Thiofensulfonylcarbamates as AT2R agonists

Abstract

The following provides compounds represented by the following structures, or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, which can be used as agonists of AT2R. JPEG2026529114000149.jpg5645

Description

Technical Field

[0001] The present invention relates to the field of medicine. Specifically, the present invention relates to thiophene sulfonyl carbamate as an angiotensin II (AngII) type 2 receptor (AT2R) agonist.

Background Art

[0002] Idiopathic pulmonary fibrosis (IPF) is a condition in which abnormal repair occurs after alveolar epithelial cells are damaged, leading to the proliferation of lung fibroblasts and their conversion to myofibroblasts, excessive secretion of extracellular matrix, deposition of collagen, and changes in alveolar structure, ultimately forming fibrosis. Its pathogenesis is not yet fully clear, and current research shows that it is closely related to oxidative stress, inflammatory response, and the regulation of the renin-angiotensin-aldosterone system (RAAS) by body fluids. Currently, the RAAS system is considered to play an important role in the progression of pulmonary fibrosis. Angiotensin converting enzyme (ACE) hydrolyzes angiotensin I (AngI) to angiotensin II (AngII), and AngII plays an important role in the occurrence and progression of various inflammations.

[0003] In the human body, two main types of AngII receptors have been identified, named AngII1 receptor (AT1R) and AngII2 receptor (AT2R). AngII exerts physiological effects such as blood pressure regulation and fluid and electrolyte homeostasis in many organs, including the kidneys, adrenal glands, heart, blood vessels, brain, gastrointestinal tract, and reproductive organs. The effects of AngII are regulated by the expression balance of two types of G protein-coupled receptors (GPCRs), AT1R and AT2R. AT1R is expressed throughout life and is mainly responsible for blood pressure regulation; its antagonists are widely used as antihypertensive drugs in clinical practice, and AT1R controls most of the physiological effects of AngII. AT2R is mainly expressed in embryonic tissues and is involved in blood pressure regulation, nerve growth, pain control, and myocardial regeneration; drugs targeting AT2R are effective in improving cardiovascular function and alleviating neuropathic pain. However, AT2R expression is significantly increased in pathological conditions such as vascular injury, wound healing, and heart failure.

[0004] Recently, AT2R agonists have shown potential for use in the treatment and / or prevention of gastrointestinal disorders such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure. There remains a need for effective and / or selective AT2R agonists, and their application to the aforementioned diseases is anticipated. [Overview of the project] [Problems that the invention aims to solve]

[0005] The object of the present invention is to provide a thiophenesulfonyl carbamate as an AT2R agonist and its use, wherein the thiophenesulfonyl carbamate has the structure shown in the first aspect of the present invention, and the thiophenesulfonyl carbamate can be used to prepare a pharmacopoeia, pharmaceutical composition or formulation for the treatment and / or prevention of diseases or symptoms related to AT2R, or can be used for the treatment and / or prevention of diseases or symptoms related to AT2R. [Means for solving the problem]

[0006] In a first aspect of the present invention, a compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, is provided, the compound having the structure shown in formula III, [ka] However, R1 is selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. Each R3 is independently selected from hydrogen, halogen, cyanide group, C1-C6 alkyl, and C3-C6 cycloalkyl, and the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxy, amino group, cyanide group, C1-C6 alkyl, and C3-C7 cycloalkyl, and if there are multiple substituents, the substituents may be the same or different. m is selected from 1, 2, 3, and 4. R4 is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R5 is selected from halogens, C1-C6 alkyl groups, and 4-7 membered heterocyclic alkyl groups, wherein the C1-C6 alkyl group is substituted with 1, 2, 3, or 4 substituents selected from halogens, hydroxyl groups, and 4-7 membered heterocyclic alkyl groups, and the 4-7 membered heterocyclic alkyl group is substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, hydroxyl groups, cyanide groups, C1-C6 alkyl groups, and 4-7 membered heterocyclic alkyl groups, and if there are multiple substituents, the substituents may be the same or different. R6 is selected from 5-7 membered heteroaromatic rings and -C(O)-X-R2. X is chosen from NRa and O. R2 is a C1-C6 alkyl, a 4-7 membered heterocyclic alkyl, or a 5-7 membered heteroaromatic ring, wherein the C1-C6 alkyl is substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, hydroxy, C1-C3 alkyl, 3-7 membered heterocyclic alkyl, or 5-7 membered heteroaromatic rings, and the 4-7 membered heterocyclic alkyl and 5-7 membered heteroaromatic rings are substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, hydroxy, cyanide, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, a 5-7 membered heteroaromatic ring, and a 3-7 membered heterocyclic alkyl, and if there are multiple substituents, the substituents may be the same or different. Ra is selected from hydrogen and C1-C3 alkyl, or Ra and R2 form a 5-8 membered heterocyclic alkyl diring with a nitrogen atom linked to them. If R5 is selected from the halogens Cl, R3 is selected from hydrogen, R1 is selected from the C1-C6 alkyl group methyl, and R6 is selected from -C(O)-O-R2, then R2 is not methyl, If R6 is selected from a 5-7 membered heteroaromatic ring, then R3 is hydrogen or fluorine.

[0007] In this specification, the phrase “base A is selected from A1, ..., and An” is synonymous with “base A is selected from A1, ..., or An.”

[0008] According to embodiments of the present invention, the compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are further provided. [ka] I, However, R1 is selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. X is chosen from NRa and O. R2 is a C1-C6 alkyl, 5-7 membered heteroaromatic ring, and the C1-C6 alkyl is substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, hydroxyls, C1-C3 alkyls, and 5-7 membered heteroaromatic rings, and if there are multiple substituents, the substituents may be the same or different. Each R3 is independently selected from hydrogen, halogen, cyanide group, C1-C6 alkyl, and C3-C6 cycloalkyl, and the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxy, amino group, cyanide group, C1-C6 alkyl, and C3-C7 cycloalkyl, and if there are multiple substituents, the substituents may be the same or different. m is selected from 1, 2, 3, and 4. R4 is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R5 is selected from halogens and C1-C6 alkyl groups, and the C1-C6 alkyl group is substituted with 1, 2, 3, or 4 substituents selected from halogens and hydroxyls, and if there are multiple substituents, the substituents may be the same or different. Ra is selected from hydrogen and C1-C3 alkyl groups. Alternatively, Ra and R2 form a 5-8 membered heterocyclic alkyl diring with the nitrogen atom linked to them. If R5 is selected from the halogens Cl, R3 is selected from hydrogen, R1 is selected from the C1-C6 alkyl group methyl, and X is selected from O, then R2 is not methyl.

[0009] In one preferred embodiment of the present invention, the compound is [ka] Selected from, However, R1 is selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. X is chosen from NRa and O. R2 is a C1-C6 alkyl group, and the C1-C6 alkyl group is substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, hydroxyls, and C1-C3 alkyl groups, and if there are multiple substituents, the substituents may be the same or different. R3 is selected from hydrogen, halogen, cyanide group, C1-C6 alkyl, and C3-C6 cycloalkyl, and the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxy, amino group, cyanide group, C1-C6 alkyl, and C3-C7 cycloalkyl, and if there are multiple substituents, the substituents may be the same or different. m is selected from 1, 2, 3, and 4. R4 is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R5 is selected from halogens and C1-C6 alkyl groups, and the C1-C6 alkyl group is substituted with 1, 2, 3, or 4 substituents selected from halogens and hydroxyls, and if there are multiple substituents, the substituents may be the same or different. Ra is selected from hydrogen and C1-C3 alkyl groups. If R5 is selected from the halogens Cl, R3 is selected from hydrogen, R1 is selected from the C1-C6 alkyl group methyl, and X is selected from O, then R2 is not methyl.

[0010] In one preferred embodiment of the present invention, R6 is selected from a 5-7 membered heteroaromatic ring, and the heteroatom of the 5-7 membered heteroaromatic ring is N.

[0011] In one preferred embodiment of the present invention, R6 is [ka] They are selected from among them.

[0012] In one preferred embodiment of the present invention, the compound has the structure shown in formula IV, [ka] IV.

[0013] In one preferred embodiment of the present invention, R6 is selected from a 5-7 membered heteroaromatic ring, and R3 is hydrogen or fluorine.

[0014] In one preferred embodiment of the present invention, R6 is selected from a 5-7 membered heteroaromatic ring, and R3 is hydrogen.

[0015] In one preferred embodiment of the present invention, R1 is selected from halogens, C1-C3 alkyls, and C1-C3 haloalkyls.

[0016] In one preferred embodiment of the present invention, R1 is selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, CH2F, CHF2, and CF3.

[0017] In one preferred embodiment of the present invention, R1 is selected from F, Cl, and methyl.

[0018] In one preferred embodiment of the present invention, R1 is selected from methyl.

[0019] In one preferred embodiment of the present invention, X is selected from NRa and O, and Ra is selected from hydrogen and C1-C3 alkyl.

[0020] In one preferred embodiment of the present invention, X is selected from NRa and O, and Ra is selected from hydrogen and methyl.

[0021] In one preferred embodiment of the present invention, X is selected from O.

[0022] In one preferred embodiment of the present invention, X is selected from NRa, and Ra is selected from hydrogen and methyl.

[0023] In one preferred embodiment of the present invention, X is selected from NRa, Ra and R2 form a 5-8 membered heterocyclic alkyl diring with a nitrogen atom linked to them, and the 5-8 membered heterocyclic alkyl diring contains one, two, or three heteroatoms selected from N, O, and S.

[0024] In one preferred embodiment of the present invention, X is selected from NRa, Ra and R2 form a 5-8 membered heterospirole with a nitrogen atom linked to them, and the 5-8 membered heterospirole includes one, two, or three heteroatoms selected from N, O, and S.

[0025] In one preferred embodiment of the present invention, X is selected from NRa, and Ra and R2 are nitrogen atoms linked to them. [ka] It forms.

[0026] In one preferred embodiment of the present invention, X is selected from N, Ra and R2 form a 5-8 membered heterocyclic alkyl diring with a nitrogen atom linked to them, and the 5-8 membered heterocyclic alkyl diring contains one, two or three heteroatoms selected from N, O, and S.

[0027] In one preferred embodiment of the present invention, X is selected from N, Ra and R2 form a 5-8 membered heterospirole with a nitrogen atom linked to them, and the 5-8 membered heterospirole includes one, two, or three heteroatoms selected from N, O, and S.

[0028] In one preferred embodiment of the present invention, X is selected from N, and Ra and R2 are nitrogen atoms linked thereto. [ka] It forms.

[0029] In one preferred embodiment of the present invention, the compound is [ka] Selected from, However, Ra was selected from hydrogen, R2 is selected from a 5-7 membered heteroaromatic ring and a C1-C4 alkyl-5-7 membered heteroaromatic ring. Alternatively, Ra and R2 form a 5-8 membered heterocyclic alkyl diring with the nitrogen atom linked to them. The definitions of R1, R3, R4, R5, and m are as described in the first aspect of the present invention.

[0030] In one preferred embodiment of the present invention, R2 is selected from a C1-C4 alkyl group, a 4-7 member heterocyclic alkyl group, or a 5-7 member heteroaromatic ring, the C1-C4 alkyl group is substituted with 0, 1, 2, 3, or 4 substituents selected from a halogen, hydroxyl group, C1-C3 alkyl group, a 3-7 member heterocyclic alkyl group, a 5-7 member heteroaromatic ring, or a 4-7 member heterocyclic alkyl group, the 4-7 member heterocyclic alkyl group and the 5-7 member heteroaromatic ring are substituted with 0, 1, 2, 3, or 4 substituents selected from a halogen, hydroxyl group, a C1-C3 alkyl group, or a 5-7 member heteroaromatic ring, and if there are multiple substituents, the substituents are the same or different.

[0031] In one preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, 4-7 member heterocyclic alkyl, -C1-C4 alkyl-4-7 member heterocyclic alkyl, -C1-C4 alkyl-5-7 member heteroaromatic ring, and -4-7 member heterocyclic alkyl-C1-C4 alkyl, and the C1-C4 alkyl is substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxy, and C1-C3 alkyl.

[0032] In one preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, azetidinyl, oxyranil, oxetanil, tetrahydrofuranil, -C1-C4 alkyl-azetidinyl, -C1-C4 alkyl-oxyranil, -C1-C4 alkyl-oxetanil, -C1-C4 alkyl-tetrahydrofuranil, -C1-C4 alkyl-pyridyl ring, pyrimidinyl ring, pyridyl ring, pyridadinyl ring, and pyrazinyl ring, and the methyl, ethyl, propyl, isopropyl, butyl, and isobutyl are substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxy, and C1-C3 alkyl.

[0033] In one preferred embodiment of the present invention, R2 is selected from ethyl, propyl, butyl, isobutyl, pyridyl ring, pyrimidinyl ring, -methyl-pyridyl ring, -methyl-oxetanyl, and -oxetanyl-methylmethyl, and the ethyl, propyl, isopropyl, butyl, and isobutyl are substituted with hydroxyl.

[0034] In one preferred embodiment of the present invention, R2 is methyl, ethyl, [ka] Butyl, pyrimidinyl ring, [ka] They are selected from among them.

[0035] In one preferred embodiment of the present invention, R2 is selected from a C1-C4 alkyl, 5-7 membered heteroaromatic ring, and the C1-C4 alkyl, 5-7 membered heteroaromatic ring is substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxy, C1-C3 alkyl, or 5-7 membered heteroaromatic rings, wherein if there are multiple substituents, the substituents are the same or different.

[0036] In one preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pyrimidinyl ring, pyridyl ring, pyridadinyl ring, and pyrazinyl ring, and R2 is substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, hydroxy, C1-C3 alkyl, pyridyl ring, pyrimidinyl ring, pyridadinyl ring, and pyrazinyl ring.

[0037] In one preferred embodiment of the present invention, R2 is methyl, ethyl, [ka] Butyl, pyrimidinyl ring, [ka] They are selected from among them.

