Thiophene sulfonyl carbamates as AT2R agonists

Abstract

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

Description

[0001] Priority information

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

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

[0004] Idiopathic pulmonary fibrosis (IPF) refers to the abnormal repair of alveolar epithelial cells after injury, which causes the proliferation of lung fibroblasts to transform into myofibroblasts, excessive secretion of extracellular matrix, collagen deposition, changes in alveolar structure, and ultimately fibrosis. Its pathogenesis has not yet been fully clarified. Current studies believe that it is closely related to oxidative stress, inflammatory response, and the regulation of the renin-angiotensin-aldosterone system (RAAS) by body fluids. It is currently believed that the RAAS system plays an important role in the process of pulmonary fibrosis. Angiotensin converting enzyme (ACE) can hydrolyze angiotensin I (Ang I) into angiotensin II (Ang II), which plays an important role in the occurrence and development of various inflammations.

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

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

[0007] The object of the present invention is to provide a thiophenesulfonylcarbamate as an AT2R agonist and its use. The thiophenesulfonylcarbamate has a structure as shown in the first aspect of the present invention, and the thiophenesulfonylcarbamate 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.

[0008] In a first aspect of the present invention, a compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof is provided, wherein the compound has a structure shown in Formula III:

[0009]

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

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

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

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

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

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

[0016] X is selected from NRa and O;

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

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

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

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

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

[0022] According to an embodiment of the present invention, there is also provided a compound of Formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

[0023]

[0024] Wherein, R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0025] X is selected from NRa and O;

[0026] R2 is C1-C6 alkyl, 5-7 membered heteroaromatic ring; the C1-C6 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents are the same or different;

[0027] Each R3 is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

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

[0029] R4 is selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0030] R5 is selected from halogen and C1-C6 alkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; when there are multiple substituents, the substituents are the same or different;

[0031] Ra is selected from hydrogen and C1-C3 alkyl;

[0032] Alternatively, Ra and R2 form a 5-8 membered heterocycloalkyl bicyclic ring with the nitrogen atom to which they are attached;

[0033] When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and X is selected from O, R2 is not methyl.

[0034] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0035]

[0036] Wherein, R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0037] X is selected from NRa and O;

[0038] R2 is C1-C6 alkyl; the C1-C6 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different;

[0039] R3 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

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

[0041] R4 is selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0042] R5 is selected from halogen and C1-C6 alkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; when there are multiple substituents, the substituents are the same or different;

[0043] Ra is selected from hydrogen and C1-C3 alkyl;

[0044] When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and X is selected from O, R2 is not methyl.

[0045] In a preferred embodiment of the present invention, R6 is selected from a 5-7 membered heteroaromatic ring, wherein the heteroatom in the 5-7 membered heteroaromatic ring is N.

[0046] In a preferred embodiment of the present invention, R6 is selected from

[0047] In a preferred embodiment of the present invention, the compound has a structure shown in Formula IV:

[0048]

[0049] In a preferred embodiment of the present invention, when R6 is selected from a 5-7 membered heteroaromatic ring, R3 is hydrogen or F.

[0050] In a preferred embodiment of the present invention, when R6 is selected from a 5-7 membered heteroaromatic ring, R3 is hydrogen.

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

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

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

[0054] In a preferred embodiment of the present invention, the R1 is selected from methyl.

[0055] In a preferred embodiment of the present invention, the X is selected from NRa and O; and the Ra is selected from hydrogen and C1-C3 alkyl.

[0056] In a preferred embodiment of the present invention, the X is selected from NRa and O; and the Ra is selected from hydrogen and methyl.

[0057] In a preferred embodiment of the present invention, X is selected from O.

[0058] In a preferred embodiment of the present invention, said X is selected from NRa, and said Ra is selected from hydrogen and methyl.

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

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

[0061] In a preferred embodiment of the present invention, X is selected from NRa, Ra and R2 and the nitrogen atom connected thereto to form

[0062] In a preferred embodiment of the present invention, X is selected from N, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring, wherein the 5-8 membered heterocycloalkyl bicyclic ring contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0063] In a preferred embodiment of the present invention, X is selected from N, Ra and R2 and the nitrogen atom to which they are connected form a 5-8 membered heterospiro ring, and the 5-8 membered heterospiro ring contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0064] In a preferred embodiment of the present invention, X is selected from N, Ra and R2 are connected to the nitrogen atom to form

[0065] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0066]

[0067] wherein Ra is selected from hydrogen;

[0068] R2 is selected from a 5-7 membered heteroaromatic ring, a C1-C4 alkyl-5-7 membered heteroaromatic ring;

[0069] Alternatively, Ra and R2 form a 5-8 membered heterocycloalkyl bicyclic ring with the nitrogen atom to which they are attached;

[0070] R1, R3, R4, R5 and m are defined as described in the first aspect of the present invention.

[0071] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring; the C1-C4 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring, 4-7 membered heterocycloalkyl; the 4-7 membered heterocycloalkyl and 5-7 membered heteroaromatic ring are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents are the same or different.

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

[0073] In a preferred embodiment of the present invention, the R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, azetidinyl, oxirane, oxetanyl, tetrahydrofuran ring, -C1-C4 alkyl-azetidinyl, -C1-C4 alkyl-oxirane, -C1-C4 alkyl-oxetanyl, -C1-C4 alkyl-tetrahydrofuran ring, -C1-C4 alkyl-pyridine ring, pyrimidine ring, pyridine ring, pyridazine ring, pyrazine ring; the methyl, ethyl, propyl, isopropyl, butyl, isobutyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0074] In a preferred embodiment of the present invention, the R2 is selected from methyl, ethyl, propyl, butyl, isobutyl, pyridine ring, pyrimidine ring, -methyl-pyridine ring, -methyl-oxetanyl, -oxetanyl-methyl; the ethyl, propyl, isopropyl, butyl, isobutyl is substituted by hydroxyl.

[0075] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, Butyl, pyrimidine ring,

[0076] In a preferred embodiment of the present invention, R2 is selected from C1-C4 alkyl, 5-7 membered heteroaromatic ring; the C1-C4 alkyl, 5-7 membered heteroaromatic ring is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents are the same or different.

[0077] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pyrimidine ring, pyridine ring, pyridazine ring, pyrazine ring; R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring.

[0078] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, Butyl, pyrimidine ring,

[0079] In a preferred embodiment of the present invention, said R2 is selected from C1-C4 alkyl; said C1-C4 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; when there are multiple substituents, said substituents are the same or different.

[0080] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl; R2 is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl.

[0081] In a preferred embodiment of the present invention, R2 is selected from methyl, ethyl, Butyl.

[0082] In a preferred embodiment of the present invention, the R3 is selected from hydrogen, halogen, cyano, C1-C3 alkyl, C3-C4 cycloalkyl; the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different;

[0083] m is selected from 1, 2, 3 and 4.

[0084] In a preferred embodiment of the present invention, the R3 is selected from hydrogen, F, Cl, methyl, cyano; and the m is selected from 1, 2, 3 and 4.

[0085] In a preferred embodiment of the present invention, R3 is selected from hydrogen, F, Cl, Br, I, methyl; and m is selected from 1, 2, 3 and 4.

[0086] In a preferred embodiment of the present invention, said R3 is selected from hydrogen, F and Cl.

[0087] In a preferred embodiment of the present invention, said R3 is selected from hydrogen and F.

[0088] In a preferred embodiment of the present invention, said R4 is selected from hydrogen, C1-C3 alkyl and C1-C3 haloalkyl.

[0089] In a preferred embodiment of the present invention, said R4 is selected from hydrogen and C1-C3 alkyl.

[0090] In a preferred embodiment of the present invention, the R4 is selected from hydrogen and methyl.

[0091] In a preferred embodiment of the present invention, said R4 is selected from hydrogen.

[0092] In a preferred embodiment of the present invention, the R5 is selected from halogen, C1-C3 alkyl and 4-5 membered heterocycloalkyl; the C1-C3 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 4-7 membered heterocycloalkyl; the 4-5 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different.

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

[0094] In a preferred embodiment of the present invention, said R5 is selected from Cl, CF3,

[0095] In a preferred embodiment of the present invention, the R5 is selected from halogen and C1-C3 alkyl; the C1-C3 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; when there are multiple substituents, the substituents are the same or different.

[0096] In a preferred embodiment of the present invention, R5 is selected from F, Cl, Br, I, CF3 and

[0097] In a preferred embodiment of the present invention, R5 is selected from Cl, CF3 and

[0098] In a preferred embodiment of the present invention, the R5 is selected from Cl in halogen, R3 is selected from hydrogen, R1 is selected from methyl in C1-C6 alkyl, and when X is selected from O, R2 is selected from methyl, C2-C6 alkyl and 4-7 membered heterocycloalkyl; the methyl in R2 is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl; the C2-C6 alkyl in R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl; the 4-7 membered heterocycloalkyl in R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different;

[0099] Preferably, R2 is selected from ethyl, Butyl,

[0100] In a preferred embodiment of the present invention, the R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and when X is selected from O, R2 is selected from methyl and C2-C6 alkyl; the methyl in R2 is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; the C2-C6 alkyl in R2 is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl; when there are multiple substituents, the substituents are the same or different;

[0101] Preferably, R2 is selected from ethyl, Butyl.

[0102] In a preferred embodiment of the present invention, R5 is selected from Cl, R3 is selected from hydrogen, R4 is selected from hydrogen, R1 is selected from methyl, X is selected from O, R2 is selected from ethyl, butyl,

[0103] In a preferred embodiment of the present invention, R3 is selected from hydrogen, R4 is selected from hydrogen, R1 is selected from methyl, X is selected from NH, R2 is selected from

[0104] In a preferred embodiment of the present invention, when R1 is selected from methyl, R3 is selected from hydrogen and F, R4 is selected from hydrogen, R6 is selected from -C(O)-O-R2, R2 is selected from methyl, butyl, R5 is selected from -CF3, Cl,

[0105] In a preferred embodiment of the present invention, R1 is selected from methyl, R3 is selected from Cl, R4 is selected from hydrogen, R6 is selected from -C(O)-O-R2, R2 is selected from butyl, and R5 is selected from -CF3 and Cl.

[0106] In a preferred embodiment of the present invention, when R1 is selected from methyl, R3 is selected from hydrogen, and R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, and the heteroatom in the 5-7 membered heteroaromatic ring is N.

[0107] In a preferred embodiment of the present invention, when R1 is selected from methyl, R3 is selected from hydrogen, and R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, the heteroatom in the 5-7 membered heteroaromatic ring is N, and R5 is selected from -CF3, Cl.

[0108] In a preferred embodiment of the present invention, when R1 is selected from methyl, R3 is selected from hydrogen, R4 is selected from hydrogen, R6 is selected from a 5-7 membered heteroaromatic ring, the heteroatom in the 5-7 membered heteroaromatic ring is N, and R5 is selected from Cl.

[0109] In a preferred embodiment of the present invention, R1 is selected from methyl, R3 is selected from hydrogen, R4 is selected from hydrogen, X is selected from NRa, Ra and R2 form a nitrogen atom connected to it.

[0110] In a preferred embodiment of the present invention, when R1 is selected from methyl, R2 is selected from methyl, R4 is selected from hydrogen, X is selected from O, R3 is selected from F and Cl, or, R5 is selected from -CF3 and

[0111] In a preferred embodiment of the present invention, the compound, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that the compound comprises:

[0112]

[0113]

[0114]

[0115] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound as described in the first aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

[0116] In a preferred embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0117] In a third aspect of the present invention, the compound as described in the first aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of the pharmaceutical composition as described in the second aspect, the use comprising:

[0118] As an AT2R agonist;

[0119] and / or, preventing and / or treating diseases in which endogenous production of Ang II is insufficient;

[0120] and / or, preventing and / or treating diseases in which an increased effect of Ang II is desired or required;

[0121] 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.

[0122] Provided is a compound as described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as described in the second aspect, which is expected to be used to treat diseases of the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive system or central nervous system (CNS).

[0123] Gastrointestinal diseases that should be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome, inflammatory enteritis, pancreatitis, liver disease (such as hepatitis), gallbladder disease, multiple organ failure, and sepsis. Other gastrointestinal diseases that should be mentioned include xerostomia, gastritis, gastric stasis, hyperacidity, biliary tract disease, abdominal disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, acute colic, dysphagia, nausea, vomiting, and Sjögren's syndrome.

[0124] 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.

[0125] Kidney diseases that should be mentioned include renal failure, nephritis, and renal hypertension.

[0126] Eye diseases that should be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microvascularization.

[0127] Female reproductive system diseases that should be mentioned include disorders of the ovulatory mechanism.

[0128] Cardiovascular diseases that should be mentioned include hypertension, myocardial hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, stenosis after balloon angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic damage, erectile dysfunction, and neointimal hyperplasia.

[0129] CNS diseases that should be mentioned include cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, and cerebral infarction.

[0130] The compound as described in the first aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect can also be used for the regulation of growth metabolism and proliferation, for example, for the treatment of hypertrophy, prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, nerve regeneration, ulcer healing, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer (such as gastrointestinal cancer, lung cancer, etc.), apoptosis, tumors (generally), proliferative diabetes, nerve damage and organ rejection.

[0131] The compound 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.

[0132] The fourth aspect of the present invention provides a method for treating a disease, wherein the endogenous production of AngII is insufficient, and / or a disease in which it is desired or necessary to increase the action of AngII, and / or a disease in which AT2R is expressed and stimulation is desired or necessary, the method comprising administering a therapeutically effective amount of the compound of the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of the second aspect to a person suffering from or susceptible to the disease.

[0133] According to an embodiment of the present invention, the disease type refers to the description in the use described in the third aspect of the present invention.

[0134] 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.

[0135] Terms and Definitions

[0136] 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.

[0137] 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.

[0138] 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.

[0139] Definitions of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THE ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. The above-mentioned techniques and methods can usually be implemented according to the descriptions in the multiple summaries and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0140] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2. As used herein, As used herein, "R1", "R2" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] In this application, "AT2 receptor" and "AT2R" have the same definition.

[0145] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, iodine.

[0146] As used herein, the term "amino" by itself or as part of another substituent refers to -NH2.

[0147] As used herein, the term "hydroxy" by itself or as part of another substituent refers to -OH.

[0148] As used herein, the term "alkyl" means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond, when alone or as part of other substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of natural abundance alkyl groups rich in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0149] The term "C1-C6 alkyl" when used alone or as part of another substituent is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof. In particular, such radicals have 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, methylene, ethyl, n-propyl or isopropyl.

[0150] The term "oxo" when used alone or as part of another substituent refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, ie, the methylene group is replaced by a carbonyl group, representing =0.

[0151] The term "cycloalkyl" or "carbocyclyl" when used alone or as part of another substituent refers to a cyclic alkyl group. m -C n "Cycloalkyl" is understood to mean a saturated or partially saturated carbon ring having m to n atoms. For example, "3-15 membered cycloalkyl" or "C3-C 15 "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "5-8 membered cycloalkyl" contains 5-8 carbon atoms. It includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. The cycloalkyl group may be substituted with one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused to an aryl or heteroaryl group. The term "C3-C6 cycloalkyl" should be understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic systems. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0152] "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.

[0153] "Haloalkyl" when used alone or as part of other substituents refers to saturated aliphatic hydrocarbon groups including branched and straight chains having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0154] The term "5-7 membered heteroaromatic ring" is used interchangeably with "5-7 membered heteroaryl" when used alone or as part of other substituents, and is understood to be an aromatic ring group having 5, 6 or 7 ring atoms and containing 1-3 heteroatoms independently selected from N, O and S. The term "5-7 membered heteroaromatic ring" is understood to be an aromatic ring group having 5, 6 or 7 ring atoms and containing 1-3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl.

[0155] The term "heterocycloalkyl" or "heterocyclyl" when alone or as part of other substituents refers to a saturated cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as but not limited to N, O, S and P. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl include, but are not limited to, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl. "Heterocycloalkyl" or "heterocyclyl" can also contain 1, 2 or 3 rings, including cyclic, bridged and spirocyclic structures. The term "3-7 membered heterocycloalkyl" should be understood to mean a cycloalkyl group having 3, 4, 5, 6, or 7 atoms, containing 1, 2, or 3 heteroatoms, wherein the heteroatoms are selected from N, O, S, and P. The term "5-8 membered heterocycloalkyl bicyclic ring" is understood to mean two rings having 5 to 8 atoms, including fused rings, bridged rings and spiro ring structures, wherein the heteroatoms are preferably selected from N, O and S. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. Examples of "5-8 membered heterocycloalkyl bicyclic ring" include, but are not limited to:

[0156] 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.

[0157] 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.

[0158] "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refers to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.

[0159] The term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid. The acid includes the inorganic acid or organic acid described in the present application.

[0160] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] The term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

[0167] 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.

[0168] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0169] 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.

[0170] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0171] (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;

[0172] (ii) inhibiting a disease or condition, i.e. arresting its development;

[0173] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0174] (iv) alleviating the symptoms caused by the disease or condition.

[0175] Beneficial Effects

[0176] The inventors have unexpectedly developed a thiophenesulfonylcarbamate compound as an AT2R agonist through extensive and in-depth research, and the compound has the structure shown in the present invention. The thiophenesulfonylcarbamate compound of the present invention can prevent or treat diseases or conditions related to AT2R, exhibits excellent pharmacokinetic properties, and has high safety and drug properties. DETAILED DESCRIPTION

[0177] 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.

[0178] This application has the following definitions:

[0179] Symbol or unit:

[0180] IC 50 : Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0181] 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

[0182] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0183] RT: retention time

[0184] Reagents:

[0185] DCM: dichloromethane

[0186] DMF: N,N-dimethylformamide

[0187] DIPEA: N,N-diisopropylethylamine

[0188] EA: Ethyl acetate

[0189] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0190] MeOH: Methanol

[0191] PE: Petroleum ether

[0192] Toluene: Toluene

[0193] THF: Tetrahydrofuran

[0194] XPhos Pd G4: Methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)

[0195] SPhos Pd G3: methanesulfonate (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0196] Test method:

[0197] LCMS: Liquid chromatography-mass spectrometry

[0198] TLC: Thin layer chromatography

[0199] Intermediate A1: Preparation of Intermediate A1

[0200] N-(tert-Butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0201]

[0202] The synthetic route of intermediate A1 is as follows:

[0203]

[0204] Step 1: Synthesis of 3-bromo-2-isobutylthiophene

[0205]

[0206] Under nitrogen protection, add azobisisobutyronitrile (241 mg, 1.47 mmol) to a solution of carbon tetrachloride (100 mL) containing 3-bromo-2-methylthiophene (2.6 g, 14.7 mmol) and N-bromosuccinimide (2.62 g, 14.7 mmol). Then heat to 80 ° C for 2 hours. The reaction solution is cooled to room temperature, solids are precipitated, filtered, and the filtrate is dried to obtain a crude product (3.2 g), which is directly used in the next step. Under nitrogen protection, the above-obtained crude product (3.2 g) is dissolved in anhydrous tetrahydrofuran (70 mL), and the resulting solution is cooled to 0 ° C. Then, a tetrahydrofuran solution of isopropylmagnesium chloride (1.3M, 14.7 mL) was added dropwise to the reaction solution. After reacting at 0°C for 2 hours, 20 mL of ice water was added to quench the reaction. The mixture was extracted three times with 50 mL of ethyl acetate. The organic phase was concentrated to dryness and then mixed. The mixture was separated and purified by silica gel column (eluent: petroleum ether) to obtain 3-bromo-2-isobutylthiophene (2 g, yield: 62%).

[0207] LC-MS, M / Z(ESI):219.0[M+H] +

[0208] Step 2: Synthesis of (4-bromo-5-isobutylthiophen-2-yl)trimethylsilane

[0209]

[0210] Under nitrogen protection and -78°C, a tetrahydrofuran solution (2M, 5.2 mL) containing lithium diisopropylamide was added dropwise to a tetrahydrofuran solution (45 mL) containing 3-bromo-2-isobutylthiophene (1.88 g, 8.6 mmol). After reacting at -78°C for 0.5 hours, trimethylsilyl chloride (1.4 g) was added dropwise to the reaction solution, and then the reaction solution was slowly warmed to room temperature and reacted for 16 hours at room temperature. 50 mL of water was added to quench the reaction, and 50 mL of ethyl acetate was used to extract three times. The organic phase was concentrated to dryness and then mixed with a sample, and separated and purified by a silica gel column (eluent: petroleum ether) to obtain (4-bromo-5-isobutylthiophene-2-yl)trimethylsilane (2.4 g, yield: 95%).

[0211] LC-MS, M / Z(ESI):291.0[M+H] +

[0212] 1 H NMR(400MHz, CDCl3)δ7.01(s,1H),2.68(d,2H),2.03-1.91(m,1H),0.97(d,6H),0.29(s,9H)

[0213] Step 3: Synthesis of (4-fluoro-5-isobutylthiophen-2-yl)trimethylsilane

[0214]

[0215] Under nitrogen protection and -78°C, a tetrahydrofuran solution (2.5M, 5mL) containing n-butyl lithium was added dropwise to a tetrahydrofuran solution (45mL) containing (4-bromo-5-isobutylthiophen-2-yl)trimethylsilane (2.4g, 8.2mmol), and the mixture was reacted at -78°C for 1 hour. Then, a tetrahydrofuran solution (10mL) containing N-fluorobisbenzenesulfonamide (4.67g, 14.8mmol) was added dropwise. After the reaction was continued at -78°C for 0.5 hour, the temperature of the reaction solution was slowly raised to room temperature and stirred overnight. 50mL of water was added to quench the reaction, and the mixture was extracted three times with 50mL of ethyl acetate. The organic phase was concentrated to dryness and then mixed with a sample, and separated and purified with a silica gel column (eluent: petroleum ether) to obtain (4-fluoro-5-isobutylthiophen-2-yl)trimethylsilane (1.7g, yield: 89.9%).

[0216] LC-MS, M / Z(ESI):231.1[M+H] +

[0217] 1 H NMR(400MHz, CDCl3)δ7.0(s,1H),2.67(d,2H),2.02-1.91(m,1H),0.96(d,6H),0.29(s,9H)ppm

[0218] Step 4: Synthesis of 3-fluoro-2-isobutylthiophene

[0219]

[0220] Under nitrogen protection and 0°C, trifluoroacetic acid (10 mL) was added to dichloromethane (10 mL) containing (4-fluoro-5-isobutylthiophen-2-yl)trimethylsilane (1.7 g, 7.4 mmol). Then the mixture was reacted at 0°C for 2 hours. 50 mL of water was added to quench the reaction, and 50 mL of ethyl acetate was used to extract the mixture three times. The organic phase was concentrated to dryness and then mixed with the sample. The mixture was separated and purified by silica gel column (eluent: petroleum ether) to obtain 3-fluoro-2-isobutylthiophene (1.0 g, yield: 85.6%).

[0221] LC-MS, M / Z(ESI):159.1[M+H] +

[0222] 1 H NMR (400MHz, CDCl3) δ6.97(dd,1H),6.74(dd,1H),2.59(dd,2H),1.95-1.81(m,1H),0.96(s,3H),0.94(d,3H)

[0223] Step 5: Synthesis of N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0224]

[0225] Under nitrogen protection and 0°C, chlorosulfonic acid (3.68 g, 31.6 mmol) was added to dichloromethane (30 mL) containing 3-fluoro-2-isobutylthiophene (1.0 g, 6.3 mmol). Then the mixture was reacted at 0°C for 1 hour, 50 mL of water was added to quench the reaction, and the mixture was extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was dissolved in anhydrous dichloromethane (30 mL). Triethylamine (1.93 g, 19 mmol) and tert-butylamine (0.7 g, 9.5 mmol) were added in sequence at 0°C, and then the mixture was reacted at room temperature for 2 hours. 50 mL of water was added to quench the reaction, and the mixture was extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V:V) = 20:1-10:1) to obtain N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (1.2 g, yield: 64.9%).

[0226] Step 6: Synthesis of 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0227]

[0228] Under nitrogen protection and -78°C, a tetrahydrofuran solution containing n-butyl lithium (2.5M, 1.5 mL) was added dropwise to an anhydrous tetrahydrofuran solution (8 mL) containing N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (470 mg, 1.6 mmol), the reaction liquid temperature was raised to -20°C, the reaction was continued for 2 hours, then the reaction liquid temperature was lowered to -78°C, bromine (380 mg, 5 mmol) was added dropwise, and finally the reaction liquid temperature was raised to room temperature and the reaction was continued overnight. 50 mL of water was added to quench the reaction, and the mixture was extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and dried, and the obtained crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V:V) = 20:1-10:1) to obtain 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (410 mg, yield: 68.8%).

[0229] LC-MS, M / Z(ESI):372.3[M+H] + .

[0230] 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),2.69(d,2H),1.92-1.78(m,1H),1.15(s,9H),0.88(d,6H)

[0231] Step 7: Synthesis of N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0232]

[0233] Under nitrogen protection, 3-bromo-N-(tert-butyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (325 mg, 0.87 mmol), 4-hydroxymethylphenylboronic acid (395.1 mg, 2.6 mmol), potassium carbonate (360 mg, 2.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (64 mg, 0.087 mmol) were suspended in anhydrous 1,4-dioxane solution (10 mL), and then reacted at 75 ° C overnight. The reaction solution was cooled to room temperature and filtered. The filtrate was washed with 50 mL of water, extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and dried. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V: V) = 10: 1-2: 1) to give N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (320 mg, yield: 92.06%).

[0234] LC-MS, M / Z(ESI):400.1[M+H] +

[0235] 1 H NMR (400MHz, CDCl3) δ7.61-7.55(m,2H),7.51-7.45(m,2H),4.77(s,2H),4.06(s,1H),2.68(dd,2H),1.98-1.91(m,1H),1.03(s,9H),0.99(d,6H)

[0236] Step 8: Synthesis of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0237]

[0238] Under nitrogen protection and 0°C, dichlorothionyl (238 mg, 2 mmol) was added dropwise to a dichloromethane (4 mL) solution containing N-(tert-butyl)-4-fluoro-3-(4-(hydroxymethyl)phenyl)-5-isobutylthiophene-2-sulfonamide (320 mg, 0.8 mmol), and then reacted at room temperature for 3 hours. The solvent was spin-dried, and the crude product was purified by silica gel column (petroleum ether: ethyl acetate (V:V) = 10:1-4:1) to obtain N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (220 mg, yield: 66%).

[0239] LC-MS, M / Z(ESI):418.1[M+H] +

[0240] Intermediate A2: Preparation of Intermediate A2

[0241] (2-(N-(tert-Butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid

[0242]

[0243] The synthetic route of intermediate A2 is as follows:

[0244]

[0245] Step 1: Synthesis of 2-isobutyl-3-methylthiophene

[0246]

[0247] Dissolve zinc chloride (13.8 g, 101 mmol) in tetrahydrofuran (100 mL), add isobutylmagnesium bromide (2.00 M, 45.1 mL), 2-bromo-3-methyl-thiophene (10.0 g, 56.5 mmol) and di(tri-tert-butylphosphine)palladium (1.44 g, 2.82 mmol), replace nitrogen after addition, slowly raise to 90 ° C for 1 hour. Pour the reaction solution into water (200 mL), add ethyl acetate (200 mL) and extract three times, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain 2-isobutyl-3-methylthiophene (6.00 g, yield 65.3%).

[0248] Step 2: Synthesis of 5-isobutyl-4-methylthiophene-2-sulfonyl chloride

[0249]

[0250] Dissolve 2-isobutyl-3-methylthiophene (6.00 g, 36.9 mmol) in dichloromethane (30 mL), add chlorosulfonic acid (13.6 g, 116 mmol), and stir at room temperature for 1 hour. Concentrate the reaction solution to obtain the product 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (9.80 g, crude product). Step 3: Synthesis of N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0251]

[0252] Dissolve 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (9.80 g, 38.7 mmol) in dichloromethane (40 mL), add N,N-diisopropylethylamine (10.0 g, 77.5 mmol) and 2-methylpropane-2-amine (3.40 g, 46.5 mmol) and heat to 40 ° C for 1 hour. Pour the reaction solution into water (40 mL), add ethyl acetate (200 mL) and extract three times. The organic phase is washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product is separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-5:1, R f =0.4) to give N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (1.50 g, yield 13.4%).

[0253] LC-MS, M / Z(ESI):288.1[MH] + .

[0254] Step 4: Synthesis of (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid

[0255]

[0256] Dissolve N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (900 mg, 3.34 mmol) in tetrahydrofuran (20 mL), cool the reaction solution to -60 ° C with a dry ice ethanol bath, slowly add n-butyl lithium (2.50 M, 3.98 mL) under nitrogen protection, stir for 0.5 hours after addition, then add triisopropyl borate (1.17 g, 6.22 mmol), and react at -60 ° C for 1 hour. Pour the reaction solution into water (20 mL), add ethyl acetate (20 mL) and extract three times, wash the organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify the crude product with a silica gel column (petroleum ether: ethyl acetate (V / V) = 5:1-1:1, R f =0.1) to give (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (0.7 g, yield 62.8%).

[0257] LC-MS,M / Z(ESI):332.1[MH] +

[0258] Example 1: Preparation of target compound I-1

[0259] Methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0260]

[0261] The synthetic route of the target compound I-1 is as follows:

[0262]

[0263] Step 1: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide

[0264]

[0265] Under nitrogen protection, anhydrous DMF (3 mL) was added to a mixture of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (220 mg, 0.53 mmol), 2-chloroimidazole (81 mg, 0.79 mmol) and potassium carbonate (220 mg, 1.59 mmol), and the mixture was reacted at 60°C overnight. The reaction solution was cooled to room temperature, 50 mL of water was added to quench the reaction, and the mixture was extracted three times with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-1:1) to give N-(tert-butyl)-3-(4-((2-chloro-1H-imidazole-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (200 mg, yield: 78.1%).

[0266] LC-MS, M / Z(ESI):484.1[M+H] +

[0267] Step 2: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (12)

[0268]

[0269] Under nitrogen protection, trifluoroacetic acid (4 mL) was added to a dichloromethane (4 mL) solution containing N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (200 mg, 0.41 mmol). Then the reaction was continued overnight at room temperature, the solvent was spin-dried, the crude product was mixed with silica gel, and separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-1:4) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (140 mg, yield: 80%).

[0270] LC-MS, M / Z(ESI):428.1[M+H] +

[0271] Step 3: Synthesis of methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0272]

[0273] Under nitrogen protection and 0°C, to dichloromethane (2 mL) containing 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (140 mg, 0.33 mmol) was added N,N-diisopropylethylamine (0.23 mL, 1.37 mmol) and methyl chloroformate (34.3 mg, 0.36 mmol) in sequence, and then reacted at 0°C for 2 hours, 20 mL of water was added to quench the reaction, and extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then separated and purified by silica gel column (dichloromethane: methanol (V / V) = 10:1) to obtain methyl ((3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-4-fluoro-5-isobutylthiophene-2-yl)sulfonyl)carbamate (55 mg, yield: 34%).

[0274] LC-MS, M / Z(ESI):486.1[M+H] +

[0275] 1 H NMR (400MHz, CDCl3) δ7.48-7.43(m,2H),7.25 -7.20(m,2H),6.95 -6.88(m,2H),5.15(s,2H),3.66(s,3H),2.71(d,2H),2.03-1.91(m,1H),1.0(d,6H)

[0276] Example 2: Preparation of target compound I-2

[0277] Methyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0278]

[0279] The synthetic route of the target compound I-2 is as follows:

[0280]

[0281] Step 1: Synthesis of N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0282]

[0283] Under nitrogen protection, anhydrous DMF (5 mL) was added to a mixture of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (308 mg, 0.74 mmol), 2-(trifluoromethyl)-1H-imidazole (151 mg, 1.11 mmol) and potassium carbonate (307 mg, 2.22 mmol), and then reacted at 60°C overnight. The reaction solution was cooled to At room temperature, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 20 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-1:1) to give N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (360 mg, yield: 94%).

[0284] LC-MS, M / Z(ESI):518.2[M+H] +

[0285] Step 2: Synthesis of 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0286]

[0287] Under nitrogen protection, trifluoroacetic acid (6 mL) was added to a dichloromethane (6 mL) solution containing N-(tert-butyl)-4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (360 mg, 0.69 mmol). Then the reaction was allowed to proceed overnight at room temperature, the solvent was spin-dried, the crude product was mixed with silica gel, and separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-1:4) to obtain 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (230 mg, yield: 72%).

[0288] LC-MS, M / Z(ESI):462.1[M+H] +

[0289] Step 3: Synthesis of methyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0290]

[0291] Under nitrogen protection, at 0°C, to a solution of dichloromethane (2 mL) containing 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (100 mg, 0.22 mmol) was added N,N-diisopropylethylamine (0.153 mL, 0.88 mmol) and methyl chloroformate (23 mg, 0.24 mmol) in sequence, and then reacted at 0°C for 2 hours. The reaction was quenched by adding 20 mL of water, and extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then separated and purified by a silica gel column (dichloromethane: methanol (V / V) = 10:1) to obtain methyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-yl)sulfonyl)carbamate (43 mg, yield: 38%).

[0292] LC-MS, M / Z(ESI):520.1[M+H] +

[0293] 1 H NMR (400MHz, CDCl3) δ7.52-7.46(m,2H),7.22-7.17(m,2H),7.13-7.08(m,1H),7.03 -6.99(m,1H),5.27(s,2H),3.52(t,3H),2.65(d,2H),1.98-1.86(m,1H),0.97(d,6H)

[0294] Example 3: Preparation of target compound I-3

[0295] Butyl ((4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0296]

[0297] The synthetic route of the target compound I-3 is as follows:

[0298]

[0299] Step 1: Synthesis of N-(tert-butyl)-4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0300]

[0301] Under nitrogen protection, anhydrous DMF (2 mL) was added to a mixture of N-(tert-butyl)-3-(4-(chloromethyl)phenyl)-4-fluoro-5-isobutylthiophene-2-sulfonamide (80 mg, 0.22 mmol), 2-(1H-imidazol-2-yl)propan-2-ol (29 mg, 0.23 mmol) and potassium carbonate (98 mg, 0.71 mmol), and the mixture was reacted at 55° C. overnight, and the reaction solution was cooled to room temperature. The reaction was quenched by adding 20 mL of water, extracted three times with 20 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-1:1) to give N-(tert-butyl)-4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (60 mg, yield: 53.7%).

[0302] LC-MS, M / Z(ESI):508.7[M+H] +

[0303] Step 2: Synthesis of 4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide

[0304]

[0305] Under nitrogen protection, trifluoroacetic acid (2 mL) was added to a dichloromethane (2 mL) solution containing N-(tert-butyl)-4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (60 mg, 0.12 mmol). Then the reaction was allowed to proceed overnight at room temperature, the solvent was spin-dried, the crude product was mixed with silica gel, and separated and purified by silica gel column (dichloromethane: methanol (V / V) = 50:1-10:1) to obtain 4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (25 mg, yield: 50%).

[0306] LC-MS, M / Z(ESI):452.6[M+H] +

[0307] Step 3: Synthesis of butyl ((4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate

[0308]

[0309] Under nitrogen protection and 0°C, N,N-diisopropylethylamine (0.04 mL, 0.22 mmol) and butyl chloroformate (8.2 mg, 0.06 mmol) were added to a solution of dichloromethane (1 mL) containing 4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide (25 mg, 0.055 mmol) in sequence, and then the mixture was stirred for 2 h. The reaction was then carried out at 0°C for 2 hours, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then separated and purified using a silica gel column (dichloromethane: methanol (V / V) = 10:1) to obtain butyl ((4-fluoro-3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (13 mg, yield: 43%).

[0310] LC-MS, M / Z(ESI):552.2[M+H] +

[0311] 1 H NMR (400MHz, CDCl3) δ7.48-7.43(m,2H),7.17 -7.12(m,2H),6.97 -6.95(m,1H),6.85-6.83(m,1H),5.48(s,2H),4.05-3.98(t,2H),2.72-2.67(d,2H),1.98 -1.86(m,1H),1.65(s.6H),1.54-1.46(m,2H),1.30-1.24(m,2H),0.97(d,6H),0.88(t,3H)

[0312] Example 4: Preparation of target compound I-4

[0313] Butyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0314]

[0315] The synthetic route of the target compound I-4 is shown in the figure below:

[0316]

[0317] Step 1: Synthesis of butyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0318]

[0319] Under nitrogen protection and 0°C, to a solution of dichloromethane (2 mL) containing 4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (130 mg, 0.28 mmol) was added N,N-diisopropylethylamine (0.2 mL, 1.13 mmol) and methyl chloroformate (42.3 mg, 0.31 mmol) in sequence, and then reacted at 0°C for 2 hours. 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was concentrated to dryness and then separated and purified by a silica gel column (dichloromethane: methanol (V / V) = 10:1) to obtain butyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-yl)sulfonyl)carbamate (35 mg, yield: 22%).

[0320] LC-MS, M / Z(ESI):562.1[M+H] +

[0321] 1 H NMR (400MHz, CDCl3) δ7.52-7.46(m,2H),7.23-7.19(m,2H),7.13 -7.11(m,1H),7.03-6.99(m,1H),5.29(s,2H),4.01(t,3H),2.69(d,2H),2.01 -1.89(m,1H),1.54-1.45(m,2H),1.29-1.20(m,2H),0.99(d,6H),0.87(t,3H)

[0322] Example 5: Preparation of target compound I-9

[0323] Methyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0324]

[0325] The synthetic route of the target compound I-9 is as follows:

[0326]

[0327] Step 1: Synthesis of 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole

[0328]

[0329] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-(trifluoromethyl)-1H-imidazole (544 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (1.66 mg, 12.0 mmol) was added to react at 50°C for 2 hours. The reaction solution was poured into water (100 mL), extracted three times with ethyl acetate (80 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole (1.20 g, yield 98.3%).

[0330] LC-MS, M / Z(ESI):304.9[M+H] +

[0331] Step 2: Synthesis of N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0332]

[0333] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), 1-(4-bromobenzyl)-2-(trifluoromethyl)-1H-imidazole (330 mg, 1.08 mmol) was added, potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol) were added, and then the reaction was stirred at 60 ° C under nitrogen protection for 2 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-0:1) to obtain the compound N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (560 mg, yield 90.8%).

[0334] LC-MS, M / Z(ESI):514.0[M+H] +

[0335] Step 3: Synthesis of 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0336]

[0337] N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (550 mg, 1.07 mmol) was dissolved in trifluoroacetic acid (8 mL) and dichloromethane (4 mL) and reacted at 40°C for 2 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-1:1) to obtain compound 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (470 mg, yield 95.9%).

[0338] LC-MS, M / Z(ESI):458.1[M+H] +

[0339] Step 4: Synthesis of methyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0340]

[0341] 5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (470 mg, 1.03 mmol) and methyl chloroformate (194 mg, 2.05 mmol) were dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (398 mg, 3.08 mmol) was added, and the reaction was stirred at 0°C for 0.5 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL), extracted three times with dichloromethane (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate 150*25mm*5μm; solvent: A=water+0.05 volume formic acid (30%), B=acetonitrile; gradient: 58%-78%, 10 minutes) to obtain the product (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (319 mg, yield 61.1%).

[0342] LC-MS, M / Z(ESI):516.1[M+H] +

[0343] 1H NMR(400MHz,DMSO-d6)δ:11.83(s,1H),7.60(d,1H),7.17-7.23(m,4H),7.15(d,1H) ,5.42(s,2H),3.53(s,3H),2.67(d,2H),1.81-1.91(m,1H),1.75(s,3H),0.93(d,6H)

[0344] Example 6: Preparation of target compound I-10

[0345] 2-Hydroxy-2-methylpropyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0346]

[0347] The synthetic route of the target compound I-10 is as follows:

[0348]

[0349] Step 1: Synthesis of phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0350]

[0351] 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (300 mg, 656 μmol) and diphenyl carbonate (211 mg, 984 μmol) were dissolved in acetonitrile (5 mL), potassium carbonate (181 mg, 1.31 mmol) was added, and the mixture was stirred at 60°C for 4 hours under nitrogen. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated in vacuo to obtain the compound (phenyl 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-yl)sulfonylcarbamate (370 mg, yield 97.7%).

[0352] LC-MS, M / Z(ESI):578.1[M+H] +

[0353] Step 2: Synthesis of 2-hydroxy-2-methylpropyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0354]

[0355] Phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (370 mg, 650 μmol) was dissolved in dioxane (8 mL), isobutylene glycol (173 mg, 1.92 mmol) was added, and the mixture was stirred at 100 °C under nitrogen for 4 hours. The reaction solution was concentrated and separated and purified by high performance liquid chromatography (column: C18 150*30 mm; mobile phase: A = water + 0.05 volume formic acid (30%), B = acetonitrile; gradient: 58%-88%, 7 minutes) to obtain the product (2-hydroxy-2-methylpropyl 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (38.6 mg, yield 10.5%).

[0356] LC-MS, M / Z(ESI):574.1[M+H] +

[0357] 1 H NMR(400MHz, CDCl3)δ:7.29(s,1H),7.21-7.25(m,2H),7.17(d,1H),7.08(d,2H),5.33(s ,2H),3.97(s,2H),2.69(d,2H),1.92-2.00(m,1H),1.86(s,3H),1.19(s,6H),1.01(d,6H)

[0358] Example 7: Preparation of target compound I-11

[0359] (2S)-2-hydroxypropyl ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0360]

[0361] The synthetic route of the target compound I-11 is as follows:

[0362]

[0363] Step 1: Synthesis of (2S)-2-hydroxypropyl ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0364]

[0365] Phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (250 mg, 433 μmol) was dissolved in tetrahydrofuran (2.00 mL), (2S)-propane-1,2-diol (330 mg, 4.33 mmol) and triethylamine (131 mg, 1.30 mmol) were added, and the reaction was stirred at 20 ° C under nitrogen for 10 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), and then extracted three times with ethyl acetate (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid chromatography (column: C18 150*30 mm; mobile phase: A = water + 0.05 volume of formic acid (30%), B = acetonitrile; gradient: 55%-85%, 7 minutes) to obtain the product ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamic acid-(2S)-2-hydroxypropyl ester (79.6 mg, yield 32.8%).

[0366] LC-MS, M / Z(ESI):560.3[M+H] +

[0367] 1 H NMR(400MHz, CDCl3)δ:7.40-7.45(m,1H),7.20-7.27(m,4H),7.12-7.17(m,1H),7.06-7.10(m,1H),5.33(s,2H),4.0 5-4.18(m,1H),3.86-4.04(m,2H),2.69(d,2H),1.93-2.02(m,1H),1.84-1.87(m,3H),1.10-1.20(m,3H),1.01(d,6H)

[0368] Example 8: Preparation of target compound I-12

[0369] (2R)-2-hydroxypropyl ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0370]

[0371] The synthetic route of the target compound I-12 is as follows:

[0372]

[0373] Step 1: Synthesis of (2R)-2-hydroxypropyl ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate

[0374]

[0375] (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonamidotoluene ester (250 mg, 433 μmol) was dissolved in tetrahydrofuran (2 mL), (2R)-propane-1,2-diol (330 mg, 4.33 mmol) and triethylamine (131 mg, 1.30 mmol) were added, and the reaction was stirred at 20 ° C under nitrogen for 10 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), and then extracted three times with ethyl acetate (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by high performance liquid chromatography (column: Welch xextreme C18 150*30 mm; mobile phase: A = water + 0.05 volume of formic acid (30%), B = acetonitrile; gradient: 55%-85%, 7 minutes) to obtain the product ((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamic acid-(2R)-2-hydroxypropyl ester (67.7 mg, yield 27.9%).

[0376] LC-MS, M / Z(ESI):560.3[M+H] +

[0377] 1 H NMR(400MHz, CDCl3)δ:7.39-7.48(m,1H),7.28-7.30(m,1H),7.20-7.26(m,3H),7.12-7.17(m,1H),7.04-7.10(m,1 H),5.33(s,2H),4.11(d,1H),3.85-4.03(m,2H),2.69(d,2H),1.97(dt,1H),1.86(s,3H),1.16(d,3H),1.02(d,6H)

[0378] Example 9: Preparation of target compound I-13

[0379] 2-Hydroxyethyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0380]

[0381] The synthetic route of the target compound I-13 is as follows:

[0382]

[0383] Step 1: (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylamino acid-2-hydroxyethyl ester

[0384]

[0385] Phenyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (365 mg, 632 μmol) was dissolved in dioxane (5 mL), ethylene glycol (118 mg, 1.90 mmol) was added, and the mixture was stirred at 100 °C under nitrogen for 2 hours. The reaction solution was concentrated and separated and purified by high performance liquid chromatography (column: Welch xextreme C18 150*25mm*5μm; mobile phase: A=water+0.05 volume formic acid (30%), B=acetonitrile; gradient: 53%-73%, 10 minutes) to obtain the product (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamic acid-2-hydroxyethyl ester (38.91 mg, yield 11.3%).

[0386] LC-MS, M / Z(ESI):546.3[M+H] +

[0387] 1 H NMR(400MHz, CDCl3)δ:7.27-7.30(d,1H),7.26(d,1H),7.21-7.24(d,2H),7.15(d,1H),7.08(d,1H),5 .33(s,2H),4.17-4.23(t,2H),3.72-3.77(t,2H),2.69(d,2H),1.97(m,1H),1.86(s,3H),1.02(d,6H)

[0388] Example 10: Preparation of target compound I-14

[0389] Methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0390]

[0391] The synthetic route of the target compound I-14 is as follows:

[0392]

[0393] Step 1: Synthesis of 1-(4-bromo-2-fluorobenzyl)-2-chloro-1H-imidazole

[0394]

[0395] 4-Bromo-1-(bromomethyl)-2-fluorobenzene (500 mg, 1.87 mmol) and 2-chloro-1H-imidazole (210 mg, 2.05 mmol) were dissolved in N,N-dimethylformamide (5.00 mL), and potassium carbonate (774 mg, 5.60 mmol) was added to react at 50°C for 2 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), and then extracted three times with ethyl acetate (40 mL). The organic phase was collected, washed five times with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Then, it was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:0-3:1) to obtain 1-(4-bromo-2-fluorobenzyl)-2-chloro-1H-imidazole (450 mg, yield 83.3%).

[0396] LC-MS, M / Z(ESI):290.9[M+H] +

[0397] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0398]

[0399] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (350 mg, 1.05 mmol) was dissolved in tetrahydrofuran (5.00 mL) and water (1.00 mL), 1-(4-bromo-2-fluorobenzyl)-2-chloro-1H-imidazole (274 mg, 945 μmol) was added, potassium phosphate (1.11 mg, 5.25 mmol) and XPhos Pd G4 (90.4 mg, 105 μmol) were added, and then the reaction was stirred at 60 ° C under nitrogen protection for 1 hour. The reaction solution was concentrated to obtain a crude product, which was separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-3:1) to obtain N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (450 mg, yield 86.0%).

[0400] LC-MS, M / Z(ESI):498.2[M+H] +

[0401] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0402]

[0403] N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (450 mg, 904 μmol) was dissolved in trifluoroacetic acid (4.00 mL) and dichloromethane (4.00 mL) and reacted at 40°C for 1 hour. The reaction solution was poured into water (20 mL), then extracted three times with dichloromethane (40 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Then, it was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:0-0:1) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (350 mg, yield 87.7%).

[0404] LC-MS, M / Z(ESI):442.1[M+H] +

[0405] Step 4: Synthesis of methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0406]

[0407] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (350 mg, 792 μmol) and methyl chloroformate (150 mg, 1.58 mmol) were dissolved in dichloromethane (5.00 mL) at 0°C, N,N-diisopropylethylamine (307 mg, 2.38 mmol) was added, and the reaction was stirred at 0°C for 0.5 hours. The reaction solution was concentrated and separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*30 mm; solvent: A = water + 0.05 volume of formic acid (30%), B = acetonitrile; gradient: 55%-85%, 7 minutes) to give methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (50.0 mg, yield 12.6%).

[0408] LC-MS, M / Z(ESI):500.0[M+H] +

[0409] 1 H NMR(400MHz, CDCl3)δ7.76(s,1H),7.16(t,1H),7.02-7.08(m,3H),7.00(s,1H),5 .22(s,2H),3.72(s,3H),2.69(d,2H),1.92-2.00(m,1H),1.87(s,3H),1.02(d,6H)

[0410] Example 11: Preparation of target compound I-18

[0411] 2-Hydroxyethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0412]

[0413] The synthetic route of the target compound I-18 is as follows:

[0414]

[0415] Step 1: Synthesis of 1-(4-bromobenzyl)-2-chloro-1H-imidazole

[0416]

[0417] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-chloro-1H-imidazole (410 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1.66 g, 12.0 mmol) was added, and the mixture was reacted at 55°C for 1 hour. The reaction solution was poured into water (50 mL), extracted three times with ethyl acetate (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-1:1) to obtain 1-(4-bromobenzyl)-2-chloro-1H-imidazole (900 mg, yield 82.8%).

[0418] LC-MS, M / Z(ESI):271.0[M+H] +

[0419] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0420]

[0421] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (400 mg, 1.20 mmol) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), 1-(4-bromobenzyl)-2-chloro-1H-imidazole (293 mg, 1.08 mmol) was added, potassium phosphate (1.27 g, 6.00 mmol) and XPhos Pd G4 (103 mg, 120 μmol) were added, and then the reaction was stirred at 60 ° C under nitrogen protection for 2 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-0:1) to obtain N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (510 mg, yield 88.5%).

[0422] LC-MS, M / Z(ESI):480.2[M+H] +

[0423] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0424]

[0425] N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (500 mg, 1.04 mmol) was dissolved in trifluoroacetic acid (15 mL) and dichloromethane (5 mL) and reacted at 40°C for 1 hour. The reaction solution was poured into water (10 mL), then extracted three times with dichloromethane (20 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1-1:1) to obtain a brown oily compound 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (400 mg, yield 90.6%).

[0426] LC-MS, M / Z(ESI):424.1[M+H] +

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

[0428]

[0429] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (200 mg, 472 μmol) and potassium carbonate (131 mg, 944 μmol) were dissolved in acetonitrile (2 mL), diphenyl carbonate (152 mg, 708 μmol) was added, and the mixture was stirred at 50°C for 2 hours. The reaction solution was poured into water (20 mL), and then extracted three times with ethyl acetate (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-yl)sulfonylcarbamate phenyl ester (240 mg, yield 93.5%).

[0430] LC-MS, M / Z(ESI):544.2[M+H] +

[0431] Step 5: Synthesis of 2-hydroxyethyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0432]

[0433] Phenyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (240 mg, 441 μmol) was dissolved in tetrahydrofuran (3 mL), ethylene glycol (274 mg, 4.41 mmol) and triethylamine (134 mg, 1.32 mmol) were added, and the mixture was stirred at 25 °C for 10 hours. The reaction solution was poured into water (20 mL), then extracted three times with ethyl acetate (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by high performance liquid chromatography (column: C18 150*30 mm; solvent: A = water + 0.05 volume of formic acid (30%), B = acetonitrile; gradient: 48%-78%, 7 minutes) to give the product (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamic acid-2-hydroxyethyl ester (115 mg, yield 50.9%).

[0434] LC-MS, M / Z(ESI):512.2[M+H] +

[0435] 1 H NMR (400MHz, CDCl3) δ7.22-7.27(m,4H),6.97(s,2H),5.17(s,2H),4.18-4.22( m,2H),3.74(dd,2H),2.69(d,2H),1.93-1.99(m,1H),1.87(s,3H),1.02(d,6H).

[0436] Example 12: Preparation of target compound I-19

[0437] Methyl (3-(4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0438]

[0439] The synthetic route of the target compound I-19 is as follows:

[0440]

[0441] Step 1: Synthesis of 2-(1-(4-bromobenzyl)-1H-imidazol-2-yl)propan-2-ol

[0442]

[0443] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-(1H-imidazol-2-yl)propane-2-ol (505 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.66 mg, 12.0 mmol) was added to react at 50 ° C for 2 hours. After the reaction was completed, the reaction solution was poured into water (40 mL), extracted three times with ethyl acetate (40 mL), and the organic phase was collected, washed five times with water (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:1 to ethyl acetate: methanol (V / V) = 10:1) to obtain 2-(1-(4-bromobenzyl)-1H-imidazol-2-yl)propane-2-ol (830 mg, yield 70.3%).

[0444] LC-MS, M / Z(ESI):295.0[M+H] +

[0445] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0446]

[0447] Dissolve (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (350 mg, 1.05 mmol) in tetrahydrofuran (7 mL) and water (3 mL), add 2-(1-(4-bromobenzyl)-1H-imidazol-2-yl)propan-2-ol (279 mg, 945 μmol), then add potassium phosphate (1.11 g, 5.25 mmol) and XPhos Pd G4 (90.4 mg, 105 μmol), and then stir at 60 ° C under nitrogen protection for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-0:1) to obtain N-(tert-butyl)-3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (420 mg, yield 79.4%).

[0448] LC-MS, M / Z(ESI):504.1[M+H] +

[0449] Step 3: Synthesis of 3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0450]

[0451] N-(tert-butyl)-3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (410 mg, 814 μmol) was dissolved in trifluoroacetic acid (8 mL) and dichloromethane (3 mL) and reacted at 40° C. for 2 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V)=0:1 to dichloromethane:methanol (V / V)=5:1) to obtain compound 3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (500 mg, crude product).

[0452] LC-MS, M / Z(ESI):448.2[M+H] +

[0453] Step 4: Synthesis of methyl (3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0454]

[0455] 3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (500 mg, 1.12 mmol) was dissolved in dichloromethane (8 mL), N,N-diisopropylethylamine (433 mg, 3.35 mmol) and methyl chloroformate (211 mg, 2.23 mmol) were added at 0°C, and the reaction was stirred for 0.5 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL), extracted three times with dichloromethane (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18150*25mm*5μm; solvent: A=water+0.05 volume formic acid (30%), B=acetonitrile; gradient: 23%-43%, 10 minutes) to obtain the product (3-(4-((2-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (168 mg, yield 39.9%).

[0456] LC-MS, M / Z(ESI):506.2[M+H] +

[0457] 1 H NMR(400MHz,CD3OD)δ:7.28-7.31(m,2H),7.24-7.27(m,2H),7.16(d,1H),7.08(d,1H),5.68 (s,2H),3.54(s,3H),2.70(d,2H),1.91-1.98(m,1H),1.85(s,3H),1.66(s,6H),1.01(d,6H)

[0458] Example 13: Preparation of target compound I-21

[0459] Methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0460]

[0461] The synthetic route of the target compound I-21 is as follows:

[0462]

[0463] Step 1: Synthesis of 1-(4-bromo-3,5-difluorobenzyl)-2-chloro-1H-imidazole

[0464]

[0465] 2-Bromo-5-(bromomethyl)-1,3-difluorobenzene (500 mg, 1.75 mmol) and 2-chloro-1H-imidazole (197 mg, 1.92 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (725 mg, 5.25 mmol) was added to react at 25°C for 1 hour. The reaction solution was poured into water (30 mL), and then extracted three times with ethyl acetate (60 mL), washed five times with water (60 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Then, it was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:0-3:1) to obtain 1-(4-bromo-3,5-difluorobenzyl)-2-chloro-1H-imidazole (520 mg, yield 96.7%).

[0466] LC-MS, M / Z(ESI):308.9[M+H] +

[0467] Step 2: Synthesis of N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0468]

[0469] (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (500 mg, 1.50 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), 1-(4-bromo-3,5-difluorobenzyl)-2-chloro-1H-imidazole (415 mg, 1.35 mmol) was added, potassium phosphate (955 mg, 4.50 mmol), SPhos Pd G3 (117 mg, 150 μmol) were added, and then the reaction was stirred at 60 ° C under nitrogen protection for 1 hour. The reaction solution was concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*30 mm; solvent: A = water + 0.05 volume of formic acid (30%), B = acetonitrile; gradient: 65%-95%, 7 minutes), and dried to give N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, yield 19.4%).

[0470] LC-MS, M / Z(ESI):516.1[M+H] +

[0471] Step 3: Synthesis of 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide

[0472]

[0473] N-(tert-butyl)-3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, 291 μmol) was dissolved in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) and reacted at 40°C for 1 hour. The reaction solution was poured into water (10 mL), then extracted three times with dichloromethane (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Then, it was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:0-0:1) to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (100 mg, yield 74.8%).

[0474] LC-MS, M / Z(ESI):460.0[M+H] +

[0475] Step 4: Synthesis of methyl (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate

[0476]

[0477] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (100 mg, 217 μmol) and methyl chloroformate (82.2 mg, 870 μmol) were dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (84.3 mg, 652 μmol) was added, and the reaction was stirred at 25°C for 0.5 hour. The reaction solution was concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+0.05 volume ammonia (30%), B=acetonitrile; gradient: 5%-35%, 10 minutes), and dried to give (3-(4-((2-chloro-1H-imidazol-1-yl)methyl)-2,6-difluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonylcarbamate (4.00 mg, yield 3.57%).

[0478] LC-MS, M / Z(ESI):518.2[M+H] +

[0479] 1 H NMR(400MHz, CDCl3)δ7.07(d,1H),7.01(d,1H),6.78(d,2H),5.17(s,2H),3.74(s,3H),2.71(d,2H),1.97-2.05(m,1H),1.89(s,3H),1.01(d,6H)

[0480] Example 14: Preparation of target compound I-22

[0481] N-((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0482]

[0483] The synthetic route of the target compound I-22 is as follows:

[0484]

[0485] Step 1: Synthesis of N-((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0486]

[0487] 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (200 mg, 437 μmol) and 1,1'-carbonyldiimidazole (106 mg, 656 μmol) were dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (226 mg, 1.75 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The above reaction solution was mixed with 2-oxa-6-azaspiro[3.3]heptane (43.3 mg, 437 μmol) and dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (328 mg, 2.54 mmol) was added, and the mixture was reacted at 60°C for 8 hours. The reaction solution was concentrated, separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: A=water+0.05 volume of ammonium hydroxide (30%), B=acetonitrile; gradient: 10%-40%, more than 10 minutes), and dried to give N-((5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (126 mg, yield 49.6%).

[0488] LC-MS, M / Z(ESI):583.3[M+H] +

[0489] 1 H NMR(400MHz DMSO-d6)δ:7.65(s,1H),7.08-7.32(m,6H),5.44(s,2H),4.55(s,4H),3.6 4-3.87(s,4H),2.63(d,2H),1.80-1.88(m,1H),1.74(s,3H),0.94(d,6H).

[0490] Example 15: Preparation of target compound I-23

[0491] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide

[0492]

[0493] The synthetic route of target compound I-23 is as follows:

[0494]

[0495] Step 1: 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide

[0496]

[0497] 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (150 mg, 354 μmol) and 2-chloropyrimidine (40.5 mg, 354 μmol) were dissolved in dioxane (6 mL), cesium carbonate (288 mg, 884 μmol) and XPhos Pd G3 (30.0 mg, 35.4 μmol) were added, and the mixture was stirred at 100 ° C for 1 hour under nitrogen. The reaction solution was concentrated, and the crude product was slurried with methanol (50 mL) at 25 ° C for 30 minutes to obtain 3-(4-((2-chloro-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-4-methyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide (48.1 mg, yield 26.9%).

[0498] LC-MS, M / Z(ESI):502.1[M+H] +

[0499] 1 H NMR(400MHz DMSO-d6)δ:8.46(d,2H),7.45(d,1H),7.16-7.24(d,2H),7.08-7.16(d,2H),7.02(t,1 H),6.96(d,1H),5.23(s,2H),2.62-2.67(d,2H),1.85(m,1H),1.74(s,3H),0.93(d,6H)

[0500] Example 16: Preparation of target compound I-24

[0501] N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-1-((pyridin-2-ylmethyl)amino)carboxamide

[0502]

[0503] The synthetic route of the target compound I-24 is as follows:

[0504]

[0505] Step 1: Synthesis of N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-1-((pyridin-2-ylmethyl)amino)formamide

[0506]

[0507] Under ice-bath cooling, to a solution of 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (0.228 g, 0.5 mmol) in acetonitrile (11 mL) were added phenyl N-(2-pyridylmethyl)carbamate (0.182 g, 0.8 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.152 g, 1 mmol) in sequence, and the mixture was reacted at 80 °C for 6 hours. The reaction was monitored by LCMS. After no starting material remained, the reaction solution was cooled to room temperature, extracted three times with ethyl acetate (30 mL), washed three times with water (20 mL), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated and separated by HPLC (aqueous formic acid / acetonitrile system) to give N-((4-methyl-5-isopropyl-3-(4-((2-(trifluoromethyl)imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)-1-((pyridin-2-ylmethyl)amino)formamide (0.128 g, yield 43.4%).

[0508] LC-MS, M / Z(ESI):592.1[M+H] +

[0509] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.50–8.45(m,1H),7.73(td,J=7.7,1.8Hz,1H),7.61(d,J=1.1Hz,1H),7.28–7.23(m,1H),7.23–7.15(m ,6H),6.75(t,J=5.5Hz,1H),5.40(s,2H),4.25(d,J=5.6Hz,2H),2.64(d,J=7.1Hz,2H),1.90–1.78(m,1H),1.74(s,3H),0.92(d,J=6.6Hz,6H).

[0510] Example 17: The preparation of the following compounds can be obtained by referring to the preparation methods of the above compounds.

[0511]

[0512]

[0513]

[0514] In the test example of the present invention, the preparation method of the reference compound I refers to patent WO2021229244A1, and the structure is shown below:

[0515]

[0516] Biological Testing

[0517] The following test method may be used.

[0518] Test Example 1: Compound binding to AT2R

[0519] The experiment was performed according to the instruction manual of the Angiotensin AT2 Receptor Ligand Binding Assay Kit (#C1TT1AT2, Cisbio). First, the 10mM compound stock solution was serially diluted according to the dilution factor of 5× (including 10 concentrations, each concentration was repeated twice), and 160nL of different concentrations of the compound was added to a 384-well plate. 40μL 1×TLB (TLB: Tag-lite buffer) was added to each well and shaken at room temperature for 15 minutes. A 15mL centrifuge tube with 5mL 1×TLB was prepared in advance for use. The frozen labeled cells were thawed in a 37℃ water bath (1-2 minutes), and the thawed cells were quickly transferred to the above 15mL centrifuge tube, mixed and centrifuged at 1000g for 5 minutes at room temperature. The supernatant was removed and 2.7mL 1×TLB was added to resuspend the cells. A new 384-well plate was taken and 10μL of the mixed cells were added to the corresponding wells according to the experimental design. 5 μL of 4× compound solution and 5 μL of 4× Tag-lite red fluorescent labeled ligand were added to each well. After incubation at room temperature for 1 hour, the data were read using the HTRF mode of EnVision. The excitation light intensity of 665nM and 615nM in each well was read respectively, and the ratio (Ratio = A665nM / B615nM) was calculated. IC was calculated using GraphPad Prism8 software. 50 Numerical values, X: logarithmic value of compound concentration; Y: ratio of A665nM / B615nM.

[0520] Table 1: Binding activity of compounds to AT2R

[0521] Compound No. <![CDATA[AT2R IC 50 (nM)]]> Comparative Compound I 4.46 I-1 6.67 I-2 6.56 I-3 3.21 I-4 3.46 I-9 5.13 I-10 2.31 I-11 4.49 I-12 3.88 I-13 2.60 I-14 1.39 I-16 4.49 I-17 3.88 I-18 3.52 I-19 2.91 I-23 1.79 I-24 4.41

[0522] The experimental results show that the compounds of the present invention have a strong binding effect with AT2R.

[0523] Test Example 2: CYP inhibition assay of compounds

[0524] The inhibitory effects of the compounds on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (midazolam), and CYP2B6 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 compound or positive inhibitor working solution, add 2 μL of solvent to the solvent control, and place it in a 37 °C water bath for preincubation for 10 minutes. After preincubation, 98 μL of NADPH regeneration solution was added to all samples to start the reaction. Then put it back in the water bath and incubate for a period of time. The reaction was quenched with 200 μL of stop solution. The plate was centrifuged at 3220g for 10 minutes, 100 μL of supernatant was transferred, 100 μL of water was added and mixed thoroughly to the analysis plate, and LC / MS / MS analysis was performed.

[0525] Table 2: CYP450 inhibition results of compounds

[0526]

[0527] The experimental results show that the compounds of the present invention have a weaker inhibitory effect on CYP enzymes than the control compounds and will not affect the normal metabolism of the body, indicating that the possibility of drug-drug interactions in the human body is less and the safety is higher.

[0528] Test Example 3: Free plasma protein binding (PPB) experiment of compounds

[0529] Soak the dried dialysis membrane in ultrapure water for 1 hour, then 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, measure the plasma pH after thawing, and adjust its pH to 7.4 with 1% phosphoric acid solution or 0.1M sodium hydroxide solution. Dilute the compound into the plasma preheated to 37°C, with 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 test compound and the control compound to be tested in a 96-well sample plate, duplicate, 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 for 6 hours. After 6 hours of incubation, take 20 μL of the dialyzed receiving solution and the administration 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:

[0530]

[0531] C R : The peak area ratio measured by the receiving chamber hole;

[0532] C D : The peak area ratio measured by the supply chamber hole.

[0533] The degree of freeness of a compound in plasma is related to its efficacy in the body. Experimental results show that the compound of the present invention has a higher degree of freeness than the control compound, which is beneficial for the compound to reach the target organ.

[0534] Test Example 4: Liver microsome stability test of the compound

[0535] The stability test of human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. First, the compound to be tested was prepared into a 10mM stock solution in DMSO solvent, and then the compound was diluted to 0.5mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and the solution was used to dilute 0.5mM of the compound to form a working solution. The compound concentration in the working solution was 1.5μM and the human liver microsome concentration was 0.75mg / ml. Take a deep well plate, add 30μL of working solution to each well, and then add 15μL of preheated 6mM NADPH solution to start the reaction and incubate at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, add 135μL of acetonitrile to the corresponding wells to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep well plate was vortexed for 10 minutes (600rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio for LC-MS / MS detection. The ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point was obtained. The peak area ratio of the compound at 5, 15, 30, and 45 minutes was compared with the peak area ratio at 0 minute, and the remaining percentage of the compound at each time point was calculated. Graphpad 8 software was used to calculate T 1 / 2 .

[0536] Table 3: Liver microsomal stability of compounds

[0537]

[0538] The stability of a compound in liver microsomes reflects its risk of being metabolized and eliminated in vivo. The experimental results show that the test compound has good stability in humans compared with the control compound.

[0539] Test Example 5: Bidirectional permeability study of compounds in CACO-2 cells

[0540] Caco-2 cells were cultured at 1×10 5 cells / cm 2Cells were plated onto polyethylene membrane (PET) in 96-well inserts at a rate of 100 μg / min and the medium was changed every 4-5 days until day 21-28 to form a confluent cell monolayer. The transport buffer in the experiment was HBSS and 10.0 mM HEPES, pH 7.40 ± 0.05. The test compounds were tested bidirectionally at 2.00 μM in the presence and absence of 10.0 μM GF120918. Digoxin was tested bidirectionally at 10.0 μM in the presence and absence of 10.0 μM GF120918, while nadolol and metoprolol were tested in the A to B direction at 2.00 μM in the absence of 10.0 μM GF120918, all in duplicate wells. The final DMSO concentration was adjusted to less than 1%. The plates were incubated in a CO2 incubator at 37 ± 1°C for 2 hours with 5% CO2 added under saturated humidity without shaking. All samples were mixed with acetonitrile containing the internal standard and centrifuged at 3200 g for 10 minutes. For nadolol and metoprolol, 200 μL of the supernatant was diluted with 600 μL of distilled water for LC-MS / MS analysis. For digoxin and the test compound, 200 μL of the supernatant was diluted with 200 μL of distilled water for LC-MS / MS analysis. The concentrations of the test and control compounds in the starting solution, donor solution, and acceptor solution were quantified by the LC-MS / MS method using the peak area ratio of the analyte / internal standard.

[0541] After the transport assay, the integrity of the Caco-2 cell monolayer was determined using the Lucifer Yellow exclusion assay.

[0542] Table 4: Bidirectional permeability of compounds in Caco-2 cells

[0543]

[0544] The experimental results show that the permeability of the test compound is improved compared with the control compound, which is beneficial to the absorption of the compound.

[0545] Test Example 6: Induction of CYP 3A4 enzyme by compounds

[0546] The viability of the revived hepatocytes was tested and the hepatocytes were diluted to 0.7 × 10 6Cells / μL. Pre-wet the 48-well collagen-coated plate by adding 100 μL per well of pre-warmed inoculation medium, then discard the medium. Add 200 μL of cells to each well of the 48-well plate pre-coated with collagen, and then culture in a 95% humidity 5% CO2 incubator at 37°C. 4 hours after cell attachment, aspirate the inoculation medium and add 200 μL per well of incubation medium containing 2% matrix protease. The next day, remove the cell plate, aspirate the supernatant, add 200 μL of compound solution per well, and continue to culture in the incubator. After 24 hours and 48 hours, respectively, remove the 48-well plate from the incubator and transfer 100 μL of medium per well to a clean 96-well cell culture plate for LDH determination of cell viability.

[0547] Enzyme activity assay:

[0548] At 48h, the supernatant was aspirated and washed twice with 400μL / well preheated HBSS solution. After aspirating HBSS, 100μL of enzyme-labeled substrate working solution was added to each well. Then, the cell plate was incubated in an incubator for 30 minutes, and the reaction was stopped by transferring the supernatant to a 96-well plate containing a stop solution. The plate was sealed, shaken and centrifuged to collect the supernatant. The supernatant was then diluted in 0.1% FA water at a ratio of 1:4. All samples were mixed and analyzed by liquid chromatography / mass spectrometry (LC / MS / MS). Calibration was performed using the peak area ratio of metabolites to internal standards (IS), and the activity of CYP enzymes was calculated using a standard curve consisting of 7 standard concentrations, and the fold change relative to the vehicle control (0.1% dimethyl sulfoxide) was calculated, and the induction fold = enzyme activity of compound-treated samples / enzyme activity of vehicle controls.

[0549] Enzyme gene induction assay:

[0550] 1. Extraction of Total Cell RNA

[0551] After 48 hours, the supernatant was aspirated and the plate was washed once with 400 μL / well of HBSS, and RLT buffer (QIAGEN, cat: 1015762) was added to the plate, and the RNA extraction kit of QIAGEN was followed.

[0552] 2. cDNA Synthesis

[0553] The cDNA was synthesized using the ABI high-efficiency cDNA reverse transcription kit (cat: 4368813).

[0554] 3. Real-time Quantitative PCR Reaction

[0555] Add nuclease-free water to a new plate, add cDNA sample to the plate, and mix gently to dilute. Prepare reaction mixtures for 18S rRNA and CYP3A4, respectively, where 18S rRNA is used as an internal standard. Seal the real-time quantitative PCR plate and centrifuge briefly to remove bubbles and allow the liquid to settle at the bottom of the tube. Transfer the plate to the real-time quantitative PCR instrument and analyze according to the supplier's protocol. PCR conditions: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles of the following two steps: 95°C for 15 seconds, 60°C for 1 minute.

[0556] 4. Real-time Quantitative PCR Data Analysis

[0557] Fold change of relative expression = 2 - ΔΔCt, ΔCt = Ct (target gene) - Ct (18S rRNA), ΔΔCt = ΔCt (treated sample) - ΔCt (untreated control).

[0558] The experimental results showed that the tested compounds had no toxic effect on hepatocytes, had weak induction on CYP3A4 enzyme activity, and had weaker induction on CYP3A4 enzyme gene relative to the positive internal reference.

[0559] Test Example 7: Pharmacokinetic study of a single oral administration of a compound to cynomolgus monkeys

[0560] Dissolve the compound in the solvent 5% DMSO + 10% Solutol + 85% Saline to prepare a concentration of 1 mg / mL and a dosage of 5 mpk. Weigh before administration, calculate the dosage based on body weight, and administer orally by gavage. Blood is collected through the femoral vein or other appropriate methods, and the blood collection time points are 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Each sample is collected at approximately 1 mL / time point, anticoagulated with sodium heparin, and placed on ice after collection. After blood sample collection, place it on ice, and the blood sample is centrifuged within 1 hour to separate plasma (centrifugation conditions: 2200g, 10 minutes, 2-8°C). Plasma samples are stored in a -80°C refrigerator before analysis.

[0561] The biological sample analysis method and analysis of all samples are completed by the analytical laboratory of Medicipia Pharmaceutical Technology (Shanghai) Co., Ltd. While analyzing the samples, the intra-day accuracy of the quality control samples is evaluated, and it is required that more than 66.7% of the quality control samples have an accuracy between 80-120%.

[0562] Table 5: Pharmacokinetics of Compounds in Monkeys

[0563]

[0564] The experimental results show that the Cmax and exposure of the test compound are higher than those of the control compound, indicating that it can have a better stimulatory effect. Test Example 8: IPF efficacy test of the compound in mice

[0565] 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).

[0566] The experimental steps include:

[0567] 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.

[0568] 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.

[0569] 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.

[0570] 4. Dosage: The day of bleomycin injection is regarded as the 0th day of the experiment. The dosing schedule is as follows:

[0571] Table 6-1 Grouping and Dosage Scheme

[0572]

[0573]

[0574] a: The solvent is 5% DMSO + 10% solutol + 85% saline;

[0575] 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.

[0576] 5. Pulmonary function test: On the 22nd day, all experimental animals were anesthetized with Zotal (25-50 mg / kg) and xylazine (5-10 mg / kg), and then subjected to pulmonary function test (PFT) using pulmonary function test, including PV curve, FVC, IC, VC, Cdyn, and Cchord (quasi-static lung compliance) indicators.

[0577] 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 cut horizontally 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:

[0578] Table 6-2 Fibrosis scoring criteria

[0579] score standard 0 normal 1 Microfibrous thickening of the alveolar or bronchiolar walls 2 Moderate thickening of the lung wall, no obvious damage to the lung structure 3 Increased fibrosis, with clear damage to lung architecture, forming fibrous bands or small fibrous masses 4 Severe structural distortion and extensive fibrosis, presenting a "honeycomb" appearance 5 Total fibrous visual field occlusion

[0580] 7. Animal euthanasia: All experimental animals will be euthanized by CO2 and cervical dislocation after the in vivo experiment.

[0581] Statistical analysis: The experimental data were expressed as mean ± standard error (mean ± SEM) and analyzed using SPSS or Graphpad Prism. P < 0.05 was considered statistically significant.

[0582] The experimental results show that compared with the control compound, the compound of the present invention can significantly improve the FVC, IC, VC lung function indicators and can significantly improve the pulmonary fibrosis score.

[0583] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the compound has a structure shown in Formula III: in, R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl; Each R3 is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different; m is selected from 1, 2, 3 and 4; R4 is selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl; R5 is selected from halogen, C1-C6 alkyl and 4-7 membered heterocycloalkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, 4-7 membered heterocycloalkyl; the 4-7 membered heterocycloalkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, C1-C6 alkyl, 4-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; R6 is selected from a 5-7 membered heteroaromatic ring and -C(O)-X-R2; X is selected from NRa and O; R2 is C1-C6 alkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring; the C1-C6 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 3-7 membered heterocycloalkyl, 5-7 membered heteroaromatic ring; the 4-7 membered heterocycloalkyl and 5-7 membered heteroaromatic ring are substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, 5-7 membered heteroaromatic ring and 3-7 membered heterocycloalkyl; when there are multiple substituents, the substituents are the same or different; Ra is selected from hydrogen and C1-C3 alkyl; or, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring; When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and R6 is selected from -C(O)-O-R2, R2 is not methyl; When R6 is selected from a 5-7 membered heteroaromatic ring, R3 is hydrogen or F.

2. The compound according to claim 1, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound has the compound shown in formula I: Wherein, R1 is selected from halogen, C1-C6 alkyl and C1-C6 haloalkyl; X is selected from NRa and O; R2 is C1-C6 alkyl, 5-7 membered heteroaromatic ring; the C1-C6 alkyl is substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, C1-C3 alkyl, 5-7 membered heteroaromatic ring; when there are multiple substituents, the substituents are the same or different; Each R3 is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl; the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C3-C7 cycloalkyl; when there are multiple substituents, the substituents are the same or different; m is selected from 1, 2, 3 and 4; R4 is selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl; R5 is selected from halogen and C1-C6 alkyl; the C1-C6 alkyl is substituted by 1, 2, 3 or 4 substituents selected from the following: halogen, hydroxyl; when there are multiple substituents, the substituents are the same or different; Ra is selected from hydrogen and C1-C3 alkyl; or, Ra and R2 and the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl bicyclic ring; When R5 is selected from Cl among halogen, R3 is selected from hydrogen, R1 is selected from methyl among C1-C6 alkyl, and X is selected from O, R2 is not methyl.

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

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

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

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

11. Use of a compound according to any one of claims 1 to 9, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to claim 10, comprising: As an AT2R agonist; and / or, preventing and / or treating diseases in which endogenous production of Ang II is insufficient; and / or, preventing and / or treating diseases in which an increased effect of Ang II is desired or required; and / or, preparing 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.

12. The use according to claim 11, characterized in that The disease is a disease of the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, eyes, female reproductive system or central nervous system.

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

14. The use according to claim 13, characterized in that The diseases are asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, and idiopathic pulmonary fibrosis.

Images