: (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamine-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate

[0133] Test Method: LCMS: Liquid Chromatography TLC: Thin Layer Chromatography

[0134] Intermediate A1: Preparation of Intermediate A1 (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid

[0135] [ka]

[0136] The synthetic route of intermediate A1 is as follows.

[0137] [ka]

[0138] Step 1: Synthesis of N-(t-butyl)-5-isobutylthiophene-2-sulfonamide

[0139] [ka]

[0140] Add zinc chloride (20.0mL, 1mol / L THF solution) and isobutylmagnesium chloride (13.0mL, 2mol / L) to a 100mL three-neck flask and stir at room temperature for 10 minutes in a N2 atmosphere. Then, add 5-bromothiophene-2-tert-butylsulfonamide (5.0g, 16.77mmol) and di(tri-t-butylphosphorus)palladium (428mg, 0.83mmol) in Toluene (50mL) dropwise and react at 120°C for 1 hour while heating and stirring. TLC (PE:EA(V / V)=3:1) thin layer chromatography showed that the raw material was completely consumed and the target point was clearly produced. The reaction solution is filtered, and the resulting mother liquor is spin-dried, kneaded, and separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-3:1) to obtain N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (3.8 g, yield 82.3%). 1 H NMR (400 MHz, DMSO-d6) δ 7.66(s, 1H), 7.39(d, J = 3.7 Hz, 1H), 6.84(d, J = 3.7 Hz, 1H), 2.70(d, J = 7.1 Hz, 2H), 1.91-1.71(m, 1H), 1.20-1.07(m, 9H), 0.89(d, J = 6.6 Hz, 6H)

[0141] Step 2: Synthesis of (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid

[0142] [ka]

[0143] N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (2.0g, 7.26mmol) was added to a 50mL three-neck flask and dissolved in THF (20mL). N2 atmosphere was added dropwise to n-butyllithium (7.3mL, 2.5mol / L n-hexane) solution at room temperature, and stirred for half an hour, and then triisopropyl borate (2.05g, 10.89mmol) was added to the reaction system, at this time, solids gradually precipitated in the solution, and the solution turned pale yellow, and the reaction system was stirred overnight under room temperature conditions. TLC (PE:EA(V / V)=3:1) thin layer chromatography monitoring showed that the reaction of raw materials was complete, and there was a new point of formation of the target compound. Slowly add HCl aqueous solution (5.0mL, 2.0mol / L) dropwise to the reaction liquid to adjust the pH to 2, add 30mL to dilute with water, extract with ethyl acetate (50mL×2), wash and extract the organic phase with saturated saline (30mL), dry the obtained organic phase with anhydrous sodium sulfate and then filter, spin-dry and knead the mother liquor, separate and purify with a silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-3:1), and obtain (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (A1) (1.8g, yield 77.6%).

[0144] Intermediate A2: Preparation of Intermediate A2 1-(4-chlorophenylmethyl)-1H-imidazole

[0145] [ka]

[0146] The synthetic route of intermediate A2 is as follows.

[0147] [ka]

[0148] 1H-imidazole (1.90 g, 27.9 mmol) and 1-chloro-4-(chloromethyl)benzene (3.00 g, 18.6 mmol) were dissolved in acetonitrile (40.0 mL), potassium carbonate (7.72 g, 55.8 mmol) was added, and the mixture was heated to 80° C. for 2 hours. The reaction solution was concentrated, and the crude product was purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-10:1, R f =0.5) to give 1-(4-chlorophenylmethyl)-1H-imidazole (3.00 g, 15.5 mmol, 83.3% yield). LC-MS, M / Z(ESI): 193.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.21(s, 2H), 7.48(d, 2H), 7.34(d, 2H), 7.06(s, 1H), 5.28(s, 2H)

[0149] Example 1: Preparation of target compound I-1 ((3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0150] [ka]

[0151] The synthetic route to the target compound I-1 is as follows.

[0152] [ka]

[0153] Step 1: Synthesis of 1-(4-bromo-3-methylbenzyl)-1H-imidazole

[0154] [ka]

[0155] Add imidazole (0.2 g, 2.9 mmol) to 4 mL of dimethyl sulfoxide, add potassium hydroxide (0.81 g, 14.5 mmol), react at room temperature for 3 h, then add 1-bromo-4-(bromomethyl)-2-methylbenzene (0.92 g, 3.5 mmol), react at room temperature overnight. LCMS shows that the reaction of the raw material is complete, add 30 mL of water to dilute, extract with ethyl acetate (50 mL x 2), concentrate the organic phase to dryness, and purify the residue by separating it with a silica gel column (DCM:MeOH (V / V) = 10:1) to obtain 1-(4-bromo-3-methylbenzyl)-1H-imidazole (600 mg, yield 82.4%). LC-MS, M / Z(ESI): 251.0 [M+H] +

[0156] Step 2: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide

[0157] [ka]

[0158] 1-(4-Bromo-3-methylbenzyl)-1H-imidazole (0.15 g, 0.6 mmol) is added to 2 mL of N,N-dimethylformamide, followed by (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (0.287 g, 0.9 mmol), 1,1'-bis(diphenylphosphine group)ferrocene palladium(II) dichloride (0.16 g, 0.2 mmol), and potassium carbonate (0.33 g, 2.4 mmol), and the mixture is heated to 90°C and reacted overnight. LCMS shows the reaction of the raw material is finished, add 5mL of water to dilute, extract with ethyl acetate (10mL x 2), wash the organic phase with water (10mL x 5), collect the organic phase and concentrate to dryness, and purify the residue by separation on a silica gel column (PE:EA (V / V) = 1:1) to obtain 3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (200mg, yield 74.9%). LC-MS, M / Z(ESI): 446.2 [M+H] +

[0159] Step 3: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide

[0160] [ka]

[0161] Add 3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (0.2 g, 0.45 mmol) to 5 mL of trifluoroacetic acid and react overnight at room temperature. LCMS shows the reaction of the raw material is complete, concentrate to dryness to obtain 3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide (256 mg, 100% yield). LC-MS, M / Z(ESI): 390.1 [M+H] +

[0162] Step 4: Synthesis of ((3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0163] [ka]

[0164] 3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide (0.2 g, 0.5 mmol) is added to 5 mL of dichloromethane, then triethylamine (0.3 g, 3.0 mmol), butyl chloroformate (0.14 g, 1.0 mmol) are added, and the mixture is reacted at room temperature overnight. LCMS shows that the reaction of the raw material is complete, and the mixture is diluted with 5 mL of water, extracted with ethyl acetate (10 mL x 2), the organic phase is concentrated to dryness, and the residue is purified by separation on a silica gel column (DCM:MeOH (V / V) = 10:1) to obtain ((3-(4-((1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-yl)sulfonyl)butylcarbamate (I-1) (87 mg, yield 34.7%). LC-MS, M / Z(ESI): 490.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.04(s, 1H), 7.45(d, 1H), 7.41(s, 1H), 7.26(s, 1H), 7.10(d, 1H), 6.92(d, 1H), 6. 84(s, 1H), 5.29(s, 2H), 3.80(t, 2H), 2.65(d, 2H), 2.27(s, 3H), 1.87-1.83(m, 1H) , 1.39-1.34(m, 2H), 1.21-1.16(m, 2H), 0.92(d, 6H), 0.81(t, 3H)

[0165] Example 2: Preparation of target compound I-2 ((3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0166] [ka]

[0167] The synthetic route to the target compound I-2 is as follows.

[0168] [ka]

[0169] Step 1: Synthesis of 1-(4-bromo-2-methylbenzyl)-1H-imidazole

[0170] [ka]

[0171] Add imidazole (0.2 g, 2.9 mmol) to 4 mL of dimethyl sulfoxide, add potassium hydroxide (0.81 g, 14.5 mmol), react at room temperature for 3 h, then add 4-bromo-1-(bromomethyl)-2-methylbenzene (0.92 g, 3.5 mmol), react at room temperature overnight. LCMS shows that the reaction of the raw material is complete, add 30 mL of water to dilute, extract with ethyl acetate (50 mL x 2), wash the organic phase with water (50 mL x 5), collect the organic phase and concentrate to dryness, and purify the residue by separation on a silica gel column (DCM:MeOH (V:V) = 10:1) to obtain 1-(4-bromo-2-methylbenzyl)-1H-imidazole (600 mg, yield 82.4%). LC-MS, M / Z(ESI): 251.0 [M+H] +

[0172] Step 2: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide

[0173] [ka]

[0174] 1-(4-Bromo-2-methylbenzyl)-1H-imidazole (0.15 g, 0.6 mmol) is added to 2 mL of N,N-dimethylformamide, followed by (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (0.287 g, 0.9 mmol), 1,1'-bis(diphenylphosphine group)ferrocene palladium(II) dichloride (0.16 g, 0.2 mmol), and potassium carbonate (0.33 g, 2.4 mmol), and the mixture is heated to 90°C and reacted overnight. LCMS shows the reaction of the raw material is finished, add 5mL of water to dilute, extract with ethyl acetate (10mL x 2), wash the organic phase with water (10mL x 5), collect the organic phase and concentrate to dryness, and purify the residue by separation on a silica gel column (PE:EA (V:V) = 1:1) to obtain 3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (210mg, yield 78.6%). LC-MS, M / Z(ESI): 446.2 [M+H] +

[0175] Step 3: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-5-isobutylthiophene-2-sulfonamide

[0176] [ka]

[0177] Add 3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (0.21 g, 0.47 mmol) to 5 mL of trifluoroacetic acid and react overnight at room temperature. LCMS shows the reaction of the raw material is complete, concentrate to dryness to obtain 3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-5-isobutylthiophene-2-sulfonamide (260 mg, 100% yield). LC-MS, M / Z(ESI): 390.1 [M+H] +

[0178] Step 4: Synthesis of ((3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0179] [ka]

[0180] 3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-5-isobutylthiophene-2-sulfonamide (0.2 g, 0.5 mmol) is added to 5 mL of dichloromethane, then triethylamine (0.3 g, 3.0 mmol), butyl chloroformate (0.14 g, 1.0 mmol) are added, and the mixture is reacted at room temperature overnight. LCMS shows that the reaction of the raw material is complete, and the mixture is diluted with 5 mL of water, extracted with ethyl acetate (10 mL x 2), and the organic phase is concentrated to dryness. The residue is purified by separation on a silica gel column (DCM:MeOH (V:V) = 10:1) to obtain ((3-(4-((1H-imidazol-1-yl)methyl)-3-methylphenyl)-5-isobutylthiophene-2-yl)sulfonyl)butylcarbamate (I-2) (62 mg, yield 24.7%). LC-MS, M / Z(ESI):490.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 7.75(s, 1H), 7.20(s, 1H), 7.12(d, 1H), 7.01(s, 1H), 6.93(d, 1H), 6.90(s, 1H), 6. 44(s, 1H), 5.15(s, 2H), 3.59(t, 2H), 2.58(d, 2H), 2.02(s, 3H), 1.82-1.79(m, 1H) , 1.37-1.31(m, 2H), 1.25-1.19(m, 2H), 0.90(d, 6H), 0.83(t, 3H)

[0181] Example 3: Preparation of target compound I-3 ((3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0182] [ka]

[0183] The synthetic route to the target compound I-3 is as follows.

[0184] [ka]

[0185] Step 1: Synthesis of 5-((1H-imidazol-1-yl)methyl)-2-bromobenzonitrile

[0186] [ka]

[0187] Add imidazole (136mg, 2.00mmol) to a 50mL single-neck flask and dissolve in DMF (5mL). Then add sodium hydrogen (183mg, 60%, 4.55mmol) in batches to the reaction solution under N2 atmosphere and stir for half an hour, then add 2-bromo-5-(bromomethyl)benzonitrile (500mg, 1.82mmol) in DMF (2.5mL) solution to the reaction solution and stir the reaction system at room temperature for 1 hour. TLC (DCM:MeOH (V / V)=10:1) thin layer chromatography monitoring shows that the raw material is completely reacted and a new spot of the target compound is formed. The reaction mixture is poured into a cold saturated solution of NH4Cl (aq. 10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase is washed with water (10 mL x 5), then washed with saturated saline (10 mL), the obtained organic phase is dried over anhydrous sodium sulfate and then filtered, the mother liquor is spin-dried and kneaded, and the mixture is separated and purified on a silica gel column (dichloromethane:methanol (V / V) = 50:1-10:1) to obtain 5-((1H-imidazol-1-yl)methyl)-2-bromobenzonitrile (350.0 mg, yield 73.4%). LC-MS, M / Z(ESI): 262.2[M+H] +

[0188] Step 2: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide

[0189] [ka]

[0190] In a 50 mL single-neck flask, 5-((1H-imidazol-1-yl)methyl)-2-bromobenzonitrile (300 mg, 1.14 mmol) and (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (365 mg, 1.14 mmol) are dissolved in toluene (6 mL), followed by sodium carbonate (243 mg, 2.29 mmol) and tetraphenylphosphopalladium (133 mg, 0.11 mmol) under N2 atmosphere. The reaction is heated to 120 °C and stirred for 24 h. TLC (PE:EA (V / V) = 1:2) thin layer chromatography monitoring shows the formation of a new spot of the target compound. The reaction solution is filtered, and the mother liquor is spin-dried and kneaded, and then separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-0:1) to obtain 3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (120.0 mg, yield 23.0%). LC-MS, M / Z(ESI): 457.3[M+H] +

[0191] Step 3: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide

[0192] [ka]

[0193] Add 3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (120 mg, 0.26 mmol) to a 50 mL single-neck flask and dissolve in trifluoroacetic acid (2 mL), and stir the reaction system at room temperature for 24 hours. At this time, the solution turns dark brown, and TLC (PE:EA (V / V) = 1:2) thin layer chromatography monitoring indicates that the reaction of the raw materials is complete. The reaction solution is directly spin-dried to obtain the crude product 3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (100 mg), which is used directly in the next step reaction. LC-MS, M / Z(ESI): 401.3[M+H] +

[0194] Step 4: Synthesis of ((3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0195] [ka]

[0196] In a 50mL single-neck flask, add the crude product of 3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (100mg) and dissolve it in dichloromethane (2mL). Then add triethylamine (0.1mL) to the reaction solution and stir for half an hour, then add butyl chloroformate (100mg, 0.73mmol) to the reaction solution and stir the reaction system at room temperature for 16 hours. TLC (DCM:MeOH (V / V)=10:1) thin layer chromatography monitoring shows that the raw material is completely reacted and one new spot is formed. The reaction solution is poured gradually into a saturated solution of NH4Cl (aq. 10 mL), extracted with ethyl acetate (5 mL × 3), the obtained organic phase is dried over anhydrous sodium sulfate, then filtered, the mother liquor is spin-dried to prepare, separated and purified (basic column: Solomon Titank C18 10μ Bulk 30 mm * 40 cm, A (HO) / ​​B (ACN) = 100% / 0 ~ 40% / 60%) to obtain ((3-(4-((1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate (9.0 mg, yield 7.2%). LC-MS, M / Z(ESI): 499.1 [MH] + 1 H NMR (400 MHz, DMSO-d6) δ 8.13(s, 1H), 7.77(d, 1H), 7.67(d, 1H), 7.58(dd, 1H), 7.39(s, 1H), 7.10(s, 1H), 6.81(s, 1H), 5.33(s,2H), 3.76(t, 2H), 3.08(dd, 2H), 2.66(d, 1H), 1.94 - 1.73(m, 1H), 1.48 - 1.30(m, 2H), 1.19(dt, 4H), 0.92(d, 3H), 0.83(t, 3H).

[0197] Example 4: Preparation of target compound I-4 ((3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0198] [ka]

[0199] The synthetic route to the target compound I-4 is as follows.

[0200] [ka]

[0201] Step 1: Synthesis of 2-((1H-imidazol-1-yl)methyl)-5-bromobenzonitrile

[0202] [ka]

[0203] Add imidazole (136mg, 2.00mmol) to a 50mL single-neck flask and dissolve in DMF (5mL). Then add sodium hydrogen (183mg, 60%, 4.55mmol) batchwise to the reaction solution under N2 atmosphere. Stir for 0.5h, then add 5-bromo-2-(bromomethyl)benzonitrile (500mg, 1.82mmol) dissolved in DMF (2.5mL) slowly to the reaction solution. Stir the reaction system at room temperature for 1h. Then, TLC (DCM:MeOH (V / V)=10:1) monitors the reaction of raw materials and shows the formation of a new spot of target compound. The reaction mixture is poured slowly into a cold saturated solution of NH4Cl (aq. 10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase is washed with water (10 mL x 5), then washed with saturated saline (10 mL), the obtained organic phase is dried over anhydrous sodium sulfate and then filtered, the mother liquor is spin-dried and kneaded, and the mixture is separated and purified on a silica gel column (dichloromethane:methanol (V / V) = 50:1-10:1) to obtain 2-((1H-imidazol-1-yl)methyl)-5-bromobenzonitrile (350 mg, yield 73.4%). LC-MS, M / Z(ESI): 264.1 [M+H] +

[0204] Step 2: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide

[0205] [ka]

[0206] 2-((1H-imidazol-1-yl)methyl)-5-bromobenzonitrile (300 mg, 1.14 mmol) and (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (365 mg, 1.14 mmol) were added to a 50 mL single-neck flask and dissolved in toluene (6 mL), then sodium carbonate (243 mg, 2.29 mmol) was added, and tetraphenylphosphopalladium (133 mg, 0.11 mmol) was added under N2 atmosphere, and the reaction system was heated to 120 °C and stirred for 24 h. TLC (PE:EA (V / V) = 1:2) monitoring showed that the raw materials were completely reacted and one new dot was formed. The reaction solution is filtered, and the mother liquor is spin-dried and kneaded, and then separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-0:1) to obtain 3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (120 mg, yield 23.0%). LC-MS, M / Z(ESI): 457.3 [M+H] +

[0207] Step 3: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide

[0208] [ka]

[0209] Add 3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (120 mg, 0.26 mmol) to a 50 mL single-neck flask and dissolve in trifluoroacetic acid (2 mL), and stir the reaction system at room temperature for 24 h. At this time, the solution turns dark brown, and TLC (PE:EA (V / V) = 1:2) monitoring indicates that the reaction of the raw materials is complete. The reaction solution is directly spin-dried to obtain the crude product 3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (100 mg), which is used directly in the next step reaction. LC-MS, M / Z(ESI): 401.3 [M+H] +

[0210] Step 4: Synthesis of ((3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0211] [ka] In a 50 mL single-neck flask, add the crude product of 3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (100 mg) and dissolve it in DCM (2 mL). Then add pyridine (0.2 mL) to the reaction solution and stir for 0.5 h. Then add butyl chloroformate (100 mg, 0.73 mmol) to the reaction solution and stir the reaction system at room temperature for 16 h. TLC (DCM:MeOH (V / V)=10:1) thin layer chromatography monitoring shows the reaction of the raw material is complete and one new spot is formed. The reaction solution is poured gradually into a saturated solution of NH4Cl (aq. 10 mL), extracted with ethyl acetate (5 mL × 3), the organic phase is washed with saturated saline solution (10 mL), the obtained organic phase is dried over anhydrous sodium sulfate, then filtered, the mother liquor is spin-dried to prepare, separate and purify (preparation purification: basic column: Solomon Titank C18 10μ Bulk 30 mm * 40 cm, A (H2O) / B (ACN) = 100% / 0 ~ 40% / 60%) to obtain ((3-(4-((1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonyl) butylcarbamate (12.0 mg, yield 9.6%). LC-MS, M / Z(ESI): 500.9[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.41(s, 1H), 8.13(d, 1H), 7.92(dd, 1H), 7.46(s, 1H), 7.33(d, 2H), 6.99(s, 1H), 5.59(s, 2H), 3.85(t, 2H), 2.69(d, 2H), 1.98 - 1.73(m, 1H), 1.39(dd, 2H), 1.20(dd, 2H), 0.93(t, 6H), 0.83(t, 3H)

[0212] Example 5: Preparation of target compound I-5 ((3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0213] [ka]

[0214] The synthetic route to the target compound I-5 is as follows.

[0215] [ka]

[0216] Step 1: Synthesis of 5-((1H-imidazol-1-yl)methyl)-2-bromopyridine

[0217] [ka]

[0218] Add 2-bromo-5-(bromomethyl)pyridine (1.0 g, 3.98 mmol), imidazole (0.56 g, 8.38 mmol), potassium carbonate (0.88 g, 6.38 mmol) to DMF (10 ml) at room temperature and stir at 25 °C for 12 h under nitrogen gas protection. When the reaction is complete, dilute with water (30 mL), extract with ethyl acetate (20 mL x 3), separate, combine the organic phase, wash the organic phase with water (20 mL x 5), dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by chromatography column separation (dichloromethane:methanol (V / V) = 10:1) to obtain 5-((1H-imidazol-1-yl)methyl)-2-bromopyridine (0.7 g, 73.12% yield). LC-MS, M / Z(ESI): 238.0 [M+H] +

[0219] Step 2: Synthesis of 3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide

[0220] [ka]

[0221] Compound 5-((1H-imidazol-1-yl)methyl)-2-bromopyridine (0.3 g, 1.26 mmol), (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (0.44 g, 1.38 mmol), potassium carbonate (0.522 g, 3.78 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (0.092 g, 0.126 mmol) were dissolved in dioxane (5 ml), replaced with nitrogen gas, heated to 90 ° C, and stirred for 10 hours. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (10 mL x 3), separate, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and separate the residue by chromatography column (dichloromethane:methanol (V / V) = 10:1) to obtain 3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (0.1 g, yield 18.35%). LC-MS, M / Z(ESI): 433.2 [M+H] +

[0222] Step 3: 3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-isobutylthiophene-2-sulfonamide

[0223] [ka]

[0224] The raw material 3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (0.1 g, 0.231 mmol) is dissolved in dichloromethane (1 mL), 1.0 mL of trifluoroacetic acid is added thereto, and the mixture is stirred at room temperature for 12 h. The reaction mixture is diluted with water (5 mL), the pH is adjusted to 9-10 with 2 M aqueous sodium hydroxide solution, and the mixture is extracted with dichloromethane (5 mL x 3), separated, and the organic phase is combined. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue is separated and purified with a thin layer silicone rubber plate (dichloromethane:methanol (V / V) = 10:1) to obtain 3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-isobutylthiophene-2-sulfonamide (0.04 g, yield 46%). LC-MS, M / Z(ESI): 377.1 [M+H] +

[0225] Step 4: Synthesis of ((3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0226] [ka]

[0227] Compound 3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-isobutylthiophene-2-sulfonamide (0.04 g, 0.106 mmol), triethylamine (0.021 g, 0.212 mmol) and 4-dimethylaminopyridine (7 mg, 0.053 mmol) are added to DMF (0.5 mL) and dichloromethane (0.5 mL) at room temperature, and finally, butyl chloroformate (0.029 g, 0.212 mmol) is added dropwise to the reaction system and stirred for 12 h. Dilute with water (5 mL), extract with ethyl acetate (5 mL × 3), separate, combine the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and prepare, separate, and purify the residue by high performance liquid chromatography (preparation purification: column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: A = water + 0.01% volumetric trifluoroacetic acid (99%), B = acetonitrile; gradient 35%-65% B, 10 min) to obtain ((3-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate (7 mg, yield 13.82%). LC-MS, M / Z(ESI): 477.2 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.57(s, 1H), 7.67 - 7.59(m, 2H), 7.54 - 7.48(m, 1H), 7.16(s, 1H), 7.05(d, 1H), 6.94(s, 1H), 5.23(s, 2H), 4.15(t, 2H), 2.73(d, 2H), 1.96(dt, 1H), 1.61(dd, 2H), 1.34(dd, 2H), 1.04 - 0.93(m, 6H), 0.90(t, 3H).

[0228] Example 6: Preparation of target compound I-6 ((3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0229] [ka]

[0230] The synthetic route to the target compound I-6 is as follows.

[0231] [ka]

[0232] Step 1: 2-((1H-imidazol-1-yl)methyl)-5-bromopyridine

[0233] [ka]

[0234] Add compound 5-bromo-2-(bromomethyl)pyridine (1.0 g, 3.98 mmol), imidazole (0.56 g, 8.38 mmol), potassium carbonate (0.88 g, 6.38 mmol) to DMF (10.0 mL) at room temperature and stir at 25 °C for 12 h under nitrogen gas protection. When the reaction is complete, add water (30 mL) to dilute, extract with ethyl acetate (20 mL × 3), wash with water (20 mL × 5), separate, combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by chromatography column separation (dichloromethane:methanol (V / V) = 10:1) to obtain 2-((1H-imidazol-1-yl)methyl)-5-bromopyridine (0.7 g, yield 73.12%). LC-MS, M / Z(ESI): 238.0 [M+H] +

[0235] Step 2: Synthesis of 3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide

[0236] [ka]

[0237] Compound 2-((1H-imidazol-1-yl)methyl)-5-bromopyridine (0.3 g, 1.26 mmol), (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (0.44 g, 1.38 mmol), potassium carbonate (0.522 g, 3.78 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (0.092 g, 0.126 mmol) were dissolved in dioxane (5 mL), substituted with nitrogen gas, heated to 90 ° C, and stirred for 10 h. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (10 mL x 3), separate the liquids, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and separate the residue using a chromatography column (dichloromethane:methanol (V / V) = 10:1) to obtain 3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (0.3 g, yield 60.2%). LC-MS, M / Z(ESI): 433.2 [M+H] +

[0238] Step 3: Synthesis of 3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide

[0239] [ka]

[0240] Dissolve 3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (0.3 g, 0.693 mmol) in dichloromethane (3 mL), add 3 mL of trifluoroacetic acid, and stir at room temperature for 12 h. Dilute with water (5 mL), adjust pH to 9-10, extract with dichloromethane (5 mL x 3), separate, and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. Separate and purify the residue with a thin layer silicone rubber plate (dichloromethane:methanol (V / V) = 10:1) to obtain 3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (0.18 g, yield 69.2%). LC-MS, M / Z(ESI): 377.1[M+H] +

[0241] Step 4: Synthesis of ((3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0242] [ka]

[0243] Compound 3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (0.18 g, 0.477 mmol), triethylamine (0.095 g, 0.951 mmol) and 4-dimethylaminopyridine (29.3 mg, 0.239 mmol) are added to DMF (2.0 mL) and dichloromethane (2.0 mL) at room temperature, and finally, butyl chloroformate (0.131 g, 0.954 mmol) is added dropwise to the reaction system and stirred for 12 h. Dilute with water (5 mL), extract with ethyl acetate (5 mL × 3), separate, combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, prepare the residue by high performance liquid chromatography, separate and purify (preparation purification: column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: A = water + 0.01% volume trifluoroacetic acid (99%), B = acetonitrile; gradient 35%-65% B, 10 min), obtain ((3-(6-((1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate (50 mg, yield 22.2%). LC-MS, M / Z(ESI): 477.2 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.77(s, 1H), 7.88(dd, 1H), 7.57(s, 1H), 6.99 - 6.85(m, 3H), 6.68(d, 1H), 5.16(s, 2H), 3.70(t, 2H), 2.59(d, 2H), 1.84(dt, 1H), 1.32(dd, 2H), 1.13(dd, 2H), 0.95 - 0.86(m, 6H), 0.75(t, 3H)

[0244] Example 7: Preparation of target compound I-7 ((3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0245] [ka]

[0246] The synthetic route to the target compound I-7 is as follows.

[0247] [ka]

[0248] Step 1: Synthesis of 1-(1-(4-bromophenyl)ethyl)-1H-imidazole

[0249] [ka]

[0250] Add the compound 1-bromo-4-(1-bromoethyl)benzene (1.0 g, 3.82 mmol), imidazole (0.56 g, 8.38 mmol), potassium carbonate (0.88 g, 6.38 mmol) to DMF (10.0 mL) at room temperature and stir for 12 h at 25 °C under nitrogen gas protection. When the reaction is complete, dilute with water (30 mL), extract with ethyl acetate (20 mL x 3), wash with water (20 mL x 5), separate, combine the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and purify the residue by separation with a chromatographic column (dichloromethane:methanol (V / V) = 10:1) to obtain 1-(1-(4-bromophenyl)ethyl)-1H-imidazole (0.7 g, yield 73.68%). LC-MS, M / Z(ESI): 251.0 [M+H] +

[0251] Step 2: Synthesis of 3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide

[0252] [ka]

[0253] Compound 1-(1-(4-bromophenyl)ethyl)-1H-imidazole (0.3 g, 1.26 mmol), (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (0.44 g, 1.38 mmol), potassium carbonate (0.522 g, 3.78 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (0.092 g, 0.126 mmol) were dissolved in dioxane (5 ml), substituted with nitrogen gas, heated to 90 ° C, and stirred for 10 h. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (10 mL x 3), separate the liquids, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and separate the residue with a chromatography column (dichloromethane:methanol (V / V) = 10:1) to obtain 3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (0.4 g, yield 75.41%). LC-MS, M / Z(ESI): 446.1 [M+H] +

[0254] Step 3: Synthesis of 3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0255] [ka]

[0256] The raw material 3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-N-(t-butyl)-5-isobutylthiophene-2-sulfonamide (0.3 g, 0.693 mmol) is dissolved in dichloromethane (3 ml), 3 mL of trifluoroacetic acid is added thereto, and the mixture is stirred at room temperature for 12 hours. Water (5 mL) is added to dilute the mixture, the pH is adjusted to 9-10, and the mixture is extracted with dichloromethane (5 mL x 3), separated, and the organic phase is combined. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue is separated and purified with a thin layer silicone rubber plate (dichloromethane:methanol (V / V) = 10:1) to obtain 3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (0.21 g, yield 80.71%). LC-MS, M / Z(ESI): 390.1 [M+H] +

[0257] Step 4: Synthesis of ((3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0258] [ka]

[0259] Add 3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (0.21 g, 0.557 mmol), triethylamine (0.110 g, 1.103 mmol) and 4-dimethylaminopyridine (34 mg, 0.277 mmol) in DMF (2 mL) and dichloromethane (2 mL) at room temperature, and finally add butyl chloroformate (0.152 g, 1.103 mmol) dropwise to the reaction system and stir for 12 h. Dilute with water (5 mL), extract with ethyl acetate (5 mL × 3), wash with water (5 mL × 5), separate, combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, prepare, separate and purify the residue by high performance liquid chromatography (preparation purification: column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: A = water + 0.01% volume trifluoroacetic acid (99%), B = acetonitrile; gradient 35%-65% B, 10 min), obtain ((3-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate (140 mg, yield 53.85%). LC-MS, M / Z(ESI): 490.2 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.96(s, 1H), 7.61 - 7.52(m, 2H), 7.13(d, 2H), 6.94(s, 1H), 6.87(s, 1H), 6.78 - 6.73(m, 1H), 5.40(q, 1H), 4.05(t, 2H), 2.87 - 2.69(m, 2H), 1.99 - 1.91(m, 1H), 1.83(t, 3H), 1.52(tt, 2H), 1.31 - 1.24(m, 2H), 1.04 - 0.93(m, 6H), 0.88(t, 3H).

[0260] Example 8: Preparation of target compound I-8 ((3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)butylcarbamate

[0261] [ka]

[0262] The synthetic route to the target compound I-8 is as follows.

[0263] [ka]

[0264] Step 1: Synthesis of 2-isobutyl-3-methylthiophene

[0265] [ka]

[0266] Dissolve zinc chloride (13.8g, 101mmol) in tetrahydrofuran (100mL), add isobutyl magnesium bromide (2.00M, 45.1mL), 2-bromo-3-methyl-thiophene (10.0g, 56.5mmol) and di(tri-t-butylphosphine)palladium (1.44g, 2.82mmol), and after the addition is complete, replace with nitrogen gas, gradually raise the temperature to 90°C and react for 1 hour. Pour the reaction liquid into water (200mL), add ethyl acetate (200mL) and extract three times, wash the organic phase with saturated saline (50mL), dry with anhydrous sodium sulfate, filter and concentrate to obtain 2-isobutyl-3-methylthiophene (6.00g, yield 65.3%).

[0267] Step 2: Synthesis of 5-isobutyl-4-methylthiophene-2-sulfonyl chloride

[0268] [ka]

[0269] Dissolve 2-isobutyl-3-methylthiophene (6.00 g, 36.9 mmol) in dichloromethane (30.0 mL), add chlorosulfonic acid (13.6 g, 116 mmol), and react at room temperature with stirring for 1 hour. Concentrate the reaction mixture to obtain the product, 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (9.80 g, crude product).

[0270] Step 3: Synthesis of N-(t-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0271] [ka]

[0272] 5-Isobutyl-4-methylthiophene-2-sulfonyl chloride (9.80 g, 38.7 mmol) was dissolved in dichloromethane (40.0 mL), N,N-diisopropylethylamine (10.0 g, 77.5 mmol) and 2-methylpropan-2-amine (3.40 g, 46.5 mmol) were added, and the mixture was heated to 40°C and reacted for 1 hour. The reaction solution was poured into water (40.0 mL), and extracted three times with ethyl acetate (200 mL). The organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-5:1, R f =0.4) to give N-(t-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (1.50 g, 13.4% yield). LC-MS, M / Z(ESI): 288.1 [MH] + .

[0273] Step 4: Synthesis of (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid

[0274] [ka]

[0275] N-(t-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (900 mg, 3.34 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction solution was cooled to -60 ° C in a dry ice ethanol bath, n-butyllithium (2.50 M, 3.98 mL) was slowly added dropwise under nitrogen gas protection, and after the addition was completed, the mixture was stirred for 0.5 hours, and then triisopropyl borate (1.17 g, 6.22 mmol) was added and reacted at -60 ° C for 1 hour. The reaction solution was poured into water (20 mL), and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by separation using a silica gel column (petroleum ether: ethyl acetate (V / V) = 5: 1-1: 1, R f =0.1), (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (0.7 g, 62.8% yield) was obtained. LC-MS, M / Z(ESI): 332.1 [MH] +

[0276] Step 6: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)phenyl)-N-(t-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0277] [ka]

[0278] (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (700 mg, 2.10 mmol) and 1-(4-chlorophenylmethyl)-1H-imidazole (610 mg, 3.15 mmol) are dissolved in tetrahydrofuran (10 mL), potassium phosphate (1.34 g, 6.30 mmol) and (2-dicyclohexylphosphonyl-2,6-dimethoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium methanesulfonate (78 mg, 100 μmol) are added, the mixture is purged with nitrogen gas three times, and the temperature is raised to 60°C under nitrogen gas protection to react for 6 hours. After concentrating the reaction solution, the crude product is separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 75*30mm*3μm; solvent: A = water + 0.05% volumetric formic acid (99.0%), B = acetonitrile; gradient: 20%-50%, 7 min) to obtain 3-(4-((1H-imidazol-1-yl)methyl)phenyl)-N-(t-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, yield 15.7%). LC-MS, M / Z(ESI): 446.1 [M+H] +

[0279] Step 7: Synthesis of 3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0280] [ka]

[0281] 3-(4-((1H-imidazol-1-yl)methyl)phenyl)-N-(t-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, 330 μmol) is added to dichloromethane (5 mL) and trifluoroacetic acid (5 mL), heated to 40° C. and reacted for 6 hours. The reaction solution is adjusted to pH=5 with saturated aqueous sodium bicarbonate solution, and then the reaction solution is concentrated to obtain 3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (200 mg, crude product). LC-MS, M / Z(ESI): 388.1 [MH] +

[0282] Step 8: Synthesis of ((3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)butylcarbamate

[0283] [ka]

[0284] Dissolve 3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (200 mg, crude product) and N,N-diisopropylethylamine (129.1 mg, 0.99 mmol) in dichloromethane (10 mL), add n-butyl chlorocarboxylate (67.32 mg, 0.5 mmol), and react at 25°C for 2 hours. The reaction solution is concentrated, and the crude product is separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*50mm*10μm; solvent: A = water + 0.05% volumetric formic acid (99.0%), B = acetonitrile; gradient: 22% - 52%, 10 min) to obtain the product ((3-(4-((1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)butylcarbamate (I-8) (4.25 mg, 8.31 μmol). LCMS, M / Z(ESI): 490.1 [M+H]+ 1 HNMR (400 MHz, CDCl3) δ 7.54(s, 1 H), 7.19-7.21(m, 2H), 7.11(d, 2H), 6.87(s, 1H), 6.79(s, 1H), 5.07(s, 2H), 4.01(t, 2H), 2.60(d, 2) H), 1.78(s, 3H), 1.75-1.76(m, 1H), 1.46-1.52(m, 2H), 1.19-1.26(m, 2H), 0.94(d, 6H), 0.83(t, 3H)

[0285] Example 9: Preparation of target compound I-10 (3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0286] [ka]

[0287] The synthetic route to the target compound I-10 is as follows.

[0288] [ka]

[0289] Step 1: Synthesis of 2-bromo-5-((2-methyl-1H-imidazol-1-yl)methyl)benzonitrile

[0290] [ka]

[0291] Dissolve 2-bromo-5-(bromomethyl)benzonitrile (1.00 g, 1.41 mmol) and 2-methyl-1H-imidazole (895 mg, 10.9 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (1.51 g, 10.9 mmol) and react at 50 °C for 2 hours. Pour the reaction mixture into water (50 mL), extract with ethyl acetate (100 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 2-bromo-5-((2-methyl-1H-imidazol-1-yl)methyl)benzonitrile (800 mg, 79.6% yield). LC-MS, M / Z(ESI): 276.0 [M+H] +

[0292] Step 2: Synthesis of N-(t-butyl)-3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0293] [ka]

[0294] (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (500 mg, 1.57 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and 2-bromo-5-((2-methyl-1H-imidazol-1-yl)methyl)benzonitrile (432 mg, 1.57 mmol) was added, and potassium phosphate (1.66 g, 7.83 mmol) and XPhos Pd G4 (134 mg, 156 μmol) were further added. The mixture was then replaced with nitrogen gas three times and reacted at 60° C. under nitrogen gas protection with stirring for 4 hours. The reaction solution is concentrated to obtain the crude product, which is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (650 mg, yield 88.1%). LC-MS, M / Z(ESI): 471.1 [M+H] +

[0295] Step 3: Synthesis of 3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0296] [ka]

[0297] N-(t-butyl)-3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (600 mg, 1.27 mmol) is dissolved in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) and reacted at 20°C for 8 hours. The reaction solution is poured into water (10 mL), then extracted three times with dichloromethane (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to obtain 3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (500 mg, yield 94.6%). LC-MS, M / Z(ESI): 415.1 [M+H] +

[0298] Step 4: Synthesis of (3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0299] [ka]

[0300] Dissolve 3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (500 mg, 1.21 mmol) and N,N-diisopropylethylamine (467 mg, 3.62 mmol) in dichloromethane (10 mL), add methyl chloroformate (455 mg, 4.82 mmol), and react at 0° C. for 0.5 hours with stirring. The reaction solution is concentrated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+0.05% volumetric ammonia water (30%), B=acetonitrile; gradient: 5%-35%, 8 min) to obtain (3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (I-10) (82.9 mg, yield 18.6%). LC-MS, M / Z(ESI): 473.2 [M+H] + 1 H NMR(DMSO-d6) δ 7.71-7.84(m, 2H), 7.52-7.64(m, 2H), 7.40(s, 1H), 6.78(s, 1H), 5.39(s, 2) H), 3.31(s, 3H), 2.66(d, 2H), 2.54(s, 3H), 1.82-1.89(m, 1H), 0.93(d, 6H)

[0301] Example 10: Preparation of target compound I-11 (5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0302] [ka]

[0303] The synthetic route to the target compound I-11 is as follows.

[0304] [ka]

[0305] Step 1: Synthesis of 1-(4-bromo-3-methylbenzyl)-2-methyl-1H-imidazole

[0306] [ka]

[0307] Dissolve 1-bromo-4-(bromomethyl)-2-methylbenzene (1.00 g, 3.79 mmol) and 2-methyl-1H-imidazole (933 mg, 11.3 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (1.51 g, 11.3 mmol), and react at 50 °C for 2 hours. Pour the reaction mixture into water (50 mL), extract with ethyl acetate (100 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromo-3-methylbenzyl)-2-methyl-1H-imidazole (900 mg, 89.6% yield). LC-MS, M / Z(ESI): 267.0 [M+H] +

[0308] Step 2: Synthesis of N-(t-butyl)-5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0309] [ka]

[0310] (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (500 mg, 1.57 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and 1-(4-bromo-3-methylbenzyl)-2-methyl-1H-imidazole (415 mg, 1.57 mmol) was added. Potassium phosphate (1.66 g, 7.83 mmol) and XPhos Pd G4 (134 mg, 156 μmol) were added. The mixture was then replaced with nitrogen gas three times and reacted at 60° C. under nitrogen gas protection with stirring for 4 hours. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (650 mg, yield 90.2%). LC-MS, M / Z(ESI): 460.1 [M+H] +

[0311] Step 3: Synthesis of 5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0312] [ka]

[0313] N-(t-butyl)-5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (550 mg, 1.20 mmol) is dissolved in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) and reacted at 20° C. for 8 hours. The reaction solution is poured into water (10 mL), then extracted three times with dichloromethane (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V)=10:1-0:1) to obtain 5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (400 mg, 89.4% yield). LC-MS, M / Z(ESI): 404.1 [M+H] +

[0314] Step 4: Synthesis of (5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0315] [ka]

[0316] Dissolve 5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (400 mg, 991 μmol) and N,N-diisopropylethylamine (384 mg, 2.97 mmol) in dichloromethane (10.0 mL), add methyl chloroformate (374 mg, 3.96 mmol), and react at 0° C. for 0.5 hours with stirring. The reaction solution is concentrated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; solvent: A = water + 0.05% volumetric ammonia water (30%), B = acetonitrile; gradient: 9% - 39%, 8 min) to obtain (5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (172mg, yield 47.1%). LC-MS, M / Z(ESI): 462.2 [M+H] + 1 H NMR(DMSO-d6) δ:7.48(s, 1H), 7.26(s, 1H), 7.16(d, 1H), 7.11(s, 1H), 7.00(d, 1H), 6.57(s, 1H), 5.24(s , 2H), 3.31(s, 3H), 2.64(d, 2H), 2.48(s, 3H), 2.05(s, 3H), 1.85-1.86(m, 1H), 0.92(d, 6H)

[0317] Example 11: Preparation of target compound I-12 ((3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0318] [ka]

[0319] The synthetic route to the target compound I-12 is as follows.

[0320] [ka]

[0321] Step 1: Synthesis of 5-bromo-2-((2-methyl-1H-imidazol-1-yl)methyl)benzonitrile

[0322] [ka]

[0323] Add 5-bromo-2-(bromomethyl)benzonitrile (300 mg, 1.1 mmol), 2-methyl-1H-imidazole (131.4 mg, 1.6 mmol) and potassium carbonate (221.1 mg, 1.6 mmol) to N,N-dimethylformamide (4.5 mL) and react at 20 °C for 3 h, LCMS shows the reaction is complete. Add 50 mL of water, extract three times with ethyl acetate (20 mL × 3), collect the organic phase and concentrate to dryness, and purify the residue by separating with a reverse phase column (0.1% formic acid) to obtain 5-bromo-2-((2-methyl-1H-imidazol-1-yl)methyl)benzonitrile (250 mg, 83% yield). LC-MS, M / Z(ESI): 275.9 [M+H] +

[0324] Step 2: Synthesis of N-(t-butyl)-3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0325] [ka]

[0326] 5-Bromo-2-((2-methyl-1H-imidazol-1-yl)methyl)benzonitrile (100mg, 0.4mmol) was added to 2mL of N,N-dimethylformamide, and further (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (191.5mg, 0.9mmol), 1,1'-bis(diphenylphosphine)ferrocene dichloride palladium(II) (73.1mg, 0.1mmol), potassium carbonate (221.1mg, 1.6mmol) were added, and the mixture was replaced with nitrogen gas three times. The mixture was heated to 90°C under nitrogen gas protection and reacted overnight, and LCMS showed that the reaction of the raw material was completed. Dilute with 30 mL of water, extract with ethyl acetate (10 mL × 3), collect the organic phase and concentrate to dryness, and purify the residue by separation on a silica gel column (DCM: MeOH (V / V) = 10:1) to obtain N-(t-butyl)-3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (170 mg, yield 80%). LC-MS, M / Z(ESI): 471.1 [M+H] +

[0327] Step 3: Synthesis of 3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0328] [ka]

[0329] Add N-(t-butyl)-3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (170 mg, 0.4 mmol) to 3.5 mL of trifluoroacetic acid and react overnight at room temperature, LCMS shows that the reaction of the raw material is complete. Concentrate to dryness to obtain 3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (145 mg, 83% yield). LC-MS, M / Z(ESI): 415.0 [M+H] +

[0330] Step 4: Synthesis of ((3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butylcarbamate

[0331] [ka]

[0332] 3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (145 mg, 0.3 mmol) was added to 4.5 mL of dichloromethane, triethylamine (303.6 mg, 3.0 mmol) and butyl chloroformate (122.9 mg, 0.9 mmol) were added, and the mixture was reacted at room temperature for 2 h. LCMS showed that the reaction of the raw material was completed. The mixture was diluted with 30 mL of water, extracted with ethyl acetate (10 mL × 3), the organic phase was collected and concentrated to dryness, and the residue was purified by preparation with a reverse phase column (0.1% trifluoroacetic acid) to obtain ((3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-yl)sulfonyl)butylcarbamate (59 mg, yield 32.8%). LC-MS, M / Z(ESI): 515.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.24(d, 1H), 8.02(dd, 1H), 7.45(s, 1H), 7.38(s, 1H), 7.17(d, 1H), 6.92(s, 1H), 5. 56(s, 2H), 3.72(t, 2H), 2.64(d, 2H), 2.51(s, 3H), 1.86(dt, 1H), 1.36(tt, 2H), 1.26 - 1.13(m, 2H), 0.93(s, 3H), 0.92(s, 3H), 0.81(t, 3H)

[0333] Example 12: Preparation of target compound I-13 ((3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0334] [ka]

[0335] The synthetic route to the target compound I-13 is as follows.

[0336] [ka]

[0337] Step 1: Synthesis of 5-bromo-2-((2-(t-butyl)-1H-imidazol-1-yl)methyl)benzonitrile

[0338] [ka]

[0339] Add 5-bromo-2-(bromomethyl)benzonitrile (300 mg, 1.1 mmol), 2-(t-butyl)-1H-imidazole (198.7 mg, 1.6 mmol) and potassium carbonate (221.1 mg, 1.6 mmol) to N,N-dimethylformamide (6 mL) and react at 20 °C for 3 h, LCMS shows the reaction is complete. Add 50 mL of water, extract with ethyl acetate (20 mL × 3), collect the organic phase and concentrate to dryness, and purify the residue by separating with a reverse phase column (0.1% formic acid) to obtain 5-bromo-2-((2-(t-butyl)-1H-imidazol-1-yl)methyl)benzonitrile (300 mg, 86.4% yield). LC-MS, M / Z(ESI): 320.0 [M+H] +

[0340] Step 2: Synthesis of N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide

[0341] [ka]

[0342] 5-Bromo-2-((2-(t-butyl)-1H-imidazol-1-yl)methyl)benzonitrile (100mg, 0.3mmol) was added to 2mL of N,N-dimethylformamide, followed by (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (127.7mg, 0.4mmol), 1,1'-bis(diphenylphosphine)ferrocene dichloride palladium(II) (73.1mg, 0.1mmol), and potassium carbonate (165.8mg, 1.2mmol). The mixture was purged with nitrogen gas three times, and the mixture was heated to 90°C under nitrogen gas protection and reacted overnight. LCMS showed that the reaction of the raw material was complete. Dilute with 30 mL of water, extract with ethyl acetate (10 mL × 2), collect the organic phase and concentrate to dryness, and purify the residue by separation on a silica gel column (DCM: MeOH (V / V) = 10:1) to obtain N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (160 mg, yield 60%). LC-MS, M / Z(ESI): 513.2 [M+H] +

[0343] Step 3: Synthesis of 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide

[0344] [ka]

[0345] Add N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (160 mg, 0.3 mmol) to 3.5 mL of trifluoroacetic acid and react overnight at room temperature, LCMS shows the reaction of the raw material is complete. Concentrate to dryness to obtain 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (140 mg, 50% yield). LC-MS, M / Z(ESI): 457.1 [M+H] +

[0346] Step 4: Synthesis of methyl ((3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0347] [ka]

[0348] 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (140 mg, 0.3 mmol) was added to 3 mL of dichloromethane, and triethylamine (303.6 mg, 3.0 mmol) and methyl chloroformate (85 mg, 0.9 mmol) were added and reacted at room temperature for 2 h. LCMS showed that the reaction of the raw material was completed. Dilute with 30 mL of water, extract with ethyl acetate (10 mL x 2), concentrate the organic phase to dryness, and purify the residue by preparing it with a reverse phase column (0.1% formic acid) to obtain methyl ((3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-3-cyanophenyl)-5-isobutylthiophene-2-yl)sulfonyl)carbamate (27 mg, yield 17.1%). LC-MS, M / Z(ESI): 515.1 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 8.32(s, 1H), 8.09 - 7.98(m, 1H), 7.18(d, 1H), 7.09(d, 1H), 6.92(s, 1H), 6.84(d, 1H), 5.65(s, 2H) , 3.35(s, 3H), 2.64(d, 2H), 1.86(dt, 1H), 1.37(s, 9H), 0.94(s, 3H), 0.93(s, 3H)

[0349] Example 13: Preparation of target compound I-14 ((3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0350] [ka]

[0351] The synthetic route to the target compound I-14 is as follows.

[0352] [ka]

[0353] Step 1: Synthesis of 5-bromo-2-((2-ethyl-1H-imidazol-1-yl)methyl)benzonitrile

[0354] [ka]

[0355] 5-Bromo-2-(bromomethyl)benzonitrile (300 mg, 1.1 mmol), 2-ethyl-1H-imidazole (153.8 mg, 1.6 mmol) and potassium carbonate (221.1 mg, 1.6 mmol) are added to N,N-dimethylformamide (6 mL) and reacted at 20 °C for 3 h, LCMS shows the reaction is complete. Add 50 mL of water, extract with ethyl acetate (20 mL x 3), collect the organic phase and concentrate to dryness, and purify the residue by separation on a reverse phase column (0.1% formic acid) to obtain 5-bromo-2-((2-ethyl-1H-imidazol-1-yl)methyl)benzonitrile (300 mg, 94.8% yield). LC-MS, M / Z(ESI): 290.5 [M+H] +

[0356] Step 2: Synthesis of N-(t-butyl)-3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0357] [ka]

[0358] 5-Bromo-2-((2-ethyl-1H-imidazol-1-yl)methyl)benzonitrile (100mg, 0.3mmol) was added to 2mL of N,N-dimethylformamide, (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (127.7mg, 0.4mmol), 1,1'-bis(diphenylphosphine)ferrocene dichloride palladium(II) (73.1mg, 0.1mmol), potassium carbonate (165.8mg, 1.2mmol) were added, and the mixture was replaced with nitrogen gas three times. The mixture was heated to 90°C under nitrogen gas protection and reacted overnight, and LCMS showed that the reaction of the raw material was completed. Dilute with 30 mL of water, extract with ethyl acetate (10 mL × 2), collect the organic phase and concentrate to dryness, and purify the residue by separation on a silica gel column (DCM: MeOH (V / V) = 10:1) to obtain N-(t-butyl)-3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (160 mg, 66% yield). LC-MS, M / Z(ESI): 485.1 [M+H] +

[0359] Step 3: Synthesis of 3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0360] [ka]

[0361] Add N-(t-butyl)-3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (160 mg, 0.3 mmol) to 3.5 mL of trifluoroacetic acid and react overnight at room temperature, LCMS shows that the reaction of the raw material is complete. Concentrate to dryness to obtain the crude product 3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (140 mg, 48.5% yield). LC-MS, M / Z(ESI): 429.1 [M+H] +

[0362] Step 4: Synthesis of methyl ((3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0363] [ka]

[0364] Add 3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (140 mg, 0.3 mmol) to 3 mL of dichloromethane, add triethylamine (303.6 mg, 3.0 mmol), methyl chloroformate (85 mg, 0.9 mmol), react at room temperature for 2 h, LCMS shows that the reaction of the raw material is over. Add 30 mL of water to dilute, extract with ethyl acetate (10 mL × 2), collect the organic phase and concentrate to dryness, and purify the residue by preparation with a reverse phase column (0.1% formic acid) to obtain methyl ((3-(3-cyano-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-yl)sulfonyl)carbamate (43 mg, yield 27.0%). LC-MS, M / Z(ESI): 487.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.27(d, 1H), 8.03(dd, 1H), 7.49(s, 2H), 7.15(d, 1H), 6.92(s, 1H), 5.60(s, 2H), 3.32( s, 3H), 2.90(q, 2H), 2.64(d, 2H), 1.86(dt, 1H), 1.22(t, 3H), 0.94(s, 3H), 0.92(s, 3H)

[0365] Example 14: Preparation of target compound I-17 (3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0366] [ka]

[0367] The synthetic route to the target compound I-17 is as follows.

[0368] [ka]

[0369] Step 1: Synthesis of 2-bromo-5-((2-(t-butyl)-1H-imidazol-1-yl)methyl)benzonitrile

[0370] [ka]

[0371] Dissolve 2-bromo-5-(bromomethyl)benzonitrile (1.00 g, 3.64 mmol) and 2-(t-butyl)-1H-imidazole (1.36 g, 10.9 mmol) in N,N-dimethylformamide (20 mL), add potassium carbonate (1.51 g, 10.9 mmol) and react at 50 °C for 2 hours. Pour the reaction mixture into water (50 mL), extract with ethyl acetate (100 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 2-bromo-5-((2-(t-butyl)-1H-imidazol-1-yl)methyl)benzonitrile (1.00 g, 86.4% yield). LC-MS, M / Z(ESI): 318.0 [M+H] +

[0372] Step 2: Synthesis of N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide

[0373] [ka]

[0374] (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (500 mg, 1.57 mmol) is dissolved in tetrahydrofuran (10 mL) and water (5 mL), and 2-bromo-5-((2-(t-butyl)-1H-imidazol-1-yl)methyl)benzonitrile (498 mg, 1.57 mmol) is added, followed by potassium phosphate (1.66 g, 7.83 mmol) and XPhos Pd G4 (134 mg, 156 μmol). The mixture is then stirred at 60° C. under nitrogen gas protection for 4 hours. The reaction mixture is concentrated to obtain a crude product, which is then purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (550 mg, yield 68.4%). LC-MS, M / Z(ESI): 513.1 [M+H] +

[0375] Step 3: Synthesis of 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide

[0376] [ka]

[0377] N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (500 mg, 957 μmol) is dissolved in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) and reacted at 20 °C for 8 hours. The reaction solution is poured into water (10 mL), extracted three times with dichloromethane (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10: 1-0: 1) to obtain 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (410 mg, yield 92.1%). LC-MS, M / Z(ESI): 457.1 [M+H] +

[0378] Step 4: Synthesis of (3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0379] [ka]

[0380] Dissolve 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophene-2-sulfonamide (400 mg, 876 μmol) and N,N-diisopropylethylamine (339 mg, 2.63 mmol) in dichloromethane (10 mL), add methyl chloroformate (248 mg, 2.63 mmol), and react at 0° C. for 0.5 hours with stirring. The reaction solution is concentrated and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; solvent: A=water+0.05% volumetric ammonia water (30%), B=acetonitrile; gradient: 0% -30%, 10 min) to obtain (3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-cyanophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (191mg, yield 45.4%). LC-MS, M / Z(ESI): 515.2 [M+H] + 1 H NMR(DMSO-d6) δ:7.75(d, 1H), 7.55(s, 1H), 7.30-7.39(m, 2H), 7.24(s, 1H), 6.82(s, 1H), 5.59 (s, 2H), 3.36(s, 3H), 2.67(d, 2H), 1.82-1.86(m, 1H), 1.38(s, 9H), 0.93(d, 6H)

[0381] Example 15: Preparation of target compound I-16 (5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0382] [ka]

[0383] The synthetic route to the target compound I-16 is as follows.

[0384] [ka]

[0385] Step 1: Synthesis of 1-(4-bromobenzyl)-2-methyl-1H-imidazole

[0386] [ka]

[0387] Dissolve 1-bromo-4-(bromomethyl)benzene (1.50 g, 6.00 mmol) and 2-methyl-1H-imidazole (492 mg, 6.00 mmol) in N,N-dimethylformamide (30.0 mL), add potassium carbonate (2.49 g, 18.0 mmol) and react at 50 °C for 2 hours. Pour the reaction mixture into water (25 mL), extract with ethyl acetate (100 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromobenzyl)-2-methyl-1H-imidazole (1.40 g, yield 92.8%). LC-MS, M / Z(ESI): 253.2 [M+H] +

[0388] Step 2: Synthesis of N-(t-butyl)-5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0389] [ka]

[0390] (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (2.00 g, 6.00 mmol) is dissolved in tetrahydrofuran (20 mL) and water (10 mL), and 1-(4-bromobenzyl)-2-methyl-1H-imidazole (1.36 g, 5.40 mmol) is added, followed by potassium phosphate (6.37 g, 30.0 mmol) and XPhos Pd G4 (258 mg, 300 μmol). The mixture is then stirred at 60° C. under nitrogen gas protection for 4 hours. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (2.20 g, yield 79.7%). LC-MS, M / Z(ESI): 460.3 [M+H] +

[0391] Step 3: Synthesis of 5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0392] [ka]

[0393] N-(t-butyl)-5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (2.10 g, 4.57 mmol) is dissolved in trifluoroacetic acid (20 mL) and dichloromethane (20 mL) and reacted at 40 °C for 8 hours. The reaction solution is poured into water (10 mL), extracted three times with dichloromethane (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10: 1-1: 1) to obtain 5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (1.80 g, yield 97.6%). LC-MS, M / Z(ESI): 404.2 [M+H] +

[0394] Step 4: Synthesis of (5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0395] [ka]

[0396] Dissolve 5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (1.80 g, 4.46 mmol) and N,N-diisopropylethylamine (1.73 g, 13.4 mmol) in dichloromethane (20 mL), add methyl chloroformate (1.26 g, 13.4 mmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*40mm*15um; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 15%-45%, 15 min), concentrated and dried to obtain (5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (833mg, yield 43.8%). 1 H NMR (400 MHz, CDCl3) δ 7.36(d, 2H), 7.16(d, 2H), 6.69(d, 1H), 6.52(d, 1H), 5.03(s, 2H), 3.61(s, 3 H), 2.66(d, 2H), 2.45(s, 3H), 1.92-2.03(m, 1H), 1.83(s, 3H), 1.01(d, 6H). LC-MS, M / Z(ESI): 462.4 [M+H] +

[0397] Example 16: Preparation of target compound I-18 3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-((3,3,3-trifluoropropyl)carbamoyl)thiophene-2-sulfonamide

[0398] [ka]

[0399] The synthetic route to the target compound I-18 is as follows.

[0400] [ka]

[0401] Step 1: Synthesis of (3,3,3-trifluoropropyl)phenylcarbamate

[0402] [ka]

[0403] Dissolve 3,3,3-trifluoropropan-1-amine (500 mg, 4.42 mmol) in tetrahydrofuran (10 mL), then add triethylamine (671 mg, 6.63 mmol) and phenylchloroformate (831 mg, 5.31 mmol) and react for 1 hour at 25° C. Pour the reaction mixture into water (50 mL), extract three times with ethyl acetate (50 mL), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to obtain (3,3,3-trifluoropropyl)phenylcarbamate (200 mg, 19.4% yield). LC-MS, M / Z(ESI): 234.1 [M+H] +

[0404] Step 2: Synthesis of 3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-((3,3,3-trifluoropropyl)carbamoyl)thiophene-2-sulfonamide

[0405] [ka]

[0406] Dissolve 3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (200 mg, 482 μmol) and 1,8-diazabicyclo[5.4.0]undequa-7-ene (220 mg, 1.45 mmol) in acetonitrile (5 mL), add (3,3,3-trifluoropropyl)phenylcarbamate (124 mg, 531 μmol), and react at 25° C. for 1 hour with stirring. After the reaction is complete, add water (20mL) to quench, then extract with ethyl acetate (25mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and the crude product is purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume ammonia water (30%), B=acetonitrile; gradient: 5%-35%, 8 min), concentrate and dry to obtain 3-(2-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-((3,3,3-trifluoropropyl)carbamoyl)thiophene-2-sulfonamide (36.5mg, yield 18.3%). 1 H NMR (400 MHz, DMSO_d6) δ 7.72(s, 1H), 7.63-7.65(m, 1H), 7.47-7.49(m, 1H), 7.33(s, 1H), 7.00(s, 1H), 6.89(s, 1H), 6.22(s, 1H), 5. 39(s, 2H), 3.15-3.17(m, 2H), 2.70(d, 2H), 2.36(s, 3H), 2.32-2.34(m, 2H), 1.85-1.89(m, 1H), 0.93(d, 6H). LC-MS, M / Z(ESI): 554.3 [M+H] +

[0407] Example 17: Preparation of target compound I-19 5-Isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-((pyridin-2-ylmethyl)carbamoyl)thiophene-2-sulfonamide

[0408] [ka]

[0409] The synthetic route to the target compound I-19 is as follows.

[0410] [ka]

[0411] Step 1: Synthesis of (pyridin-2-ylmethyl)phenylcarbamate

[0412] [ka]

[0413] Pyridin-2-ylmethylamine (3.00 g, 27.7 mmol) is dissolved in dichloromethane (30 mL), then triethylamine (2.81 g, 27.7 mmol) and phenylchloroformate (5.21 g, 33.3 mmol) are added and reacted for 1 hour at 25° C. The reaction solution is poured into water (50 mL), extracted three times with ethyl acetate (50 mL), the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (pyridin-2-ylmethyl group) phenylcarbamate (3.00 g, 47.4% yield). LC-MS, M / Z(ESI): 229.1 [M+H] +

[0414] Step 2: Synthesis of 5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-((pyridin-2-ylmethyl)carbamoyl)thiophene-2-sulfonamide

[0415] [ka]

[0416] Dissolve 5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (40.0 mg, 99.1 μmol) and (pyridin-2-ylmethyl)phenylcarbamate (22.6 mg, 99.1 μmol) in acetonitrile (4.00 mL), add 1,8-diazabicyclo[5.4.0]undequa-7-ene (15.1 mg, 99.1 μmol), and react at 60°C for 1 hour with stirring. After the reaction is complete, add water (10 mL) to quench, then extract with dichloromethane (20 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and separate and purify the crude product by high performance liquid chromatography (column: Waters Xbridge 150 * 25 mm * 5 um; solvent: A = water + 0.05 volume ammonia water (30%), B = acetonitrile; gradient: %-35%, 8 min), concentrate and dry to obtain 5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-((pyridin-2-ylmethyl)carbamoyl)thiophene-2-sulfonamide (9.25 mg, yield 17.4%). 1 H NMR (400 MHz, CDCl3) δ 8.33(s, 1H), 7.47-7.49(m, 1H), 7.09-7.14(m, 2H), 7.02-7.03(m, 1H), 6.76-6.84(m, 4H), 6.43(s, 1H) ), 4.91(s, 2H), 4.13(s, 2H), 2.51(d, 2H), 2.25(s, 3H), 1.93(s, 3H), 1.82-1.86(m, 1H), 0.87(d, 6H). LC-MS, M / Z(ESI): 538.2 [M+H] +

[0417] Example 18: Preparation of target compound I-21 ((5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0418] [ka]

[0419] The synthetic route to the target compound I-21 is as follows.

[0420] [ka]

[0421] Step 1: Synthesis of 4-bromo-1-(bromomethyl)-2-methylbenzene

[0422] [ka]

[0423] (4-Bromo-2-methyl-phenyl)methanol (1 g, 4.97 mmol) is dissolved in dichloromethane (20 mL), carbon tetrabromide (1.98 g, 5.97 mmol) is added, and triphenylphosphine (1.57 g, 5.97 mmol) is added after the addition is complete, and the reaction solution is reacted at 20 °C for 2 hours. The reaction solution is then poured into water (50 mL), extracted three times with ethyl acetate (100 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-20:1) to obtain 4-bromo-1-(bromomethyl)-2-methylbenzene (1.1 g, 83.8% yield).

[0424] Step 2: Synthesis of 1-(4-bromo-2-methylbenzenemethyl)-2-methyl-1H-imidazole

[0425] [ka]

[0426] 4-Bromo-1-(bromomethyl)-2-methylbenzene (1.00 g, 3.79 mmol) and 2-methyl-1H-imidazole (311 mg, 3.79 mmol) are dissolved in N,N-dimethylformamide (10.0 mL), and then potassium carbonate (1.57 g, 11.4 mmol) is added and reacted at 50 °C for 2 hours. The reaction solution is poured into water (20 mL), extracted three times with ethyl acetate (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromo-2-methylbenzenemethyl)-2-methyl-1H-imidazole (800 mg, yield 79.6%). LC-MS, M / Z(ESI): 265.2 [M+H] + .

[0427] Step 3: Synthesis of N-(t-butyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0428] [ka]

[0429] (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (260 mg, 814 μmol) is dissolved in tetrahydrofuran (5.00 mL) and water (5.00 mL), and 1-(4-bromo-2-methylbenzenemethyl)-2-methyl-1H-imidazole (216 mg, 814 μmol) is added, and potassium phosphate (864 mg, 4.07 mmol) and Xphos Pd G4 (70.1 mg, 81.4 μmol) are added, and then the mixture is reacted for 1 hour with stirring at 60° C. under nitrogen gas protection. The reaction solution is concentrated to obtain the crude product, which is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-1:1) to obtain N-(t-butyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (300 mg, yield 80.1%). LC-MS, M / Z(ESI): 460.4 [M+H] + .

[0430] Step 4: Synthesis of 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0431] [ka]

[0432] N-(t-butyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (300 mg, 653 μmol) is dissolved in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) and reacted at 25 °C for 1 hour. The reaction solution is poured into water (10 mL), adjusted to pH = 9 with saturated sodium bicarbonate, and then extracted with dichloromethane (20 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10: 1-1: 1) to obtain 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (200 mg, yield 75.9%). LC-MS, M / Z(ESI): 404.6 [M+H] + .

[0433] Step 5: Synthesis of methyl ((5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0434] [ka]

[0435] Dissolve 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (100 mg, 248 μmol) and N,N-diisopropylethylamine (96.1 mg, 743 μmol) in dichloromethane (10.0 mL), add methyl chloroformate (141 mg, 1.49 mmol), and react at 0°C for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 12%-42%, 15 min), concentrated and dried to obtain methyl ((5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (100mg, yield 87.4%). 1 H NMR (CDCl3, 400 MHz) δ: 7.50(d, 1H), 7.44(s, 1H), 6.86(s, 1H), 6.73-6.77(m, 2H), 6.64(s, 1H), 5.07(s, 2H), 3.61(s, 3H), 2.70(d, 2H), 2.60(s, 3H), 2.19(s, 3H), 1.93-2.00(m, 1H), 1.00(d, 6H). LC-MS, M / Z(ESI): 462.6 [M+H] + .

[0436] Example 19: Preparation of target compound I-22 N-(ethylcarbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0437] [ka]

[0438] The synthetic route to the target compound I-22 is as follows.

[0439] [ka]

[0440] Step 1: Synthesis of N-(ethylcarbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0441] [ka]

[0442] Dissolve 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (100 mg, 248 μmol) and triethylamine (50.2 mg, 496 μmol) in dichloromethane (5 mL), add ethyl isocyanate (17.6 mg, 248 μmol), and react at 0°C for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume ammonia water (30%), B=acetonitrile; gradient: 3%-33%, 9 min), concentrated and dried to obtain N-(ethylcarbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (45.1 mg, yield 36.4%). 1 H NMR (400 MHz, DMSO_d6) δ 7.41-7.43(m, 2H), 7.10(s, 1H), 6.83-6.84(m, 2H), 6.49(d, 1H), 5.17(s, 2H), 2.89-2.92(m , 2H), 2.66(d, 2H), 2.30(s, 3H), 2.23(s, 3H), 1.84-1.86(m, 1H), 1.14(t, 3H), 0.93(d, 6H). LC-MS, M / Z(ESI): 475.2 [M+H] +

[0443] Example 20: Preparation of target compound I-23 N-((2-hydroxyethyl)carbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0444] [ka]

[0445] The synthetic route to the target compound I-23 is as follows.

[0446] [ka]

[0447] Step 1: Synthesis of (2-((t-butyldimethylsilyl)oxy)ethyl)phenylcarbamate

[0448] [ka]

[0449] Dissolve 2-((t-butyldimethylsilyl)oxy)ethan-1-amine (1.00 g, 5.70 mmol) in dichloromethane (10 mL), then add triethylamine (1.15 g, 11.4 mmol) and phenylchloroformate (1.07 g, 6.84 mmol) and react at 25° C. for 1 hour. Pour the reaction mixture into water (50 mL), extract with dichloromethane (50 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate to obtain (2-((t-butyldimethylsilyl)oxy)ethyl)phenylcarbamate (800 mg, 47.5% yield). LC-MS, M / Z(ESI): 296.2 [M+H] +

[0450] Step 2: Synthesis of N-((2-((t-butyldimethylsilyl)oxy)ethyl)carbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfame potassium

[0451] [ka]

[0452] Dissolve 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (150 mg, 372 μmol) and 1,8-diazabicyclo[5.4.0]undequa-7-ene (170 mg, 1.12 mmol) in acetonitrile (5 mL), add (2-((t-butyldimethylsilyl)oxy)ethyl)phenylcarbamate (132 mg, 446 μmol), and react at 25° C. for 1 hour with stirring. After the reaction is complete, add water (20 mL) and quench, then extract with ethyl acetate (25 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and separate and purify the crude product by high performance liquid chromatography (column: Waters Xbridge 150*25 mm* 5 um; solvent: A = water + 0.05 volume ammonia water (30%), B = acetonitrile; gradient: 15%-45%, 8 min), concentrate and dry to obtain N-((2-((t-butyldimethylsilyl)oxy)ethyl)carbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (150 mg, yield 66.7%). LC-MS, M / Z(ESI): 605.1 [M+H] +

[0453] Step 3: Synthesis of N-((2-hydroxyethyl)carbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0454] [ka]

[0455] Dissolve N-((2-((t-butyldimethylsilyl)oxy)ethyl)carbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (100 mg, 165 μmol) in ethyl acetate (2 mL), add hydrochloric acid ethyl acetate solution (4 M, 1 mL), and react for 1 hour with stirring at 25 °C. Concentrate the reaction solution, pulp the residue with dichloromethane (2 mL), and filter to obtain N-((2-hydroxyethyl)carbamoyl)-5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (12.0 mg, 13.6% yield). 1 H NMR (400 MHz, DMSO_d6) δ 7.64(s, 1H), 7.52(s, 1H), 7.36-7.39(m, 2H), 6.90(s, 1H), 6.83(d, 1H), 6.37(t, 1H), 5.43(s, 2H), 4.73(brs, 1H) ), 3.30-3.31(m, 2H), 2.97-3.01(m, 2H), 2.71(d, 2H), 2.58(s, 3H), 2.33(s, 3H), 1.86-1.90(m, 1H), 0.93(d, 6H). LC-MS, M / Z(ESI): 491.3 [M+H] +

[0456] Example 21: Preparation of target compound I-24 ((3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0457] [ka]

[0458] The synthetic route to the target compound I-24 is as follows.

[0459] [ka]

[0460] Step 1: Synthesis of methyl ((3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate Dissolve 3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (100 mg, 241 μmol) and N,N-diisopropylethylamine (93.5 mg, 724 μmol) in dichloromethane (5 mL), add methyl chloroformate (137 mg, 248 μmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume ammonia water (30%), B=acetonitrile; gradient: 5%-35%, 8 min), concentrated and dried to obtain methyl ((3-(3-cyano-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (93.3mg, yield 81.8%). 1 H NMR (400 MHz, CDCl3) δ 8.01(d, 1H), 7.87(dd, 1H), 7.28(d, 1H), 6.80(d, 1H), 6.66(s, 1H), 6.30(s, 1H), 5. 12(s, 2H), 3.52(s, 3H), 2.72(s, 3H), 2.63(d, 2H), 1.85-1.90(m, 1H), 0.92(d, 6H). LC-MS, M / Z(ESI): 473.2 [M+H] +

[0461] Example 22: Preparation of target compound I-25 ((3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0462] [ka]

[0463] The synthetic route to the target compound I-25 is as follows.

[0464] [ka]

[0465] Step 1: Synthesis of 1-(4-bromo-3-methylbenzenemethyl)-2-(t-butyl)-1H-imidazole

[0466] [ka]

[0467] Dissolve 1-bromo-4-(bromomethyl)-2-methylbenzene (500 mg, 1.89 mmol) and 2-(t-butyl)-1H-imidazole (235 mg, 1.89 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (785 mg, 5.68 mmol), and react at 50 °C for 2 hours. Pour the reaction mixture into water (25 mL), extract with ethyl acetate (50 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromo-3-methylbenzenemethyl)-2-(t-butyl)-1H-imidazole (400 mg, yield 68.7%). LC-MS, M / Z(ESI): 309.2 [M+H] +

[0468] Step 2: Synthesis of N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide

[0469] [ka]

[0470] (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (250 mg, 783 μmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL), and added to 1-(4-bromo-3-methylbenzenemethyl)-2-(t-butyl)-1H-imidazole (241 mg, 783 μmol), potassium phosphate (830 mg, 3.92 mmol), and XPhos Pd G4 (67.4 mg, 78.3 μmol), and then the mixture was stirred at 60° C. under nitrogen gas protection for 4 hours. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide (300 mg, yield 76.4%). LC-MS, M / Z(ESI): 502.3 [M+H] +

[0471] Step 3: Synthesis of 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide

[0472] [ka]

[0473] N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide (200 mg, 399 μmol) is dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) and reacted at 25 °C for 8 hours. The reaction solution is poured into water (10 mL), extracted three times with dichloromethane (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10: 1-1: 1) to obtain 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide (150 mg, yield 84.4%). LC-MS, M / Z(ESI): 446.2 [M+H] +

[0474] Step 4: Synthesis of methyl ((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0475] [ka]

[0476] Dissolve 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophene-2-sulfonamide (100 mg, 224 μmol) and N,N-diisopropylethylamine (87.0 mg, 673 μmol) in dichloromethane (2 mL), add methyl chloroformate (137 mg, 1.45 mmol), and react at 0°C for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume ammonia water (30%), B=acetonitrile; gradient: 8%-38%, 9 min), concentrated and dried to obtain methyl ((3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)-2-methylphenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (38.7mg, yield 38.7%). 1 H NMR (400 MHz, DMSO d6) δ 7.15(d, 1H), 7.01(s, 1H), 6.86-6.89(m, 2H), 6.75-6.78(m, 1H), 6.51(s, 1H), 5.36(s, 2) H), 3.25(s, 3H), 3.17(s, 3H), 2.61(d, 2H), 1.82-1.87(m, 1H), 1.34(s, 9H), 0.93(d, 6H). LC-MS, M / Z(ESI): 504.4 [M+H] +

[0477] Example 23: Preparation of target compound I-26 ((3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0478] [ka]

[0479] The synthetic route to the target compound I-26 is as follows.

[0480] [ka]

[0481] Step 1: Synthesis of 1-(4-bromobenzyl)-2-(t-butyl)-1H-imidazole

[0482] [ka]

[0483] 1-Bromo-4-(bromomethyl)benzene (500 mg, 2.00 mmol) and 2-t-butyl-1H-imidazole (248 mg, 2.00 mmol) are dissolved in N,N-dimethylformamide (5 mL), and then potassium carbonate (830 mg, 6.00 mmol) is added and reacted at 55 °C for 1 h. The reaction solution is poured into water (25 mL), extracted three times with ethyl acetate (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromobenzyl)-2-(t-butyl)-1H-imidazole (400 mg, yield 68.2%). LC-MS, M / Z(ESI): 293.1 [M+H] +

[0484] Step 2: Synthesis of N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0485] [ka]

[0486] (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (250 mg, 750 μmol) is dissolved in tetrahydrofuran (5 mL) and water (2 mL), and 1-(4-bromobenzyl)-2-(t-butyl)-1H-imidazole (220 mg, 750 μmol) is added, followed by potassium phosphate (796 mg, 3.75 mmol) and XPhos Pd G4 (64.6 mg, 75.0 μmol). The mixture is then stirred at 60° C. under nitrogen gas protection for 2 hours. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (250 mg, yield 66.4%). LC-MS, M / Z(ESI): 502.3 [M+H] +

[0487] Step 3: Synthesis of 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0488] [ka]

[0489] N-(t-butyl)-3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (200 mg, 399 μmol) is dissolved in trifluoroacetic acid (5 mL) and dichloromethane (4 mL) and reacted at 30° C. for 2 hours. The reaction solution is poured into water (10 mL), then extracted with dichloromethane (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V)=10:1-1:1) to obtain 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, yield 84.4%). LC-MS, M / Z(ESI): 446.2 [M+H] +

[0490] Step 4: Synthesis of methyl ((3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate

[0491] [ka]

[0492] Dissolve 3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (100 mg, 224 μmol) and N,N-diisopropylethylamine (87.0 mg, 673 μmol) in dichloromethane (2.00 mL), add methyl chloroformate (127 mg, 1.35 mmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 20%-50%, 15 min), concentrated and dried to obtain methyl ((3-(4-((2-(t-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (330mg, yield 33.0%). 1 H NMR (400 MHz, CDCl3) δ 7.24(d, 2H), 7.13(d, 2H), 6.95(s, 1H), 6.78(s, 1H), 5.38(s, 2H), 3.68(s, 3 H), 2.68(d, 2H), 1.92-1.97(m, 1H), 1.85(s, 3H), 1.45(s, 9H), 1.01(d, 6H). LC-MS, M / Z(ESI): 504.2 [M+H] +

[0493] Example 24: Preparation of target compound I-27 ((3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0494] [ka]

[0495] The synthetic route to the target compound I-27 is as follows.

[0496] [ka]

[0497] Step 1: Synthesis of 5-bromo-2-((2-isopropyl-1H-imidazol-1-yl)methyl)benzonitrile

[0498] [ka]

[0499] 5-Bromo-2-(bromomethyl)benzonitrile (200 mg, 727 μmol) and 2-isopropyl-1H-imidazole (80.1 mg, 727 μmol) are dissolved in N,N-dimethylformamide (10 mL), and then potassium carbonate (302 mg, 2.18 mmol) is added and reacted at 50 °C for 2 hours. The reaction solution is poured into water (25 mL), extracted with ethyl acetate (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 5-bromo-2-((2-isopropyl-1H-imidazol-1-yl)methyl)benzonitrile (150 mg, 67.8% yield). LC-MS, M / Z(ESI): 304.0 [M+H] +

[0500] Step 2: Synthesis of N-(t-butyl)-3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0501] [ka]

[0502] (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (150 mg, 470 μmol) is dissolved in tetrahydrofuran (10 mL) and water (2 mL), and 5-bromo-2-((2-isopropyl-1H-imidazol-1-yl)methyl)benzonitrile (143 mg, 470 μmol) is added, followed by potassium phosphate (299 mg, 1.41 mmol) and XPhos Pd G4 (40.4 mg, 47.0 μmol). The mixture is then stirred at 60° C. under nitrogen gas protection for 2 hours. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (200 mg, yield 85.4%). LC-MS, M / Z(ESI): 499.2 [M+H] +

[0503] Step 3: Synthesis of 3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0504] [ka]

[0505] N-(t-butyl)-3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (180 mg, 361 μmol) is dissolved in trifluoroacetic acid (5 mL) and dichloromethane (3 mL) and reacted at 30° C. for 2 hours. The reaction solution is poured into water (10 mL), then extracted with dichloromethane (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V)=10:1-1:1) to obtain 3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (150 mg, yield 93.9%). LC-MS, M / Z(ESI): 443.2 [M+H] +

[0506] Step 4: Synthesis of methyl ((3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0507] [ka]

[0508] 3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (5) (130 mg, 294 μmol) and N,N-diisopropylethylamine (114 mg, 881 μmol) are dissolved in dichloromethane (10.0 mL), methyl chloroformate (179 mg, 1.89 mmol) is added, and the mixture is reacted at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume ammonia water (30%), B=acetonitrile; gradient: 8%-38%, 9 min), concentrated and dried to obtain methyl ((3-(3-cyano-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (120mg, yield 81.6%). 1 H NMR (400 MHz, CDCl3) δ 7.95(s, 1H), 7.83(d, 1H), 7.12(s, 1H), 7.04(d, 1H), 6.73(s, 2H), 5.35(s, 2H), 3.67( s, 3H), 3.16-3.20(m, 1H), 2.72(d, 2H), 1.94-1.96(m, 1H), 1.40(d, 6H), 1.01(d, 6H). LC-MS, M / Z(ESI): 501.2 [M+H] +

[0509] Example 25: Preparation of target compound I-28 Ethyl ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0510] [ka]

[0511] The synthetic route to the target compound I-28 is as follows.

[0512] [ka]

[0513] Step 1: Synthesis of ethyl ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0514] [ka]

[0515] Dissolve 5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (300 mg, 743 μmol) and N,N-diisopropylethylamine (288 mg, 2.23 mmol) in dichloromethane (5 mL), add ethyl chloroformate (242 mg, 2.23 mmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 15%-45%, 15 min), concentrated and dried to obtain ethyl ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (300mg, yield 84.9%). 1 H NMR (400 MHz, DMSO_d6) δ 7.44(s, 1H), 7.20-7.26(m, 5H), 5.30(s, 2H), 3.81(q, 2H), 2.63(d, 2H), 1.82-1.85(m, 1H), 1.74(s, 3H), 1.03(t, 6H), 0.95(d, 6H). LC-MS, M / Z(ESI): 476.2 [M+H] +

[0516] Example 26: Preparation of target compound I-29 ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate propyl

[0517] [ka]

[0518] The synthetic route to the target compound I-29 is as follows.

[0519] [ka]

[0520] Step 1: Synthesis of ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate propyl

[0521] [ka]

[0522] Dissolve 5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (90.0 mg, 223 μmol) and N,N-diisopropylethylamine (86.5 mg, 669 μmol) in dichloromethane (5.00 mL), add propyl chloroformate (27.3 mg, 223 μmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume ammonia water (30%), B=acetonitrile; gradient: 13%-43%, 35 min), concentrated and dried to obtain ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)propyl carbamate (12.6 mg, yield 13.9%). 1 H NMR (400 MHz, DMSO d6) δ 7.40(s, 1H), 7.19-7.25(m, 4H), 7.13(s, 1H), 5.28(s, 2H), 3.70(t, 2H), 2.62(d, 2H), 2. 41(s, 3H), 1.84-1.87(m, 1H), 1.77(s, 3H), 1.41-1.43(m, 2H), 0.95(d, 6H), 0.79(t, 3H). LC-MS, M / Z(ESI): 490.2 [M+H] +

[0523] Example 27: Preparation of target compound I-31 ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)butylcarbamate

[0524] [ka]

[0525] The synthetic route to the target compound I-31 is as follows.

[0526] [ka]

[0527] Step 1: Synthesis of ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)butylcarbamate

[0528] [ka]

[0529] Dissolve 5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (100 mg, 248 μmol) and N,N-diisopropylethylamine (64.1 mg, 496 μmol) in dichloromethane (5 mL), add butyl chloroformate (67.7 mg, 496 μmol), and react at 0° C. for 0.5 hours with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Phenomenex Luna C18 150*25mm*10um; solvent: A=water+0.05 volume trifluoroacetic acid (99%), B=acetonitrile; gradient: 33%-63%, 9 min), concentrated and dried to obtain ((5-isobutyl-4-methyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)butylcarbamate (42.4mg, yield 34.0%). 1 H NMR (400 MHz, DMSO d6): δ 11.65(brs, 1H), 7.71(d, 1H), 7.64(d, 1H), 7.38(d, 2H), 7.25(d, 2H), 5.44(s, 2H), 3.96(t, 2H), 2.70(d, 2H), 2.61(s, 3H), 1.84-1.93(m, 1H), 1.80(s, 3H), 1.38-1.47(m, 2H), 1.16-1.26(m, 2H), 0.96(d, 6H), 0.84(t, 3H). LC-MS, M / Z(ESI): 504.2 [M+H] +

[0530] Example 28: Preparation of target compound I-32 ((3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0531] [ka]

[0532] The synthetic route to the target compound I-32 is as follows.

[0533] [ka]

[0534] Step 1: Synthesis of 1-(4-bromobenzyl)-2-ethyl-1H-imidazole

[0535] [ka]

[0536] Dissolve 1-bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-ethyl-1H-imidazole (384 mg, 4.00 mmol) in N,N-dimethylformamide (30 mL), add potassium carbonate (1.66 g, 12.0 mmol), and react at 50 °C for 2 hours. Pour the reaction mixture into water (25 mL), extract with ethyl acetate (100 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromobenzyl)-2-ethyl-1H-imidazole (900 mg, 84.8% yield). LC-MS, M / Z(ESI): 267.2 [M+H] +

[0537] Step 2: Synthesis of N-(t-butyl)-3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0538] [ka]

[0539] (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) is dissolved in tetrahydrofuran (5 mL) and water (5 mL), and 1-(4-bromobenzyl)-2-ethyl-1H-imidazole (318 mg, 1.20 mmol) is added. Potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol) are further added, and the mixture is then reacted for 4 hours at 60° C. with stirring under nitrogen gas protection. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (450 mg, yield 79.1%). LC-MS, M / Z(ESI): 474.3 [M+H] +

[0540] Step 3: Synthesis of 3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0541] [ka]

[0542] N-(t-butyl)-3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (400 mg, 844 μmol) is dissolved in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) and reacted at 40 °C for 8 hours. The reaction solution is poured into water (10 mL), extracted three times with dichloromethane (50 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10: 1-1: 1) to obtain 3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (320 mg, yield 90.6%). LC-MS, M / Z(ESI): 418.4 [M+H] +

[0543] Step 4: Synthesis of methyl ((3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate

[0544] [ka]

[0545] Dissolve 3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (316 mg, 759 μmol) and N,N-diisopropylethylamine (294 mg, 2.28 mmol) in dichloromethane (5 mL), add methyl chloroformate (430 mg, 4.55 mmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Phenomenex Luna C18 150*25mm*10um; solvent: A= water + 0.05 volume formic acid (99%), B=acetonitrile; gradient: 25%-55%, 9 min), concentrated and dried to obtain methyl ((3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (241 mg, yield 80.3%). 1 H NMR (400 MHz, CDCl3) δ: 7.33(d, 2H), 7.17(d, 2H), 6.70(s, 2H), 5.08(s, 2H), 3.65(s, 3H), 2.80-2.85( m, 2H), 2.67(d, 2H), 1.92-2.01(m, 1H), 1.84(s, 3H), 1.28(t, 3H), 1.01(d, 6H). LC-MS, M / Z(ESI): 476.4 [M+H] +

[0546] Example 29: Preparation of target compound I-33 ((5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0547] [ka]

[0548] The synthetic route to the target compound I-33 is as follows.

[0549] [ka]

[0550] Step 1: Synthesis of 1-(4-bromobenzyl)-2-isopropyl-1H-imidazole

[0551] [ka]

[0552] Dissolve 1-bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-isopropyl-1H-imidazole (441 mg, 4.00 mmol) in N,N-dimethylformamide (15 mL), add potassium carbonate (1.66 g, 12.0 mmol), and react at 55 °C for 1 hour. Pour the reaction mixture into water (50 mL), extract with ethyl acetate (50 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromobenzyl)-2-isopropyl-1H-imidazole (900 mg, 80.6% yield). LC-MS, M / Z(ESI): 279.0 [M+H] +

[0553] Step 2: Synthesis of N-(t-butyl)-5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophene-2-sulfonamide

[0554] [ka]

[0555] (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) is dissolved in tetrahydrofuran (6 mL) and water (2 mL), and 1-(4-bromobenzyl)-2-isopropyl-1H-imidazole (302 mg, 1.08 mmol) is added. Potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol) are further added. The mixture is then reacted for 2 hours at 60° C. with stirring under nitrogen gas protection. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophene-2-sulfonamide (430 mg, yield 73.5%). LC-MS, M / Z(ESI): 488.2 [M+H] +

[0556] Step 3: Synthesis of 5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophene-2-sulfonamide [ka]

[0557] N-(t-butyl)-5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophene-2-sulfonamide (430 mg, 882 μmol) is dissolved in trifluoroacetic acid (15 mL) and dichloromethane (5 mL) and reacted at 40° C. for 1 hour. The reaction solution is poured into water (10 mL), then extracted three times with dichloromethane (20 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V)=10:1-1:1) to obtain 5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophene-2-sulfonamide (350 mg, yield 92.0%). LC-MS, M / Z(ESI): 432.2 [M+H] +

[0558] Step 4: Synthesis of methyl ((5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophen-2-yl)sulfonyl)carbamate

[0559] [ka]

[0560] Dissolve 5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophene-2-sulfonamide (300 mg, 695 μmol) and N,N-diisopropylethylamine (270 mg, 2.09 mmol) in dichloromethane (5 mL), add methyl chloroformate (394 mg, 4.17 mmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 17%-47%, 10 min), concentrated and dried to obtain methyl ((5-isobutyl-3-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-4-methylthiophen-2-yl)sulfonyl)carbamate (182 mg, yield 53.4%). 1 H NMR (400 MHz, CDCl3): δ 7.26(d, 2H), 7.15(d, 2H), 6.90(d, 1H), 6.78(d, 1H), 5.15(s, 2H), 3.67(s, 3H), 3.02- 3.09(m, 1H), 2.68(d, 2H), 1.93-1.97(m, 1H), 1.83(s, 3H), 1.31(d, 6H), 1.01(d, 6H). LC-MS, M / Z(ESI): 490.2 [M+H] +

[0561] Example 30: Preparation of target compound I-34 ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0562] [ka]

[0563] The synthetic route to the target compound I-34 is as follows.

[0564] [ka]

[0565] Step 1: Synthesis of 1-(4-bromobenzyl)-2-chloro-1H-imidazole

[0566] [ka]

[0567] Dissolve 1-bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-chloro-1H-imidazole (410 mg, 4.00 mmol) in N,N-dimethylformamide (20.0 mL), add potassium carbonate (1.66 g, 12.0 mmol), and react at 55 °C for 1 h. Pour the reaction mixture into water (50 mL), extract with ethyl acetate (50 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromobenzyl)-2-chloro-1H-imidazole (900 mg, 82.8% yield). LC-MS, M / Z(ESI): 271.0 [M+H] +

[0568] Step 2: Synthesis of N-(t-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0569] [ka]

[0570] (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) is dissolved in tetrahydrofuran (6 mL) and water (2 mL), and 1-(4-bromobenzyl)-2-chloro-1H-imidazole (293 mg, 1.08 mmol) is added. Potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol) are then added. The mixture is then stirred at 60° C. under nitrogen gas protection for 2 hours. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (510 mg, yield 88.5%). LC-MS, M / Z(ESI): 480.2 [M+H] +

[0571] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0572] [ka]

[0573] N-(t-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (500 mg, 1.04 mmol) is dissolved in trifluoroacetic acid (15 mL) and dichloromethane (5 mL) and reacted at 40° C. for 1 hour. The reaction solution is poured into water (10 mL), then extracted three times with dichloromethane (20 mL), and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V)=10:1-1:1) to obtain the brown oily compound 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (400 mg, 90.6% yield). LC-MS, M / Z(ESI): 424.1 [M+H] +

[0574] Step 4: Synthesis of methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate

[0575] [ka]

[0576] Dissolve 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (350 mg, 826 μmol) and N,N-diisopropylethylamine (320 mg, 2.48 mmol) in dichloromethane (5 mL), add methyl chloroformate (468 mg, 4.95 mmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 48%-78%, 10 min), concentrated and dried to obtain methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (155mg, yield 38.9%). 1 H NMR (400 MHz, CDCl3): δ 7.23-7.26(m, 4H), 6.99-7.01(d, 1H), 6.97(d, 1H), 5.17(s, 2H), 3.70(s, 3H), 2.69(d, 2H), 1.95-2.01(m, 1H), 1.86(s, 3H), 1.02(d, 6H). LC-MS, M / Z(ESI): 482.1 [M+H] +

[0577] Example 31: Preparation of target compound I-15 ((5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0578] [ka]

[0579] The synthetic route to the target compound I-15 is as follows.

[0580] [ka]

[0581] Step 1: Synthesis of 1-(1-(4-bromophenyl)ethyl)-2-methyl-1H-imidazole

[0582] [ka]

[0583] Dissolve 1-bromo-4-(1-bromoethyl)benzene (1.00 g, 3.79 mmol) and 2-methyl-1H-imidazole (933 mg, 11.3 mmol) in N,N-dimethylformamide (20 mL), add potassium carbonate (1.57 g, 11.3 mmol), and react at 50 °C for 2 hours. Pour the reaction mixture into water (50 mL), extract with ethyl acetate (100 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(1-(4-bromophenyl)ethyl)-2-methyl-1H-imidazole (900 mg, 89.6% yield). LC-MS, M / Z(ESI): 267.0 [M+H] +

[0584] Step 2: Synthesis of N-(t-butyl)-5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophene-2-sulfonamide

[0585] [ka]

[0586] (2-(N-(t-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (500 mg, 1.57 mmol) is dissolved in tetrahydrofuran (10 mL) and water (5 mL), 1-(1-(4-bromophenyl)ethyl)-2-methyl-1H-imidazole (415 mg, 1.57 mmol) is added, potassium phosphate (1.66 g, 7.83 mmol), and XPhos Pd G4 (134 mg, 156 μmol) are further added, and the mixture is reacted for 4 hours with stirring at 60° C. under nitrogen gas protection. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophene-2-sulfonamide (610 mg, yield 84.7%). LC-MS, M / Z(ESI): 460.1 [M+H] +

[0587] Step 3: Synthesis of 5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophene-2-sulfonamide

[0588] [ka]

[0589] N-(t-butyl)-5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophene-2-sulfonamide (500 mg, 1.09 mol) is dissolved in trifluoroacetic acid (5 mL) and dichloromethane (10 mL) and reacted at 20° C. for 8 hours. The reaction solution is poured into water (10 mL) and extracted three times with dichloromethane (50 mL). The organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V)=10:1-0:1) to obtain 5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophene-2-sulfonamide (410 mg, yield 93.4%). LC-MS, M / Z(ESI): 404.1 [M+H] +

[0590] Step 4: Synthesis of methyl ((5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0591] [ka]

[0592] Dissolve 5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophene-2-sulfonamide (400 mg, 991 μmol) and N,N-diisopropylethylamine (384 mg, 2.91 mmol) in dichloromethane (10 mL), add methyl chloroformate (93.5 mg, 991 μmol), and react at 0° C. for 0.5 hours with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; solvent: A=water+0.05 volume ammonia water (30%), B=acetonitrile; gradient: 0%-20%, 10 min), concentrated and dried to obtain methyl ((5-isobutyl-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (220mg, yield 52.2%). 1 H NMR (400 MHz, DMSO_d6) δ 7.69-7.81(m, 3H), 7.36(s, 1H), 7.28(d, 2H), 6.80(s, 1H), 5.66-5.69(m, 1 H), 3.27(s, 3H), 2.62(d, 2H), 2.48(s, 3H), 1.80-1.88(m, 4H), 0.93(d, 6H). LC-MS, M / Z(ESI): 462.2 [M+H] +

[0593] Example 32: Preparation of target compound I-30 Methyl ((5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0594] [ka]

[0595] The synthetic route to the target compound I-30 is as follows.

[0596] [ka]

[0597] Step 1: Synthesis of N-(t-butyl)-5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0598] [ka]

[0599] (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) is dissolved in tetrahydrofuran (10 mL) and water (5 mL), and 1-(4-bromo-3-methylbenzyl)-2-methyl-1H-imidazole (286 mg, 1.08 mmol) is added, followed by potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (102 mg, 120 μmol). The mixture is then stirred at 60° C. under nitrogen gas protection for 2 hours. The reaction mixture is concentrated to obtain a crude product, which is then purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (300 mg, crude product). LC-MS, M / Z(ESI): 474.2 [M+H] +

[0600] Step 3: Synthesis of 5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0601] [ka]

[0602] Dissolve N-(t-butyl)-5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (300 mg, 633 μmol) in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) and react at 40° C. for 2 hours. Pour the reaction mixture into water (10 mL), extract with dichloromethane (50 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (200 mg, crude product). LC-MS, M / Z(ESI): 418.2 [M+H] +

[0603] Step 4: Synthesis of methyl ((5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0604] [ka]

[0605] Dissolve 5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (200 mg, 479 μmol) and methyl chloroformate (90.5 mg, 958 μmol) in dichloromethane (5 mL), add N,N-diisopropylethylamine (186 mg, 1.44 mmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 25%-55%, 7 min), concentrated and dried to obtain methyl ((5-isobutyl-4-methyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (10.6 mg, yield 5.30%). 1 H NMR (400 MHz, CDCl3) δ 7.18(d, 1H), 7.06(s, 1H), 6.99(d, 1H), 6.66(d, 1H), 6.49(d, 1H), 4.97(s, 2H), 3.68(s, 3 H), 2.68(d, 2H), 2.41(s, 3H), 2.05(s, 3H), 1.94-2.01(m, 1H), 1.72(s, 3H), 1.00(d, 6H). LC-MS, M / Z(ESI): 476.1 [M+H] +

[0606] Example 33: Preparation of target compound I-35 ((5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamic acid methyl ester

[0607] [ka]

[0608] The synthetic route to the target compound I-35 is as follows.

[0609] [ka]

[0610] Step 1: Synthesis of N-(t-butyl)-5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0611] [ka]

[0612] (2-(N-(t-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) is dissolved in tetrahydrofuran (5 mL) and water (5 mL), and 1-(4-bromo-2-methylbenzyl)-2-methyl-1H-imidazole (254 mg, 960 μmol) is added, followed by potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol). The mixture is then stirred at 60° C. under nitrogen gas protection for 4 hours. The reaction solution is concentrated to obtain the crude product, which is separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(t-butyl)-5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (450 mg, yield 79.1%). LC-MS, M / Z(ESI): 474.3 [M+H] +

[0613] Step 2: Synthesis of 5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0614] [ka]

[0615] Dissolve N-(t-butyl)-5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (400 mg, 844 μmol) in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) and react at 40 °C for 8 hours. Pour the reaction mixture into water (10 mL), extract with dichloromethane (50 mL) three times, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separating it on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10: 1-1: 1) to obtain 5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (320 mg, yield 90.7%). LC-MS, M / Z(ESI): 418.4 [M+H] +

[0616] Step 3: Synthesis of methyl ((5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0617] [ka]

[0618] Dissolve 5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (300 mg, 718 μmol) and N,N-diisopropylethylamine (278 mg, 2.16 mmol) in dichloromethane (5 mL), add methyl chloroformate (339 mg, 3.59 mmol), and react at 0° C. for 1 hour with stirring. The reaction solution is concentrated, separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 22%-52%, 9 min), concentrated and dried to obtain methyl ((5-isobutyl-4-methyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (153 mg, yield 51.0%). 1 H NMR (400 MHz, CDCl3) δ 7.16-7.23(m, 2H), 6.96(d, 1H), 6.66(d, 1H), 6.54(d, 1H), 4.99(s, 2H), 3.66(s, 3H), 2.67(d, 2H), 2.52(s, 3H), 2.19(s, 3H), 1.94-1.97(m, 1H), 1.86(s, 3H), 1.02(d, 6H). LC-MS, M / Z(ESI): 476.4 [M+H] +

[0619] Example 34: Preparation of target compound I-36 ((5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)butylcarbamate

[0620] [ka]

[0621] The synthetic route to the target compound I-36 is as follows.

[0622] [ka]

[0623] Step 1: Synthesis of ((5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)butylcarbamate Dissolve 5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (400 mg, 991 μmol) and butyl chloroformate (406 mg, 2.97 mmol) in dichloromethane (6 mL), add N,N-diisopropylethylamine (384 mg, 2.97 mmol), and react at 0° C. for 0.5 hours with stirring. After the reaction is complete, add water (50 mL) to quench, then extract with dichloromethane (25 mL × 4), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and separate and purify the crude product by high performance liquid chromatography (column: Phenomenex luna C18 150 * 40 mm; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 22%-52%, 15 min), concentrate and dry to obtain ((5-isobutyl-3-(2-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)butylcarbamate (96.0 mg, yield 18.3%). 1 H NMR (400 MHz, CDCl3) δ 7.31(d, 1H), 7.03(s, 1H), 6.93(d, 1H), 6.68(s, 1H), 6.58(s, 1H), 6.55(s, 1H), 4.97(s, 2H), 4.08(t, 2H), 2.71(d, 2H), 2.43(s, 3H), 2.15(s, 3H), 1.91-2.00(m, 1H), 1.53-1.61(m, 2H), 1.26-1.35(m, 2H), 1.00(d, 6H), 0.90(t, 3H). LC-MS, M / Z(ESI): 504.2 [M+H] +

[0624] Example 35: The preparation of the following compounds can be obtained by reference to the preparation methods of the above compounds.

[0625] [Table 1]

[0626] In the test examples of the present disclosure, the preparation method of the control compound I refers to patent WO2021229244A1, and its structure is as follows:

[0627] [ka] Control Compound I

[0628] Biological testing The following test methods can be used:

[0629] Test Example 1: Binding test of compounds and AT2R The experiment was carried out according to the experimental operating instructions of the Angiotensin AT2 Receptor Ligand Binding Assay Reagent Kit (#C1TT1AT2, Cisbio). First, gradient dilution (containing 10 concentrations, each concentration repeated twice) of 10 mM compound mother solution with 5x dilution factor was performed, and 160 nL of different concentrations of compounds were added to a 384-well plate. Add 40 μL 1xTLB to each well and shake at room temperature for 15 minutes. Prepare a 15 mL centrifuge tube containing 5 mL 1xTLB in advance and wait for use. Thaw the frozen labeled cells in a 37°C water bath (1-2 minutes), quickly transfer the thawed cells to the above 15 mL centrifuge tube, mix uniformly, and then centrifuge at 1000 g for 5 minutes at room temperature. Remove the supernatant and add 2.7 mL 1xTLB heavy suspension cells. Take a new 384-well plate and add 10 μL of the uniformly mixed cells into the corresponding wells according to the test design. Add 5 μL 4× compound solution and 5 μL 4× Tag-lite red fluorescent-labeled ligand to each well. After 1 hour of incubation at room temperature, read the data in HTRF mode on EnVision. Read the excitation emission intensity of 665nM and 615nM in each well, respectively, and calculate the ratio (Ratio = A665nM / B615nM). GraphPad Prism8 software is used to calculate IC50 values, X: logarithmic value of compound concentration; Y: ratio of A665nM / B615nM.

[0630] [Table 2]

[0631] The compounds in the present disclosure have a strong binding activity to AT2R, and the test compounds in the present disclosure have a very weak binding activity to AT1R, and the compounds have strong selectivity.

[0632] Test Example 2: CYP inhibition experiment of some compounds The inhibitory effect of the compound on seven enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (midazolam), CYP2B6, and CYP2C8, is evaluated at 10 μM. Mixed human liver microsomes are stored in a -80°C freezer before use, and are removed and thawed in a 37°C water bath before use, and placed on ice for manipulation. Take 100 μL of microsome working solution, add 2 μL of test product or positive inhibitor working solution, add 2 μL of solvent to the solvent control, and place it in a 37°C water bath to preincubate for 10 minutes. After preincubation, add 98 μL of NADPH regenerating solution to all samples to start the reaction. Then, place it back in the water bath and incubate for a while. Quench the reaction with 200 μL of stop solution. The plate is centrifuged at 3220 g for 10 min, 100 μL of the supernatant is transferred and 100 μL of water is added to the analysis plate, mixed thoroughly and subjected to LC / MS / MS analysis.

[0633] [Table 3]

[0634] Compared with the control compounds, the compounds disclosed herein have a weaker inhibitory effect on CYP enzymes, do not affect the normal metabolism of the body, are less likely to cause drug-drug interactions in the body, and are therefore highly safe.

[0635] Test Example 3: Free plasma protein binding (PPB) experiments of some compounds Soak the dried dialysis membrane in ultrapure water for 1 hour, then soak in 20% ethanol for 20 minutes, and rinse the membrane with ultrapure water 2-3 times. Finally, soak in ultrapure water for 20 minutes to prepare it. Thaw the frozen plasma in a 37 °C water bath for about 20 minutes, and measure the pH value of the plasma after thawing is complete, and adjust its pH value to 7.4 with 1% phosphoric acid solution or 0.1 M sodium hydroxide solution. When the compound to be measured was diluted in plasma preheated to 37 °C, the final concentration was 1 μM, and the final concentration of the control compound warfarin in plasma was 2 μM. Assemble the dialysis membrane pretreated according to the product's instructions into the dialysis plate, and add 100 μL of receiving solution (100 mM phosphate buffer solution plus 0.002% Twain 80) to one side of the permeable membrane for each dialysis hole. 20μL of the final solution of the target compound and the control compound were taken and placed in a 96-well sample plate for measurement, and the T0 sample was obtained after two retests and stored in a freezer at -20℃. 100μL of the above final solution was added to the other side of the membrane in the dialysis device, and incubated at 37℃ for 6h with constant temperature shaking for two retests. After 6h of incubation, 20μL of the receiving solution and the administered plasma after dialysis were taken and samples B and A were obtained after two retests. Equivalent volumes of blank plasma or receiving solution were added to samples B and A, respectively, to make the volume ratio of plasma to buffer in each sample well 1:1. 300μL of the sample of acetonitrile solution containing internal standard was added to all sample wells, mixed uniformly, and then placed in a centrifuge and centrifuged at 5500×g for 10 minutes. 150μL of the corresponding ultrapure water was added to the corresponding sample wells of the 96-well sample plate, and 150μL of the supernatant was taken and placed in the sample well, mixed uniformly, and then LC / MS / MS analysis was performed. u Calculation formula:

[0636]

number

[0637] [Table 4]

[0638] The degree of release of a compound in plasma is related to its pharmacological effect in the body, and the compounds disclosed herein have a higher degree of release than the control compound, which is advantageous for the compounds to reach the target organs.

[0639] Test Example 4: Liver microsome stability experiment of some compounds The human liver microsome stability test is detected by in vitro co-incubation of the compound with human liver microsomes. First, the compound to be measured is prepared in DMSO solvent to a stock solution of 10 mM, and then the compound is diluted to 0.5 mM using acetonitrile. Human liver microsomes (Corning) are diluted with PBS to a microsome / buffer solution, and the compound is diluted to 0.5 mM with the solution to a working solution, in which the concentration of the compound is 1.5 μM and the concentration of human liver microsomes is 0.75 mg / ml. Take a deep well plate and add 30 μL of working solution to each well, then add 15 μL of pre-warmed 6 mM NADPH solution to start the reaction and incubate at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile is added to the corresponding well to terminate the reaction. Finally, the reaction was terminated with acetonitrile at 45 min, and the deep well plate was vortexed for 10 min (600 rpm / min), then centrifuged for 15 min. After centrifugation, the supernatant was taken and purified water was added at a ratio of 1:1, followed by LC-MS / MS detection. The peak area ratios of the compounds at each time point and the internal standard peak area were obtained, and the peak area ratios of the compounds at 5, 15, 30, and 45 min were compared with the peak area ratio at 0 min. The remaining percentage of the compounds at each time point was calculated, and the T was analyzed using Graphpad 8 software. 1 / 2 Calculate.

[0640] [Table 5]

[0641] The stability of a compound in liver microsomes reflects the risk of metabolic elimination in the body. The test compound has better stability in humans than the control compound.

[0642] Test Example 5: Bidirectional permeability study of compounds into CACO-2 cells 1 × 10 Caco-2 cells 5 Cells / cm 2 The cells are inoculated onto polyethylene films (PET) in 96-well insert plates at a rate of 100 μM, and the medium is changed every 4-5 days until days 21-28, forming a confluent cell monolayer. The transport buffer during the experiment is HBSS and 10.0 mM HEPES, with a pH of 7.40 ± 0.05. Test compounds are tested bidirectionally at 2.00 μM in the presence / absence of 10.0 μM GF120918. Digoxin is tested bidirectionally at 10.0 μM in the presence / absence of 10.0 μM GF120918, and nadolol and metoprolol are tested in the A to B direction at 2.00 μM in the absence of 10.0 μM GF120916, all of which are two bi-holes. The final concentration of DMSO is adjusted to less than 1%. The plates are incubated for 2 h in a CO2 incubator at 37 ± 1 °C with 5% CO2 at saturated humidity, without shaking. All samples were mixed with acetonitrile containing the internal standard and then centrifuged at 3200g for 10 min. For nadolol and metoprolol, dilute 200 μL of supernatant with 600 μL of distilled water and perform LC-MS / MS analysis. For digoxin and test compounds, dilute 200 μL of supernatant with 200 μL of distilled water and perform LC-MS / MS analysis. Using the analyte / internal standard peak area ratio, the LC-MS / MS method quantifies the concentrations of test and control compounds in the starting, donor and acceptor solutions.

[0643] After transport measurements, the integrity of the Caco-2 cell monolayer was measured using a fluorescent yellow repulsion assay.

[0644] [Table 6]

[0645] The test compound has improved permeability compared to the control compound, which is favorable for the absorption of the compound.

[0646] In the present description, a statement referring to terms such as "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" means that a particular feature, structure, material, or characteristic described with reference to the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, general expressions of the above terms do not necessarily refer to the same embodiment or example. In addition, a particular feature, structure, material, or characteristic described may be incorporated in any one or more embodiments or examples in an appropriate manner. Furthermore, a person skilled in the art may combine and combine the various embodiments or examples described herein and the features of the various embodiments or examples without mutual inconsistency.

[0647] Although the embodiments of the present disclosure have been shown and described above, the above embodiments are merely illustrative and do not limit the present disclosure, and it is understood that those skilled in the art can change, modify, substitute, and modify the above embodiments within the scope of the present disclosure.

[0648] This disclosure claims priority to and the benefit of patent application No. 202210359646.3 filed with the State Intellectual Property Office of China on April 6, 2022, patent application No. 202210715417.0 filed with the State Intellectual Property Office of China on June 22, 2022, patent application No. 202211281172.1 filed with the State Intellectual Property Office of China on October 19, 2022, and patent application No. 202310325262.4 filed with the State Intellectual Property Office of China on March 29, 2023, all of which are incorporated by reference herein in their entireties.

Claims

1. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof, 【Chemistry 1】 I Ring B is selected from a benzene ring or a 5- or 6-membered heteroaromatic ring; Ring B is a benzene ring, and R ６ is hydrogen, m is selected from 1, 2, 3 or 4, L is unsubstituted or substituted with one or more substituents C １ -C ６ is an alkyl group, each substituent being independently selected from halogen, C １ -C ６ Alkyl group, C １ -C ６ halogenated alkyl group, and oxo (=O); when there are multiple substituents, the substituents may be the same or different; Alternatively, ring B is a benzene ring and R ６ is hydrogen, and m is selected from 0, L is C substituted with one or more substituents. １ -C ６ is an alkyl group, each substituent being independently selected from halogen, C １ -C ６ Alkyl group, C １ -C ６ halogenated alkyl group, and oxo (=O), and when there are multiple substituents, the substituents may be the same or different; Alternatively, ring B is a benzene ring and R ６ is a halogen, a hydroxyl group, a cyano group, an amino group, C １ -C ６ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, —O—C ３ -C ７ When selected from cycloalkyl groups, m is selected from 0, 1, 2, 3 or 4, and L is an unsubstituted or substituted C １ -C ６ is an alkyl group, each substituent being independently selected from halogen, C １ -C ６ Alkyl group, C １ -C ６ halogenated alkyl group, and oxo (=O), ６ are independently a halogen, a hydroxyl group, an amino group, a cyano group, １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, and in the case of a plurality of substituents, said substituents may be the same or different; Alternatively, when ring B is a 5-6 membered heteroaromatic ring, m is selected from 0, 1, 2, 3 or 4, and L is a C ring that is unsubstituted or substituted with one or more substituents. １ -C ６ is an alkyl group, each substituent being independently selected from halogen, C １ -C ６ Alkyl group, C １ -C ６ halogenated alkyl group, and oxo (=O); R ６ is hydrogen, or a halogen, a hydroxyl group, a cyano group, an amino group, C １ -C ６ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, —O—C ３ -C ７ cycloalkyl groups, and the R ６ are independently a halogen, a hydroxyl group, an amino group, a cyano group, １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, and in the case of a plurality of substituents, said substituents may be the same or different; R １ and R ３ are each independently a hydroxyl group, a cyano group, an amino group, an oxo group (=O), １ -C ６ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, —O—C ３ -C ７ cycloalkyl groups, The R １ and R ３ are each independently a halogen, a hydroxyl group, an amino group, a cyano group, or C １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, and in the case of a plurality of substituents, said substituents may be the same or different; R ２ is C １ -C ６ Alkyl group, C １ -C ６ Halogenated alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, C ３ -C ７ Cycloalkyl Group -C １ -C ６ selected from alkyl groups, The R ２ is a halogen, a hydroxyl group, an amino group, a cyano group, C １ -C ６ Alkyl group, C ３ -C ７ is substituted with 0, 1, 2, 3 or 4 substituents selected from a cycloalkyl group, a 5- to 6-membered aryl group, and a 5- to 6-membered heteroaryl group, and when there are a plurality of substituents, said substituents may be the same or different; Z is -O- or -NR ４ Selected from - R ４ is C １ -C ３ is an alkyl group or H, Ring A is a 5-6 membered heteroaryl group; n is selected from 1, 2, 3, 4 or 5; ５ When there are more than one, the substituents may be the same or different, R ５ is H, halogen, -CN, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ３ -C ７ Cycloalkyl group, —O—C ３ -C ７ cycloalkyl groups, The R ５ C in １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ３ -C ７ Cycloalkyl group, —O—C ３ -C ７ The cycloalkyl group is independently selected from halogen, hydroxyl, C １ -C ６ Alkyl group, C ３ -C ７ A compound of formula I, tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs thereof, wherein the compound is substituted with 0, 1, 2, 3 or 4 substituents selected from cycloalkyl groups, and when multiple substituents are present, the substituents may be the same or different.

2. The compound is selected from the following structures: 【Chemistry 2】 II L is unsubstituted or substituted with one or more substituents. １ -C ６ is an alkyl group, each substituent being independently selected from halogen, C １ -C ６ Alkyl group, C １ -C ６ halogenated alkyl group, and oxo (=O); Ring B is selected from a benzene ring or a 6-membered heteroaromatic ring; When ring B is a benzene ring, m is selected from 1, 2, 3, or 4; Ring B is a 6-membered heteroaromatic ring; m is selected from 0, 1, 2, 3, or 4; R １ and R ３ are each independently a hydroxyl group, a cyano group, an amino group, an oxo group (=O), １ -C ６ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, —O—C ３ -C ７ cycloalkyl groups, The R １ and R ３ are each independently a halogen, a hydroxyl group, an amino group, a cyano group, or C １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, and in the case of a plurality of substituents, said substituents may be the same or different; R ２ is C １ -C ６ Alkyl group, C １ -C ６ Halogenated alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, C ３ -C ７ Cycloalkyl Group -C １ -C ６ selected from alkyl groups, The R ２ is a halogen, a hydroxyl group, an amino group, a cyano group, C １ -C ６ Alkyl group, C ３ -C ７ is substituted with 0, 1, 2, 3 or 4 substituents selected from a cycloalkyl group, a 5- to 6-membered aryl group, and a 5- to 6-membered heteroaryl group, and when there are a plurality of substituents, said substituents may be the same or different; Z is -O- or -NR ４ Selected from - R ４ is C １ -C ３ is an alkyl group or H, Ring A is a 5-6 membered heteroaryl group; n is selected from 1, 2, 3, 4 or 5; ５ When there are more than one, the substituents may be the same or different, R ５ is H, halogen, -CN, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ３ -C ７ Cycloalkyl group, —O—C ３ -C ７ cycloalkyl groups, The R ５ C in １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ３ -C ７ Cycloalkyl group, —O—C ３ -C ７ The cycloalkyl group is independently selected from halogen, hydroxyl, C １ -C ６ Alkyl group, C ３ -C ７ 2. The compound of formula I according to claim 1, which is substituted with 0, 1, 2, 3 or 4 substituents selected from cycloalkyl groups, and in the case of multiple substituents, the substituents are the same or different, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof.

3. The compound is selected from the following structures: 【Chemistry 3】 III L is C substituted with one or more substituents. １ -C ６ is an alkyl group, each substituent being independently selected from halogen, C １ -C ６ Alkyl group, C １ -C ６ halogenated alkyl group, and oxo (=O); 2. The compound of formula I according to claim 1, wherein m is selected from 0, 1, 2, 3 or 4, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof.

4. The compound is selected from the following structures: 【Chemistry 4】 IV R ６ is a halogen, a hydroxyl group, a cyano group, an amino group, C １ -C ６ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, —O—C ３ -C ７ When R is selected from cycloalkyl groups, ６ are independently a halogen, a hydroxyl group, an amino group, a cyano group, １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, and in the case of a plurality of substituents, said substituents may be the same or different; m is selected from 0, 1, 2, 3 or 4; L is unsubstituted or substituted with one or more substituents. １ -C ６ is an alkyl group, each substituent being independently selected from halogen, C １ -C ６ Alkyl group, C １ -C ６ 2. The compound of formula I according to claim 1, selected from halogenated alkyl groups, oxo (=O), tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs thereof.

5. The compound is selected from the following structures: 【Chemistry 5】 V Ring B is selected from 5-6 membered heteroaryl groups; R ５ is selected from H, R ６ is hydrogen, or a halogen, a hydroxyl group, a cyano group, an amino group, C １ -C ６ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, —O—C ３ -C ７ When R is selected from cycloalkyl groups, ６ is independently substituted with 0, 1, 2, 3 or 4 substituents, such as halogen, hydroxyl, amino, cyano, C １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, and when the substituents are multiple, the substituents may be the same or different; m is selected from 0, 1, 2, 3 or 4; L is unsubstituted or substituted with one or more substituents. １ -C ６ is an alkyl group, each substituent being independently selected from halogen, C １ -C ６ Alkyl group, C １ -C ６ halogenated alkyl group, and oxo (=O); Preferably, Ring B is a 5-6 membered heteroaryl group, R ５ and R ６ is hydrogen, m is 0, 【Chemistry 6】 teeth, 【Chemistry 7】 With R １ is selected from an isobutyl group, Z is selected from -O-; R ２ is C １ -C ６ selected from alkyl groups, Preferably, the 5-6 membered heteroaryl group is selected from a pyridine ring. The compound of formula I according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs thereof.

6. L is C １ -C ３ is an alkyl group, The L is a halogen, C １ -C ６ Alkyl group, C １ -C ６ halogenated alkyl groups, oxo (=O) and optionally substituted with substituents; Preferably, L is C １ -C ３ Alkyl group, C １ -C ６ C substituted with alkyl group １ -C ３ is an alkyl group, More preferably, L is -CH ２ - or -CH(CH ３ 6. The compound according to any one of claims 1 to 5, wherein R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R, R is -R,

7. R ３ is a hydroxyl group, a cyano group, an amino group, an oxo group (=O), １ -C ３ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ３ Alkoxy group, —O—C ３ -C ７ cycloalkyl groups, The R ３ are independently a halogen, a hydroxyl group, an amino group, a cyano group, １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, and in the case of a plurality of substituents, said substituents may be the same or different; Preferably, R ３ is selected from a cyano group, a methyl group, a methoxy group, a halomethyl group, and a cyclopropyl group; More preferably, R ３ is selected from a cyano group and a methyl group, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof according to any one of claims 1 to 5.

8. Ring B is a 5-6 membered heteroaromatic ring having 1 or 2 heteroatoms which are N; Preferably, the ring B is selected from a pyridine ring, a pyrimidine ring, a pyrazine ring, or a pyridazine ring; R ３ is a hydroxyl group, a cyano group, an amino group, an oxo group (=O), １ -C ６ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, —O—C ３ -C ７ cycloalkyl groups, The R ３ are independently a halogen, a hydroxyl group, an amino group, a cyano group, １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, wherein the substituents are the same or different, and Preferably, R ３ is a cyano group, C １ -C ３ Alkyl group, C ３ -C ６ Cycloalkyl group, C １ -C ３ Halogenated alkyl group, C １ -C ３ selected from alkoxy groups, More preferably, R ３ is selected from a cyano group, a methyl group, a methoxy group, a halomethyl group, and a cyclopropyl group; Preferably, m is 0. The compound of claim 1, a tautomer, a stereoisomer, a hydrate, a solvate, a pharma- ceutically acceptable salt or a prodrug thereof.

9. Ring B is a benzene ring, and the benzene ring is substituted with 1, 2, 3 or 4 R ３ is substituted with R ３ is a hydroxyl group, a cyano group, an amino group, an oxo group (=O), １ -C ６ Alkyl group, C ３ -C ７ Cycloalkyl group, C １ -C ６ Alkoxy group, —O—C ３ -C ７ cycloalkyl groups, The R ３ are independently a halogen, a hydroxyl group, an amino group, a cyano group, １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, wherein the substituents are the same or different, and Preferably, R ３ is a cyano group, C １ -C ３ Alkyl group, C ３ -C ６ Cycloalkyl group, C １ -C ３ Halogenated alkyl group, C １ -C ３ selected from alkoxy groups, More preferably, R ３ is selected from a cyano group, a methyl group, a methoxy group, a halomethyl group, and a cyclopropyl group; More preferably, R ３ is selected from a cyano group and a methyl group, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof according to any one of claims 1 to 4.

10. R １ is C １ -C ６ Alkyl group, C １ -C ６ Halogenated alkyl group, C ３ -C ７ Cycloalkyl group, C ３ -C ７ Cycloalkyl Group -C １ -C ６ selected from alkyl groups, Preferably, R １ is C １ -C ６ selected from alkyl groups, More preferably, R １ is an isobutyl group, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof according to any one of claims 1 to 5.

11. R ２ is C １ -C ６ Alkyl group, C １ -C ６ selected from halogenated alkyl groups, The R ２ is a halogen, a hydroxyl group, an amino group, a cyano group, C １ -C ６ Alkyl group, C ３ -C ７ is substituted with 0, 1, 2, 3 or 4 substituents selected from a cycloalkyl group, a 5- to 6-membered aryl group, and a 5- to 6-membered heteroaryl group, and when there are a plurality of substituents, said substituents may be the same or different; Preferably, R ２ is a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoropropyl group, a butyl group, an isobutyl group, １ -C ３ selected from the group consisting of an alkyl group and a 6-membered heteroaryl group; Preferably, R ２ is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group; More preferably, R ２ is a methyl group, a trifluoropropyl group, a butyl group, or a pyridylmethyl group, More preferably, R ２ is a butyl group, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof.

12. Z is -O-, -NH- or -NC １ -C ３ alkyl group, Preferably, Z is -O- or -NH-; The compound according to any one of claims 1 to 5, wherein Z is -NH-, a tautomer, a stereoisomer, a hydrate, a solvate, a pharma- ceutically acceptable salt or a prodrug thereof.

13. Ring A is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms; n is 1, 2, 3, 4 or 5; Preferably, the heteroatom is selected from N, O, S, more preferably, the heteroatom is N; Preferably, ring A is selected from pyrrole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine; More preferably, 【Chemistry 8】 teeth, 【Chemistry 9】 having R ５ is H, halogen, -CN, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ３ -C ７ Cycloalkyl group, —O—C ３ -C ７ cycloalkyl groups, R ５ When there are more than one, the substituents may be the same or different, Preferably, R ５ is selected from H, halogen, methyl, ethyl, t-butyl, cyclopropyl, and halomethyl groups; Preferably, R ５ is selected from H, halogen, a methyl group, a cyclopropyl group, and a halomethyl group; More preferably, 【Chemistry 10】 teeth, 【Chemistry 11】 The compound according to any one of claims 1 to 5, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof, having the formula:

14. R ６ is H, halogen, hydroxyl group, cyano group, amino group, C １ -C ３ Alkyl group, C １ -C ３ Alkoxy group, C ３ -C ７ Cycloalkyl group, —O—C ３ -C ７ cycloalkyl groups, The R ６ are independently a halogen, a hydroxyl group, an amino group, a cyano group, １ -C ６ Alkyl group, C ３ -C ７ cycloalkyl groups, and in the case of a plurality of substituents, said substituents may be the same or different; Preferably, R ６ is H, halogen, hydroxyl group, cyano group, amino group, C １ -C ３ Alkyl group, C １ -C ３ Alkoxy group or C ３ -C ７ cycloalkyl groups, Preferably, R ６ is H, halogen or C １ -C ３ selected from alkyl groups, More preferably, R ６ The compound according to any one of claims 1 to 5, wherein is selected from H, fluorine or a methyl group, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof.

15. Ring B is a benzene ring, and R ６ is H and m is selected from 1, 2, 3 or 4, L is C １ -C ３ Alkyl group, C １ -C ６ C substituted with alkyl group １ -C ３ is an alkyl group 【Chemistry 12】 teeth, 【Chemistry 13】 having R １ is selected from an isobutyl group, R ３ is selected from a cyano group and a methyl group, Z is selected from -O- or -NH-; R ２ is C １ -C ６ selected from alkyl groups, The R ２ is substituted with 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, and 5- to 6-membered heteroaryl groups; Preferably, L is -CH ２ - or -CH(CH ３ 2. The compound of claim 1, wherein R is -R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R

16. Ring B is a benzene ring, and R ６ is H and m is 0, then L is C １ -C ３ Alkyl group, C １ -C ６ C substituted with alkyl group １ -C ３ is an alkyl group, 【Chemistry 14】 teeth, 【Chemistry 15】 having R １ is selected from an isobutyl group, R ３ is selected from a cyano group and a methyl group, Z is selected from -O-; R ２ is C １ -C ６ selected from alkyl groups, Preferably, L is -CH ２ - or -CH(CH ３ 2. The compound of claim 1, wherein R is -R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R

17. Ring B is a benzene ring, and R ６ is not hydrogen and is halogen or C １ -C ３ alkyl group, and when m is 0 or 1, L is C １ -C ３ Alkyl group, C １ -C ６ C substituted with alkyl group １ -C ３ is an alkyl group, 【Chemistry 16】 teeth, 【Chemistry 17】 having R １ is selected from an isobutyl group, R ３ is selected from a methyl group and a halogen; Z is selected from -O-; R ２ is C １ -C ６ selected from alkyl groups, Preferably, R ６ is selected from fluorine or a methyl group, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof according to claim 1.

18. The compound is as follows: 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 6. The compound according to any one of claims 1 to 5, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof, comprising:

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof, and a pharma- ceutically acceptable carrier.

20. Use as an AT2 receptor agonist; and / or for the prevention and / or treatment of diseases in which an endogenous deficiency of Ang II occurs, and / or prevention and / or treatment of diseases in which increased Ang II activity is expected or required; and / or the use of a compound according to any one of claims 1 to 18, a tautomer, a stereoisomer, a hydrate, a solvate, a pharma- ceutically acceptable salt or a prodrug thereof or a pharmaceutical composition according to claim 19 as an AT2 receptor agonist and / or for the preparation of a drug, pharmaceutical composition or formulation for the prevention and / or treatment of a disease in which the AT2 receptor is expressed and which expects or requires stimulation.

21. 21. The use according to claim 20, wherein the disease is a disease of the gastrointestinal, cardiovascular, respiratory tract, kidney, eye, female reproductive system or central nervous system.

22. The diseases include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia, gastroesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease, gallbladder disease, multiple organ failure, sepsis, xerostomia, gastritis, gastric fistula, hyperacidity, biliary tract disease, abdominal disease, segmental ileitis, ulcerative colitis, diarrhea, constipation, colic, dysphagia, nausea, vomiting, Sjogren's syndrome, inflammatory diseases, asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, renal failure, nephritis, renal hypertension, diabetic retinopathy, retinopathy of prematurity, retinal microvascularization, disorders of the ovulation mechanism, hypertension, myocardial hypertrophy, 22. The use according to claim 21, which is for the treatment of heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, stenosis after balloon dilatation, angiogenesis, diabetic complications, microvascular dysfunction, angina, arrhythmia, intermittent claudication, pre-eclampsia, myocardial infarction, reinfarction, ischemic disorders, erectile dysfunction, neointimal hyperplasia, cognitive dysfunction, eating dysfunction, dry mouth, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, hypertrophy, prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, nerve regeneration, ulcers, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, carcinoma, apoptosis, tumor, proliferative diabetes, neuropathy or organ rejection.

23. 23. The use according to claim 22, wherein the disease is asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis.

24. 20. A method for preventing and / or treating diseases in which an endogenous deficiency of Ang II occurs and / or in which increased Ang II action is expected or required and / or in which AT2 receptors are expressed and stimulation is expected or required, said method comprising administering to a person suffering from or susceptible to the disease a therapeutically effective amount of a compound according to any one of claims 1 to 18, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof or a pharmaceutical composition according to claim 19.

25. 25. The method of claim 24, wherein the disease is a disease of the gastrointestinal, cardiovascular, respiratory tract, kidney, eye, female reproductive system or central nervous system.

26. Said diseases include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia, gastroesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease, gallbladder disease, multiple organ failure, sepsis, xerostomia, gastritis, gastric fistula, hyperacidity, biliary tract disease, abdominal disease, segmental ileitis, ulcerative colitis, diarrhea, constipation, colic, dysphagia, nausea, vomiting, Sjogren's syndrome, inflammatory diseases, asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, renal failure, nephritis, renal hypertension, diabetic retinopathy, retinopathy of prematurity, retinal microvascularization, disorders of the ovulation mechanism, hypertension, myocardial hypertrophy. , heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, stenosis after balloon dilatation, angiogenesis, diabetic complications, microvascular dysfunction, angina, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic disorder, erectile dysfunction, neointimal hyperplasia, cognitive dysfunction, eating dysfunction, dry mouth, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, hypertrophy, prostatic hyperplasia, autoimmune disease, psoriasis, obesity, nerve regeneration, ulcer, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, carcinoma, apoptosis, tumor, proliferative diabetes, neuropathy or organ rejection.

27. 27. The method of claim 26, wherein the disease is asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis.

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