Fused ring compound as at2r agonist

Abstract

Provided are a compound as shown in formula (IB), and a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The compound can be used as an AT2R agonist.

Description

A cyclic compound as an AT2R agonist

[0001] Priority information

[0002] The present invention claims priority to and the benefits of patent application 202410008284.2 filed with the State Intellectual Property Office of China on January 3, 2024, patent application 202410299768.7 filed with the State Intellectual Property Office of China on March 14, 2024, and patent application 202411002306.0 filed with the State Intellectual Property Office of China on July 24, 2024, and is incorporated herein by reference in its entirety. Technical Field

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

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

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

[0006] AT2R agonists have been suggested as potentially useful for the treatment and / or prevention of digestive tract disorders such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure.

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

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

[0009] In a first aspect of the present invention, there is provided a compound of formula IB, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0010] wherein each R1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl; m is selected from 1, 2, 3, 4, 5, 6;

[0011] Alternatively, when m is selected from 2, 3, 4, 5, or 6, two R1s may form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group with the carbon atom to which they are attached;

[0012] X 1 and X 2 The atoms are each independently selected from O, S, and C; the S may be in the form of its oxide;

[0013] Ring B is selected from a benzene ring and a 5-6 membered heteroaromatic ring;

[0014] R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; when there are multiple substituents, the substituents are the same or different;

[0015] n is selected from 0, 1, 2, 3 and 4;

[0016] R4 is selected from hydrogen, oxo (=O), C1-C3 alkyl and C1-C3 haloalkyl;

[0017] R5 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; when there are multiple substituents, the substituents are the same or different;

[0018] p is selected from 1, 2 and 3;

[0019] Q is selected from -C(=O)-Z-R2, a 5-8 membered heteroaromatic ring; the 5-8 membered heteroaromatic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0020] Z is selected from NRa and O;

[0021] R2 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl; said R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl; when there are multiple substituents, said substituents are the same or different;

[0022] Ra is selected from hydrogen and C1-C3 alkyl.

[0023] In a preferred embodiment of the present invention, the Selected from

[0024] In a preferred embodiment of the present invention, the Selected from

[0025] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0026] wherein each R1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl; m is selected from 1, 2, 3, 4, 5, 6;

[0027] Alternatively, when m is selected from 2, 3, 4, 5, or 6, two R1s may form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group with the carbon atom to which they are attached;

[0028] X 1 and X 2 The atoms are each independently selected from O, S, and C; the S may be in the form of its oxide;

[0029] Ring B is selected from a benzene ring and a 5-6 membered heteroaromatic ring;

[0030] R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; when there are multiple substituents, the substituents are the same or different;

[0031] n is selected from 0, 1, 2, 3 and 4;

[0032] R4 is selected from hydrogen, oxo (=O), C1-C3 alkyl and C1-C3 haloalkyl;

[0033] R5 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; when there are multiple substituents, the substituents are the same or different;

[0034] Q is selected from -C(=O)-Z-R2, a 5-8 membered heteroaromatic ring; the 5-8 membered heteroaromatic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0035] Z is selected from NRa and O;

[0036] R2 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl; said R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl; when there are multiple substituents, said substituents are the same or different;

[0037] Ra is selected from hydrogen and C1-C3 alkyl.

[0038] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0039] Among them, R1, R2, R3, R4, R5, Z, X 1 、X 2 , m and n are defined as described in the first aspect of the present invention.

[0040] In a preferred embodiment of the present invention, in formula I, R1 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

[0041] m is selected from 1, 2, 3, 4, 5, 6;

[0042] Alternatively, when m is selected from 2, 3, 4, 5, or 6, two R1s may form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group with the carbon atom to which they are attached;

[0043] X 1 and X 2 The atoms are each independently selected from O, S, and C; the S may be in the form of its oxide;

[0044] Z is selected from NRa and O;

[0045] R2 is selected from C1-C6 alkyl, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; said R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; when there are multiple substituents, said substituents are the same or different;

[0046] R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; when there are multiple substituents, the substituents are the same or different;

[0047] n is selected from 0, 1, 2, 3 and 4;

[0048] R4 is selected from hydrogen, oxo (=O), C1-C3 alkyl and C1-C3 haloalkyl;

[0049] R5 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; when there are multiple substituents, the substituents are the same or different;

[0050] Ra is selected from hydrogen and C1-C3 alkyl.

[0051] In a preferred embodiment of the present invention, the R1 is selected from hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl.

[0052] In a preferred embodiment of the present invention, R1 is selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, CH2F, CHF2 and CF3.

[0053] In a preferred embodiment of the present invention, R1 is selected from hydrogen and methyl.

[0054] In a preferred embodiment of the present invention, the two R1s may form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group with the carbon atoms to which they are connected.

[0055] In a preferred embodiment of the present invention, the two R1s may form a C3-C5 cycloalkyl group or a 3-5 membered heterocycloalkyl group with the carbon atoms to which they are connected.

[0056] In a preferred embodiment of the present invention, the two R1 can form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxirane group, an aziridine group, an oxetanyl group, an azetidinyl group, or a tetrahydrofuran group with the carbon atom to which they are connected.

[0057] In a preferred embodiment of the present invention, m is selected from 1, 2, 3, 4, 5, and 6.

[0058] In a preferred embodiment of the present invention, m is selected from 1, 2, 3, and 4.

[0059] In a preferred embodiment of the present invention, the ring B is selected from a benzene ring and a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0060] In a preferred embodiment of the present invention, the ring B is selected from benzene ring, furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0061] In a preferred embodiment of the present invention, the ring B is selected from a benzene ring and a pyridine ring.

[0062] In a preferred embodiment of the present invention, the group fragment With structure

[0063] In a preferred embodiment of the present invention, the ring A is selected from C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl.

[0064] In a preferred embodiment of the present invention, the ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxirane, aziridine, oxetanyl, azetidinyl, and tetrahydrofuran.

[0065] In a preferred embodiment of the present invention, the group fragment With structure

[0066] In a preferred embodiment of the present invention, the group fragment With structure

[0067] In a preferred embodiment of the present invention, the group fragment With structure

[0068] In a preferred embodiment of the present invention, the group fragment With structure

[0069] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0070] wherein V1, V2, V3, and V4 are each independently CH or N;

[0071] n、X 1 、X 2, Z, R2, R3, R4, and R5 are defined as described in the first aspect of the present invention.

[0072] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0073] Among them, X 1 Atoms are O, X 2 Atom is C; or X 1 Atoms are C, X 2 The atom is O;

[0074] V1, V2, V3, and V4 are each independently CH or N;

[0075] n、X 1 、X 2 , Z, R2, R3, R4, and R5 are defined as described in the first aspect of the present invention.

[0076] In a preferred embodiment of the present invention, n is 0.

[0077] In a preferred embodiment of the present invention, R4 is hydrogen.

[0078] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0079] Among them, X 1 Atoms are O, X 2 Atom is C; or X 1 Atoms are C, X 2 The atom is O;

[0080] V1, V2, V3, and V4 are each independently CH or N;

[0081] n、X 1 、X 2 , Z, R2, R3, R4, and R5 are as defined in the first aspect of the present invention;

[0082] Preferably, n is 0;

[0083] Preferably, R4 is hydrogen.

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

[0085] Among them, X 1 、X 2 The atoms are not all C at the same time;

[0086] The X 1 、X 2, Z, R2, R3, R4, and R5 are defined as described in the first aspect of the present invention.

[0087] In a preferred embodiment of the present invention, R4 is selected from hydrogen, C1-C3 alkyl and C1-C3 haloalkyl.

[0088] In a preferred embodiment of the present invention, R4 is selected from hydrogen, methyl, trifluoromethyl, difluoromethyl, and CH2F.

[0089] In a preferred embodiment of the present invention, said R4 is selected from hydrogen.

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

[0091] Among them, X 1 、X 2 The atoms are not all C at the same time;

[0092] The X 1 、X 2 , R2 and R5 are as defined in the first aspect of the present invention.

[0093] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0094] Among them, X 1 、X 2 The atoms are not all C at the same time;

[0095] The X 1 、X 2 , R2 and R5 are as defined in the first aspect of the present invention.

[0096] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0097] Among them, X 1 、X 2 The atoms are not all C at the same time;

[0098] The X 1 、X 2 , R2 and R5 are as defined in the first aspect of the present invention.

[0099] In a preferred embodiment of the present invention, Q is selected from -C(=O)-Z-R2, a 5-6 membered heteroaromatic ring; the 5-6 membered heteroaromatic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0100] The 5-6 membered heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0101] In a preferred embodiment of the present invention, the 5-6 membered heteroaromatic ring is selected from furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0102] In a preferred embodiment of the present invention, Z is selected from O or NH.

[0103] In a preferred embodiment of the present invention, Z is selected from O or NH2.

[0104] In a preferred embodiment of the present invention, Z is selected from O.

[0105] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, C3-C5 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl; and the C1-C4 alkyl, C3-C5 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl.

[0106] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl; the C1-C4 alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl contain 1, 2, or 3 heteroatoms selected from N, O, and S.

[0107] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, C3-C5 cycloalkyl, 3-7 membered heterocycloalkyl, C1-C4 alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl; and the C1-C4 alkyl, C3-C5 cycloalkyl, 3-7 membered heterocycloalkyl, C1-C4 alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 hydroxyl groups or halogens.

[0108] In a preferred embodiment of the present invention, R2 is selected from furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, -CH2-pyridine, -CH2-pyrimidine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, oxirane, oxetane, azetidine, tetrahydrofuran, tetrahydropyran, tetrahydropyrrole, hexahydropyridine; and R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl.

[0109] In a preferred embodiment of the present invention, said R2 is selected from methyl, butyl,

[0110] In a preferred embodiment of the present invention, Q is selected from pyridine, pyrimidine, -C(=O)-O-CH3, -C(=O)-O-CH2CH2CH2CH3, -C(=O)-NH-CH3, -C(=O)-NH-CH2CH2CH2CH3,

[0111] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, C3-C5 cycloalkyl and 3-7 membered heterocycloalkyl; and the C1-C4 alkyl, C3-C5 cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl.

[0112] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, C3-C5 cycloalkyl, 3-7 membered heterocycloalkyl and C1-C4 alkyl optionally substituted with 1, 2, 3 or 4 hydroxyl groups or halogen.

[0113] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, oxirane, oxetane, azetidine, tetrahydrofuran, tetrahydropyran, tetrahydropyrrole, hexahydropyridine; and R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl.

[0114] In a preferred embodiment of the present invention, said R2 is selected from methyl, butyl,

[0115] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl.

[0116] In a preferred embodiment of the present invention, R2 is selected from methyl and butyl.

[0117] In a preferred embodiment of the present invention, R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy and C3-C5 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy and C3-C5 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano; when there are multiple substituents, the substituents are the same or different.

[0118] In a preferred embodiment of the present invention, R3 is selected from hydrogen, F, methyl, methoxy, trifluoromethyl, difluoromethyl, CH2F, cyclopropyl, and cyano.

[0119] In a preferred embodiment of the present invention, R3 is selected from hydrogen, F, and methyl.

[0120] In a preferred embodiment of the present invention, n is selected from 0, 1, 2, 3 and 4.

[0121] In a preferred embodiment of the present invention, n is selected from 0, 1, and 2.

[0122] In a preferred embodiment of the present invention, n is selected from 0.

[0123] In a preferred embodiment of the present invention, R5 is selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; and the C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl.

[0124] In a preferred embodiment of the present invention, said R5 is selected from Cl, CF3, Cyclopropyl, oxetane.

[0125] In a preferred embodiment of the present invention, R5 is selected from Cl and CF3.

[0126] In a preferred embodiment of the present invention, the X 1 and X 2 The atoms are each independently selected from O, S, and C.

[0127] In a preferred embodiment of the present invention, the X 1 and X 2 When the atoms are each independently selected from S, the S may be in the form of an oxide thereof.

[0128] In a preferred embodiment of the present invention, the X 1 and X 2 The atoms are each independently selected from sulfone and sulfoxide.

[0129] In a preferred embodiment of the present invention, the X 1 and X 2 At least one of the atoms is O.

[0130] In a preferred embodiment of the present invention, the X 1 and X 2 There is only one O in the atom.

[0131] In a preferred embodiment of the present invention, the X 1 Atoms are C, X 2 The atom is O.

[0132] In a preferred embodiment of the present invention, the X 1 Atoms are O, X 2 The atom is C.

[0133] In a preferred embodiment of the present invention, the compound represented by formula IB, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, wherein the compound comprises:

[0134] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound of formula IB as described in the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier.

[0135] In a third aspect, the present invention provides uses of the compound of formula IB according to the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to the second aspect, the uses comprising:

[0136] As an AT2R agonist;

[0137] and / or, preventing and / or treating diseases in which endogenous production of Ang II is insufficient;

[0138] and / or, preventing and / or treating diseases in which an increased effect of Ang II is desired or required;

[0139] 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.

[0140] Provided are compounds of formula IB as described in the first aspect, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, or the pharmaceutical composition described in the second aspect, which are expected to be used to treat gastrointestinal diseases, cardiovascular diseases, respiratory diseases, kidney diseases, eye diseases, female reproductive system diseases, central nervous system diseases, and growth, metabolism, and proliferation-related diseases.

[0141] Provided are compounds of formula IB as described in the first aspect, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, or the pharmaceutical composition described in the second aspect, which are expected to be used to treat diseases of the gastrointestinal tract, cardiovascular system, respiratory system, kidneys, eyes, female reproductive system, central nervous system (CNS), or growth, metabolism, and proliferation.

[0142] 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.

[0143] The compound of formula IB described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect, are suitable for the treatment and / or preventive treatment of the above-mentioned diseases.

[0144] The fourth aspect of the present invention provides a method for treating a disease, wherein the disease is a disease in which the endogenous production of Ang II is insufficient, and / or a disease in which it is desired or necessary to increase the effect of Ang II, and / or a disease in which AT2R expression and stimulation is desired or necessary, the method comprising administering to a person suffering from or susceptible to the disease a therapeutically effective amount of a compound of formula IB 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.

[0145] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0146] Detailed Description of the Invention

[0147] Terms and Definitions

[0148] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0149] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0150] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0151] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0152] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, As used herein, "R1", "R2" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.

[0153] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0154] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0155] When a numerical range is described in the specification and claims of this application and is understood as an "integer," it should be understood to include both endpoints of the range as well as every integer within the range. For example, "an integer from 1 to 6" should be understood to include every integer from 0, 1, 2, 3, 4, 5, and 6.

[0156] In this application, "AT2 receptor" and "AT2R" have the same definition.

[0157] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, or iodine.

[0158] As used herein, the term "amino" by itself or as part of another substituent refers to -NH2.

[0159] As used herein, the term "hydroxy" by itself or as part of another substituent refers to -OH.

[0160] As used herein, the term "cyano" by itself or as part of another substituent refers to -CN.

[0161] As used herein, the term "amino" by itself or as part of another substituent refers to -NH2.

[0162] In this application, the term "alkyl" when used alone or as part of another substituent means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of naturally abundant alkyl groups that are rich in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds. The alkyl, alkenyl, and alkynyl groups described herein can also serve as linking groups (i.e., groups that link two or more moieties of a compound as described), in which case the alkyl, alkenyl, and alkynyl groups can be monovalent, divalent, or multivalent.

[0163] In the present application, the term "C1-C6 alkyl" alone or as part of another substituent is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. 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. The radical has 1, 2, 3 or 4 carbon atoms ("C1-C4 alkyl"), for example methyl, methylene, ethyl, n-propyl, isopropyl, butyl or isobutyl. In particular, the radical has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, methylene, ethyl, n-propyl or isopropyl.

[0164] In this application, when alone or as part of other substituents, the term "C1-C6 alkoxy" should be understood to mean a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, which can be represented by the definition of -O-C1-C6 alkyl as described in this specification, or the oxygen atom can be attached to any carbon atom of the straight or branched chain of the C1-C6 alkyl. Including but not limited to: methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-), butoxy (C4H9-O-), ethyloxyethyl (-C2H4-O-C2H5). For example, the term "C1-C3 alkoxy" includes but is not limited to: methoxy (CH3-O-), ethoxy (C2H5-O-).

[0165] In this application, the term "oxo" when used alone or as part of other substituents refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, ie, the methylene group is replaced by a carbonyl group, representing =0.

[0166] In this application, the term "cycloalkyl" or "carbocyclyl" when used alone or as part of another substituent refers to a cyclic alkyl group. m -C n "Cycloalkyl" should be understood to mean a saturated, unsaturated or partially saturated carbon ring having m to n atoms. It includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of unsubstituted cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon ring 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. For example, the term "3-7 membered cycloalkyl" or "C3-C7 cycloalkyl" refers to a cyclic alkyl group containing 3 to 7, 3 to 6, 3 to 6 or 3 to 4 carbon atoms, which may represent a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The term "C3-C5 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3-5 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl.

[0167] As used herein, "halocycloalkyl" by itself or as part of another substituent refers to a cycloalkyl group as defined above, wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl group are replaced by fluorine, chlorine, bromine, or iodine.

[0168] In this application, "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 by one or more halogens (such as -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. The term "C α-β "Haloalkyl" refers to an alkyl group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine. For example, the term "C 1-3 "Haloalkyl" refers to an alkyl group having 1 to 3 carbon atoms, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine, including but not limited to trifluoromethyl, trichloromethyl, pentafluoroethyl.

[0169] As used herein, "haloalkoxy" when used alone or as part of another substituent refers to an alkoxy group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkoxy group are replaced by fluorine, chlorine, bromine or iodine. For example, the term "C 1-6 "Haloalkoxy" refers to an alkyl group having 1 to 6 carbon atoms and oxygen atoms, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine, including but not limited to trifluoromethoxy, trichloromethoxy, pentafluoroethoxy.

[0170] As used herein, the term "heterocycloalkyl" or "heterocyclyl" when used alone or as part of another substituent refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P. "Heterocycloalkyl" or "heterocyclyl" may be saturated or unsaturated, but not aromatic. "Heterocycloalkyl" or "heterocyclyl" may also contain 1, 2, or 3 rings, including fused, bridged, and spirocyclic structures. The term "3-7 membered heterocyclyl" or "3-7 membered heterocycloalkyl" should be understood to mean a monocyclic or bicyclic ring having 3 to 7 atoms, wherein the heteroatoms are preferably selected from N, O, and S. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, the heteroatoms are not adjacent to each other. Examples of heterocycloalkyl include, but are not limited to, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiopyranyl.

[0171] In this application, when alone or as part of other substituents, the terms "heteroaromatic ring" and "heteroaryl" can be used interchangeably, and heteroaryl can be connected to the rest of the molecule by a heteroatom or carbon atom. The term "5-8 membered heteroaryl" refers to a cyclic group with a conjugated π electron system consisting of 5 to 8 ring atoms, 1, 2 or 3 of which are heteroatoms independently selected from O, S, P and N, and the rest are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur and phosphorus heteroatoms are optionally oxidized (i.e., NO, S(O)p and P(O)p, p is 1 or 2). The term "5-6 membered heteroaromatic ring" includes 5- and 6-membered heteroaromatic rings. Examples of the 5-6 membered heteroaromatic ring include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrazinyl or pyrimidinyl.

[0172] In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0173] In this application, the term "optionally substituted by" or "optionally substituted by" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from the possible substituents. For example, "aryl is optionally substituted by 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 "Alkyl" means that the aryl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 The term "alkyl" refers to an alkyl group, and the description includes both substituted and unsubstituted aryl groups.

[0174] In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0175] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. A "pharmaceutically acceptable base addition salt" 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 herein. These salts may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used in the identification, characterization, or purification of the compounds of the invention.

[0176] In the present application, the term "amine salt" refers to a product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid, including an inorganic acid or an organic acid as described in the present application.

[0177] In the present application, 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.

[0178] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in one of the possible isomers or in a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (–) are used to designate the signs for the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0179] When bonds to chiral carbon atoms in the present formulae are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formula. The diagrammatic representation of racemates or enantiomerically pure compounds herein is adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0180] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0181] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0182] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0183] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0184] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0185] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0186] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression.

[0187] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0188] (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;

[0189] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0190] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0191] (iv) Alleviate the symptoms of the disease or condition. Beneficial effects

[0192] After extensive and intensive research, the inventors unexpectedly discovered a paracyclic compound that acts as an AT2R agonist. The compound has the structure shown in the present invention. The paracyclic compound can prevent or treat diseases or conditions associated with the AT2R, exhibits excellent pharmacokinetic properties, and possesses high safety and drugability. DETAILED DESCRIPTION

[0193] The present invention will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0194] This application has the following definitions:

[0195] Symbol or unit:

[0196] IC 50 : Half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0197] 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

[0198] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0199] RT: retention time

[0200] Reagents:

[0201] Pd(dppf)Cl2-DCM:1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride complex with dichloromethane

[0202] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0203] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[0204] Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride

[0205] DMF: N,N-dimethylformamide

[0206] DIPEA: N,N-diisopropylethylamine

[0207] EA: ethyl acetate

[0208] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0209] MeOH: methanol

[0210] PE: Petroleum ether

[0211] Toluene: Toluene

[0212] THF: Tetrahydrofuran

[0213] XPhos Pd G4: Palladium(II) methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)

[0214] Test method:

[0215] LCMS: Liquid chromatography-mass spectrometry

[0216] TLC: Thin layer chromatography

[0217] Example 1: Preparation of target compound I-1

[0218] Methyl ((5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0219] The synthetic route of target compound I-1 is as follows:

[0220] Step 1: Synthesis of 5-bromo-2-(2-methylprop-1-en-1-yl)phenol

[0221] At 25°C, the starting materials 5-bromo-2-iodophenol (5 g, 16.73 mmol) and 1,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (3.05 g, 16.73 mmol) were dissolved in dioxane (50 mL) and water (5 mL). Potassium phosphate (7.10 g, 33.46 mmol) and Pd(dppf)Cl2-DCM (613.68 mg, 836.39 μmol) were then added. After nitrogen was replaced, the reaction mixture was stirred at 25°C for 3 hours. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 2) and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified using a silica gel column to give 5-bromo-2-(2-methylprop-1-en-1-yl)phenol (3.0 g).

[0222] LC-MS, M / Z(ESI):227.1[M+H] +

[0223] Step 2: Synthesis of 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran

[0224] At 25°C, the starting material, 5-bromo-2-(2-methylprop-1-en-1-yl)phenol (7.2 g, 31.70 mmol), was dissolved in dichloromethane (100 mL), followed by the addition of iodine (4.02 g, 15.85 mmol). The reaction mixture was stirred at 25°C for 16 hours. LCMS confirmed the complete reaction and the formation of the desired product. After the reaction, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (100 × 2). The organic phase was washed with saturated sodium thiosulfate (100 × 2) and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel column chromatography to yield 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (6.0 g).

[0225] LC-MS, M / Z(ESI):227.1[M+H] +

[0226] Step 3: Synthesis of 6-(benzylthio)-2,2-dimethyl-2,3-dihydro-1-benzofuran

[0227] At 25°C, the starting materials 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (1 g, 4.40 mmol) and benzyl mercaptan (601.61 mg, 4.84 mmol) were dissolved in dioxane (20 mL). Xantphos (509.03 mg, 880.68 μmol), Pd2(dba)3 (402.9 mg, 440.34 μmol), and N,N-diisopropylethylamine (1.71 g, 13.21 mmol) were then added. After nitrogen was replaced, the reaction mixture was stirred at 100°C for 16 hours. LCMS monitoring indicated that the starting materials had reacted completely and the desired product had been produced. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (20 mL x 2) and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to give 6-(benzylthio)-2,2-dimethyl-2,3-dihydro-1-benzofuran (700 mg).

[0228] LC-MS, M / Z(ESI):271.0[M+H] +

[0229] Step 4: Synthesis of 6-(benzylthio)-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran

[0230] At 25°C, the starting material, 6-(benzylthio)-2,2-dimethyl-2,3-dihydro-1-benzofuran (360 mg, 1.33 mmol), was dissolved in acetonitrile (10 mL). N-bromosuccinimide (355.45 mg, 2.0 mmol) and trifluoroacetic acid (182.17 mg, 1.60 mmol) were then added. After nitrogen was replaced, the reaction mixture was stirred at 25°C for 16 hours. LCMS confirmed the complete reaction of the starting material and the formation of the desired product. After the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (20 mL x 2) and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated under reduced pressure to obtain 6-(benzylthio)-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (350.0 mg).

[0231] LC-MS,M / Z(ESI):348.7 / 350.7[M+H] +

[0232] Step 5: Synthesis of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonyl chloride

[0233] At 25°C, the raw material 6-(benzylthio)-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (240 mg, 687.12 μmol) was dissolved in tetrahydrofuran (1 mL), glacial acetic acid (8 mL), and water (1 mL). N-chlorosuccinimide (917.51 ​​mg, 6.87 mmol) was then added. The reaction mixture was stirred at 50°C for 2 hours. LCMS monitoring indicated that the raw material reaction was complete and the desired product was generated. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine (10 mL × 2) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain the crude product 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonyl chloride (240.0 mg, crude product).

[0234] LC-MS,M / Z(ESI):320.0 / 321.8[M+H] +

[0235] Step 6: Synthesis of 5-bromo-N-(tert-butyl)-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonamide

[0236] At 25°C under nitrogen, the starting material, 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonyl chloride (240 mg, 737.09 μmol), was added portionwise to a mixture of tert-butylamine (80.86 mg, 1.11 mmol) and triethylamine (223.76 mg, 2.21 mmol) in dichloromethane (5 mL). After the addition was complete, the reaction mixture was stirred at 25°C for 16 hours. LCMS confirmed the complete reaction of the starting material and the formation of the desired product. After the reaction was complete, the reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with brine (5 mL x 2) and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to yield 5-bromo-N-(tert-butyl)-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonamide (160.0 mg).

[0237] LC-MS,M / Z(ESI):305.8 / 307.8[M+H-56] +

[0238] Step 7: Synthesis of N-(tert-butyl)-5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide

[0239] At 25°C, the starting materials 5-bromo-N-(tert-butyl)-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonamide (160.0 mg, 441.65 μmol) and 2-chloro-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)imidazole (168.85 mg, 529.97 μmol) were dissolved in dioxane (5 mL) and water (0.3 mL). Potassium carbonate (134.08 mg, 0.97 mmol) and Pd(dppf)Cl2 (32.40 mg, 44.16 μmol) were then added. After nitrogen was replaced, the reaction mixture was stirred at 80°C for 16 hours. LCMS monitoring indicated that the starting materials had reacted completely, and the desired product had been produced. After the reaction was complete. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with brine (5 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain N-(tert-butyl)-5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (100.0 mg).

[0240] LC-MS, M / Z(ESI):474.0[M+H] +

[0241] Step 8: Synthesis of 5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide

[0242] The starting material, N-(tert-butyl)-5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (100.0 mg, 210.96 μmol), was dissolved in dichloromethane (3 mL) at 25°C, followed by the addition of trifluoroacetic acid (28.86 mg, 253.16 μmol, 1 mL). The reaction mixture was stirred at 60°C for 16 hours. LCMS monitoring indicated that the reaction of the starting material was complete and the desired product was generated. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the crude product, 5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (100 mg, crude).

[0243] LC-MS, M / Z(ESI):418.0[M+H] +

[0244] Step 9: Synthesis of methyl ((5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0245] In an ice-water bath, the raw material 5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (100.0 mg, 239.29 μmol) was dissolved in dichloromethane (3 mL), and then N,N-diisopropylethylamine (92.60 mg, 0.717 mmol) and methyl chloroformate (22.61 mg, 239.29 μmol) were added. The reaction mixture was stirred in an ice bath for 2 hours. LCMS monitoring showed that the raw material reaction was complete and the desired product was generated. After the reaction was completed, water (10 mL) was added to dilute the reaction solution and extracted with dichloromethane (10 mL × 2). 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 then purified by Pre-HPLC (FA) to give methyl ((5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate (10.35 mg).

[0246] LC-MS, M / Z(ESI):475.9[M+H] +

[0247] 1H NMR (400MHz, CDCl3) δ7.55(s,1H),7.31(d,J=7.8Hz,2H),7.17(d,J=7.8Hz,2H),7.01(d,J =3.0Hz,2H),6.96(s,1H),6.79(s,1H),5.16(s,2H),3.63(s,3H),3.06(s,2H),1.51(s,6H)

[0248] Example 2: Preparation of target compound I-2

[0249] Methyl ((6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl)carbamate

[0250] The synthetic route of target compound I-2 is as follows:

[0251] Step 1: Synthesis of 6-bromo-5-iodo-2,2-dimethyl-2,3-dihydro-1-benzofuran

[0252] At 25°C, the starting material, 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (1 g, 4.40 mmol), was dissolved in acetonitrile (20 mL). N-iodosuccinimide (1.19 g, 5.28 mmol) and trifluoroacetic acid (602.51 mg, 5.28 mmol, 404.64 μL) were then added. After replacing the nitrogen atmosphere, the reaction mixture was stirred at 25°C for 16 hours. LCMS confirmed the complete reaction of the starting material and the formation of the desired product. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (20 mL x 2) and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated under reduced pressure to obtain 6-bromo-5-iodo-2,2-dimethyl-2,3-dihydrobenzofuran (800.0 mg).

[0253] LC-MS,M / Z(ESI):351.6 / 351.7[M+H] +

[0254] Step 2: Synthesis of 5-(benzylthio)-6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran

[0255] At 25°C, the starting materials 6-bromo-5-iodo-2,2-dimethyl-2,3-dihydrobenzofuran (680.0 mg, 1.93 mmol) and benzyl mercaptan (263.18 mg, 2.12 mmol) were dissolved in dioxane (10 mL). Xantphos (222.69 mg, 385.28 μmol), Pd2(dba)3 (176.26 mg, 192.64 μmol), and N,N-diisopropylethylamine (746.90 mg, 5.78 mmol) were then added. After nitrogen was replaced, the reaction mixture was stirred at 100°C for 16 hours. LCMS monitoring indicated that the starting materials had reacted completely and the desired product had been produced. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (20 mL x 2) and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography to give 5-(benzylthio)-6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (590.0 mg).

[0256] LC-MS,M / Z(ESI):348.9 / 350.9[M+H] +

[0257] Step 3: Synthesis of 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride

[0258] At 25°C, 5-(Benzylthio)-6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (300.0 mg, 858.90 μmol) was dissolved in tetrahydrofuran (1 mL), glacial acetic acid (8 mL), and water (1 mL). N-chlorosuccinimide (1.15 g, 8.59 mmol) was then added. The reaction mixture was stirred at 50°C for 2 hours. LCMS monitoring indicated that the reaction of the starting material was complete and the desired product was generated. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine (10 mL × 2) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain the crude product 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (270.0 mg, crude product).

[0259] LC-MS,M / Z(ESI):319.7 / 321.9[M+H] +

[0260] Step 4: Synthesis of 6-bromo-N-(tert-butyl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide

[0261] At 25°C, under nitrogen, the starting material, 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (280 mg, 859.93 μmol), was added portionwise to a mixture of tert-butylamine (157.23 mg, 2.15 mmol) and N,N-diethylethylamine (435.08 mg, 4.30 mmol) in dichloromethane (5 mL). After the addition, the reaction mixture was stirred at 25°C for 16 hours. LCMS confirmed the complete reaction of the starting material and the formation of the desired product. After the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with brine (5 mL x 2) and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to give 6-bromo-N-(tert-butyl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide (130.0 mg).

[0262] LC-MS, M / Z(ESI):362.3[M+H] +

[0263] Step 5: Synthesis of N-(tert-butyl)-6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide

[0264] At 25°C, the starting materials 6-bromo-N-(tert-butyl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide (130.0 mg, 358.84 μmol) and 2-chloro-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)imidazole (125.76 mg, 394.72 μmol) were dissolved in dioxane (3 mL) and water (0.3 mL). Potassium carbonate (148.78 mg, 1.08 mmol) and Pd(dppf)Cl2 (52.66 mg, 71.77 μmol) were then added. After nitrogen was replaced, the reaction mixture was stirred at 80°C for 16 hours. LCMS monitoring indicated that the starting materials had reacted completely, and the desired product had been produced. After the reaction was complete. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with brine (5 mL × 2) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain N-(tert-butyl)-6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide (130.0 mg).

[0265] LC-MS, M / Z(ESI):474.0[M+H]+

[0266] Step 6: Synthesis of 6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide

[0267] The starting material, N-(tert-butyl)-6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide (120.0 mg, 253.16 μmol), was dissolved in dichloromethane (3 mL) at 25°C, followed by the addition of trifluoroacetic acid (28.86 mg, 253.16 μmol, 1 mL). The reaction mixture was stirred at 60°C for 16 hours. LCMS monitoring indicated that the starting material had reacted completely and the desired product had been generated. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the crude product, 6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide (105 mg, crude).

[0268] LC-MS, M / Z(ESI):417.9[M+H] +

[0269] Step 7: Synthesis of methyl ((6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl)carbamate

[0270] In an ice-water bath, the starting material 6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide (130.0 mg, 311.07 μmol) was dissolved in dichloromethane (3 mL), followed by the addition of N,N-diisopropylethylamine (201.02 mg, 1.56 mmol, 270.91 μL) and methyl carbon tetrachloride (26.46 mg, 279.97 μmol). The reaction mixture was stirred in an ice bath for 2 hours. LCMS monitoring indicated that the reaction of the starting material was complete and the desired product was generated. After the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 2). 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 purified by preparative thin layer chromatography (Prep TLC) and then by preparative separation and purification to give methyl ((6-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl)carbamate (21.01 mg, purity 98.254%).

[0271] LC-MS, M / Z(ESI):475.9[M+H] +

[0272] 1 H NMR(400MHz,DMSO-d6)δ11.45(s,1H),7.88(s,1H),7.45(s,1H),7.26–7.21(m,4H), 6.95(s,1H),6.59–6.50(m,1H),5.23(s,2H),3.53(s,3H),3.14(s,2H),1.46(s,6H)

[0273] Example 3: Preparation of target compound I-9

[0274] Tetrahydropyran-4-yl ((5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0275] The synthetic route of target compound I-9 is as follows:

[0276] Step 1: Synthesis of tetrahydropyran-4-yl ((5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0277] In an ice-water bath, the raw material 5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (150.0 mg, 358.93 μmol) was dissolved in dichloromethane (10 mL), and then triethylamine (139.16 mg, 1.38 mmol) and tetrahydro-2H-pyran-4-ylcarbonyl chloride (59.08 mg, 358.93 μmol) were added. The reaction mixture was stirred under ice-water conditions for 2 hours. LCMS monitoring showed that the raw material reaction was complete and the desired product was generated. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 2). 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 then purified by Pre-HPLC (FA) to give tetrahydropyran-4-yl ((5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate (48.50 mg, 24.75% yield).

[0278] LC-MS, M / Z(ESI):546.3[M+H] +

[0279] 1 H NMR (400MHz, CDCl3) δ7.55(s,1H),7.32(s,2H),7.18(s,2H),7.06-6.99(m,2H),6.69(s,1H),5.18(s,2H),4.80 (s,1H),3.73-3.67(m,2H),3.48-3.43(m,2H),3.06(s,2H),1.84-4.80(m,2H),1.57–1.52(m,2H),1.50(s,6H).

[0280] Example 4: Preparation of target compound I-5

[0281] Butyl (5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonyl)carbamate

[0282] The synthetic route of target compound I-5 is as follows:

[0283] Step 1: Synthesis of butyl (5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonyl)carbamate

[0284] Methyl ((5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate (50 mg, 0.105 mmol) was dissolved in n-butanol (1 mL) at room temperature and then stirred in a microwave at 120°C for 0.5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the solid was washed with a small amount of n-butanol and dried to give butyl (5-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonyl)carbamate (39.7 mg, 73.1% yield).

[0285] LC / MS (ESI) (m / z): 518.1 [M+H] + ;

[0286] 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),7.41(s,1H),7.23(d,J=6.8Hz,3H),7.18(d,J=8.0Hz,2H),7.07(s,1H),6.92(s,1H),5.21( s,2H),3.90(s,2H),3.06(s,2H),1.43(s,6H),1.37(dd,J=14.4,6.4Hz,2H),1.16(dd,J=14.8,7.4Hz,2H),0.81(t,J=7.2Hz,3H).

[0287] Example 5: Preparation of target compound I-8

[0288] Butyl ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0289] The synthetic route of target compound I-8 is as follows:

[0290] Step 1: Synthesis of 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-2-(trifluoromethyl)-1H-imidazole

[0291] 2-(Trifluoromethyl)-1H-imidazole (916 mg, 6.73 mmol) was dissolved in N,N-dimethylformamide (12 mL) at room temperature, followed by the addition of potassium carbonate (1.86 g, 13.5 mmol) and 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.00 g, 6.73 mmol). The mixture was reacted at 25°C for 12 hours. After the reaction is completed, ethyl acetate (50 mL) is added for dilution, and the mixture is washed with water (50 mL). The aqueous phase is extracted three times with ethyl acetate (20 mL). The organic phases are combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product is purified by column chromatography (PE:EA=100 / 1-1 / 1) to give 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-2-(trifluoromethyl)-1H-imidazole (1.50 g, yield 62.5%).

[0292] LC / MS (ESI) (m / z): 353.1 [M+H] +

[0293] Step 2: Synthesis of N-tert-butyl-2,2-dimethyl-5-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-2,3-dihydro-1-benzofuran-6-sulfonamide

[0294] 5-Bromo-N-tert-butyl-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (400 mg, 1.10 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL) at room temperature. 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-2-(trifluoromethyl)-1H-imidazole (467 mg, 1.32 mmol), potassium carbonate (336 mg, 2.43 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride (81.0 mg, 0.110 mmol) were then added. After the addition was complete, the mixture was reacted at 80°C under a nitrogen atmosphere for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), and then washed with water (20 mL). The aqueous phase was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=100 / 1-1 / 1) to give N-tert-butyl-2,2-dimethyl-5-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-2,3-dihydro-1-benzofuran-6-sulfonamide (400 mg, yield 71.6%).

[0295] LC / MS (ESI) (m / z): 508.6 [M+H] +

[0296] Step 3: Synthesis of 2,2-dimethyl-5-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-2,3-dihydro-1-benzofuran-6-sulfonamide

[0297] At room temperature, N-tert-butyl-2,2-dimethyl-5-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-2,3-dihydro-1-benzofuran-6-sulfonamide (200 mg, 0.394 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) was added. After the addition, the mixture was reacted at 60°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the trifluoroacetic acid was removed under reduced pressure. The mixture was diluted with dichloromethane (10 mL) and washed with saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted three times with dichloromethane (10 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2,2-dimethyl-5-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-2,3-dihydro-1-benzofuran-6-sulfonamide (150 mg, yield 84.7%).

[0298] LC / MS (ESI) (m / z): 452.5 [M+H] +

[0299] Step 4: Synthesis of methyl ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0300] 2,2-Dimethyl-5-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-2,3-dihydro-1-benzofuran-6-sulfonamide (50 mg, 0.110 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and then N-methylmorpholine (37 μL, 0.330 mmol) and methyl chloroformate (16.0 mg, 0.170 mmol) were added at 0°C. After the addition was complete, the reaction was allowed to proceed at room temperature (25°C) for 1 hour. After completion of the reaction, the reaction solution was cooled to 0°C and quenched with a saturated sodium bicarbonate solution (2 mL). The mixture was separated and the aqueous phase was extracted three times with dichloromethane (5 mL). The organic phases were combined and washed with a saturated sodium chloride solution (10 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The mixture was concentrated to give methyl ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate (56 mg, 100% yield).

[0301] LC / MS (ESI) (m / z): 510.5 [M+H] +

[0302] Step 5: Synthesis of butyl ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0303] Methyl ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate (56 mg, 0.110 mmol) was dissolved in n-butanol (2 mL) at room temperature and then subjected to microwave reaction at 120 ° C for 1 hour. After completion of the reaction, the reaction was concentrated under reduced pressure and the resulting crude product was purified by column chromatography (PE:EA=100 / 1-0 / 1) and dried to give butyl ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate (13 mg, 21.6% yield).

[0304] LC / MS (ESI) (m / z): 552.1 [M+H] + ;

[0305] 1H NMR (400MHz, CDCl3) δ7.54(s,1H),7.32(d,J=8.0Hz,2H),7.16(d,J=8.8Hz,3H),7.02(s,2H),5.30(s,2H),4.01 (t,J=6.4Hz,2H),3.05(s,2H),1.51(s,6H),1.46(d,J=8.0Hz,2H),1.20(d,J=7.6Hz,2H),0.86(t,J=7.6Hz,3H).

[0306] Example 6: Preparation of target compound I-10

[0307] Tetrahydropyran-4-yl ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0308] The synthetic route of target compound I-10 is as follows:

[0309] Step 1: Synthesis of tetrahydropyran-4-yl ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate

[0310] 2,2-Dimethyl-5-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-2,3-dihydro-1-benzofuran-6-sulfonamide (50 mg, 0.110 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and then N-methylmorpholine (24.0 μL, 0.220 mmol) and oxan-4-yl chloroformate (27.0 mg, 0.170 mmol) were added at 0°C. After the addition was complete, the reaction was allowed to proceed at room temperature (25°C) for 1 hour. After the reaction was completed, the reaction solution was cooled to 0° C. and saturated sodium bicarbonate solution (2 mL) was added to quench the reaction solution. The aqueous phase was extracted three times with dichloromethane (5 mL). The organic phases were combined and washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The solid obtained by concentration was purified by column chromatography (PE:EA=100 / 1-0 / 1) and dried to give tetrahydropyran-4-yl (5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamate (18 mg, yield 28.1%).

[0311] LC / MS (ESI) (m / z): 580.2 [M+H] + ;

[0312] 1 H NMR (400MHz, CDCl3) δ7.54(s,1H),7.31(d,J=7.6Hz,2H),7.15(d,J=8.8Hz,3H),7.03(d,J=2.8Hz,2H),5.30(s,2H),4.8 0–4.74(m,1H),3.72–3.65(m,2H),3.44(t,J=8.8Hz,2H),3.05(s,2H),1.80(d,J=10.4Hz,2H),1.50(s,6H),1.29(s,2H).

[0313] Example 7: The preparation of the following compounds can be obtained by referring to the preparation methods of the above compounds.

[0314] Biological testing

[0315] Test Example 1: Compound Binding to AT2R

[0316] The Angiotensin AT2 Receptor Ligand Binding Assay Kit (#C1TT1AT2, Cisbio) was used according to the protocol. First, a 10 mM stock solution of compound was serially diluted 5× (10 concentrations, each with two replicates). 160 nL of each compound concentration was added to a 384-well plate. 40 μL of 1× TLB (Tag-lite buffer) was added to each well and shaken at room temperature for 15 minutes. A 15-mL centrifuge tube containing 5 mL of 1× TLB was prepared for future use. Frozen labeled cells were thawed in a 37°C water bath (1-2 minutes). The thawed cells were quickly transferred to the 15-mL centrifuge tube, mixed thoroughly, and centrifuged at 1000 g for 5 minutes at room temperature. The supernatant was discarded and the cells were resuspended in 2.7 mL of 1× TLB. A new 384-well plate was prepared and 10 μL of the mixed cells were added to the appropriate wells according to the experimental design. Add 5 μL of 4× compound solution and 5 μL of 4× Tag-lite red fluorescent ligand to each well. After incubation at room temperature for 1 hour, read the data using the EnVision HTRF mode. Read the excitation intensity at 665 nM and 615 nM in each well, calculate the ratio (Ratio = A665 nM / B615 nM), and calculate the IC50 value using GraphPad Prism 8 software, where X is the logarithm of the compound concentration; Y is the ratio of A665 nM / B615 nM.

[0317] Table 1: AT2R binding activity of compounds

[0318] The experimental results show that the compound of the present invention has a strong binding effect with AT2R.

[0319] Test Example 2: CYP inhibition assay of compounds

[0320] The inhibitory activity of the compounds against seven enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (midazolam), CYP2B6, and CYP2C8, was evaluated at 10 μM. Pooled human liver microsomes were stored at -80°C prior to use. Thawed in a 37°C water bath before use and placed on ice. 100 μL of microsomal working solution was added to 2 μL of the test product or positive inhibitor working solution. 2 μL of solvent was added to the solvent control and preincubated in a 37°C water bath for 10 minutes. Following preincubation, 98 μL of NADPH (reduced coenzyme II) regeneration solution was added to all samples to initiate the reaction. The samples were then returned to the water bath for incubation. The reaction was quenched with 200 μL of stop solution. The plate was centrifuged at 3220 g for 10 min, 100 μL of supernatant was transferred, 100 μL of water was added and mixed thoroughly to the assay plate for LC-MS / MS analysis.

[0321] Table 2: CYP450 inhibition results of compounds

[0322] 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.

[0323] Test Example 3: Free Plasma Protein Binding (PPB) Experiment of Compounds

[0324] Soak the dried dialysis membrane in ultrapure water for 1 hour, then in 20% ethanol for 20 minutes, and rinse the membrane 2-3 times with ultrapure water. Finally, soak in ultrapure water for 20 minutes before use. Thaw the frozen plasma in a 37°C water bath for approximately 20 minutes. Once thawed, measure the plasma pH and adjust it to 7.4 using 1% phosphoric acid solution or 0.1M sodium hydroxide solution. Dilute the test compound into plasma preheated to 37°C to a final concentration of 1 μM. The final concentration of internal reference warfarin in plasma is 2 μM. Assemble the pretreated dialysis membrane into the dialysis plate according to the product instructions, and add 100 μL of receiving solution (100 mM phosphate buffer solution plus 0.002% Tween 80) to one side of the membrane in each dialysis well. Take 20 μL of the final solution of the test compound to be tested and transfer it to a 96-well sample plate. Repeat the test in duplicate to obtain the T0 sample, which is stored in a -20°C refrigerator. Take another 100 μL of the above final solution to the other side of the membrane in the dialysis device, duplicate samples, and incubate at 37°C with constant temperature shaking for 6 hours. After 6 hours of incubation, take 20 μL each of the dialyzed receiving solution and the administered plasma, duplicate samples, to obtain samples B and A. Add the corresponding volume of blank plasma or receiving solution to sample B and sample A, respectively, so that the volume ratio of plasma to buffer in each sample well is 1:1. Add 300 μL of sample containing internal standard acetonitrile solution to all sample wells, mix well, and then centrifuge at 5500×g for 10 minutes. Add 150 μL of corresponding ultrapure water to the corresponding sample wells of the 96-well sample plate, take 150 μL of the supernatant, take it to the sample well, mix well, and perform LC / MS / MS analysis. f u Calculation formula:

[0325] C R : Peak area ratio measured in the receiving chamber

[0326] C D : Peak area ratio measured by supply chamber pore

[0327] The degree of dissociation of a compound in plasma is related to its efficacy in the body. Experimental results show that the compound of the present invention has a high degree of dissociation, which is beneficial for the compound to reach the target organ.

[0328] Test Example 4: Liver microsome stability test of the compound

[0329] The stability test for human liver microsomes was performed by incubating the compounds with human liver microsomes in vitro. The test compound was first prepared as a 10 mM stock solution in DMSO and then diluted to 0.5 mM in acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and this solution was used to dilute a 0.5 mM working solution of the compound to a concentration of 1.5 μM and 0.75 mg / mL in human liver microsomes. In a deep-well plate, 30 μL of the working solution was added to each well. The reaction was then initiated by adding 15 μL of preheated 6 mM NADPH (reduced coenzyme II) solution and incubated at 37°C. The reaction was terminated by adding 135 μL of acetonitrile to the corresponding wells at 0, 5, 15, 30, and 45 minutes of incubation. After terminating the reaction with acetonitrile at the final 45-minute time point, the plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio. LC-MS / MS was then performed to obtain the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minute. The remaining percentage of the compound at each time point was calculated. T was calculated using Graphpad 8 software. 1 / 2 .

[0330] The stability of a compound in liver microsomes reflects its risk of being metabolized and eliminated in the body. The experimental results showed that the test compound had good stability in human liver microsomes.

[0331] Test Example 5: Bidirectional permeability study of compounds in CACO-2 cells

[0332] Caco-2 cells were cultured at a rate of 1 × 10 5 cells / cm 2Cells were plated onto polyethylene membrane (PET) membranes in 96-well inserts at a rate of 100 μg / mL, with medium changes every 4-5 days until day 21-28, to allow for the formation of a confluent cell monolayer. The transport buffer used in the experiments was HBSS (1×) and 10.0 mM HEPES, pH 7.40 ± 0.05. Test compounds were tested at 2.00 μM in both directions in the presence and absence of 10.0 μM GF120918. Digoxin was tested at 10.0 μM in both directions in the presence and absence of 10.0 μM GF120918, while nadolol and metoprolol were tested at 2.00 μM in the A to B direction in the absence of 10.0 μM GF120918, all in duplicate. The final DMSO concentration was adjusted to less than 1%. The plates were incubated for 2 hours in a CO2 incubator at 37 ± 1°C with 5% CO2 in a humidified atmosphere without shaking. All samples were mixed with acetonitrile containing an internal standard and centrifuged at 3200 g for 10 minutes. For nadolol and metoprolol, 200 μL of supernatant was diluted with 600 μL of distilled water for LC-MS / MS analysis. For digoxin and the test compound, 200 μL of supernatant was diluted with 200 μL of distilled water for LC-MS / MS analysis. The concentrations of the test compound in the starting, donor, and acceptor solutions were quantified by LC-MS / MS using the analyte / internal standard peak area ratio. Following the transport assay, the integrity of the Caco-2 cell monolayer was determined using a Lucifer Yellow exclusion assay.

[0333] The experimental results showed that the test compounds had good permeability, which was conducive to compound absorption.

[0334] Test Example 6: Pharmacokinetics of Compounds

[0335] Mouse pharmacokinetic studies were performed using male ICR mice fasted overnight. Three mice were orally gavaged at 10 mg / kg. Blood samples were collected before dosing and at 5, 15, and 30 minutes, as well as 1, 2, 4, 6, 8, and 24 hours after dosing. Approximately 0.05 mL of each sample was anticoagulated with EDTAK2 and placed on wet ice. Plasma was separated by centrifugation within 1 hour (centrifugation conditions: 6000 g, 3 minutes, 2-8°C) and stored at -80°C. Plasma was collected at each time point, completely thawed, mixed for 10-30 seconds, and centrifuged at 4000 rpm at 4°C for 0.5 minutes. 20.0 μL of plasma sample (blank sample and internal standard blank sample plus 20.0 μL of blank plasma) was transferred to a 96-well plate, and 200 μL of a 50% methanol-acetonitrile solution containing the internal standard (100 ng / mL) was added (blank sample plus 200 μL of a 50% methanol-acetonitrile solution). The sample was vortexed for 5 minutes and centrifuged at 4000 rpm and 4°C for 10 minutes. 100 μL of the sample was added to 100 μL of water and mixed thoroughly. An appropriate amount of the mixture was used for LC-MS / MS analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 based on plasma concentration data at different time points.

[0336] For the rat pharmacokinetic study, male SD rats were fasted overnight. Three rats were orally administered 10 mg / kg. Other procedures were the same as for the mouse pharmacokinetic study.

[0337] Table 3: Pharmacokinetics of the test compounds in mice

[0338] Table 4: Pharmacokinetics of the test compounds in rats

[0339] The experimental results show that the test compounds of the present invention have a good exposure in mice, and the test compounds have a good exposure in rats.

[0340] Test Example 7: IPF efficacy test of the compound in mice

[0341] This experiment requires a specific mouse IPF model, which Shanghai Pengli Company is responsible for establishing and conducting the efficacy experiments of the compounds. All animal experimental operation plans are approved by Pengli IACUC (Institute Animal Care and Use Committee).

[0342] The experimental steps include:

[0343] 1. Compound Preparation: Weigh an appropriate amount of compound powder and prepare a DMSO stock solution. Aliquot the required daily dose and prepare it immediately on the day of use. Add the required amount of 10% solutol according to the dilution ratio, vortex to dissolve and mix thoroughly. Finally, add the required amount of 85% saline according to the dilution ratio, with a final DMSO content of 5%, to prepare a clear solution of 0.03 mg / mL.

[0344] 2. Animal Grouping: On the day of modeling, 10 animals were randomly selected and placed directly in the G1 blank group. All other animals received an intratracheal injection of bleomycin for model establishment. After bleomycin injection, animals were randomly assigned to groups using BioBook based on weight changes, body weight, and animal status before the first dose to achieve similar average weights within each group and reduce intergroup variation.

[0345] 3. Model Construction: Dissolve an appropriate amount of bleomycin in commercially available saline. Model group animals were anesthetized with 1-4% isoflurane inhalation and administered 2 units / kg of bleomycin intratracheally. The specific dosage was calculated based on animal weight. G1 group mice were anesthetized with 1-4% isoflurane and injected with an equal volume of saline intratracheally.

[0346] 4. Dosing: The day of bleomycin injection is considered as day 0 of the study. The dosing schedule is as follows:

[0347] Table 5 Grouping and dosing regimen a: The solvent was 5% DMSO + 10% solutol + 85% saline; b: Bi-dose, once in the morning and once in the afternoon, with an interval of approximately 6 hours; no medication was given in the morning on day 22.

[0348] 5. Pulmonary function test: On day 22, all experimental animals were anesthetized with Zoltrate (25-50 mg / kg) and xylazine (5-10 mg / kg), and pulmonary function tests (PFT) were performed on the animals, including PV curve, FVC, IC, VC, Cdyn, and Cchord (quasi-static lung compliance) indicators.

[0349] 6. Lung section pathology examination: Lung tissue was collected, rinsed twice, dried with filter paper, and weighed. After weighing, the left lung was perfused and fixed with 10% neutral formaldehyde solution, and then immersed in 10% neutral formaldehyde solution for fixation and preservation for histopathological scoring. The left lung after formaldehyde fixation was cut transversely into three sections: upper, middle, and lower, and embedded in the same wax block, sliced, and stained with Masson's staining. The pathologist performed histopathological evaluation. The scoring criteria refer to the following table:

[0350] Table 6 Fibrosis scoring criteria

[0351] 7. Animal Euthanasia: All experimental animals will be euthanized by CO2 and cervical dislocation after the in vivo experiment.

[0352] 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.

[0353] The experimental results show that the compound of the present invention can significantly improve FVC, IC, VC lung function indicators, and can significantly improve pulmonary fibrosis scores.

[0354] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound of formula IB, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: Among them, Each R1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl; m is selected from 1, 2, 3, 4, 5, 6; Alternatively, when m is selected from 2, 3, 4, 5, 6, two R1s may form a C3-C7 cycloalkyl or a 3-7 membered heteroalkyl ring with the carbon atom to which they are attached; X 1 and X 2 The atoms are each independently selected from O, S, C; the S may be in the form of its oxide; Ring B is selected from a benzene ring, a 5-6 membered heteroaryl ring; R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; when there are multiple substituents, the substituents are the same or different; n is selected from 0, 1, 2, 3 and 4; R4 is selected from hydrogen, oxo(=O), C1-C3 alkyl and C1-C3 haloalkyl; R5 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and 3-7 membered heteroalkyl ring; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl and 3-7 membered heteroalkyl ring are optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; when there are multiple substituents, the substituents are the same or different; p is selected from 1, 2 and 3; Q is selected from -C(=O)-Z-R2, a 5-8 membered heteroaryl ring; the 5-8 membered heteroaryl ring is optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl and 3-7 membered heteroalkyl ring; when there are multiple substituents, the substituents are the same or different; Z is selected from NRa and O; R2 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heteroalkyl ring; the R2 is optionally substituted with 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, 5-6 membered heteroaryl and 3-7 membered heteroalkyl ring; when there are multiple substituents, the substituents are the same or different; Ra is selected from hydrogen and C1-C3 alkyl.

2. The compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein, The compound is selected from the following structures: Among them, R1, R3, R4, R5, Q, X 1 , X 2 , m and n are defined as described in claim 1.

3. A compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein, The compound is selected from the following structures: Among them, R1, R2, R3, R4, R5, Z, X 1 , X 2 , m and n are defined as described in claim 1.

4. A compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein, The R1 satisfies one or more of the following conditions: a), The R1 is selected from hydrogen, halogen, C1-C3 alkyl and C1-C3 haloalkyl; b), The R1 is selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, CH2F, CHF2 and CF3; c), The R1 is selected from hydrogen, methyl; d), The two R1s may form a C3-C7 cycloalkyl or a 3-7 membered heteroalkyl ring with the carbon atom to which they are attached; e), The two R1s may form a C3-C5 cycloalkyl or a 3-5 membered heteroalkyl ring with the carbon atom to which they are attached; f) The two R1s may form cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, or tetrahydrofuran with the carbon atoms to which they are attached.

5. A compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein, Ring B is selected from a benzene ring and a 5- or 6-membered heteroaromatic ring, and the 5- or 6-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms selected from N, O, and S. And / or, ring B is selected from a benzene ring, furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine. And / or, ring B is selected from a benzene ring and pyridine.

6. A compound of formula IB, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in any one of claims 1-3, wherein, Group fragment having a structure Ring A is selected from C3-C7 cycloalkyl and 3- to 7-membered heteroalkyl. and / or, said group fragment With a structure And / or, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, and tetrahydrofuran. and / or, the group fragment Having a structure and / or, said group fragment With structure 7. A compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein, The compound is selected from the following structures: Wherein, V1, V2, V3, and V4 are each independently CH or N. n, X 1 , X 2 The definitions of Z, R2, R3, R4, and R5 are as described in claim 1; Preferably, n is 0. Preferably, X 1 atom is O, X 2 atom is C; or X 1 atom is C, X 2 atom is O; Preferably, R4 is hydrogen.

8. A compound of formula IB, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as described in any one of claims 1, 2, 3 or 7, wherein, The compound is selected from the following structures: wherein, X 1 and X 2 atoms are not both C at the same time; The said X 1 and X 2 The definitions of R2 and R5 are as described in claim 1.

9. A compound of formula IB, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as described in any one of claims 1, 2, 3 or 7, wherein, R4 is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl. And / or, R3 is selected from hydrogen, F, Cl, methyl, methoxy, trifluoromethyl, difluoromethyl, CH2F, cyclopropyl, and cyano; n is selected from 0, 1, and 2. Optionally, n is selected from 0. Optionally, R4 is selected from hydrogen, methyl, trifluoromethyl, difluoromethyl, and -CH2F. Optionally, R4 is selected from hydrogen.

10. A compound of formula IB, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1, 2, 3 or 7, wherein, The compound is selected from the following structures: Among them, X 1 , X 2 atoms are not C at the same time; The X 1 , X 2 , R2 and R5 are defined as described in claim 1.

11. The compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein, Q is selected from -C(=O)-Z-R2 and a 5- or 6-membered heteroaromatic ring; the 5- or 6-membered heteroaromatic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the following: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, and 3- to 7-membered heteroalkyl; when there are multiple substituents, the substituents are the same or different. The 5- or 6-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms selected from N, O, and S. And / or, the 5- or 6-membered heteroaromatic ring is selected from furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine. And / or, R2 is selected from C1-C4 alkyl, C3-C5 cycloalkyl, 5- or 6-membered heteroaryl, and 3- to 7-membered heteroalkyl; the C1-C4 alkyl, C3-C5 cycloalkyl, 5- or 6-membered heteroaryl, and 3- to 7-membered heteroalkyl are optionally substituted with 1, 2, 3, or 4 substituents selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, and 3- to 7-membered heteroalkyl. And / or, R2 is selected from C1-C4 alkyl-5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl; the C1-C4 alkyl-5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl contain 1, 2, or 3 heteroatoms selected from N, O, and S. And / or, R2 is selected from C1-C4 alkyl, C3-C5 cycloalkyl, 3-7 membered heterocycloalkyl, C1-C4 alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl; the C1-C4 alkyl, C3-C5 cycloalkyl, 3-7 membered heterocycloalkyl, C1-C4 alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 hydroxyl groups or halogens; And / or, R2 is selected from furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, -CH2-pyridine, -CH2-pyrimidine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, oxirane, oxetane, azetidine, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine; R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl.

12. The compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein, Z is selected from O or NH; and / or, said R2 is selected from methyl, butyl, and / or, Q is selected from pyridine, pyrimidine, -C(=O)-O-CH3, -C(=O)-O-CH2CH2CH2CH3, -C(=O)-NH-CH3, -C(=O)-NH-CH2CH2CH2CH3, 13. A compound of formula IB, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as described in any one of claims 1, 2, 3 or 7, wherein, R5 is selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl; the C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl and 3-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; Optionally, said R5 is selected from Cl, CF3, cyclopropyl, oxetane; Optionally, R5 is selected from Cl, CF3.

14. A compound of formula IB, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as described in any one of claims 1, 2, 3 or 7, wherein, The said X 1 and X 2 atoms are each independently selected from O, S, C; the said S may be in the form of its oxide; Optionally, said X 1 and X 2 at least one of the atoms is O; Optionally, only one of said X 1 and X 2 atoms is O; Optionally, said X 1 atom is C, and X 2 atom is O; Optionally, said X 1 atom is O, and the X 2 atom is C.

15. The compound represented by formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein, The compounds include:

16. A pharmaceutical composition, wherein, The pharmaceutical composition comprises: the compound of formula IB as claimed in any one of claims 1-15, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.

17. Use of a compound of formula IB as claimed in any one of claims 1-15, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition as claimed in claim 16, said use comprising: As an AT2R agonist; And / or, preventing and / or treating diseases with insufficient endogenous production of Ang II; And / or, preventing and / or treating diseases where an increased action of Ang II is desired or required; And / or, preparing a drug, pharmaceutical composition or preparation as an AT2R agonist, and / or for preventing and / or treating diseases in which AT2R is expressed and in which stimulation thereof is desired or necessary.

18. The use according to claim 17, wherein, The diseases are gastrointestinal diseases, cardiovascular system diseases, respiratory system diseases, kidney diseases, eye diseases, female reproductive system diseases, central nervous system diseases, diseases related to growth, metabolism and proliferation; Optionally, the respiratory system disease is asthma, obstructive lung disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis.

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