Thienylsulfonyl carbamates as at2r agonists

Abstract

Compounds represented by the following structure, or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof. Said compounds can be used as AT2R agonists.

Description

Thiophenesulfonylcarbamates as AT2R agonists

[0001] Priority information

[0002] This application claims priority and benefits of patent application 202311089313.4 filed with the State Intellectual Property Office of China on August 25, 2023, patent application 202410298612.7 filed with the State Intellectual Property Office of China on March 14, 2024, and patent application 202411103404.3 filed with the State Intellectual Property Office of China on August 12, 2024, and incorporates the entire text of each of them herein by reference. Technical Field

[0003] The present invention belongs to the field of medicine, and in particular relates to a thiophenesulfonyl carbamate as an angiotensin II (Ang II) type 2 receptor (AT2R) agonist. Background Art

[0004] Idiopathic pulmonary fibrosis (IPF) refers to abnormal repair of damaged alveolar epithelial cells, leading to the proliferation of pulmonary fibroblasts, their transformation into myofibroblasts, excessive secretion of extracellular matrix, collagen deposition, altered alveolar architecture, and ultimately the development of fibrosis. While its pathogenesis remains unclear, current research suggests that it is closely related to oxidative stress, inflammation, and humoral regulation of the renin-angiotensin-aldosterone system (RAAS). The RAAS is currently believed to play a key role in the progression of pulmonary fibrosis. Angiotensin converting enzyme (ACE) hydrolyzes angiotensin I (Ang I) to angiotensin II (Ang II), which plays a crucial role in the development and progression of various inflammatory processes.

[0005] In humans, two major types of Ang II receptors have been identified, designated Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R). Ang II exerts physiological effects in numerous organs, including the kidneys, adrenal glands, heart, blood vessels, brain, gastrointestinal tract, and reproductive organs, regulating blood pressure, fluid and electrolyte homeostasis. The effects of Ang II are regulated by the balance of expression of two G protein-coupled receptors (GPCRs), AT1R and AT2R. AT1R is expressed throughout life and primarily regulates blood pressure. Its blockers are widely used clinically as antihypertensive drugs, controlling most of the physiological effects of Ang II. AT2R, primarily expressed in embryonic tissues, is implicated in blood pressure regulation, neural growth, pain control, and myocardial regeneration. Drugs targeting AT2R can improve cardiovascular function and alleviate neuropathic pain. However, AT2R expression is significantly elevated in pathological conditions, such as vascular injury, wound healing, and heart failure.

[0006] Recently, it has been suggested that AT2R agonists may be useful in the treatment and / or prevention of digestive tract disorders such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure. There remains a need for potent and / or selective AT2R agonists that are expected to be useful in the aforementioned disorders.

[0007] Summary of the Invention

[0008] The present invention aims to provide a thiophenesulfonylcarbamate as an AT2R agonist and its use. The thiophenesulfonylcarbamate has the structure shown in the first aspect of the present invention. The thiophenesulfonylcarbamate can be used to prepare a drug, pharmaceutical composition or preparation for treating and / or preventing diseases or conditions related to AT2R; or to treat and / or prevent diseases or conditions related to AT2R.

[0009] In a first aspect of the present invention, a compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, is provided, wherein the compound has a structure shown in Formula III:

[0010] wherein R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0011] Each R3 is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0012] m is selected from 1, 2, 3 and 4;

[0013] R4 is selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0014] R5 is selected from halogen, C1-C6 alkyl and 4-7 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 4-7 membered heterocycloalkyl; the 4-7 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, C1-C6 alkyl, 4-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0015] R6 is selected from a 5-7 membered heteroaromatic ring and -C(O)-X-R2;

[0016] X is selected from NRa and O;

[0017] R2 is C1-C6 alkyl, 4-7 membered heterocycloalkyl or 5-7 membered heteroaromatic ring; the C1-C6 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, C1-C3 alkyl, 3-7 membered heterocycloalkyl, and 5-7 membered heteroaromatic ring; the 4-7 membered heterocycloalkyl and 5-7 membered heteroaromatic ring are substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, 5-7 membered heteroaromatic ring and 3-7 membered heterocycloalkyl; when there are multiple substituents, the substituents may be the same or different;

[0018] Ra is selected from hydrogen and C1-C3 alkyl; or, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring;

[0019] When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and R6 is selected from -C(O)-O-R2, R2 is not methyl;

[0020] When R6 is selected from a 5-7 membered heteroaromatic ring, R3 is hydrogen or F.

[0021] Herein, the term "group A is selected from A1, ... and An" means that A is selected from one of A1, ... and An, which is synonymous with "group A is selected from A1, ..., or An".

[0022] According to an embodiment of the present invention, there is also provided a compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0023] wherein R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0024] X is selected from NRa and O;

[0025] R2 is a C1-C6 alkyl group or a 5-7 membered heteroaromatic ring; the C1-C6 alkyl group is substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, C1-C3 alkyl group or a 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents may be the same or different;

[0026] Each R3 is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0027] m is selected from 1, 2, 3 and 4;

[0028] R4 is selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0029] R5 is selected from halogen and C1-C6 alkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; when there are multiple substituents, the substituents are the same or different;

[0030] Ra is selected from hydrogen and C1-C3 alkyl;

[0031] Alternatively, Ra and R2 form a 5-8 membered heterocycloalkyl bicyclic ring with the nitrogen atom to which they are attached;

[0032] When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and X is selected from O, R2 is not methyl.

[0033] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0034] wherein R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0035] X is selected from NRa and O;

[0036] R2 is a C1-C6 alkyl group; the C1-C6 alkyl group is substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, and C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different;

[0037] R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0038] m is selected from 1, 2, 3 and 4;

[0039] R4 is selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0040] R5 is selected from halogen and C1-C6 alkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; when there are multiple substituents, the substituents are the same or different;

[0041] Ra is selected from hydrogen and C1-C3 alkyl;

[0042] When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and X is selected from O, R2 is not methyl.

[0043] In a preferred embodiment of the present invention, R6 is selected from a 5-7 membered heteroaromatic ring, wherein the heteroatom in the 5-7 membered heteroaromatic ring is N.

[0044] In a preferred embodiment of the present invention, R6 is selected from

[0045] In a preferred embodiment of the present invention, the compound has a structure shown in Formula IV:

[0046] In a preferred embodiment of the present invention, when R6 is selected from a 5-7 membered heteroaromatic ring, R3 is hydrogen or F.

[0047] In a preferred embodiment of the present invention, when R6 is selected from a 5-7 membered heteroaromatic ring, R3 is hydrogen.

[0048] In a preferred embodiment of the present invention, the R1 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl.

[0049] In a preferred embodiment of the present invention, R1 is selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, CH2F, CHF2 and CF3.

[0050] In a preferred embodiment of the present invention, the R1 is selected from F, Cl and methyl.

[0051] In a preferred embodiment of the present invention, the R1 is selected from methyl.

[0052] In a preferred embodiment of the present invention, the X is selected from NRa and O; and the Ra is selected from hydrogen and C1-C3 alkyl.

[0053] In a preferred embodiment of the present invention, the X is selected from NRa and O; and the Ra is selected from hydrogen and methyl.

[0054] In a preferred embodiment of the present invention, X is selected from O.

[0055] In a preferred embodiment of the present invention, said X is selected from NRa, and said Ra is selected from hydrogen and methyl.

[0056] In a preferred embodiment of the present invention, X is selected from NRa, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0057] In a preferred embodiment of the present invention, X is selected from NRa, Ra and R2 and the nitrogen atom to which they are connected form a 5-8 membered heterospiro ring, and the 5-8 membered heterospiro ring contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0058] In a preferred embodiment of the present invention, X is selected from NRa, Ra and R2 and the nitrogen atom to which they are attached to form

[0059] In a preferred embodiment of the present invention, X is selected from N, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0060] In a preferred embodiment of the present invention, X is selected from N, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterospiro ring, and the 5-8 membered heterospiro ring contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0061] In a preferred embodiment of the present invention, X is selected from N, Ra and R2 and the nitrogen atom to which they are attached form

[0062] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0063] wherein Ra is selected from hydrogen;

[0064] R2 is selected from a 5-7 membered heteroaromatic ring, a C1-C4 alkyl-5-7 membered heteroaromatic ring;

[0065] Alternatively, Ra and R2 form a 5-8 membered heterocycloalkyl bicyclic ring with the nitrogen atom to which they are attached;

[0066] R1, R3, R4, R5 and m are as defined in the first aspect of the present invention.

[0067] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring; the C1-C4 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring, 4-7 membered heterocycloalkyl; the 4-7 membered heterocycloalkyl and 5-7 membered heteroaromatic ring are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents are the same or different.

[0068] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, 4-7 membered heterocycloalkyl, -C1-C4 alkyl-4-7 membered heterocycloalkyl, -C1-C4 alkyl-5-7 membered heteroaromatic ring, -4-7 membered heterocycloalkyl-C1-C4 alkyl; and the C1-C4 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0069] In a preferred embodiment of the present invention, the R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, azetidinyl, oxirane, oxetanyl, tetrahydrofuran ring, -C1-C4 alkyl-azetidinyl, -C1-C4 alkyl-oxirane, -C1-C4 alkyl-oxetanyl, -C1-C4 alkyl-tetrahydrofuran ring, -C1-C4 alkyl-pyridine ring, pyrimidine ring, pyridine ring, pyridazine ring, pyrazine ring; the methyl, ethyl, propyl, isopropyl, butyl, isobutyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0070] In a preferred embodiment of the present invention, the R2 is selected from methyl, ethyl, propyl, butyl, isobutyl, pyridine ring, pyrimidine ring, -methyl-pyridine ring, -methyl-oxetanyl, -oxetanyl-methyl; the ethyl, propyl, isopropyl, butyl, isobutyl is substituted by hydroxyl.

[0071] In a preferred embodiment of the present invention, said R2 is selected from methyl, ethyl, Butyl, pyrimidine ring,

[0072] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, 5-7 membered heteroaromatic ring; the C1-C4 alkyl, 5-7 membered heteroaromatic ring is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents are the same or different.

[0073] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pyrimidine ring, pyridine ring, pyridazine ring, pyrazine ring; and R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring.

[0074] In a preferred embodiment of the present invention, said R2 is selected from methyl, ethyl, Butyl, pyrimidine ring,

[0075] In a preferred embodiment of the present invention, said R2 is selected from C1-C4 alkyl; said C1-C4 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; when there are multiple substituents, said substituents are the same or different.

[0076] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and R2 is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0077] In a preferred embodiment of the present invention, said R2 is selected from methyl, ethyl, Butyl.

[0078] In a preferred embodiment of the present invention, the R3 is selected from hydrogen, halogen, cyano, C1-C3 alkyl, C3-C4 cycloalkyl; the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0079] m is selected from 1, 2, 3 and 4.

[0080] In a preferred embodiment of the present invention, R3 is selected from hydrogen, F, Cl, methyl, and cyano; and m is selected from 1, 2, 3, and 4.

[0081] In a 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.

[0082] In a preferred embodiment of the present invention, said R3 is selected from hydrogen, F and Cl.

[0083] In a preferred embodiment of the present invention, R3 is selected from hydrogen and F.

[0084] In a preferred embodiment of the present invention, R4 is selected from hydrogen, C1-C3 alkyl and C1-C3 haloalkyl.

[0085] In a preferred embodiment of the present invention, R4 is selected from hydrogen and C1-C3 alkyl.

[0086] In a preferred embodiment of the present invention, R4 is selected from hydrogen and methyl.

[0087] In a preferred embodiment of the present invention, said R4 is selected from hydrogen.

[0088] In a preferred embodiment of the present invention, the R5 is selected from halogen, C1-C3 alkyl and 4-5 membered heterocycloalkyl; the C1-C3 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 4-7 membered heterocycloalkyl; the 4-5 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different.

[0089] In a preferred embodiment of the present invention, said R5 is selected from F, Cl, CF3,

[0090] In a preferred embodiment of the present invention, said R5 is selected from Cl, CF3,

[0091] In a preferred embodiment of the present invention, the R5 is selected from halogen and C1-C3 alkyl; the C1-C3 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; when there are multiple substituents, the substituents are the same or different.

[0092] In a preferred embodiment of the present invention, said R5 is selected from F, Cl, Br, I, CF3 and

[0093] In a preferred embodiment of the present invention, said R5 is selected from Cl, CF3 and

[0094] In a preferred embodiment of the present invention, R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and when X is selected from O, R2 is selected from methyl, C2-C6 alkyl and 4-7 membered heterocycloalkyl; the methyl in R2 is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl; the C2-C6 alkyl in R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl; the 4-7 membered heterocycloalkyl in R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different;

[0095] Preferably, R2 is selected from ethyl, Butyl,

[0096] In a preferred embodiment of the present invention, R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and when X is selected from O, R2 is selected from methyl and C2-C6 alkyl; the methyl in R2 is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; the C2-C6 alkyl in R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different;

[0097] Preferably, R2 is selected from ethyl, Butyl.

[0098] In a 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, X is selected from O, R2 is selected from ethyl, butyl,

[0099] In a 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, R2 is selected from

[0100] In a 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, R2 is selected from methyl, butyl, R5 is selected from -CF3, Cl,

[0101] In a preferred embodiment of the present invention, R1 is selected from methyl, R3 is selected from Cl, R4 is selected from hydrogen, R6 is selected from -C(O)-O-R2, R2 is selected from butyl, and R5 is selected from -CF3 and Cl.

[0102] In a preferred embodiment of the present invention, when R1 is selected from methyl, R3 is selected from hydrogen, and R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, and the heteroatom in the 5-7 membered heteroaromatic ring is N.

[0103] In a preferred embodiment of the present invention, when R1 is selected from methyl, R3 is selected from hydrogen, and R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, the heteroatom in the 5-7 membered heteroaromatic ring is N, and R5 is selected from -CF3 and Cl.

[0104] In a preferred embodiment of the present invention, when R1 is selected from methyl, R3 is selected from hydrogen, and R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, the heteroatom in the 5-7 membered heteroaromatic ring is N, and R5 is selected from Cl.

[0105] In a 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, Ra and R2 form a nitrogen atom to which they are connected.

[0106] In a preferred embodiment of the present invention, when 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 selected from -CF3 and

[0107] In a preferred embodiment of the present invention, the compound, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that the compound comprises:

[0108] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound according to the first aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

[0109] In a preferred embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0110] In a third aspect of the present invention, the compound according to the first aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to the second aspect, is used, wherein the use comprises:

[0111] As an AT2R agonist;

[0112] and / or, preventing and / or treating diseases in which endogenous production of Ang II is insufficient;

[0113] and / or, preventing and / or treating diseases in which an increased effect of Ang II is desired or required;

[0114] and / or, preparing a medicament, pharmaceutical composition or formulation that is an AT2R agonist, and / or prevents and / or treats a disease in which AT2R is expressed and its stimulation is desired or necessary.

[0115] Provided are compounds as described in the first aspect, or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition as described in the second aspect, which are expected to be used to treat diseases of the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, eyes, female reproductive system or central nervous system (CNS).

[0116] Gastrointestinal diseases that should be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease (such as hepatitis), gallbladder disease, multiple organ failure, and sepsis. Other gastrointestinal diseases that should be mentioned include xerostomia, gastritis, gastric stasis, hyperacidity, biliary tract disease, abdominal disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, angina, dysphagia, nausea, vomiting, and Sjögren's syndrome.

[0117] Respiratory diseases that should be mentioned include inflammatory diseases such as asthma, obstructive lung disease (such as chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, adult respiratory distress syndrome, and idiopathic pulmonary fibrosis.

[0118] Kidney diseases that should be mentioned include renal failure, nephritis, and renal hypertension.

[0119] Eye diseases that should be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microvascularization.

[0120] Female reproductive system disorders that should be mentioned include disorders of the ovulatory mechanism.

[0121] Cardiovascular diseases that should be mentioned include hypertension, myocardial hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, stenosis after balloon angiogenesis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic damage, erectile dysfunction, and neointimal hyperplasia.

[0122] CNS diseases that should be mentioned include cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, and cerebral infarction.

[0123] The compound as described in the first aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect can also be used for the regulation of growth metabolism and proliferation, for example, for the treatment of hypertrophy, prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, nerve regeneration, ulcer healing, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer (such as gastrointestinal cancer, lung cancer, etc.), apoptosis, tumors (generally), hyperplastic diabetes, nerve damage and organ rejection.

[0124] The compound described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect, are suitable for the treatment and / or preventive treatment of the above-mentioned diseases.

[0125] The fourth aspect of the present invention provides a method for treating a disease, wherein the endogenous production of AngII is insufficient, and / or a disease in which it is desired or necessary to increase the action of AngII, and / or a disease in which AT2R is expressed and stimulation is desired or necessary, the method comprising administering to a person suffering from or susceptible to the disease a therapeutically effective amount of the compound of the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of the second aspect.

[0126] According to an embodiment of the present invention, the disease type refers to the description of the use described in the third aspect of the present invention.

[0127] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0128] Terms and Definitions

[0129] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0130] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0131] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0132] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0133] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, As used herein, "R1", "R2" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.

[0134] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0135] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0136] When a numerical range is described in the specification and claims of this application and is understood as an "integer," it should be understood to include both endpoints of the range as well as every integer within the range. For example, "an integer from 1 to 6" should be understood to include every integer from 0, 1, 2, 3, 4, 5, and 6.

[0137] In this application, "AT2 receptor" and "AT2R" have the same definition.

[0138] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, or iodine.

[0139] As used herein, the term "amino" by itself or as part of another substituent refers to -NH2.

[0140] As used herein, the term "hydroxy" by itself or as part of another substituent refers to -OH.

[0141] As used herein, the term "alkyl" when used alone or as part of another substituent means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of naturally abundant alkyl groups that are enriched in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0142] The term "C1-C6 alkyl" alone or as part of another substituent is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as 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 isomers thereof. In particular, such groups have 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, methylene, ethyl, n-propyl or isopropyl.

[0143] The term "oxo" when used alone or as part of another substituent refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, ie, the methylene group is replaced by a carbonyl group, representing =0.

[0144] The term "cycloalkyl" or "carbocyclyl" when used alone or as part of another substituent refers to a cyclic alkyl group. m -C n "Cycloalkyl" is understood to mean a saturated or partially saturated carbon ring having m to n atoms. For example, "3-15 membered cycloalkyl" or "C3-C 15 "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "5-8 membered cycloalkyl" contains 5-8 carbon atoms. It includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of unsubstituted cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. The cycloalkyl group may be substituted with one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused to an aryl or heteroaryl group. The term "C3-C6 cycloalkyl" should be understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0145] "Halocycloalkyl," by itself or as part of another substituent, refers to a cycloalkyl group as defined above wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl group are replaced by fluorine, chlorine, bromine, or iodine.

[0146] "Haloalkyl" when used alone or as part of another substituent refers to a saturated aliphatic hydrocarbon group, including branched and straight chains, having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3 and w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0147] The term "5-7 membered heteroaromatic ring" is used interchangeably with "5-7 membered heteroaryl" when used alone or as part of another substituent and is understood to mean an aromatic ring group having 5, 6 or 7 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S. The term "5-7 membered heteroaromatic ring" is understood to mean an aromatic ring group having 5, 6 or 7 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl.

[0148] The term "heterocycloalkyl" or "heterocyclyl" when alone or as part of another substituent refers to a saturated cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl group exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl groups include, but are not limited to, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiopyranyl. "Heterocycloalkyl" or "heterocyclyl" can also contain 1, 2, or 3 rings, including fused, bridged, and spirocyclic structures. The term "3-7 membered heterocycloalkyl" is understood to mean a cycloalkyl group having 3, 4, 5, 6, or 7 atoms, containing 1, 2, or 3 heteroatoms selected from N, O, S, and P. The term "5-8 membered heterocycloalkyl bicyclic ring" is understood to mean two rings having 5 to 8 atoms, including fused, bridged, and spirocyclic structures, wherein the heteroatoms are preferably selected from N, O, and S. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. Examples of "5-8 membered heterocycloalkyl bicyclic rings" include, but are not limited to:

[0149] In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0150] In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0151] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These salts may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used in the identification, characterization, or purification of the compounds of the present invention.

[0152] The term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid, wherein the acid includes an inorganic acid or an organic acid as described in the present application.

[0153] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0154] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in one of the possible isomers or in a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (–) are used to designate the signs for the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0155] When bonds to chiral carbon atoms in the present formulae are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formula. The diagrammatic representation of racemates or enantiomerically pure compounds herein is adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0156] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0157] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0158] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0159] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0160] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0161] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0162] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression.

[0163] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0164] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0165] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0166] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0167] (iv) Alleviate the symptoms of the disease or condition. Beneficial effects

[0168] After extensive and intensive research, the inventors unexpectedly discovered a thiophenesulfonylcarbamate compound as an AT2R agonist, having the structure shown herein. The thiophenesulfonylcarbamate compound of the present invention can prevent or treat diseases or conditions associated with AT2R, exhibits excellent pharmacokinetic properties, and possesses high safety and drugability. DETAILED DESCRIPTION

[0169] The present invention will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0170] This application has the following definitions:

[0171] Symbol or unit:

[0172] IC 50 : Half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0173] M: mol / L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L

[0174] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0175] RT: retention time

[0176] Reagents:

[0177] DCM: dichloromethane

[0178] DMF: N,N-dimethylformamide

[0179] DIPEA: N,N-diisopropylethylamine

[0180] EA: ethyl acetate

[0181] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0182] MeOH: methanol

[0183] PE: Petroleum ether

[0184] Toluene: Toluene

[0185] THF: Tetrahydrofuran

[0186] XPhos Pd G4: Palladium(II) methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)

[0187] SPhos Pd G3: methanesulfonate (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II)

[0188] Test method:

[0189] LCMS: Liquid chromatography-mass spectrometry

[0190] TLC: Thin layer chromatography

[0191] Intermediate A1: Preparation of Intermediate A1

[0192] N-(tert-Butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0193] The synthetic route of intermediate A1 is as follows:

[0194] Step 1: Synthesis of 3-bromo-2-isobutylthiophene

[0195] Under nitrogen protection, azobisisobutyronitrile (241 mg, 1.47 mmol) was added to a solution of 3-bromo-2-methylthiophene (2.6 g, 14.7 mmol) and N-bromosuccinimide (2.62 g, 14.7 mmol) in carbon tetrachloride (100 mL). The mixture was then heated to 80°C and reacted for 2 hours. The reaction solution was cooled to room temperature, and a solid precipitated. The solid was filtered and the filtrate was dried to obtain a crude product (3.2 g) which was used directly in the next reaction. Under nitrogen protection, the crude product (3.2 g) was dissolved in anhydrous tetrahydrofuran (70 mL) and the resulting solution was cooled to 0°C. Then, a tetrahydrofuran solution of isopropylmagnesium chloride (1.3 M, 14.7 mL) was added dropwise to the reaction solution. After reacting at 0°C for 2 hours, 20 mL of ice water was added to quench the reaction. The mixture was extracted three times with 50 mL of ethyl acetate. The organic phase was concentrated to dryness and then mixed. The mixture was separated and purified by silica gel column (eluent: petroleum ether) to obtain 3-bromo-2-isobutylthiophene (2 g, yield: 62%).

[0196] LC-MS, M / Z(ESI):219.0[M+H] +

[0197] Step 2: Synthesis of (4-bromo-5-isobutylthiophen-2-yl)trimethylsilane

[0198] Under nitrogen protection and at -78°C, a solution of 3-bromo-2-isobutylthiophene (1.88 g, 8.6 mmol) in tetrahydrofuran (45 mL) was added dropwise containing a 2 M solution of lithium diisopropylamide in tetrahydrofuran (5.2 mL). After reacting at -78°C for 0.5 hour, trimethylsilyl chloride (1.4 g) was added dropwise to the reaction solution. The reaction solution was then slowly warmed to room temperature and allowed to react at room temperature for 16 hours. The reaction was quenched by adding 50 mL of water and extracted three times with 50 mL of ethyl acetate. The organic phase was concentrated to dryness, mixed, and purified using a silica gel column (eluent: petroleum ether) to obtain (4-bromo-5-isobutylthiophen-2-yl)trimethylsilane (2.4 g, yield: 95%).

[0199] LC-MS, M / Z(ESI):291.0[M+H] +

[0200] 1 H NMR(400MHz, CDCl3)δ7.01(s,1H),2.68(d,2H),2.03-1.91(m,1H),0.97(d,6H),0.29(s,9H)

[0201] Step 3: Synthesis of (4-fluoro-5-isobutylthiophen-2-yl)trimethylsilane

[0202] Under nitrogen protection at -78°C, a tetrahydrofuran solution (45 mL) containing (4-bromo-5-isobutylthiophen-2-yl)trimethylsilane (2.4 g, 8.2 mmol) was added dropwise with a tetrahydrofuran solution (2.5 M, 5 mL) of n-butyllithium. The mixture was allowed to react at -78°C for 1 hour. Then, a tetrahydrofuran solution (10 mL) containing N-fluorobisbenzenesulfonamide (4.67 g, 14.8 mmol) was added dropwise. After a further 0.5 hour at -78°C, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched by adding 50 mL of water and extracted three times with 50 mL of ethyl acetate. The organic phase was concentrated to dryness, mixed, and purified by silica gel column chromatography (eluent: petroleum ether) to obtain (4-fluoro-5-isobutylthiophen-2-yl)trimethylsilane (1.7 g, yield: 89.9%).

[0203] LC-MS, M / Z(ESI):231.1[M+H] +

[0204] 1 H NMR(400MHz, CDCl3)δ7.0(s,1H),2.67(d,2H),2.02-1.91(m,1H),0.96(d,6H),0.29(s,9H)pp m

[0205] Step 4: Synthesis of 3-fluoro-2-isobutylthiophene

[0206] Under nitrogen protection 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 mixture was then allowed to react at 0°C for 2 hours. The reaction was quenched by adding 50 mL of water and extracted three times with 50 mL of ethyl acetate. The organic phase was concentrated to dryness, mixed, and purified using a silica gel column (eluent: petroleum ether) to obtain 3-fluoro-2-isobutylthiophene (1.0 g, yield: 85.6%).

[0207] LC-MS, M / Z(ESI):159.1[M+H] +

[0208] 1H NMR (400MHz, CDCl3) δ6.97(dd,1H),6.74(dd,1H),2.59(dd,2H),1.95-1.81(m,1H),0.96(s,3H),0.94(d,3H)

[0209] Step 5: Synthesis of N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0210] Under nitrogen protection and 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, quenched by the addition of 50 mL of water, extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and dried. The 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, and then reacted 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 spin-dried, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V: V) = 20:1-10:1) to give N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (1.2 g, yield: 64.9%).

[0211] Step 6: Synthesis of 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0212] To a solution of N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (470 mg, 1.6 mmol) in anhydrous tetrahydrofuran (8 mL) was added dropwise a 2.5 M solution of n-butyllithium in tetrahydrofuran (1.5 mL) under nitrogen at -78°C. The reaction mixture was heated to -20°C and allowed to react for 2 hours. The temperature was then lowered to -78°C, and bromine (380 mg, 5 mmol) was added dropwise. The reaction mixture was allowed to react at room temperature overnight. The reaction mixture was quenched with 50 mL of water, extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate (v:v) = 20:1 to 10:1) to afford 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (410 mg, yield: 68.8%).

[0213] LC-MS, M / Z(ESI):372.3[M+H] + .

[0214] 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),2.69(d,2H),1.92-1.78(m,1H),1.15(s,9H),0.88(d,6H)

[0215] Step 7: Synthesis of N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0216] Under nitrogen protection, 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (325 mg, 0.87 mmol), 4-hydroxymethylphenylboronic 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 anhydrous 1,4-dioxane solution (10 mL) and then reacted at 75 ° C overnight. The reaction solution 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 dried. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V:V) = 10:1-2:1) to give N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (320 mg, yield: 92.06%).

[0217] LC-MS, M / Z(ESI):400.1[M+H] +

[0218] 1 H NMR (400MHz, CDCl3) δ7.61-7.55(m,2H),7.51-7.45(m,2H),4.77(s,2H),4.06(s,1H),2.68(dd,2H),1.98-1.91(m,1H),1.03(s,9H),0.99(d,6H)

[0219] Step 8: Synthesis of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0220] To a solution of N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (320 mg, 0.8 mmol) in dichloromethane (4 mL) was added dropwise thionyl chloride (238 mg, 2 mmol) under nitrogen at 0°C, followed by reaction at room temperature for 3 hours. The solvent was evaporated, and the crude product was purified on a silica gel column (petroleum ether:ethyl acetate (v:v) = 10:1-4:1) to afford N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (220 mg, 66% yield).

[0221] LC-MS, M / Z(ESI):418.1[M+H] +

[0222] Intermediate A2: Preparation of Intermediate A2

[0223] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid

[0224] The synthetic route of intermediate A2 is as follows:

[0225] Step 1: Synthesis of 2-isobutyl-3-methylthiophene

[0226] Dissolve zinc chloride (13.8 g, 101 mmol) in tetrahydrofuran (100 mL), add isobutylmagnesium bromide (2.00 M, 45.1 mL), 2-bromo-3-methylthiophene (10.0 g, 56.5 mmol), and bis(tri-tert-butylphosphine)palladium (1.44 g, 2.82 mmol). After the addition is complete, replace the nitrogen atmosphere and slowly heat the temperature to 90°C for 1 hour. Pour the reaction solution into water (200 mL) and extract three times with ethyl acetate (200 mL). The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-isobutyl-3-methylthiophene (6.00 g, 65.3% yield).

[0227] Step 2: Synthesis of 5-isobutyl-4-methylthiophene-2-sulfonyl chloride

[0228] Dissolve 2-isobutyl-3-methylthiophene (6.00 g, 36.9 mmol) in dichloromethane (30 mL), add chlorosulfonic acid (13.6 g, 116 mmol), and stir at room temperature for 1 hour. The reaction solution is concentrated to obtain the product 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (9.80 g, crude product). Step 3: Synthesis of N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0229] 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (9.80 g, 38.7 mmol) was dissolved in dichloromethane (40 mL), and N,N-diisopropylethylamine (10.0 g, 77.5 mmol) and 2-methylpropane-2-amine (3.40 g, 46.5 mmol) were added and the temperature was raised to 40°C for 1 hour. The reaction solution was poured into water (40 mL), and ethyl acetate (200 mL) was added and extracted three times. The organic phase was washed with saturated brine (100 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) = 20:1-5:1, R f =0.4) to give N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (1.50 g, yield 13.4%).

[0230] LC-MS, M / Z (ESI): 288.1 [MH] + .

[0231] Step 4: Synthesis of (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid

[0232] Dissolve N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (900 mg, 3.34 mmol) in tetrahydrofuran (20 mL). Cool the reaction solution to -60°C in a dry ice-ethanol bath. Slowly add n-butyllithium (2.50 M, 3.98 mL) dropwise under nitrogen protection. Stir for 0.5 hours after addition. Then add triisopropylborate (1.17 g, 6.22 mmol) and react at -60°C for 1 hour. Pour the reaction solution into water (20 mL) and extract three times with ethyl acetate (20 mL). The organic phase is washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1-1:1, R f =0.1) to give (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (0.7 g, yield 62.8%).

[0233] LC-MS, M / Z(ESI):332.1[MH] +

[0234] Example 1: Preparation of target compound I-1

[0235] Methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0236] The synthetic route of target compound I-1 is as follows:

[0237] Step 1: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0238] Under nitrogen protection, to 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 added anhydrous DMF (3 mL), and the mixture was reacted at 60°C overnight. The reaction solution was cooled to room temperature, quenched with 50 mL of water, extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1-1:1) to give N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (200 mg, yield: 78.1%).

[0239] LC-MS, M / Z(ESI):484.1[M+H] +

[0240] Step 2: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (12)

[0241] Under nitrogen protection, trifluoroacetic acid (4 mL) was added to a solution of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (200 mg, 0.41 mmol) in dichloromethane (4 mL). The reaction was then allowed to proceed overnight at room temperature. The solvent was then dried by rotary evaporation, and the crude product was mixed with silica gel and purified by silica gel column separation (petroleum ether:ethyl acetate (V / V) = 20:1-1:4) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (140 mg, yield: 80%).

[0242] LC-MS, M / Z(ESI):428.1[M+H] +

[0243] Step 3: Synthesis of methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0244] Under nitrogen protection and 0°C, to a solution of dichloromethane (2 mL) containing 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (140 mg, 0.33 mmol) was added N,N-diisopropylethylamine (0.23 mL, 1.37 mmol) and methyl chloroformate (34.3 mg, 0.36 mmol) in sequence. The mixture was reacted at 0°C for 2 hours, quenched by adding 20 mL of water, and extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then purified by silica gel column chromatography (dichloromethane:methanol (V / V)=10:1) to give methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophen-2-yl)sulfonyl)carbamate (55 mg, yield: 34%).

[0245] LC-MS, M / Z(ESI):486.1[M+H] +

[0246] 1 H NMR (400MHz, CDCl3) δ7.48-7.43(m,2H),7.25 -7.20(m,2H),6.95 -6.88(m,2H),5.15(s,2H),3.66(s,3H),2.71(d,2H),2.03-1.91(m,1H),1.0(d,6H)

[0247] Example 2: Preparation of target compound I-2

[0248] Methyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0249] The synthetic route of target compound I-2 is as follows:

[0250] Step 1: Synthesis of N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0251] Under nitrogen protection, anhydrous DMF (5 mL) was added to 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), and then the mixture was reacted at 60°C overnight and the reaction solution was cooled to 40°C. At 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, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-1:1) to give N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (360 mg, yield: 94%).

[0252] LC-MS, M / Z(ESI):518.2[M+H] +

[0253] Step 2: Synthesis of 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0254] Under nitrogen protection, trifluoroacetic acid (6 mL) was added to a solution of N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (360 mg, 0.69 mmol) in dichloromethane (6 mL). The reaction was then allowed to proceed overnight at room temperature. The solvent was then dried by spin-drying, and the crude product was mixed with silica gel and purified by silica gel column separation (petroleum ether:ethyl acetate (V / V) = 20:1-1:4) to obtain 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (230 mg, yield: 72%).

[0255] LC-MS, M / Z(ESI):462.1[M+H] +

[0256] Step 3: Synthesis of methyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0257] Under nitrogen protection, to a solution of 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (100 mg, 0.22 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.153 mL, 0.88 mmol) and methyl chloroformate (23 mg, 0.24 mmol) in sequence at 0°C. The mixture was reacted at 0°C for 2 hours, quenched by adding 20 mL of water, and extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give methyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-yl)sulfonyl)carbamate (43 mg, yield: 38%).

[0258] LC-MS, M / Z(ESI):520.1[M+H] +

[0259] 1 H NMR (400MHz, CDCl3) δ7.52-7.46(m,2H),7.22-7.17(m,2H),7.13-7.08(m,1H),7.03 -6.99(m,1H),5.27(s,2H),3.52(t,3H),2.65(d,2H),1.98-1.86(m,1H),0.97(d,6H)

[0260] Example 3: Preparation of target compound I-3

[0261] Butyl ((4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0262] The synthetic route of target compound I-3 is as follows:

[0263] 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

[0264] Under nitrogen protection, anhydrous DMF (2 mL) was added to a mixture of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (80 mg, 0.22 mmol), 2-(1H-imidazol-2-yl)propan-2-ol (29 mg, 0.23 mmol) and potassium carbonate (98 mg, 0.71 mmol), and the mixture was reacted at 55° C. overnight. The reaction solution was cooled to room temperature. The reaction was quenched by adding 20 mL of water, extracted three times with 20 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1-1:1) to give N-(tert-butyl)-4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (60 mg, yield: 53.7%).

[0265] LC-MS, M / Z(ESI):508.7[M+H] +

[0266] Step 2: Synthesis of 4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0267] Under nitrogen protection, trifluoroacetic acid (2 mL) was added to a dichloromethane (2 mL) solution containing N-(tert-butyl)-4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (60 mg, 0.12 mmol). The reaction was then allowed to proceed overnight at room temperature. The solvent was then dried by spin-drying, and the crude product was mixed with silica gel and purified by silica gel column separation (dichloromethane:methanol (V / V) = 50:1-10:1) to obtain 4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (25 mg, yield: 50%).

[0268] LC-MS, M / Z(ESI):452.6[M+H] +

[0269] Step 3: Synthesis of butyl ((4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0270] Under nitrogen protection and 0 ° C, to a solution of dichloromethane (1 mL) containing 4-fluoro-3-(4-((2-(2-hydroxypropyl-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (25 mg, 0.055 mmol) was added N,N-diisopropylethylamine (0.04 mL, 0.22 mmol) and butyl chloroformate (8.2 mg, 0.06 mmol) in sequence, and then The reaction was then allowed to react 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 on a silica gel column (dichloromethane:methanol (V / V) = 10:1) to give butyl ((4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (13 mg, yield: 43%).

[0271] LC-MS, M / Z(ESI):552.2[M+H] +

[0272] 1 H NMR (400MHz, CDCl3) δ7.48-7.43(m,2H),7.17 -7.12(m,2H),6.97 -6.95(m,1H),6.85-6.83(m,1H),5.48(s,2H),4.05-3.98(t,2H),2.72-2.67(d,2H),1.98 -1.86(m,1H),1.65(s.6H),1.54-1.46(m,2H),1.30-1.24(m,2H),0.97(d,6H),0.88(t,3H)

[0273] Example 4: Preparation of target compound I-4

[0274] Butyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0275] The synthetic route of target compound I-4 is shown in the figure below:

[0276] Step 1: Synthesis of butyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0277] To a solution of 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (130 mg, 0.28 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.2 mL, 1.13 mmol) and methyl chloroformate (42.3 mg, 0.31 mmol) in sequence under nitrogen protection at 0°C. The mixture was reacted at 0°C for 2 hours, quenched by adding 20 mL of water, and extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give butyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-yl)sulfonyl)carbamate (35 mg, yield: 22%).

[0278] LC-MS, M / Z(ESI):562.1[M+H] +

[0279] 1 H NMR (400MHz, CDCl3) δ7.52-7.46(m,2H),7.23-7.19(m,2H),7.13 -7.11(m,1H),7.03-6.99(m,1H),5.29(s,2H),4.01(t,3H),2.69(d,2H),2.01 -1.89(m,1H),1.54-1.45(m,2H),1.29-1.20(m,2H),0.99(d,6H),0.87(t,3H)

[0280] Example 5: Preparation of target compound I-9

[0281] Methyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0282] The synthetic route of target compound I-9 is as follows:

[0283] Step 1: Synthesis of 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole

[0284] 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). Potassium carbonate (1.66 mg, 12.0 mmol) was then added and reacted at 50°C for 2 hours. The reaction solution was poured into water (100 mL) and extracted three times with ethyl acetate (80 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole (1.20 g, 98.3% yield).

[0285] LC-MS, M / Z(ESI):304.9[M+H] +

[0286] Step 2: Synthesis of N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0287] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), and 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole (330 mg, 1.08 mmol) was added. 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 under nitrogen protection for 2 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified on a 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-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (560 mg, 90.8% yield).

[0288] LC-MS, M / Z(ESI):514.0[M+H] +

[0289] Step 3: Synthesis of 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0290] N-(tert-Butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-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 solution was concentrated to obtain a crude product, which was then purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (470 mg, 95.9% yield).

[0291] LC-MS, M / Z(ESI):458.1[M+H] +

[0292] Step 4: Synthesis of methyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0293] 5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-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), N,N-diisopropylethylamine (398 mg, 3.08 mmol) was added, and the reaction was stirred at 0°C for 0.5 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL), extracted three times with dichloromethane (20 mL), and the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate 150*25mm*5μm; solvent: A=water+0.05 volume formic acid (30%), B=acetonitrile; gradient: 58%-78%, 10 minutes) to give the product (methyl 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (319 mg, yield 61.1%).

[0294] LC-MS, M / Z(ESI):516.1[M+H] +

[0295] 1H 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)

[0296] Example 6: Preparation of target compound I-10

[0297] 2-Hydroxy-2-methylpropyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0298] The synthetic route of target compound I-10 is as follows:

[0299] Step 1: Synthesis of phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0300] 5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-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 under nitrogen for 4 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated in vacuo to obtain phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-yl)sulfonylcarbamate (370 mg, 97.7% yield).

[0301] LC-MS, M / Z(ESI):578.1[M+H] +

[0302] Step 2: Synthesis of 2-hydroxy-2-methylpropyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0303] Phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (370 mg, 650 μmol) was dissolved in dioxane (8 mL), and isobutylene glycol (173 mg, 1.92 mmol) was added. The mixture was stirred at 100 °C under nitrogen for 4 hours. The reaction solution was concentrated and separated and purified by high performance liquid chromatography (column: C18 150*30 mm; mobile phase: A = water + 0.05 volume formic acid (30%), B = acetonitrile; gradient: 58%-88%, 7 minutes) to give the product (2-hydroxy-2-methylpropyl 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (38.6 mg, yield 10.5%).

[0304] LC-MS, M / Z(ESI):574.1[M+H] +

[0305] 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)

[0306] Example 7: Preparation of target compound I-11

[0307] (2S)-2-hydroxypropyl ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0308] The synthetic route of target compound I-11 is as follows:

[0309] Step 1: Synthesis of (2S)-2-hydroxypropyl ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0310] Phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (250 mg, 433 μmol) was dissolved in tetrahydrofuran (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 at 20°C under nitrogen for 10 hours. After completion of the reaction, the reaction solution was diluted with water (20 mL), and then extracted three times with ethyl acetate (20 mL). The organic phase was collected, 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 volume formic acid (30%), B = acetonitrile; gradient: 55%-85%, 7 minutes) to give the product ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamic acid-(2S)-2-hydroxypropyl ester (79.6 mg, yield 32.8%).

[0311] LC-MS, M / Z(ESI):560.3[M+H] +

[0312] 1 H 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),4.0 5-4.18(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)

[0313] Example 8: Preparation of target compound I-12

[0314] (2R)-2-hydroxypropyl ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0315] The synthetic route of target compound I-12 is as follows:

[0316] Step 1: Synthesis of (2R)-2-hydroxypropyl ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0317] (5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonamidotoluene (250 mg, 433 μmol) was dissolved in tetrahydrofuran (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 at 20°C under nitrogen for 10 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), and then extracted three times with ethyl acetate (20 mL). The organic phase was collected, 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 give the product (2R)-2-hydroxypropyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (67.7 mg, yield 27.9%).

[0318] LC-MS, M / Z(ESI):560.3[M+H] +

[0319] 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,1 H),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)

[0320] Example 9: Preparation of target compound I-13

[0321] 2-Hydroxyethyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0322] The synthetic route of target compound I-13 is as follows:

[0323] Step 1: (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylamino acid-2-hydroxyethyl ester

[0324] Phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (365 mg, 632 μmol) was dissolved in dioxane (5 mL), ethylene glycol (118 mg, 1.90 mmol) was added, and the reaction was stirred at 100°C under nitrogen for 2 hours. The reaction solution 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 give the product (2-hydroxyethyl 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (38.91 mg, yield 11.3%).

[0325] LC-MS, M / Z(ESI):546.3[M+H] +

[0326] 1 H 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)

[0327] Example 10: Preparation of target compound I-14

[0328] Methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0329] The synthetic route of target compound I-14 is as follows:

[0330] Step 1: Synthesis of 1-(4-bromo-2-fluorobenzyl)-2-chloro-1H-imidazole

[0331] 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). Potassium carbonate (774 mg, 5.60 mmol) was then added and reacted at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (20 mL) and extracted three times with ethyl acetate (40 mL). The organic phase was collected, 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 on a silica gel column (petroleum ether:ethyl acetate (v / v) = 1:0-3:1) to obtain 1-(4-bromo-2-fluorobenzyl)-2-chloro-1H-imidazole (450 mg, 83.3% yield).

[0332] LC-MS, M / Z(ESI):290.9[M+H] +

[0333] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0334] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (350 mg, 1.05 mmol) was dissolved in tetrahydrofuran (5.00 mL) and water (1.00 mL), and 1-(4-bromo-2-fluorobenzyl)-2-chloro-1H-imidazole (274 mg, 945 μmol) was added. Potassium phosphate (1.11 mg, 5.25 mmol) and XPhos Pd G4 (90.4 mg, 105 μmol) were added, and the mixture was stirred at 60 ° C under nitrogen protection for 1 hour. The reaction solution was concentrated to obtain a crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-3:1) to give N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (450 mg, yield 86.0%).

[0335] LC-MS, M / Z(ESI):498.2[M+H] +

[0336] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0337] N-(tert-Butyl)-3-(4-((2-chloro-1H-imidazol-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 solution was poured into water (20 mL) and extracted three times with dichloromethane (40 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was then separated and purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 1:0-0:1) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (350 mg, 87.7% yield).

[0338] LC-MS, M / Z(ESI):442.1[M+H] +

[0339] Step 4: Synthesis of methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0340] 3-(4-((2-chloro-1H-imidazol-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) at 0°C, and N,N-diisopropylethylamine (307 mg, 2.38 mmol) was added. The mixture was stirred at 0°C for 0.5 h. The reaction solution was concentrated and separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*30 mm; solvent: A = water + 0.05 volume of formic acid (30%), B = acetonitrile; gradient: 55%-85%, 7 minutes) to give methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (50.0 mg, yield 12.6%).

[0341] LC-MS, M / Z(ESI):500.0[M+H] +

[0342] 1H NMR(400MHz, CDCl3)δ7.76(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)

[0343] Example 11: Preparation of target compound I-18

[0344] 2-Hydroxyethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0345] The synthetic route of the target compound I-18 is as follows:

[0346] Step 1: Synthesis of 1-(4-bromobenzyl)-2-chloro-1H-imidazole

[0347] 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 allowed to react at 55°C for 1 hour. The reaction mixture was poured into water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 50:1 to 1:1) to afford 1-(4-bromobenzyl)-2-chloro-1H-imidazole (900 mg, 82.8% yield).

[0348] LC-MS, M / Z(ESI):271.0[M+H] +

[0349] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0350] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and 1-(4-bromobenzyl)-2-chloro-1H-imidazole (293 mg, 1.08 mmol) was added. Potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol) were added, and the reaction was stirred at 60 ° C under nitrogen protection for 2 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to give N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (510 mg, 88.5% yield).

[0351] LC-MS, M / Z(ESI):480.2[M+H] +

[0352] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0353] N-(tert-Butyl)-3-(4-((2-chloro-1H-imidazol-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 solution was poured into water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 to 1:1) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (400 mg, 90.6% yield) as a brown oil.

[0354] LC-MS, M / Z(ESI):424.1[M+H] +

[0355] Step 4: Synthesis of phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0356] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (200 mg, 472 μmol) and potassium carbonate (131 mg, 944 μmol) were dissolved in acetonitrile (2 mL). Diphenyl carbonate (152 mg, 708 μmol) was added and stirred at 50°C for 2 hours. The reaction solution was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (240 mg, 93.5% yield).

[0357] LC-MS, M / Z(ESI):544.2[M+H] +

[0358] Step 5: Synthesis of 2-hydroxyethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0359] Phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (240 mg, 441 μmol) was dissolved in tetrahydrofuran (3 mL), and ethylene glycol (274 mg, 4.41 mmol) and triethylamine (134 mg, 1.32 mmol) were added. The mixture was stirred at 25 °C for 10 hours. The reaction solution was poured into water (20 mL), then extracted three times with ethyl acetate (20 mL). The organic phases were collected, 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 volume formic acid (30%), B = acetonitrile; gradient: 48%-78%, 7 minutes) to give the product (2-hydroxyethyl 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (115 mg, yield 50.9%).

[0360] LC-MS, M / Z(ESI):512.2[M+H] +

[0361] 1H NMR (400MHz, CDCl3) δ7.22-7.27(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).

[0362] Example 12: Preparation of target compound I-19

[0363] Methyl (3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0364] The synthetic route of the target compound I-19 is as follows:

[0365] Step 1: Synthesis of 2-(1-(4-bromobenzyl)-1H-imidazol-2-yl)propan-2-ol

[0366] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-(1H-imidazol-2-yl)propan-2-ol (505 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (20 mL). Potassium carbonate (1.66 mg, 12.0 mmol) was then added and the mixture was allowed to react at 50°C for 2 hours. After completion, the reaction solution was poured into water (40 mL) and 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 purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1 to ethyl acetate:methanol (v / v) = 10:1) to obtain 2-(1-(4-bromobenzyl)-1H-imidazol-2-yl)propan-2-ol (830 mg, 70.3% yield).

[0367] LC-MS, M / Z(ESI):295.0[M+H] +

[0368] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0369] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (350 mg, 1.05 mmol) was dissolved in tetrahydrofuran (7 mL) and water (3 mL), and 2-(1-(4-bromobenzyl)-1H-imidazol-2-yl)propan-2-ol (279 mg, 945 μmol) was added. Potassium phosphate (1.11 g, 5.25 mmol) and XPhos Pd G4 (90.4 mg, 105 μmol) were then added, and the mixture was stirred at 60 ° C under nitrogen protection for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:0-0:1) to give N-(tert-butyl)-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (420 mg, yield 79.4%).

[0370] LC-MS, M / Z(ESI):504.1[M+H] +

[0371] Step 3: Synthesis of 3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0372] N-(tert-Butyl)-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-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 solution was concentrated to obtain a crude product, which was then separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 0:1 to dichloromethane:methanol (V / V) = 5:1) to obtain compound 3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (500 mg, crude product).

[0373] LC-MS, M / Z(ESI):448.2[M+H] +

[0374] Step 4: Synthesis of methyl (3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0375] 3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (500 mg, 1.12 mmol) was dissolved in dichloromethane (8 mL), and N,N-diisopropylethylamine (433 mg, 3.35 mmol) and methyl chloroformate (211 mg, 2.23 mmol) were added at 0°C, and the reaction was stirred for 0.5 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL), extracted three times with dichloromethane (20 mL), and the organic phase was collected, 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*25mm*5μm; solvent: A=water+0.05 volume formic acid (30%), B=acetonitrile; gradient: 23%-43%, 10 minutes) to give the product (methyl 3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (168 mg, yield 39.9%).

[0376] LC-MS, M / Z(ESI):506.2[M+H] +

[0377] 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)

[0378] Example 13: Preparation of target compound I-21

[0379] Methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0380] The synthetic route of target compound I-21 is as follows:

[0381] Step 1: Synthesis of 1-(4-bromo-3,5-difluorobenzyl)-2-chloro-1H-imidazole

[0382] 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). Potassium carbonate (725 mg, 5.25 mmol) was added and reacted at 25°C for 1 hour. The reaction solution was poured into water (30 mL), extracted three times with ethyl acetate (60 mL), and washed five times with water (60 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated and purified on a 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, 96.7% yield).

[0383] LC-MS, M / Z(ESI):308.9[M+H] +

[0384] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0385] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (500 mg, 1.50 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and 1-(4-bromo-3,5-difluorobenzyl)-2-chloro-1H-imidazole (415 mg, 1.35 mmol) was added. Potassium phosphate (955 mg, 4.50 mmol) and SPhos Pd G3 (117 mg, 150 μmol) were added, and the reaction was stirred at 60 ° C under nitrogen protection for 1 hour. The reaction solution was concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*30 mm; solvent: A = water + 0.05 volume of formic acid (30%), B = acetonitrile; gradient: 65%-95%, 7 minutes), and dried to give N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, yield 19.4%).

[0386] LC-MS, M / Z(ESI):516.1[M+H] +

[0387] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0388] N-(tert-Butyl)-3-(4-((2-chloro-1H-imidazol-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 solution was poured into water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was then separated and purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 1:0-0:1) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (100 mg, 74.8% yield).

[0389] LC-MS, M / Z(ESI):460.0[M+H] +

[0390] Step 4: Synthesis of methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0391] 3-(4-((2-chloro-1H-imidazol-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 h. The reaction solution was concentrated and separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+0.05 volume ammonia (30%), B=acetonitrile; gradient: 5%-35%, 10 minutes) and dried to give methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (4.00 mg, yield 3.57%).

[0392] LC-MS, M / Z(ESI):518.2[M+H] +

[0393] 1H NMR(400MHz, CDCl3)δ7.07(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)

[0394] Example 14: Preparation of target compound I-22

[0395] N-((5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0396] The synthetic route of target compound I-22 is as follows:

[0397] Step 1: Synthesis of N-((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0398] 5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-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). N,N-diisopropylethylamine (226 mg, 1.75 mmol) was added and 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) and dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (328 mg, 2.54 mmol) was added and the mixture was reacted at 60°C for 8 hours. The reaction solution was concentrated and separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: A=water+0.05 volume of ammonium hydroxide (30%), B=acetonitrile; gradient: 10%-40%, over 10 minutes) and dried to give N-((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (126 mg, 49.6% yield).

[0399] LC-MS, M / Z(ESI):583.3[M+H] +

[0400] 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),3.6 4-3.87(s,4H),2.63(d,2H),1.80-1.88(m,1H),1.74(s,3H),0.94(d,6H).

[0401] Example 15: Preparation of target compound I-23

[0402] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide

[0403] The synthetic route of target compound I-23 is as follows:

[0404] Step 1: 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide

[0405] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, 354 μmol) and 2-chloropyrimidine (40.5 mg, 354 μmol) were dissolved in dioxane (6 mL), and cesium carbonate (288 mg, 884 μmol) and XPhos Pd G3 (30.0 mg, 35.4 μmol) were added. The reaction was stirred at 100°C under nitrogen for 1 hour. The reaction solution was concentrated, and the crude product was slurried in methanol (50 mL) at 25°C for 30 minutes to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide (48.1 mg, 26.9% yield).

[0406] LC-MS, M / Z(ESI):502.1[M+H] +

[0407] 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,1 H),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)

[0408] Example 16: Preparation of target compound I-24

[0409] N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-1-((pyridin-2-ylmethyl)amino)formamide

[0410] The synthetic route of target compound I-24 is as follows:

[0411] Step 1: Synthesis of N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-1-((pyridin-2-ylmethyl)amino)formamide

[0412] Under ice-cooling conditions, to a solution of 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (0.228 g, 0.5 mmol) in acetonitrile (11 mL) were added phenyl N-(2-pyridylmethyl)carbamate (0.182 g, 0.8 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.152 g, 1 mmol) in sequence, and the reaction was carried out at 80 ° C for 6 hours. The reaction was monitored by LCMS. After no starting material remained, the reaction solution was cooled to room temperature, extracted three times with ethyl acetate (30 mL), washed three times with water (20 mL), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by high performance liquid chromatography (aqueous formic acid / acetonitrile system) to give N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-1-((pyridin-2-ylmethyl)amino)formamide (0.128 g, 43.4% yield).

[0413] LC-MS, M / Z(ESI):592.1[M+H] +

[0414] 1H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.50–8.45(m,1H),7.73(td,J=7.7,1.8Hz,1H),7.61(d,J=1.1Hz,1H),7.28–7.23(m,1H),7.23–7.15(m ,6H),6.75(t,J=5.5Hz,1H),5.40(s,2H),4.25(d,J=5.6Hz,2H),2.64(d,J=7.1Hz,2H),1.90–1.78(m,1H),1.74(s,3H),0.92(d,J=6.6Hz,6H).

[0415] Example 17: The preparation of the following compounds can be obtained by referring to the preparation methods of the above compounds.

[0416] In the test examples of the present invention, the preparation method of the control compound I refers to patent WO2021229244A1, and the structure is shown below:

[0417] Biological testing

[0418] The following test method may be used.

[0419] Test Example 1: Compound Binding to AT2R

[0420] The Angiotensin AT2 Receptor Ligand Binding Assay Kit (#C1TT1AT2, Cisbio) was used according to the protocol. First, a 10 mM stock solution of compound was serially diluted 5× (10 concentrations, each with two replicates). 160 nL of each compound concentration was added to a 384-well plate. 40 μL of 1× TLB (Tag-lite buffer) was added to each well and shaken at room temperature for 15 minutes. A 15-mL centrifuge tube containing 5 mL of 1× TLB was prepared for future use. Frozen labeled cells were thawed in a 37°C water bath (1-2 minutes). The thawed cells were quickly transferred to the 15-mL centrifuge tube, mixed thoroughly, and 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 the mixed cells were added to the appropriate wells according to the experimental design. 5 μL of 4× compound solution and 5 μL of 4× Tag-lite red fluorescent labeled ligand were added to each well. After incubation at room temperature for 1 hour, data were read using the EnVision HTRF mode. The excitation intensity at 665 nM and 615 nM in each well was measured, and the ratio (Ratio = A665 nM / B615 nM) was calculated. IC was then calculated using GraphPad Prism 8 software. 50 Numerical values: X: logarithmic value of compound concentration; Y: ratio of A665nM / B615nM.

[0421] Table 1: AT2R binding activity of compounds

[0422] The experimental results show that the compound of the present invention has a strong binding effect with AT2R.

[0423] Test Example 2: CYP inhibition assay of compounds

[0424] Compounds were evaluated for their inhibitory activity against six enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (midazolam), and CYP2B6 at 10 μM. Pooled human liver microsomes were stored at -80°C prior to use. Thawed in a 37°C waterbath and placed on ice. 100 μL of microsomal working solution was added to 2 μL of compound or positive inhibitor working solution. 2 μL of solvent was added to the solvent control and preincubated in a 37°C waterbath for 10 minutes. Following preincubation, 98 μL of NADPH regeneration solution was added to all samples to initiate the reaction. The samples were then returned to the waterbath and incubated for a desired period. The reaction was quenched with 200 μL of stop solution. The plate was centrifuged at 3220 g for 10 minutes. 100 μL of supernatant was transferred, 100 μL of water was added, and the mixture was thoroughly mixed onto the assay plate for LC / MS / MS analysis.

[0425] Table 2: CYP450 inhibition results of compounds

[0426] The experimental results show that the compounds of the present invention have weaker inhibitory effects on CYP enzymes than the control compounds and will not affect the normal metabolism of the body, indicating that the possibility of drug-drug interactions in the human body is less and the safety is higher.

[0427] Test Example 3: Free Plasma Protein Binding (PPB) Experiment of Compounds

[0428] Soak the dried dialysis membrane in ultrapure water for 1 hour, then in 20% ethanol for 20 minutes. Rinse the membrane two to three times with ultrapure water. Finally, soak in ultrapure water for 20 minutes before use. Thaw frozen plasma in a 37°C waterbath for approximately 20 minutes. Once thawed, measure the plasma pH and adjust it to 7.4 using 1% phosphoric acid solution or 0.1M sodium hydroxide solution. Dilute the compound into plasma preheated to 37°C to a final concentration of 1 μM. The final concentration of internal reference warfarin in plasma is 2 μM. Assemble the pretreated dialysis membrane into the dialysis plate according to the product instructions. Add 100 μL of receiving solution (100 mM phosphate buffer with 0.002% Tween 80) to one side of the membrane in each dialysis well. Dispense 20 μL of each final solution of the test compound and control compound into a 96-well sample plate. Repeat in duplicate to obtain the T0 sample, which is stored in a -20°C refrigerator. Take another 100 μL of the above final solution to the other side of the membrane in the dialysis device, duplicate samples, and incubate at 37°C with constant temperature shaking for 6 hours. After 6 hours of incubation, take 20 μL each of the dialyzed receiving solution and the administered plasma, duplicate samples, to obtain samples B and A. Add the corresponding volume of blank plasma or receiving solution to sample B and sample A, respectively, so that the volume ratio of plasma to buffer in each sample well is 1:1. Add 300 μL of sample containing internal standard acetonitrile solution to all sample wells, mix well, and then centrifuge at 5500×g for 10 minutes. Add 150 μL of corresponding ultrapure water to the corresponding sample wells of the 96-well sample plate, take 150 μL of the supernatant, take it to the sample well, mix well, and perform LC / MS / MS analysis. f u Calculation formula:

[0429] C R : Peak area ratio measured in the receiving chamber well;

[0430] C D : The peak area ratio measured by the supply chamber hole.

[0431] The degree of dissociation of a compound in plasma is related to its efficacy in the body. Experimental results show that the compound of the present invention has a higher degree of dissociation than the control compound, which is beneficial for the compound to reach the target organ.

[0432] Test Example 4: Liver microsome stability test of the compound

[0433] The stability test for human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. The test compound was first prepared as a 10 mM stock solution in DMSO solvent, and then diluted to 0.5 mM using acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and this solution was used to dilute 0.5 mM of the compound to form a working solution. The working solution contained 1.5 μM compound and 0.75 mg / mL human liver microsomes. A deep-well plate was prepared, and 30 μL of the working solution was added to each well. The reaction was then initiated by adding 15 μL of preheated 6 mM NADPH solution and incubated at 37°C. The reaction was terminated by adding 135 μL of acetonitrile to the corresponding wells at 0, 5, 15, 30, and 45 minutes of incubation. After terminating the reaction with acetonitrile at the final 45-minute time point, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio. LC-MS / MS was then performed to obtain the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard 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 minute. The remaining percentage of the compound at each time point was calculated. T was calculated using Graphpad 8 software. 1 / 2 .

[0434] Table 3: Liver microsomal stability of compounds

[0435] The stability of a compound in liver microsomes reflects its risk of being metabolized and eliminated in the body. The experimental results show that the test compound has good stability in humans compared with the control compound.

[0436] Test Example 5: Bidirectional permeability study of compounds in CACO-2 cells

[0437] Caco-2 cells were cultured at a rate of 1 × 10 5 cells / cm 2Cells were plated onto polyethylene membrane (PET) membranes in 96-well inserts at a rate of 100 μg / mL. Medium was changed every 4-5 days until day 21-28, allowing for the formation of a confluent cell monolayer. The transport buffer used in the experiment was HBSS and 10.0 mM HEPES, pH 7.40 ± 0.05. Test compounds were tested at 2.00 μM in both directions in the presence and absence of 10.0 μM GF120918. Digoxin was tested at 10.0 μM in both directions in the presence and absence of 10.0 μM GF120918, while nadolol and metoprolol were tested at 2.00 μM in the A to B direction in the absence of 10.0 μM GF120918, all in duplicate. The final DMSO concentration was adjusted to less than 1%. The plates were incubated for 2 hours in a CO2 incubator at 37 ± 1°C with 5% CO2 in a humidified atmosphere without shaking. All samples were mixed with acetonitrile containing an internal standard and centrifuged at 3200 g for 10 minutes. For nadolol and metoprolol, 200 μL of the supernatant was diluted with 600 μL of distilled water for LC-MS / MS analysis. For digoxin and the test compound, 200 μL of the supernatant was diluted with 200 μL of distilled water for LC-MS / MS analysis. The concentrations of the test and control compounds in the starting, donor, and acceptor solutions were quantified by LC-MS / MS using the analyte / internal standard peak area ratio.

[0438] After the transport assay, the integrity of the Caco-2 cell monolayer was determined using a Lucifer Yellow exclusion assay.

[0439] Table 4: Bidirectional permeability of compounds in Caco-2 cells

[0440] The experimental results showed that the permeability of the test compound was improved compared with the control compound, which was beneficial to the absorption of the compound.

[0441] Test Example 6: Induction of CYP 3A4 Enzyme by Compounds

[0442] The viability of the revived hepatocytes was tested and the hepatocytes were diluted to 0.7×10 6Cells / μL. Pre-wet the 48-well collagen-coated plate by adding 100 μL of pre-warmed seeding medium to each well, then discard the medium. Add 200 μL of cells to each well of the 48-well plate pre-coated with collagen, and then culture in a 95% humidity, 5% CO2 incubator at 37°C. 4 hours after cell attachment, aspirate the seeding medium and add 200 μL of incubation medium containing 2% matrix protease to each well. The next day, remove the cell plate, aspirate the supernatant, add 200 μL of compound solution to each well, and continue culturing in the incubator. After 24 hours and 48 hours, respectively, remove the 48-well plate from the incubator and transfer 100 μL of medium per well to a clean 96-well cell culture plate for LDH assay of cell viability.

[0443] Enzyme activity assay:

[0444] At 48 h, the supernatant was aspirated and washed twice with 400 μL / well preheated HBSS solution. After aspirating the HBSS, 100 μL of enzyme-labeled substrate working solution was added to each well. The cell plate was then incubated in an incubator for 30 minutes and the reaction was stopped by transferring the supernatant to a 96-well plate containing a stop solution. The plate was sealed, shaken and centrifuged to collect the supernatant. The supernatant was then diluted in 0.1% FA water at a ratio of 1:4. All samples were mixed and analyzed by liquid chromatography / mass spectrometry (LC / MS / MS). Calibration was performed using the peak area ratio of metabolites to internal standards (IS), and the activity of the CYP enzyme was calculated using a standard curve consisting of 7 standard concentrations. The fold change relative to the vehicle control (0.1% dimethyl sulfoxide) was calculated, and the induction fold = enzyme activity of the compound-treated sample / enzyme activity of the vehicle control.

[0445] Enzyme gene induction assay:

[0446] 1. Extraction of Total Cell RNA

[0447] After 48 h, the supernatant was aspirated and the plate was washed once with 400 μL / well of HBSS, and RLT buffer (QIAGEN, cat: 1015762) was added to the plate. The RNA extraction kit was then used according to the procedure.

[0448] 2. cDNA Synthesis

[0449] cDNA was synthesized using ABI's high-efficiency cDNA reverse transcription kit (cat: 4368813).

[0450] 3. Real-time Quantitative PCR Reaction

[0451] Add nuclease-free water to a new plate, add the cDNA sample to the plate, and gently mix to dilute. Prepare separate reaction mixtures for 18S rRNA and CYP3A4, with 18S rRNA serving as an internal standard. Seal the real-time PCR plate and briefly centrifuge to remove air bubbles and allow the liquid to settle at the bottom of the tube. Transfer the plate to the real-time PCR instrument and analyze according to the supplier's protocol. PCR conditions: 50°C for 2 minutes, 95°C for 10 minutes, and 40 cycles of two steps: 95°C for 15 seconds and 60°C for 1 minute.

[0452] 4. Real-time Quantitative PCR Data Analysis

[0453] Fold change of relative expression = 2-ΔΔCt, ΔCt = Ct (target gene) - Ct (18S rRNA), ΔΔCt = ΔCt (treated sample) - ΔCt (untreated control).

[0454] The experimental results showed that the test compound had no toxic effect on hepatocytes, had a weak induction on CYP3A4 enzyme activity, and had a weaker induction on CYP3A4 enzyme gene relative to the positive internal control.

[0455] Test Example 7: Pharmacokinetic study of a single oral administration of a compound to cynomolgus monkeys

[0456] The compound was dissolved in a solvent of 5% DMSO + 10% Solutol + 85% Saline to a concentration of 1 mg / mL and a dosage of 5 mpk. Weigh the subjects before administration, calculate the dosage based on body weight, and administer orally by gavage. Blood was collected via the femoral vein or other appropriate method at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Approximately 1 mL of each sample was collected per time point, anticoagulated with sodium heparin, and placed on ice after collection. Blood samples were placed on ice after collection, and the blood samples were centrifuged within 1 hour to separate the plasma (centrifugation conditions: 2200g, 10 minutes, 2-8°C). Plasma samples were stored in a -80°C freezer before analysis.

[0457] The biological sample analysis method and analysis of all samples are completed by the analytical laboratory of Medicipia Pharmaceutical Technology (Shanghai) Co., Ltd. While analyzing the samples, the intra-day accuracy evaluation of quality control samples is carried out, and it is required that the accuracy of more than 66.7% of the quality control samples is between 80-120%.

[0458] Table 5: Pharmacokinetics of the compounds in monkeys

[0459] The experimental results showed that the Cmax and exposure of the test compound were higher than those of the control compound, indicating that it could have a better stimulatory effect.

[0460] Test Example 8: IPF efficacy test of the compound in mice

[0461] This experiment requires a specific mouse IPF model, which Shanghai Pengli Company is responsible for establishing and conducting the efficacy experiments of the compounds. All animal experimental operation plans are approved by Pengli IACUC (Institute Animal Care and Use Committee).

[0462] The experimental steps include:

[0463] 1. Compound Preparation: Weigh an appropriate amount of compound powder and prepare a DMSO stock solution. Aliquot the required daily dose and prepare it immediately on the day of use. Add the required amount of 10% solutol according to the dilution ratio, vortex to dissolve and mix thoroughly. Finally, add the required amount of 85% saline according to the dilution ratio, with a final DMSO content of 5%, to prepare a clear solution of 0.03 mg / mL.

[0464] 2. Animal Grouping: On the day of modeling, 10 animals were randomly selected and placed directly in the G1 blank group. All other animals received an intratracheal injection of bleomycin for model establishment. After bleomycin injection, animals were randomly assigned to groups using BioBook based on weight changes, body weight, and animal status before the first dose to achieve similar average weights within each group and reduce intergroup variation.

[0465] 3. Model Construction: Dissolve an appropriate amount of bleomycin in commercially available saline. Model group animals were anesthetized with 1-4% isoflurane inhalation and administered 2 units / kg of bleomycin intratracheally. The specific dosage was calculated based on animal weight. G1 group mice were anesthetized with 1-4% isoflurane and injected with an equal volume of saline intratracheally.

[0466] 4. Dosing: The day of bleomycin injection is considered as day 0 of the study. The dosing schedule is as follows:

[0467] Table 6-1 Grouping and Dosage Scheme a: The solvent was 5% DMSO + 10% solutol + 85% saline; b: Bi-dose, once in the morning and once in the afternoon, with an interval of approximately 6 hours; no medication was given in the morning on day 22.

[0468] 5. Pulmonary function test: On day 22, all experimental animals were anesthetized with Zoltrate (25-50 mg / kg) and xylazine (5-10 mg / kg), and pulmonary function tests (PFT) were performed on the animals, including PV curve, FVC, IC, VC, Cdyn, and Cchord (quasi-static lung compliance) indicators.

[0469] 6. Lung section pathology examination: Lung tissue was collected, rinsed twice, dried with filter paper, and weighed. After weighing, the left lung was perfused and fixed with 10% neutral formaldehyde solution, and then immersed in 10% neutral formaldehyde solution for fixation and preservation for histopathological scoring. The left lung after formaldehyde fixation was cut transversely into three sections: upper, middle, and lower, and embedded in the same wax block, sliced, and stained with Masson's staining. The pathologist performed histopathological evaluation. The scoring criteria refer to the following table:

[0470] Table 6-2 Fibrosis scoring criteria

[0471] 7. Animal Euthanasia: All experimental animals will be euthanized by CO2 and cervical dislocation after the in vivo experiment.

[0472] Statistical analysis: The experimental data were expressed as mean ± standard error (mean ± SEM) and analyzed using SPSS or Graphpad Prism. P < 0.05 was considered statistically significant.

[0473] The experimental results show that compared with the control compound, the compound of the present invention can significantly improve FVC, IC, VC lung function indicators and can significantly improve the pulmonary fibrosis score.

[0474] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the compound has a structure shown in Formula III: in, R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl; Each R3 is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are 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 halogen, C1-C6 alkyl and 4-7 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 4-7 membered heterocycloalkyl; the 4-7 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, C1-C6 alkyl, 4-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; R6 is selected from a 5-7 membered heteroaromatic ring and -C(O)-X-R2; X is selected from NRa and O; R2 is C1-C6 alkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring; the C1-C6 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring; the 4-7 membered heterocycloalkyl and 5-7 membered heteroaromatic ring are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, 5-7 membered heteroaromatic ring and 3-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; Ra is selected from hydrogen and C1-C3 alkyl; or, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring; When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and R6 is selected from -C(O)-O-R2, R2 is not methyl; When R6 is selected from a 5-7 membered heteroaromatic ring, R3 is hydrogen or F.

2. The compound according to claim 1, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound has the compound shown in formula I: Wherein, R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl; X is selected from NRa and O; R2 is C1-C6 alkyl, 5-7 membered heteroaromatic ring; the C1-C6 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents are the same or different; Each R3 is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are 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 halogen and C1-C6 alkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; when there are multiple substituents, the substituents are the same or different; Ra is selected from hydrogen and C1-C3 alkyl; or, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring; When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and X is selected from O, R2 is not methyl.

3. The compound according to claim 1, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R6 is selected from a 5-7 membered heteroaromatic ring, wherein the heteroatom in the 5-7 membered heteroaromatic ring is N; and / or, R6 is selected from And / or, the compound has a structure shown in Formula IV:

4. The compound according to any one of claims 1 to 3, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Said R1 is selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl; Preferably, R1 is selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, CH2F, CHF2 and CF3; More preferably, said R1 is selected from F, Cl and methyl; More preferably, the R1 is selected from methyl.

5. The compound according to any one of claims 1 to 2, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The X is selected from NRa and O; the Ra is selected from hydrogen and methyl; And / or, X is selected from O; And / or, said X is selected from NRa, said Ra is selected from hydrogen and methyl; and / or, X is selected from NRa, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring, wherein the 5-8 membered heterocycloalkyl bicyclic ring contains 1, 2 or 3 heteroatoms selected from N, O and S; And / or, X is selected from NRa, Ra and R2 and the nitrogen atom connected thereto form a 5-8 membered heterospiro ring, and the 5-8 membered heterospiro ring contains 1, 2 or 3 heteroatoms selected from N, O and S; And / or, X is selected from NRa, Ra and R2 and the nitrogen atom connected thereto to form 6. The compound according to any one of claims 1 to 2, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The R2 is selected from C1-C4 alkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring; the C1-C4 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring, 4-7 membered heterocycloalkyl; the 4-7 membered heterocycloalkyl and 5-7 membered heteroaromatic ring are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents are the same or different; Preferably, R2 is selected from C1-C4 alkyl, 4-7 membered heterocycloalkyl, -C1-C4 alkyl-4-7 membered heterocycloalkyl, -C1-C4 alkyl-5-7 membered heterocycloalkyl Aromatic ring, -4-7 membered heterocycloalkyl-C1-C4 alkyl; the C1-C4 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; Preferably, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pyrimidine ring, pyridine ring, pyridazine ring, pyrazine ring; said R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring; Preferably, the R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, azetidinyl, oxirane, oxetanyl, tetrahydrofuran ring, -C1-C4 alkyl-azetidinyl, -C1-C4 alkyl-oxirane, -C1-C4 alkyl-oxetanyl, -oxetanyl-C1-C4 alkyl, -C1-C4 alkyl-tetrahydrofuran ring, -C1-C4 alkyl-pyridine ring, pyrimidine ring, pyridine ring, pyridazine ring, pyrazine ring; the methyl, ethyl, propyl, isopropyl, butyl, isobutyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; Preferably, the R2 is selected from methyl, ethyl, propyl, butyl, isobutyl, pyridine ring, pyrimidine ring, -methyl-pyridine ring, -methyl-oxetanyl, -oxetanyl-methyl; the ethyl, propyl, isopropyl, butyl, isobutyl is substituted by hydroxyl; More preferably, the R2 is selected from methyl, ethyl, Butyl, pyrimidine ring, 7. The compound according to any one of claims 1 to 3, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: One or more of the following conditions are met: a) R3 is selected from hydrogen, halogen, cyano, C1-C3 alkyl, C3-C4 cycloalkyl; the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different; m is selected from 1, 2, 3 and 4; Preferably, the R3 is selected from hydrogen, F, Cl, methyl, cyano; the m is selected from 1, 2, 3 and 4; More preferably, said R3 is selected from hydrogen, F and Cl; b) R4 is selected from hydrogen, C1-C3 alkyl; Preferably, said R4 is selected from hydrogen and methyl; More preferably, said R4 is selected from hydrogen; c) R5 is selected from halogen, C1-C3 alkyl and 4-5 membered heterocycloalkyl; the C1-C3 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 4-7 membered heterocycloalkyl; the 4-5 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; Preferably, said R5 is selected from F, Cl, CF3, More preferably, said R5 is selected from Cl, CF3, 8. The compound according to claim 1, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: One or more of the following conditions are met: 1) When R5 is selected from Cl, R3 is selected from hydrogen, R1 is selected from methyl, X is selected from O, R2 is selected from methyl and C2-C6 alkyl; the methyl in R2 is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; the C2-C6 alkyl in R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different; Preferably, R2 is selected from ethyl, Butyl; 2) R5 is selected from Cl, R3 is selected from hydrogen, R4 is selected from hydrogen, R1 is selected from methyl, X is selected from O, R2 is selected from ethyl, butyl, 3) R3 is selected from hydrogen, R4 is selected from hydrogen, R1 is selected from methyl, X is selected from NH, R2 is selected from 4) When 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, R2 is selected from methyl, butyl, R5 is selected from -CF3, Cl, 5) when R1 is selected from methyl, R3 is selected from Cl, R4 is selected from hydrogen, R6 is selected from -C(O)-O-R2, R2 is selected from butyl, and R5 is selected from -CF3 and Cl; 6) when R1 is selected from methyl, R3 is selected from hydrogen, and R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, and the heteroatom in the 5-7 membered heteroaromatic ring is N; Preferably, R5 is selected from -CF3, Cl; More preferably, R5 is selected from Cl; 7) R1 is selected from methyl, R3 is selected from hydrogen, R4 is selected from hydrogen, X is selected from NRa, Ra and R2 form a nitrogen atom connected to it 8) When 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 selected from -CF3 and 9. The compound according to claim 1, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compounds include:

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a compound according to any one of claims 1 to 9, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof; and optionally a pharmaceutically acceptable carrier.

11. Use of a 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, comprising: As an AT2R agonist; and / or, preventing and / or treating diseases in which endogenous production of Ang II is insufficient; and / or, preventing and / or treating diseases in which an increased effect of Ang II is desired or required; and / or, preparing an AT2R agonist; And / or, the preparation of a medicament, pharmaceutical composition or formulation for preventing and / or treating a disease in which AT2R is expressed and its stimulation is desired or necessary.

12. A method for preventing and / or treating a disease, characterized in that: The diseases are: Diseases in which endogenous production of Ang II is insufficient. and / or diseases where increased Ang II action is desirable or necessary, and / or diseases in which AT2R is expressed and stimulation is desired or necessary; The method comprises: 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 is administered to a person suffering from or susceptible to the 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 tract, kidneys, eyes, female reproductive system or central nervous system.

14. The use according to claim 11 or the method according to claim 12, characterized in that The diseases are esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, indigestion, gastroesophageal reflux, irritable bowel syndrome, inflammatory enteritis, pancreatitis, liver disease, gallbladder disease, multiple organ failure, sepsis, xerostomia, gastritis, gastric stasis, hyperacidity, biliary tract disease, abdominal disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, acute colic, 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 prematurity, retinal microvascularization, ovulation mechanism disorders, high Blood pressure, myocardial hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, stenosis after balloon angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, pre-eclampsia, myocardial infarction, reinfarction, ischemic damage, erectile dysfunction, neointimal hyperplasia, cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, hypertrophy, prostatic hyperplasia, autoimmune disease, psoriasis, obesity, nerve regeneration, ulcer, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer, apoptosis, tumor, hyperplastic diabetes, nerve damage or organ rejection.

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

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