Thiophene sulfonyl carbamate as at2r agonist, and use thereof

Abstract

Provided are a compound represented by formula I, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The compound can be used as an AT2R agonist.

Description

A thiophenesulfonyl carbamate as an AT2R agonist and its use

[0001] Priority information

[0002] This application claims priority to and the benefits of patent application 202311083663.X filed with the State Intellectual Property Office of China on August 25, 2023, patent application 202311343449.3 filed with the State Intellectual Property Office of China on October 13, 2023, patent application 202410169513.9 filed with the State Intellectual Property Office of China on February 5, 2024, patent application 202410296193.3 filed with the State Intellectual Property Office of China on March 14, 2024, and patent application 202411105309.7 filed with the State Intellectual Property Office of China on August 12, 2024, and the entire text of which is incorporated 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 and its use. 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] 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 (see International Patent Application WO 99 / 43339).

[0007] There remains a need for potent and / or selective AT2R agonists that are expected to be useful in the above-mentioned diseases.

[0008] Summary of the Invention

[0009] 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 compound 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.

[0010] In a first aspect of the present invention, there is provided a compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0011] wherein X1 and X2 are independently selected from CRa and N;

[0012] R1 is selected from halogen, C1-C6 haloalkyl and 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0013] R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0014] Each R3 is independently selected from hydrogen, I, Br, Cl, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0015] m is selected from 1, 2, 3 and 4;

[0016] R4 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); said C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are each independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo (=O), hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, said substituents are the same or different;

[0017] R is selected from hydrogen, I, Br, Cl and C1-C3 alkyl;

[0018] When X1 and X2 are both CRa, and Ra is hydrogen, one or two of the following conditions are met:

[0019] (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0020] (2) R4 is selected from C1-C6 alkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[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] In a preferred embodiment of the present invention, there is provided a compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0023] wherein X1 and X2 are independently selected from CRa and N;

[0024] R1 is selected from halogen, C1-C6 haloalkyl and 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl groups;

[0025] R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0026] R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 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 C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo (=O), hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl and 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0029] Ra is selected from hydrogen, halogen and C1-C3 alkyl;

[0030] When both X1 and X2 are CH, one or both of the following conditions are met:

[0031] (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0032] (2) R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0033] In a preferred embodiment of the present invention, there is provided a compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0034] wherein X1 and X2 are independently selected from CRa and N;

[0035] R1 is selected from halogen, C1-C6 haloalkyl and 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl groups;

[0036] R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0037] R3 is selected from hydrogen, I, Br, Cl, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 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 C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo (=O), hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl and 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0040] R is selected from hydrogen, I, Br, Cl and C1-C3 alkyl;

[0041] When both X1 and X2 are CH, one or both of the following conditions are met:

[0042] (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0043] (2) R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0044] In a preferred embodiment of the present invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0045] wherein X1 and X2 are independently selected from CRa and N;

[0046] R1 is selected from halogen and C1-C6 haloalkyl;

[0047] R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0048] R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0049] m is selected from 1, 2, 3 and 4;

[0050] R4 is selected from C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo (=O), hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl and 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0051] Ra is selected from hydrogen, halogen and C1-C3 alkyl;

[0052] When both X1 and X2 are CH, one or both of the following conditions are met:

[0053] (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0054] (2) R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0055] In a preferred embodiment of the present invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0056] wherein X1 and X2 are independently selected from CRa and N;

[0057] R1 is selected from halogen and C1-C6 haloalkyl;

[0058] R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0059] R3 is selected from hydrogen, I, Br, Cl, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0060] m is selected from 1, 2, 3 and 4;

[0061] R4 is selected from C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo (=O), hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl and 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0062] R is selected from hydrogen, I, Br, Cl and C1-C3 alkyl;

[0063] When both X1 and X2 are CH, one or both of the following conditions are met:

[0064] (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0065] (2) R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0066] In a preferred embodiment of the present invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0067] wherein X1 and X2 are independently selected from CRa and N;

[0068] R1 is selected from halogen and C1-C6 haloalkyl;

[0069] R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0070] R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0071] m is selected from 1, 2, 3 and 4;

[0072] R4 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0073] Ra is selected from hydrogen, halogen and C1-C3 alkyl;

[0074] When X1 and X2 are both selected from CH, R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0075] In a preferred embodiment of the present invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0076] wherein X1 and X2 are independently selected from CRa and N;

[0077] R1 is selected from halogen and C1-C6 haloalkyl;

[0078] R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0079] R3 is selected from hydrogen, I, Br, Cl, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0080] m is selected from 1, 2, 3 and 4;

[0081] R4 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0082] R is selected from hydrogen, I, Br, Cl and C1-C3 alkyl;

[0083] When X1 and X2 are both selected from CH, R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0084] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0085] wherein R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0086] R1 is selected from halogen, C1-C6 haloalkyl, 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl groups;

[0087] R3, R4 and m are as defined in the first aspect of the present invention.

[0088] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0089] wherein R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0090] R1 is selected from halogen and C1-C6 haloalkyl;

[0091] R3, R4 and m are as defined in the first aspect of the present invention.

[0092] In a preferred embodiment of the present invention, in the compound represented by formula II, R2 is selected from C1-C3 alkyl and C1-C3 haloalkyl.

[0093] In a preferred embodiment of the present invention, in the compound represented by formula II, R2 is selected from methyl.

[0094] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0095] wherein R4 is selected from C1-C6 alkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0096] R1, R3 and m are as defined in the first aspect of the present invention.

[0097] In a preferred embodiment of the present invention, in the compound represented by formula III, R1 is selected from 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl groups.

[0098] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0099] wherein R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0100] R1, R3 and m are as described in the first aspect of the present invention.

[0101] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0102] wherein R1 is selected from a 3-6 membered heterocycloalkyl group; the 3-6 membered heterocycloalkyl group is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl groups;

[0103] R3, R4 and m are as defined in the first aspect of the present invention.

[0104] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0105] wherein R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0106] R1, R3 and m are as defined in the first aspect of the present invention.

[0107] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0108] wherein R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0109] R1, R3 and m are as described in the first aspect of the present invention.

[0110] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0111] wherein R1 is selected from a 3-6 membered heterocycloalkyl group; the 3-6 membered heterocycloalkyl group is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl groups;

[0112] R3, R4 and m are as defined in the first aspect of the present invention.

[0113] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0114] wherein R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0115] R1, R3 and m are as defined in the first aspect of the present invention.

[0116] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0117] wherein R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0118] R1, R3 and m are as described in the first aspect of the present invention.

[0119] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0120] wherein R1 is selected from a 3-6 membered heterocycloalkyl group; the 3-6 membered heterocycloalkyl group is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl groups;

[0121] R3, R4 and m are as defined in the first aspect of the present invention.

[0122] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0123] wherein R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0124] R1, R3 and m are as defined in the first aspect of the present invention.

[0125] In a preferred embodiment of the present invention, R1 is selected from halogen, C1-C3 haloalkyl and 3-6 membered heterocycloalkyl substituted by C1-C3 alkyl; the 3-6 membered heterocycloalkyl contains 1, 2 or 3 identical or different heteroatoms; the heteroatoms are selected from N, O and S.

[0126] In a preferred embodiment of the present invention, R1 is selected from halogen, C1-C3 haloalkyl and 4-6 membered heterocycloalkyl optionally substituted by C1-C3 alkyl, and the heteroatom is O.

[0127] In a preferred embodiment of the present invention, R1 is selected from 4-6 membered heterocycloalkyl optionally substituted by C1-C3 alkyl, and the heteroatom is O.

[0128] In a preferred embodiment of the present invention, R1 is selected from Cl, Br, I, CH2F, CHF2, CF3 and a 4-membered heterocycloalkyl group substituted with a methyl group.

[0129] In a preferred embodiment of the present invention, R1 is selected from Cl, CF3 and oxetanyl substituted by methyl.

[0130] In a preferred embodiment of the present invention, said R1 is selected from Cl, CF3 and

[0131] In a preferred embodiment of the present invention, the R1 is selected from halogen and C1-C3 haloalkyl.

[0132] In a preferred embodiment of the present invention, R1 is selected from Cl, Br, I, CH2F, CHF2 and CF3.

[0133] In a preferred embodiment of the present invention, said R1 is selected from Cl and CF3.

[0134] In a preferred embodiment of the present invention, R2 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl; the C1-C3 alkyl and C3-C4 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0135] In a preferred embodiment of the present invention, R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl; and R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0136] In a preferred embodiment of the present invention, R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl; and R2 is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0137] In a preferred embodiment of the present invention, said R2 is selected from hydrogen and methyl.

[0138] In a preferred embodiment of the present invention, X1 and X2 are independently selected from CRa and N; and Ra is selected from hydrogen and halogen.

[0139] In a preferred embodiment of the present invention, X1 is selected from CH or N, and X2 is selected from N.

[0140] In a preferred embodiment of the present invention, X1 and X2 are independently selected from CH and N.

[0141] In a preferred embodiment of the present invention, X1 and X2 are independently selected from N.

[0142] In a preferred embodiment of the present invention, when X1 is selected from CH or N, and X2 is selected from N, R1 is selected from Cl, CF3 and R2 and R3 are selected from hydrogen, and R4 is selected from C1-C5 alkyl optionally substituted by one or more substituents, wherein the substituents are selected from halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl, and when there are multiple substituents, the substituents are the same or different.

[0143] In a preferred embodiment of the present invention, when X1 is selected from CH or N, and X2 is selected from N, R1 is selected from Cl, CF3 and R2 and R3 are selected from hydrogen, and R4 is selected from C1-C5 alkyl.

[0144] In a preferred embodiment of the present invention, when X1 is selected from CH or N, and X2 is selected from N, R1 is selected from Cl, CF3 and R2 and R3 are selected from hydrogen, and R4 is selected from C2-C5 alkyl.

[0145] In a preferred embodiment of the present invention, the R3 is selected from hydrogen, halogen, cyano, C1-C3 alkyl and C3-C4 cycloalkyl; the C1-C3 alkyl and C3-C4 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0146] m is selected from 1, 2, 3 and 4.

[0147] In a preferred embodiment of the present invention, the R3 is selected from hydrogen, I, Br, Cl, cyano, C1-C3 alkyl and C3-C4 cycloalkyl; the C1-C3 alkyl and C3-C4 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0148] m is selected from 1, 2, 3 and 4.

[0149] In a preferred embodiment of the present invention, the R3 is selected from hydrogen, halogen, cyano, C1-C3 alkyl; the C1-C3 alkyl is independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: hydroxyl and halogen;

[0150] m is selected from 1, 2, 3 and 4.

[0151] In a preferred embodiment of the present invention, the R3 is selected from hydrogen, I, Br, Cl, cyano, C1-C3 alkyl; the C1-C3 alkyl is independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: hydroxyl and halogen;

[0152] m is selected from 1, 2, 3 and 4.

[0153] In a preferred embodiment of the present invention, R3 is selected from hydrogen, I, Br, and Cl.

[0154] In a preferred embodiment of the present invention, R3 is selected from hydrogen and Cl.

[0155] In a preferred embodiment of the present invention, said R3 is selected from hydrogen.

[0156] In a preferred embodiment of the present invention, said R3 is selected from Cl.

[0157] In a preferred embodiment of the present invention, R4 is selected from C1-C5 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); the C1-C5 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0158] The 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) contain 1, 2, or 3 identical or different heteroatoms; the heteroatoms are selected from N, O, and S, and the S atom may be in the form of an oxide thereof.

[0159] In a preferred embodiment of the present invention, R4 is selected from C1-C5 alkyl, C3-C5 cycloalkyl and 3-6 membered heterocycloalkyl; the C1-C5 alkyl, C3-C5 cycloalkyl and 3-6 membered heterocycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0160] The 3-6 membered heterocycloalkyl group contains 1, 2 or 3 identical or different heteroatoms; the heteroatoms are selected from N, O and S, and the S atom may be in the form of an oxide thereof.

[0161] In a preferred embodiment of the present invention, R4 is selected from 3-6 membered heterocycloalkyl, C1-C5 alkyl optionally substituted by -OH, -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) optionally substituted by C1-C3 alkyl; and the heteroatom is O.

[0162] In a preferred embodiment of the present invention, R4 is selected from 4-6 membered heterocycloalkyl, C1-C5 alkyl optionally substituted by -OH, -(C1-C3)alkylene-(4-6 membered heterocycloalkyl) optionally substituted by C1-C3 alkyl; and the heteroatom is O.

[0163] In a preferred embodiment of the present invention, R4 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, oxetane, azetidine, tetrahydrofuran, tetrahydropyrrole, tetrahydropyran, hexahydropyridine, oxazinane, thiazinane; and R4 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-6 membered heterocycloalkyl.

[0164] In a preferred embodiment of the present invention, said R4 is selected from methyl, Butyl, tetrahydrofuran, tetrahydropyran,

[0165] In a preferred embodiment of the present invention, said R4 is selected from methyl, Butyl,

[0166] In a preferred embodiment of the present invention, R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different.

[0167] In a preferred embodiment of the present invention, R4 is selected from C1-C4 alkyl and 3-6 membered heterocycloalkyl substituted by 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl contains 1, 2, or 3 identical or different heteroatoms; the heteroatoms are selected from N, O, and S, and the S atom can be in the form of its oxide.

[0168] In a preferred embodiment of the present invention, the R4 is selected from 4-6 membered heterocycloalkyl, or -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) optionally substituted by C1-C3 alkyl; the heteroatom is O.

[0169] In a preferred embodiment of the present invention, the R4 is selected from C1-C3 alkyl; the C1-C3 alkyl is substituted by a 3-6 membered heterocycloalkyl and a C1-C3 alkyl.

[0170] In a preferred embodiment of the present invention, the R4 is selected from a 4-6 membered heterocycloalkyl group, and the heteroatom is O.

[0171] In a preferred embodiment of the present invention, the R4 is selected from -(C1-C6)alkylene-(3-6 membered heterocycloalkyl), wherein the heteroatom is O; the -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) is substituted by C1-C3 alkyl; more preferably, R4 is selected from tetrahydrofuran, tetrahydropyran,

[0172] In a preferred embodiment of the present invention, said R4 is selected from

[0173] In a preferred embodiment of the present invention, R4 is selected from C1-C5 alkyl and C3-C5 cycloalkyl; the C1-C5 alkyl and C3-C5 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0174] In a preferred embodiment of the present invention, R4 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and R4 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0175] In a preferred embodiment of the present invention, said R4 is selected from methyl, ethyl, Butyl.

[0176] In a preferred embodiment of the present invention, said R4 is selected from methyl, Butyl.