[0038] In one preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl groups, and the C1-C4 alkyl group is substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, hydroxyls, or C1-C3 alkyl groups, wherein if there are multiple substituents, the substituents are the same or different.

[0039] In one preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl, and R2 is substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxy, and C1-C3 alkyl.

[0040] In one preferred embodiment of the present invention, R2 is methyl, ethyl, [ka] Selected from butyl.

[0041] In one preferred embodiment of the present invention, R3 is selected from hydrogen, halogen, cyanide group, C1-C3 alkyl, and C3-C4 cycloalkyl, and the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxy, amino group, cyanide group, C1-C6 alkyl, and C3-C7 cycloalkyl, and if there are multiple substituents, the substituents may be the same or different. m is selected from 1, 2, 3, and 4.

[0042] In one preferred embodiment of the present invention, R3 is selected from hydrogen, F, Cl, methyl, and cyanide, and m is selected from 1, 2, 3, and 4.

[0043] In one preferred embodiment of the present invention, R3 is selected from hydrogen, F, Cl, Br, I, and methyl, and m is selected from 1, 2, 3, and 4.

[0044] In one preferred embodiment of the present invention, R3 is selected from hydrogen, F, and Cl.

[0045] In one preferred embodiment of the present invention, R3 is selected from hydrogen and F.

[0046] In one preferred embodiment of the present invention, R4 is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0047] In one preferred embodiment of the present invention, R4 is selected from hydrogen and C1-C3 alkyl groups.

[0048] In one preferred embodiment of the present invention, R4 is selected from hydrogen and methyl.

[0049] In one preferred embodiment of the present invention, R4 is selected from hydrogen.

[0050] In one preferred embodiment of the present invention, R5 is selected from halogens, C1-C3 alkyl groups, and 4-5 member heterocyclic alkyl groups, the C1-C3 alkyl group is substituted with 1, 2, 3, or 4 substituents selected from halogens, hydroxyl groups, and 4-7 member heterocyclic alkyl groups, and the 4-5 member heterocyclic alkyl group is substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, hydroxyl groups, cyanide groups, and C1-C6 alkyl groups, wherein if there are multiple substituents, the substituents are the same or different.

[0051] In one preferred embodiment of the present invention, R5 is F, Cl, CF3, [ka] They are selected from among them.

[0052] In one preferred embodiment of the present invention, R5 is Cl, CF3, [ka] They are selected from among them.

[0053] In one preferred embodiment of the present invention, R5 is selected from halogens and C1-C3 alkyl groups, and the C1-C3 alkyl group is substituted with one, two, three, or four substituents selected from halogens and hydroxyls, wherein if there are multiple substituents, the substituents are the same or different.

[0054] In one preferred embodiment of the present invention, R5 is F, Cl, Br, I, CF3 and [ka] They are selected from among them.

[0055] In one preferred embodiment of the present invention, R5 is Cl, CF3 and [ka] They are selected from among them.

[0056] In one preferred embodiment of the present invention, R5 is selected from Cl among halogens, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyls, and X is selected from O, then R2 is selected from methyl, C2-C6 alkyl and 4-7 member heterocyclic alkyl, the methyl in R2 is substituted with 1, 2, 3 or 4 substituents selected from halogens, hydroxy, C1-C3 alkyl and 3-7 member heterocyclic alkyls, the C2-C6 alkyl in R2 is substituted with 0, 1, 2, 3 or 4 substituents selected from halogens, hydroxy, C1-C3 alkyl and 3-7 member heterocyclic alkyls, and the 4-7 member heterocyclic alkyl in R2 is substituted with 0, 1, 2, 3 or 4 substituents selected from halogens, hydroxy, and C1-C3 alkyls, and if there are multiple substituents, the substituents may be the same or different. Preferably, R2 is ethyl [ka] Butyl, [ka] They are selected from among them.

[0057] In one preferred embodiment of the present invention, R5 is selected from Cl among halogens, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyls, and X is selected from O, then R2 is selected from methyl and C2-C6 alkyls, the methyl in R2 is substituted with 1, 2, 3 or 4 substituents selected from halogens, hydroxy, and C1-C3 alkyls, and the C2-C6 alkyl in R2 is substituted with 0, 1, 2, 3 or 4 substituents selected from halogens, hydroxy, and C1-C3 alkyls, and if there are multiple substituents, the substituents may be the same or different. Preferably, R2 is ethyl [ka] Selected from butyl.

[0058] In one preferred embodiment of the present invention, R5 is selected from Cl, R3 is selected from hydrogen, R4 is selected from hydrogen, R1 is selected from methyl, and X is selected from O, and R2 is ethyl, butyl, [ka] They are selected from among them.

[0059] In one preferred embodiment of the present invention, R3 is selected from hydrogen, R4 is selected from hydrogen, R1 is selected from methyl, X is selected from NH, and R2 is [ka] They are selected from among them.

[0060] In one preferred embodiment of the present invention, R1 is selected from methyl, R3 is selected from hydrogen and F, R4 is selected from hydrogen, R6 is selected from -C(O)-O-R2, and R2 is methyl, butyl, [ka] Selected from, R5 is -CF3, Cl, [ka] They are selected from among them.

[0061] In one preferred embodiment of the present invention, R1 is selected from methyl, R3 from Cl, and R4 from hydrogen, R6 is selected from -C(O)-O-R2, R2 is selected from butyl, and R5 is selected from -CF3 and Cl.

[0062] In one preferred embodiment of the present invention, R1 is selected from methyl, R3 is selected from hydrogen, R4 is selected from hydrogen, and R6 is selected from a 5-7 membered heteroaromatic ring, wherein the heteroatom of the 5-7 membered heteroaromatic ring is N.

[0063] In one preferred embodiment of the present invention, R1 is selected from methyl, R3 is selected from hydrogen, R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, the heteroatom of the 5-7 membered heteroaromatic ring is N, and R5 is selected from -CF3, Cl.

[0064] In one preferred embodiment of the present invention, R1 is selected from methyl, R3 is selected from hydrogen, R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, the heteroatom of the 5-7 membered heteroaromatic ring is N, and R5 is selected from Cl.

[0065] In one preferred embodiment of the present invention, R1 is selected from methyl, R3 is selected from hydrogen, R4 is selected from hydrogen, X is selected from NRa, and Ra and R2 are nitrogen atoms linked to them. [ka] It forms.

[0066] In one preferred embodiment of the present invention, R1 is selected from methyl, R2 is selected from methyl, R4 is selected from hydrogen, X is selected from O, R3 is selected from F and Cl, or R5 is -CF3. [ka] They are selected from among them.

[0067] In one preferred embodiment of the present invention, the compound, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are provided, the compound is [ka] [ka] It is characterized by including.

[0068] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs.

[0069] In one preferred embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0070] A third aspect of the present invention is the use of the compound described in the first aspect, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect, wherein the use is To be used as an AT2R agonist, and / or to prevent and / or treat diseases in which endogenous production of AngII is insufficient. and / or to prevent and / or treat diseases in which enhanced action of AngII is desired or necessary. and / or, the preparation of a pharmaceutical, pharmaceutical composition, or formulation for the prevention and / or treatment of a disease in which AT2R is expressed and stimulation is desired or required, as an AT2R agonist.

[0071] The compounds described in the first embodiment, or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical compositions described in the second embodiment are expected to be used in the treatment of diseases of the gastrointestinal tract, cardiovascular system, respiratory system, kidney, eye, female reproductive system, or central nervous system (CNS).

[0072] Gastrointestinal disorders to be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, indigestion (including non-ulcerative indigestion), gastroesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease (e.g., hepatitis), cholecystitis, multiple organ failure, and sepsis. Other gastrointestinal disorders to be mentioned include xerostomia, gastritis, gastric stasis, hyperacidity, biliary tract disease, celiac disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, cramps, dysphagia, nausea, vomiting, and Sjögren's syndrome.

[0073] Respiratory diseases that should be mentioned include asthma, obstructive pulmonary disease (e.g., chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, adult respiratory distress syndrome, and inflammatory diseases such as idiopathic pulmonary fibrosis.

[0074] Kidney diseases that should be mentioned include renal failure, nephritis, and renal hypertension.

[0075] Eye diseases that should be mentioned include diabetic retinopathy, retinopathy of premature birth, and retinal microangiopathy.

[0076] Among the female reproductive system disorders that should be mentioned is ovulation disorder.

[0077] Cardiovascular diseases to be mentioned include hypertension, myocardial hypertrophy, heart failure, arteriosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, post-balloon angiography stenosis, neovascularization, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmias, intermittent claudication, pre-eclampsia, myocardial infarction, reinfarction, ischemic injury, erectile dysfunction, and neointimal thickening.

[0078] CNS disorders that should be mentioned include cognitive impairment, feeding disorders, thirst, stroke, cerebral hemorrhage, cerebral embolism, and cerebral infarction.

[0079] The compounds described in the first embodiment, or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical compositions described in the second embodiment may also be used to regulate growth metabolism and proliferation, for example, in the treatment of hypertrophy, benign prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, nerve regeneration, ulcerative healing, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer (e.g., gastrointestinal cancer, lung cancer, etc.), cell apoptosis, tumors (common ones), proliferative diabetes, neuropathy and organ rejection.

[0080] A compound according to the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition according to the second aspect of the present invention, is applicable to the treatment and / or prophylactic treatment of the above-mentioned diseases.

[0081] A fourth aspect of the present invention provides a method for treating a disease, the disease being a disease of insufficient endogenous production of AngII, and / or a disease in which enhancement of the action of AngII is desired or required, and / or a disease in which AT2R is expressed and stimulation is desired or required, the method comprising using a therapeutically effective amount of a compound according to the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to the second aspect, to a person suffering from or susceptible to the disease.

[0082] According to embodiments of the present invention, the type of disease is as described in the description of use in the third aspect of the present invention.

[0083] Additional aspects and advantages of the present invention are partially shown in the following description, partially become apparent from that description, or are understood through the practice of the present invention.

[0084] ▲Terms and Definitions

[0085] Unless otherwise specified, the definitions of groups and terms in the specification and claims of this application include illustrative definitions, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in examples, which may be combined or linked in any way. The definitions of groups and structures of compounds resulting from such combinations or linkages shall be within the scope described in the description of this application.

[0086] Unless otherwise defined, all scientific and technical terms in this specification have the same meaning as that commonly understood by an expert in the art relating to the subject matter of the claims. Unless otherwise stated, all patents, patent applications, and published materials referenced throughout this specification are incorporated herein by reference in their entirety. If multiple definitions exist for a term in this specification, the definition in this chapter shall prevail.

[0087] It should be understood that the subject matter is not limited in any way, and the above summary and the detailed explanation below are merely illustrative and for interpretation purposes only. In this application, unless otherwise specifically provided, the singular form is to include the plural form. It should be noted that the singular form used in this specification and claims includes the plural form of the thing it refers to unless otherwise explicitly stated in the text. Furthermore, unless otherwise stated, "or" and "or else" used refer to "and / or". Other forms of terminology used, such as "include" and "contain," and "contain" and "include," are not in any way limiting.

[0088] For definitions of standard chemical terms, please refer to the references (Carey and Sundberg, "Advanced Organic Chemistry 4th Edition," Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, common methods in the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are employed. Unless otherwise specified, terms used in this specification relating to analytical chemistry, organic synthesis, and pharmaceuticals and medicinal chemistry are all well known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, preparation, formulation and delivery of pharmaceuticals, and treatment of patients. For example, reactions and purifications can be carried out according to the instructions for use of the manufacturer's kit, or according to methods well known in the art or described in the present invention. Generally, the summaries and specific literature descriptions cited and discussed herein can be carried out by common methods widely known in the art. In this specification, groups and their substituents can be selected so as to provide stable structural parts and compounds for those skilled in the art.

[0089] When substituents are represented by a conventional chemical formula written from left to right, the substituents include chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2. When used herein, [ka] The 'R' indicates the binding site of the group. As used herein, "R1", "R1", and "R 1 The symbols "R2" and "R2" have the same meaning and are interchangeable. Other symbols such as R2 also have the same meaning in the same definition.

[0090] The section titles used in this specification are for the sole purpose of constructing the text and should not be interpreted as limiting the subject matter. All documents or parts of documents cited herein, including patents, patent applications, articles, books, operating manuals, and research papers, are incorporated herein by reference in their entirety.

[0091] Except as otherwise stated, when used in the specification and claims of this application, the following terms shall have the meanings set forth below, unless otherwise expressly defined.

[0092] Numerical ranges described in the specification and claims of this application shall be understood as listing the numbers at both ends of the range and the individual integers within that range, if such ranges are understood as “integers.” For example, “integers from 1 to 6” shall be interpreted as listing the integers 0, 1, 2, 3, 4, 5, and 6.

[0093] In this application, "AT2 receptor" and "AT2R" have the same definition.

[0094] In this application, the term "halogen" refers to fluorine, chlorine, brome, and iodine, either alone or as part of other substituents.

[0095] In this application, the term "amino group" refers to -NH2 when used alone or as part of another substituent.

[0096] In this application, the term "hydroxy" means -OH when used alone or as part of another substituent.

[0097] As used herein, when used alone or as part of other substituents, the term “alkyl” means a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturated bonds, and having, for example, 1 to 6 carbon atoms connected to the rest of the molecule by single bonds. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyls may be unsubstituted or substituted with one or more suitable substituents. Alkyls may be isotopic isomers of naturally abundant alkyls having carbon and / or hydrogen-rich isotopes (i.e., deuterium or tritium). As used herein, the term “alkenyl” means a branched or unbranched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term “alkynyl” means a branched or unbranched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0098] When used alone or as part of other substituents, the term “C1-C6 alkyl” refers to a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2, or 3 carbon atoms ("C1-C3 alkyl"), such as methyl, methylene, ethyl, n-propyl, or isopropyl.

[0099] When used alone or as part of another substituent, the term "oxy" indicates that two hydrogen atoms on the methylene group are replaced by oxygen, i.e., the methylene group is replaced by a carbonyl group, and =O.

[0100] When used alone or as part of other substituents, the term "cycloalkyl" or "carbocyclic group" means a cyclic alkyl group. m -C n "Cycloalkyl" is interpreted as representing a saturated or partially saturated carbon ring having m to n atoms. For example, "3-15 member cycloalkyl" or "C3-C 15 "Cycloalkyl" refers to a cyclic alkyl group having 3-15, 3-9, 3-6, or 3-5 carbon atoms, and may contain 1-4 rings. "5-8 membered cycloalkyl" contains 5-8 carbon atoms. It includes monocyclic, dicyclic, tricyclic, spirocyclic, or bridging rings. Examples of unsubstituted cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as the decalin ring. Cycloalkyls can be substituted with one or more substituents. In some embodiments, the cycloalkyl may be a cycloalkyl condensed with an aryl group or a heteroaryl group. The term "C3-C6 cycloalkyl" represents a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3-6 carbon atoms, and includes condensed or bridging polycyclic systems. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0101] When used alone or as part of other substituents, "halocycloalkyl" refers to the cycloalkyl groups described above, wherein any number (at least one) of the hydrogen atoms bonded to the cycloalkyl group are substituted with fluorine, chlorine, bromine, or iodine.

[0102] When used alone or as part of other substituents, "haloalkyl" refers to a branched or straight saturated aliphatic hydrocarbon group (e.g., -CvFw, where v=1 to 3, w=1 to (2v+1)) having a specific number of carbon atoms and substituted with one or more halogens. Examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0103] When used alone or as part of other substituents, the term "5-7 membered heteroaromatic ring" can be used interchangeably with "5-7 membered heteroaryl group" and refers to an aromatic ring group having 5, 6, or 7 ring atoms and containing 1-3 heteroatoms independently selected from N, O, and S. In particular, heteroaryl groups are selected from thiophene, furan, pyrrolyl, oxazole, thiazole, imidazole, pyrazolyl, or pyridine, pyridadinyl, pyrimidinyl, and pyrazinyl groups.

[0104] When used alone or as part of other substituents, the term “heterocycloalkyl” or “heterocyclic group” means a saturated cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are substituted with heteroatoms, the heteroatoms being, but not limited to, N, O, S, and P. It should be understood that if the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl groups include, but are not limited to, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrahydrofuryl, and tetrahydrothiopyranyl groups. A “heterocycloalkyl” or “heterocyclic group” may have one, two, or three rings, including fused rings, bridging rings, and spiro-ring structures. The term “3-7 membered heterocyclic alkyl” is understood to refer to a cycloalkyl group having 3, 4, 5, 6, or 7 atoms, including one, two, or three heteroatoms, the heteroatoms being selected from N, O, S, and P. The term "5-8 membered heterocyclic alkyl dicycle" refers to two rings having 5 to 8 atoms, including fused rings, bridging rings, and spiro ring structures. The heteroatoms are preferably selected from N, O, and S. It should be understood that if the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms will not be adjacent to each other. Examples of "5-8 membered heterocyclic alkyl dicycles" include: [ka] This includes, but is not limited to, the following:

[0105] In this application, the terms “any” or “optionally” usually mean that the events or circumstances described below may or may not occur, and that the description includes both cases in which such events or circumstances occur and cases in which they do not occur. For example, “optionally substituted aryl group” means that an aryl group is either substituted or unsubstituted, and that the description includes both substituted and unsubstituted aryl groups.

[0106] In this application, the terms “salt” or “pharmaceutically acceptable salt” include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable alkali addition salts. The term “pharmaceutically acceptable” means a compound, material, composition and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, within the bounds of sound medical judgment, and that is commensurate with a reasonable benefit / risk ratio.

[0107] A "pharmaceutically acceptable acid-added salt" refers to a salt formed with an inorganic or organic acid that can maintain the biological efficacy of a free base without other side effects. A "pharmaceutically acceptable alkali-added salt" refers to a salt formed with an inorganic or organic base that can maintain the biological efficacy of a free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are also considered in this invention. These can be used as intermediates in the purification of compounds, or in the production of other pharmaceutically acceptable salts, or in the identification, characterization, and purification of the compounds of this invention.

[0108] The term "amine salt" refers to a product obtained by neutralizing an alkyl group primary amine, secondary amine, or tertiary amine with an acid. The acid includes the inorganic or organic acids described in this application.

[0109] The term "stereoisomer" refers to isomers that arise from differences in the arrangement of atoms within a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0110] Depending on the selection of raw materials and methods, the compounds of the present invention may exist as one of the possible isomers or as mixtures thereof, for example, as pure optical isomers or as mixtures of isomers, such as racemates and diastereomer mixtures, which are determined by the number of chiral carbon atoms. When describing optically active compounds, the prefixes D and L or R and S indicate the absolute configuration of the molecule with respect to the intramolecular chiral center (or multiple chiral centers). The prefixes D and L or (+) and (-) are signs to specify the rotation of plane polarization by the compound, with (-) or L indicating that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0111] When the bond with the chiral carbon in the formulas of this disclosure is depicted by a straight line, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures are within the range of this general formula. In this specification, the method of illustrating racemic or enantiomerically pure compounds is from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of a single stereocenter is indicated by wedge-shaped keys and dashed keys.

[0112] The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom within a molecule at two different positions. The compounds of the present invention can exhibit the phenomenon of tautomerism. Tautomer compounds may have two or more interconvertible forms. Proton-shift tautomers arise from the movement of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium form, and attempting to separate a single tautomer usually produces a mixture whose physical and chemical properties match those of the compound mixture. The equilibrium position is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone type is dominant, while in phenols, the enol type is dominant. The present invention encompasses all tautomer forms of compounds.

[0113] In this application, "pharmaceutical composition" refers to a formulation of a medium for transporting the compound of the present invention and a bioactive compound generally accepted in the art to a mammal (e.g., human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to the living organism and to enhance the absorption of the active ingredient to exert its bioactivity.

[0114] In this application, “pharmaceutically acceptable carrier” includes, but is not limited to, those permitted by the relevant government regulatory body as acceptable adjuvants, carriers, excipients, facilitators, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspension aids, stabilizers, isotonic agents, solvents, or emulsifiers for use in humans or livestock.

[0115] The term "solvate" refers to a solvent containing the compound or salt of the present invention, bonded by non-covalent intermolecular forces, whether stoichiometric or non-stoichiometric, and means a hydrate when the solvent is water.

[0116] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrugs of the present invention are produced by modifying a functional group in the compound, and such modification can be removed by conventional procedures or in the body to obtain the parent compound. The prodrug includes a compound formed by the attachment of one hydroxyl group or amino group in the compound of the present invention to any group, and when a prodrug of the compound of the present invention is administered to a mammalian organism, the prodrug is cleaved to form a free hydroxyl group or a free amino group.

[0117] The compounds of the present invention may contain non-natural proportion atomic isotopes on one or more atoms constituting the compound. For example, deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14Radioactive isotope-labeled compounds such as C) can be used. All isotopic compositional transformations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0118] "Additives" refer to medicinal, inert components. Examples of the term "excipients" 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 its fluidity and / or viscosity, making the formulation suitable for direct compression.

[0119] As used herein, the term “treatment” and other similar synonyms include the following meanings: (i) To prevent the disease or condition from occurring in mammals, especially those mammals that are susceptible to the disease or condition but have not been diagnosed with it. (ii) To inhibit a disease or condition, that is, to suppress its development. (iii) To alleviate a disease or condition, that is, to resolve the state of the disease or condition, or (iv) To alleviate the symptoms caused by the disease or condition. [Effects of the Invention]

[0120] Through extensive and in-depth research, the inventors unexpectedly developed a thiophenesulfonyl carbamate compound as an AT2R agonist, and the compound has the structure shown in the present invention. The thiophenesulfonyl carbamate compound described in the present invention can prevent or treat diseases or symptoms related to AT2R, exhibits excellent pharmacokinetic properties, and has high safety and drug viability. [Modes for carrying out the invention]

[0121] The following will further illustrate the present invention by combining specific examples. It should be understood that the following description is only a preferred embodiment of the present invention and should not be regarded as limiting the protection scope of the present invention. Without fully understanding the present disclosure, for experimental methods where specific conditions are not indicated in the following examples, usually, according to conventional conditions or conditions proposed by the manufacturer, 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 included in the protection scope of the present invention.

[0122] ▲This application has the following definitions. ●Symbol or unit: IC 50 : Half inhibitory concentration, the concentration when reaching half of the maximum inhibitory effect M: mol / L. For example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M normal hexane solution) indicates a normal hexane solution of n-butyllithium with a molar concentration of 2.5 mol / L. N: Normality. For example, 2N hydrochloric acid indicates a 2 mol / L hydrochloric acid solution. RT: Retention time ●Reagent: DCM: Methylene chloride DMF: N,N-Dimethylformamide DIPEA: N,N-Diisopropylethylamine EA: Ethyl acetate HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate MeOH: Methanol PE: Petroleum ether Toluene: Toluene THF: Tetrahydrofuran XPhos Pd G4: Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) SPhos Pd G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) ●Test method: LCMS: Liquid Chromatography TLC: Thin-layer chromatography

[0123] ▲Intermediate A1: Preparation of intermediate A1 N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide [ka] The synthesis route for intermediate A1 is as follows: [ka] Step 1: Synthesis of 3-bromo-2-isobutylthiophene [ka]

[0124] Under a nitrogen atmosphere, azobisisobutyronitrile (241 mg, 1.47 mmol) was added to a carbon tetrachloride (100 mL) solution containing 3-bromo-2-methylthiophene (2.6 g, 14.7 mmol) and N-bromosuccinimide (2.62 g, 14.7 mmol). The mixture was then heated to 80°C and reacted for 2 hours. The reaction mixture was cooled to room temperature, where a solid precipitated. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (3.2 g), which was then used in the next step of the reaction. Under a nitrogen atmosphere, the crude product (3.2 g) obtained above was dissolved in anhydrous tetrahydrofuryl (70 mL), and the resulting solution was cooled to 0°C. Next, a tetrahydrofuryl solution of isopropylmagnesium chloride (1.3 M, 14.7 mL) was added dropwise to the reaction mixture, and the reaction was carried out at 0°C for 2 hours. Then, 20 mL of ice water was added to quench the reaction, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phase was concentrated to dryness, and the sample was mixed in. The mixture was separated and purified by silica gel column (elution solvent: petroleum ether) to obtain 3-bromo-2-isobutylthiophene (2 g, yield: 62%). LC-MS, M / Z (ESI): 219.0 [M+H] +

[0125] Step 2: Synthesis of (4-bromo-5-isobutylthiophen-2-yl)trimethylsilane [ka] Under a nitrogen atmosphere and at -78°C, a tetrahydrofuryl solution (2M, 5.2mL) containing diisopropylaminolithium was added dropwise to a tetrahydrofuryl solution (45mL) containing 3-bromo-2-isobutylthiophene (1.88g, 8.6 mmol). After reacting at -78°C for 0.5 hours, trimethylchlorosilane (1.4g) was added dropwise to the reaction mixture, and the reaction mixture was slowly raised to room temperature and reacted at room temperature for 16 hours. The reaction was quenched by adding 50mL of water, extracted three times with 50mL of ethyl acetate, and the organic phase was concentrated to dryness. The sample was then mixed and separated and purified by silica gel column (elution solvent: petroleum ether) to obtain (4-bromo-5-isobutylthiophene-2-yl)trimethylsilane (2.4g, yield: 95%). LC-MS, M / Z (ESI): 291.0 [M+H] + 1 H NMR (400MHz,CDCl3) δ 7.01 (s,1 H),2.68 (d,2 H),2.03-1.91 (m,1 H),0.97 (d,6 H),0.29 (s,9 H)

[0126] Step 3: Synthesis of (4-fluoro-5-isobutylthiophen-2-yl)trimethylsilane [ka] Under a nitrogen atmosphere and at -78°C, a tetrahydrofuryl solution (2.5 M, 5 mL) containing n-butyllithium was added dropwise to a tetrahydrofuryl solution (45 mL) containing (4-bromo-5-isobutylthiophen-2-yl)trimethylsilane (2.4 g, 8.2 mmol), and the reaction was allowed to proceed for 1 hour at -78°C. Then, a tetrahydrofuryl solution (10 mL) containing N-fluorodiphenylsulfonamide (4.67 g, 14.8 mmol) was added dropwise, and the reaction was continued for 0.5 hours at -78°C. After that, the temperature of the reaction mixture was slowly raised to room temperature and stirred overnight. The reaction was quenched by adding 50 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phase was concentrated to dryness. The sample was then mixed and separated and purified by silica gel column (elution solvent: petroleum ether) to obtain (4-fluoro-5-isobutylthiophen-2-yl)trimethylsilane (1.7 g, yield: 89.9%). LC-MS, M / Z (ESI): 231.1 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.0 (s, 1 H), 2.67 (d, 2 H), 2.02 - 1.91 (m, 1 H), 0.96 (d, 6 H), 0.29 (s, 9 H) ppm

[0127] Step 4: Synthesis of 3-fluoro-2-isobutylthiophene [ka] Under nitrogen atmosphere and at 0°C, trifluoroacetic acid (10 mL) was added to dichloromethane (10 mL) containing (4-fluoro-5-isobutylthiophen-2-yl)trimethylsilane (1.7 g, 7.4 mmol). The reaction was then allowed to proceed at 0°C for 2 hours. The reaction was quenched with 50 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phase was concentrated to dryness. The sample was then mixed and separated and purified by silica gel column (elution solvent: petroleum ether) to obtain 3-fluoro-2-isobutylthiophene (1.0 g, yield: 85.6%). LC-MS, M / Z (ESI): 159.1 [M+H] + 1 H NMR (400MHz,CDCl3) δ 6.97 (dd,1 H),6.74 (dd,1 H),2.59 (dd,2 H),1.95-1.81 (m,1 H),0.96 (s,3 H),0.94 (d,3 H)

[0128] Step 5: Synthesis of N-(tert-butyl)-4-fluoro-5-isobutylthiophen-2-sulfonamide [ka] Under a nitrogen atmosphere and at 0°C, chlorosulfonic acid (3.68 g, 31.6 mmol) was added to dichloromethane (30 mL) containing 3-fluoro-2-isobutylthiophene (1.0 g, 6.3 mmol). The mixture was then reacted at 0°C for 1 hour, the reaction was quenched with 50 mL of water, extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was dissolved in anhydrous dichloromethane (30 mL), and triethylamine (1.93 g, 19 mmol) and tert-butylamine (0.7 g, 9.5 mmol) were added sequentially at 0°C, followed by reaction at room temperature for 2 hours. The reaction was quenched by adding 50 mL of water, extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V:V) = 20:1-10:1) to obtain N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (1.2 g, yield: 64.9%).

[0129] Step 6: Synthesis of 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide [ka] Under a nitrogen atmosphere and at -78°C, a tetrahydrofuryl solution (2.5M, 1.5mL) containing n-butyllithium was added dropwise to an anhydrous tetrahydrofuryl solution (8mL) containing N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (470mg, 1.6 mmol). The reaction mixture was then heated to -20°C and allowed to react for 2 hours. Subsequently, the reaction mixture was cooled to -78°C, bromine (380mg, 5 mmol) was added dropwise, and finally the reaction mixture was heated to room temperature and allowed to react overnight. The reaction was quenched by adding 50 mL of water, extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting crude product was separated and purified using a silica gel column (petroleum ether:ethyl acetate (V:V) = 20:1-10:1) to obtain 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (410 mg, yield: 68.8%). LC-MS, M / Z (ESI): 372.3 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1 H),2.69 (d,2 H),1.92-1.78 (m,1 H),1.15 (s,9 H),0.88 (d,6 H)

[0130] Step 7: Synthesis of N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide [ka] Under a nitrogen atmosphere, 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (325 mg, 0.87 mmol), 4-hydroxymethylphenylboric acid (395.1 mg, 2.6 mmol), potassium carbonate (360 mg, 2.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (64 mg, 0.087 mmol) were suspended in 10 mL of anhydrous 1,4-dioxane solution and then reacted overnight at 75°C. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with 50 mL of water, extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting crude product was separated and purified using a silica gel column (petroleum ether:ethyl acetate (V:V) = 10:1-2:1) to obtain N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (320 mg, yield: 92.06%). LC-MS, M / Z (ESI): 400.1 [M+H] + 1 H NMR (400MHz,CDCl3) δ 7.61-7.55 (m,2 H),7.51-7.45 (m,2 H),4.77 (s,2 H),4.06 (s,1 H),2.68 (dd,2 H),1.98-1.91 (m,1 H),1.03 (s,9 H),0.99 (d,6 H)

[0131] Step 8: Synthesis of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide [ka] Under nitrogen atmosphere and 0°C conditions, thionyl chloride (238 mg, 2 mmol) was added dropwise to a solution of dichloromethane (4 mL) containing N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (320 mg, 0.8 mmol), and the mixture was reacted at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and the crude product was purified by silica gel column (petroleum ether:ethyl acetate (V:V) = 10:1-4:1) to obtain N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (220 mg, yield: 66%). LC-MS, M / Z (ESI): 418.1 [M+H] +

[0132] ▲Intermediate A2: Preparation of intermediate A2 (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boric acid [ka] The synthesis route for intermediate A2 is as follows: [ka]

[0133] Step 1: Synthesis of 2-isobutyl-3-methylthiophene [ka] Zinc chloride (13.8 g, 101 mmol) was dissolved in tetrahydrofuryl (100 mL), and isobutylmagnesium bromide (2.00 M, 45.1 mL), 2-bromo-3-methylthiophene (10.0 g, 56.5 mmol), and bis(tritert-butylfino)palladium (1.44 g, 2.82 mmol) were added. After the additions were complete, the mixture was purged with nitrogen, and the temperature was slowly raised to 90°C and the reaction was allowed to proceed for 1 hour. The reaction mixture was poured into water (200 mL), ethyl acetate (200 mL) was added, and the mixture was extracted three times. The organic phase was washed with saturated saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-isobutyl-3-methylthiophene (6.00 g, yield 65.3%).

[0134] Step 2: Synthesis of 5-isobutyl-4-methylthiophene-2-sulfonyl chloride [ka] 2-Isobutyl-3-methylthiophene (6.00 g, 36.9 mmol) was dissolved in dichloromethane (30 mL), chlorosulfonic acid (13.6 g, 116 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain the product, 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (9.80 g, crude product).

[0135] Step 3: Synthesis of N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] Dissolve 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (9.80 g, 38.7 mmol) in dichloromethane (40 mL), add N,N-diisopropylethylamine (10.0 g, 77.5 mmol) and 2-methylpropan-2-amine (3.40 g, 46.5 mmol), and heat to 40°C and react for 1 hour. Pour the reaction mixture into water (40 mL), add ethyl acetate (200 mL) and extract three times. Wash the organic phase with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate, and separate and purify the crude product using silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1-5:1, R f =0.4), N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (1.50 g, yield 13.4%) was obtained. LC-MS, M / Z (ESI): 288.1 [MH] + .

[0136] Step 4: Synthesis of (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boric acid [ka] Dissolve N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (900 mg, 3.34 mmol) in tetrahydrofuryl (20 mL). Cool the reaction mixture to -60°C using a dry ice-ethanol bath. Slowly add n-butyllithium (2.50 M, 3.98 mL) dropwise under a nitrogen atmosphere. After the addition is complete, stir for 0.5 hours, then add triisopropyl borate (1.17 g, 6.22 mmol) and react at -60°C for 1 hour. Pour the reaction mixture into water (20 mL), add ethyl acetate (20 mL) and extract three times. Wash the organic phase with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, concentrate, and separate and purify the crude product using silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1-1:1, R f(=0.1), (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boric acid (0.7g, yield 62.8%) was obtained. LC-MS, M / Z (ESI): 332.1 [MH] +

[0137] ▲Example 1: Preparation of target compound I-1 ((3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophen-2-yl)sulfonyl)methyl carbamate [ka] The synthesis route for target compound I-1 is as follows: [ka] Step 1: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide [ka] Under a nitrogen atmosphere, a mixture of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (220 mg, 0.53 mmol), 2-chloroimidazole (81 mg, 0.79 mmol), and potassium carbonate (220 mg, 1.59 mmol) was mixed with anhydrous DMF (3 mL), and the mixture was then reacted overnight at 60°C. After the reaction mixture was cooled to room temperature, 50 mL of water was added to complete the reaction. The mixture was enemed, extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-1:1) to obtain N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (200 mg, yield: 78.1%). LC-MS, M / Z (ESI): 484.1 [M+H] +

[0138] Step 2: Synthesis of 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (1-2) [ka] Under a nitrogen atmosphere, trifluoroacetic acid (4 mL) was added to a solution of dichloromethane (4 mL) containing N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (200 mg, 0.41 mmol). The mixture was then reacted overnight at room temperature, and after concentrating the solvent under reduced pressure, the crude product was mixed with silica gel and separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-1:4) to obtain 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (140 mg, yield: 80%). LC-MS, M / Z (ESI): 428.1 [M+H] +

[0139] Step 3: Synthesis of Methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophen-2-yl)sulfonyl)carbamate

Chemical formula

[0140] ▲Example 2: Preparation of Target Compound I-2 ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)methyl carbamate [ka] The synthesis route for target compound I-2 is as follows: [ka] Step 1: Synthesis of N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-sulfonamide [ka] Under a nitrogen atmosphere, a mixture of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (308 mg, 0.74 mmol), 2-(trifluoromethyl)-1H-imidazole (151 mg, 1.11 mmol), and potassium carbonate (307 mg, 2.22 mmol) was mixed with anhydrous DMF (5 mL), and the mixture was reacted overnight at 60°C. After the reaction mixture was cooled to room temperature, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 20 mL of ethyl acetate. After drying with anhydrous sodium sulfate and filtering, the mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-1:1) N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-sulfonamide (360 mg, yield: 94%) was obtained. LC-MS, M / Z (ESI): 518.2 [M+H] +

[0141] Step 2: Synthesis of 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-sulfonamide [ka] Under a nitrogen atmosphere, trifluoroacetic acid (6 mL) was added to a solution of dichloromethane (6 mL) containing N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (360 mg, 0.69 mmol). The mixture was then allowed to react overnight at room temperature, the solvent was concentrated under reduced pressure, and the crude product was mixed with silica gel and separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-1:4) to obtain 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (230 mg, yield: 72%). LC-MS, M / Z (ESI): 462.1 [M+H] +

[0142] Step 3: Synthesis of ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)methyl carbamate [ka] Under nitrogen atmosphere and 0°C conditions, 2 mL of dichloromethane containing 100 mg, 0.22 mmol of 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide was sequentially mixed with N,N-diisopropylethylamine (0.153 mL, 0.88 mmol) and methyl chloroformate (23 mg, 0.24 mmol). The mixture was then reacted at 0°C for 2 hours, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)methyl carbamate (43 mg, yield: 38%) was obtained. LC-MS, M / Z (ESI): 520.1 [M+H] + 1 H NMR (400MHz,CDCl3) δ 7.52 - 7.46 (m,2 H),7.22 - 7.17 (m,2 H),7.13 - 7.08 (m,1 H),7.03 - 6.99 (m,1 H),5.27 (s,2 H),3.52 (t,3 H),2.65 (d,2 H),1.98-1.86 (m,1 H),0.97 (d,6 H)

[0143] ▲Example 3: Preparation of target compound I-3 ((4-Fluoro-3-(4-((2-(2-Hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butyl carbamate [ka] The synthesis route for target compound I-3 is as follows: [ka] Step 1: Synthesis of N-(tert-butyl)-4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

Chemical formula

[0144] Step 2: Synthesis of 4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

Chemical formula

[0145] Step 3: Synthesis of ((4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate butyl [ka] Under nitrogen atmosphere and 0°C conditions, 1 mL of dichloromethane containing 25 mg of 4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (25 mg, 0.055 mmol) was sequentially mixed with N,N-diisopropylethylamine (0.04 mL, 0.22 mmol) and butyl chloroformate (8.2 mg, 0.06 mmol). The mixture was then reacted at 0°C for 2 hours, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 20 mL of ethyl acetate. After concentrating the organic phase to dryness, it was separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) ((4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)butyl carbamate (13 mg, yield: 43%) was obtained. LC-MS, M / Z (ESI): 552.2 [M+H] + 1 H NMR (400MHz,CDCl3) δ 7.48 - 7.43 (m,2 H),7.17 -7.12 (m,2 H),6.97 -6.95 (m,1 H),6.85 - 6.83 (m,1 H),5.48 (s,2 H),4.05 - 3.98 (t,2 H),2.72 - 2.67 (d,2 H),1.98 - 1.86 (m,1 H),1.65 (s. 6 H),1.54 - 1.46 (m,2 H),1.30 - 1.24 (m,2 H),0.97 (d,6 H),0.88 (t,3 H)

[0146] ▲Example 4: Preparation of target compound I-4 ((4-Fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate butyl [ka] The synthesis route for target compound I-4 is shown in the following diagram. [ka]

[0147] Step 1: Synthesis of ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate butyl [ka] Under nitrogen atmosphere and 0°C conditions, 2 mL of dichloromethane containing 130 mg of 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (130 mg, 0.28 mmol) was sequentially mixed with N,N-diisopropylethylamine (0.2 mL, 1.13 mmol) and methyl chloroformate (42.3 mg, 0.31 mmol). The mixture was then reacted at 0°C for 2 hours, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)butyl carbamate (35 mg, yield: 22%) was obtained. LC-MS, M / Z (ESI): 562.1 [M+H] + 1H NMR (400MHz,CDCl3) δ 7.52 - 7.46 (m,2 H),7.23 - 7.19 (m,2 H),7.13 -7.11 (m,1 H),7.03 - 6.99 (m,1 H),5.29 (s,2 H),4.01 (t,3 H),2.69 (d,2 H),2.01 - 1.89 (m,1 H),1.54 - 1.45 (m,2 H),1.29 - 1.20 (m,2 H),0.99 (d,6 H),0.87 (t,3 H)

[0148] ▲Example 5: Preparation of target compound I-9 (5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate methyl [ka] The synthesis route for target compound I-9 is as follows: [ka]

[0149] Step 1: Synthesis of 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole [ka] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-(trifluoromethyl)-1H-imidazole (544 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (10 mL), and then potassium carbonate (1.66 mg, 12.0 mmol) was added and the mixture was reacted at 50°C for 2 hours. The reaction mixture was poured into water (100 mL), extracted three times with ethyl acetate (80 mL), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole (1.20 g, yield 98.3%). LC-MS, M / Z (ESI): 304.9 [M+H] +

[0150] Step 2: Synthesis of N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-sulfonamide [ka] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boric acid (400 mg, 1.20 mmol) is dissolved in tetrahydrofuryl (10 mL) and water (3 mL), 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole (330 mg, 1.08 mmol) is added, potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol) are added, and the mixture is stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated to obtain the crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-0:1) to obtain the compound N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (560 mg, yield 90.8%). LC-MS, M / Z (ESI): 514.0 [M+H] +

[0151] Step 3: Synthesis of 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-sulfonamide [ka] N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (550 mg, 1.07 mmol) was dissolved in trifluoroacetic acid (8 mL) and dichloromethane (4 mL) and reacted at 40°C for 2 hours. The reaction mixture was concentrated to obtain the crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-1:1) to obtain compound 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (470 mg, yield 95.9%). LC-MS, M / Z (ESI): 458.1 [M+H] +

[0152] Step 4: Synthesis of (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate methyl [ka] 5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (470 mg, 1.03 mmol) and methyl chloroformate (194 mg, 2.05 mmol) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (398 mg, 3.08 mmol) was added. The mixture was stirred at 0°C for 0.5 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (20 mL), extracted three times with dichloromethane (20 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high-performance liquid chromatography (column: Welch Xtimate 150*25 mm* 5 μm, solvent: A = water + 0.05 vol formic acid (30%), B = acetonitrile, gradient: 58%-78%, 10 minutes) to obtain the product (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate methyl (319 mg, yield 61.1%). LC-MS, M / Z (ESI): 516.1 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ: 11.83 (s,1H),7.60 (d,1H),7.17-7.23 (m,4H),7.15 (d,1H),5.42 (s,2H),3.53 (s,3H),2.67 (d,2H),1.81-1.91 (m,1H),1.75 (s,3H),0.93 (d,6H)

[0153] ▲Example 6: Preparation of target compound I-10 (5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate-2-hydroxy-2-methylpropyl [ka] The synthesis route for target compound I-10 is as follows: [ka]

[0154] Step 1: Synthesis of (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate phenyl [ka] 5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (300 mg, 656 μmol) and diphenyl carbonate (211 mg, 984 μmol) were dissolved in acetonitrile (5 mL), potassium carbonate (181 mg, 1.31 mmol) was added, and the mixture was stirred at 60 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated under vacuum to obtain the compound (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-yl)sulfonylcarbamate phenyl (370 mg, yield 97.7%). LC-MS, M / Z (ESI): 578.1 [M+H] +

[0155] Step 2: Synthesis of (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate-2-hydroxy-2-methylpropyl [ka] (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate phenyl (370 mg, 650 μmol) was dissolved in dioxane (8 mL), 2-methylpropane-1,2-diol (173 mg, 1.92 mmol) was added, and the mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated and separated and purified by high-performance liquid chromatography (column: C18 150*30 mm, mobile phase: A = water + 0.05 vol. formic acid (30%), B = acetonitrile, gradient: 58% - 88%, 7 minutes) to obtain the product (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate-2-hydroxy-2-methylpropyl (38.6 mg, yield 10.5%). LC-MS, M / Z (ESI): 574.1 [M+H] + 1 H NMR (400MHz,CDCl3) δ: 7.29 (s,1H),7.21-7.25 (m,2H),7.17 (d,1H),7.08 (d,2H),5.33 (s,2H),3.97 (s,2H),2.69 (d,2H),1.92-2.00 (m,1H),1.86 (s,3H),1.19 (s,6H),1.01 (d,6H)

[0156] ▲Example 7: Preparation of target compound I-11 ((5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate-(2S)-2-hydroxypropyl [ka] The synthesis route for target compound I-11 is as follows: [ka]

[0157] Step 1: Synthesis of ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate-(2S)-2-hydroxypropyl [ka] (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate phenyl (250 mg, 433 μmol) was dissolved in tetrahydrofuryl (2.00 mL), and (2S)-propane-1,2-diol (330 mg, 4.33 mmol) and triethylamine (131 mg, 1.30 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 20°C for 10 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), then extracted three times with ethyl acetate (20 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high-performance liquid chromatography (column: C18 150*30 mm, mobile phase: A = water + 0.05 vol. formic acid (30%), B = acetonitrile, gradient: 55% - 85%, 7 minutes) to obtain the product ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate-(2S)-2-hydroxypropyl (79.6 mg, yield 32.8%). LC-MS, M / Z (ESI): 560.3 [M+H] + 1H NMR (400MHz,CDCl3) δ: 7.40-7.45 (m,1H),7.20-7.27 (m,4H),7.12-7.17 (m,1H),7.06-7.10 (m,1H),5.33 (s,2H),4.05-4.18 (m,1H),3.86-4.04 (m,2H),2.69 (d,2H),1.93-2.02 (m,1H),1.84-1.87 (m,3H),1.10-1.20 (m,3H),1.01 (d,6H)

[0158] ▲Example 8: Preparation of target compound I-12 ((5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate-(2R)-2-hydroxypropyl [ka] The synthesis route for target compound I-12 is as follows: [ka]

[0159] Step 1: Synthesis of ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate-(2R)-2-hydroxypropyl [ka] (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate tolyl (250 mg, 433 μmol) was dissolved in tetrahydrofuryl (2 mL), and (2R)-propane-1,2-diol (330 mg, 4.33 mmol) and triethylamine (131 mg, 1.30 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 20°C for 10 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), then extracted three times with ethyl acetate (20 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high-performance liquid chromatography (column: Welch xextreme C18 150*30 mm, mobile phase: A = water + 0.05 volume formic acid (30%), B = acetonitrile, gradient: 55% - 85%, 7 minutes) to obtain the product ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate-(2R)-2-hydroxypropyl (67.7 mg, yield 27.9%). LC-MS, M / Z (ESI): 560.3 [M+H] + 1 H NMR (400MHz,CDCl3) δ: 7.39-7.48 (m,1H),7.28-7.30 (m,1H),7.20-7.26 (m,3H),7.12-7.17 (m,1H),7.04-7.10 (m,1H),5.33 (s,2H),4.11 (d,1H),3.85-4.03 (m,2H),2.69 (d,2H),1.97 (dt,1H),1.86 (s,3H),1.16 (d,3H),1.02 (d,6H)

[0160] ▲Example 9: Preparation of target compound I-13 (5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl [ka] The synthesis route for target compound I-13 is as follows: [ka] Step 1: (5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl [ka] (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate phenyl (365 mg, 632 μmol) was dissolved in dioxane (5 mL), ethylene glycol (118 mg, 1.90 mmol) was added, and the mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated and separated and purified by high-performance liquid chromatography (column: Welch xextreme C18 150*25mm*5μm, mobile phase: A=water + 0.05 volume formic acid (30%), B=acetonitrile, gradient: 53% - 73%, 10 minutes) to obtain the product (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl (38.91 mg, yield 11.3%). LC-MS, M / Z (ESI): 546.3 [M+H] + 1H NMR (400MHz,CDCl3) δ: 7.27-7.30 (d,1H),7.26 (d,1H),7.21-7.24 (d,2H),7.15 (d,1H),7.08 (d,1H),5.33 (s,2H),4.17-4.23 (t,2H),3.72-3.77 (t,2H),2.69 (d,2H),1.97 (m,1H),1.86 (s,3H),1.02 (d,6H)

[0161] ▲Example 10: Preparation of target compound I-14 (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate methyl [ka] The synthesis route for target compound I-14 is as follows: [ka] Step 1: Synthesis of 1-(4-bromo-2-fluorobenzenemethyl)-2-chloro-1H-imidazole [ka] 4-Bromo-1-(bromomethyl)-2-fluorobenzene (500 mg, 1.87 mmol) and 2-chloro-1H-imidazole (210 mg, 2.05 mmol) were dissolved in N,N-dimethylformamide (5.00 mL), then potassium carbonate (774 mg, 5.60 mmol) was added, and the mixture was reacted at 50°C for 2 hours. After the reaction was complete, the reaction mixture was poured into water (20 mL), then extracted three times with ethyl acetate (40 mL), and the organic phase was collected. The mixture was washed five times with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-3:1) to obtain 1-(4-bromo-2-fluorobenzenemethyl)-2-chloro-1H-imidazole (450 mg, yield 83.3%). LC-MS, M / Z (ESI): 290.9 [M+H] +

[0162] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boric acid (350 mg, 1.05 mmol) was dissolved in tetrahydrofuryl (5.00 mL) and water (1.00 mL), 1-(4-bromo-2-fluorobenzenemethyl)-2-chloro-1H-imidazole (274 mg, 945 μmol) was added, followed by potassium phosphate (1.11 mg, 5.25 mmol) and XPhos Pd G4 (90.4 mg, 105 μmol). The mixture was then stirred at 60°C for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated to obtain the crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-3:1) to obtain N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (450 mg, yield 86.0%). LC-MS, M / Z (ESI): 498.2 [M+H] +

[0163] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (450 mg, 904 μmol) was dissolved in trifluoroacetic acid (4.00 mL) and dichloromethane (4.00 mL) and reacted at 40°C for 1 hour. The reaction mixture was poured into water (20 mL) and then extracted three times with dichloromethane (40 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-0:1) to obtain 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (350 mg, yield 87.7%). LC-MS, M / Z (ESI): 442.1 [M+H] +

[0164] Step 4: Synthesis of methyl (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate [ka] Under 0°C conditions, 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (350 mg, 792 μmol) and methyl chloroformate (150 mg, 1.58 mmol) were dissolved in dichloromethane (5.00 mL), N,N-diisopropylethylamine (307 mg, 2.38 mmol) was added, and the mixture was stirred at 0°C for 0.5 hours. The reaction mixture was concentrated and separated and purified by high-performance liquid chromatography (column: Waters Xbridge 150 * 30 mm, solvent: A = water + 0.05 vol. formic acid (30%), B = acetonitrile, gradient: 55% - 85%, 7 minutes) to obtain (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate methyl (50.0 mg, yield 12.6%). LC-MS, M / Z (ESI): 500.0 [M+H] + 1 H NMR (400MHz,CDCl3) δ 7.76 (s,1H),7.16 (t,1H),7.02-7.08 (m,3H),7.00 (s,1H),5.22 (s,2H),3.72 (s,3H),2.69 (d,2H),1.92-2.00 (m,1H),1.87 (s,3H),1.02 (d,6H)

[0165] ▲Example 11: Preparation of target compound I-18 (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl [ka] The synthesis route for target compound I-18 is as follows: [ka]

[0166] Step 1: Synthesis of 1-(4-bromobenzyl)-2-chloro-1H-imidazole [ka] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-chloro-1H-imidazole (410 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1.66 g, 12.0 mmol) was added, and the mixture was reacted at 55°C for 1 hour. The reaction mixture was poured into water (50 mL), extracted three times with ethyl acetate (50 mL), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromobenzyl)-2-chloro-1H-imidazole (900 mg, yield 82.8%). LC-MS, M / Z (ESI): 271.0 [M+H] +

[0167] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boric acid (400 mg, 1.20 mmol) was dissolved in tetrahydrofuryl (6 mL) and water (2 mL), 1-(4-bromobenzyl)-2-chloro-1H-imidazole (293 mg, 1.08 mmol) was added, then potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol) were added, and the mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated to obtain the crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (510 mg, yield 88.5%). LC-MS, M / Z (ESI): 480.2 [M+H] +

[0168] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (500 mg, 1.04 mmol) was dissolved in trifluoroacetic acid (15 mL) and dichloromethane (5 mL) and reacted at 40°C for 1 hour. The reaction mixture was poured into water (10 mL) and then extracted three times with dichloromethane (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to obtain 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (400 mg, yield 90.6%), a brown oily compound. LC-MS, M / Z (ESI): 424.1 [M+H] +

[0169] Step 4: Synthesis of (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate phenyl [ka] 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-sulfonamide (200 mg, 472 μmol) and potassium carbonate (131 mg, 944 μmol) were dissolved in acetonitrile (2 mL), and diphenyl carbonate (152 mg, 708 μmol) was added. The mixture was stirred at 50°C for 2 hours. The reaction mixture was poured into water (20 mL), then extracted three times with ethyl acetate (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate phenyl (240 mg, yield 93.5%). LC-MS, M / Z (ESI): 544.2 [M+H] +

[0170] Step 5: Synthesis of (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl [ka] (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate phenyl (240 mg, 441 μmol) was dissolved in tetrahydrofuryl (3 mL), ethylene glycol (274 mg, 4.41 mmol) and triethylamine (134 mg, 1.32 mmol) were added, and the mixture was stirred at 25°C for 10 hours. The reaction mixture was poured into water (20 mL), then extracted three times with ethyl acetate (20 mL), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high-performance liquid chromatography (column: C18 150 * 30 mm, solvent: A = water + 0.05 vol. formic acid (30%), B = acetonitrile, gradient: 48% - 78%, 7 minutes) to obtain the product (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl (115 mg, yield 50.9%). LC-MS, M / Z (ESI): 512.2 [M+H] + 1 H NMR (400MHz,CDCl3) δ 7.22-7.27 (m,4H),6.97 (s,2H),5.17 (s,2H),4.18-4.22 (m,2H),3.74 (dd,2H),2.69 (d,2H),1.93-1.99 (m,1H),1.87 (s,3H),1.02 (d,6H).

[0171] ▲Example 12: Preparation of target compound I-19 (3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate methyl [ka] The synthesis route for target compound I-19 is as follows: [ka]

[0172] Step 1: Synthesis of 2-(1-(4-bromobenzyl)-1H-imidazole-2-yl)propan-2-ol [ka] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-(1H-imidazole-2-yl)propan-2-ol (505 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (20 mL), and then potassium carbonate (1.66 mg, 12.0 mmol) was added and the mixture was reacted at 50°C for 2 hours. After the reaction was complete, the reaction solution was poured into water (40 mL), extracted three times with ethyl acetate (40 mL), the organic phase was collected, washed five times with water (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:1 to ethyl acetate:methanol (V / V) = 10:1) to obtain 2-(1-(4-bromobenzyl)-1H-imidazole-2-yl)propan-2-ol (830 mg, yield 70.3%). LC-MS, M / Z (ESI): 295.0 [M+H] +

[0173] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boric acid (350 mg, 1.05 mmol) was dissolved in tetrahydrofuryl (7 mL) and water (3 mL), and 2-(1-(4-bromobenzyl)-1H-imidazole-2-yl)propan-2-ol (279 mg, 945 μmol) was added, followed by potassium phosphate (1.11 g, 5.25 mmol) and XPhos Pd G4 (90.4 mg, 105 μmol). The mixture was then stirred at 60°C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated to obtain the crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-0:1) to obtain N-(tert-butyl)-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-sulfonamide (420 mg, yield 79.4%). LC-MS, M / Z (ESI): 504.1 [M+H] +

[0174] Step 3: Synthesis of 3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] N-(tert-butyl)-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (410 mg, 814 μmol) was dissolved in trifluoroacetic acid (8 mL) and dichloromethane (3 mL) and reacted at 40°C for 2 hours. The reaction mixture was concentrated to obtain the crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 0:1 ~ dichloromethane:methanol (V / V) = 5:1) to obtain compound 3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (500 mg, crude product). LC-MS, M / Z (ESI): 448.2 [M+H] +

[0175] Step 4: Synthesis of (3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate methyl [ka] 3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-sulfonamide (500 mg, 1.12 mmol) is dissolved in dichloromethane (8 mL), and N,N-diisopropylethylamine (433 mg, 3.35 mmol) and methyl chloroformate (211 mg, 2.23 mmol) are added at 0°C, followed by stirring for 0.5 hours. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (20 mL), extracted three times with dichloromethane (20 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high-performance liquid chromatography (column: Welch Xtimate C18 150*25 mm* 5 μm, solvent: A = water + 0.05 vol. formic acid (30%), B = acetonitrile, gradient: 23% - 43%, 10 minutes) to obtain the product (3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate methyl (168 mg, yield 39.9%). LC-MS, M / Z (ESI): 506.2 [M+H] + 1 H NMR (400MHz,CD3OD) δ: 7.28-7.31 (m,2H),7.24-7.27 (m,2H),7.16 (d,1H),7.08 (d,1H),5.68 (s,2H),3.54 (s,3H),2.70 (d,2H),1.91-1.98 (m,1H),1.85 (s,3H),1.66 (s,6H),1.01 (d,6H)

[0176] ▲Example 13: Preparation of target compound I-21 (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate methyl [ka] The synthesis route for target compound I-21 is as follows: [ka]

[0177] Step 1: Synthesis of 1-(4-bromo-3,5-difluorobenzyl)-2-chloro-1H-imidazole [ka] 2-Bromo-5-(bromomethyl)-1,3-difluorobenzene (500 mg, 1.75 mmol) and 2-chloro-1H-imidazole (197 mg, 1.92 mmol) were dissolved in N,N-dimethylformamide (5 mL), then potassium carbonate (725 mg, 5.25 mmol) was added, and the mixture was reacted at 25°C for 1 hour. The reaction mixture was poured into water (30 mL), then extracted three times with ethyl acetate (60 mL), washed five times with water (60 mL), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-3:1) to obtain 1-(4-bromo-3,5-difluorobenzyl)-2-chloro-1H-imidazole (520 mg, yield 96.7%). LC-MS, M / Z (ESI): 308.9 [M+H] +

[0178] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boric acid (500 mg, 1.50 mmol) was dissolved in tetrahydrofuryl (5 mL) and water (1 mL), 1-(4-bromo-3,5-difluorobenzyl)-2-chloro-1H-imidazole (415 mg, 1.35 mmol) was added, followed by potassium phosphate (955 mg, 4.50 mmol) and SPhos Pd G3 (117 mg, 150 μmol), and the mixture was then stirred at 60°C for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated and separated and purified by high-performance liquid chromatography (column: Waters Xbridge 150 * 30 mm, solvent: A = water + 0.05 vol. formic acid (30%), B = acetonitrile, gradient: 65%-95%, 7 minutes), dried, and obtained N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, yield 19.4%). LC-MS, M / Z (ESI): 516.1 [M+H] +

[0179] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide [ka] N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, 291 μmol) was dissolved in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) and reacted at 40°C for 1 hour. The reaction mixture was poured into water (10 mL) and then extracted three times with dichloromethane (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. It was then separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-0:1) to obtain 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (100 mg, yield 74.8%). LC-MS, M / Z (ESI): 460.0 [M+H] +

[0180] Step 4: Synthesis of methyl (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate [ka] 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (100 mg, 217 μmol) and methyl chloroformate (82.2 mg, 870 μmol) were dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (84.3 mg, 652 μmol) was added. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated and separated and purified by high-performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm, solvent: A=water + 0.05 volume of ammonia (30%), B=acetonitrile, gradient: 5%-35%, 10 minutes), dried, and obtained methyl (3-(4-((2-chloro-1H-imidazole-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (4.00 mg, yield 3.57%). LC-MS, M / Z (ESI): 518.2 [M+H] + 1 H NMR (400MHz,CDCl3) δ 7.07 (d,1H),7.01 (d,1H),6.78 (d,2H),5.17 (s,2H),3.74 (s,3H),2.71 (d,2H),1.97-2.05 (m,1H),1.89 (s,3H),1.01 (d,6H)

[0181] ▲Example 14: Preparation of target compound I-22 N-((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptan-6-carboxamide [ka] The synthesis route for target compound I-22 is as follows: [ka] Step 1: Synthesis of N-((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptan-6-carboxamide [ka] 5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (200 mg, 437 μmol) and 1,1'-carbonyldiimidazole (106 mg, 656 μmol) were dissolved in dichloromethane (4 mL), and then dissolved in N,N-diisopropylethylamine (226 mg, 1.75 mmol). The mixture was stirred at room temperature for 4 hours. The above reaction solution was mixed with 2-oxa-6-azaspiro[3,3]heptane (43.3 mg, 437 μmol), dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (328 mg, 2.54 mmol) was added. The mixture was reacted at 60°C for 8 hours. The reaction mixture was concentrated and separated and purified by high-performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm, mobile phase: A=water + 0.05 volume ammonium hydroxide (30%), B=acetonitrile, gradient: 10%-40%, over 10 minutes), dried, and N-((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptan-6-carboxamide (126 mg, yield 49.6%). LC-MS, M / Z (ESI): 583.3 [M+H] + 1 H NMR (400MHz DMSO-d6) δ: 7.65 (s,1H),7.08-7.32 (m,6H),5.44 (s,2H),4.55 (s,4H),3.64-3.87 (s,4H),2.63 (d,2H),1.80-1.88 (m,1H),1.74 (s,3H),0.94 (d,6H).

[0182] ▲Example 15: Preparation of target compound I-23 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidinyl-2-yl)thiophene-2-sulfonamide [ka] The synthesis route for target compound I-23 is as follows: [ka]

[0183] Step 1: 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidinyl-2-yl)thiophene-2-sulfonamide [ka] 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, 354 μmol) and 2-chloropyrimidinyl (40.5 mg, 354 μmol) were dissolved in dioxane (6 mL), cesium carbonate (288 mg, 884 μmol) and XPhos Pd G3 (30.0 mg, 35.4 μmol) were added, and the mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated, and the crude product was slurryed with methanol (50 mL) at 25 °C for 30 minutes to obtain 3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidinyl-2-yl)thiophene-2-sulfonamide (48.1 mg, yield 26.9%). LC-MS, M / Z (ESI): 502.1 [M+H] + 1H NMR (400MHz DMSO-d6) δ: 8.46 (d,2H),7.45 (d,1H),7.16-7.24 (d,2H),7.08-7.16 (d,2H),7.02 (t,1H),6.96 (d,1H),5.23 (s,2H),2.62-2.67 (d,2H),1.85 (m,1H),1.74 (s,3H),0.93 (d,6H)

[0184] ▲Example 16: Preparation of target compound I-24 N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-1-((pyridine-2-ylmethyl)amino)carboxamide [ka] The synthesis route for target compound I-24 is as follows: [ka]

[0185] Step 1: Synthesis of N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazole-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-1-((pyridine-2-ylmethyl)amino)carboxamide [ka] Under ice bath cooling conditions, 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (0.228 g, 0.5 mmol) was sequentially added to an acetonitrile (11 mL) solution, and phenyl N-(2-pyridylmethyl)carbamate (0.182 g, 0.8 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (0.152 g, 1 mmol) were reacted at 80°C for 6 hours. The reaction was monitored by LC-MS to confirm that no starting materials remained. The reaction mixture was then cooled to room temperature, extracted three times with ethyl acetate (30 mL), washed three times with water (20 mL), washed once with saturated saline solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and then separated and prepared by high-performance liquid chromatography (formic acid aqueous solution / acetonitrile system). After purification, N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazole-1-yl)methyl)phenyl)thiophene-2-yl)sulfonyl)-1-((pyridine-2-ylmethyl)amino)carboxamide (0.128 g, yield 43.4%) was obtained. LC-MS, M / Z (ESI): 592.1 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 10.50 (s,1H),8.50 - 8.45 (m,1H),7.73 (td,J=7.7,1.8 Hz,1H),7.61 (d,J=1.1 Hz,1H),7.28 - 7.23 (m,1H),7.23 - 7.15 (m,6H),6.75 (t,J=5.5 Hz,1H),5.40 (s,2H),4.25 (d,J=5.6 Hz,2H),2.64 (d,J=7.1 Hz,2H),1.90 - 1.78 (m,1H),1.74 (s,3H),0.92 (d,J=6.6 Hz,6H).

[0186] ▲Example 17: The following compounds can be prepared by referring to the preparation method of the above compounds. [Table 1-1] [Table 1-2] [Table 1-3]

[0187] In the test example of the present invention, the method for preparing control compound I is based on patent WO2021229244A1, and its structure is as follows. [ka] Control compound I.

[0188] ▲Biology Exam The following test methods can be used.

[0189] ▲Test Example 1: Binding test between compound and AT2R The experiment was carried out according to the operating instructions for the Angiotensin AT2 Receptor Ligand Binding Assay Kit (#C1TT1AT2, Cisbio). First, the 10 mM compound mother liquor was serially diluted 5 times (including 10 concentrations, with each concentration repeated twice), and 160 nL of each concentration of the compound was added to a 384-well plate. 40 μL of 1×TLB (TLB: Tag-lite buffer) was added to each well, and the mixture was shaken at room temperature for 15 minutes. 5 mL of 1×TLB was added to a 15 mL centrifuge tube and set aside. The cryopreserved labeled cells were thawed in a 37°C water bath (1-2 minutes), and the thawed cells were quickly transferred to the 15 mL centrifuge tube. After mixing well, the cells were centrifuged at 1000 g for 5 minutes at room temperature. The supernatant was discarded, and the cells were resuspended in 2.7 mL of 1×TLB. A new 384-well plate was prepared, and 10 μL of well-mixed cells were added to the corresponding wells according to the test design. 5 μL of 4× compound solution and 5 μL of 4× Tag-lite red fluorescently labeled ligand were added to each well. After incubation at room temperature for 1 hour, data were read using EnVision's HTRF mode. The 665 nM and 615 nM excitation light intensities for each well were read, and the ratio (Ratio = A665nM / B615nM) was calculated and analyzed using GraphPad Prism8 software. 50 The values ​​were calculated as follows: X: logarithm of the compound concentration, Y: ratio of A665nM / B615nM.

[0190] Table 1: Binding activity of compounds to AT2R [Table 1-4]

[0191] Experimental results revealed that the compound in this invention exhibits a strong binding effect with AT2R.

[0192] ▲Test Example 2: CYP Inhibition Experiment of Compounds The inhibitory effects of the compound on six enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (midazolam), and CYP2B6, were evaluated at 10 μM. Human liver microsome mixtures were stored in a -80°C freezer before use, removed and thawed in a 37°C water bath before use, and the work was performed on ice. 100 μL of microsome working solution was taken, 2 μL of the compound or positive inhibitor working solution was added, and 2 μL of solvent was added to the solvent control group. This was then pre-incubated in a 37°C water bath for 10 minutes. After pre-incubation, 98 μL of NADPH regeneration solution was added to all samples to initiate the reaction. This was then incubated again in a water bath for the specified time. The reaction was quenched with 200 μL of stop solution. Centrifuge the plate at 3220g for 10 minutes, transfer 100μL of the supernatant, add 100μL of water, mix thoroughly into the analysis plate, and perform LC / MS / MS analysis.

[0193] Table 2: Results of CYP450 inhibition by compounds [Table 2]

[0194] Experimental results revealed that the compound in this invention exhibits weaker inhibitory activity against CYP enzymes compared to the control compound, does not affect normal metabolic processes in the body, has a low probability of drug-drug interactions occurring in the human body, and is therefore highly safe.

[0195] ▲Test Example 3: Experiment on free plasma protein binding (PPB) of compounds The dried dialysis membrane was immersed in ultrapure water for 1 hour, then immersed in a 20% ethanol solution for 20 minutes, and the membrane was rinsed 2-3 times with ultrapure water. Finally, it was pre-treated by immersion in ultrapure water for 20 minutes. Frozen plasma was thawed in a 37°C water bath for approximately 20 minutes. After thawing was complete, the pH of the plasma was measured and adjusted to 7.4 with a 1% phosphoric acid solution or a 0.1M sodium hydroxide solution. The compound was diluted in plasma preheated to 37°C to a final concentration of 1 μM, and the final concentration of warfarin, the internal standard, in the plasma was 2 μM. The dialysis membranes pre-treated according to the product specifications were assembled on a dialysis plate, and 100 μL of receiving solution (100 mM phosphate buffer solution + 0.002% Tween 80) was added to one side of the dialysis membrane in each dialysis well. 20 μL each of the final solutions of the test compound and the control compound were transferred to a 96-well sample plate, duplicated twice to obtain the T0 sample, and stored in a -20°C freezer. Additionally, 100 μL of the above final solutions were transferred to the other side of the dialysis membrane, duplicated twice, and incubated at 37°C with shaking for 6 hours. After 6 hours of incubation, 20 μL each of the post-dialysis recipient fluid and administered plasma were taken, duplicated twice to obtain samples B and A. The corresponding volumes of blank plasma or recipient fluid were added to each sample well to achieve a 1:1 volume ratio of plasma to buffer in each sample well. 300 μL of acetonitrile solution containing an internal standard was added to all sample wells, mixed well, and then centrifuged at 5500 × g for 10 minutes. 150 μL of the corresponding ultrapure water was added to the sample wells of the 96-well sample plate, 150 μL of the supernatant was added to the sample wells, mixed well, and then LC / MS / MS analysis was performed. u Formula:

number

[0196] The release rate of compounds into plasma is related to their pharmacological efficacy in vivo. Experimental results revealed that the compounds in this invention have a higher release rate compared to the control compounds, which is advantageous for the compounds to reach their target organs.

[0197] ▲Test Example 4: Stability experiment of compounds in liver microsomes The stability of human liver microsomes was detected by co-incubating the compound and human liver microsomes in vitro. First, the test compound was prepared in a 10 mM stock solution in DMSO solvent, and then diluted to 0.5 mM using acetonitrile. Human liver microsomes (Corning) were diluted in PBS in a microsome / buffer solution, and a 0.5 mM compound was diluted in this solution to form a working solution. The compound concentration in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. A deep-well plate was taken, 30 μL of the working solution was added to each well, and then 15 μL of preheated 6 mM NADPH solution was added to initiate the reaction, which was incubated at 37°C. After incubation, 135 μL of acetonitrile was added to the corresponding well for 0, 5, 15, 30, and 45 minutes to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep-well plate was vortex-shaked for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, purified water was added in a 1:1 ratio, and LC-MS / MS detection was performed to obtain the compound peak area and internal standard peak area ratio at each time point. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minutes, and the remaining percentage of the compound at each time point was calculated. These results were then analyzed using Graphpad 8 software. 1 / 2 Calculate.

[0198] [Table 3]

[0199] The stability of a compound in liver microsomes reflects the risk of metabolic removal in the body. Experimental results clearly showed that the test compound exhibited better stability in humans compared to the control compound.

[0200] ▲Test Example 5: Study on the bidirectional permeability of compounds in CACO-2 cells Caco-2 cells 1 × 10⁻¹⁶ 5 cells / cm 2 Cells were inoculated onto polyethylene film (PET) in 96-well insert plates at a certain rate, and the medium was changed every 4-5 days until 21-28 days, allowing fused cell monolayers to form. The transport buffer during the experiment was HBSS and 10.0 mM HEPES, with a pH of 7.40 ± 0.05. The test compounds were tested bidirectionally at 2.00 μM, both in the presence and absence of 10.0 μM GF120918. Digoxin was tested bidirectionally at 10.0 μM, both in the presence and absence of 10.0 μM GF120918, while nadolol and metoprolol were tested in the A-to-B direction at 2.00 μM without 10.0 μM GF120918, with all of the above tests using two multi-well samples. The final DMSO concentration was adjusted to less than 1%. The plates were incubated in a CO2 incubator at 37±1°C for 2 hours, then 5% CO2 was added under saturated humidity without shaking. After mixing all samples with acetonitrile containing the internal standard, the mixture was centrifuged at 3200 g for 10 minutes. For nadolol and metoprolol, 200 μL of the supernatant was diluted with 600 μL of distilled water and LC-MS / MS analysis was performed. For digoxin and the test compound, 200 μL of the supernatant was diluted with 200 μL of distilled water and LC-MS / MS analysis was performed. The concentrations of the test compound and control compound in the starting solution, donor solution, and receiver solution were quantified by LC-MS / MS using the analyte / internal standard peak area ratio.

[0201] After transport measurements, the integrity of the Caco-2 cell monolayer was measured using the fluorescein isothiocyanate exclusion test.

[0202] [Table 4] The experimental results showed that the permeability of the test compound was improved compared to the control compound, indicating that it is advantageous for the absorption of the compound.

[0203] ▲Test Example 6: Induction of CYP 3A4 enzyme by compound After detecting the cell viability of the resuscitated liver cells, the liver cells were inoculated in a culture medium at a rate of 0.7 × 10⁶. 6 The cells were diluted to 1 / μL. 100 μL of preheated inoculum was added to each well, and the 48-well collagen-coated plates were pre-moistened with the inoculum, then the inoculum was discarded. 200 μL of cells were added to each well of the pre-coated collagen-coated 48-well plates, and the cells were then cultured in a CO2 incubator at 37°C, 95% humidity, and 5% humidity. Four hours after cell attachment, the inoculum was aspirated, and 200 μL of incubation medium containing 2% matrix protease was added to each well. On day 2, the cell plates were removed, the supernatant was aspirated, 200 μL of compound solution was added to each well, and the plates were placed in the incubator for continued culture. After 24 and 48 hours, the 48-well plates were removed from the incubator, and the cells were transferred to a clean 96-well cell culture plate with 100 μL of medium in each well. Cell viability was measured by LDH.

[0204] Enzyme activity measurement: At 48 hours, the supernatant was aspirated, washed twice with 400 μL / well of preheated HBSS solution, and after aspirating the HBSS, 100 μL of enzyme-labeled substrate working solution was added to each well. The cell plates were then incubated in an incubator for 30 minutes, and the supernatant was transferred to a 96-well plate containing stop solution to stop the reaction. The sealed plates were shaken and centrifuged, and the supernatant was collected. The supernatant was then diluted with 0.1% FA water in a 1:4 ratio. All samples were mixed and analyzed by liquid-phase chromatography / mass spectrometry (LC / MS / MS). Calibration was performed by the peak area ratio of metabolites and internal standards (IS), and CYP enzyme activity was calculated using a standard curve consisting of seven standard concentrations. The factor change relative to the carrier control (0.1% dimethyl sulfoxide) was also calculated, with the derived factor = enzyme activity of the compound-treated sample / enzyme activity of the carrier control.

[0205] Enzyme gene induction measurement: 1. Extraction of total RNA from cells After 48 hours, the supernatant was aspirated, washed once with 400 μL / well HBSS, and RLT buffer (QIAGEN, cat:1015762) was added to the plate. The procedure was followed according to the steps of the QIAGEN RNA extraction kit. 2.CDNA synthesis cDNA synthesis will be performed using ABI's high-efficiency cDNA reverse transcription kit (cat:4368813). 3. Real-time quantitative PCR reaction A new plate was added with water free of nucleic acid enzymes, the cDNA sample was added to the plate, and it was gently mixed and diluted. Reactions for 18S rRNA and CYP3A4 were prepared separately, with 18S rRNA used as the internal standard. The real-time quantitative PCR plate was sealed and gently centrifuged to remove air bubbles and deposit the liquid at the bottom of the tube. The plate was transferred to a real-time quantitative PCR instrument and analyzed according to the manufacturer's instructions. PCR conditions: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles, followed by the following two steps: 95°C for 15 seconds, 60°C for 1 minute. 4. Real-time quantitative PCR data analysis Relative expression level change = 2 - ΔΔCt, ΔCt = Ct(target gene) - Ct(18S rRNA), ΔΔCt = ΔCt(treated sample) - ΔCt(untreated control). The experimental results revealed that the test compound did not show toxicity to hepatocytes, had a weak induction of CYP3A4 enzyme activity, and exhibited a weak positive internal standard for CYP3A4 enzyme gene induction.

[0206] ▲Example 7: Pharmacokinetic study of a compound after single oral forced administration to cynomolgus monkeys. The compound was dissolved in the solvent 5% DMSO + 10% Solutol + 85% Saline to prepare a concentration of 1 mg / mL and a dose of 5 mpk. Body weight was measured before administration, and the dose was calculated based on body weight and administered by oral forced ingestion. Blood was collected via femoral vein or other appropriate method, at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h. 1 mL / time sample was taken for each time point, treated with heparin sodium for anticoagulation, and stored on ice after collection. After blood sample collection, the samples were stored on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 2200 g, 10 minutes, 2-8°C). Plasma samples were stored in a -80°C freezer before analysis. The biological sample analysis methods and the analysis of all samples are carried out by the analytical laboratory of Medicipure Medical Technology (Shanghai) Co., Ltd. Simultaneously with the analysis of the samples, a day-to-day accuracy evaluation of the quality control samples is also conducted, with a required accuracy of 80-120% for quality control samples with an accuracy of 66.7% or higher.

[0207] [Table 5] The experimental results suggest that the test compound exhibits superior agonist effects, with higher Cmax and exposure levels compared to the control compound.

[0208] ▲Test Example 8: IPF drug efficacy experiment in mice using a compound This experiment required a specific mouse IPF model, which was constructed and the efficacy testing of the compound was carried out by Shanghai Pengli Co., Ltd. All animal testing procedures were reviewed and approved by the Pengli IACUC (Experimental Animal Management and Use Committee).

[0209] Experimental steps: 1. Compound preparation: An appropriate amount of compound powder was weighed out and prepared in DMSO mother liquor. This was then dispensed into the required daily dose and prepared on the same day. The required amount of 10% solutol was added according to the dilution ratio, and dissolved uniformly by swirling. Subsequently, the required amount of 85% saline according to the dilution ratio was added to adjust the final DMSO content to 5%, and a clear solution of 0.03 mg / mL was prepared. 2. Animal grouping: On the day of model creation, 10 animals are randomly selected and directly assigned to the G1 blank group, while all other animals are injected with bleomycin intratracheally to build the model. After bleomycin injection, the animals' weight changes, weight, and animal condition are used to randomly assign and group the animals using BioBook before the first dose, approximating the average weight of each group and reducing the error between groups. 3. Model Construction: An appropriate amount of bleomycin was dissolved in commercially available saline solution. Model animals were anesthetized by inhaling 1-4% isoflurane, and then administered 2 U / kg of bleomycin intratracheally. The specific dose was calculated based on the animal's body weight. G1 mice were injected with isovolume saline solution intratracheally under 1-4% isoflurane anesthesia conditions. 4. Administration: The day on which bleomycin is injected is defined as day 0 of the study. The methods of administration are as shown in the table below.

[0210] Table 6-1 Grouping and Administration Methods [Table 6-1] a: The solvent is 5% DMSO + 10% solutol + 85% saline. b:bid, administered in the morning and afternoon, with an interval of approximately 6 hours, and not administered on the morning of day 22. 5. Lung function detection: On day 22, all experimental animals were anesthetized by administering Zoletil (tiretamine hydrochloride / zolazepam hydrochloride injection) (25-50 mg / kg) and xylazine (5-10 mg / kg). Lung function was then detected using a pulmonary function test (PFT), including PV curve, FVC, IC, VC, Cdyn, and Cchord (quasi-static lung compliance) indices. 6. Pathological detection of lung sections: Lung tissue was collected, washed twice, and after wiping off moisture with filter paper, the subject's weight was measured. After weight measurement, the left lung was perfused and fixed using a 10% neutral formalin solution, and then immersed in a 10% neutral formalin solution for fixation and preservation, and subjected to histopathological evaluation. The formalin-fixed left lung was cut transversely into three sections: upper, middle, and lower, embedded in the same paraffin block, sectioned, and subjected to Masson's staining, after which a pathologist performed histopathological evaluation. The evaluation criteria are as shown in the table below.

[0211] Table 6-2 Standards for evaluating fibrosis [Table 6-2] 7. Euthanasia of animals: All experimental animals were euthanized using CO2 and cervical vertebral resection methods after the completion of in vivo testing.

[0212] Statistical analysis: Test data were expressed as mean ± standard error (mean ± SEM). Data were analyzed using SPSS or Graphpad Prism, and a P < 0.05 value was considered statistically significant.

[0213] Experimental results revealed that the compound of the present invention significantly improves FVC, IC, and VC pulmonary function indicators, as well as significantly improves the assessment of pulmonary fibrosis, compared to the control compound.

[0214] Although embodiments of the present invention have been described above, it should be understood that the above embodiments are illustrative and not limiting to the present invention, and those skilled in the art can change, modify, substitute, and transform the above embodiments within the scope of the present invention. Cross-reference to related applications

[0215] This application claims priority and interest in patent application number 202311089313.4, submitted to the China National Intellectual Property Administration on August 25, 2023; patent application number 202410298612.7, submitted to the China National Intellectual Property Administration on March 14, 2024; and patent application number 202411103404.3, submitted to the China National Intellectual Property Administration on August 12, 2024, the entire contents of which are incorporated into this application by reference.

Claims

1. A compound, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, wherein the compound has the structure shown in formula III, 【Chemistry 1】 However, R １ is halogen, C １ -C ６ Alkyl and C １ -C ６ Selected from haloalkyls, Each R ３ is independently selected from hydrogen, halogen, a cyano group, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, and the C １ -C ６ alkyl and C ３ -C ６ cycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, hydroxy, an amino group, a cyano group, C １ -C ６ alkyl, C ３ -C ７ cycloalkyl, and when there are a plurality of substituents, the substituents are the same or different. m is selected from 1, 2, 3, and 4. R ４ is hydrogen, C １ -C ６ Alkyl and C １ -C ６ Selected from haloalkyls, R ５ is halogen, C １ -C ６ Selected from alkyl and 4-7 membered heterocyclic alkyl, the C １ -C ６ The alkyl group is substituted with one, two, three, or four substituents selected from halogens, hydroxyls, and 4-7 membered heterocyclic alkyl groups, wherein the 4-7 membered heterocyclic alkyl group is substituted with halogens, hydroxyls, cyanide groups, and C １ -C ６ Substituting with 0, 1, 2, 3, or 4 substituents selected from alkyl groups and 4-7 membered heterocyclic alkyl groups, and if there are multiple substituents, the substituents may be the same or different. R ６ It consists of a 5-7 membered complex aromatic ring and -C(O)-X-R ２ Selected from, X is selected from NRa and O. R ２ is C １ -C ６ Alkyl, 4-7 membered heterocyclic alkyl, 5-7 membered heteroaromatic ring, and the C １ -C ６ Alkyls are halogens, hydroxyls, and C １ -C ３ Substituted with 0, 1, 2, 3, or 4 substituents selected from alkyl, 3-7 membered heterocyclic alkyl, and 5-7 membered heteroaromatic rings, wherein the 4-7 membered heterocyclic alkyl and 5-7 membered heteroaromatic rings are halogen, hydroxyl, cyanide, amino, or C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, C ３ -C ７ Substituted with 0, 1, 2, 3, or 4 substituents selected from cycloalkyl, 5-7 membered heteroaromatic rings, and 3-7 membered heterocyclic alkyl groups, and if there are multiple substituents, the substituents may be the same or different. Ra is hydrogen and C １ -C ３ Selected from alkyl groups, or Ra and R ２ These form a 5-8 membered heterocyclic alkyl diring with the nitrogen atom linked to them, R ５ The halogen is selected from Cl, and R ３ It is selected from hydrogen, R １ C １ -C ６ Selected from methyl alkyl groups, R ６ ha-C(O)-O-R ２ If selected from, R ２ It is not methyl, R ６ When selected from 5-7 member complex aromatic rings, R ３ A compound, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, wherein the compound is hydrogen or F.

2. The aforementioned compound comprises the compound shown in formula I, 【Chemistry 2】 However, R １ is halogen, C １ -C ６ Alkyl and C １ -C ６ Selected from haloalkyls, X is selected from NRa and O. R ２ is C １ -C ６ Alkyl, 5-7 membered heteroaromatic ring, and the C １ -C ６ Alkyls are halogens, hydroxyls, and C １ -C ３ Substituted with 0, 1, 2, 3, or 4 substituents selected from alkyl or 5-7 membered heteroaromatic rings, and if there are multiple substituents, the substituents may be the same or different. Each R ３ These are independently hydrogen, halogen, cyanide, and C １ -C ６ Alkyl, C ３ -C ６ Selected from cycloalkyl, the C １ -C ６ Alkyl and C ３ -C ６ Cycloalkyl groups may optionally include halogens, hydroxyl groups, amino groups, cyanide groups, and C １ -C ６ Alkyl, C ３ -C ７ Substituting with one, two, three, or four substituents selected from cycloalkyl groups, and if there are multiple substituents, the substituents may be the same or different. m is selected from 1, 2, 3, and 4. R ４ is selected from hydrogen, C １ -C ６ -alkyl and C １ -C ６ -haloalkyl, R ５ is selected from halogen and C １ -C ６ -alkyl, and the C １ -C ６ -alkyl is substituted with 1, 2, 3 or 4 substituents selected from halogen and hydroxy, and when there are a plurality of substituents, the substituents are the same or different. Ra is hydrogen and C １ -C ３ Selected from alkyl groups, or Ra and R ２ These form a 5-8 membered heterocyclic alkyl diring with the nitrogen atom linked to them, R ５ The halogen is selected from Cl, and R ３ It is selected from hydrogen, R １ is C １ -C ６ If methyl is selected from the alkyl group, and X is selected from O, then R ２ The compound according to claim 1, characterized in that it is not methyl, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs.

3. R ６ It is selected from a 5-7 membered heteroaromatic ring, and the heteroatom of the 5-7 membered heteroaromatic ring is N. and / or, R ６ teeth 【Transformation 3】 Selected from, and / or the compound having the structure shown in formula IV, 【Chemistry 4】 A compound according to claim 1, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in that...

4. The aforementioned R １ is halogen, C １ -C ３ Alkyl and C １ -C ３ Selected from haloalkyls, Preferably, the R １ F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, CH ２ F, CHF ２ and CF ３ Selected from, More preferably, the R １ It is selected from F, Cl and methyl, More preferably, the R １ A compound according to any one of claims 1 to 3, characterized in that the compound is selected from methyl, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

5. The aforementioned X is selected from NRa and O, and the aforementioned Ra is selected from hydrogen and methyl, and / or, X is selected from O, and / or, X is selected from NRa, and Ra is selected from hydrogen and methyl, and / or, X is selected from NRa, and Ra and R ２ These form a 5-8 member heterocyclic alkyl diring with nitrogen atoms linked to them, and the 5-8 member heterocyclic alkyl diring contains 1, 2, or 3 heteroatoms selected from N, O, and S. and / or, X is selected from NRa, and Ra and R ２ These atoms form a 5-8 membered heterospirone ring with nitrogen atoms linked to them, and the 5-8 membered heterospirone ring contains one, two, or three heteroatoms selected from N, O, and S. and / or, X is selected from NRa, and Ra and R ２ The nitrogen atoms that are linked to them 【Transformation 5】 A compound according to any one of claims 1 to 2, characterized by forming a compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

6. The aforementioned R ２ is C １ -C ４ Selected from alkyl, 4-7 membered heterocyclic alkyl, and 5-7 membered heteroaromatic ring, the C １ -C ４ Alkyls are halogens, hydroxyls, and C １ -C ３ Substituted with 0, 1, 2, 3, or 4 substituents selected from alkyl, 3-7 membered heterocyclic alkyl, 5-7 membered heteroaromatic ring, and 4-7 membered heterocyclic alkyl, wherein the 4-7 membered heterocyclic alkyl and 5-7 membered heteroaromatic ring are halogen, hydroxyl, or C １ -C ３ Substituted with 0, 1, 2, 3, or 4 substituents selected from alkyl or 5-7 membered heteroaromatic rings, and if there are multiple substituents, the substituents may be the same or different. Preferably, the R ２ is C １ -C ４ Alkyl, 4-7 membered heterocyclic alkyl, -C １ -C ４ Alkyl-4-7 membered heterocyclic alkyl, -C １ -C ４ Alkyl-5-7 membered heteroaromatic ring, -4-7 membered heteroaromatic ring alkyl-C １ -C ４ Selected from alkyl, the C １ -C ４ Alkyls are halogens, hydroxyls, and C １ -C ３ Substituted with 0, 1, 2, 3, or 4 substituents selected from alkyl groups, Preferably, R ２ R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pyrimidinyl ring, pyridyl ring, pyridadinyl ring, and pyrazinyl ring, and the above R ２ is halogen, hydroxy, C １ -C ３ Substituted with 0, 1, 2, 3, or 4 substituents selected from alkyl, pyridyl, pyrimidinyl, pyridadinyl, and pyrazinyl rings, Preferably, the R ２ Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, azetidinyl, oxyranil, oxetanil, tetrahydrofuranil, -C １ -C ４ Alkyl-azetidinyl, -C １ -C ４ Alkyl-oxyranyl, -C １ -C ４ Alkyl-oxetanyl, -oxetanyl-C １ -C ４ Alkyl, -C １ -C ４ Alkyl-tetrahydrofuranyl, -C １ -C ４ Selected from alkyl-pyridyl ring, pyrimidinyl ring, pyridyl ring, pyridadinyl ring, and pyrazinyl ring, the methyl, ethyl, propyl, isopropyl, butyl, and isobutyl are halogens, hydroxy, and C １ -C ３ Substituted with 0, 1, 2, 3, or 4 substituents selected from alkyl groups, Preferably, the R ２ The elements are selected from methyl, ethyl, propyl, butyl, isobutyl, pyridyl ring, pyrimidinyl ring, -methyl-pyridyl ring, -methyl-oxetanyl, and -oxetanyl-methyl, and the ethyl, propyl, isopropyl, butyl, and isobutyl elements are substituted with hydroxyl. More preferably, the R ２ is methyl, ethyl, 【Transformation 6】 Butyl, pyrimidinyl ring, 【Transformation 7】 A compound according to any one of claims 1 to 2, characterized by being selected from, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

7. Includes one or more of the following conditions: a) The R ３ is hydrogen, halogen, cyanide group, C １ -C ３ Alkyl, C ３ -C ４ Selected from cycloalkyl, the C １ -C ３ Alkyl and C ３ -C ４ Cycloalkyl groups may optionally include halogens, hydroxyl groups, amino groups, cyanide groups, and C １ -C ６ Alkyl, C ３ -C ７ Substituting with one, two, three, or four substituents selected from cycloalkyl groups, and if there are multiple substituents, the substituents may be the same or different. m is selected from 1, 2, 3, and 4. Preferably, the R ３ m is selected from hydrogen, F, Cl, methyl, and cyanide groups, and m is selected from 1, 2, 3, and 4. More preferably, the R ３ It is selected from hydrogen, F and Cl, b) The R ４ is hydrogen, C １ -C ３ Selected from alkyl groups, Preferably, the R ４ It is selected from hydrogen and methyl, More preferably, the R ４ It was selected from hydrogen, c) Said R ５ is halogen, C １ -C ３ Selected from alkyl and 4-5 membered heterocyclic alkyl, the C １ -C ３ The alkyl group is substituted with one, two, three, or four substituents selected from halogens, hydroxyls, and 4-7 membered heterocyclic alkyl groups, and the 4-5 membered heterocyclic alkyl group is substituted with halogens, hydroxyls, cyanide groups, and C １ -C ６ Substituting with 0, 1, 2, 3, or 4 substituents selected from alkyl, and if there are multiple substituents, the substituents may be the same or different. Preferably, the R ５ F, Cl, CF ３ , 【Transformation 8】 Selected from, More preferably, the R ５ Cl, CF ３ , 【Chemistry 9】 A compound according to any one of claims 1 to 3, characterized by being selected from, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

8. Includes one or more of the following conditions: 1) The above R ５ Selected from Cl, R ３ It is selected from hydrogen, R １ When is selected from methyl and X is selected from O, R ２ is methyl and C ２ -C ６ Selected from alkyl, the R ２ Among them, methyl is halogen, hydroxy, C １ -C ３ Substituted with 1, 2, 3, or 4 substituents selected from alkyl groups, and the R ２ C inside ２ -C ６ Alkyls are halogens, hydroxyls, and C １ -C ３ Substituting with 0, 1, 2, 3, or 4 substituents selected from alkyl, and if there are multiple substituents, the substituents may be the same or different. Preferably, R ２ is ethyl, 【Chemistry 10】 Selected from butyl, 2) R ５ Selected from Cl, R ３ It is selected from hydrogen, R ４ It is selected from hydrogen, R １ When is selected from methyl and X is selected from O, R ２ ethyl, butyl, 【Chemistry 11】 Selected from, 3) R ３ It is selected from hydrogen, R ４ It is selected from hydrogen, R １ If is selected from methyl and X is selected from NH, then R ２ teeth 【Chemistry 12】 Selected from, 4) R １ R is selected from methyl, ３ R is selected from hydrogen and F. ４ When selected from hydrogen, R ６ ha-C(O)-O-R ２ Selected from, R ２ methyl, butyl, 【Chemistry 13】 Selected from, R ５ Ha-CF ３ Cl, 【Chemistry 14】 Selected from, 5) R １ R is selected from methyl, ３ Selected from Cl, R ４ When selected from hydrogen, R ６ ha-C(O)-O-R ２ Selected from, R ２ R is selected from butyl, ５ Ha-CF ３ and selected from Cl, 6) R １ R is selected from methyl, ３ It is selected from hydrogen, R ４ When selected from hydrogen, R ６ It is selected from a 5-7 membered heteroaromatic ring, and the heteroatom of the 5-7 membered heteroaromatic ring is N. Preferably, R ５ Ha-CF ３ Selected from Cl, More specifically, R ５ He was selected from Cl. 7) The R １ R is selected from methyl, ３ It is selected from hydrogen, R ４ X is selected from hydrogen, X is selected from NRa, and Ra and R ２ The nitrogen atoms that are linked to them 【Chemistry 15】 Forming, 8) The R １ R is selected from methyl, ２ R is selected from methyl, ４ When is chosen from hydrogen and X is chosen from O, R ３ is selected from F and Cl, or R ５ Ha-CF ３ and 【Chemistry 16】 A compound according to claim 1, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized by being selected from among the above.

9. The aforementioned compound, 【Chemistry 17】 [Chemistry 18] The compound according to claim 1, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized by containing the above.

10. A pharmaceutical composition comprising a compound described in any one of claims 1 to 9, a tautomer thereof, a stereoisomer thereof, a hydrate, a solvate thereof, a pharmaceutically acceptable salt or prodrug, and optionally a pharmaceutically acceptable carrier.

11. The use of a compound according to any one of claims 1-9, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 10, wherein the use is To be used as an AT2R agonist, and / or to prevent and / or treat diseases in which endogenous production of AngII is insufficient. and / or to prevent and / or treat diseases in which enhanced action of AngII is desired or necessary. and / or prepare an AT2R agonist. Uses including and / or preparing a pharmaceutical, pharmaceutical composition, or formulation for the prevention and / or treatment of a disease in which AT2R is expressed and stimulation is desired or required.

12. A method for preventing and / or treating a disease, wherein the disease is Diseases characterized by insufficient endogenous production of AngII. and / or diseases in which enhancement of the action of AngII is desired or required, and / or diseases in which AT2R is expressed and stimulation is desired or required, The aforementioned method, A method characterized by using a therapeutically effective amount of the compound according to any one of claims 1 to 9, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 10, in a person suffering from or susceptible to the aforementioned disease.

13. The use according to claim 11 or the method according to claim 12, characterized in that the disease is a disease of the gastrointestinal tract, cardiovascular system, respiratory system, kidney, eye, female reproductive system, or central nervous system.

14. The aforementioned diseases include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, indigestion, gastroesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease, cholecystitis, multiple organ failure, sepsis, xerostomia, gastritis, gastric stasis, hyperacidity, biliary tract disease, celiac disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, convulsions, dysphagia, nausea, vomiting, Sjögren'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 premature birth, retinal microangiopathy, ovulation disorder, hypertension, myocardial hypertrophy, heart failure, arteriosclerosis, and arterial thrombosis. The use described in claim 11 or the method described in claim 12, characterized in that the adverse effects are venous thrombosis, endothelial dysfunction, endothelial damage, stenosis after balloon dilation, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, pre-eclampsia, myocardial infarction, reinfarction, ischemic injury, erectile dysfunction, neointimal thickening, cognitive impairment, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, hypertrophy, benign prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, promotion of nerve regeneration, ulcerative disorders, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer, cell apoptosis, tumors, proliferative diabetes, neuropathy, or organ rejection.

15. The use according to claim 11 or the method according to claim 12, characterized in that the disease is asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, or idiopathic pulmonary fibrosis.

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