Thiophene sulfonyl carbamate as AT2R agonist and application thereof

Abstract

The invention provides a compound as shown in a formula I, and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. These compounds useful as agonists of AT2R, # imgabs0

Description

[0001] Priority information

[0002] This application claims the priority and rights 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 the abnormal repair of alveolar epithelial cells after injury, which causes the proliferation of lung fibroblasts to transform into myofibroblasts, excessive secretion of extracellular matrix, collagen deposition, changes in alveolar structure, and ultimately fibrosis. Its pathogenesis has not yet been fully clarified. Current studies believe that it is closely related to oxidative stress, inflammatory response, and the regulation of the renin-angiotensin-aldosterone system (RAAS) by body fluids. It is currently believed that the RAAS system plays an important role in the process of pulmonary fibrosis. Angiotensin converting enzyme (ACE) can hydrolyze angiotensin I (Ang I) into angiotensin II (Ang II), which plays an important role in the occurrence and development of various inflammations.

[0005] In humans, two major types of AngⅡ receptors have been identified, named AngⅡ type 1 receptor (AT1R) and AngⅡ type 2 receptor (AT2R). AngⅡ has shown physiological effects in many organs, including kidneys, adrenal glands, heart, blood vessels, brain, gastrointestinal tract, and reproductive organs, such as regulating blood pressure, body fluid and electrolyte balance. The effects of AngⅡ are regulated by the balance of expression of two G protein-coupled receptors (GPCRs), AT1R and AT2R. AT1R is expressed throughout the life cycle and is mainly responsible for regulating blood pressure. Its blockers are widely used as antihypertensive drugs in clinical practice. AT1R controls most of the physiological effects of AngⅡ. AT2R is mainly expressed in embryonic tissues and is related to blood pressure regulation, nerve growth, pain control, and myocardial regeneration. Drugs targeting AT2R can improve cardiovascular function and relieve neuropathic pain. However, under pathological conditions, the expression of AT2R is significantly increased, 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, and multiple organ failure (see International Patent Application WO 99 / 43339).

[0007] There remains a need for potent and / or selective AT2R agonists that would be useful in the above-mentioned diseases. Summary of the invention

[0008] The object of the present invention is to provide a thiophenesulfonylcarbamate as an AT2R agonist and its use. The thiophenesulfonylcarbamate has a structure as shown in the first aspect of the present invention. The thiophenesulfonylcarbamate compound can be used to prepare a drug, a pharmaceutical composition or a preparation for treating and / or preventing a disease or condition associated with AT2R; or to treat and / or prevent a disease or condition associated with AT2R.

[0009] In the first aspect of the present invention, there is provided a compound of formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

[0010]

[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); 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;

[0017] Ra 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, hydroxyl, 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, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0023]

[0024] Wherein, X1 and X2 are independently selected from CRa and N;

[0025] 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;

[0026] 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;

[0027] 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;

[0028] m is selected from 1, 2, 3 and 4;

[0029] 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;

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

[0031] When X1 and X2 are both CH, one or two of the following conditions are met:

[0032] (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;

[0033] (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.

[0034] 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:

[0035]

[0036] Wherein, X1 and X2 are independently selected from CRa and N;

[0037] 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;

[0038] 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;

[0039] 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;

[0040] m is selected from 1, 2, 3 and 4;

[0041] 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;

[0042] Ra is selected from hydrogen, I, Br, Cl and C1-C3 alkyl;

[0043] When X1 and X2 are both CH, one or two of the following conditions are met:

[0044] (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;

[0045] (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.

[0046] 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:

[0047]

[0048] Wherein, X1 and X2 are independently selected from CRa and N;

[0049] R1 is selected from halogen and C1-C6 haloalkyl;

[0050] 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;

[0051] 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;

[0052] m is selected from 1, 2, 3 and 4;

[0053] 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;

[0054] Ra is selected from hydrogen, halogen and C1-C3 alkyl;

[0055] When X1 and X2 are both CH, one or two of the following conditions are met:

[0056] (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;

[0057] (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.

[0058] 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:

[0059]

[0060] Wherein, X1 and X2 are independently selected from CRa and N;

[0061] R1 is selected from halogen and C1-C6 haloalkyl;

[0062] 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;

[0063] 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;

[0064] m is selected from 1, 2, 3 and 4;

[0065] 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;

[0066] Ra is selected from hydrogen, I, Br, Cl and C1-C3 alkyl;

[0067] When X1 and X2 are both CH, one or two of the following conditions are met:

[0068] (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;

[0069] (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.

[0070] 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:

[0071]

[0072] Wherein, X1 and X2 are independently selected from CRa and N;

[0073] R1 is selected from halogen and C1-C6 haloalkyl;

[0074] 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;

[0075] 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;

[0076] m is selected from 1, 2, 3 and 4;

[0077] 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;

[0078] Ra is selected from hydrogen, halogen and C1-C3 alkyl;

[0079] 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.

[0080] 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:

[0081]

[0082] Wherein, X1 and X2 are independently selected from CRa and N;

[0083] R1 is selected from halogen and C1-C6 haloalkyl;

[0084] 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;

[0085] 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;

[0086] m is selected from 1, 2, 3 and 4;

[0087] 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;

[0088] Ra is selected from hydrogen, I, Br, Cl and C1-C3 alkyl;

[0089] 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.

[0090] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0091]

[0092] 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;

[0093] 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;

[0094] R3, R4 and m are as defined in the first aspect of the present invention.

[0095] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0096]

[0097] 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;

[0098] R1 is selected from halogen and C1-C6 haloalkyl;

[0099] R3, R4 and m are as defined in the first aspect of the present invention.

[0100] 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.

[0101] In a preferred embodiment of the present invention, in the compound represented by formula II, R2 is selected from methyl.

[0102] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0103]

[0104] 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;

[0105] R1, R3 and m are as defined in the first aspect of the present invention.

[0106] 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.

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

[0108]

[0109] 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;

[0110] R1, R3 and m are as described in the first aspect of the present invention.

[0111] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0112]

[0113] wherein 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;

[0114] R3, R4 and m are as defined in the first aspect of the invention.

[0115] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0116]

[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 defined 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]

[0121] 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;

[0122] R1, R3 and m are as described in the first aspect of the present invention.

[0123] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0124]

[0125] wherein 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;

[0126] R3, R4 and m are as defined in the first aspect of the invention.

[0127] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0128]

[0129] 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;

[0130] R1, R3 and m are as defined in the first aspect of the present invention.

[0131] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0132]

[0133] 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;

[0134] R1, R3 and m are as described in the first aspect of the present invention.

[0135] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0136]

[0137] wherein 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;

[0138] R3, R4 and m are as defined in the first aspect of the invention.

[0139] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0140]

[0141] 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;

[0142] R1, R3 and m are as defined in the first aspect of the present invention.

[0143] 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.

[0144] In a preferred embodiment of the present invention, 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.

[0145] In a preferred embodiment of the present invention, the R1 is selected from 4-6 membered heterocycloalkyl optionally substituted by C1-C3 alkyl, and the heteroatom is O.

[0146] In a preferred embodiment of the present invention, R1 is selected from Cl, Br, I, CH2F, CHF2, CF3 and a 4-membered heterocycloalkyl substituted with a methyl group.

[0147] In a preferred embodiment of the present invention, the R1 is selected from Cl, CF3 and oxetanyl substituted with methyl.

[0148] In a preferred embodiment of the present invention, R1 is selected from Cl, CF3 and

[0149] In a preferred embodiment of the present invention, the R1 is selected from halogen and C1-C3 haloalkyl.

[0150] In a preferred embodiment of the present invention, said R1 is selected from Cl, Br, I, CH2F, CHF2 and CF3.

[0151] In a preferred embodiment of the present invention, said R1 is selected from Cl and CF3.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] In a preferred embodiment of the present invention, said R2 is selected from hydrogen and methyl.

[0156] 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.

[0157] In a preferred embodiment of the present invention, X1 is selected from CH or N, and X2 is selected from N.

[0158] In a preferred embodiment of the present invention, X1 and X2 are independently selected from CH and N.

[0159] In a preferred embodiment of the present invention, X1 and X2 are independently selected from N.

[0160] 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, and 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.

[0161] 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.

[0162] 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.

[0163] 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;

[0164] m is selected from 1, 2, 3 and 4.

[0165] 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;

[0166] m is selected from 1, 2, 3 and 4.

[0167] 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;

[0168] m is selected from 1, 2, 3 and 4.

[0169] 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;

[0170] m is selected from 1, 2, 3 and 4.

[0171] In a preferred embodiment of the present invention, said R3 is selected from hydrogen, I, Br, Cl.

[0172] In a preferred embodiment of the present invention, said R3 is selected from hydrogen and Cl.

[0173] In a preferred embodiment of the present invention, said R3 is selected from hydrogen.

[0174] In a preferred embodiment of the present invention, said R3 is selected from Cl.

[0175] In a preferred embodiment of the present invention, 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;

[0176] 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.

[0177] In a preferred embodiment of the present invention, 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;

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] In a preferred embodiment of the present invention, said R4 is selected from methyl, Butyl, tetrahydrofuran, tetrahydropyran,

[0183] In a preferred embodiment of the present invention, said R4 is selected from methyl, Butyl,

[0184] 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.

[0185] In a preferred embodiment of the present invention, the 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 heteroatom is selected from N, O, S, and the S atom can be in the form of its oxide.

[0186] 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.

[0187] In a preferred embodiment of the present invention, the R4 is selected from C1-C3 alkyl; the C1-C3 alkyl is substituted by 3-6 membered heterocycloalkyl and C1-C3 alkyl.

[0188] In a preferred embodiment of the present invention, the R4 is selected from 4-6 membered heterocycloalkyl, and the heteroatom is O.

[0189] In a preferred embodiment of the present invention, 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,

[0190] In a preferred embodiment of the present invention, said R4 is selected from

[0191] 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.

[0192] In a preferred embodiment of the present invention, the R4 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and the R4 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0193] In a preferred embodiment of the present invention, said R4 is selected from methyl, ethyl, Butyl.

[0194] In a preferred embodiment of the present invention, said R4 is selected from methyl, Butyl.

[0195] 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.

[0196] 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.

[0197] 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 following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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:

[0202] (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 following: halogen, oxo (=O), hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0203] (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, hydroxyl, C1-C3 alkyl, C3-C5 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0204] (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.

[0205] 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:

[0206] (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;

[0207] (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.

[0208] In a preferred embodiment of the present invention, when X1 and X2 are both CH, one or two of the following conditions are satisfied:

[0209] (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;

[0210] (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 an oxide thereof.

[0211] In a preferred embodiment of the present invention, when X1 and X2 are both CH, R1 is selected from 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.

[0212] 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 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.

[0213] In a preferred embodiment of the present invention, when X1 and X2 are simultaneously selected from CH; R2 is selected from C1-C3 alkyl and C1-C3 haloalkyl.

[0214] In a preferred embodiment of the present invention, when X1 and X2 are both selected from CH, R2 is selected from methyl.

[0215] In a preferred embodiment of the present invention, when X1 and X2 are CH at the same time; 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.

[0216] 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.

[0217] In a preferred embodiment of the present invention, when X1 and X2 are CH at the same time; R4 is selected from C1-C4 alkyl and 3-6-membered heterocycloalkyl substituted by 1, 2, 3 or 4 3-6-membered heterocycloalkyl; the 3-6-membered heterocycloalkyl contains 1, 2, 3 identical or different heteroatoms; the heteroatom is selected from N, O, S, and the S atom can be in the form of its oxide.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from tetrahydrofuran, tetrahydropyran,

[0223] In a preferred embodiment of the present invention, when X1 and X2 are both CH; R4 is selected from

[0224] In a preferred embodiment of the present invention, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that the compound comprises:

[0225]

[0226]

[0227] In a preferred embodiment of the present invention, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that the compound comprises:

[0228]

[0229]

[0230] The second aspect of the present invention provides a pharmaceutical composition, comprising the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.

[0231] In a third aspect of the present invention, the use of the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, the use comprising:

[0232] As an AT2R agonist;

[0233] and / or, preventing and / or treating diseases in which endogenous production of Ang II is insufficient;

[0234] and / or, preventing and / or treating diseases in which an increased effect of Ang II is desired or required;

[0235] 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.

[0236] Provided is a compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, which is expected to be used to treat diseases of the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive system or central nervous system (CNS).

[0237] 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 enteritis, 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, acute colic, dysphagia, nausea, vomiting, and Sjögren's syndrome.

[0238] 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.

[0239] Kidney diseases that should be mentioned include renal failure, nephritis, and renal hypertension.

[0240] Eye diseases that should be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microvascularization.

[0241] Female reproductive system diseases that should be mentioned include disorders of the ovulatory mechanism.

[0242] 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, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic damage, erectile dysfunction, and neointimal hyperplasia.

[0243] CNS diseases that should be mentioned include cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, and cerebral infarction.

[0244] The compound shown in formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect can also be used for the regulation of growth metabolism and proliferation, for example, for the treatment of hypertrophy, prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, nerve regeneration, ulcer healing, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer (such as gastrointestinal cancer, lung cancer, etc.), apoptosis, tumors (generally), hyperplastic diabetes, nerve damage and organ rejection.

[0245] The compound of formula I described in the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect, is suitable for the treatment and / or preventive treatment of the above-mentioned diseases.

[0246] 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 action of Ang II, and / or a disease in which AT2R is expressed and stimulation is desired or necessary, the method comprising administering to a person suffering from or susceptible to the disease a therapeutically effective amount of 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.

[0247] 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.

[0248] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

[0249] Terms and Definitions

[0250] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combination and combination shall fall within the scope recorded in the specification of this application.

[0251] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

[0252] 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 form used in this specification and claims includes the plural form of the referred thing. It should also be noted that unless otherwise stated, the "or" and "or" used mean "and / or". In addition, the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.

[0253] Definitions of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THE D." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. The above-mentioned techniques and methods can usually be implemented according to the descriptions in the multiple summaries and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0254] 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 if the formula were written from right to left. For example, CH2O is equivalent to OCH2. 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.

[0255] The section headings used herein are only for the purpose of organizing the article and should not be interpreted 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, operating manuals and papers, are incorporated herein by reference in their entirety.

[0256] In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0257] When the numerical range described in the specification and claims of this application is understood as an "integer", it should be understood that the two endpoints of the range and each integer in the range are recorded. For example, "an integer from 1 to 6" should be understood as recording each integer of 0, 1, 2, 3, 4, 5 and 6.

[0258] In this application, "AT2 receptor" and "AT2R" have the same definition.

[0259] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, iodine.

[0260] As used herein, the term "amino" by itself or as part of another substituent refers to -NH2.

[0261] As used herein, the term "hydroxy" by itself or as part of another substituent refers to -OH.

[0262] As used herein, the term "cyano" by itself or as part of another substituent refers to -CN.

[0263] As used herein, the term "alkyl" means a straight or branched hydrocarbon chain group consisting only of carbon atoms 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, when alone or as part of other substituents. 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 natural abundance alkyl groups rich in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" means 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.

[0264] The term "C1-C6 alkyl" when used 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. The alkyl radical is, for example, 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 the like or isomers thereof. In particular, such radicals have 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, methylene, ethyl, n-propyl or isopropyl.

[0265] When alone or as part of other substituents, the term "C1-C6 alkylene" should be understood to mean a straight-chain divalent hydrocarbon group having 1 to 6 carbon atoms or a branched divalent hydrocarbon group having 3 to 6 carbon atoms, unless otherwise specified, such as methylene, ethylene, propylene, isopropylene, 1-methylpropylene, butylene, etc. When alone or as part of other substituents, the term "oxo" means that two hydrogens on a methylene group are replaced by oxygen, that is, a methylene group is replaced by a carbonyl group, representing =O.

[0266] 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 cycloalkyl groups 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 systems. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0267] "Halocycloalkyl" by itself or as part of another substituent refers to a cycloalkyl as described above wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl are replaced by fluorine, chlorine, bromine or iodine.

[0268] "Haloalkyl" when used alone or as part of other substituents refers to saturated aliphatic hydrocarbon groups 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, 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.

[0269] The term "3-6 membered heterocycloalkyl" when used alone or as part of other substituents shall be 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, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl include, but are not limited to, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl. When used alone or as part of other substituents, the term "substituted" 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 state of the particular atom is normal and the substituted compound is stable.

[0270] In the present application, "optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

[0271] In the present 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 possible substituents. For example, "aryl is optionally substituted by 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxyl, 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, hydroxyl, C 1-6 The term "alkyl" refers to an alkyl group, and the description includes both substituted and unsubstituted aryl groups.

[0272] In the present 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 suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0273] "Pharmaceutically acceptable acid addition salts" refers 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" refers 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. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.

[0274] The term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid. The acid includes the inorganic acid or organic acid described in the present application.

[0275] 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.

[0276] Depending on the choice of starting materials and methods, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, 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 multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify 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.

[0277] When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

[0278] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics 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.

[0279] In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0280] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, 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.

[0281] The term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

[0282] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0283] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up 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( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0284] 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 can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and / or adhesion.

[0285] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0286] (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;

[0287] (ii) inhibiting a disease or condition, i.e. arresting its development;

[0288] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0289] (iv) alleviating the symptoms caused by the disease or condition.

[0290] Beneficial Effects

[0291] The inventors have unexpectedly developed a thiophenesulfonylcarbamate compound as an AT2R agonist after extensive and in-depth research, and the compound has the structure shown in the present invention. The thiophenesulfonylcarbamate compound of the present invention can prevent or treat diseases or conditions related to AT2 receptors, exhibits excellent pharmacokinetic properties, and has high safety and drug properties. DETAILED DESCRIPTION

[0292] The present invention is 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. On the basis of a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are usually 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 solution of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention.

[0293] This application has the following definitions:

[0294] Symbol or unit:

[0295] IC 50 : Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0296] 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

[0297] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0298] RT: retention time

[0299] Reagents:

[0300] DCM: dichloromethane

[0301] DMF: N,N-dimethylformamide

[0302] DIPEA: N,N-diisopropylethylamine

[0303] EA: Ethyl acetate

[0304] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0305] MeOH: Methanol

[0306] PE: Petroleum ether

[0307] Toluene: Toluene

[0308] THF: Tetrahydrofuran

[0309] XPhos Pd G4: Methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)

[0310] Test method:

[0311] LCMS: Liquid chromatography-mass spectrometry

[0312] TLC: Thin layer chromatography

[0313] Intermediate A1: Preparation of Intermediate A1

[0314] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid

[0315]

[0316] The synthetic route of intermediate A1 is as follows:

[0317]

[0318] Step 1: Synthesis of N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide

[0319]

[0320] Zinc chloride (20 mL, 1 mol / L THF solution) and isobutyl magnesium chloride (13 mL, 2 mol / L) were added to a 100 mL three-necked flask, stirred at room temperature for 10 minutes under N2 atmosphere, and then 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, and the reaction was heated and stirred at 120°C for 1 hour. TLC (PE:EA (V / V) = 3:1) spot plate showed that the raw material completely disappeared and obvious target spots were generated. The reaction solution was filtered, the obtained mother liquor was spin-dried and mixed, and separated and purified by 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, yield 82.3%).

[0321] 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)

[0322] Step 2: Synthesis of (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid

[0323]

[0324] In a 50mL three-necked flask, add N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (2.0g, 7.26mmol) and dissolve it in THF (20mL). Add n-butyl lithium (7.3mL, 2.5mol / L n-hexane) solution dropwise at room temperature under N2 atmosphere. After stirring for half an hour, add triisopropyl borate (2.05g, 10.89mmol) to the reaction system. At this time, solids slowly precipitate in the solution, and the solution is light yellow. The reaction system is stirred overnight at room temperature. TLC (PE:EA (V / V) = 3:1) spot plate monitoring shows that the raw material reacts completely and new spots of the target compound are generated. Slowly add HCl aqueous solution (5.0 mL, 2.0 mol / L) to the reaction solution to adjust the pH to 2, add 30 mL of water to dilute, extract with ethyl acetate (50 mL×2), wash the organic phase with saturated brine (30 mL), dry the obtained organic phase with anhydrous sodium sulfate and filter, spin dry the mother liquor, mix the sample, separate and purify 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)boric acid (A1) (1.8 g, yield 77.6%).

[0325] Intermediate A2: Preparation of Intermediate A2

[0326] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide

[0327]

[0328] The synthetic route of intermediate A2 is as follows:

[0329]

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

[0331]

[0332] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-chloro-1H-imidazole (410 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1.66 g, 12.0 mmol) was added, and the mixture was reacted at 55°C for 1 hour. The reaction solution was poured into water (50 mL), extracted three times with ethyl acetate (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromobenzyl)-2-chloro-1H-imidazole (900 mg, yield 82.8%).

[0333] LC-MS, M / Z(ESI):271.0[M+H] +

[0334] Step 2: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl-3-yl)-N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide

[0335]

[0336] (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boric acid (400 mg, 1.20 mmol) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), 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 for 2 hours under nitrogen protection. The reaction solution was concentrated to obtain a crude product, which was separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl-3-yl)-N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (510 mg, yield 88.5%).

[0337] LC-MS, M / Z(ESI):467.4[M+H] +

[0338] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl-3-yl)-5-isobutylthiophene-2-sulfonamide

[0339]

[0340] 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), then extracted three times with dichloromethane (20 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1-1:1) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl-3-yl)-5-isobutylthiophene-2-sulfonamide (A2) (400 mg, yield 90.6%).

[0341] LC-MS, M / Z(ESI):410.3[M+H] +

[0342] Example 1: Preparation of target compound I-2

[0343] Butyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0344]

[0345] The synthetic route of the target compound I-2 is as follows:

[0346]

[0347] Step 1: Synthesis of 1-(1-(4-bromophenyl)ethyl)-2-chloro-1H-imidazole

[0348]

[0349] 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), and potassium carbonate (1.57 g, 11.4 mmol) was added, and the mixture was reacted at 50°C for 2 hours. The reaction solution was poured into water (30 mL), extracted three times with ethyl acetate (30 mL), and the organic phase was collected, washed five times with water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily compound 1-(1-(4-bromophenyl)ethyl)-2-chloro-1H-imidazole (1.00 g, yield 92.4%).

[0350] LC-MS, M / Z(ESI):286.9[M+H] +

[0351] Step 2: Synthesis of N-(tert-butyl)-3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0352]

[0353] Dissolve (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (400 mg, 1.25 mmol) in tetrahydrofuran (4 mL) and water (2 mL), add 1-(1-(4-bromophenyl)ethyl)-2-chloro-1H-imidazole (358 mg, 1.25 mmol), potassium phosphate (1.33 g, 6.26 mmol), XPhos Pd G4 (108 mg, 125 μmol), and then stir 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. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1-1:1) to obtain compound N-(tert-butyl)-3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (200 mg, yield 33.3%).

[0354] LC-MS, M / Z(ESI):480.1[M+H] +

[0355] Step 3: Synthesis of 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0356]

[0357] 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 by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1-1:1) to obtain compound 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonamide) (170 mg, crude product).

[0358] LC-MS, M / Z(ESI):424.1[M+H] +

[0359] Step 4: Synthesis of butyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0360]

[0361] 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 hours. 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 of formic acid (30%), B = acetonitrile; gradient: 65%-95%, 7 minutes) to give the product (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamic acid butyl ester (15.8 mg, yield 18.3%).

[0362] LC-MS, M / Z(ESI):524.2[M+H] +

[0363] 1 H 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)

[0364] Example 2: Preparation of target compound I-6

[0365] Butyl (3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0366]

[0367] The synthetic route of the target compound I-6 is as follows:

[0368]

[0369] Step 1: Synthesis of 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyridine

[0370]

[0371] 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), and potassium carbonate (2.95 g, 21.3 mmol) was added, and the reaction was stirred at 70 ° C for 2 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), and then extracted three times with ethyl acetate (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Then, it was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:0-3:1) to obtain 5-bromo-2-((2-chloro-1H-imidazole-1-yl)methyl)pyridine (2.00 g, yield 75.8%).

[0372] LC-MS, M / Z(ESI):273.8[M+H] +

[0373] Step 2: Synthesis of N-(tert-butyl)-3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide

[0374]

[0375] Dissolve (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boric acid (400 mg, 1.25 mmol) in tetrahydrofuran (4 mL) and water (1 mL), add 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyridine (341 mg, 1.25 mmol), potassium phosphate (798 mg, 3.76 mmol), XPhos Pd G4 (108 mg, 125 μmol), and then stir at 60 ° C under nitrogen protection for 1 hour. After the reaction was completed, 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 obtain a crude product, which was then separated and purified using a silica gel column (petroleum ether: ethyl acetate (V / V) = 1:0-2:1) to obtain N-(tert-butyl)-3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide (500 mg, yield 85.4%).

[0376] LC-MS, M / Z(ESI):467.1[M+H] +

[0377] Step 3: Synthesis of 3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophene-2-sulfonamide

[0378]

[0379] 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 the reaction was stirred at 40 ° C for 10 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), and then extracted three times with dichloromethane (30 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Then, it was separated and purified by 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, yield 95.5%).

[0380] LC-MS, M / Z(ESI):411.0[M+H] +

[0381] Step 4: Synthesis of butyl (3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0382]

[0383] 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, N,N-diisopropylethylamine (94.4 mg, 730 μmol) was added, and the reaction was stirred at 0°C for 0.5 hours. After the reaction was completed, 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 (3-(6-((2-chloro-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (51.0 mg, yield 27.3%).

[0384] LC-MS, M / Z(ESI):511.2[M+H]+

[0385] 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)

[0386] Example 3: Preparation of target compound I-7

[0387] Butyl (3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0388]

[0389] The synthetic route of the target compound I-7 is as follows:

[0390]

[0391] Step 1: Synthesis of 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidine

[0392]

[0393] 2-Chloro-1H-imidazole (407 mg, 3.97 mmol) and potassium carbonate (1.10 g, 7.94 mmol) were added to a solution of 5-bromo-2-(bromomethyl)pyrimidine (1.00 g, 3.97 mmol) in acetonitrile (15.0 mL), and the reaction was stirred at 25 ° C for 10 hours. After the reaction was completed, 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-imidazole-1-yl)methyl)pyrimidine.

[0394] LC-MS, M / Z(ESI):274.8[M+H] +

[0395] Step 2: Synthesis of N-(tert-butyl)-3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide

[0396]

[0397] Dissolve (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boric acid (300 mg, 940 μmol) in tetrahydrofuran (5 mL) and water (1 mL), add 5-bromo-2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidine (231 mg, 846 μmol), potassium phosphate (598 mg, 2.82 mmol), XPhos Pd G4 (80.9 mg, 94.0 μmol), and then stir at 60 ° C under nitrogen protection for 5 hours. After the reaction is completed, the reaction solution is poured into water (10 mL), and then extracted three times with ethyl acetate (10 mL). The organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which is then separated and purified on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1 to 1:1) to obtain N-(tert-butyl)-3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide.

[0398] LC-MS, M / Z(ESI):468.3[M+H] +

[0399] Step 3: Synthesis of 3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophene-2-sulfonamide

[0400]

[0401] 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 the reaction was completed, the reaction solution was poured into water (20 mL), and then extracted three times with dichloromethane (20 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Then, it was separated and purified by 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.

[0402] LC-MS, M / Z(ESI):412.2[M+H] +

[0403] Step 4: Synthesis of butyl (3-(2-((2-chloro-1H-imidazol-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0404]

[0405] 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, N,N-diisopropylethylamine (94.1 mg, 728 μmol) and butyl chloroformate (53.7 mg, 393 μmol) were added, 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 of formic acid (30%), B=acetonitrile; gradient: 48%-78%, 9 minutes) to obtain (3-(2-((2-chloro-1H-imidazole-1-yl)methyl)pyrimidin-5-yl)-5-isobutylthiophen-2-yl)sulfonylcarbamate.

[0406] LC-MS, M / Z(ESI):512.2[M+H] +

[0407] 1 H 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).

[0408] Example 4: Preparation of target compound I-14

[0409] 3-Methyloxetan-3-ylmethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0410]

[0411] The synthetic route of the target compound I-14 is as follows:

[0412]

[0413] Step 1: Synthesis of phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0414]

[0415] Under nitrogen protection, diphenyl carbonate (470 mg, 2.20 mmol) and potassium carbonate (405 mg, 2.93 mmol) were added 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), and the reaction was stirred at 50°C for 1 hour. After the reaction was completed, the reaction solution was poured into water (20 mL), and then extracted three times with ethyl acetate (20 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-yl)sulfonylcarbamate.

[0416] LC-MS, M / Z(ESI):530.1[M+H] +

[0417] Step 2: Synthesis of 3-methyloxetane-3-ylmethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0418]

[0419] 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), triethylamine (145 mg, 1.44 mmol) and (3-methyloxacycloalkane-3-yl)methanol (482 mg, 4.72 mmol) were added, and the reaction was stirred at 25 ° C for 10 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), and then extracted three times with ethyl acetate (10 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a 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 obtain 3-methyloxetane-3-ylmethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate.

[0420] LC-MS, M / Z(ESI):538.2[M+H] +

[0421] 1H 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).

[0422] Example 5: Preparation of target compound I-15A

[0423] (3S)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate tetrahydrofuran-3-yl ester

[0424]

[0425] The synthetic route of the target compound I-15A is as follows:

[0426]

[0427] Step 1: Synthesis of tetrahydrofuran-3-yl (3S)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0428]

[0429] 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), triethylamine (143 mg, 1.41 mmol) and (S)-3-hydroxytetrahydrofuran (416 mg, 4.72 mmol) were added, and the reaction was stirred at 25 ° C for 10 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), and then extracted three times with ethyl acetate (10 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a 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)sulfonylcarbamic acid tetrahydrofuran-3-yl ester.

[0430] LC-MS, M / Z(ESI):524.2[M+H] +

[0431] 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).

[0432] Example 6: Preparation of target compound I-15B

[0433] (3R)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate tetrahydrofuran-3-yl ester

[0434]

[0435] The synthetic route of the target compound I-15B is as follows:

[0436]

[0437] Step 1: Synthesis of (3R)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate tetrahydrofuran-3-yl ester

[0438]

[0439] 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), triethylamine (143 mg, 1.41 mmol) and (R)-3-hydroxytetrahydrofuran (416 mg, 4.72 mmol) were added, and the reaction was stirred at 25 ° C for 10 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), and then extracted three times with ethyl acetate (10 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a 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 obtain (3R)(3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamic acid tetrahydrofuran-3-yl ester.

[0440] LC-MS, M / Z(ESI):524.2[M+H] +

[0441] 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).

[0442] Example 7: Preparation of target compound I-1

[0443] 2-Hydroxyethyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0444]

[0445] The synthetic route of the target compound I-1 is as follows:

[0446]

[0447] Step 1: Synthesis of phenyl 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonylcarbamate

[0448]

[0449] 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), and then potassium carbonate (65.2 mg, 472 μmol) and diphenyl carbonate (75.8 mg, 354 μmol) were added, and the reaction was stirred at 20°C for 10 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain a crude product of phenyl 3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophene-2-sulfonylcarbamate (130 mg, crude product).

[0450] LC-MS, M / Z(ESI):544.3[M+H] +

[0451] Step 2: Synthesis of 2-hydroxyethyl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0452]

[0453] 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), 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), 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 of formic acid (30%), B=acetonitrile; gradient: 40%-70%, 9 minutes) and (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.05 volume of ammonia water (30%), B=acetonitrile; gradient: 0%-28%, 10 minutes), and dried to give (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamic acid-2-hydroxyethyl ester (11.7 mg, yield 9.49%).

[0454] LC-MS, M / Z(ESI):512.2[M+H] +

[0455] 1 H 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)

[0456] Example 8: Preparation of target compound I-16

[0457] Tetrahydropyran-4-yl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0458]

[0459] The synthetic route of the target compound I-16 is as follows:

[0460]

[0461] Referring to the preparation method of intermediate A2, p-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).

[0462] Step 1: Synthesis of tetrahydropyran-3-yl (3-(4-(1-(2-chloro-1H-imidazol-1-yl)ethyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0463]

[0464] Under 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), and then N,N-diisopropylethylamine (331.02 mg, 2.56 mmol) was added. Then 4-tetrahydropyranyl chloroformic acid (67.45 mg, 409.80 μmol) was slowly added, and the reaction mixture was stirred under ice-water bath for 2 hours. LCMS monitored that most of the raw materials reacted completely and the desired product was generated. After the reaction was completed. Water (20 mL) was added to dilute the reaction solution, and it was extracted with dichloromethane (20 mL×2). The organic phase was washed with brine (20 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 then purified by preparative separation to give (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%).

[0465] LC-MS, M / Z(ESI):538.2[M+H] +

[0466] 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 = 6.5 Hz, 2H), 2.06–1.57 (m, 5H), 0.99 (d, J = 6.2 Hz, 6H). Example 9: Preparation of target compound I-20

[0467] Methyl (5-isobutyl-3-(4-((2-(3-methyloxetan-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0468]

[0469] The synthetic route of the target compound I-20 is as follows:

[0470]

[0471] Step 1: Synthesis of 2-(3-methyloxetane-3-yl)-1H-imidazole

[0472]

[0473] At 0°C, ammonia water (1.40 g, 9.99 mmol) was added to a solution of 3-methyloxetane-3-carboxaldehyde (1.00 g, 9.99 mmol) and glyoxal (870 mg, 15.0 mmol) in ethanol (10 mL), and the reaction was stirred at 25°C for 10 hours. After the reaction was completed, the reaction solution was concentrated to obtain 2-(3-methyloxetane-3-yl)-1H-imidazole (1.40 g, crude product).

[0474] LC-MS, M / Z(ESI):139.1[M+H] +

[0475] Step 2: Synthesis of 1-((4-bromophenyl)methyl)-2-(3-methyloxetane-3-yl)-1H-imidazole

[0476]

[0477] Potassium carbonate (2.49 g, 18.0 mmol) and 2-(3-methyloxetane-3-yl)-1H-imidazole (995 mg, 7.20 mmol) were added to a solution of 1-bromo-4-(bromomethyl)benzene (1.50 g, 6.00 mmol) in N,N-dimethylformamide (10 mL), and then stirred at 50 ° C for 8 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), and then 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 a crude product, which was then separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1 to 0:1) to obtain 1-((4-bromophenyl)methyl)-2-(3-methyloxetane-3-yl)-1H-imidazole (800 mg, yield 43.4%).

[0478] LC-MS, M / Z(ESI):309.0[M+H]+

[0479] 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

[0480]

[0481] Under N2 protection, (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophene-3-yl)boronic acid (150 mg, 0.47 mmol), 1-((4-bromophenyl)methyl)-2-(3-methyloxetane-3-yl)-1H-imidazole (144.43 mg, 0.47 mmol) were dissolved in 8 mL toluene and 2 mL ethanol, sodium carbonate (199 mg, 1.88 mmol, 2M), tetrakistriphenylphosphine palladium (54.29 mg, 46.99 μmol) were added, and nitrogen was replaced three times. The reaction solution was stirred at 80 ° C for 4 hours, and the raw material disappeared when detected by LCMS. Water (10 mL) was added to dilute the reaction solution, and it was 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 by silica gel column chromatography (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, yield 63.63%).

[0482] LC-MS(ESI):502.4[M+H] +

[0483] Step 4: Synthesis of 5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0484]

[0485] At 25°C, N-(tert-butyl)-5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (150 mg, 298.98 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (4.4 g, 38.5 mmol, 3 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. LCMS monitored the disappearance of the starting material, and the reaction solution was concentrated under reduced pressure to remove the solvent to obtain the crude product 5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (133.0 mg, yield 99.95%).

[0486] LC-MS(ESI):446.3[M+1] +

[0487] Step 5: Synthesis of methyl (5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-yl)sulfonylcarbamate

[0488]

[0489] Under ice-water bath, 5-isobutyl-3-(4-((2-(3-methyloxetane-3-yl)-1H-imidazole-1-yl)methyl)phenyl)thiophene-2-sulfonamide (120.0 mg, 215.44 μmol) was dissolved in dichloromethane (5 mL), and then N,N-diisopropylethylamine (55.69 mg, 430.88 μmol) was added. Methyl chloroformate (20.36 mg, 215.44 μmol) was slowly added, and the reaction mixture was stirred under ice-water bath for 2 hours. LCMS monitoring showed that most of the raw materials reacted completely and the desired product was generated. Water (20 mL) was added to dilute the reaction solution, and it was extracted with dichloromethane (20 mL×3). The organic phase was washed with brine (20 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 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%).

[0490] 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).

[0491] LC-MS(ESI):504.3.[M+H] +

[0492] Example 10: The preparation of the following compounds can be obtained by referring to the preparation methods of the above compounds.

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499] In the test example of the present invention, the preparation method of the reference compound I refers to patent WO2021229244A1, and the structure is shown below:

[0500]

[0501] Biological Testing

[0502] The following test method may be used.

[0503] Test Example 1: Compound binding to AT2R

[0504] The experiment was performed according to the instruction manual of the Angiotensin AT2 Receptor Ligand Binding Assay Kit (#C1TT1AT2, Cisbio). First, the 10mM compound stock solution was serially diluted according to the dilution factor of 5× (including 10 concentrations, each concentration was repeated twice), and 160nL of different concentrations of the compound was added to a 384-well plate. 40μL 1×TLB (TLB: Tag-lite buffer) was added to each well and shaken at room temperature for 15 minutes. A 15mL centrifuge tube with 5mL 1×TLB was prepared in advance for use. The frozen labeled cells were thawed in a 37℃ water bath (1-2 minutes), and the thawed cells were quickly transferred to the above 15mL centrifuge tube, mixed and centrifuged at 1000g for 5 minutes at room temperature. The supernatant was removed and 2.7mL 1×TLB was added to resuspend the cells. A new 384-well plate was taken and 10μL of the mixed cells were added to the corresponding 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, the data were read using the HTRF mode of EnVision. The excitation light intensity of 665nM and 615nM in each well was read respectively, and the ratio (Ratio = A665nM / B615nM) was calculated. IC was calculated using GraphPad Prism8 software. 50 Numerical values, X: logarithmic value of compound concentration; Y: ratio of A665nM / B615nM.

[0505] Table 1. IC values ​​of compounds tested for AT2R binding activity 50 value

[0506]

[0507]

[0508] The experimental results show that the compounds of the present invention have a strong binding effect with AT2R.

[0509] Test Example 2: CYP inhibition assay of compounds

[0510] The inhibitory effects of the compounds on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (midazolam), CYP2B6, and CYP2C8 were evaluated at 10 μM. The mixed human liver microsomes were stored in a -80 °C refrigerator before use, taken out and melted in a 37 °C water bath before use, and placed on ice for operation. Take 100 μL of microsome working solution, add 2 μL of test product or positive inhibitor working solution, add 2 μL of solvent to the solvent control, and place it in a 37 °C water bath for preincubation for 10 minutes. After preincubation, 98 μL of NADPH regeneration solution was added to all samples to start the reaction. Then put it back in the water bath and incubate for a period of time. The reaction was quenched with 200 μL of stop solution. The plate was centrifuged at 3220g for 10 minutes, 100 μL of supernatant was transferred, 100 μL of water was added and mixed thoroughly to the analysis plate, and LC / MS / MS analysis was performed.

[0511] Table 2: CYP450 inhibition results of compounds

[0512]

[0513] 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.

[0514] Test Example 3: Liver microsome stability test of compounds

[0515] The stability test of human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. First, the compound to be tested was prepared into a 10mM stock solution in DMSO solvent, and then the compound was diluted to 0.5mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and the solution was used to dilute 0.5mM of the compound to form a working solution. The compound concentration in the working solution was 1.5μM and the human liver microsome concentration was 0.75mg / mL. Take a deep well plate, add 30μL of working solution to each well, and then add 15μL of preheated 6mM NADPH solution to start the reaction and incubate at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, add 135μL of acetonitrile to the corresponding wells to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep well plate was vortexed for 10 minutes (600rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio for LC-MS / MS detection. The ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point was obtained. The peak area ratio of the compound at 5, 15, 30, and 45 minutes was compared with the peak area ratio at 0 minute, and the remaining percentage of the compound at each time point was calculated. Graphpad 8 software was used to calculate T1 / 2 .

[0516] The stability of the compound in liver microsomes reflects its risk of being metabolized and eliminated in the body. The experimental results show that the tested compound has good stability in humans.

[0517] Test Example 4: Bidirectional permeability study of compounds in CACO-2 cells

[0518] Caco-2 cells were cultured at 1×10 5 cells / cm 2 Cells were plated onto polyethylene membrane (PET) in 96-well inserts at a rate of 100 μg / min and the medium was changed every 4-5 days until day 21-28 to form a confluent cell monolayer. The transport buffer in the experiment was HBSS and 10.0 mM HEPES, pH 7.40 ± 0.05. The test compounds were tested bidirectionally at 2.00 μM in the presence and absence of 10.0 μM GF120918. Digoxin was tested bidirectionally at 10.0 μM in the presence and absence of 10.0 μM GF120918, while nadolol and metoprolol were tested in the A to B direction at 2.00 μM in the absence of 10.0 μM GF120918, all in duplicate wells. The final DMSO concentration was adjusted to less than 1%. The plates were incubated in a CO2 incubator at 37 ± 1°C for 2 hours with 5% CO2 added under saturated humidity without shaking. All samples were mixed with acetonitrile containing the 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 solution, donor solution, and acceptor solution were quantified by the LC-MS / MS method using the peak area ratio of the analyte / internal standard.

[0519] After the transport assay, the integrity of the Caco-2 cell monolayer was determined using the Lucifer Yellow exclusion assay.

[0520] The experimental results showed that the test compounds had good permeability, which was beneficial to the absorption of the compounds.

[0521] Test Example 5: IPF efficacy experiment of the compound in mice

[0522] This experiment requires a specific mouse IPF model, which is established and conducted by Shanghai Pengli Company. All animal experimental operation plans are approved by Pengli IACUC (Institute Animal Care and Use Committee).

[0523] The experimental steps include:

[0524] 1. Compound preparation: Weigh an appropriate amount of compound powder, prepare a DMSO stock solution, and dispense into the actual daily dose required, and prepare it on the day of use. Add the required amount of 10% solutol according to the dilution ratio, vortex to dissolve and mix, and finally add the required amount of 85% saline according to the dilution ratio. The final DMSO content is 5%, and a clear solution of 0.03 mg / mL is prepared.

[0525] 2. Animal grouping: On the day of modeling, 10 animals were randomly selected and directly included in the G1 blank group, and all other animals received bleomycin injection through the trachea for model construction. After bleomycin injection, animals were randomly assigned to groups using BioBook before the first administration based on animal weight changes, weight and animal status, in order to achieve similar average weights for each group and reduce inter-group deviations.

[0526] 3. Model construction: Dissolve an appropriate amount of bleomycin in commercial saline. The model group animals inhaled 1-4% isoflurane for anesthesia and were given 2U / kg of bleomycin through the trachea. The specific dosage was calculated based on the animal's body weight. The mice in the G1 group were injected with an equal volume of saline through the trachea under 1-4% isoflurane anesthesia.

[0527] 4. Dosage: The day of bleomycin injection is regarded as the 0th day of the experiment. The dosing schedule is as follows:

[0528] Table 3 Grouping and dosing regimen

[0529]

[0530]

[0531] a: The solvent is 5% DMSO + 10% solutol + 85% saline;

[0532] b: bid, once in the morning and once in the afternoon, with an interval of about 6 hours; no medication in the morning of day 22.

[0533] 5. Pulmonary function test: On the 22nd day, all experimental animals were anesthetized with Zotal (25-50 mg / kg) and xylazine (5-10 mg / kg), and then subjected to pulmonary function test (PFT) using pulmonary function test, including PV curve, FVC, IC, VC, Cdyn, and Cchord (quasi-static lung compliance) indicators.

[0534] 6. Pathological examination of lung sections: Collect lung tissue, rinse twice, dry with filter paper and weigh. After weighing, the left lung is 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 fixed with formaldehyde is cut horizontally into three sections, upper, middle and lower, and embedded in the same wax block, sliced, and stained with Masson's staining. The pathologist performs histopathological evaluation. The scoring criteria refer to the following table:

[0535] Table 4 Fibrosis scoring criteria

[0536] score standard 0 normal 1 Microfibrous thickening of the alveolar or bronchiolar walls 2 Moderate thickening of the lung wall, no obvious damage to the lung structure 3 Increased fibrosis, with clear damage to lung architecture, forming fibrous bands or small fibrous masses 4 Severe structural distortion and extensive fibrosis, presenting a "honeycomb" appearance 5 Total fibrous visual field occlusion

[0537] 7. Animal euthanasia: All experimental animals will be euthanized by CO2 and cervical dislocation after the in vivo experiment.

[0538] 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.

[0539] The experimental results show that compared with the control compound, the compound of the present invention can significantly improve the FVC, IC, VC lung function indicators and can significantly improve the pulmonary fibrosis score.

[0540] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. The compound of 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 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, 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; 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.

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. The use according to claim 15, 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.

17. The use 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.

18. The use according to claim 17, 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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