[0177] In a preferred embodiment of the present invention, at least one of R1 and R4 contains a 3-6 membered heterocycloalkyl group, and the 3-6 membered heterocycloalkyl group is independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0178] In a preferred embodiment of the present invention, one of R1 and R4 contains a 3-6 membered heterocycloalkyl group, and the 3-6 membered heterocycloalkyl group is independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0179] In a preferred embodiment of the present invention, R1 is a 3-6 membered heterocycloalkyl group optionally substituted by a C1-C3 alkyl group, wherein the heteroatom is O; R4 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo (=O), hydroxyl, and C1-C3 alkyl; when there are multiple substituents, the substituents may be the same or different.

[0180] In a preferred embodiment of the present invention, R1 is halogen, or C1-C6 haloalkyl; R4 is selected from 3-6 membered heterocycloalkyl, or -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); the 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different.

[0181] In a preferred embodiment of the present invention, R1 is a 3-6 membered heterocycloalkyl group optionally substituted by a C1-C3 alkyl group, wherein the heteroatom is O; R4 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by 0 or 1 substituent selected from the following: halogen, hydroxyl.

[0182] In a preferred embodiment of the present invention, R1 is halogen, or C1-C6 haloalkyl; R4 is selected from 4-6 membered heterocycloalkyl, or -(C1-C3)alkylene-(4-6 membered heterocycloalkyl); the -(C1-C3)alkylene-(4-6 membered heterocycloalkyl) is independently substituted by 0 or 1 substituent selected from the following: halogen, C1-C3 alkyl.

[0183] In a preferred embodiment of the present invention, when X1 and X2 are both CRa and Ra is hydrogen, one or more of the following conditions are satisfied:

[0184] (1) R1 is selected from a 3-6 membered heterocycloalkyl group; the 3-6 membered heterocycloalkyl group is substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo (=O), hydroxyl, C1-C3 alkyl, and C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0185] (2) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0186] (3) R4 is selected from C1-C4 alkyl, 3-6 membered heterocycloalkyl, and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) substituted by 1, 2, 3 or 4 3-6 membered heterocycloalkyl groups; the 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) contain 1, 2 or 3 identical or different heteroatoms; the heteroatoms are selected from N, O and S, and the S atom may be in the form of its oxide.

[0187] In a preferred embodiment of the present invention, when X1 and X2 are both CRa, and Ra is hydrogen, one or two of the following conditions are satisfied:

[0188] (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0189] (2) R4 is selected from C1-C6 alkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0190] In a preferred embodiment of the present invention, when X1 and X2 are both CH, one or two of the following conditions are satisfied:

[0191] (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0192] (2) R4 is selected from C1-C4 alkyl and 3-6 membered heterocycloalkyl substituted by 1, 2, 3 or 4 3-6 membered heterocycloalkyl groups; the 3-6 membered heterocycloalkyl group contains 1, 2 or 3 identical or different heteroatoms; the heteroatoms are selected from N, O and S, and the S atom may be in the form of its oxide.

[0193] In a preferred embodiment of the present invention, when X1 and X2 are both CH, R1 is selected from a 3-6 membered heterocycloalkyl group; the 3-6 membered heterocycloalkyl group is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0194] In a preferred embodiment of the present invention, X1 and X2 are simultaneously selected from CH; R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted with 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0195] In a preferred embodiment of the present invention, when X1 and X2 are both selected from CH, R2 is selected from C1-C3 alkyl and C1-C3 haloalkyl.

[0196] In a preferred embodiment of the present invention, when X1 and X2 are both selected from CH, R2 is selected from methyl.

[0197] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different.

[0198] In a preferred embodiment of the present invention, X1 and X2 are simultaneously selected from CH; R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different.

[0199] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from C1-C4 alkyl and 3-6 membered heterocycloalkyl substituted by 1, 2, 3 or 4 3-6 membered heterocycloalkyl groups; the 3-6 membered heterocycloalkyl group contains 1, 2 or 3 identical or different heteroatoms; the heteroatoms are selected from N, O and S, and the S atom may be in the form of an oxide thereof.

[0200] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from 4-6 membered heterocycloalkyl, or -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) optionally substituted by C1-C3 alkyl; and the heteroatom is O.

[0201] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from C1-C3 alkyl; and the C1-C3 alkyl is substituted by a 3-6 membered heterocycloalkyl and a C1-C3 alkyl.

[0202] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from 4-6 membered heterocycloalkyl, and the heteroatom is O.

[0203] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from -(C1-C6)alkylene-(3-6 membered heterocycloalkyl), the heteroatom is O; and the -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) is substituted by C1-C3 alkyl.

[0204] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from tetrahydrofuran, tetrahydropyran,

[0205] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from

[0206] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, is characterized in that the compound comprises:

[0207] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, is characterized in that the compound comprises:

[0208] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound of formula I as described in the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier.

[0209] In a third aspect of the present invention, the compound of formula I according to the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to the second aspect are used, wherein the use includes:

[0210] Acts as an AT2R agonist;

[0211] and / or, preventing and / or treating diseases in which endogenous production of Ang II is insufficient;

[0212] and / or, preventing and / or treating diseases in which an increased effect of Ang II is desired or required;

[0213] 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.

[0214] Provided are compounds of formula I as described in the first aspect, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition 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).

[0215] 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.

[0216] 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.

[0217] Kidney diseases that should be mentioned include renal failure, nephritis, and renal hypertension.

[0218] Eye diseases that should be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microvascularization.

[0219] Female reproductive system disorders that should be mentioned include disorders of the ovulatory mechanism.

[0220] 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.

[0221] CNS diseases that should be mentioned include cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, and cerebral infarction.

[0222] The compound of formula I as described in the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect can also be used to regulate 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.

[0223] The compound of formula I 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.

[0224] The fourth aspect of the present invention provides a method for treating a disease, wherein the endogenous production of Ang II is insufficient, and / or a disease in which it is desired or necessary to increase the effect of Ang II, and / or a disease in which AT2R expression 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 a compound of formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition as described in the second aspect.

[0225] In an optional embodiment of the present invention, the disease includes a disease of the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive system or central nervous system (CNS), specifically as defined in the use described in the third aspect.

[0226] 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.

[0227] Terms and Definitions

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] In this application, "AT2 receptor" and "AT2R" have the same definition.

[0237] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, or iodine.

[0238] As used herein, the term "amino" by itself or as part of another substituent refers to -NH2.

[0239] As used herein, the term "hydroxy" by itself or as part of another substituent refers to -OH.

[0240] As used herein, the term "cyano" by itself or as part of another substituent refers to -CN.

[0241] 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.

[0242] 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.

[0243] The term "C1-C6 alkylene" when used alone or as part of another substituent is understood to mean a straight-chain divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched divalent hydrocarbon radical having 3 to 6 carbon atoms, unless otherwise indicated, such as methylene, ethylene, propylene, isopropylene, 1-methylpropylene, butylene, etc. The term "oxo" when used alone or as part of another substituent means that two hydrogen atoms on a methylene group are replaced by oxygen, i.e., a methylene group is replaced by a carbonyl group, representing =0.

[0244] 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.

[0245] "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.

[0246] "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.

[0247] The term "3-6 membered heterocycloalkyl" when used alone or as part of another substituent is understood to mean a monocyclic, bicyclic or tricyclic ring having 3 to 6 atoms, wherein the heteroatoms are preferably selected from N, O and S, it being understood that when the total number of S atoms and O atoms in the heterocycloalkyl exceeds 1, the heteroatoms are not adjacent to each other. Examples of heterocycloalkyl include, but are not limited to, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiopyranyl. The term "substituted" when used alone or as part of another substituent means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the particular atom is normal and the substituted compound is stable.

[0248] 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.

[0249] In this application, the term "optionally substituted by" or "optionally substituted by" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from the possible substituents. For example, "aryl is optionally substituted by 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 "Alkyl" means that the aryl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 The term "alkyl" refers to an alkyl group, and the description includes both substituted and unsubstituted aryl groups.

[0250] 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.

[0251] "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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0264] (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;

[0265] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0266] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0267] (iv) Alleviate the symptoms of the disease or condition. Beneficial effects

[0268] After extensive and intensive research, the inventors unexpectedly developed a thiophenesulfonylcarbamate compound as an AT2 receptor agonist, having the structure shown herein. The thiophenesulfonylcarbamate compound of the present invention can prevent or treat diseases or conditions associated with the AT2 receptor, exhibits excellent pharmacokinetic properties, and possesses high safety and drugability. DETAILED DESCRIPTION

[0269] 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.

[0270] This application has the following definitions:

[0271] Symbol or unit:

[0272] IC 50 : Half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0273] 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

[0274] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0275] RT: retention time

[0276] Reagents:

[0277] DCM: dichloromethane

[0278] DMF: N,N-dimethylformamide

[0279] DIPEA: N,N-diisopropylethylamine

[0280] EA: ethyl acetate

[0281] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0282] MeOH: methanol

[0283] PE: Petroleum ether

[0284] Toluene: Toluene

[0285] THF: Tetrahydrofuran

[0286] XPhos Pd G4: Palladium(II) methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)

[0287] Test method:

[0288] LCMS: Liquid chromatography-mass spectrometry

[0289] TLC: Thin layer chromatography

[0290] Intermediate A1: Preparation of Intermediate A1

[0291] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid

[0292] The synthetic route of intermediate A1 is as follows:

[0293] Step 1: Synthesis of N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide

[0294] Zinc chloride (20 mL, 1 mol / L THF solution) and isobutylmagnesium chloride (13 mL, 2 mol / L) were added to a 100 mL three-necked flask and stirred at room temperature under a nitrogen atmosphere for 10 minutes. Then, a solution of 5-bromothiophene-2-tert-butylsulfonamide (5.0 g, 16.77 mmol) and di(tri-tert-butylphosphine)palladium (428 mg, 0.83 mmol) in toluene (50 mL) were added dropwise. The reaction was stirred and heated at 120°C for 1 hour. TLC (PE:EA (v / v) = 3:1) showed complete disappearance of the starting material and the formation of distinct target spots. The reaction solution was filtered, and the resulting mother liquor was dried and purified using a silica gel column (petroleum ether:ethyl acetate (v / v) = 20:1-3:1) to obtain N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (3.8 g, 82.3% yield).

[0295] 1 H NMR (400MHz, DMSO-d6) δ7.66 (s, 1H), 7.39 (d, J = 3.7Hz, 1H), 6.84 (d, J = 3.7Hz, 1H), 2.70(d,J=7.1Hz,2H),1.91–1.71(m,1H),1.20–1.07(m,9H),0.89(d,J=6.6Hz,6H)

[0296] Step 2: Synthesis of (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid

[0297] In a 50 mL three-necked flask, N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (2.0 g, 7.26 mmol) was dissolved in THF (20 mL). Under a nitrogen atmosphere, a solution of n-butyllithium (7.3 mL, 2.5 mol / L n-hexane) was added dropwise at room temperature. After stirring for half an hour, triisopropylborate (2.05 g, 10.89 mmol) was added to the reaction system. Solids gradually precipitated from the solution, giving it a pale yellow color. The reaction system was stirred at room temperature overnight. TLC (PE:EA (V / V) = 3:1) spot plate monitoring showed complete reaction of the starting material and the formation of new spots of the target compound. To the reaction solution was slowly added dropwise an aqueous HCl solution (5.0 mL, 2.0 mol / L) to adjust the pH to 2. The mixture was diluted with 30 mL of water and extracted with ethyl acetate (50 mL × 2). The organic phase was washed and extracted with saturated brine (30 mL). The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The mother liquor was spin-dried and mixed with the sample. The mixture was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-3:1) to obtain (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (A1) (1.8 g, yield 77.6%).

[0298] Intermediate A2: Preparation of Intermediate A2

[0299] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide

[0300] The synthetic route of intermediate A2 is as follows:

[0301] Step 1: Synthesis of 1-(4-bromobenzyl)-2-chloro-1H-imidazole

[0302] 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).

[0303] LC-MS, M / Z(ESI):271.0[M+H] +

[0304] Step 2: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl-3-yl)-N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide

[0305] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutylthiophen-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, followed by potassium phosphate (1.27 g, 6.00 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (103 mg, 120 μmol), 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) = 50:1-0:1) to give 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl-3-yl)-N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (510 mg, 88.5% yield).

[0306] LC-MS, M / Z(ESI):467.4[M+H] +

[0307] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl-3-yl)-5-isobutylthiophene-2-sulfonamide

[0308] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl-3-yl)-N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (500 mg, 1.04 mmol) was dissolved in trifluoroacetic acid (15 mL) and dichloromethane (5 mL) and reacted at 40°C for 18 hours. 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-3-yl)-5-isobutylthiophene-2-sulfonamide (A2) (400 mg, 90.6% yield).

[0309] LC-MS, M / Z(ESI):410.3[M+H] +

[0310] Example 1: Preparation of target compound I-2

[0311] Butyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0312] The synthetic route of target compound I-2 is as follows:

[0313] Step 1: Synthesis of 1-(1-(4-bromophenyl)ethyl)-2-chloro-1H-imidazole

[0314] 1-Bromo-4-(1-bromoethyl)benzene (1.00 g, 3.79 mmol) and 2-chloro-1H-imidazole (583 mg, 5.68 mmol) were dissolved in N,N-dimethylformamide (6 mL). Potassium carbonate (1.57 g, 11.4 mmol) was then added and the mixture was allowed to react at 50°C for 2 hours. The reaction solution was poured into water (30 mL) and extracted three times with ethyl acetate (30 mL). The organic phase was collected, washed five times with water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-(1-(4-bromophenyl)ethyl)-2-chloro-1H-imidazole (1.00 g, 92.4% yield) as a yellow oil.

[0315] LC-MS, M / Z(ESI):286.9[M+H] +

[0316] Step 2: Synthesis of N-(tert-butyl)-3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0317] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (400 mg, 1.25 mmol) was dissolved in tetrahydrofuran (4 mL) and water (2 mL), and 1-(1-(4-bromophenyl)ethyl)-2-chloro-1H-imidazole (358 mg, 1.25 mmol) was added, followed by potassium phosphate (1.33 g, 6.26 mmol) and XPhos Pd G4 (108 mg, 125 μmol), and the mixture was stirred at 60 ° C under nitrogen protection for 2 hours. The reaction solution was poured into water (10 mL), extracted three times with ethyl acetate (10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to give the compound N-(tert-butyl)-3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (200 mg, yield 33.3%).

[0318] LC-MS, M / Z(ESI):480.1[M+H] +

[0319] Step 3: Synthesis of 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0320] N-(tert-Butyl)-3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (150 mg, 312 μmol) was dissolved in trifluoroacetic acid (8 mL) and dichloromethane (2 mL) and reacted at 40°C for 2 hours. The reaction solution was poured into water (5 mL) and extracted three times with dichloromethane (5 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to obtain the compound 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide) (170 mg, crude product).

[0321] LC-MS, M / Z(ESI):424.1[M+H] +

[0322] Step 4: Synthesis of butyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0323] 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (70 mg, 165 μmol) and butyl chloroformate (22.6 mg, 165 μmol) were dissolved in dichloromethane (3 mL), N,N-diisopropylethylamine (64.0 mg, 495 μmol) was added, and the reaction was stirred at 0°C for 0.5 hour. The reaction solution was poured into water (10 mL), extracted three times with dichloromethane (30 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by high performance liquid chromatography (chromatographic column: C18 150*30 mm; solvent: A = water + 0.05 volume formic acid (30%), B = acetonitrile; gradient: 65%-95%, 7 minutes) to give the product (butyl 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (15.8 mg, yield 18.3%).

[0324] LC-MS, M / Z(ESI):524.2[M+H] +

[0325] 1H NMR(400MHz, CDCl3)δ:7.49(d,2H),7.22(d,2H),7.02(s,2H),6.77(s,1H),5.59(m,1H),4.06(t,2H), 2.73(d,2H),1.92-2.01(m,1H),1.87(d,3H),1.50-1.55(t,2H),1.27(m,2H),1.02(d,6H),0.90(t,3H)

[0326] Example 2: Preparation of target compound I-6

[0327] Butyl (3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0328] The synthetic route of target compound I-6 is as follows:

[0329] Step 1: Synthesis of 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyridine

[0330] 5-Bromo-2-(chloromethyl)pyridine (2.00 g, 9.69 mmol) and 2-chloro-1H-imidazole (1.09 g, 10.7 mmol) were dissolved in acetonitrile (20 mL), followed by the addition of potassium carbonate (2.95 g, 21.3 mmol). The reaction was stirred at 70°C for 2 hours. After completion, the reaction solution 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 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 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyridine (2.00 g, 75.8% yield).

[0331] LC-MS, M / Z(ESI):273.8[M+H] +

[0332] Step 2: Synthesis of N-(tert-butyl)-3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide

[0333] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (400 mg, 1.25 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyridine (341 mg, 1.25 mmol) was added, followed by potassium phosphate (798 mg, 3.76 mmol) and XPhos Pd G4 (108 mg, 125 μmol), and the reaction was stirred at 60 ° C under nitrogen protection for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and then extracted three times with ethyl acetate (30 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was then separated and purified on a silica gel column (petroleum ether: ethyl acetate (V / V) = 1:0-2:1) to give N-(tert-butyl)-3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (500 mg, yield 85.4%).

[0334] LC-MS, M / Z(ESI):467.1[M+H] +

[0335] Step 3: Synthesis of 3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide

[0336] N-(tert-Butyl)-3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (500 mg, 1.07 mmol) was dissolved in trifluoroacetic acid (4 mL) and dichloromethane (4 mL) and stirred at 40°C for 10 hours. After completion of the reaction, the reaction solution was poured into water (30 mL) and extracted three times with dichloromethane (30 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) = 1:0-1:2) to obtain 3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (420 mg, 95.5% yield).

[0337] LC-MS, M / Z(ESI):411.0[M+H] +

[0338] Step 4: Synthesis of butyl (3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0339] 3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (150 mg, 365 μmol) and butyl chloroformate (74.8 mg, 548 μmol) were dissolved in dichloromethane (3 mL) at 0°C, and N,N-diisopropylethylamine (94.4 mg, 730 μmol) was added. The reaction was stirred at 0°C for 0.5 h. After completion of the reaction, the reaction solution was poured into water (30 mL), and then extracted three times with ethyl acetate (30 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 (chromatographic column: C18 150×30 mm; solvent: A=water+0.05 volume formic acid (30%), B=acetonitrile; gradient: 55%-85%, 7 minutes) and lyophilized to give butyl (3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (51.0 mg, yield 27.3%).

[0340] LC-MS, M / Z(ESI):511.2[M+H] +

[0341] 1 H NMR(400MHz, CDCl3)δ8.70(d,1H),7.85(dd,1H),6.95-7.05(m,3H),6.77(s,1H),5.25(s,2H),4.10 (t,2H),2.74(d,2H),1.97(td,1H),1.50-1.60(m,2H),1.24-1.33(m,2H),1.01(d,6H),0.89(t,3H)

[0342] Example 3: Preparation of target compound I-7

[0343] Butyl (3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0344] The synthetic route of target compound I-7 is as follows:

[0345] Step 1: Synthesis of 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidine

[0346] To a solution of 5-bromo-2-(bromomethyl)pyrimidine (1.00 g, 3.97 mmol) in acetonitrile (15.0 mL) were added 2-chloro-1H-imidazole (407 mg, 3.97 mmol) and potassium carbonate (1.10 g, 7.94 mmol), and the reaction was stirred at 25°C for 10 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), then extracted three times with ethyl acetate (20 mL). The organic phase was collected, washed twice with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidine.

[0347] LC-MS, M / Z(ESI):274.8[M+H] +

[0348] Step 2: Synthesis of N-(tert-butyl)-3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide

[0349] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (300 mg, 940 μmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidine (231 mg, 846 μmol) was added, followed by potassium phosphate (598 mg, 2.82 mmol) and XPhos Pd G4 (80.9 mg, 94.0 μmol), and the mixture was stirred at 60 ° C under nitrogen protection for 5 hours. After completion of the reaction, the reaction solution was poured into water (10 mL), and then extracted three times with ethyl acetate (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was then separated and purified on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1 to 1:1) to give N-(tert-butyl)-3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide.

[0350] LC-MS, M / Z(ESI):468.3[M+H] +

[0351] Step 3: Synthesis of 3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide

[0352] N-(tert-Butyl)-3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide (500 mg, 1.07 mmol) was dissolved in trifluoroacetic acid (5.00 mL) and the reaction was stirred at 25°C for 8 hours. After completion of the reaction, the reaction solution was poured into water (20 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) = 5:1 to 1:3) to obtain 3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide.

[0353] LC-MS, M / Z(ESI):412.2[M+H] +

[0354] Step 4: Synthesis of butyl (3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0355] To a solution of 3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide (120 mg, 291 μmol) in dichloromethane (3 mL) at 0°C were added N,N-diisopropylethylamine (94.1 mg, 728 μmol) and butyl chloroformate (53.7 mg, 393 μmol), and the reaction was stirred at 0°C for 0.5 h. After the reaction is completed, the reaction solution is poured into water (10 mL), and then extracted three times with dichloromethane (10 mL). The organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 250*50mm*15um; solvent: A=water+0.05 volume formic acid (30%), B=acetonitrile; gradient: 48%-78%, 9 minutes) to obtain butyl (3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate.

[0356] LC-MS, M / Z(ESI):512.2[M+H] +

[0357] 1H NMR(400MHz, CDCl3)δ8.85(s,2H),7.09(d,1H),7.01(d,1H),6.77(s,1H),5.37(s,2H),4.09(t,2H ),2.75(d,2H),1.96-2.00(m,1H),1.50-1.54(m,2H),1.26-1.31(m,2H),1.01(d,6H),0.89(t,3H).

[0358] Example 4: Preparation of target compound I-14

[0359] 3-Methyloxetan-3-ylmethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0360] The synthetic route of target compound I-14 is as follows:

[0361] Step 1: Synthesis of phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0362] Under nitrogen, to a solution of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (600 mg, 1.46 mmol) in acetonitrile (5.00 mL) were added diphenyl carbonate (470 mg, 2.20 mmol) and potassium carbonate (405 mg, 2.93 mmol). The reaction was stirred at 50°C for 1 hour. After completion of the reaction, 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 obtain crude phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate.

[0363] LC-MS, M / Z(ESI):530.1[M+H] +

[0364] Step 2: Synthesis of 3-methyloxetane-3-ylmethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0365] To a solution of phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (250 mg, 472 μmol) in tetrahydrofuran (3.00 mL) were added triethylamine (145 mg, 1.44 mmol) and (3-methyloxetan-3-yl)methanol (482 mg, 4.72 mmol). The reaction was stirred at 25°C for 10 hours. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted three times with ethyl acetate (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume of aqueous ammonia (30%), B=acetonitrile; gradient: 3%-33%, 10 minutes) to give 3-methyloxetane-3-ylmethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate.

[0366] LC-MS, M / Z(ESI):538.2[M+H] +

[0367] 1 H NMR (400MHz, CDCl3) δ7.55(d,2H),7.19(d,2H),6.94(d,2H),6.74(s,1H),5.10(s,2H),4.25-4.40(m,4H),3.95(br s,2H),2.67(d,2H),1.89-1.96(m,1H),1.17(s,3H),0.98(d,6H).

[0368] Example 5: Preparation of target compound I-15A

[0369] (3S)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate tetrahydrofuran-3-yl ester

[0370] The synthetic route of the target compound I-15A is as follows:

[0371] Step 1: Synthesis of tetrahydrofuran-3-yl (3S)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0372] To a solution of phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (250 mg, 472 μmol) in tetrahydrofuran (3.00 mL) were added triethylamine (143 mg, 1.41 mmol) and (S)-3-hydroxytetrahydrofuran (416 mg, 4.72 mmol). The reaction was stirred at 25°C for 10 hours. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted three times with ethyl acetate (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume of aqueous ammonia (30%), B=acetonitrile; gradient: 0%-30%, 10 minutes) to give (3S)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate tetrahydrofuran-3-yl ester.

[0373] LC-MS, M / Z(ESI):524.2[M+H] +

[0374] 1 H NMR(400MHz, CDCl3)δ7.53(d,2H),7.18(d,2H),6.87-6.99(m,2H),6.75(s,1H),5.12(s, 3H),3.64-3.80(m,4H),2.69(d,2H),1.97-2.01(m,1H),1.84-1.93(m,2H),0.98(d,6H).

[0375] Example 6: Preparation of target compound I-15B

[0376] (3R)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate tetrahydrofuran-3-yl ester

[0377] The synthetic route of the target compound I-15B is as follows:

[0378] Step 1: Synthesis of (3R)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate tetrahydrofuran-3-yl ester

[0379] To a solution of phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (250 mg, 472 μmol) in tetrahydrofuran (3.00 mL) were added triethylamine (143 mg, 1.41 mmol) and (R)-3-hydroxytetrahydrofuran (416 mg, 4.72 mmol). The reaction was stirred at 25°C for 10 hours. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted three times with ethyl acetate (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume of aqueous ammonia (30%), B=acetonitrile; gradient: 0%-30%, 10 minutes) to give (3R)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamic acid tetrahydrofuran-3-yl ester.

[0380] LC-MS, M / Z(ESI):524.2[M+H] +

[0381] 1 H NMR (400MHz, CDCl3) δ7.56(br d,2H),7.18(br d,2H),6.92(br d,2H),6.75(s,1H),4.92-5.26(m,3H),3.56-3.86(m,4H),2.67(br d,2H),1.78-2.09(m,3H),0.98(d,6H).

[0382] Example 7: Preparation of target compound I-1

[0383] 2-Hydroxyethyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0384] The synthetic route of target compound I-1 is as follows:

[0385] Step 1: Synthesis of phenyl 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonylcarbamate

[0386] 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (100 mg, 236 μmol) was dissolved in acetonitrile (3.00 mL), followed by the addition of potassium carbonate (65.2 mg, 472 μmol) and diphenyl carbonate (75.8 mg, 354 μmol). The reaction was stirred at 20°C under nitrogen for 10 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to obtain crude phenyl 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonylcarbamate (130 mg, crude).

[0387] LC-MS, M / Z(ESI):544.3[M+H] +

[0388] Step 2: Synthesis of 2-hydroxyethyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0389] Phenyl 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonylcarbamate (130 mg, 239 μmol) was dissolved in tetrahydrofuran (3 mL), and ethylene glycol (74.2 mg, 1.19 mmol) and triethylamine (72.5 mg, 717 μmol) were added, and then stirred at 25 ° C under nitrogen protection for 10 hours. After the reaction was completed, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified twice by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.05 volume formic acid (30%), B=acetonitrile; gradient: 40%-70%, 9 minutes) and (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume ammonia water (30%), B=acetonitrile; gradient: 0%-28%, 10 minutes), and dried to give 2-hydroxyethyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (11.7 mg, yield 9.49%).

[0390] LC-MS, M / Z(ESI):512.2[M+H] +

[0391] 1H NMR(400MHz CDCl3)δ:7.55(d,2H),7.15(d,2H),7.01(d,1H),6.91(d,1H),6.70(s,1H),5.48(q,1H),3.88(br d,2H),3.54(br d,2H),2.63(br d,2H),1.88(dt,1H),1.76(d,3H),0.94(d,6H)

[0392] Example 8: Preparation of target compound I-16

[0393] Tetrahydropyran-4-yl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0394] The synthetic route of target compound I-16 is as follows:

[0395] Referring to the preparation method of intermediate A2, 4-iodobenzyl bromide was used instead of 1-bromo-4-(bromomethyl)benzene to synthesize 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (intermediate A2).

[0396] Step 1: Synthesis of tetrahydropyran-3-yl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0397] Under an ice-water bath, 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (210.0 mg, 512.25 μmol) was dissolved in dichloromethane (10 mL), followed by the addition of N,N-diisopropylethylamine (331.02 mg, 2.56 mmol). 4-Tetrahydropyranylchloroformic acid (67.45 mg, 409.80 μmol) was then slowly added, and the reaction mixture was stirred under an ice-water bath for 2 hours. LCMS analysis indicated that most of the starting material had reacted completely, yielding the desired product. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 2). The organic phase was washed with brine (20 mL x 2) and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was then purified by preparative separation to give tetrahydropyran-4-yl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (127.0 mg, yield 45.55%, purity 98.85%).

[0398] LC-MS, M / Z(ESI):538.2[M+H] +

[0399] 1 H NMR(400MHz, CDCl3)δ9.09(s,1H),7.50(m,2H),7.19(m,2H),6.93(m,2H),6.76(s,1H),5.15(m,2H),4 .83(m,1H),3.74(s,2H),3.46(s,2H),2.71(d,J=6.5Hz,2H),2.06–1.57(m,5H),0.99(d,J=6.2Hz,6H).

[0400] Example 9: Preparation of target compound I-20

[0401] Methyl (5-isobutyl-3-(4-((2-(3-methyloxetan-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0402] The synthetic route of target compound I-20 is as follows:

[0403] Step 1: Synthesis of 2-(3-methyloxetane-3-yl)-1H-imidazole

[0404] To a solution of 3-methyloxetan-3-carbaldehyde (1.00 g, 9.99 mmol) and glyoxal (870 mg, 15.0 mmol) in ethanol (10 mL) was added aqueous ammonia (1.40 g, 9.99 mmol) at 0°C, and the reaction was stirred at 25°C for 10 hours. After completion of the reaction, the reaction solution was concentrated to yield 2-(3-methyloxetan-3-yl)-1H-imidazole (1.40 g, crude product).

[0405] LC-MS, M / Z(ESI):139.1[M+H] +

[0406] Step 2: Synthesis of 1-((4-bromophenyl)methyl)-2-(3-methyloxetane-3-yl)-1H-imidazole

[0407] To a solution of 1-bromo-4-(bromomethyl)benzene (1.50 g, 6.00 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (2.49 g, 18.0 mmol) and 2-(3-methyloxetan-3-yl)-1H-imidazole (995 mg, 7.20 mmol), followed by stirring at 50°C for 8 hours. After completion of the reaction, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was collected, washed with water (20 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was then separated and purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 10:1 to 0:1) to obtain 1-((4-bromophenyl)methyl)-2-(3-methyloxetan-3-yl)-1H-imidazole (800 mg, 43.4% yield).

[0408] LC-MS, M / Z(ESI):309.0[M+H] +

[0409] Step 3: Synthesis of N-(tert-butyl)-5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0410] Under nitrogen protection, (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (150 mg, 0.47 mmol) and 1-((4-bromophenyl)methyl)-2-(3-methyloxetan-3-yl)-1H-imidazole (144.43 mg, 0.47 mmol) were dissolved in 8 mL of toluene and 2 mL of ethanol. Sodium carbonate (199 mg, 1.88 mmol, 2 M) and tetrakistriphenylphosphine palladium (54.29 mg, 46.99 μmol) were added, and the atmosphere was replaced with nitrogen three times. The reaction mixture was stirred at 80°C for 4 hours. LCMS analysis indicated the disappearance of the starting material. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with brine (10 mL × 2) and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-2:1, gradient elution) to give N-(tert-butyl)-5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (150.0 mg, 63.63% yield).

[0411] LC-MS(ESI):502.4[M+H] +

[0412] Step 4: Synthesis of 5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0413] N-(tert-Butyl)-5-isobutyl-3-(4-((2-(3-methyloxetan-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (150 mg, 298.98 μmol) was dissolved in dichloromethane (3 mL) at 25°C, followed by the addition of trifluoroacetic acid (4.4 g, 38.5 mmol, 3 mL). The reaction mixture was stirred at 25°C for 16 hours. LCMS monitoring revealed the disappearance of the starting material, and the reaction solution was concentrated under reduced pressure to remove the solvent, affording the crude product, 5-isobutyl-3-(4-((2-(3-methyloxetan-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (133.0 mg, 99.95% yield).

[0414] LC-MS(ESI):446.3[M+1] +

[0415] Step 5: Synthesis of methyl (5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0416] 5-Isobutyl-3-(4-((2-(3-methyloxetan-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (120.0 mg, 215.44 μmol) was dissolved in dichloromethane (5 mL) under an ice-water bath, followed by the addition of N,N-diisopropylethylamine (55.69 mg, 430.88 μmol). Methyl chloroformate (20.36 mg, 215.44 μmol) was then slowly added, and the reaction mixture was stirred under an ice-water bath for 2 hours. LCMS analysis indicated that most of the starting material had reacted completely, yielding the desired product. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was washed with brine (20 mL x 2) and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was then purified by preparative separation to give methyl (5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (33.46 mg, yield 30.84%, purity 96.55%).

[0417] 1H NMR (400MHz, DMSO-d6) δ7.54(d,J=8.3Hz,2H),7.17–7.10(m,3H),7.02(s,1H),6.90(s,1H),5.04(s,2H),4.91( d,J=5.8Hz,2H),4.44(d,J=5.8Hz,2H),3.43(s,3H),2.67(s,2H),1.88-1.80(m,1H),1.58(s,3H),0.91(s,6H).

[0418] LC-MS(ESI):504.3.[M+H] +

[0419] Example 10: The preparation of the following compounds can be obtained by referring to the preparation methods of the above compounds.

[0420] 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:

[0421] Biological testing

[0422] The following test method may be used.

[0423] Test Example 1: Compound Binding to AT2R

[0424] 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.

[0425] Table 1. IC values ​​of compounds tested for AT2R binding activity 50 value

[0426] The experimental results show that the compound of the present invention has a strong binding effect with AT2R.

[0427] Test Example 2: CYP inhibition assay of compounds

[0428] Compounds were evaluated for their inhibitory activity against seven enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (midazolam), CYP2B6, and CYP2C8 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 the test product 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.

[0429] Table 2: CYP450 inhibition results of compounds

[0430] The experimental results show that the compounds of the present invention have a weak inhibitory effect on CYP enzymes and will not affect the normal metabolism of the body, indicating that the possibility of drug-drug interactions in the human body is low and the safety is high.

[0431] Test Example 3: Liver microsome stability test of the compound

[0432] 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 .

[0433] 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.

[0434] Test Example 4: Bidirectional permeability study of compounds in CACO-2 cells

[0435] Caco-2 cells were cultured at a rate of 1 × 10 5 cells / cm 2 Cells 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.

[0436] After the transport assay, the integrity of the Caco-2 cell monolayer was determined using the Lucifer Yellow exclusion assay. The results showed that the test compounds had good permeability, which facilitated compound absorption.

[0437] Test Example 5: IPF efficacy test of the compound in mice

[0438] 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).

[0439] The experimental steps include:

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 4. Dosing: The day of bleomycin injection is considered as day 0 of the study. The dosing schedule is as follows:

[0444] Table 3 Grouping and dosing regimen

[0445] a: The solvent is 5% DMSO + 10% solutol + 85% saline;

[0446] b: Bi-dose, once in the morning and once in the afternoon, approximately 6 hours apart; no medication in the morning of day 22.

[0447] 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.

[0448] 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 are as follows:

[0449] Table 4 Fibrosis scoring criteria

[0450] 7. Animal Euthanasia: All experimental animals will be euthanized by CO2 and cervical dislocation after the in vivo experiment.

[0451] 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.

[0452] 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.

[0453] 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. The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, X1 and X2 are independently selected from CRa and N; R1 is selected from halogen, C1-C6 haloalkyl and 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different; Each R3 is independently selected from hydrogen, I, Br, Cl, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 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 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl and -(C1-C6) alkylene-(3-6 membered heterocycloalkyl); the C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl and -(C1-C6) alkylene-(3-6 membered heterocycloalkyl) are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; Ra is selected from hydrogen, I, Br, Cl and C1-C3 alkyl; When X1 and X2 are both CRa, and Ra is hydrogen, one or two of the following conditions are met: (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different; (2) R4 is selected from C1-C6 alkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

2. The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, X1 and X2 are independently selected from CRa and N; R1 is selected from halogen, C1-C6 haloalkyl and 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl; R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituted by a substituent selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different; R3 is selected from hydrogen, I, Br, Cl, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 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 C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; Ra is selected from hydrogen, I, Br, Cl and C1-C3 alkyl; When X1 and X2 are both CH, one or two of the following conditions are met: (1) R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different; (2) R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

3. The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, X1 and X2 are independently selected from CRa and N; R1 is selected from halogen and C1-C6 haloalkyl; R2 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different; R3 is selected from hydrogen, I, Br, Cl, cyano, C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 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 C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different; Ra is selected from hydrogen, I, Br, Cl and C1-C3 alkyl; When X1 and X2 are both selected from CH, R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

4. The compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound is selected from the following structures: Wherein, R2 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different; R1 is selected from halogen and C1-C6 haloalkyl; R3, R4 and m have the meanings as defined in claim 1; Preferably, R2 is selected from C1-C3 alkyl and C1-C3 haloalkyl; More preferably, R2 is selected from methyl.

5. The compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound is selected from the following structures: wherein R4 is selected from C1-C6 alkyl, 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; R1, R3 and m have the meanings as defined in claim 1; and / or, R1 is selected from 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 C1-C6 alkyl groups; R3, R4 and m have the meanings as defined in any one of claims 1 to 3; Preferably, R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different.

6. The compound of formula I as described in any one of claims 1 to 5, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Said R1 is selected from halogen, C1-C3 haloalkyl and 3-6 membered heterocycloalkyl substituted by C1-C3 alkyl; The 3-6 membered heterocycloalkyl group contains 1, 2, or 3 identical or different heteroatoms; the heteroatoms are selected from N, O, and S; Preferably, the R1 is selected from halogen, C1-C3 haloalkyl and 4-6 membered heterocycloalkyl optionally substituted by C1-C3 alkyl, and the heteroatom is O; Preferably, the R1 is selected from a 4-6 membered heterocycloalkyl group optionally substituted by a C1-C3 alkyl group, and the heteroatom is O; Preferably, R1 is selected from Cl, Br, I, CH2F, CHF2, CF3 and a 4-membered heterocycloalkyl substituted with a methyl group; Preferably, the R1 is selected from Cl, CF3 and oxetane substituted with methyl; More preferably, the R1 is selected from Cl, CF3 and 7. The compound of formula (I) as described in any one of claims 1 to 4, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The R2 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl; the C1-C3 alkyl and C3-C4 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different; Preferably, R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl; R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; More preferably, said R2 is selected from hydrogen and methyl.

8. The compound of formula I as described in any one of claims 1 to 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The X1 and X2 are independently selected from CRa and N; the Ra is selected from hydrogen and halogen; Preferably, X1 and X2 are independently selected from CH and N; Preferably, X1 and X2 are independently selected from N.

9. The compound of formula (I) as described in any one of claims 1 to 4, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The R3 is selected from hydrogen, I, Br, Cl, cyano, C1-C3 alkyl and C3-C4 cycloalkyl; the C1-C3 alkyl and C3-C4 cycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C3-C5 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, I, Br, Cl, cyano, C1-C3 alkyl; the C1-C3 alkyl is independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: hydroxyl and halogen; Preferably, said R3 is selected from hydrogen, I, Br, Cl; Preferably, said R3 is selected from hydrogen, Cl; More preferably, said R3 is selected from hydrogen; Preferably, said R3 is selected from Cl.

10. The compound of formula I as described in any one of claims 1 to 5, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The R4 is selected from C1-C5 alkyl, C3-C5 cycloalkyl, 3-6-membered heterocycloalkyl and -(C1-C6)alkylene-(3-6-membered heterocycloalkyl); the C1-C5 alkyl, C3-C5 cycloalkyl, 3-6-membered heterocycloalkyl and -(C1-C6)alkylene-(3-6-membered heterocycloalkyl) are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6-membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; The 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) contain 1, 2, 3 identical or different heteroatoms; the heteroatoms are selected from N, O, S, and the S atom may be in the form of an oxide thereof; Preferably, the R4 is selected from C1-C5 alkyl, C3-C5 cycloalkyl and 3-6 membered heterocycloalkyl; the C1-C5 alkyl, C3-C5 cycloalkyl and 3-6 membered heterocycloalkyl are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; The 3-6 membered heterocycloalkyl group contains 1, 2, or 3 identical or different heteroatoms; the heteroatoms are selected from N, O, and S, and the S atom may be in the form of an oxide thereof; Preferably, the R4 is selected from 3-6 membered heterocycloalkyl, C1-C5 alkyl optionally substituted by -OH, -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) optionally substituted by C1-C3 alkyl; the heteroatom is O; Preferably, the R4 is selected from 4-6 membered heterocycloalkyl, C1-C5 alkyl optionally substituted by -OH, -(C1-C3)alkylene-(4-6 membered heterocycloalkyl) optionally substituted by C1-C3 alkyl; the heteroatom is O; Preferably, the R4 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, oxetane, azetidine, tetrahydrofuran, tetrahydropyrrole, tetrahydropyran, hexahydropyridine, oxazinane, thiazinane; the R4 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-6 membered heterocycloalkyl; Preferably, the R4 is selected from methyl, Butyl, tetrahydrofuran, tetrahydropyran, More preferably, the R4 is selected from methyl, Butyl, and / or, at least one of said R1 and R4 contains a 3-6 membered heterocycloalkyl group, said 3-6 membered heterocycloalkyl group being independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl group; when there are multiple substituents, said substituents are the same or different; Preferably, one of R1 and R4 contains a 3-6 membered heterocycloalkyl group, and the 3-6 membered heterocycloalkyl group is independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; Preferably, R1 is a 3-6 membered heterocycloalkyl group optionally substituted by a C1-C3 alkyl group, wherein the heteroatom is O; R4 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different; or The R1 is halogen or C1-C6 haloalkyl; the R4 is selected from 3-6 membered heterocycloalkyl or -(C1-C6)alkylene-(3-6 membered heterocycloalkyl); the 3-6 membered heterocycloalkyl and -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) are independently substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different; More preferably, the R1 is a 3-6 membered heterocycloalkyl group optionally substituted by a C1-C3 alkyl group, and the heteroatom is O; The R4 is a C1-C6 alkyl group, and the C1-C6 alkyl group is substituted by 0 or 1 substituent selected from the following: halogen, hydroxyl; More preferably, said R1 is halogen or C1-C6 haloalkyl; The R4 is selected from 4-6 membered heterocycloalkyl, or -(C1-C3)alkylene-(4-6 membered heterocycloalkyl); the -(C1-C3)alkylene-(4-6 membered heterocycloalkyl) is independently substituted by 0 or 1 substituent selected from the following: halogen, C1-C3 alkyl.

11. The compound of formula (I) according to claim 5, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R4 is selected from C1-C6 alkyl and 3-6 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: 3-6 membered heterocycloalkyl; the 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different; Preferably, R4 is selected from C1-C4 alkyl and 3-6-membered heterocycloalkyl substituted by 3-6-membered heterocycloalkyl; the 3-6-membered heterocycloalkyl contains 1, 2, 3 identical or different heteroatoms; the heteroatoms are selected from N, O, S, and the S atom may be in the form of an oxide thereof; Preferably, R4 is selected from 4-6 membered heterocycloalkyl, or -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) optionally substituted by C1-C3 alkyl; the heteroatom is O; Preferably, R4 is selected from C1-C3 alkyl; the C1-C3 alkyl is substituted by a 3-6 membered heterocycloalkyl and a C1-C3 alkyl; Preferably, R4 is selected from 4-6 membered heterocycloalkyl, wherein the heteroatom is O; Preferably, R4 is selected from -(C1-C6)alkylene-(3-6 membered heterocycloalkyl), wherein the heteroatom is O; wherein the -(C1-C6)alkylene-(3-6 membered heterocycloalkyl) is substituted by C1-C3 alkyl; More preferably, R4 is selected from tetrahydrofuran, tetrahydropyran, More preferably, R4 is selected from and / or, R1 is selected from 3-6 membered heterocycloalkyl; said 3-6 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: Halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different.

12. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compounds include:

13. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compounds include:

14. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a compound according to any one of claims 1 to 13, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof; and a pharmaceutically acceptable carrier.

15. Use of the compound according to any one of claims 1 to 13, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to claim 14, 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 a medicament, pharmaceutical composition or formulation as 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.

16. A method for treating a disease, characterized in that: Such diseases include diseases in which endogenous production of Ang II is insufficient, diseases in which increased action of Ang II is desired or necessary, and / or diseases in which AT2R is expressed and stimulation of its production is desired or necessary; The method comprises administering a therapeutically effective amount of a compound, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition according to claim 14 to a person suffering from or susceptible to the disease.

17. The use according to claim 15 or the method according to claim 16, 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.

18. The use according to claim 15 or the method according to claim 16, 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.

19. The use according to claim 15 or the method according to claim 16, 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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