WO2025146172A1 - Fused ring compound as at2r agonist - Google Patents

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 cyclopentane compound as an AT2R agonist

Priority information

The present invention claims priority and benefits of patent application 202410008284.2 filed with China National Intellectual Property Administration on January 3, 2024, patent application 202410299768.7 filed with China National Intellectual Property Administration on March 14, 2024, and patent application 202411002306.0 filed with China National Intellectual Property Administration on July 24, 2024, and the entire texts of which are incorporated herein by reference.

Technical Field

The present invention belongs to the field of medicine, and in particular, relates to a paracyclic compound as an angiotensin II (Ang II) type 2 receptor (AT2R) agonist.

Background Art

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

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

It has been suggested that AT2R agonists may be useful in the treatment and/or prevention of digestive tract disorders, such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure.

There remains a need for potent and/or selective AT2R agonists that would be useful in the above-mentioned diseases.

Summary of the invention

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, a pharmaceutical composition or a preparation for treating and/or preventing a disease or condition associated with AT2R; or to treat and/or prevent a disease or condition associated with AT2R.

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:

wherein each R ₁ is independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; m is selected from 1, 2, 3, 4, 5, 6;

Alternatively, when m is selected from 2, 3, 4, 5, and 6, two R _1s may form a C ₃ -C ₇ cycloalkyl or a 3-7 membered heterocycloalkyl with the carbon atom to which they are attached;

^X1 and ^X2 atoms are each independently selected from O, S, C; said S may be in the form of its oxide;

Ring B is selected from a benzene ring, a 5-6 membered heteroaromatic 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 by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 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;

R ₄ is selected from hydrogen, oxo (=O), C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl;

_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 by 1, 2, ₃ or 4 substituents selected from the following: halogen, hydroxyl, 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)-ZR ₂ , 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, hydroxyl, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ -C ₇ cycloalkyl and 3-7 membered heterocycloalkyl; 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 heterocycloalkyl; said _R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 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;

Ra is selected from hydrogen and C ₁ -C ₃ alkyl.

In a preferred embodiment of the present invention, the Selected from

In a preferred embodiment of the present invention, the Selected from

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

wherein each R ₁ is independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; m is selected from 1, 2, 3, 4, 5, 6;

Alternatively, when m is selected from 2, 3, 4, 5, and 6, two R _1s may form a C ₃ -C ₇ cycloalkyl or a 3-7 membered heterocycloalkyl with the carbon atom to which they are attached;

^X1 and ^X2 atoms are each independently selected from O, S, C; said S may be in the form of its oxide;

Ring B is selected from a benzene ring, a 5-6 membered heteroaromatic 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 by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 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;

R ₄ is selected from hydrogen, oxo (=O), C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl;

_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 by 1, 2, ₃ or 4 substituents selected from the following: halogen, hydroxyl, cyano, _C1 - _C6 alkyl, _C1 - _C6 alkoxy; when there are multiple substituents, the substituents are the same or different;

Q is selected from -C(=O)-ZR ₂ , 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, hydroxyl, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ -C ₇ cycloalkyl and 3-7 membered heterocycloalkyl; 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 heterocycloalkyl; said _R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 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;

Ra is selected from hydrogen and C ₁ -C ₃ alkyl.

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

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , Z, X ¹ , X ² , m and n are as defined in the first aspect of the present invention.

In a preferred embodiment of the present invention, in Formula I, R ₁ is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

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

Alternatively, when m is selected from 2, 3, 4, 5, and 6, two R _1s may form a C ₃ -C ₇ cycloalkyl or a 3-7 membered heterocycloalkyl with the carbon atom to which they are attached;

^X1 and ^X2 atoms are each independently selected from O, S, C; said S may be in the form of its oxide;

Z is selected from NRa and O;

_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, hydroxyl, 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;

_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 by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 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;

R ₄ is selected from hydrogen, oxo (=O), C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl;

_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 by 1, 2, ₃ or 4 substituents selected from the following: halogen, hydroxyl, cyano, _C1 - _C6 alkyl, _C1 - _C6 alkoxy; when there are multiple substituents, the substituents are the same or different;

Ra is selected from hydrogen and C ₁ -C ₃ alkyl.

In a preferred embodiment of the present invention, R ₁ is selected from hydrogen, halogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl.

In a preferred embodiment of the present invention, said R ₁ is selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, CH ₂ F, CHF ₂ and CF ₃ .

In a preferred embodiment of the present invention, the R ₁ is selected from hydrogen and methyl.

In a preferred embodiment of the present invention, the two R _1s may form a C ₃ -C ₇ cycloalkyl group or a 3-7 membered heterocycloalkyl group with the carbon atoms to which they are connected.

In a preferred embodiment of the present invention, the two R _1s may form a C ₃ -C ₅ cycloalkyl group or a 3-5 membered heterocycloalkyl group with the carbon atoms to which they are connected.

In a preferred embodiment of the present invention, the two R ₁ can form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxirane group, an azirane group, an oxetanyl group, an azetidinyl group, or a tetrahydrofuran group with the carbon atoms to which they are connected.

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

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

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.

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.

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

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

In a preferred embodiment of the present invention, the ring A is selected from C ₃ -C ₇ cycloalkyl and 3-7 membered heterocycloalkyl.

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

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

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

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

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

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

wherein V ₁ , V ₂ , V ₃ , and V ₄ are each independently CH or N;

n, X ¹ , X ² , Z, R ₂ , R ₃ , R ₄ and R ₅ are as defined in the first aspect of the present invention.

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

wherein the ^X1 atom is O and the ^X2 atom is C; or the ^X1 atom is C and the ^X2 atom is O;

V ₁ , V ₂ , V ₃ , and V ₄ are each independently CH or N;

n, X ¹ , X ² , Z, R ₂ , R ₃ , R ₄ and R ₅ are as defined in the first aspect of the present invention.

In a preferred embodiment of the present invention, n is zero.

In a preferred embodiment of the present invention, _R4 is hydrogen.

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

wherein the ^X1 atom is O and the ^X2 atom is C; or the ^X1 atom is C and the ^X2 atom is O;

V ₁ , V ₂ , V ₃ , and V ₄ are each independently CH or N;

n, X ¹ , X ² , Z, R ₂ , R ₃ , R ₄ , and R ₅ are as defined in the first aspect of the present invention;

Preferably, n is 0;

Preferably, _R4 is hydrogen.

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

Wherein, the atoms X ¹ and X ² are not C at the same time;

The definitions of X ¹ , X ² , Z, R ₂ , R ₃ , R ₄ and R ₅ are the same as those described in the first aspect of the present invention.

In a preferred embodiment of the present invention, R ₄ is selected from hydrogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl.

In a preferred embodiment of the present invention, R ₄ is selected from hydrogen, methyl, trifluoromethyl, difluoromethyl, and CH ₂ F.

In a preferred embodiment of the present invention, said R ₄ is selected from hydrogen.

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

Wherein, the atoms X ¹ and X ² are not C at the same time;

The definitions of X ¹ , X ² , R ₂ and R ₅ are as described in the first aspect of the present invention.

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

Wherein, the atoms X ¹ and X ² are not C at the same time;

The definitions of X ¹ , X ² , R ₂ and R ₅ are as described in the first aspect of the present invention.

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

Wherein, the atoms X ¹ and X ² are not C at the same time;

The definitions of X ¹ , X ² , R ₂ and R ₅ are as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, Q is selected from -C(=O)-ZR ₂ , 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, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ -C ₇ cycloalkyl and 3-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different;

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

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.

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

In a preferred embodiment of the present invention, Z is selected from O or NH ₂ .

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

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; 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.

In a preferred embodiment of the present invention, R ₂ is selected from C ₁ -C ₄ alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl; the C ₁ -C ₄ alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O and S.

_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; 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.

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

In a preferred embodiment of the present invention, the R ₂ is selected from methyl, butyl,

In a preferred embodiment of the present invention, Q is selected from pyridine, pyrimidine, -C(=O)-O-CH ₃ , -C(=O)-O-CH ₂ CH ₂ CH ₂ CH ₃ , -C(=O)-NH-CH ₃ , -C(=O)-NH-CH ₂ CH ₂ CH ₂ CH ₃ ,

In a preferred embodiment of the present invention, _R2 is selected from _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl and 3-7 membered heterocycloalkyl; 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.

In a preferred embodiment of the present invention, R ₂ is selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, 3-7 membered heterocycloalkyl and C ₁ -C ₄ alkyl optionally substituted by 1, 2, 3 or 4 hydroxyl groups or halogens.

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

In a preferred embodiment of the present invention, the R ₂ is selected from methyl, butyl,

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

In a preferred embodiment of the present invention, the R ₂ is selected from methyl and butyl.

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 with 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.

In a preferred embodiment of the present invention, the R ₃ is selected from hydrogen, F, methyl, methoxy, trifluoromethyl, difluoromethyl, CH ₂ F, cyclopropyl, and cyano.

In a preferred embodiment of the present invention, said R ₃ is selected from hydrogen, F, and methyl.

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

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

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

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; 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.

In a preferred embodiment of the present invention, said R ₅ is selected from Cl, CF ₃ , Cyclopropyl, oxetane.

In a preferred embodiment of the present invention, said R ₅ is selected from Cl and CF ₃ .

In a preferred embodiment of the present invention, the ^X1 and ^X2 atoms are each independently selected from O, S, and C.

In a preferred embodiment of the present invention, when the ^X1 and ^X2 atoms are each independently selected from S, the S may be in the form of an oxide thereof.

In a preferred embodiment of the present invention, the ^X1 and ^X2 atoms are each independently selected from sulfone and sulfoxide.

In a preferred embodiment of the present invention, at least one of the ^X1 and ^X2 atoms is O.

In a preferred embodiment of the present invention, only one of the ^X1 and ^X2 atoms is O.

In a preferred embodiment of the present invention, the ^X1 atom is C, and the ^X2 atom is O.

In a preferred embodiment of the present invention, the ^X1 atom is O and the ^X2 atom is C.

In a preferred embodiment of the present invention, the compound represented by formula IB, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound comprises:

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

In a third aspect, the present invention provides uses of the compound of formula IB as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, the uses comprising:

As an AT2R agonist;

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

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

and/or, preparing a medicament, pharmaceutical composition or formulation 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.

Provided is a compound of formula IB as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, which is expected to be used to treat gastrointestinal diseases, cardiovascular system diseases, respiratory system diseases, kidney diseases, eye diseases, female reproductive system diseases, central nervous system diseases, and growth metabolism and proliferation-related diseases.

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

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.

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

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

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

DETAILED DESCRIPTION OF THE INVENTION

Terms and Definitions

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

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

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

Definitions of standard chemical terms can be found in the literature, 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 specific definitions are provided, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for the use of the kit can be used, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention. The above techniques and methods can generally be carried out 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 parts and compounds.

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH ₂ O is equivalent to OCH ₂ . As used herein, Indicates the attachment site of a group. As used herein, "R ₁ ", "R1" and "R ¹ " have the same meaning and can be replaced with each other. For other symbols such as R ₂ , similar definitions have the same meaning.

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

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

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

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

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

As used herein, the term "amino" by itself or as part of another substituent means _-NH2 .

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

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

As used herein, the term "amino" by itself or as part of another substituent means _-NH2 .

In the present application, when alone or as part of other substituents, the term "alkyl" means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl. Alkyl can be unsubstituted or substituted with one or more suitable substituents. Alkyl can also be an isotope isomer of a natural abundance alkyl rich in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds. The alkyl, alkenyl, and alkynyl groups as described herein may 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 may be monovalent, divalent, or multivalent.

In the present application, the term "C ₁ -C ₆ 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 ("C ₁ -C ₄ alkyl"), for example methyl, methylene, ethyl, n-propyl, isopropyl, butyl or isobutyl. In particular, the radical has 1, 2 or 3 carbon atoms ("C ₁ -C ₃ alkyl"), for example methyl, methylene, ethyl, n-propyl or isopropyl.

In the present application, when alone or as part of other substituents, the term "C ₁ -C ₆ alkoxy" is 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 -OC ₁ -C ₆ alkyl as defined in the present specification, or the oxygen atom can be attached to any carbon atom of the straight or branched chain of the C ₁ -C ₆ alkyl. Including but not limited to: methoxy (CH ₃ -O-), ethoxy (C ₂ H ₅ -O-), propoxy (C ₃ H ₇ -O-), butoxy (C ₄ H ₉ -O-), ethyloxyethyl (-C ₂ H ₄ -OC ₂ H ₅ ). For example, the term "C ₁ -C ₃ alkoxy" includes but is not limited to: methoxy (CH ₃ -O-), ethoxy (C ₂ H ₅ -O-).

In the present application, the term "oxo" alone or as part of other substituents refers to the replacement of two hydrogen atoms on a methylene group by oxygen, that is, the methylene group is replaced by a carbonyl group, representing =0.

In the present application, when alone or as part of other substituents, the term "cycloalkyl" or "carbocyclyl" refers to a cyclic alkyl group. The term "mn-membered cycloalkyl" or "C _m -C _n cycloalkyl" should be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring with m to n atoms. Including monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of unsubstituted cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or bicyclic hydrocarbon groups such as decalin rings. Cycloalkyl groups may be substituted by one or more substituents. In some embodiments, cycloalkyl groups may be cycloalkyl groups fused to aryl or heteroaryl groups. For example, the term "3-7-membered cycloalkyl" or "C ₃ -C ₇ 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 "C ₃ -C ₅ cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 5 carbon atoms, such as cyclopropyl, cyclobutyl, and cyclopentyl.

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

In the present application, "haloalkyl" refers to saturated aliphatic hydrocarbon groups including branched and straight chains having a specific number of carbon atoms, substituted with one or more halogens (such as -CvFw, where v = 1 to 3, w = 1 to (2v+1)) when alone or as part of other substituents. 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 1-3 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.

In the present application, "haloalkoxy" refers to an alkoxy group as described above, either alone or as part of another substituent, wherein any number (at least one) of 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 1-6 carbon atoms and oxygen atoms, wherein any number (at least one) of hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine, including but not limited to trifluoromethoxy, trichloromethoxy, pentafluoroethoxy.

In the present application, when alone or as part of other substituents, the term "heterocycloalkyl" or "heterocyclyl" 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" can be saturated or unsaturated, but not aromatic. "Heterocycloalkyl" or "heterocyclyl" can also contain 1, 2 or 3 rings, including cyclic, 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 with 3 to 7 atoms, wherein the heteroatoms are preferably selected from N, O and S, and it should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl include, but are not limited to, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl.

In the present 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 heteroatoms or carbon atoms. The term "5-8 heteroaryl" means 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 nitrogen, sulfur and phosphorus heteroatoms can be optionally oxidized (i.e., NO, S(O)p and P(O)p, p is 1 or 2). The term "5-6 heteroaromatic ring" includes 5 and 6 heteroaromatic rings. Examples of the 5-6 heteroaromatic rings include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrazinyl or pyrimidinyl.

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

In the present application, the term "optionally substituted by" or "optionally substituted by" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from possible substituents. For example, "aryl is optionally substituted by 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C _1-6 alkyl" means that aryl is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, cyano, hydroxyl, C _1-6 alkyl, and the description includes both substituted aryl and unsubstituted aryl.

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

In this application, the term "pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or organic acid that retains the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or organic base that retains the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.

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

In the present application, the term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in molecules, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

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

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

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

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

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

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 forces between molecules. When the solvent is water, it is a hydrate.

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

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds. For example, radioactive isotope labeled compounds may be used, such as deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ) or carbon-14 ( ^14C ). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.

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

(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;

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

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

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

Beneficial Effects

The inventors have unexpectedly developed a paracyclic compound as an AT2R agonist through extensive and in-depth research, wherein the compound has the structure shown in the present invention. The paracyclic compound of the present invention can prevent or treat diseases or conditions related to AT2R, exhibits excellent pharmacokinetic properties, and has high safety and drug-forming properties.

DETAILED DESCRIPTION

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

This application has the following definitions:

Symbol or unit:

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

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

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

RT: retention time

Reagents:

Pd(dppf)Cl ₂ -DCM: 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride complex

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

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)Cl ₂ ：(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride

DMF: N,N-dimethylformamide

DIPEA: N,N-diisopropylethylamine

EA: Ethyl acetate

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

MeOH: Methanol

PE: Petroleum ether

Toluene: Toluene

THF: Tetrahydrofuran

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

Test method:

LCMS: Liquid chromatography-mass spectrometry

TLC: Thin layer chromatography

Example 1: Preparation of target compound I-1

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

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

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

At 25°C, the raw 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), and then potassium phosphate (7.10 g, 33.46 mmol) and Pd(dppf)Cl ₂ -DCM (613.68 mg, 836.39 μmol) were added. After nitrogen was replaced, the reaction mixture was stirred at 25°C for 3 hours. LCMS was used to monitor the reaction progress. After the reaction was completed. Water (50 mL) was added to dilute the reaction solution, and it was extracted with ethyl acetate (50 mL×2). The organic phase was washed with saturated brine (50 mL×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 obtain 5-bromo-2-(2-methylprop-1-en-1-yl)phenol (3.0 g).

LC-MS, M/Z(ESI):227.1[M+H] ⁺

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

At 25°C, the raw material 5-bromo-2-(2-methylprop-1-en-1-yl)phenol (7.2g, 31.70mmol) was dissolved in dichloromethane (100mL), and then iodine (4.02g, 15.85mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. LCMS monitored that the raw material reaction was complete and the desired product was generated. After the reaction was completed, water (100mL) was added to dilute the reaction solution, and dichloromethane (100×2) was extracted. The organic phase was washed with saturated sodium thiosulfate (100×2) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain the product 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (6.0g).

LC-MS, M/Z(ESI):227.1[M+H] ⁺

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

At 25°C, the raw material 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), and then Xantphos (509.03 mg, 880.68 μmol) and Pd ₂ (dba) ₃ (402.9 mg, 440.34 μmol) and N,N-diisopropylethylamine (1.71 g, 13.21 mmol) were added. After replacing nitrogen, the reaction mixture was stirred at 100°C for 16 hours. LCMS monitored that the raw material reaction was complete and the desired product was generated. After the reaction was completed. Water (20 mL) was added to dilute the reaction solution, and it was extracted with ethyl acetate (20 mL×3). The organic phase was washed with brine (20 mL×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 obtain 6-(benzylthio)-2,2-dimethyl-2,3-dihydro-1-benzofuran (700 mg).

LC-MS, M/Z(ESI):271.0[M+H] ⁺

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

At 25°C, the raw material 6-(benzylthio)-2,2-dimethyl-2,3-dihydro-1-benzofuran (360 mg, 1.33 mmol) was dissolved in acetonitrile (10 mL), and then N-bromosuccinimide (355.45 mg, 2.0 mmol) and trifluoroacetic acid (182.17 mg, 1.60 mmol) were added. After replacing the nitrogen, the reaction mixture was stirred at 25°C for 16 hours. LCMS monitored 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, extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with brine (20 mL × 2) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column to obtain 6-(benzylthio)-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (350.0 mg).

LC-MS,M/Z(ESI):348.7/350.7[M+H] ⁺

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

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), and then N-chlorosuccinimide (917.51 mg, 6.87 mmol) was added. The reaction mixture was stirred at 50°C for 2 hours. LCMS monitored 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 it was 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).

LC-MS,M/Z(ESI):320.0/321.8[M+H] ⁺

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

At 25°C, under nitrogen protection, the raw material 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonyl chloride (240 mg, 737.09 μmol) was added in batches to a mixed solvent of dichloromethane (5 mL) of tert-butylamine (80.86 mg, 1.11 mmol) and triethylamine (223.76 mg, 2.21 mmol). After the addition was completed, the reaction mixture was stirred at 25°C for 16 hours. LCMS monitored that the raw material reaction was complete and the desired product was generated. After the reaction was completed. Water (5 mL) was added to dilute the reaction solution, extracted with ethyl acetate (5 mL×3), and 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 separated and purified by silica gel column chromatography to obtain 5-bromo-N-(tert-butyl)-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonamide (160.0 mg).

LC-MS,M/Z(ESI):305.8/307.8[M+H-56] ⁺

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

At 25°C, the raw material 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), and then potassium carbonate (134.08 mg, 0.97 mmol) and Pd(dppf)Cl ₂ (32.40 mg, 44.16 μmol) were added. After replacing nitrogen, the reaction mixture was stirred at 80°C for 16 hours. LCMS monitored 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 (5 mL), extracted with ethyl acetate (5 mL × 3), and the organic phase was washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was 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).

LC-MS, M/Z(ESI):474.0[M+H] ⁺

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

At 25°C, the raw 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), and trifluoroacetic acid (28.86 mg, 253.16 μmol, 1 mL) was added. The reaction mixture was stirred at 60°C for 16 hours. LCMS monitored that the raw material reaction was complete and the desired product was generated. After the reaction was completed. 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 product).

LC-MS, M/Z(ESI):418.0[M+H] ⁺

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

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 (100.0mg, 239.29μmol) was dissolved in dichloromethane (3mL), and then N,N-diisopropylethylamine (92.60mg, 0.717mmol) and methyl chloroformate (22.61mg, 239.29μmol) were added. The reaction mixture was stirred for 2 hours under ice-water bath conditions. LCMS monitored that the raw material reaction was complete and the desired product was generated. After the reaction was completed, water (10mL) was added to dilute the reaction solution, and it was extracted with dichloromethane (10mL×2). The organic phase was washed with brine (10mL×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 Pre-HPLC (FA) to give the product 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).

LC-MS, M/Z(ESI):475.9[M+H] ⁺

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

Example 2: Preparation of target compound I-2

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

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

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

At 25°C, the raw material 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (1g, 4.40mmol) was dissolved in acetonitrile (20mL), and then N-iodosuccinimide (1.19g, 5.28mmol) and trifluoroacetic acid (602.51mg, 5.28mmol, 404.64μL) were added. After replacing the nitrogen, the reaction mixture was stirred at 25°C for 16 hours. LCMS monitored that the raw material reaction was complete and the desired product was generated. After the reaction was completed. Water (20mL) was added to dilute the reaction solution, extracted with ethyl acetate (20mL×3), and the organic phase was washed with brine (20mL×2) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column to obtain 6-bromo-5-iodo-2,2-dimethyl-2,3-dihydrobenzofuran (800.0mg).

LC-MS,M/Z(ESI):351.6/351.7[M+H] ⁺

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

At 25°C, the raw material 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), and then Xantphos (222.69 mg, 385.28 μmol) and Pd ₂ (dba) ₃ (176.26 mg, 192.64 μmol) and N,N-diisopropylethylamine (746.90 mg, 5.78 mmol) were added. After replacing nitrogen, the reaction mixture was stirred at 100°C for 16 hours. LCMS monitored that the raw material reaction was complete and the desired product was generated. After the reaction was completed. Water (20 mL) was added to dilute the reaction solution, and it was extracted with ethyl acetate (20 mL×3). The organic phase was washed with brine (20 mL×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 obtain 5-(benzylthio)-6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (590.0 mg).

LC-MS,M/Z(ESI):348.9/350.9[M+H] ⁺

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

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), and then N-chlorosuccinimide (1.15 g, 8.59 mmol) was added. The reaction mixture was stirred at 50°C for 2 hours. LCMS monitored 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 it was 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).

LC-MS,M/Z(ESI):319.7/321.9[M+H] ⁺

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

At 25°C, under nitrogen protection, the raw material 6-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (280 mg, 859.93 μmol) was added in batches to a mixed solvent 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 was completed, the reaction mixture was stirred at 25°C for 16 hours. LCMS monitored that the raw material reaction was complete and the target product was generated. After the reaction was completed. Water (5 mL) was added to dilute the reaction solution, extracted with ethyl acetate (5 mL × 3), and the organic phase was washed with brine (5 mL × 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).

LC-MS, M/Z(ESI):362.3[M+H] ⁺

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

At 25°C, the raw material 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), and then potassium carbonate (148.78 mg, 1.08 mmol) and Pd(dppf)Cl ₂ (52.66 mg, 71.77 μmol) were added. After replacing nitrogen, the reaction mixture was stirred at 80°C for 16 hours. LCMS monitored 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 (5 mL), extracted with ethyl acetate (5 mL × 3), and the organic phase was washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was 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).

LC-MS, M/Z(ESI):474.0[M+H] ⁺

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

At 25°C, the raw 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), and then trifluoroacetic acid (28.86 mg, 253.16 μmol, 1 mL) was added. The reaction mixture was stirred at 60°C for 16 hours. LCMS monitored that the raw material reaction was complete and the desired product was generated. After the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a 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 product).

LC-MS, M/Z(ESI):417.9[M+H] ⁺

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

In an ice-water bath, the raw 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), and then N,N-diisopropylethylamine (201.02 mg, 1.56 mmol, 270.91 μL) and methyl carbon tetrachloride (26.46 mg, 279.97 μmol) were added. The reaction mixture was stirred for 2 hours under ice-bath conditions. LCMS monitored 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 it was 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. The crude product was purified by preparative thin layer chromatography (Prep TLC) and then purified by preparative separation to obtain 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%).

LC-MS, M/Z(ESI):475.9[M+H] ⁺

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)

Example 3: Preparation of target compound I-9

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

The synthetic route of the target compound I-9 is as follows:

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

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 (150.0mg, 358.93μmol) was dissolved in dichloromethane (10mL), and then triethylamine (139.16mg, 1.38mmol,) and tetrahydro-2H-pyran-4-ylcarbonyl chloride (59.08mg, 358.93μmol) were added. The reaction mixture was stirred under ice-water bath conditions for 2 hours. LCMS monitored that the raw material reaction was complete and the desired product was generated. Water (10mL) was added to dilute the reaction solution, and it was extracted with dichloromethane (10mL×2). The organic phase was washed with brine (10mL×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 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, yield 24.75%).

LC-MS, M/Z(ESI):546.3[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )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).

Example 4: Preparation of target compound I-5

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

The synthetic route of the target compound I-5 is as follows:

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

At room temperature, 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), and then stirred in a microwave at 120° C. for 0.5 hours. After the reaction was completed, 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, yield 73.1%).

LC/MS(ESI)(m/z):518.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )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),3.9 0(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).

Example 5: Preparation of target compound I-8

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

The synthetic route of the target compound I-8 is as follows:

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

At room temperature, 2-(trifluoromethyl)-1H-imidazole (916 mg, 6.73 mmol) was dissolved in N,N-dimethylformamide (12 mL), and potassium carbonate (1.86 g, 13.5 mmol) and 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.00 g, 6.73 mmol) were added. After the addition, the mixture was reacted at 25°C for 12 hours. After the reaction was completed, ethyl acetate (50 mL) was added for dilution, and the mixture was washed with water (50 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. The crude product was 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%).

LC/MS(ESI)(m/z):353.1[M+H] ⁺

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

At room temperature, 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), and then 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 added. After the addition was completed, the mixture was reacted at 80° C. under a nitrogen atmosphere for 12 hours. After the reaction was completed, 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. 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%).

LC/MS(ESI)(m/z):508.6[M+H] ⁺

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

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, 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 obtain 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%).

LC/MS(ESI)(m/z):452.5[M+H] ⁺

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

At room temperature, 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), 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, the mixture was reacted at room temperature of 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 and then separated. The aqueous phase was extracted three times with dichloromethane (5 mL), and the organic phases were combined and washed with saturated sodium chloride solution (10 mL). After drying over anhydrous sodium sulfate, it was filtered and concentrated to give ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamic acid methyl ester (56 mg, yield 100%).

LC/MS(ESI)(m/z):510.5[M+H] ⁺

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

At room temperature, 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), and then microwaved at 120° C. for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure and the 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, yield 21.6%).

LC/MS(ESI)(m/z):552.1[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ )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＝6.4 Hz,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).

Example 6: Preparation of target compound I-10

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

The synthetic route of the target compound I-10 is as follows:

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

At room temperature, 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), 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 completed, the mixture was reacted at room temperature of 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 and then separated. The aqueous phase was extracted three times with dichloromethane (5 mL), and 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 ((5-(4-((2-trifluoromethyl-1H-imidazol-1-yl)methyl)phenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)sulfonyl)carbamic acid tetrahydropyran-4-yl ester (18 mg, yield 28.1%).

LC/MS(ESI)(m/z):580.2[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ )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),4.80–4.74(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).

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

Biological Testing

Test Example 1: Compound binding to AT2R

The experiment was performed according to the experimental operation manual of the Angiotensin AT2 Receptor Ligand Binding Assay Kit (#C1TT1AT2, Cisbio). First, the 10mM compound stock solution was diluted in a gradient manner according to the dilution multiple of 5× (including 10 concentrations, each concentration was repeated twice), and 160nL of different concentrations of the compound was added to a 384-well plate. 40μL 1×TLB (TLB: Tag-lite buffer) was added to each well and shaken at room temperature for 15 minutes. A 15mL centrifuge tube with 5mL 1×TLB was prepared in advance for use. The frozen labeled cells were thawed in a 37℃ water bath (1-2 minutes), and the thawed cells were quickly transferred to the above 15mL centrifuge tube. After mixing, centrifuge at 1000g for 5 minutes at room temperature. The supernatant was removed and 2.7mL 1×TLB was added to resuspend the cells. Take a new 384-well plate and add 10μL of the mixed cells to the corresponding wells according to the experimental design. Add 5 μL 4× compound solution and 5 μL 4× Tag-lite red fluorescent labeled ligand to each well. After incubation at room temperature for 1 hour, read the data using the HTRF mode of EnVision. Read the 665nM and 615nM excitation light intensities in each well, calculate the ratio (Ratio＝A665nM/B615nM), and use GraphPad Prism8 software to calculate the IC50 value, X: logarithm of compound concentration; Y: ratio of A665nM/B615nM.

Table 1: Binding activity of compounds to AT2R

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

Test Example 2: CYP inhibition assay of compounds

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

Table 2: CYP450 inhibition results of compounds

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.

Test Example 3: Free plasma protein binding (PPB) experiment of compounds

After soaking the dried dialysis membrane in ultrapure water for 1 hour, soak it in 20% ethanol for 20 minutes, and then rinse the membrane with ultrapure water 2-3 times. Finally, soak it in ultrapure water for 20 minutes for use. Thaw the frozen plasma in a 37°C water bath for about 20 minutes. After thawing completely, measure the plasma pH value and adjust its pH value to 7.4 with 1% phosphoric acid solution or 0.1M sodium hydroxide solution. Dilute the compound to be tested into plasma preheated to 37°C to a final concentration of 1μM, and the final concentration of internal reference warfarin in plasma is 2μM. Assemble the pretreated dialysis membrane into the dialysis plate according to the product instructions, and add 100μL of receiving solution (100mM phosphate buffer solution plus 0.002% Tween 80) to one side of the permeable membrane in each dialysis well. Take 20μL of the final solution of the compound to be tested to a 96-well sample plate, duplicate it, and obtain T0 samples, which are 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, make two duplicate samples, and incubate at 37°C with constant temperature shaking for 6 hours. After 6 hours of incubation, take 20 μL of the dialyzed receiving solution and the administered plasma, make two duplicate samples, and 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 supernatant, take it to the sample well, mix well, and perform LC/MS/MS analysis. _{f u} calculation formula:

_CR : Peak area ratio measured in the receiving chamber well

C _D : Peak area ratio measured by the supply chamber hole

The degree of dissociation of the 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 conducive to the compound reaching the target organ.

Test Example 4: Liver microsome stability test of the compound

The stability test of human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. First, the compound to be tested was prepared into a 10mM stock solution in DMSO solvent, and then the compound was diluted to 0.5mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome/buffer solution, and the solution was used to dilute 0.5mM of the compound to form a working solution. The compound concentration in the working solution was 1.5μM and the human liver microsome concentration was 0.75mg/mL. Take a deep well plate, add 30μL of working solution to each well, and then add 15μL of preheated 6mM NADPH (reduced coenzyme II) solution to start the reaction and incubate at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135μL of acetonitrile was added to the corresponding wells to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep well plate was vortexed for 10 minutes (600rpm/min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio for LC-MS/MS detection. The ratio of the peak area of the compound to the peak area of the internal standard at each time point was obtained. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minute, and the remaining percentage of the compound at each time point was calculated. T _1/2 was calculated using Graphpad 8 software.

The stability of a compound in liver microsomes reflects its risk of being metabolized and eliminated in vivo. The experimental results show that the tested compound has good stability in human liver microsomes.

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

Caco-2 cells were seeded at 1×10 ⁵ cells/cm ² onto polyethylene membrane (PET) in 96-well inserts, and the medium was changed every 4-5 days until day 21-28 to form a confluent cell monolayer. The transport buffer in the experiment was HBSS (1×) and 10.0 mM HEPES, pH 7.40±0.05. The test compounds were tested bidirectionally at 2.00 μM in the presence and absence of 10.0 μM GF120918. Digoxin was tested bidirectionally at 10.0 μM in the presence and absence of 10.0 μM GF120918, while nadolol and metoprolol were tested in the A to B direction at 2.00 μM in the absence of 10.0 μM GF120918, all in duplicate wells. The final DMSO concentration was adjusted to less than 1%. The plates were incubated for 2 h in a CO ₂ incubator at 37 ± 1 °C with 5% CO ₂ added under saturated humidity without shaking. All samples were mixed with acetonitrile containing internal standard and centrifuged at 3200 g for 10 min. For nadolol and metoprolol, 200 μL of supernatant was diluted with 600 μL of distilled water for LC-MS/MS analysis. For digoxin and test compounds, 200 μL of supernatant was diluted with 200 μL of distilled water for LC-MS/MS analysis. The concentrations of test compounds in the starting solution, donor solution, and acceptor solution were quantified by LC-MS/MS method using the peak area ratio of analyte/internal standard. After the transport assay, the integrity of the Caco-2 cell monolayer was determined by the Lucifer yellow exclusion assay.

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

Test Example 6: Pharmacokinetics of Compounds

Mouse pharmacokinetic test, using male ICR mice, fasted overnight. Three mice were taken and 10 mg/kg was orally administered by gavage. Blood was collected before administration and at 5, 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours after administration. About 0.05 mL of each sample was collected, anticoagulated with EDTAK2, placed on wet ice after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6000g, 3 minutes, 2-8°C), and stored at -80°C. Take the plasma at each time point, after complete melting, mix for 10 to 30 seconds, and centrifuge at 4000rpm and 4°C for 0.5 minutes. Transfer 20.0 μL of plasma sample (blank sample and internal standard blank sample plus 20.0 μL of blank plasma) to a 96-well plate, and add 200 μL of 50% methanol acetonitrile solution containing internal standard (100 ng/mL) (blank sample adds 200 μL 50% methanol acetonitrile solution). After vortexing the sample for 5 minutes, centrifuge at 4000 rpm and 4°C for 10 minutes, pipette 100 μL into 100 μL of water, mix well, and take an appropriate amount of the mixture for LC-MS/MS analysis. The blood drug concentration data at different time points were used to calculate the pharmacokinetic parameters using Phoenix WinNonlin8.2.0.

For the rat pharmacokinetic test, male SD rats were used and fasted overnight. Three rats were taken and 10 mg/kg was administered orally by gavage. The rest of the operation was the same as the mouse pharmacokinetic test.

Table 3: Pharmacokinetics of the test compounds in mice

Table 4: Pharmacokinetics of the test compounds in rats

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.

Test Example 7: IPF efficacy experiment of compound in mice

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

The experimental steps include:

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

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

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

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

Table 5 Grouping and dosing regimen

a: The solvent is 5% DMSO + 10% solutol + 85% saline;
b: bid, once in the morning and once in the afternoon, with an interval of about 6 hours; no medication in the morning of day 22.

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

6. Pathological examination of lung sections: Collect lung tissue, rinse twice, wipe dry with filter paper and weigh. After weighing, the left lung is perfused and fixed with 10% neutral formaldehyde solution, and then immersed in 10% neutral formaldehyde solution for fixation and preservation for histopathological scoring. The left lung fixed with formaldehyde is transversely cut into three sections, upper, middle and lower, and embedded in the same wax block, sliced, and stained with Masson’s, and then evaluated by a pathologist for histopathology. The scoring criteria refer to the following table:

Table 6 Fibrosis scoring criteria

7. Animal euthanasia: All experimental animals will be euthanized by _CO2 and cervical dislocation after the in vivo experiment.

Statistical analysis: The experimental data were expressed as mean ± standard error (mean ± S.E.M). SPSS or Graphpad Prism was used to analyze the data. P < 0.05 was considered to be statistically significant.

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

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

Claims (18)

The compound represented by formula IB, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
wherein each R ₁ is independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; m is selected from 1, 2, 3, 4, 5, 6; Alternatively, when m is selected from 2, 3, 4, 5, and 6, two R _1s may form a C ₃ -C ₇ cycloalkyl or a 3-7 membered heterocycloalkyl with the carbon atom to which they are attached; ^X1 and ^X2 atoms are each independently selected from O, S, C; said S may be in the form of its oxide; Ring B is selected from a benzene ring, a 5-6 membered heteroaromatic 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 by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 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; R ₄ is selected from hydrogen, oxo (=O), C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl; _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 by 1, 2, ₃ or 4 substituents selected from the following: halogen, hydroxyl, 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)-ZR ₂ , 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, hydroxyl, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ -C ₇ cycloalkyl and 3-7 membered heterocycloalkyl; 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 heterocycloalkyl; said _R2 is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 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; Ra is selected from hydrogen and C ₁ -C ₃ alkyl. The compound of formula IB according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the following structures:
wherein R ₁ , R ₃ , R ₄ , R ₅ , Q, X ¹ , X ² , m and n are as defined in claim 1. The compound of formula IB according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the following structures:
wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , Z, X ¹ , X ² , m and n are as defined in claim 1. The compound of formula IB according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein _R1 satisfies one or more of the following conditions: a), said R ₁ is selected from hydrogen, halogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl; b), said R ₁ is selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, CH ₂ F, CHF ₂ and CF ₃ ; c), said R ₁ is selected from hydrogen and methyl; d) The two R _1s may form a C ₃ -C ₇ cycloalkyl or a 3-7 membered heterocycloalkyl with the carbon atoms to which they are connected; e), the two R _1s may form a C ₃ -C ₅ cycloalkyl or a 3-5 membered heterocycloalkyl with the carbon atom to which they are connected; f) The two R _1s can form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxirane group, an azirane group, an oxetanyl group, an azetidinyl group, or a tetrahydrofuran group with the carbon atoms to which they are connected. The compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the ring B is selected from a benzene ring, 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; and/or, the ring B is selected from benzene ring, furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine; And/or, the ring B is selected from benzene ring and pyridine. The compound represented by formula IB as described in any one of claims 1 to 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the group fragment With structure Ring A is selected from C ₃ -C ₇ cycloalkyl, 3-7 membered heterocycloalkyl; and/or, the group fragment With structure and/or, the ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuran; and/or, the group fragment With structure and/or, the group fragment With structure The compound of formula IB according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the following structures:
wherein V ₁ , V ₂ , V ₃ , and V ₄ are each independently CH or N; n, X ¹ , X ² , Z, R ₂ , R ₃ , R ₄ , and R ₅ are as defined in claim 1; Preferably, n is 0; Preferably, the ^X1 atom is O and the ^X2 atom is C; or the ^X1 atom is C and the ^X2 atom is O; Preferably, _R4 is hydrogen. A compound of formula IB as described in any one of claims 1, 2, 3 or 7, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, wherein the compound is selected from the following structures:
Wherein, the atoms X ¹ and X ² are not C at the same time; The definitions of X ¹ , X ² , R ₂ and R ₅ are as described in claim 1. The compound of formula IB according to any one of claims 1, 2, 3 or 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein R ₄ is selected from hydrogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl; and/or, said R ₃ is selected from hydrogen, F, Cl, methyl, methoxy, trifluoromethyl, difluoromethyl, CH ₂ F, cyclopropyl, cyano; said n is selected from 0, 1, 2; Optionally, said n is selected from 0; Optionally, said R ₄ is selected from hydrogen, methyl, trifluoromethyl, difluoromethyl, -CH ₂ F; Optionally, said R ₄ is selected from hydrogen. A compound of formula IB as described in any one of claims 1, 2, 3 or 7, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, wherein the compound is selected from the following structures:
Wherein, the atoms X ¹ and X ² are not C at the same time; The definitions of X ¹ , X ² , R ₂ and R ₅ are as described in claim 1. 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)-ZR ₂ , 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, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ -C ₇ cycloalkyl and 3-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; The 5-6 membered heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O and S; and/or, the 5-6 membered heteroaromatic ring is selected from furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine; and/or, said _R2 is selected from _C1 - _C4 alkyl, C3- _C5 cycloalkyl, 5-6- _membered heteroaryl and 3-7-membered heterocycloalkyl; said _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; and/or, said R ₂ is selected from C ₁ -C ₄ alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl; said C ₁ -C ₄ alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl contains 1, 2, 3 heteroatoms selected from N, O, S; and/or, said _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; said _C1 - _C4 alkyl, _C3 - _C5 cycloalkyl, 3-7 membered heterocycloalkyl, _C1 - _C4 alkyl-5-6 membered heteroaryl, 5-6 membered heteroaryl are optionally substituted by 1, 2, 3 or 4 hydroxyl groups or halogens; And/or, R ₂ is selected from furan, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, -CH _{2 -pyridine, -CH 2 -pyrimidine} , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, oxirane, oxetane, azetidine, tetrahydrofuran, tetrahydropyran, tetrahydropyrrole, hexahydropyridine; and R ₂ is optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl. The compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein: Said Z is selected from O or NH; And/or, said R ₂ is selected from methyl, butyl, and/or, Q is selected from pyridine, pyrimidine, -C(=O)-O-CH ₃ , -C(=O)-O-CH ₂ CH ₂ CH ₂ CH ₃ , -C(=O)-NH-CH ₃ , -C(=O)-NH-CH ₂ CH ₂ CH ₂ CH ₃ , The compound of formula IB as claimed in any one of claims 1, 2, 3 or 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the R ₅ is selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₇ cycloalkyl and 3-7 membered heterocycloalkyl; the C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₇ cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; Optionally, the R ₅ is selected from Cl, CF ₃ , Cyclopropyl, oxetane; Optionally, said R ₅ is selected from Cl, CF ₃ . The compound of formula IB as claimed in any one of claims 1, 2, 3 or 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the ^X1 and ^X2 atoms are each independently selected from O, S, C; the S may be in the form of an oxide thereof; Optionally, at least one of the ^X1 and ^X2 atoms is O; Optionally, only one of the ^X1 and ^X2 atoms is O; Optionally, the ^X1 atom is C, and the ^X2 atom is O; Optionally, the ^X1 atom is O and the ^X2 atom is C. The compound of formula IB as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound comprises:

A pharmaceutical composition, wherein the pharmaceutical composition comprises: a compound represented by formula IB as described in any one of claims 1 to 15, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier. A use of a compound of formula IB as claimed in any one of claims 1 to 15, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 16, comprising: As an AT2R agonist; and/or, preventing and/or treating diseases in which endogenous production of Ang II is insufficient; and/or, preventing and/or treating diseases in which an increased effect of Ang II is desired or required; and/or, preparing a medicament, pharmaceutical composition or formulation 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. The use according to claim 17, wherein the disease is a gastrointestinal disease, a cardiovascular system disease, a respiratory system disease, a kidney disease, an eye disease, a female reproductive system disease, a central nervous system disease, or a growth metabolism and proliferation-related disease; Optionally, the respiratory disease is asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis.