Novel benzazepine derivatives

Abstract

The present application relates to benzazepine derivatives of the formula (I) or pharmaceutically acceptable salts thereof, and the use of the compounds for the diagnosis, prevention and / or treatment of diseases associated with vasopressin receptors.

Description

[0001] This invention claims the following priority:

[0002] CN202110264947.3, application date: March 5, 2021;

[0003] CN202110559685.3, application date: May 21, 2021;

[0004] CN202210198716.1, application date: March 2, 2022. Technical Field

[0005] This invention relates to novel benzozazepine cyclic derivatives and their salts. It also relates to pharmaceuticals comprising benzozazepine cyclic derivatives and their salts as active ingredients, which can be used for the diagnosis, prevention, and / or treatment of diseases related to angiotensin receptors. Background Technology

[0006] Hormones play a crucial role in regulating homeostasis within the human body, with arginine vasopressin (AVP) being closely related to the regulation of water and sodium metabolism. Disorders of arginine vasopressin (AVP) metabolism can cause various diseases, including hyponatremia, syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, cirrhosis, kidney disease, hypertension, and edema. Arginine vasopressin (AVP) receptor antagonists inhibit the binding of AVP to its receptors, thereby treating these diseases. Arginine vasopressin V2 receptor antagonists, such as tolvaptan, can increase free water excretion without affecting electrolyte metabolism, making them ideal drugs for treating these conditions. However, marketed AVP V2 receptor antagonists, such as tolvaptan, are metabolized by hepatic enzymes, producing large amounts of metabolites in the body and leading to severe drug-induced hepatotoxicity. The FDA has issued a black box warning on these drugs' product labels, restricting their use. Therefore, developing novel, highly effective V2 receptor antagonists with low side effects is crucial. Summary of the Invention

[0007] In a first aspect, the present invention provides compounds of formula (I), their optical isomers, or pharmacologically acceptable salts thereof.

[0008]

[0009] in,

[0010] Ring A is selected from 4-6 membered heterocyclic groups and C 3-6 Cycloalkyl groups, the 4-6 membered heterocyclic groups or C 3-6 Cycloalkyl groups may be optionally surrounded by 1, 2, or 3 R groups. ASubstitution; ring B is selected from phenyl and 5-6 heteroaryl, wherein the phenyl or 5-6 heteroaryl is optionally substituted by 1, 2 or 3 R3s;

[0011] The ring C is selected from phenyl and 5-6 heteroaryl, wherein the phenyl or 5-6 heteroaryl is optionally substituted by 1, 2 or 3 R4s;

[0012] T1 and T2 are independently selected from N and C(R) respectively. T );

[0013] R1, R2, R3, R A R T Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0014] R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, and 5-6 heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, or 5-6 heteroaryl groups are optionally surrounded by 1, 2, or 3 R groups. 4a replace;

[0015] R, R 4a Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkylamino group may be optionally substituted with 1, 2 or 3 R's;

[0016] R' is selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 alkyl;

[0017] m1 and m2 are independently selected from 0, 1 or 2 respectively;

[0018] Furthermore, when ring A is selected from 4-6 membered heterocyclic groups, the compound shown in formula (I) is not selected from...

[0019] The 4-6 member heterocyclic group, C 1-6 Heteroalkyl or 5-6-membered heteroaryl groups contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0020] In a second aspect, the invention also provides compounds of formula (II), their optical isomers, or pharmacologically acceptable salts thereof.

[0021]

[0022] Among them, X1, X2, and X3 are independently selected from O and C(R) respectively. A )2 and NR A ;

[0023] Ring B is selected from phenyl and 5-6 heteroaryl groups, wherein the phenyl or 5-6 heteroaryl group is optionally substituted by 1, 2 or 3 R3 groups;

[0024] The ring C is selected from phenyl and 5-6 heteroaryl, wherein the phenyl or 5-6 heteroaryl is optionally substituted by 1, 2 or 3 R4s;

[0025] T1 and T2 are independently selected from N and C(R) respectively. T );

[0026] R1, R2, R3, R A R T Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0027] R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, and 5-6 heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, or 5-6 heteroaryl groups are optionally surrounded by 1, 2, or 3 R groups. 4a replace;

[0028] R, R 4a Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C.1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkylamino group may be optionally substituted with 1, 2 or 3 R's;

[0029] R' is selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 alkyl;

[0030] m1, m2, and n are each independently selected from 0, 1, or 2;

[0031] Furthermore, when X1 and X3 are both selected from O, the compound shown in formula (II) is not selected from O.

[0032] The C 1-6 Heteroalkyl or 5-6-membered heteroaryl groups contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0033] In another aspect of the invention, the invention also provides compounds of formulas (II-1), (II-2), (II-3), and (II-4), their optical isomers, or their pharmacologically acceptable salts.

[0034] Among them, ring B, ring C, X1, X2, X3, T1, T2, R1, R2, m1, m2, and n are as defined above.

[0035] In another aspect, the present invention also proposes the compound of formula (III), its optical isomer, or a pharmacologically acceptable salt thereof.

[0036]

[0037] Among them, X1, X2, and X3 are independently selected from O and C(R) respectively. A )2 and NR A ;

[0038] T1 and T2 are independently selected from N and C(R) respectively. T );

[0039] Y1 and Y2 are independently selected from N and C(R) respectively. Y );

[0040] R1, R2, R3, R A R T R YEach of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0041] R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, and 5-6 heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, or 5-6 heteroaryl groups are optionally surrounded by 1, 2, or 3 R groups. 4a replace;

[0042] R, R 4a Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkylamino group may be optionally substituted with 1, 2 or 3 R's;

[0043] R' is selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 alkyl;

[0044] m1, m2, m3, m4, and n are each independently selected from 0, 1, or 2;

[0045] Furthermore, when X1 and X3 are both selected from O, the compound shown in formula (III) is not selected from O.

[0046] The C 1-6 Heteroalkyl or 5-6-membered heteroaryl groups contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0047] In another aspect, the present invention also proposes compounds of formulas (III-1), (III-2), (III-3), and (III-4), their optical isomers, or their pharmacologically acceptable salts.

[0048] Among them, X1, X2, X3, T1, T2, Y1, Y2, R1, R2, R3, R4, m1, m2, m3, m4, and n are as defined above.

[0049] In another aspect, the present invention also proposes the compound of formula (IV), its optical isomer, or a pharmacologically acceptable salt thereof.

[0050]

[0051] Wherein, T1 and T2 are independently selected from O, N, and C(R) respectively. T );

[0052] Y1 and Y2 are independently selected from N and C(R) respectively. Y );

[0053] R1, R2, R3, R A R T R Y Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0054] R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, and 5-6 heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, or 5-6 heteroaryl groups are optionally surrounded by 1, 2, or 3 R groups. 4a replace;

[0055] R, R 4a Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkylamino group may be optionally substituted with 1, 2 or 3 R's;

[0056] R' is selected from H, F, Cl, Br, I, CN, OH, NH2, and C.1-6 alkyl;

[0057] m2, m3, and n are each independently selected from 0, 1, or 2;

[0058] The C 1-6 Heteroalkyl or 5-6-membered heteroaryl groups contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0059] In another aspect, the present invention also proposes compounds of formulas (V-1), (V-2), (V-3), and (V-4), their optical isomers, or their pharmacologically acceptable salts.

[0060] Among them, T1, T2, Y1, Y2, R1, R2, R3, R4, R A m2, m3, and n are as defined above.

[0061] In some embodiments of the present invention, R4 is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CF3, Cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, thiophene, and thiazolyl, with the remaining variables as defined in this invention.

[0062] In some embodiments of the present invention, the aforementioned ring A is selected from aziridine, oxadiidine, pyrrolidinyl, tetrahydrofuranyl, cyclobutane, cyclopentane, and cyclohexane, wherein the aziridine, oxadiidine, pyrrolidinyl, tetrahydrofuranyl, cyclobutane, cyclopentane, or cyclohexane is optionally represented by one or two Rs. A Replace, the remaining variables are as defined in this invention.

[0063] In some embodiments of the present invention, the ring A is selected from... The remaining variables are as defined in this invention.

[0064] In some embodiments of the present invention, the ring B is selected from phenyl and pyridyl, wherein the phenyl or pyridyl group is optionally substituted with 1, 2 or 3 R3 groups, and the remaining variables are as defined in the present invention.

[0065] In some embodiments of the present invention, the ring B is selected from... The remaining variables are as defined in this invention.

[0066] In some embodiments of the present invention, the ring C is selected from... The remaining variables are as defined in this invention.

[0067] In another aspect, the present invention also provides compounds of the following formula, their optical isomers, or their pharmacologically acceptable salts, selected from...

[0068]

[0069] In another aspect, the present invention also provides compounds of the following formula, their optical isomers, or their pharmacologically acceptable salts, selected from...

[0070]

[0071] In another aspect of the invention, the invention also proposes the use of the aforementioned compounds, their optical isomers, or their pharmacologically acceptable salts in the preparation of medicaments for the prevention or treatment of diseases associated with arginine vasopressin V1a receptors, arginine vasopressin V1b receptors, arginine vasopressin V2 receptors, the sympathetic nervous system, or the renin-angiotensin-aldosterone system.

[0072] In some embodiments of the present invention, the diseases associated with arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, the sympathetic nervous system, or the renin-angiotensin-aldosterone system include: hypertension, Reye's syndrome, dysmenorrhea, premature birth, adrenocorticotropic hormone-releasing hormone secretion disorder, adrenal hyperplasia, depression, chronic congestive heart failure, cirrhosis, antidiuretic hormone secretion disorder syndrome, hyponatremia caused by chronic heart failure / cirrhosis / antidiuretic hormone secretion disorder, or polycystic kidney disease.

[0073] This invention has at least one of the following technical effects:

[0074] 1) Compared with existing technologies (such as positive control drugs such as tolvaptan), the compounds of the present invention have lower hepatotoxicity, specifically including but not limited to: the compounds of the present invention can reduce the inhibition of bile excretion into the bile duct, do not capture GSH (glutathione) and / or do not produce DM4103-like metabolites;

[0075] 2) Compared with the prior art, the proportional dose-effect of the compound of the present invention does not have a hook effect in AVP-induced LLC-PK1 cell proliferation, thus the compound of the present invention has better therapeutic effect;

[0076] 3) Compared with existing technologies (such as positive control drugs like Lixivaptan), the compounds of the present invention do not inhibit CYP;

[0077] 4) Compared with the prior art, the compound of the present invention has a longer half-life, thus prolonging the efficacy;

[0078] 5) Compared with the prior art, the compound of the present invention has high selectivity for V2 receptor.

[0079] Definitions and Explanations

[0080] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0081] As used in this invention, the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase "at least one," whether related to or unrelated to those specifically identified elements.

[0082] The term “pharmacologically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0083] The term "pharmacologically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a specific substituent, as discovered in this invention, with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmacologically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmacologically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and also include salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0084] The pharmacologically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0085] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of protection claimed by this invention.

[0086] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Relative configurations representing the center of a solid, such as The straight solid and straight dashed lines at the C1 and C2 atoms indicate that the two bonds connected to C1 and C2 face inward and outward, respectively, representing... Compounds with two trans configurations can be used, while compounds with a cis configuration can be represented by two straight solid lines. Or two straight dashed keys Indicates, that is and They all represent

[0087] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0088] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention. "Optional" or "optionally" means that the events or conditions described below may occur but are not necessary, and the description includes both the occurrence of said events or conditions and the non-occurrence of said events or conditions.

[0089] When the group valence bond is marked with a dashed line At times, for example, in In the diagram, the dashed line represents the connection point between the group and other parts of the molecule. When the single bond has... At times, for example, in In the diagram, the dashed line represents a single bond or the absence of a bond, which also means... Represents a single key Or dual-key

[0090] The terms “substituted” or “replaced by” refer to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The terms “optionally substituted” or “optionally replaced by” mean that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on a chemically feasible basis.

[0091] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1, 2, or 3 R's, the group can optionally be substituted by 1, 2, or 3 R's, and R' has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0092] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected, for example... When L1 represents a single bond, it means that the structure is actually

[0093] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium substituent can be attached to the substituted group by any carbon atom on the pyridine ring.

[0094] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linking group L is -CH2O-. In this case, -CH2O- can be connected to a phenyl group and a cyclopentyl group in the same direction as the reading order from left to right to form a structure. Alternatively, the phenyl and cyclopentyl groups can be connected in the reverse order of reading from left to right to form the phenyl group. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0095] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “3-6 elemental ring” refers to a “ring” with 3-6 atoms arranged around it.

[0096] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g., hypo-alkyl groups). C 1-6 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0097] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 C 3-4 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g., alkyl groups). C 1-4 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0098] Unless otherwise specified, "C 2-3 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-3 Alkenyl groups include C3 and C2 alkenyl groups; the C 2-3 Alkenes can be monovalent, divalent, or polyvalent. C 2-3 Examples of alkenes include, but are not limited to, those that are alkenyl groups. wait.

[0099] Unless otherwise specified, "C 2-3 "Alkyne" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located at any position within the group. It can be monovalent, divalent, or polyvalent. The C... 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, those that are not part of the list. wait.

[0100] The term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom or heterogroup. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 Heteroalkyl; in other embodiments, the heteroalkyl group is C10. 1-3 Heteroalkyl. Heteroatoms or heteroatomic groups can be located in any internal position of a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a conventional expression and refers to those alkyl groups that are attached to the rest of the molecule by an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and at most two heteroatoms can be consecutive, such as -CH2-NH-OCH3.

[0101] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0102] Unless otherwise specified, the term "C"1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkoxy groups, etc. C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0103] Unless otherwise specified, the term "C" 1-6 "Alkylamino" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-6 Alkylamino groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylamino groups, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0104] Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-3 Alkylamino groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0105] Unless otherwise specified, the term "C" 1-6 "Alkylthio" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-6 Alkyl thio groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylthio groups, etc. C 1-6Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0106] Unless otherwise specified, the term "C" 1-3 "Alkylthio" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-3 Alkyl thio groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkylthio groups, etc. C 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0107] Unless otherwise specified, "C 4-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which can be monocyclic or bicyclic. 4-6 Cycloalkyl groups include C 4-5 C 5-6 C4 and C5 cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. 4-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0108] Unless otherwise specified, the term "4-6 membered heterocyclic group" on its own or in combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "4-6 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 4-6 membered heterocyclic alkyl includes 4-5, 4, 5, 5-6, and 6 membered heterocyclic alkyl groups, etc. Examples of 4-6 membered heterocyclic groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0109] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" are used interchangeably in this invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0110] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also include any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 5-10-membered, 6-7-membered, 6-8-membered, 6-9-membered, and 6-10-membered rings, etc.

[0111] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as affinity substitution). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

[0112] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenemethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0113] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0114] The solvent used in this invention is commercially available.

[0115] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0116] Figure 1 This is a diagram of a repeating experiment according to an embodiment of the present invention;

[0117] Figure 2 These are two repeated experiments according to an embodiment of the present invention. Detailed Implementation

[0118] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0119] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0120] Preparation of intermediates

[0121] Reference Example 1: Preparation of Intermediate I-1

[0122]

[0123] At room temperature, p-toluenesulfonyl chloride (21.9 g, 115 mmol) was added to a pyridine (150 mL) solution of 7-chloro-1,2,3,4-tetrahydrobenzo[B]azapyro-5-one (15 g, 76.7 mmol). The reaction mixture was reacted at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined. The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was purified by silica gel chromatography to give intermediate I-1.

[0124] LC-MS(ESI)[M+H] + 349.9.

[0125] 1H NMR (400MHz, CDCl3) δ7.66(d,J=2.4Hz,1H),7.58(d,J=8.3Hz,2H),7.47(dd,J=8.6,2.5Hz,1H),7.43(d,J=8 .5Hz,1H),7.28(d,J=8.0Hz,2H),3.83(t,J=6.5Hz,2H),2.43(s,3H),2.40–2.35(m,2H),2.00–1.91(m,2H).

[0126] Reference Example 2: Preparation of Intermediate I-2

[0127]

[0128] At 25°C, intermediate I-1 (37.00 g, 106.00 mmol) was dissolved in anhydrous tetrahydrofuran (350 mL). Under argon protection and ice-water bath cooling, sodium hydride (6.36 g, 60% wt, 159.00 mmol) was added in portions. After stirring in an ice-water bath for 1 hour, dimethyl carbonate (19.08 g, 212.00 mmol) was added, and the mixture was heated to 50°C and stirred for 24 hours. After cooling, the reaction mixture was slowly poured into a cold saturated ammonium chloride aqueous solution (500 mL), concentrated to remove most of the tetrahydrofuran, and filtered. The filter cake was washed with water, then slurried with petroleum ether, filtered, and the filter cake was dried under vacuum to obtain intermediate I-2.

[0129] LC-MS(ESI)[M+H] + 408.0.

[0130] Reference Example 3: Preparation of Intermediate I-3

[0131]

[0132] Intermediate I-2 (19.00 g, 46.68 mmol) was dissolved in anhydrous N,N-dimethylformamide (187 mL) at 25 °C. Sodium carbonate (14.84 g, 140.00 mmol) and 2-(2-bromoethyl)isoindoline-1,3-dione (23.71 g, 93.36 mmol) were added sequentially, and the mixture was stirred overnight at 90 °C under argon protection. After cooling, the reaction solution was diluted with ethyl acetate (500 mL), washed with water (150 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-3.

[0133] LC-MS(ESI)[M+H] + 581.2.

[0134] Reference Example 4: Preparation of Intermediate I-4

[0135]

[0136] Intermediate I-3 (20.00 g, 34.48 mmol) was dissolved in dimethyl sulfoxide / water (130 mL / 13 mL) at 25 °C, and sodium chloride (16.70 g, 28.60 mmol) was added. After purging the system three times with argon, the mixture was stirred at 150 °C for 10 hours under argon protection. After cooling, the reaction solution was diluted with ethyl acetate (400 mL), washed with water (150 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-4.

[0137] LC-MS(ESI)[M+H] + 523.2.

[0138] Reference Example 5: Preparation of Intermediate I-5

[0139]

[0140] Intermediate I-4 (200 mg, 0.38 mmol) was dissolved in ethanol (7 mL) at 25 °C, and 85% hydrazine hydrate (0.35 mL) was added. The reaction mixture was stirred at 35 °C for 4 hours. Most of the ethanol was removed by vacuum concentration, and the mixture was diluted with ethyl acetate (50 mL). The solution was washed successively with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain crude intermediate I-5. The crude product was used directly in the next reaction step.

[0141] LC-MS(ESI)[M+H] + 375.2.

[0142] Reference Example 6: Preparation of Intermediate I-6

[0143]

[0144] Intermediate I-5 (170 mg, 0.45 mmol) was dissolved in methanol (10 mL) at 25 °C. Sodium borohydride (190 mg, 5.00 mmol) was slowly added under ice-water bath cooling. After stirring the reaction solution at room temperature for 1 hour, most of the methanol was removed by concentration under reduced pressure. The solution was diluted with ethyl acetate (50 mL), washed successively with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-6. The crude product was used directly in the next reaction step.

[0145] LC-MS(ESI)[M+H] + 377.2.

[0146] Reference Example 7: Preparation of Intermediate I-7

[0147]

[0148] At 25°C, intermediate I-6 (150 mg, 0.40 mmol) was dissolved in anhydrous methanol (20 mL), and magnesium filings (2.00 g, 83.33 mmol) were added. The mixture was purged with nitrogen three times and stirred overnight at 70°C under a nitrogen atmosphere (balloon). After cooling, the mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated to dryness. It was dissolved in a dichloromethane / methanol mixture (10 / 1, 50 mL), washed with saturated ammonium chloride aqueous solution (20 mL × 3), washed with water (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-7. The crude product was used directly in the next reaction step.

[0149] LC-MS(ESI)[M+H] + 223.0.

[0150] Refer to Example 8: Preparation of Intermediate I-8

[0151]

[0152] At 25°C, intermediate I-7 (85 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL), followed by the sequential addition of triethylamine (121 mg, 1.20 mmol) and di-tert-butyl dicarbonate (124 mg, 0.57 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (50 mL), washed with dimethyl ethylenediamine aqueous solution (1 M, 10 mL × 2), then washed with water (20 mL × 2), followed by washing with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was then filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-8. The crude product was used directly in the next reaction step.

[0153] LC-MS(ESI)[M+H-56] + 267.0.

[0154] Reference Example 9: Preparation of Intermediate I-9

[0155]

[0156] At 25°C, 2-methyl-4-nitrobenzoic acid (181 mg, 1.00 mmol) was dissolved in anhydrous dichloromethane (5 mL). Under ice-water bath and argon protection, N,N-dimethylformamide (20 mg) and oxalyl chloride (591 mg, 4.65 mmol) were added sequentially. After stirring in an ice-water bath for 1 hour, the mixture was concentrated to dryness at room temperature to obtain an acyl chloride intermediate. This acyl chloride was dissolved in anhydrous dichloromethane. Under ice-water bath and argon protection, a dichloromethane solution of intermediate I-8 (110 mg, 0.34 mmol), triethylamine (343 mg, 3.4 mmol), and p-dimethylaminopyridine (1.83 mg, 0.15 mmol) was slowly added. After the addition was complete, the mixture was stirred overnight at 40°C. Quenching with methanol (0.5 mL), concentrating under reduced pressure to dryness, dissolving in ethyl acetate (50 mL), washing successively with water (30 mL × 2) and saturated brine (20 mL), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-9.

[0157] LC-MS(ESI)[M+H] + 486.2.

[0158] Reference Example 10: Preparation of Intermediate I-10

[0159]

[0160] At 25°C, intermediate I-9 (37.00 mg, 0.076 mmol) was dissolved in ethanol (5 mL), and zinc powder (130 mg, 2.00 mmol) was added. The mixture was purged with nitrogen three times, and stirred at 70°C for 3 hours under a nitrogen atmosphere (balloon). After cooling, the mixture was filtered through a diatomaceous earth liner, and the filtrate was concentrated under reduced pressure to obtain crude intermediate I-10. The crude product was used directly in the next reaction step.

[0161] LC-MS(ESI)[M+H] + 456.4.

[0162] Reference Example 11: Preparation of Intermediate I-11

[0163]

[0164] Intermediate I-10 (33 mg, 0.073 mmol) was dissolved in dichloromethane (2 mL) at 25 °C, followed by the sequential addition of triethylamine (50 mg, 0.50 mmol) and o-methylbenzoyl chloride (23.00 mg, 0.15 mmol). After stirring at room temperature for 1 hour, the solution was quenched with methanol (0.5 mL) and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-11.

[0165] LC-MS(ESI)[M+H] + 574.3.

[0166] Reference Example 12: Preparation of Intermediate I-12

[0167]

[0168] At room temperature, methyl 6-aminonicotinic acid (1.0 g, 6.57 mmol) was dissolved in pyridine (20 mL), and 2-trifluoromethylbenzoyl chloride (1.51 g, 7.25 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with water (50 mL × 5). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain intermediate I-12.

[0169] LC-MS(ESI)[M+H] + 325.0.

[0170] Reference Example 13: Preparation of Intermediate I-13

[0171]

[0172] At room temperature, intermediate I-12 (1.35 g, 4.16 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of sodium hydroxide (499 mg, 12.5 mmol) in water (2 mL) was added. After the addition was complete, the reaction mixture was stirred at 70 °C for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 5-6 with 1 N hydrochloric acid. The mixture was filtered, and the solid was dried to obtain intermediate I-13.

[0173] LC-MS(ESI)[M+H] + 311.0.

[0174] Reference Example 14: Preparation of Intermediate I-14

[0175]

[0176] At 25°C, intermediate I-8 (50 mg, 0.16 mmol) was dissolved in tetrahydrofuran (1 mL), followed by the addition of pyridine (0.79 mL, 10.00 mmol), 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 0.79 mL), and intermediate I-13 (53 mg, 0.17 mmol). The mixture was stirred overnight at 65°C in a sealed microwave-safe tube. After cooling, the solution was concentrated to dryness under reduced pressure, dissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution (30 mL × 2), washed with water (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-14. The crude product was used directly in the next reaction step.

[0177] LC-MS(ESI)[M+H] + 615.3.

[0178] Reference Example 15: Preparation of Intermediate I-15

[0179]

[0180] Intermediate I-6 (115 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (2 mL) at 25 °C. Paraformaldehyde (56 mg, 0.62 mmol) and sodium borohydride acetate (20 mg, 0.93 mmol) were added sequentially, and the mixture was stirred overnight at 90 °C under argon protection. After cooling, the reaction solution was quenched with saturated ammonium chloride aqueous solution (2 mL), concentrated under reduced pressure to remove dichloromethane, diluted with ethyl acetate (50 mL), washed successively with water (30 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-15.

[0181] LC-MS(ESI)[M+H] + 391.2.

[0182] Reference Example 16: Preparation of Intermediate I-16

[0183]

[0184] At 25°C, intermediate I-15 (100 mg, 0.26 mmol) was dissolved in anhydrous methanol (20 mL), and magnesium filings (2.00 g, 83.33 mmol) were added. The mixture was purged with nitrogen three times and stirred overnight at 70°C under a nitrogen atmosphere. After cooling, the mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated to dryness. It was then dissolved in a dichloromethane / methanol mixture (10 / 1, 50 mL), washed with saturated ammonium chloride aqueous solution (20 mL × 3), washed with water (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate I-16. The crude product was used directly in the next reaction step.

[0185] LC-MS(ESI)[M+H] + 237.2.

[0186] Reference Example 17: Preparation of Intermediate I-17

[0187]

[0188] At room temperature, 247 g (1.30 mol) of 4-toluenesulfonyl chloride was added to 1000 mL of pyridine containing 200 g (1.08 mol) of methyl 2-amino-5-chlorobenzoate. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into ice water (1500 mL) and extracted with ethyl acetate (1000 mL × 3). The organic phases were combined and washed successively with water (1500 mL) and saturated brine (1500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by slurrying with ethyl acetate / petroleum ether (5:95) to obtain intermediate I-17.

[0189] LC-MS(ESI)[M+H] + 340.0.

[0190] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),7.78(d,J=2.6Hz,1H),7.67(d,J=8.3Hz,2H),7.63(dd ,J=8.9,2.6Hz,1H),7.46(d,J=8.9Hz,1H),7.36(d,J=8.1Hz,2H),3.80(s,3H),2.34(s,3H).

[0191] Reference Example 18: Preparation of Intermediate I-18

[0192]

[0193] At room temperature, cesium carbonate (384 g, 1.18 mol) was added to a solution of intermediate I-17 (200 g, 0.589 mol) and ethyl 4-bromobutyrate (121 g, 0.620 mol) in N,N-dimethylformamide (1000 mL). The reaction mixture was stirred at 120 °C for 2 hours. The reaction solution was cooled to room temperature and poured into ice water (2 L), then extracted with ethyl acetate (1000 mL × 3). The organic phases were combined and washed successively with water (1000 mL × 3) and saturated brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by slurrying with ethyl acetate / petroleum ether (5:95) to obtain intermediate I-18.

[0194] LC-MS(ESI)[M+H] + 454.1.

[0195] 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=2.6Hz,1H),7.61(dd,J=8.6,2.6Hz,1H),7.39(s,4H),6.97(d,J=8.6Hz,1H),4.01( q,J=7.1Hz,2H),3.76(s,3H),3.70(m,1H),3.45(m,1H),2.45–2.32(m,5H),1.71–1.60(m,2H),1.14(t,J=7.1Hz,3H).

[0196] Reference Example 19: Preparation of Intermediate I-19

[0197]

[0198] Potassium tert-butoxide (69.0 g, 0.615 mol) was added to toluene (1.6 L) at room temperature, and the mixture was heated to 70 °C and stirred for 30 minutes. Then, intermediate I-18 (186 g, 0.410 mol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, and water (1 L) was added. Extraction was performed with ethyl acetate (1 L × 2). The organic phases were combined, washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding crude intermediate I-19. The crude product was used directly in the next reaction step without purification.

[0199] Reference Example 20: Preparation of Intermediate I-20

[0200]

[0201] Intermediate I-19 (5.00 g, 11.87 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at 25 °C. The solution was cooled in an ice-water bath under argon protection, and 60% sodium hydride (0.95 g, 23.74 mmol) was slowly added. The mixture was kept in an ice-water bath and stirred for 0.5 hours. Methyl bromoacetate (3.63 g, 23.74 mmol) was then added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into an ice-cold saturated ammonium chloride aqueous solution (100 mL), concentrated under reduced pressure to remove most of the tetrahydrofuran, and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with water (50 mL), then with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-20.

[0202] LC-MS(ESI)[M+H] + 494.2.

[0203] Reference Example 21: Preparation of Intermediate I-21

[0204]

[0205] Intermediate I-20 (5.50 g, 11.16 mmol) was dissolved in dimethyl sulfoxide / water (55 mL / 5 mL) at 25 °C, and sodium chloride (0.71 g, 12.00 mmol) was added. After purging the system three times with argon, the mixture was stirred at 150 °C for 10 hours under argon protection. After cooling, the reaction solution was diluted with ethyl acetate (200 mL), washed with water (50 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-21.

[0206] LC-MS(ESI)[M+H] + 422.0.

[0207] Reference Example 22: Preparation of Intermediate I-22

[0208]

[0209] Intermediate I-21 (1.00 g, 2.38 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) at 25 °C. The system was cooled in an ice-water bath under argon protection, and a solution of lithium borohydride in tetrahydrofuran (1 M, 7.14 mL, 7.14 mmol) was slowly added with stirring. After the addition was complete, the mixture was brought back to room temperature and stirred for approximately 3 hours. The reaction mixture was poured into an ice-cold saturated ammonium chloride aqueous solution (100 mL), concentrated under reduced pressure to remove most of the tetrahydrofuran, and extracted with a dichloromethane / methanol mixture (10 / 1, 50 mL × 2). The organic phases were combined, washed with water (30 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding crude intermediate I-22. The crude product was used directly in the next reaction without purification.

[0210] LC-MS(ESI)[M-H2O+H] + 378.2.

[0211] Reference Example 23: Preparation of intermediates I-23A and I-23B

[0212]

[0213] At 25°C, intermediate I-22 (900 mg, 2.27 mmol) was dissolved in anhydrous dichloromethane (30 mL), and boron trifluoride diethyl ether (1.26 mL, 10 mmol) was added. The mixture was purged with argon three times, and stirred at 40°C for 16 hours under argon protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediates I-23A (Rt = 1.342 min) and I-23B (Rt = 1.321 min).

[0214] LCMS analysis method: Column: Infinitylab Poroshell 120EC-C18 3.0×30mm, 1.9μm

[0215] Mobile phase: A: Water (0.01% trifluoroacetic acid) B: Acetonitrile (0.01% trifluoroacetic acid)

[0216] Elution gradient: 5%-95%B, 0.7 min; 95%B, 0.8 min; then 5%B, 0.5 min.

[0217] Flow rate: 1.2 mL / min

[0218] Column temperature: 40℃

[0219] Mass spectrometry scanning range: 100-1000

[0220] Intermediate I-23A (Rt = 1.342 min) LC-MS (ESI) [M+H] + 378.0.

[0221] Intermediate I-23B (Rt = 1.321 min) LC-MS (ESI) [M+H] + 378.0.

[0222] Reference Example 24: Preparation of Intermediate I-24

[0223]

[0224] Intermediate I-23A (280.00 mg, 0.74 mmol) was dissolved in anhydrous methanol (20 mL) at 25 °C, and magnesium filings (2.00 g, 83.33 mmol) were added. The mixture was purged with nitrogen three times and stirred overnight at 70 °C under a nitrogen atmosphere. After cooling, the reaction solution was filtered through a diatomaceous earth filter. The filtrate was concentrated to dryness under reduced pressure, dissolved in ethyl acetate (100 mL), washed with saturated ammonium chloride aqueous solution (30 mL × 3), washed with water (30 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding crude intermediate I-24. The crude product was used directly in the next reaction step without purification.

[0225] LC-MS(ESI)[M+H] + 224.0.

[0226] Reference Example 25: Preparation of Intermediate I-25

[0227]

[0228] At 25°C, 2-methyl-4-nitrobenzoic acid (168 mg, 0.93 mmol) was dissolved in anhydrous dichloromethane (5 mL). Under argon protection and ice-water bath cooling, dimethylformamide (20 mg) and oxalyl chloride (591 mg, 4.65 mmol) were added sequentially. The mixture was kept in an ice-water bath and stirred for 1 hour, then concentrated to dryness at room temperature to obtain an acyl chloride intermediate. This acyl chloride was dissolved in anhydrous dichloromethane, and under argon protection and ice-water bath cooling, a dichloromethane solution of intermediate I-24 (70 mg, 0.31 mmol), triethylamine (310 mg, 3.10 mmol), and p-dimethylaminopyridine (1.83 mg, 0.15 mmol) was slowly added in 2 mL. After the addition was complete, the mixture was stirred overnight at 40°C. After the reaction was complete, the mixture was quenched with methanol (0.5 mL), concentrated to dryness under reduced pressure, dissolved in ethyl acetate (50 mL), washed with water (30 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-25.

[0229] LC-MS(ESI)[M+H] + 387.2.

[0230] Reference Example 26: Preparation of Intermediate I-26

[0231]

[0232] Intermediate I-25 (40 mg, 0.10 mmol) was dissolved in ethanol (5 mL) at 25 °C, and zinc powder (130 mg, 2.00 mmol) was added. The mixture was purged with nitrogen three times and stirred at 70 °C for 3 hours under a nitrogen atmosphere. After cooling, the reaction solution was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-26. The crude product was used directly in the next reaction step without purification.

[0233] LC-MS(ESI)[M+H] + 357.2.

[0234] Reference Example 27: Preparation of Intermediate I-27

[0235]

[0236] Intermediate I-23B (280 mg, 0.74 mmol) was dissolved in anhydrous methanol (20 mL) at 25 °C, and magnesium filings (2.00 g, 83.33 mmol) were added. The mixture was purged with nitrogen three times and stirred overnight at 70 °C under a nitrogen atmosphere. After cooling, the reaction solution was filtered through a diatomaceous earth filter. The filtrate was concentrated to dryness under reduced pressure, dissolved in ethyl acetate (100 mL), washed with saturated ammonium chloride aqueous solution (30 mL × 3), washed with water (30 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding crude intermediate I-27. The crude product was used directly in the next reaction step without purification.

[0237] LC-MS(ESI)[M+H] + 224.0.

[0238] Reference Example 28: Preparation of Intermediate I-28

[0239]

[0240] At 25°C, 2-methyl-4-nitrobenzoic acid (168 mg, 0.93 mmol) was dissolved in anhydrous dichloromethane (5 mL). Under argon protection and ice-water bath cooling, dimethylformamide (20 mg) and oxalyl chloride (591 mg, 4.65 mmol) were added sequentially. The mixture was kept in an ice-water bath and stirred for 1 hour, then concentrated to dryness at room temperature to obtain an acyl chloride intermediate. This acyl chloride was dissolved in anhydrous dichloromethane, and under argon protection and ice-water bath cooling, a dichloromethane solution of intermediate I-27 (50 mg, 0.22 mmol), triethylamine (310 mg, 3.10 mmol), and p-dimethylaminopyridine (1.83 mg, 0.15 mmol) was slowly added in 2 mL. After the addition was complete, the mixture was stirred overnight at 40°C. After the reaction was complete, the mixture was quenched with methanol (0.5 mL), concentrated to dryness under reduced pressure, dissolved in ethyl acetate (50 mL), washed with water (30 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-28.

[0241] LC-MS(ESI)[M+H] + 387.2.

[0242] Reference Example 29: Preparation of Intermediate I-29

[0243]

[0244] Intermediate I-28 (30 mg, 0.078 mmol) was dissolved in ethanol (5 mL) at 25 °C, and zinc powder (130 mg, 2.00 mmol) was added. The mixture was purged with nitrogen three times and stirred at 70 °C for 3 hours under a nitrogen atmosphere. After cooling, the reaction solution was filtered through a diatomaceous earth filter, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-29. The crude product was used directly in the next reaction step without purification.

[0245] LC-MS(ESI)[M+H] + 357.2.

[0246] Reference Example 30: Preparation of Intermediate I-30

[0247]

[0248] Intermediate I-19 (5.0 g, 11.85 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature. Sodium borohydride (8.78 g, 232.09 mmol) was added to the reaction mixture under nitrogen protection, and the reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-30.

[0249] LC-MS(ESI)[M+H] + 382.2.

[0250] Reference Example 31: Preparation of Intermediate I-31

[0251]

[0252] Intermediate I-30 (3.54 g, 9.29 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Methylsulfonyl chloride (1.16 g, 10.22 mmol) and triethylamine (1.41 g, 13.93 mmol) were added sequentially. The reaction mixture was stirred at 0°C for 1 hour under argon protection. The solution was diluted with water (50 mL), extracted with dichloromethane (30 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-31. The crude product was used directly in the next reaction without purification.

[0253] Reference Example 32: Preparation of Intermediate I-32

[0254]

[0255] Intermediate I-31 (3.71 g, 8.08 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. Under argon protection, 60% sodium hydride (808 mg, 20.20 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-32.

[0256] LC-MS (ESI) [M+Na] + 386.0.

[0257] Reference Example 33: Preparation of Intermediate I-33

[0258]

[0259] Intermediate I-32 (2.34 g, 6.43 mmol) was dissolved in methanol (50 mL) at room temperature. Magnesium filings (1.54 g, 64.40 mmol) were added under nitrogen protection, and the reaction mixture was stirred at 70 °C for 1 hour. The reaction system was cooled to room temperature, diluted with saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated ammonium chloride aqueous solution (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-33.

[0260] LC-MS(ESI)[M+H] + 210.0.

[0261] Reference Example 34: Preparation of Intermediate I-34

[0262]

[0263] Intermediate I-33 (400 mg, 1.91 mmol) was dissolved in dichloromethane (20 mL) at room temperature. N,N-diisopropylethylamine (740 mg, 5.74 mmol) was added at room temperature. Under nitrogen protection, 2-methyl-4-nitrobenzoyl chloride (455 mg, 2.29 mmol) was added to the reaction solution, and the reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with water (20 mL), extracted with dichloromethane (30 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-34.

[0264] LC-MS(ESI)[M+H] + 373.2.

[0265] Reference Example 35: Preparation of Intermediate I-35

[0266]

[0267] Intermediate I-34 (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. Zinc powder (349 mg, 5.37 mmol) and ammonium chloride (284 mg, 5.37 mmol) were added under nitrogen protection, and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered and concentrated to dryness under reduced pressure to obtain the crude intermediate I-35. The crude product was used directly in the next reaction without purification.

[0268] LC-MS(ESI)[M+H] + 343.2.

[0269] Reference Example 36: Preparation of Intermediate I-36

[0270]

[0271] Intermediate I-19 (2.00 g, 4.75 mmol) was dissolved in pyridine (10 mL) at 25 °C, and methoxyamine hydrochloride (0.79 g, 9.50 mmol) was added. The mixture was stirred at 80 °C for 10 hours in a sealed microwave tube and concentrated. It was then diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride aqueous solution (50 mL × 2), washed with water (50 mL × 2), washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-36. The crude product was used directly in the next reaction without purification.

[0272] LC-MS(ESI)[M+H] + 451.2.

[0273] Reference Example 37: Preparation of Intermediate I-37

[0274]

[0275] Intermediate I-36 (2.20 g) was dissolved in boranetetrahydrofuran (24.50 mL, 22.05 mmol) at 25 °C, purged three times with argon, and stirred overnight at 50 °C under argon protection. Methanol was added dropwise under ice-water bath cooling until no more bubbles were produced, and the mixture was concentrated under reduced pressure to obtain crude intermediate I-37. The crude product was used directly in the next reaction without purification.

[0276] LC-MS(ESI)[M+H] +381.2.

[0277] Reference Example 38: Preparation of Intermediate I-38

[0278]

[0279] Intermediate I-37 (2.50 g) was dissolved in dichloromethane (20 mL) at 25 °C, followed by the addition of triethylamine (1.48 g, 14.70 mmol) and di-tert-butyl dicarbonate (2.20 g, 10.09 mmol). The mixture was stirred overnight at 25 °C. The reaction solution was concentrated, dissolved in ethyl acetate (100 mL), washed with dimethyl ethylenediamine aqueous solution (1 M, 30 mL × 2), washed with water (30 mL), washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-38. The crude product was used directly in the next reaction without purification.

[0280] LC-MS(ESI)[M+H-56] + 425.3.

[0281] Reference Example 39: Preparation of Intermediate I-39

[0282]

[0283] Intermediate I-38 (2.50 g) was dissolved in anhydrous dichloromethane (20 mL) at 25 °C. Triethylamine (1.00 g, 9.90 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (0.82 g, 7.13 mmol) under argon protection and an ice-water bath. The reaction mixture was stirred at 25 °C for 1 hour, then quenched dropwise with methanol (1 mL), concentrated under reduced pressure, dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate aqueous solution (30 mL × 2), washed with water (30 mL), washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-39.

[0284] LC-MS(ESI)[M+H-100] + 459.0.

[0285] Reference Example 40: Preparation of Intermediate I-40

[0286]

[0287] Intermediate I-39 (2.00 g, 3.58 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) at 25 °C. 60% sodium hydride (2.90 g, 72.5 mmol) was added, and the mixture was purged three times with argon gas and stirred overnight at 70 °C. The reaction mixture was cooled and poured into ice-cold saturated ammonium chloride aqueous solution (20 mL). The mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran, and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with water (30 mL × 2), washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-40.

[0288] LC-MS(ESI)[M+H-56] + 406.90.

[0289] Reference Example 41: Preparation of Intermediate I-41

[0290]

[0291] Intermediate I-40 (0.45 g, 0.97 mmol) was dissolved in a dichloromethane solution of trifluoroacetic acid (1 / 10, 5 mL) at 25 °C. After stirring for 1 hour, the solution was poured into ice-cold saturated sodium bicarbonate aqueous solution (50 mL). The mixture was concentrated at room temperature to remove most of the dichloromethane and then extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-41. The crude product was used directly in the next reaction without purification.

[0292] Reference Example 42: Preparation of Intermediate I-42

[0293]

[0294] At 25°C, intermediate I-41 (0.31 g, 0.86 mmol) was dissolved in anhydrous methanol (20 mL). Magnesium filings (1.20 g, 50.00 mmol) were added, and the mixture was purged three times with argon gas. The mixture was stirred overnight at 70°C under argon protection. After cooling, the reaction solution was filtered through a diatomaceous earth filter. The filtrate was concentrated, diluted with dichloromethane / methanol (10 / 1, 100 mL), washed with saturated ammonium chloride aqueous solution (30 mL × 2), washed with water (30 mL × 2), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-42. The crude product was used directly in the next reaction without purification.

[0295] LC-MS(ESI)[M+H] + 208.8.

[0296] Reference Example 43: Preparation of Intermediate I-43

[0297]

[0298] Intermediate I-42 (0.15 g) was dissolved in dichloromethane (3 mL) at 25 °C, followed by the addition of triethylamine (0.22 g, 2.16 mmol) and di-tert-butyl dicarbonate (0.31 g, 1.44 mmol). After stirring at 25 °C for 3 hours, the mixture was concentrated under reduced pressure. The residue was then purified by silica gel chromatography to obtain intermediate I-43.

[0299] LC-MS(ESI)[M+H] + 309.2.

[0300] Reference Example 44: Preparation of Intermediate I-44

[0301]

[0302] At 25°C, 2-methyl-4-nitrobenzoic acid (0.58 g, 3.20 mmol) was dissolved in anhydrous dichloromethane (5 mL). One drop of N,N-dimethylformamide was added, and the mixture was cooled in an ice-water bath under argon atmosphere. Oxaloyl chloride (1.63 g, 12.8 mmol) was slowly added dropwise. After stirring for 1 hour while maintaining cooling in an ice-water bath, the mixture was concentrated to dryness at room temperature to obtain an acyl chloride intermediate. This acyl chloride intermediate was dissolved in anhydrous dichloromethane (5 mL), and under ice-water bath and argon protection, triethylamine (2.56 g, 25.60 mmol), 4-dimethylaminopyridine (2.44 mg, 0.02 mmol), and intermediate I-43 (100 mg, 0.32 mmol) were added. The reaction mixture was stirred overnight at 40°C, then cooled to room temperature. The reaction was quenched dropwise with methanol (2 mL), concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL × 2), washed with water (20 mL), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-44.

[0303] LC-MS(ESI)[M+H] + 471.8.

[0304] Reference Example 45: Preparation of Intermediate I-45

[0305]

[0306] Intermediate I-44 (63 mg, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL) at 25 °C, followed by the addition of zinc powder (87 mg, 1.30 mmol) and ammonium chloride (35 mg, 0.65 mmol). The mixture was stirred at 70 °C for 5 hours under argon protection. After cooling, the reaction solution was filtered through a diatomaceous earth filter, concentrated under reduced pressure, dissolved in ethyl acetate (50 mL), washed with water (20 mL × 2), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-45. The crude product was used directly in the next reaction without purification.

[0307] LC-MS(ESI)[M+H] + 441.8.

[0308] Reference Example 46: Preparation of Intermediate I-46

[0309]

[0310] At 25°C, intermediate I-45 (50 mg) was dissolved in dichloromethane (2 mL), followed by the sequential addition of triethylamine (33 mg, 0.33 mmol) and o-chlorobenzoyl chloride (50% wt ethyl acetate solution, 0.79 mL). The mixture was stirred at 25°C for 1 hour under argon protection, then 4-aminobutanol (0.5 mL) was added, and stirring continued at 25°C for 15 minutes. The mixture was diluted with dichloromethane (30 mL), washed with water (20 mL × 2), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude intermediate I-46. The crude product was used directly in the next reaction without purification.

[0311] LC-MS(ESI)[M+H] + 580.2.

[0312] Reference Example 47: Preparation of Intermediate I-47

[0313]

[0314] At 25°C, intermediate I-7 (7.30 g, 32.89 mmol) and triethylamine (10.10 g, 100.00 mmol) were dissolved in anhydrous dichloromethane (100 mL). Under argon protection and ice-water bath cooling, fluorenyl chloroformate (12.73 g, 49.33 mmol) was slowly added, and the mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure at room temperature, slurried with petroleum ether, filtered, and the filter cake was washed with water (20 mL) and dried under vacuum to obtain intermediate I-47.

[0315] LC-MS(ESI)[M+H] + 444.8.

[0316] Reference Example 48: Preparation of intermediates I-48A and I-48B

[0317]

[0318] At 25°C, intermediate I-47 (4.70 g, 10.58 mmol) was dissolved in anhydrous tetrahydrofuran (35 mL), followed by the addition of pyridine (8.37 g, 106.00 mmol), intermediate I-13 (4.92 g, 15.87 mmol), and 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 20.00 g, 31.74 mmol). The mixture was stirred overnight at 65°C under argon protection. After cooling, the reaction solution was concentrated to remove most of the tetrahydrofuran and diluted with ethyl acetate (150 mL). The solution was washed successively with 1N hydrochloric acid (100 mL × 2), saturated sodium bicarbonate aqueous solution (100 mL × 3), water (100 mL), and saturated sodium chloride aqueous solution (100 mL). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-48A (Rt = 1.541 min) and intermediate I-48B (Rt = 1.508 min).

[0319] LCMS analysis method: Column: Waters Acquity UPLC CSH 2.1×50mm, 1.7μm

[0320] Mobile phase: A: Water (0.01% trifluoroacetic acid) B: Acetonitrile (0.01% trifluoroacetic acid)

[0321] Elution gradient: 5%-95%B, 0.7 min; 95%B, 0.8 min; then 5%B, 0.5 min.

[0322] Flow rate: 1.0 mL / min

[0323] Column temperature: 60℃

[0324] Mass spectrometry scanning range: 100-1000

[0325] Intermediate I-48A (Rt = 1.541 min) LC-MS (ESI) [M+H] + 737.3.

[0326] Intermediate I-48B (Rt = 1.508 min) LC-MS (ESI) [M+H] + 737.3.

[0327] Reference Example 49: Preparation of Intermediate I-49

[0328]

[0329] At -5°C, potassium tert-butoxide (17.81 g, 158.68 mmol) was added to a solution of p-chloronitrobenzene (10.00 g, 63.47 mmol) in N,N-dimethylformamide (300 mL), and stirred for 30 minutes. Then, ethyl chloroform (8.56 g, 69.82 mmol) was added. The reaction mixture was stirred at -5°C for 1 hour under nitrogen protection. The reaction mixture was poured into water (1000 mL), extracted with ethyl acetate (200 mL × 4), and the organic phases were combined and washed with saturated brine (800 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-49.

[0330] LC-MS(ESI)[M+H] + 244.0.

[0331] Reference Example 50: Preparation of Intermediate I-50

[0332]

[0333] Under nitrogen protection and cooling to -78°C, diisobutylaluminum hydride (1.5M in THF, 65.67mL, 98.50mmol) was added to a 200mL solution of intermediate I-49 (12.00g, 49.25mmol). The reaction mixture was stirred at -78°C for 1 hour. The reaction solution was heated to 0°C, and water (4mL) was added dropwise with stirring, followed by 4mL of 15% sodium hydroxide aqueous solution, and finally 10mL of water. The mixture was heated to room temperature and stirred for 15 minutes. An appropriate amount of anhydrous sodium sulfate was added, and the mixture was stirred for 15 minutes before filtration. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding intermediate I-50.

[0334] LC-MS(ESI)[M+H] + 200.0.

[0335] Reference Example 51: Preparation of Intermediate I-51

[0336]

[0337] At 25°C, methoxyformylmethylenetriphenylphosphine (12.06 g, 32.07 mmol) was added to a toluene (200 mL) solution of intermediate I-50 (7.20 g, 36.07 mmol). The reaction mixture was stirred at 110°C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-51.

[0338] Reference Example 52: Preparation of Intermediate I-52

[0339]

[0340] At 25°C, 10 mL of trifluoroacetic acid was added to a solution of intermediate I-51 (7.70 g, 30.12 mmol) in 150 mL of dichloromethane, followed by dropwise addition of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (20.34 g, 85.66 mmol). The reaction mixture was stirred at 25°C for 12 hours. The organic solvent was removed by vacuum concentration to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-52.

[0341] LC-MS(ESI)[M+H] + 389.2.

[0342] Reference Example 53: Preparation of Intermediate I-53

[0343]

[0344] At 25°C, zinc powder (2.35 g, 36.00 mmol) was added to a mixture of intermediate I-52 (2.8 g, 7.20 mmol) and ammonium chloride (3.08 g, 57.61 mmol) in methanol (60 mL) / water (20 mL). The reaction mixture was stirred at 70°C for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain intermediate I-53.

[0345] LC-MS(ESI)[M+H] + 359.2.

[0346] Reference Example 54: Preparation of Intermediate I-54

[0347]

[0348] At 25°C, potassium hydroxide (1.08 g, 19.29 mmol) was added to a mixed solution of intermediate I-53 (2.30 g, 6.41 mmol) in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). The reaction mixture was stirred at 25°C for 12 hours under nitrogen protection. The reaction mixture was adjusted to acidity (pH 5–6) with 1 N hydrochloric acid and extracted with ethyl acetate (30 mL × 4). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed by concentration under reduced pressure to give intermediate I-54.

[0349] LC-MS(ESI)[M+H] +345.2.

[0350] Reference Example 55: Preparation of Intermediate I-55

[0351]

[0352] At 25°C, N,N-diisopropylethylamine (2.25 g, 17.40 mmol) was added to a solution of intermediate I-54 (2.00 g, 5.80 mmol) in dichloromethane (60 mL), followed by the addition of O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (3.72 g, 11.6 mmol). The reaction mixture was stirred at 25°C for 12 hours under nitrogen protection. The organic solvent was removed by vacuum concentration to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-55.

[0353] LC-MS(ESI)[M+H] + 327.2.

[0354] Reference Example 56: Preparation of Intermediate I-56

[0355]

[0356] Under nitrogen protection and ice-water bath cooling, lithium aluminum hydride (27.23 mL, 27.23 mmol, 1 M in THF) was added to a tetrahydrofuran (30 mL) solution of intermediate I-55 (1.78 g, 5.45 mmol). The reaction mixture was stirred at 0 °C for 1 hour. While stirring, water (4 mL), 15% sodium hydroxide solution (4 mL), and water (10 mL) were added sequentially to the reaction mixture. After stirring for 15 minutes, the mixture was filtered, and the filtrate was extracted with ethyl acetate (30 mL × 4). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-56.

[0357] Reference Example 57: Preparation of Intermediate I-57

[0358]

[0359] Intermediate I-56 (250 mg, 0.799 mmol), palladium on carbon (10%, 50% water content, 200 mg), and methanol (20 mL) were added to a 100 mL autoclave. After purging with hydrogen twice, the reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere (1 MPa). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-57.

[0360] LC-MS(ESI)[M+H] +189.1.

[0361] Reference Example 58: Preparation of Intermediate I-58

[0362]

[0363] Intermediate I-57 (110 mg, 0.584 mmol) and triethylamine (295 mg, 2.92 mmol) were mixed in dichloromethane (5 mL), and di-tert-butyl dicarbonate (153 mg, 0.701 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by silica gel chromatography to obtain intermediate I-58.

[0364] LC-MS(ESI)[M+H] + 289.2.

[0365] Reference Example 59: Preparation of Intermediate I-59

[0366]

[0367] Intermediate I-58 (120 mg, 0.416 mmol), copper chloride dihydrate (213 mg, 1.25 mmol), and lithium chloride (53 mg, 1.25 mmol) were dissolved in ethanol (5 mL) at room temperature. The reaction mixture was heated to 80 °C and stirred for 6 hours. After cooling the mixture to room temperature, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and poured into water (50 mL). Ammonia (2 mL) was added, followed by extraction with ethyl acetate (10 mL × 4). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-59.

[0368] LCMS(ESI)[M+H+MeCN] + 364.3.

[0369] Reference Example 60: Preparation of Intermediate I-60

[0370]

[0371] Intermediate I-13 (38.5 mg, 0.124 mmol) was dissolved in N,N-dimethylacetamide (2 mL) at room temperature. The solution was cooled to 0 °C, and thionyl chloride (14.8 mg, 0.124 mmol) was added under argon protection. The reaction mixture was stirred at room temperature for 1 hour, then intermediate I-59 (20.0 mg, 0.062 mmol) was added. The reaction mixture was stirred at room temperature for another 16 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-60.

[0372] LC-MS(ESI)[M+H] + 615.1.

[0373] Preparation of the example:

[0374] Example 1: Preparation of Compound 1

[0375]

[0376] Intermediate I-11 (38 mg, 0.066 mmol) was dissolved in a methanol solution of hydrogen chloride (3 M, 2 mL) at 25 °C. After stirring at room temperature for 1 hour, the solution was concentrated to dryness and purified by preparative HPLC (formic acid system) to obtain compound 1.

[0377] LC-MS(ESI)[M+H] + 474.2.

[0378] 1 H NMR (400MHz, DMSO-d6) δ10.42–10.23(m,1H),7.82–7.18(m,7H),7.09(dd,J=8.3,2.5Hz,1H),6.90–6.43(m,2H),4 .94–4.72(m,1H),4.30(s,1H),3.15(m,3H),2.73–2.62(m,1H),2.43–2.27(m,6H),2.27–1.98(m,2H),1.75(m,3H).

[0379] Example 2: Preparation of Compound 2

[0380]

[0381] Intermediate I-14 (30 mg, 0.049 mmol) was dissolved in a methanol solution of hydrogen chloride (3 M, 3 mL) at 25 °C. After stirring at room temperature for 1 hour, the solution was concentrated to dryness and purified by preparative HPLC (formic acid system) to obtain compound 2.

[0382] LC-MS(ESI)[M+H] + 515.2.

[0383] 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),8.10–7.95(m,2H),7.88–7.54(m,6H),7.25–7.06(m,1H),6.95(d,J=8.4Hz,1H),4.89 (d,J=13.5Hz,1H),4.39(s,1H),3.17(s,2H),2.73–2.67(m,1H),2.54(m,1H),2.27–2.01(m,2H),1.85(m,2H),1.67(m,1H).

[0384] Example 3: Preparation of compounds 3A and 3B

[0385]

[0386] At 25°C, intermediate I-16 (70 mg, 0.30 mmol) was dissolved in tetrahydrofuran (1 mL), and pyridine (0.79 mL, 10 mmol), 1-propylphosphonic anhydride (50% wt ethyl acetate solution, 0.79 mL), and intermediate I-7 (101 mg, 0.33 mmol) were added. The mixture was sealed in a microwave-safe tube and stirred overnight at 65°C. After cooling, the solution was concentrated to dryness under reduced pressure, dissolved in ethyl acetate (50 mL), washed with water (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (formic acid system) to obtain compound 3A (Rt = 1.023 min) and compound 3B (Rt = 1.039 min).

[0387] LCMS analysis method: Column: Infinitylab Poroshell 120EC-C18 3.0×30mm, 1.9μm

[0388] Mobile phase: A: Water (0.01% trifluoroacetic acid) B: Acetonitrile (0.01% trifluoroacetic acid)

[0389] Elution gradient: 5%-95%B, 0.7 min; 95%B, 0.8 min; then 5%B, 0.5 min.

[0390] Flow rate: 1.2 mL / min

[0391] Column temperature: 40℃

[0392] Mass spectrometry scanning range: 100-1000

[0393] Compound 3A (Rt = 1.023 min):

[0394] LC-MS(ESI)[M+H] + 529.2.

[0395] 1 H NMR(400MHz,DMSO-d6)δ8.15–7.95(m,2H),7.92–7.34(m,6H),7.15–6.95(m,1H),6.87–6.60 (m,1H),5.01(m,1H),3.55–3.35(m,2H),2.80–2.32(m,5H),2.28–1.83(m,4H),1.63(m,1H).

[0396] Compound 3B (Rt = 1.039 min):

[0397] LC-MS(ESI)[M+H] + 529.2.

[0398] 1 H NMR (400MHz, DMSO-d6) δ8.17–7.90(m,2H),7.85–7.54(m,6H),7.20–7.00(m,1H),6.90–6.60(m,1H),4.70–4.50(m,1 H),4.15(m,1H),3.98(d,J=10.6Hz,1H),2.80–2.45(m,5H),2.35–2.20(m,1H),2.10–1.73(m,3H),1.59–1.37(m,1H).

[0399] Example 4: Preparation of Compound 4

[0400]

[0401] Intermediate I-26 (38 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) at 25 °C, followed by the addition of triethylamine (55 mg, 0.55 mmol) and o-methylbenzoyl chloride (34 mg, 0.22 mmol). After stirring at room temperature for 1 hour, the mixture was quenched with methanol (1 mL), concentrated to dryness under reduced pressure, and purified by preparative HPLC (formic acid system) to obtain compound 4.

[0402] LC-MS(ESI)[M+H] + 475.2.

[0403] 1 H NMR (400MHz, DMSO-d6) δ10.41–10.23(m,1H),7.80–7.58(m,1H),7.56–7.17(m,6H),7.08(dd,J=8.4,2.6Hz,1H),6.78(m,2H),4. 96–4.80(m,1H),4.75(d,J=7.8Hz,1H),4.14–3.88(m,2H),2.73–2.61(m,1H),2.45–2.30(m,6H),2.30–2.03(m,2H),1.84(m,3H).

[0404] Example 5: Preparation of Compound 5

[0405]

[0406] Intermediate I-29 (26 mg, 0.073 mmol) was dissolved in dichloromethane (2 mL) at 25 °C, followed by the addition of triethylamine (55 mg, 0.55 mmol) and o-methylbenzoyl chloride (34 mg, 0.22 mmol). After stirring at room temperature for 1 hour, the mixture was quenched with methanol (1 mL), concentrated to dryness under reduced pressure, and purified by preparative HPLC (formic acid system) to obtain compound 5.

[0407] LC-MS(ESI)[M+H] + 475.2.

[0408] 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),7.81–7.55(m,1H),7.55–6.99(m,7H),6.76(dd,J=33.3,8.3Hz,2H),5.37(d,J=9.1H z,1H),4.25–3.90(m,2H),3.79(m,1H),2.70–2.58(m,1H),2.35(m,7H),2.14–1.95(m,2H),1.28(m,1H),1.00–0.77(m,1H).

[0409] Example 6: Preparation of Compound 6

[0410]

[0411] Intermediate I-35 (90 mg, 0.26 mmol) was dissolved in dichloromethane (10 mL) at room temperature, followed by the addition of o-methylbenzoyl chloride (60.7 mg, 0.39 mmol) and triethylamine (79.6 mg, 0.79 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL), and extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was then purified by silica gel chromatography and preparative HPLC (formic acid system) to obtain compound 6.

[0412] LC-MS(ESI)[M+H] + 461.2.

[0413] 1 H NMR (400MHz, DMSO-d6) δ10.41-10.22(s,1H),7.75-7.66(m,1H),7.53-7.17(m,6H),7.09-6.79(m,3H),5.87-5.65(m,1H),4.90-4.87(m,1 H),4.72-4.68(m,1H),4.42-4.39(m,1H),2.89-2.76(m,1H),2.67-2.55(m,1H),2.39-2.33(m,6H),2.20-2.09(m,1H),1.82-1.80(m,1H).

[0414] Example 7: Preparation of Compound 7

[0415]

[0416] At 25°C, intermediate I-46 (40 mg, 0.069 mmol) was dissolved in a dichloromethane solution of trifluoroacetic acid (1 / 10, 3 mL). After stirring at room temperature for 1 hour, the solution was poured into an ice-cold saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with dichloromethane / methanol (10 / 1, 20 mL × 2). The organic phases were combined, washed with water (20 mL), concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate system) to obtain compound 7.

[0417] LC-MS(ESI)[MH] - 477.80.

[0418] 1H NMR (400MHz, DMSO-d6) δ10.67–10.35(m,1H),7.74–7.24(m,7H),7.22–6.95(m,2H),6.82–6.76(m,1H),4.95–4.50(m,2H),3.47( m,1H),3.18(t,J=6.3Hz,1H),2.99–2.70(m,1H),2.42–2.30(m,3H),2.04–1.54(m,2H),1.15(t,J=7.0Hz,1H),1.04–0.95(m,1H).

[0419] Example 8: Preparation of Compound 8

[0420]

[0421] Intermediate I-48A (14 mg, 0.019 mmol) was dissolved in N,N-dimethylformamide (3 mL) at 25 °C, and pyrrolidine (35.50 mg, 0.50 mmol) was added. The mixture was stirred at 25 °C for 1 hour. The solution was diluted with ethyl acetate (20 mL), washed with water (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by C18 reversed-phase chromatography (formic acid system) to obtain compound 8.

[0422] LC-MS(ESI)[M+H] + 515.2.

[0423] 1 H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.13–7.90(m,2H),7.88–7.52(m,6H),7.09( dd,J=8.3,2.7Hz,1H),6.89(d,J=8.3Hz,1H),4.90(dt,J=13.7,3.3Hz,1H),4.14(d ,J=9.2Hz,1H),3.80–3.35(m,1H),3.15–3.03(m,1H),3.03–2.92(m,1H),2.66(t,J =12.7Hz,1H),2.09(dd,J=12.1,4.1Hz,2H),1.86–1.64(m,2H),1.64–1.51(m,1H).

[0424] Example 9: Preparation of Compound 9

[0425]

[0426] Intermediate I-48B (4.00 mg, 0.0054 mmol) was dissolved in N,N-dimethylformamide (3 mL) at 25 °C, and pyrrolidine (35.50 mg, 0.50 mmol) was added. The mixture was stirred at 25 °C for 1 hour. The solution was diluted with ethyl acetate (20 mL), washed with water (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by C18 reversed-phase chromatography (formic acid system) to obtain compound 9.

[0427] LC-MS(ESI)[M+H] + 515.2.

[0428] 1 H NMR(400MHz, DMSO-d6)δ11.19(s,1H),8.13–7.90(m,2H),7.86–7.58(m,6H),7.12(dd,J=8.2,2.6Hz,1H),6.93–6.74(m,1H),4.70(d, J=9.4Hz,1H),3.99(td,J=13.4,3.5Hz,1H),3.37(m,1H),3.11–2.90(m,2H),2.47–2.28(m,1H),2.06–1.85(m,2H),1.20–0.78(m,3H).

[0429] Example 10: Preparation of Compound 10A and Compound 10B

[0430]

[0431] Compound 8 was chirally resolved by SFC to yield compound 10A (Rt = 1.424 min) and compound 10B (Rt = 1.993 min).

[0432] Chiral decomposition method:

[0433] Instrument: MG II preparative SFC (SFC-14)

[0434] Column: ChiralPak AD, 250×30mm ID, 10μm

[0435] Mobile phase: A: Carbon dioxide; B: Ethanol (0.1% ammonia)

[0436] Elution gradient: 35% B

[0437] Flow rate: 80 mL / min

[0438] Back pressure: 100 bar

[0439] Column temperature: 38℃

[0440] Detection wavelength: 220nm

[0441] Cycle time: ~8min

[0442] Chiral analysis methods:

[0443] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0444] Column: ChiralPak AD, 150×4.6mm ID, 3μm

[0445] Mobile phase: A: Carbon dioxide; B: Ethanol (0.05% diethylamine)

[0446] Elution gradient: 40% B

[0447] Flow rate: 2.5 mL / min

[0448] Back pressure: 1500psi

[0449] Column temperature: 35℃

[0450] Detection wavelength: 220nm

[0451] Compound 10A:

[0452] Rt = 1.424 min

[0453] LC-MS(ESI)[M+H] + 515.2.

[0454] 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),8.30–7.88(m,2H),7.88–7.55(m,6H),7.10(dd,J=8.4,2.7Hz,1H),6.89(d,J=8.3Hz,1H),4.90(dt,J= 13.5, 3.2Hz, 1H), 4.14 (d, J = 9.2Hz, 1H), 3.40–3.39 (m, 1H), 3.13–2.90 (m, 2H), 2.66 (t, J = 12.3Hz, 1H), 2.16–2.05 (m, 2H), 1.87–1.49 (m, 3H).

[0455] Compound 10B:

[0456] Rt = 1.993 min

[0457] LC-MS(ESI)[M+H] + 515.0.

[0458] 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),8.12–7.89(m,2H),7.87–7.59(m,6H),7.18–7.03(m,1H),6.90(d,J=8.4Hz,1H),4.98 –4.83(m,1H),4.17(m,1H),3.11–2.92(m,2H),2.73–2.60(m,1H),2.15–2.02(m,2H),1.86–1.66(m,2H),1.64–1.52(m,1H).

[0459] Example 11: Preparation of Compound 11

[0460]

[0461] Intermediate I-60 (15.0 mg, 0.0244 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature, and trifluoroacetic acid (0.5 mL) was added dropwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC (ammonia system) to obtain compound 11.

[0462] LC-MS(ESI)[M+H] + 515.2.

[0463] 1 H NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.10–7.94(m,2H),7.81(d,J=7.6Hz,1H ),7.78–7.58(m,4H),7.23(d,J=2.4Hz,1H),7.12(dd,J=8.6,2.4Hz,1H),6.94 (d,J=8.3Hz,1H),4.90(d,J=13.9Hz,1H),3.77–3.64(m,1H),3.59–3.50(m,1H ),3.21–3.07(m,3H),2.74–2.61(m,2H),2.10–2.01(m,1H),1.84–1.66(m,2H).

[0464] Experimental Example 1: The inhibitory IC50 of the compound on vasopressin receptor V2R activation induced by vasopressin 50 test

[0465] (1) Cells

[0466] The HeLa cell line stably expressing human vasopressin receptor V2R (HeLa-V2R) was constructed by Shanghai Jikai Gene Chemical Technology Co., Ltd. using lentiviral infection and its stable expression of human V2R was verified by qPCR.

[0467] (2) Reagents

[0468] DMEM cell culture medium: Brand: Gibco, Catalog No.: 11995065; Fetal bovine serum: Brand: Gibco, Catalog No.: FND500; 0.25% trypsin: Brand: Gibco, Catalog No.: 25200072; Puromycin Dihydrochloride: Brand: Gibco, Catalog No.: A1113803; cAMP-GS HIRANGE KIT: Brand: Cisbio, Catalog No.: 62AM6PEC; IBMX: Brand: Sigma, Catalog No.: i5879; Vasopressin AVP: Customized by Gibco Biochemical (Shanghai) Co., Ltd.

[0469] (3) Test methods

[0470] HeLa-V2R cells were cultured in DMEM medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells expressing V2R were continuously screened by adding 2 μg / mL puromycin to the medium. On the day of the experiment, cells were digested with trypsin, washed twice with stimulation buffer from the cAMP-GS HIRANGE kit, resuspended, counted, and prepared into 1.6 x 10⁻⁶ cells / mL. 6Cells / ml, add IBMX to a final concentration of 0.5 mM. Transfer 5 μL of cell suspension / well to a 384-well plate, and add 2.5 μL of different concentrations of the test compound (3-fold dilution starting from 10 μM, 10 concentration gradients) or DMSO (Min, Max control) to the corresponding wells. After incubating at room temperature for 30 minutes, add 2.5 μL of vasopressin AVP solution to the test compound wells and the maximum value wells to a final concentration of 2.25 nM, and add 2.5 μL of stimulation buffer to the minimum value wells. Incubate at 25°C for 60 minutes. Simultaneously prepare cAMP standard samples (3-fold dilution starting from 5.6 μM, 10 concentration points), and transfer 10 μL of cAMP standard to the corresponding wells of the 384-well plate. Dilute the cAMP-d2 fluorescent and anti-cAMP antibody probes provided in the cAMP-GS HIRANGE kit 20-fold with the lysis buffer provided in the kit, and add 5 μL of each to each well of a 384-well plate. After mixing, centrifuge briefly and incubate at 25°C for 2 hours before detection. Sample detection was performed using the HTRF method on an Envision microplate reader, measuring fluorescence intensity at 615 nm and 665 nm. Each sample was prepared in duplicate, with 32 replicates for both the minimum and maximum values.

[0471] (4) Data processing

[0472] Calculate the fluorescence intensity ratio FI of each well sample at 665 nm and 615 nm wavelengths. 665 / 615 With X as the logarithm of the standard concentration, FI 665 / 615 X1000 represents the Y value. A standard curve was obtained by fitting the curve using the "log(inhibitor) vs response – variable slope (four parameters)" model in Prism 8.0 software. The test well FI... 665 / 615 X1000 is the Y value. The cAMP concentration of each sample is calculated in Prism 8.0 software based on the standard curve mentioned above.

[0473] The formula for calculating % Inhibition is as follows:

[0474]

[0475] in The average calculated value of cAMP concentration in all maximum wells; Ccmpd is the average calculated cAMP concentration in all minimum wells; Ccmpd is the calculated cAMP concentration of the analyte.

[0476] Using %Inhibition (inhibition percentage) as Y and the logarithm of compound concentration as X, a nonlinear regression was performed in Prism 8.0 software using the "log(inhibitor) vs response–variable slope (four parameters)" model to calculate IC. 50 , where Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * Hill Slope)).

[0477] The experimental results are shown in Table 1:

[0478] Table 1: Evaluation of the compounds' inhibitory effect on cAMP increase in human cervical cancer cells (Human V2R Hela-Stable cell line OE2).

[0479] 1 14.65 2 32.62 3A 84.73 4 7.45 5 61.55 6 3.85 7 92.68 8 69.52 10A 30.97

[0480] Experimental Example 2: In vivo pharmacokinetic experiment of the compound of the present invention

[0481] This experiment evaluated the in vivo pharmacokinetic properties of mice via intravenous injection and oral administration.

[0482] Experimental methods and conditions: Male CD1 mice, 6-8 weeks old, were given free access to food and water. They were orally administered 10 mg / kg (solvents: 5% DMSO / 10% Solutol / 85% Saline) via gavage. Blood samples were collected at 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 10 hr, and 24 hr after administration, with 150 μL collected for each sample. Heparin sodium was used as anticoagulant. The samples were placed on ice and centrifuged within 1 hour for plasma analysis. Plasma drug concentration was determined using liquid chromatography-tandem mass spectrometry (LC / MS / MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software. Tofapultan was used as a control. The experimental results are shown in Table 2.

[0483] Table 2: Pharmacokinetics of oral administration (10 mg / kg)

[0484] Compound 10A 4.44 833.03 2026.32 73.34 Reference Standard 1 1.58 1307 1613 44

[0485] Experimental data show that the pharmacokinetic results of the compound of this invention in mice after oral administration exhibit a longer half-life T. 1 / 2 and higher in vivo exposure AUC 0-inf .

[0486] Experiment Example 3: Test on the inhibitory effect of compounds on LLC-PK1 cell proliferation

[0487] (1) Cells

[0488] porcine kidney epithelial cells LLC-PK1: purchased from ATCC, Cat#CL-101

[0489] (2) Reagents:

[0490] Medium 199,Gibco(Cat#11150059)

[0491] Fetal Bovine Serum(FBS),Australia,Jitai(Cat#FND500)

[0492] Trypsin-EDTA(0.25%),phenol red,Gibco(Cat#25200072)

[0493] PBS, pH 7.4, Gibco (Cat#10010031)

[0494] DMSO (dimethyl sulfoxide), Sigma (Cat#D8418)

[0495] Poly-D-lysine,Gibco(Cat#A3890401)

[0496] AVP (Aminovasopressin): Custom-made by Jier Biochemical (Shanghai) Co., Ltd.

[0497] Verapamil hydrochloride,MCE(Cat#HY-A0064)

[0498] AlamarBlue TM HS Cell Viability Reagent, Invitrogen(Cat#A50100)

[0499] (3) Test method:

[0500] The pathogenesis of polycystic kidney disease is associated with low intracellular calcium ion concentrations in renal collecting duct epithelial cells, leading to cAMP-dependent excessive cell proliferation. Referring to the research paper published in *The Journal of Biological Chemistry* by Tamio Yamaguchi et al. in 2004, we optimized and conducted a renal epithelial cell LLC-PK1 proliferation assay to evaluate the inhibitory effect of compounds on vasopressin-induced cell proliferation after reducing intracellular calcium ion concentration.

[0501] LLC-PK1 cells were cultured in M199 medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. On the first day of the experiment, 100 μL of 0.01% Poly-D-lysine was added to each well of a 96-well plate, incubated at room temperature for 10 min, then aspirated and air-dried at room temperature for 1 hr. The cells were then washed once with 200 μL of 1X PBS. LLC-PK1 cells were digested with trypsin, centrifuged, resuspended in serum-free M199, counted, and diluted with serum-free M199 medium to a concentration of 1×10⁻⁶. 5 Add FBS to a final concentration of 1% for each ml of cell suspension. Transfer 200 μL of cell suspension per well to a 96-well plate. After culturing cells for 24 hours, aspirate the supernatant, wash once with 200 μL of PBS, and then add 160 μL of M199 culture medium containing 0.05% FBS and 20 μL of 10X Verapamil (final concentration 5 μM), and continue culturing for another 24 hours. On the third day, add 10 μL of different concentrations of the test compound (starting from a final concentration of 3 μM, 3-fold dilution, 8 concentration gradients) or DMSO (min, maximum control) to the corresponding wells. Add 10 μL of vasopressin AVP solution to the test compound wells and the maximum control well to a final concentration of 10 nM, and add 10 μL of serum-free M199 culture medium to the minimum control well, and continue culturing for another 48 hours. On day 5, carefully aspirate the culture medium, wash the cells once with 200 μL of PBS, carefully add 90 μL of M199 serum-free culture medium, then add 10 μL of Alamarblue reagent, centrifuge at 300 rpm for 1 min, and incubate at 37°C for 2 hours before detection. Sample detection was performed using a SpectraMax instrument with excitation light at 560 nm and emission light at 595 nm. Each sample was tested in 3 replicates, and 6 replicates were performed for both the Min and Max assays.

[0502] (4) Data processing

[0503] Using compound concentration as X, the average fluorescence intensity of each sample minus the background fluorescence intensity is represented by Y, indicating the number of viable cells in that well during detection. A bar graph was created using the Grouped-Summarydata-Separated bar graph in GraphPad Prism 8.0 software to reflect the dose-response relationship of different compounds on AVP-induced cell proliferation. Tolvaptan was used as a positive control to qualitatively evaluate the inhibitory effect of compounds on proliferation: compounds with overall performance superior to tolvaptan were marked "+++", those with performance similar to tolvaptan were marked "++", those with performance weaker than tolvaptan were marked "+", and those with no proliferation inhibition were marked "-".

[0504] Data quality control: Calculate S / B, which is the maximum hole average value / minimum hole average value. A value ≥ 2 is considered a pass for QC.

[0505] Experimental results show (see) Figure 1 , Figure 2 As shown in Table 3 below, in the AVP-induced LLC-PK1 cell proliferation experiment, Tolvaptan, as a positive control, showed a high-concentration proliferative hook effect, while compound 1 had no hook effect and showed a superior dose-response effect compared to Tolvaptan.

[0506] Table 3: Inhibitory effects of compounds on LLC-PK1 cell proliferation

[0507]

[0508] Experiment Example 4: Combination Test of Compounds with V1a, V1b, and V2 Receptors

[0509] This experiment used a competitive isotope ligand binding assay to test the affinity Ki of compound 1 and control 1 for human V1aR, V1bR, and V2R.

[0510] (1) Cell membrane

[0511] Cells expressing high levels of human V1a receptor were amplified. Cells were collected, washed twice with PBS, and resuspended in PBS containing protease inhibitors. Cells were homogenized at 15000 rpm, centrifuged at 3000 rpm for 15 minutes at 4°C, and the supernatant was collected. The cells were then centrifuged at 20000 rpm for 45 minutes at 4°C, and the supernatant was discarded to obtain the cell membrane precipitate. The precipitate was resuspended in buffer to determine protein concentration, aliquoted, and stored at -80°C. Cell membranes expressing high levels of human V1b and V2 receptors were purchased from PerkinElmer, USA.

[0512] (2) Analytical buffer

[0513] 50 mM Tris-HCl, pH 7.4

[0514] 10mM MgCl2

[0515] 0.1% BSA

[0516] Protease inhibitor mixture (one tablet / 50ml)

[0517] (3) Rinse buffer

[0518] 50 mM Tris-HCl, pH 7.4

[0519] (4) Compound configuration

[0520] 1. Preparation of compound mother liquor

[0521] 1.59 mg, 1.24 mg, and 1.38 mg of the test compounds were dissolved in 100% dimethyl sulfoxide to a final concentration of 10 mM. A 10 mM stock solution of the positive control, Vasopressin, was prepared.

[0522] 2.100X compound preparation

[0523] The stock solutions of the test compound and the positive control were diluted to 1 mM (10-fold dilution) and 0.1 mM (100-fold dilution) with DMSO, respectively, and then serially diluted with DMSO four times to the 10th point.

[0524] 3. Preparation of cell membrane stock solution

[0525] Cell membranes overexpressing the human receptor were prepared to 5 mg / mL using analytical buffer.

[0526] (5) