Heterocyclic compound as at2r antagonist and use thereof

Abstract

The present invention provides a compound represented by formula I, and a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The compound can be used as an AT2R antagonist.

Description

Heterocyclic compounds as AT2R antagonists and their uses

[0001] The present invention claims:

[0002] Priority to a prior application, patent application number 202310724422.2, filed with the State Intellectual Property Office of China on June 16, 2023, entitled “Heterocyclic compounds as AT2R antagonists and their uses”;

[0003] Priority to the prior application, patent application number 202311331793.0, filed with the State Intellectual Property Office of China on October 13, 2023, entitled “Heterocyclic compounds as AT2R antagonists and uses thereof”;

[0004] Priority to a prior application, patent application number 202410010872.X, filed with the State Intellectual Property Office of China on January 3, 2024, entitled “Heterocyclic compounds as AT2R antagonists and uses thereof”;

[0005] Priority to a prior application, patent application number 202410669486.1, filed with the State Intellectual Property Office of China on May 27, 2024, entitled “Heterocyclic compounds as AT2R antagonists and their uses”;

[0006] The entire contents of said prior application are incorporated herein by reference. Technical Field

[0007] The present invention belongs to the field of medicine, and in particular, relates to a heterocyclic compound as an angiotensin II (Ang II) type 2 receptor (AT2R) antagonist and its use. Background Art

[0008] Neuropathic pain is a chronic pain disorder caused by primary damage or dysfunction in the nervous system. It can be categorized as peripheral or central neuropathic pain based on the location of the lesion. Trauma, inflammation, infection, or compression can all lead to neuropathic pain, including diabetic neuropathy (DNP), postherpetic neuralgia (PHN), primary neuropathies, secondary neuropathies, peripheral neuropathies, and neuropathies caused by mechanical or biochemical nerve damage. Currently, the main drugs used clinically to treat neuropathic pain include antiepileptic drugs, antidepressants, and narcotic analgesics, such as gabapentin, pregabalin, and tricyclic antidepressants. However, these drugs are not targeted, resulting in very limited therapeutic effects and severe side effects, including cognitive changes, sedation, nausea, and tolerance and dependence, far from meeting clinical drug needs. Therefore, there is a need to understand the pathogenesis of neuropathic pain, identify clear drug targets, and develop novel drugs that are effective in treating neuropathic pain with minimal adverse reactions.

[0009] Two major types of angiotensin II (AngII) receptors have been identified in humans, designated as AngII type 1 receptors (AT1R) and AngII type 2 receptors (AT2R). AngII exerts physiological effects in numerous organs, including the kidneys, adrenal glands, heart, blood vessels, brain, gastrointestinal tract, and reproductive organs, regulating blood pressure, fluid and electrolyte homeostasis. The effects of AngII are regulated by the balance of expression of two G protein-coupled receptors (GPCRs), AT1R and AT2R. AT1R is expressed throughout life and primarily regulates blood pressure. Its blockers are widely used clinically as antihypertensive drugs, controlling most of the physiological effects of AngII. AT2R, primarily expressed in embryonic tissues, is implicated in blood pressure regulation, nerve growth, pain control, and myocardial regeneration. Drugs targeting AT2R can improve cardiovascular function and alleviate neuropathic pain. Within the nervous system, AT2R is implicated in pain mechanisms and is primarily expressed in the dorsal root ganglia and trigeminal ganglia. Compared to normal nerves, damaged nerves and painful neuromas have higher AT2R expression. Activation of the AT2R sensitizes ion channels in neurons through G protein-coupled receptor-activated second messenger pathways. This sensitization leads to ion channel activation, which in turn excites neurons. AT2R antagonists have been shown to be effective in relieving pain through animal and clinical trials.

[0010] Although some progress has been made in the research and application of AT2R antagonists, there is still huge room for improvement, and it is still necessary to continue researching and developing new AT2R antagonists.

[0011] Summary of the Invention

[0012] The object of the present invention is to provide a compound as an AT2R antagonist and its use. The compound has the structure shown in the first aspect of the present invention, and the compound can be used to prepare a drug, pharmaceutical composition or preparation for treating and / or preventing diseases or conditions related to AT2R; or to treat and / or prevent diseases or conditions related to AT2R.

[0013] In a first aspect of the present invention, there is provided a compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0014] wherein Ring A is selected from a 5-6 membered heteroaromatic ring;

[0015] R1 is selected from halogen, hydroxy, amino, cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl is optionally substituted with 1-4 substituents selected from the following groups: halogen, hydroxy, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo;

[0016] m is selected from 0, 1, 2, 3 or 4; when there are multiple substituents R1, the R1 are the same or different;

[0017] L is absent or selected from C0-C6 alkylene-O-C0-C6 alkylene, C1-C6 alkylene; said C1-C6 alkylene-O-C1-C6 alkylene or C1-C6 alkylene is optionally substituted with 1-4 substituents selected from the following groups: deuterium, oxo (=O), methyl, ethyl, halomethyl, haloethyl;

[0018] R2 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring; the C1-C6 alkyl, C3-C6 cycloalkyl, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring are optionally substituted with 1, 2, 3, or 4 substituents selected from the following groups: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl; and R2 is not methyl, ethyl, isopropyl, or -CF3;

[0019] n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; when there are multiple substituents R2, the R2 are the same or different;

[0020] Ring E is selected from a benzene ring or a 6-membered heteroaromatic ring;

[0021] R3 is selected from halogen, hydroxy, cyano, dimethylamino, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl is optionally substituted with 1-4 substituents selected from the following groups: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl;

[0022] p is selected from 0, 1, 2, 3 or 4; when there are multiple substituents R3, the R3 are the same or different;

[0023] M is selected from carboxylic acid, -CONHSO2R5, -SO2NHCOR5, tetrazole or tetrazole bioisostere; said bioisostere includes but is not limited to phosphoric acid,

[0024] R5 is selected from H, OH, NH2, ONa, OK (potassium ion), C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, 5-6 membered heterocycle; the C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, 5-6 membered heterocycle is optionally substituted by 1-4 substituents selected from the following groups: halogen, amino, C3-C7 heterocycloalkyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy.

[0025] In a preferred embodiment of the present invention, the ring A is a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring contains 1, 2, or 3 heteroatoms;

[0026] The heteroatom is selected from N, O, and S; more preferably, the heteroatom is N.

[0027] In a preferred embodiment of the present invention, the ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, and triazine;

[0028] In a preferred embodiment of the present invention, the ring A is selected from the group consisting of pyridine, pyrimidine, pyridazine, and pyrazine.

[0029] In a preferred embodiment of the present invention, the ring A is selected from

[0030] In a preferred embodiment of the present invention, the ring E is a benzene ring or a 6-membered heteroaromatic ring;

[0031] The 6-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms;

[0032] The heteroatom is selected from N, O, and S.

[0033] In a preferred embodiment of the present invention, the ring E is selected from benzene ring, pyridine, pyrimidine, and pyridazine.

[0034] In a preferred embodiment of the present invention, the ring E is selected from a benzene ring.

[0035] In a preferred embodiment of the present invention, R1 is selected from halogen, hydroxy, amino, cyano, oxo (=O), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C7 cycloalkyl, C1-C3 alkyl-C1-C3 alkoxy, C1-C3 alkyl-C3-C7 cycloalkyl;

[0036] m is selected from 0, 1, 2, 3 or 4.

[0037] In a preferred embodiment of the present invention, R1 is selected from halogen, methyl, halomethyl, methoxy; and m is selected from 0.

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

[0039] Ring A, M, L, R1, R3, m and p are as defined in the first aspect of the present invention.

[0040] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0041] Ring A, M, L, R1, R3, m and p are as defined in the first aspect of the present invention.

[0042] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0043] M and R2 are as defined in the first aspect of the present invention;

[0044] Preferably, the compound of formula IV has structure IVa, IVb:

[0045] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0046] Preferably, it has structure IIa or IIb:

[0047] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0048] Preferably, it has structure IV-2a, IV-2b, IV-3a or IV-3b:

[0049] In a preferred embodiment of the present invention, R2 is selected from C1-C3 alkyl, C3-C6 cycloalkyl, 5-6 membered heterocycle, 5-6 membered heteroaromatic ring, benzene ring; the C1-C3 alkyl, C3-C6 cycloalkyl, 5-6 membered heterocycle, benzene ring is optionally substituted by 1, 2, 3, or 4 substituents selected from the following groups: halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl; and R2 is not methyl, ethyl, isopropyl, or -CF3.

[0050] In a preferred embodiment of the present invention, n is selected from 1, 2, and 3.

[0051] In a preferred embodiment of the present invention, n is 1.

[0052] In a preferred embodiment of the present invention, the R2 is selected from CH2F, CHF2, C1-C3 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C3 alkyl-C3-C7 cycloalkyl;

[0053] n is selected from 1, 2, 3, 4, 5, 6, 7 or 8.

[0054] In a preferred embodiment of the present invention, R2 is selected from CH2F, CHF2, C1-C3 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C3 alkyl-C3-C7 cycloalkyl.

[0055] In a preferred embodiment of the present invention, R2 is selected from CH2F, CHF2, C1-C3 alkyl-C1-C3 alkoxy, C3-C4 cycloalkyl, C1-C3 alkyl-C3-C4 cycloalkyl; n is selected from 1, 2, 3.

[0056] In a preferred embodiment of the present invention, R2 is selected from CH2F, CHF2, methyl-methoxy, ethyl-methoxy, cyclopropyl, methyl-cyclopropyl; and n is selected from 1.

[0057] In a preferred embodiment of the present invention, R2 is selected from CH2F, CHF2, methyl-methoxy, and cyclopropyl.

[0058] In a preferred embodiment of the present invention, said R2 is selected from CH2F, CHF2,

[0059] In a preferred embodiment of the present invention, R2 is selected from CH2F and CHF2.

[0060] In a preferred embodiment of the present invention, said R2 is selected from CHF2.

[0061] In a preferred embodiment of the present invention, the R3 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl is optionally substituted with 1-4 substituents selected from the following groups: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl;

[0062] p is selected from 0, 1, 2, 3 or 4.

[0063] In a preferred embodiment of the present invention, R3 is selected from F, C1-C5 alkyl, C1-C5 haloalkyl, methyl-cyclopropyl; and p is selected from 1, 2, and 3.

[0064] In a preferred embodiment of the present invention, R3 is selected from F, methyl, trifluoromethyl, isobutyl, F-substituted isobutyl, methyl-cyclopropyl; and p is selected from 2.

[0065] In a preferred embodiment of the present invention, p is selected from 2, and R3 is selected from F and isobutyl.

[0066] In a preferred embodiment of the present invention, the M is selected from carboxylic acid, -CONHSO2R5, -SO2NHCOR5, tetrazole or tetrazole bioisostere.

[0067] In a preferred embodiment of the present invention, the tetrazolium bioisostere is selected from -C(=O)-R5, -C(=O)NH-R5, -N(R5)C(=O)-R5, -ON(R e1 )C(=O)-R5, -S(=O)-R5, -S(=O)2-R5, -NH-S(=O)2-R5, -C(=O)-NH-S(=O)2-R5, -NH-C(=O)-NH-S(=O)2-R5, -NH-C(=O)-NH-C(=O)-R5, -P(=O)(-R5)2, 4-8 membered heterocycloalkyl substituted with 1, 2, 3 or 4 oxo (=O), wherein the R5 is selected from H, OH, NH2, ONa, OK (potassium ion), C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, 5-6 membered heterocycle; the C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, 5-6 membered heterocycle is optionally substituted by 1-4 substituents selected from the following groups: halogen, amino, C3-C7 heterocycloalkyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy.

[0068] In a preferred embodiment of the present invention, the M is selected from carboxylic acid, -CONHSO2R5, -SO2NHCOR5, tetrazole; and the R5 is selected from C1-C3 alkyl, C3-C5 cycloalkyl.

[0069] In a preferred embodiment of the present invention, the M is selected from carboxylic acid, tetrazole, and -CONHSO2CH2CH3.

[0070] In a preferred embodiment of the present invention, the M is selected from carboxylic acid and tetrazole.

[0071] In a preferred embodiment of the present invention, the M is selected from tetrazole.

[0072] In a preferred embodiment of the present invention, the R2 is selected from CHF2, and the M is selected from tetrazole and carboxylic acid.

[0073] In a preferred embodiment of the present invention, the R2 is selected from CH2F, and the M is selected from carboxylic acid, tetrazole, and -CONHSO2CH2CH3.

[0074] In a preferred embodiment of the present invention, the R2 is selected from CH2F, and the M is selected from carboxylic acid and tetrazole.

[0075] In a preferred embodiment of the present invention, the R2 is selected from CH2F, and the M is selected from tetrazole.

[0076] In a preferred embodiment of the present invention, the R2 is selected from CH2F, and the M is selected from carboxylic acid.

[0077] In a preferred embodiment of the present invention, said R2 is selected from CH2F, and said M is selected from -CONHSO2CH2CH3.

[0078] In a preferred embodiment of the present invention, the R2 is selected from cyclopropyl, and the M is selected from tetrazole.

[0079] In a preferred embodiment of the present invention, said R2 is selected from The M is selected from tetrazole.

[0080] In a preferred embodiment of the present invention, L is absent or selected from carbonyl, methylene, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH2CH(CH3)-, -O-CH2-.

[0081] In a preferred embodiment of the present invention, L is selected from methylene, -CH2CH2-, -CH(CH3)-, and -O-CH2-.

[0082] In a preferred embodiment of the present invention, said L is selected from methylene.

[0083] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, is characterized in that the compound comprises:

[0084] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, is characterized in that the compound comprises:

[0085] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound of formula I as described in the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and optionally a pharmaceutically acceptable carrier.

[0086] In a preferred embodiment of the present invention, the pharmaceutical composition comprises the compound of formula I as described in the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier

[0087] In a third aspect of the present invention, the compound of formula I according to the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to the second aspect are used, wherein the use includes:

[0088] Acts as an AT2R antagonist;

[0089] and / or, preventing and / or treating AT2R-mediated diseases;

[0090] and / or, preventing and / or treating diseases in which a reduction in the effect of Ang II is desired or required;

[0091] and / or, preparing a medicament, pharmaceutical composition or formulation as an AT2R antagonist;

[0092] and / or, preparing a medicament, pharmaceutical composition or formulation for preventing and / or treating a disease in which AT2R is expressed and its inhibition is desired or necessary.

[0093] In the fourth aspect of the present invention, the compound of formula I as described in the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect, is used to prevent and / or treat AT2R-mediated diseases, and / or prevent and / or treat diseases in which a reduction in AngⅡ action is desired or required.

[0094] According to an embodiment of the present invention, the uses described in the third aspect and the fourth aspect may further include at least one of the following technical features:

[0095] Provided are compounds of formula I as described in the first aspect, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition as described in the second aspect, which are expected to be used for treating neuropathy or neuropathic pain.

[0096] Neuropathies that should be mentioned include primary neuropathies, secondary neuropathies, peripheral neuropathies, neuropathies caused by mechanical or biochemical nerve damage or diabetic-related neuropathies.

[0097] Neuropathic pain that should be mentioned includes postherpetic neuralgia or diabetic neuropathy.

[0098] The compound of formula I described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect, are suitable for the treatment and / or preventive treatment of the above-mentioned diseases.

[0099] The fifth aspect of the present invention provides a method for treating a disease, which is an AT2R-mediated disease and / or a disease in which it is desired or necessary to reduce the effect of Ang II, and / or a disease in which AT2R expression and inhibition is desired or necessary. The method comprises administering a therapeutically effective amount of a compound of formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition as described in the second aspect to a person suffering from or susceptible to the disease.

[0100] In a preferred embodiment of the present invention, the disease comprises an AT2R-mediated disease, a disease in which a reduction in the effect of Ang II is desired or required.

[0101] In a preferred embodiment of the present invention, the disease comprises primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve damage or biochemical nerve damage, or diabetic-related neuropathy.

[0102] In a preferred embodiment of the present invention, the disease comprises postherpetic neuralgia or diabetic neuropathy.

[0103] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0104] Terms and Definitions

[0105] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0106] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0107] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0108] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0109] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, As used herein, "R1", "R2" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.

[0110] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0111] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0112] When a numerical range is described in the specification and claims of this application and is understood as an "integer," it should be understood to include both endpoints of the range as well as every integer within the range. For example, "an integer from 1 to 6" should be understood to include every integer from 0, 1, 2, 3, 4, 5, and 6.

[0113] In this application, when specifying the number of substituents, the term "one or more" refers to one substitution to the maximum possible number of substitutions, i.e., replacing one hydrogen to replacing all hydrogens with substituents. When specifying the number of substituents, the term "1-4" refers to 1, 2, 3, or 4 substitutions, i.e., replacing 1, 2, 3, or 4 hydrogens with substituents.

[0114] In the present application, "saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents completely unsaturated with hydrogen and substituents partially saturated with hydrogen.

[0115] In this application, "AT2 receptor" and "AT2R" have the same definition.

[0116] In this application, the term "bioisostere" when used alone or as part of other substituents has the usual meaning in the art, referring to a group or substituent with similar physical or chemical properties, and having similar biological activity as the group or substituent. Bioisosteres are usually obtained by replacing one atom or group with another substantially similar atom or group, and may have one or more enhanced properties compared to the original compound, group or substituent (such as reduced toxicity, increased bioavailability, altered or increased activity, or improved metabolism). The term "tetrazole and its bioisosteres" refers to tetrazole, as well as a substance with substantially similar or related biological activity produced by a group or substituent with similar physical and chemical properties in a biological sense to tetrazole. In some embodiments, the term "tetrazole and its bioisosteres" includes but is not limited to -C(=O)-R5, -C(=O)NH-R5, -N(R5)C(=O)-R5, -ON(R5) e1 )C(=O)-R5, -S(=O)-R5, -S(=O)2-R5, -NH-S(=O)2-R5, -C(=O)-NH-S(=O)2-R5, -NH-C(=O)-NH-S(=O)2-R5, -NH-C(=O)-NH-C(=O)-R5, -P(=O)(-R5)2, 4-8 membered heterocycloalkyl substituted with 1, 2, 3 or 4 oxo (=O), wherein said R5 is selected from H, OH, NH2, ONa, OK (potassium ion), C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, 5-6 membered heterocycle; said C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, 5-6 membered heterocycle is optionally substituted by 1-4 substituents selected from the following groups: halogen, amino, C3-C7 heterocycloalkyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy. The 4-8 membered heterocycloalkyl has the definition of the term "heterocycloalkyl" below. For example, the term "tetrazolyl and its bioisosteres" includes but is not limited to carboxylic acid, phosphoric acid,

[0117] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, or iodine.

[0118] As used herein, the term "amino" by itself or as part of another substituent refers to -NH2.

[0119] As used herein, the term "hydroxy" by itself or as part of another substituent refers to -OH.

[0120] As used herein, the term "cyano" by itself or as part of another substituent refers to -CN.

[0121] In this application, the term "alkyl" when used alone or as part of another substituent means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of naturally abundant alkyl groups that are rich in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0122] In the present application, the term "C1-C6 alkyl" alone or as part of another substituent is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof. In particular, such groups have 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, methylene, ethyl, n-propyl or isopropyl.

[0123] In the present application, the term "alkylene" is understood to mean a straight-chain divalent hydrocarbon group having 1 to 6 carbon atoms or a branched divalent hydrocarbon group having 3 to 6 carbon atoms, unless otherwise specified, for example, methylene, ethylene, propylene, 1-methylpropylene, butylene, etc.

[0124] In this application, the term "C1-C6 alkoxy" when used alone or as part of other substituents shall be understood to mean a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or represented by C1-C6 alkyl-O-C1-C6 alkyl. The definition of alkyl is as described in this specification, and the oxygen atom can be attached to any carbon atom of the straight or branched C1-C6 alkyl. Including but not limited to: methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-), butoxy (C4H9-O-).

[0125] As used herein, "haloalkoxy" by itself or as part of another substituent refers to an alkoxy group as defined above wherein any number (at least one) of the hydrogen atoms attached to the alkoxy group are replaced by fluorine, chlorine, bromine, or iodine.

[0126] In this application, the term "oxo" when used alone or as part of other substituents refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, ie, the methylene group is replaced by a carbonyl group, representing =0.

[0127] As used herein, "haloalkyl" when used alone or as part of another substituent group refers to a saturated aliphatic hydrocarbon group, including branched and straight chains, having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v+1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0128] As used herein, the term "aryl" or "aromatic ring," when used alone or as part of another substituent, refers to a monocyclic or polycyclic carbocyclic ring having from 6 to 20 carbon atoms, at least one of which is aromatic. When one of the rings is non-aromatic, the group may be attached through either the aromatic or non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthenyl.

[0129] In this application, when alone or as part of other substituents, the term "heteroaromatic ring" refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring. The group can be a carbon group or a heteroatom group (i.e., it can be C-connected or N-connected, as long as it is possible). When one of the rings is a non-aromatic ring, the group can be connected through the aromatic ring or through the non-aromatic ring. Examples of heteroaryl include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" can be used interchangeably with the term "heteroaromatic ring", "heteroaryl" or "heteroaromatic ring group". In this application, when alone or as part of other substituents, the term "5-10 membered heteroaromatic ring" can be used interchangeably with "5-10 membered heteroaryl" and should be understood as an aromatic ring group having 5-10 ring atoms and containing 1-5 heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaromatic ring" should be understood as an aromatic ring group having 5 or 6 ring atoms - and which contains 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.

[0130] In this application, the term "cycloalkyl" or "carbocyclyl" when used alone or as part of another substituent refers to a cyclic alkyl group. m -C n "Cycloalkyl" is understood to mean a saturated, unsaturated 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.

[0131] As used herein, "halocycloalkyl" by itself or as part of another substituent refers to a cycloalkyl group as defined above, wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl group are replaced by fluorine, chlorine, bromine, or iodine.

[0132] In this application, the term "heterocycloalkyl" when used alone or as part of another substituent refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P. "Heterocycloalkyl" can be saturated or unsaturated, but not aromatic. "Heterocycloalkyl" can also contain 1, 2, or 3 rings, including bridged and spirocyclic structures. The term "3-8 membered heterocycloalkyl" should be understood to mean a monocyclic, bicyclic, or tricyclic ring having 3 to 8 atoms, wherein the heteroatoms are preferably selected from N, O, and S. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocycloalkyl include, but are not limited to, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiopyranyl.

[0133] In this application, the term "monocyclic" when used alone or as part of another substituent means a group having only one ring, which may be saturated, unsaturated or partially saturated, and may be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S).

[0134] As used herein, the term "heterocycle," whether alone or as part of another substituent, includes "heterocycloalkyl" and "heteroaryl," and refers to a cycloalkyl or aromatic ring 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.

[0135] In this application, the term "inert solvent" includes, but is not limited to, toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0136] Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof."Protected derivatives" are compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as blocking groups). Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable blocking groups are well known to those of ordinary skill in the art.

[0137] As used herein, the term "substituted" refers to any one or more hydrogen atoms on a particular atom being replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the particular atom is normal and the substituted compound is stable.

[0138] In this application, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0139] In this application, the term "optionally substituted by" or "optionally substituted by" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from the possible substituents. For example, "aryl is optionally substituted by 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 "Alkyl" means that the aryl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 The term "alkyl" refers to an alkyl group, and the description includes both substituted and unsubstituted aryl groups.

[0140] In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0141] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. A "pharmaceutically acceptable base addition salt" refers to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated herein. These salts may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used in the identification, characterization, or purification of the compounds of the invention.

[0142] In the present application, the term "amine salt" refers to a product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid, including an inorganic acid or an organic acid as described in the present application.

[0143] In the present application, the term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0144] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in one of the possible isomers or in a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (–) are used to designate the signs for the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0145] When bonds to chiral carbon atoms in the present formulae are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formula. The diagrammatic representation of racemates or enantiomerically pure compounds herein is adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0146] As used herein, the term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0147] As used herein, the term "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0148] In this application, the term "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or veterinary use.

[0149] In the present application, the term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0150] As used herein, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

[0151] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0152] As used herein, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling characteristics of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0153] As used herein, the term "treat" and other similar synonyms include the following meanings:

[0154] (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;

[0155] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0156] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0157] (iv) Alleviate the symptoms of the disease or condition. Beneficial effects

[0158] After extensive and intensive research, the inventors unexpectedly discovered a compound that acts as an AT2R antagonist, having the structure shown in the present invention. The compound of the present invention can prevent or treat diseases or conditions associated with the AT2 receptor, exhibits excellent pharmacokinetic properties, and possesses high safety and drug-like properties. DETAILED DESCRIPTION

[0159] The present invention will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0160] This application has the following definitions:

[0161] Symbol or unit:

[0162] IC 50 : Half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0163] 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

[0164] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0165] RT: retention time

[0166] Reagents:

[0167] DMF: N,N-dimethylformamide

[0168] DCM: dichloromethane

[0169] DIPEA: N,N-diisopropylethylamine

[0170] MeOH: methanol

[0171] EA: ethyl acetate

[0172] PE: Petroleum ether

[0173] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0174] XPhos Pd G4: (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium

[0175] Test method:

[0176] LCMS: Liquid chromatography-mass spectrometry

[0177] TLC: Thin layer chromatography

[0178] Intermediate A1: Preparation of Intermediate A1

[0179] Synthesis of 2,6-difluoro-4-isobutylbenzonitrile

[0180] The synthetic route of intermediate A1 is as follows:

[0181] To a solution of 4-bromo-2,6-difluorobenzonitrile (10 g, 45.87 mmol) in dioxane (150 mL) were added isobutylboric acid (7.01 g, 68.81 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (3.36 g, 4.59 mmol), and potassium carbonate (19.02 g, 137.61 mmol). The reaction mixture was stirred at 115°C for 16 h. After completion of the reaction, the mixture was filtered through celite and concentrated to obtain a crude product. The crude product was purified by column chromatography (pure petroleum ether) to obtain 2,6-difluoro-4-isobutylbenzonitrile (7 g, 78.71% yield).

[0182] Example 1: Preparation of target compound I-3

[0183] (R)-3-((4-(3-Fluoro-5-isobutyl-2-(2H-tetrazol-5-yl)phenyl)-2-(methoxymethyl)piperazin-1-yl)methyl)pyridazine

[0184] The synthetic route of target compound I-3 is as follows:

[0185] Step 1: Synthesis of tert-butyl (R)-4-acetyl-3-(hydroxymethyl)piperazine-1-carboxylate

[0186] To a solution of (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1 g, 4.6 mmol) in dichloromethane (10 mL) was added triethylamine (1.4 g, 13.8 mmol) and acetyl chloride (542 mg, 6.9 mmol), followed by stirring at room temperature for 2 h. The reaction solution was poured into water (50 mL) and extracted three times with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give (R)-tert-butyl 4-acetyl-3-(hydroxymethyl)piperazine-1-carboxylate (800 mg, 67% yield).

[0187] Step 2: Synthesis of tert-butyl (R)-4-acetyl-3-(methoxymethyl)piperazine-1-carboxylate

[0188] To a solution of (R)-4-acetyl-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.5 mmol) in tetrahydrofuran (4 mL) was added sodium hydroxide (144 mg, 6 mmol, 60% purity) at 0°C and stirred for 0.5 h. Methyl iodide (284 mg, 2 mmol) was then slowly added dropwise to the reaction solution and stirred at 25°C for 5 h. The reaction solution was slowly added dropwise to a saturated ammonium chloride solution (20 mL) and extracted three times with ethyl acetate (10 mL). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 0 / 1) to obtain the product (R)-4-acetyl-3-(methoxymethyl)piperazine-1-carboxylic acid tert-butyl ester (350 mg, 83% yield).

[0189] Step 3: Synthesis of tert-butyl (R)-3-(methoxymethyl)piperazine-1-carboxylate

[0190] To a solution of (R)-tert-butyl 4-acetyl-3-(methoxymethyl)piperazine-1-carboxylate (350 mg, 1.3 mmol) in methanol (3.5 mL) was added 10 M aqueous sodium hydroxide solution (1.3 mL, 13 mmol) and stirred at 90°C for 18 h. The reaction solution was poured into water (50 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to obtain the product (R)-tert-butyl 3-(methoxymethyl)piperazine-1-carboxylate (130 mg, 43.9% yield).

[0191] Step 4: Synthesis of tert-butyl (R)-3-(methoxymethyl)-4-(pyridazin-3-ylmethyl)piperazine-1-carboxylate

[0192] To a solution of 3-(chloromethyl)pyridazine (116 mg, 0.9 mmol) in N,N-dimethylformamide (1.3 mL) were added triethylamine (182 mg, 1.8 mmol) and (R)-tert-butyl 3-(methoxymethyl)piperazine-1-carboxylate (130 mg, 0.6 mmol), followed by stirring at 50°C for 18 h. The reaction solution was poured into water (50 mL) and washed three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 0 / 1) to obtain (R)-tert-butyl 3-(methoxymethyl)-4-(pyridazin-3-ylmethyl)piperazine-1-carboxylate (120 mg, 65.9% yield).

[0193] LC-MS, M / Z(ESI):323.3[M+H] +

[0194] Step 5: Synthesis of (R)-3-((2-(methoxymethyl)piperazin-1-yl)methyl)pyridazine

[0195] To a solution of tert-butyl (R)-3-(methoxymethyl)-4-(pyridazin-3-ylmethyl)piperazine-1-carboxylate (120 mg, 0.4 mmol) in dioxane (1.2 mL) was added a hydrochloric acid / 1,4-dioxane solution (1.2 mL, 4 M) and allowed to react at room temperature for 2 h. The reaction solution was concentrated to afford (R)-3-((2-(methoxymethyl)piperazin-1-yl)methyl)pyridazine (hydrochloride salt, 100 mg).

[0196] LC-MS, M / Z(ESI):223.3[M+H] +

[0197] Step 6: Synthesis of (R)-2-fluoro-4-isobutyl-6-(3-(methoxymethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)benzonitrile

[0198] To a solution of 2,6-difluoro-4-isobutylbenzonitrile (Intermediate A1, 80 mg, 0.4 mmol) in N,N-dimethylformamide (1 mL) was added (R)-3-((2-(methoxymethyl)piperazin-1-yl)methyl)pyridazine (89 mg, 0.4 mmol) and N,N-diisopropylethylamine (146 mg, 1.2 mmol), followed by stirring at 80°C for 18 h. The reaction mixture was poured into water (50 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was washed five times with water (10 mL) and twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to give (R)-2-fluoro-4-isobutyl-6-(3-(methoxymethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)benzonitrile (80 mg, 49.1% yield).

[0199] LC-MS, M / Z(ESI):398.3[M+H] +

[0200] Step 7: Synthesis of (R)-3-((4-(3-fluoro-5-isobutyl-2-(2H-tetrazol-5-yl)phenyl)-2-(methoxymethyl)piperazin-1-yl)methyl)pyridazine

[0201] (R)-2-Fluoro-4-isobutyl-6-(3-(methoxymethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)benzonitrile (80 mg, 0.8 mmol), sodium azide (104 mg, 1.6 mmol), and tributyltin chloride (521 mg, 1.6 mmol) were dissolved in toluene (1.2 mL). The solution was poured into a sealed stainless steel can and reacted at 140°C for 12 h. The reaction solution was slowly poured into water (50 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reverse phase preparative chromatography (chromatographic column: Phenomenex Synergi C18 100*25mm*4um; solvent: A=water+0.1 volume% formic acid (99%), B=acetonitrile; gradient: 5%-95%, 7 minutes) to give the product (R)-3-((4-(3-fluoro-5-isobutyl-2-(2H-tetrazol-5-yl)phenyl)-2-(methoxymethyl)piperazin-1-yl)methyl)pyridazine (21.3 mg, purity 99.42%, yield 24%).

[0202] 1H NMR(400MHz,DMSO)δ9.10(dd,1H),7.66(qd,2H),6.92–6.83(m,2H),4.14(d,1H),3.73(d,1H),3.47(dd,2H) ,3.17(dd,1H),3.12(s,3H),2.89(d,1H),2.76–2.51(m,6H),2.22–2.15(m,1H),1.90(dq,1H),0.89(d,6H).

[0203] LC-MS, M / Z(ESI):441.1[M+H] +

[0204] Example 2: Preparation of target compound I-5

[0205] (R)-2-Fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoic acid

[0206] The synthetic route of target compound I-5 is as follows:

[0207] Step 1: Synthesis of tert-butyl (R)-3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazine-1-carboxylate

[0208] To a solution of tert-butyl (R)-3-(fluoromethyl)piperazine-1-carboxylate (1.2 g, 5.5 mmol) in N,N-dimethylformamide (20 mL) was added 3-(chloromethyl)pyridazine (1 g, 7.5 mmol) and triethylamine (2 g, 15 mmol), and the mixture was stirred at 60°C for 18 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to afford tert-butyl (R)-3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazine-1-carboxylate (500 mg, 29% yield).

[0209] LC-MS, M / Z(ESI):311.2[M+H] +

[0210] Step 2: Synthesis of (R)-3-((2-(fluoromethyl)piperazin-1-yl)methyl)pyridazine

[0211] Tert-butyl (R)-3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazine-1-carboxylate (500 mg, 1.6 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of 5 mL of a 4M solution of hydrochloric acid in dioxane. The mixture was stirred at room temperature for 1 h. The mixture was then concentrated directly to afford the product (R)-3-((2-(fluoromethyl)piperazin-1-yl)methyl)pyridazine (500 mg, 100% yield).

[0212] LC-MS, M / Z(ESI):211.2[M+H] +

[0213] Step 3: Synthesis of methyl (R)-4-bromo-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)benzoate

[0214] A solution of methyl 4-bromo-2,6-difluorobenzoate (575 mg, 2.3 mmol), (R)-3-((2-(fluoromethyl)piperazin-1-yl)methyl)pyridazine (500 mg, 2.3 mol), and potassium carbonate (950 mg, 6.9 mmol) in dimethyl sulfoxide (5 mL) was placed in a 100°C oil bath and reacted for 15 h. The reaction solution was added dropwise to a saturated aqueous sodium chloride solution (50 mL), then extracted three times with ethyl acetate (20 mL). The mixture was washed five times with water (10 mL), twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the product (R)-methyl 4-bromo-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)benzoate (150 mg, yield 15%).

[0215] LC-MS,M / Z(ESI):441.20 / 443.2[M+H] +

[0216] Step 4: Synthesis of (R)-methyl 2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoate

[0217] Under nitrogen protection, (R)-methyl 4-bromo-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)benzoate (150 mg, 0.34 mmol), potassium carbonate (94 mg, 0.68 mmol), (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (34 mg, 0.04 mmol) and isobutylboronic acid (1.7 g, 1.7 mmol) were added to anhydrous dioxane (5 mL) and reacted at 90 ° C for 2 h. The crude product was directly concentrated and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the product (R)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoic acid methyl ester (120 mg, yield 84%).

[0218] LC-MS, M / Z(ESI):419.20[M+H] +

[0219] Step 5: Synthesis of (R)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoic acid

[0220] Methyl (R)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoate (120 mg, 0.29 mmol) was dissolved in methanol (4 mL) and water (1 mL), followed by the addition of lithium hydroxide (21 mg, 0.87 mmol) and the reaction was allowed to proceed at room temperature for 18 h. The reaction solution was concentrated to yield a crude product, which was then subjected to reverse-phase preparative chromatography (column: Phenomenex Synergi C18 100*25 mm*4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95% over 7 minutes) to afford (R)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoic acid (80 mg, 68% yield).

[0221] 1H NMR(400MHz,dmso)δ13.50(s,1H),9.12(d,1H),7.74-7.65(m,2H),6.74-6.71(m,2H),4.87-4. 59(m,3H),4.20-3.94(m,3H),3.19-2.87(m,5H),2.44-2.40(m,2H),1.82(m,1H),0.84(d,6H).

[0222] LC-MS, M / Z(ESI):405.2[M+H] +

[0223] Example 3: Preparation of target compound I-6

[0224] (R)-N-(Ethylsulfonyl)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzamide

[0225] The synthetic route of target compound I-6 is as follows:

[0226] Step 1: Synthesis of (R)-N-(ethylsulfonyl)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzamide

[0227] (R)-2-Fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzoic acid (80 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (380 mg, 1.98 mmol) and 4-dimethylaminopyridine (435 mg, 3.56 mmol) were dissolved in dichloroethane (3 mL), and then nitrogen was replaced. The reaction solution was stirred at room temperature for 10 min, and then ethylsulfonamide (324 mg, 2.98 mmol) was added, and the reaction solution was reacted at 50°C for 3 h. The reaction solution was concentrated to obtain a crude product, which was subjected to reverse phase preparative chromatography (chromatographic column: Phenomenex Synergi C18 100*25mm*4um; solvent: A=water+0.1vol% formic acid (99%), B=acetonitrile; gradient: 5%-95%, 7 minutes) to obtain the product (R)-N-(ethylsulfonyl)-2-fluoro-6-(3-(fluoromethyl)-4-(pyridazin-3-ylmethyl)piperazin-1-yl)-4-isobutylbenzamide (8 mg, 8% yield).

[0228] 1H NMR(400MHz,DMSO)δ9.13(d,1H),7.75-7.73(m,2H),7.69-7.67(m,2H),6.73-6.71(m,2H),4.83- 4.74(m,3H),4.20-3.93(m,2H),3.21-2.43(m,8H),1.82(m,1H),1.24-1.23(m,3H),0.84(d,6H).

[0229] LC-MS, M / Z(ESI):496.2[M+H] +

[0230] Example 4: Preparation of target compound I-1

[0231] 3-(((2R)-2-(difluoromethyl)-4-(3-fluoro-2-(1H-1,2,3,4-tetrazol-5-yl)-5-isobutylphenyl)piperazin-1-yl)methyl)pyridazine

[0232] The synthetic route of target compound I-1 is as follows:

[0233] Step 1: Synthesis of 6-((3R)-3-(difluoromethyl)piperazin-1-yl)-2-fluoro-4-isobutylbenzonitrile

[0234] Under nitrogen, (2R)-2-(difluoromethyl)piperazine dihydrochloride (1.00 g, 4.81 mmol) and triethylamine (1.46 g, 14.43 mmol) were dissolved in DMF (20 mL). 2,6-difluoro-4-isobutylbenzonitrile (Intermediate A1, 940 mg, 4.81 mmol) was added and stirred at 80°C for 16 h. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to yield 6-((3R)-3-(difluoromethyl)piperazin-1-yl)-2-fluoro-4-isobutylbenzonitrile (710 mg, 47% yield).

[0235] LC-MS, M / Z(ESI):312.1[M+H] +

[0236] Step 2: Synthesis of 6-((3R)-4-(pyridazin-3-ylcarbonyl)-3-(difluoromethyl)piperazin-1-yl)-2-fluoro-4-isobutylbenzonitrile

[0237] 6-((3R)-3-(difluoromethyl)piperazin-1-yl)-2-fluoro-4-isobutylbenzonitrile (700 mg, 2.25 mmol), HATU (1.076 g, 2.70 mmol), 3-carboxypyridazine (308 mg, 2.48 mmol), and DIPEA (582 mg, 4.50 mmol) were dissolved in DMF (10 mL) and reacted at 25°C for 16 h. After completion, the reaction was diluted with water (50 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to yield 6-((3R)-4-(pyridazin-3-ylcarbonyl)-3-(difluoromethyl)piperazin-1-yl)-2-fluoro-4-isobutylbenzonitrile (415 mg, 44% yield).

[0238] LC-MS, M / Z (ESI): 418.1 [M+H) +

[0239] Step 3: Synthesis of ((2R)-2-(difluoromethyl)-4-(3-fluoro-2-(1H-1,2,3,4-tetrazol-5-yl)-5-isobutylphenyl)piperazin-1-yl)(pyridazin-3-yl)methanone

[0240] 6-((3R)-4-(pyridazin-3-ylcarbonyl)-3-(difluoromethyl)piperazin-1-yl)-2-fluoro-4-isobutylbenzonitrile (400 mg, 0.96 mmol), sodium azide (624 mg, 9.60 mmol), and tributyltin chloride (3.12 g, 9.60 mmol) were dissolved in toluene (2 mL), heated to 140°C in a sealed container, and stirred for 12 h. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography to give ((2R)-2-(difluoromethyl)-4-(3-fluoro-2-(1H-1,2,3,4-tetrazol-5-yl)-5-isobutylphenyl)piperazin-1-yl)(pyridazin-3-yl)methanone (233 mg, yield 53%).

[0241] LC-MS, M / Z(ESI):461.1[M+H] +

[0242] Step 4: Synthesis of 3-(((2R)-2-(difluoromethyl)-4-(3-fluoro-2-(1H-1,2,3,4-tetrazol-5-yl)-5-isobutylphenyl)piperazin-1-yl)methyl)pyridazine

[0243] ((2R)-2-(difluoromethyl)-4-(3-fluoro-2-(1H-1,2,3,4-tetrazol-5-yl)-5-isobutylphenyl)piperazin-1-yl)(pyridazin-3-yl)methanone (200 mg, 0.43 mmol) was dissolved in tetrahydrofuran (5 mL). Borane in tetrahydrofuran (3.44 mL, 4.30 mmol, 1 mol / L) was added dropwise at 0°C and stirred at room temperature for 6 h. After the reaction was completed, water (10 mL) was added at 0°C and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography to give 3-(((2R)-2-(difluoromethyl)-4-(3-fluoro-2-(1H-1,2,3,4-tetrazol-5-yl)-5-isobutylphenyl)piperazin-1-yl)methyl)pyridazine (30 mg, yield 15%).

[0244] LC-MS, M / Z(ESI):447.1[M+H] +

[0245] 1 H NMR (400MHz, DMSO) δ9.05 (s, 1H), 7.61 (s, 2H), 6.88 (d, J = 7.8Hz, 2H), 6.20 (td, J =55.7,4.1Hz,1H),4.02(dd,J=38.7,14.7Hz,2H),2.95(d,J=10.7Hz,1H),2.91–2 .83(m,1H),2.82–2.75(m,1H),2.70(d,J=8.0Hz,1H),2.66–2.53(m,2H),2.43(s, 2H), 2.24(d,J=10.9Hz,1H), 1.84(dt,J=12.8,6.5Hz,1H), 0.82(d,J=6.2Hz,6H).

[0246] Example 5: Preparation of target compound I-7

[0247] 2-((3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluoro-4-(2-methylpropanoic acid)benzoic acid

[0248] The synthetic route of the target compound I-7 is as follows:

[0249] Step 1: Synthesis of tert-butyl (3R)-3-(difluoromethyl)piperazine-1-carboxylate

[0250] (2R)-2-(Difluoromethyl)piperazine dihydrochloride (1.00 g, 4.81 mmol) and triethylamine (1.46 g, 14.43 mmol) were dissolved in DCM (20 mL). Di-tert-butyl dicarbonate (1.05 g, 4.81 mmol) was added at 0°C and stirred for 16 h. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EA (v / v) = 2 / 1) to obtain tert-butyl (3R)-3-(difluoromethyl)piperazine-1-carboxylate (920 mg, 81% yield).

[0251] LC-MS, M / Z(ESI):237.1[M+H] +

[0252] Step 2: Synthesis of tert-butyl (3R)-3-(difluoromethyl)-4-(pyridazine-3-carbonyl)piperazine-1-carboxylate

[0253] Tert-butyl (3R)-3-(difluoromethyl)piperazine-1-carboxylate (900 mg, 3.81 mmol), HATU (1.82 g, 4.57 mmol), 3-carboxypyridazine (473 mg, 3.81 mmol), and N,N-diisopropylethylamine (1.18 g, 9.14 mmol) were dissolved in DMF (10 mL) and reacted at 25°C for 16 h. After completion, the reaction was diluted with water (50 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EA (v / v) = 1 / 1) to obtain tert-butyl (3R)-3-(difluoromethyl)-4-(pyridazine-3-carbonyl)piperazine-1-carboxylate (977 mg, 75% yield).

[0254] LC-MS, M / Z(ESI):343.1[M+H] +

[0255] Step 3: Synthesis of tert-butyl (3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazine-1-carboxylate

[0256] Tert-butyl (3R)-3-(difluoromethyl)-4-(pyridazine-3-carbonyl)piperazine-1-carboxylate (950 mg, 2.78 mmol) was dissolved in tetrahydrofuran (10 mL). Borane in tetrahydrofuran (27.8 mL, 27.8 mmol, 1 mol / L) was added dropwise at 0°C and stirred at room temperature for 6 h. After completion of the reaction, water (10 mL) was added at 0°C to quench the reaction. The mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EA (v / v) = 1 / 1) to obtain tert-butyl (3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazine-1-carboxylate (170 mg, 19% yield).

[0257] LC-MS, M / Z(ESI):329.1[M+H] +

[0258] Step 4: Synthesis of 3-(((2R)-2-(difluoromethyl)piperazin-1-yl)methyl)pyridazine

[0259] Dissolve tert-butyl (3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazine-1-carboxylate (170 mg, 0.52 mmol) in dioxane (2 mL). Add hydrogen chloride in dioxane (5 mL, 20 mmol, 4 mol / L) dropwise and stir at room temperature for 2 h. After completion of the reaction, concentrate to afford 3-(((2R)-2-(difluoromethyl)piperazin-1-yl)methyl)pyridazine (118 mg, 99% yield).

[0260] LC-MS, M / Z(ESI):228.1[M+H] +

[0261] Step 5: Synthesis of methyl 4-bromo-2-((3R)-3-(difluoromethyl)-4-(((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluorobenzoate

[0262] 3-(((2R)-2-(difluoromethyl)piperazin-1-yl)methyl)pyridazine (118 mg, 0.52 mmol), methyl 3,5-difluoro-4-bromobenzoate (144 mg, 0.57 mmol), and triethylamine (263 mg, 2.6 mmol) were dissolved in DMF (5 mL) and reacted at 80°C for 16 h. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EA (v / v) = 1 / 1) to obtain methyl 4-bromo-2-((3R)-3-(difluoromethyl)-4-(((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluorobenzoate (167 mg, 70% yield).

[0263] LC-MS, M / Z(ESI):459.1[M+H] +

[0264] Step 6: Synthesis of methyl 2-((3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluoro-4-(2-methylpropyl)benzoate

[0265] Methyl 4-bromo-2-((3R)-3-(difluoromethyl)-4-(((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluorobenzoate (160 mg, 0.35 mmol), isobutylboronic acid (72 mg, 0.70 mmol), potassium carbonate (145 mg, 1.05 mmol) and XPhos Pd G4 (30 mg, 0.035 mmol) was dissolved in dioxane (5 mL) and reacted at 90°C for 3 h. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EA (v / v) = 1 / 3) to obtain methyl 2-((3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluoro-4-(2-methylpropyl)benzoate (99 mg, 65% yield).

[0266] LC-MS, M / Z(ESI):437.1[M+H] +

[0267] Step 7: Synthesis of 2-((3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluoro-4-(2-methylpropanoic acid)benzoic acid

[0268] Methyl 2-((3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluoro-4-(2-methylpropyl)benzoate (99 mg, 0.23 mmol) and lithium hydroxide (83 mg, 3.45 mmol) were dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL) and reacted at 50°C for 32 h. After completion of the reaction, the mixture was diluted with water (10 mL), the pH was adjusted to approximately 3 with 1N hydrochloric acid, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH (v / v) = 10 / 1) to give 2-((3R)-3-(difluoromethyl)-4-((pyridazin-3-yl)methyl)piperazin-1-yl)-6-fluoro-4-(2-methylpropanoic acid)benzoic acid (45 mg, yield 47%).

[0269] LC-MS, M / Z(ESI):423.3[M+H] +

[0270] 1 H NMR(400MHz,dmso)δ13.34(s,1H),9.12(dd,J=4.8,1.8Hz,1H),7.70(ddd,J=13.2,8 .4,3.3Hz,2H),6.81–6.70(m,2H),6.48(td,J=55.7,5.0Hz,1H),4.23–4.10(m,2H),3 .26–3.18(m,1H),3.15–3.01(m,2H),2.99–2.93(m,2H),2.94–2.83(m,1H),2.51–2.4 9(m,1H),2.42(d,J=7.2Hz,2H),1.84(td,J=13.3,6.6Hz,1H),0.83(d,J=6.6Hz,6H).

[0271] Example 6: The preparation of the following compounds can be obtained by referring to the preparation methods of the above compounds.

[0272] In the test examples of the present invention, the preparation method of the control compound I refers to patent WO2023006893A1, and the structure is shown below:

[0273] Control compound I.

[0274] Biological testing

[0275] The compounds prepared in the examples can be tested using the following test methods.

[0276] Test Example 1: Compound Binding to AT2R

[0277] The Angiotensin AT2 Receptor Ligand Binding Assay Kit (#C1TT1AT2, Cisbio) was used according to the protocol. First, a 10 mM stock solution of compound was serially diluted 5× (10 concentrations, each with two replicates). 160 nL of each compound concentration was added to a 384-well plate. 40 μL of 1× TLB was added to each well and shaken at room temperature for 15 minutes. A 15-mL centrifuge tube containing 5 mL of 1× TLB was prepared for future use. Frozen labeled cells were thawed in a 37°C water bath (1-2 minutes). The thawed cells were quickly transferred to the 15-mL centrifuge tube, mixed thoroughly, and centrifuged at 1000 g for 5 minutes at room temperature. The supernatant was discarded and the cells were resuspended in 2.7 mL of 1× TLB. A new 384-well plate was prepared and 10 μL of the mixed cells were added to the appropriate wells according to the experimental design. 5 μL of 4× compound solution and 5 μL of 4× Tag-lite red fluorescent labeled ligand were added to each well. After incubation at room temperature for 1 hour, data were read using the EnVision HTRF mode. The excitation intensity at 665 nM and 615 nM in each well was measured, and the ratio (Ratio = A665 nM / B615 nM) was calculated. IC was then calculated using GraphPad Prism 8 software. 50 Numerical values, X: logarithmic value of compound concentration; Y: ratio of A665nM / B615nM. The present invention exemplifies the results of some compounds, see Table 1 for details.

[0278] Table 1. IC values ​​of compounds tested for AT2R binding activity 50 value

[0279] The experimental results show that in the binding test of the test compound and AT2R, the test compound has a strong binding effect with AT2R.

[0280] Test Example 2: Pharmacokinetics test in rats

[0281] The pharmacokinetic test in rats was conducted using male SD rats, 3 per group, 180-240 g, fasted overnight, and each group was orally gavaged with 10 mg / kg. Blood was collected before administration and 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were centrifuged at 8000 rpm and 4°C for 6 minutes, and the plasma was collected and stored at -20°C. The plasma at each time point was taken, 3-5 times the amount of acetonitrile solution containing the internal standard was added and mixed, vortexed for 1 minute, centrifuged at 13000 rpm and 4°C for 10 minutes, the supernatant was taken and 3 times the amount of water was added and mixed, and an appropriate amount of the mixture was taken for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software. The results of some compounds are shown in Table 2 for details.

[0282] Table 2: Pharmacokinetic test results in rats

[0283] The experimental results show that the compound of the present invention has better pharmacokinetic properties in rats compared with the control compound I.

[0284] Test Example 3: Pharmacokinetics test in mice

[0285] Mouse pharmacokinetic studies were conducted using male ICR mice (3 mice per group, weighing 20-30 g) fasted overnight. Each group received an oral gavage of 10 mg / kg. Blood was collected before administration and at 5, 15, and 30 minutes, as well as 1, 2, 4, 6, 8, and 24 hours after administration. Blood samples were centrifuged at 6000 g / min at 2-8°C for 3 minutes, and plasma was collected and stored at -20°C. Plasma was collected at each time point, added to a 10-fold volume of a 50% methanol-acetonitrile solution containing an internal standard, mixed, vortexed for 5 minutes, centrifuged at 4000 rpm at 4°C for 10 minutes, and the supernatant was added to a 1-fold volume of water and mixed. An appropriate amount of the mixture was then analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software. The results of some compounds of the present invention are shown in Table 3.

[0286] Table 3: Pharmacokinetic test results in mice

[0287] The experimental results show that the compound of the present invention has better pharmacokinetic properties in mice compared with the control compound I.

[0288] Test Example 4: Manual patch clamp technique to detect the effect of compounds on hERG channel current

[0289] Manual patch clamp experiments were performed using HEK-293 cells stably expressing the hERG potassium channel. hERG potassium channel cells were purchased from Creacell (Cat. No. A-0320). The final concentrations of test compounds were prepared on the day of testing and dissolved in extracellular solution. The extracellular solution (mM) consisted of 40 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-glucose, 10 mM HEPES, and 1.25 mM NaH2PO4·2H2O; pH 7.4 (titrated by NaOH). The intracellular solution (mM) consisted of 20 mM KCl, 115 mM K-Aspartic acid, 1 mM MgCl2·6H2O, 5 mM EGTA, 10 mM HEPES, and 2 mM Na2-ATP; pH 7.4 (titrated by KOH).

[0290] Electrophysiological test: After whole-cell sealing, the cell membrane voltage was clamped at -80mV. The clamping voltage was depolarized from -80mV to -50mV for 0.5s (as a leakage current detection), then stepped to 30mV for 2.5s, and then quickly restored to -50mV for 4s to stimulate the tail current of the hERG channel. Data were collected every 10s to observe the effect of drugs on the hERG tail current (peak tail current compound ) effect. A 0.5s stimulation at -50mV was used as the leakage current detection. Drug administration was started after the hERG current recorded by the whole cell was stable. After each drug concentration was applied for 5 minutes (or the current was stable), the next concentration was detected. One or more concentrations were detected for each test compound. The peak tail current (peak tail current) of each cell was detected in the external solution without compound. Control ) served as their own control group. Each concentration was tested in duplicate using at least two independent replicates of two cells. All electrophysiological experiments were performed at room temperature. Data were acquired using an IPA amplifier (Sutter Instruments) and stored in Sutter Patch software.

[0291] Data analysis: Calculate the inhibition rate (1-(Peak tail current compound / Peak tail current Control ), the concentration-effect curves were fitted nonlinearly in GraphPad Prism software, and the IC of each compound was calculated using the following equation: 50 Value: Y=1 / (1+10^((LogIC50-X)*HillSlope)). The present invention exemplifies the results of some compounds, see Table 4 for details.

[0292] Table 4: Inhibitory effects of compounds on hERG

[0293] The experimental results show that compared with the control compound I, the compound of the present invention has a lower risk of hERG inhibition in an in vitro system and a lower cardiac safety risk.

[0294] Test Example 5: Rat Sciatic Nerve Chronic Constriction Injury (CCI) Model

[0295] Male Sprague-Dawley rats weighing 200-250 g were anesthetized and immobilized in the prone position. The lateral thigh to the femur was shaved and disinfected, and a 1.5 cm incision was made in the thigh skin. The fascia was separated, and the biceps femoris was bluntly dissected to expose the sciatic nerve. The nerve was freed approximately 7 mm from its main trunk anterior to the trifugal branch and gently dissected. Four 5-0 sutures were placed around the sciatic nerve 2 mm anterior to the trifugal branch, separated by 1 mm intervals, leaving the ligature approximately 4-5 mm long. The ligatures were tightened to ensure a slight twitch of the calf muscle or toes during ligation. The muscle, subcutaneous tissue, and skin were sutured sequentially. The wound was cleaned and disinfected with iodine. The skin was sutured and disinfected. On the second day of modeling, the animals were randomly divided into groups of 8 and orally administered with vehicle or the corresponding compound solution. Mechanical pain thresholds were measured using Von-Frey fibers before and after administration.

[0296] Mechanical pain threshold testing method: The animal's hind limb was continuously stimulated with Von-Frey fibers, causing them to bend, and the animal's paw withdrawal reaction was observed. The animals were stimulated one by one in ascending order of fiber weight, with each fiber weight stimulated five times continuously. If fewer than three positive reactions were observed, the procedure was repeated with a larger fiber weight. If three or more positive reactions were observed in the first test, the fiber weight was considered the animal's pain threshold (three tests per animal, with the average value taken). The fiber weights were 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, and 15.0 g; the cutoff value was 15.0 g. GraphPad Prism 8.0 was used for statistical analysis, and one-way ANOVA was used for statistical comparison. Statistical differences between groups were compared, with P < 0.05 considered statistically significant.

[0297] The experimental results show that the compound of the present invention can significantly improve the reduction of the mechanical pain threshold of animals caused by the rat sciatic nerve chronic constriction injury model, and has excellent analgesic effect.

[0298] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, Ring A is selected from a 5-6 membered heteroaromatic ring; R 1 is selected from halogen, hydroxy, amino, cyano, oxo (=O), C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl; said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 The cycloalkyl group is optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, oxo; m is selected from 0, 1, 2, 3 or 4; when the substituent R 1 When it is multiple, the R 1 Same or different; L does not exist or is selected from C 0 -C 6 Alkylene-OC 0 -C 6 Alkylene, C 1 -C 6 Alkylene; said C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene or C 1 -C 6 The alkylene group is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, oxo (=O), methyl, ethyl, halomethyl, haloethyl; R 2 Selected from C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring; the C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 5-10 membered heterocyclic ring, 6-10 membered aromatic ring are optionally substituted by 1, 2, 3, 4 substituents selected from the following groups: halogen, hydroxyl, cyano, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl; and R 2 Not methyl, ethyl, isopropyl, -CF 3 ; n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; when the substituent R 2 When it is multiple, the R 2 Same or different; Ring E is selected from a benzene ring or a 6-membered heteroaromatic ring; R 3 Selected from halogen, hydroxyl, cyano, dimethylamino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl; said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 The cycloalkyl group is optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl; p is selected from 0, 1, 2, 3 or 4; when the substituent R 3 When it is multiple, the R 3 Same or different; M is selected from carboxylic acid, -CONHSO 2 R 5 、-SO 2 NHCOR 5 , tetrazolium or tetrazolium bioisostere; the bioisostere includes but is not limited to phosphate, R 5 Selected from H, OH, NH 2 , ONa, OK (potassium ion), C 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 8 Alkoxy, 5-6 membered heterocyclic ring; the C 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 8 Alkoxy, 5-6 membered heterocyclic ring are optionally substituted by 1-4 substituents selected from the following groups: halogen, amino, C 3 -C 7 Heterocycloalkyl, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Alkoxy.

2. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The ring A is a 5-6 membered heteroaromatic ring, and the 5-6 membered heteroaromatic ring contains 1, 2 or 3 heteroatoms; Preferably, the heteroatom is selected from N, O, S; More preferably, the heteroatom is N; Preferably, ring A is selected from the group consisting of furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, and triazine; More preferably, ring A is selected from: pyridine, pyrimidine, pyridazine, pyrazine.

3. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The ring E is a benzene ring or a 6-membered heteroaromatic ring; The 6-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms; The heteroatom is selected from N, O, and S; Preferably, the ring E is selected from benzene ring, pyridine, pyrimidine, pyridazine; More preferably, the ring E is selected from a benzene ring.

4. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The R 1 is selected from halogen, hydroxy, amino, cyano, oxo (=O), C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 3 Alkyl-C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl-C 3 -C 7 Cycloalkyl; m is selected from 0, 1, 2, 3 or 4; Preferably, the R 1 is selected from halogen, methyl, halomethyl, methoxy; m is selected from 0.

5. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The compound is selected from the following structures: Ring A, M, L, R 1 , R 3 , m and p have the definitions as described in claim 1.

6. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The compound is selected from the following structures: Ring A, M, R 1 , R 3 , m and p have the definitions as described in claim 1.

7. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The compound has the following structure: M.R 2 Having the definition as claimed in claim 1; Preferably, it has structures IVa and IVb:

8. A compound according to claim 1 or claim 7, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, It is characterized in that The R 2 Selected from C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclic ring, benzene ring; the C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclic ring, benzene ring is optionally substituted by 1, 2, 3, 4 substituents selected from the following groups: halogen, hydroxyl, cyano, amino, C 1 -C 3 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl; and R 2 Not methyl, ethyl, isopropyl, -CF 3 ; and / or n is selected from 1, 2, 3; and / or n is 1.

9. The compound according to claim 1 or claim 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The R 2 Selected from CH 2 F. CHF 2 , C 1 -C 3 Alkyl-C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 3 Alkyl-C 3 -C 7 Cycloalkyl; Preferably, the R 2 Selected from CH 2 F. CHF 2 , C 1 -C 3 Alkyl-C 1 -C 3 Alkoxy, C 3 -C 4 Cycloalkyl, C 1 -C 3 Alkyl-C 3 -C 4 Cycloalkyl; n is selected from 1, 2, 3; Preferably, the R 2 Selected from CH 2 F. CHF 2 , methyl-methoxy, ethyl-methoxy, cyclopropyl, methyl-cyclopropyl; n is selected from 1; preferably, said R 2 Selected from CH 2 F. CHF 2 , Preferably, the R 2 Selected from CH 2 F. CHF 2 ; Preferably, the R 2 Selected from CHF 2 .

10. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The R 3 Selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl; said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 The cycloalkyl group is optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl; p is selected from 0, 1, 2, 3 or 4; Preferably, the R 3 Selected from F, C 1 -C 5 Alkyl, C 1 -C 5 Haloalkyl, methyl-cyclopropyl; p is selected from 1, 2, 3; More preferably, the R 3 is selected from F, methyl, trifluoromethyl, isobutyl, isobutyl substituted with F, and methyl-cyclopropyl; and p is selected from 2.

11. The compound according to any one of claims 1 and claims 5 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that The M is selected from carboxylic acid, -CONHSO 2 R 5 、-SO 2 NHCOR 5 , tetrazolium or tetrazolium bioisostere; Preferably, M is selected from carboxylic acid, -CONHSO 2 R 5 、-SO 2 NHCOR 5 , tetrazole; said R 5 Selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl; More preferably, M is selected from carboxylic acid, tetrazole, -CONHSO 2 CH 2 CH 3 ; More preferably, M is selected from carboxylic acid and tetrazole; More preferably, M is selected from tetrazole.

12. The compound of formula (I) as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that L is absent or selected from carbonyl, methylene, -CH 2 CH 2 -、-CH(CH 3 )-、-CH 2 CH 2 CH 2 -、-CH 2 CH(CH 3 )-、-O-CH 2 -; Preferably, L is selected from methylene, -CH 2 CH 2 -、-CH(CH 3 )-、-O-CH 2 -; More preferably, L is selected from methylene.

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

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

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

16. Use of a compound according to any one of claims 1 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to claim 15, said use include: Acts as an AT2R antagonist; and / or, preventing and / or treating AT2R-mediated diseases; and / or, preventing and / or treating diseases in which a reduction in the action of Ang II is desired or required; and / or, preparing a medicament, pharmaceutical composition or formulation as an AT2R antagonist; And / or, preparing a medicament, pharmaceutical composition or formulation for preventing and / or treating a disease in which AT2R is expressed and its inhibition is desired or necessary.

17. A compound as described in any one of claims 1 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition as described in claim 15, for preventing and / or treating AT2R-mediated diseases, and / or preventing and / or treating diseases in which a reduction in Ang II action is desired or required.

18. The use according to claim 16 or 17, It is characterized in that The disease is neuropathy or neuropathic pain; And / or, the disease is primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve damage or biochemical nerve damage, postherpetic neuralgia, diabetic neuropathy or diabetes-related neuropathies.

19. A method for preventing and / or treating a disease, It is characterized in that include: Using a therapeutically effective amount of a compound according to any one of claims 1 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 15, to a person suffering from or susceptible to the disease; Wherein, the disease is an AT2R-mediated disease, and / or a disease in which a reduction in the action of Ang II is desired or necessary, and / or a disease in which AT2R is expressed and its inhibition is desired or necessary.

20. The method of claim 19, It is characterized in that The disease is neuropathy or neuropathic pain; And / or, the disease is primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve damage or biochemical nerve damage, postherpetic neuralgia, diabetic neuropathy or diabetes-related neuropathies.

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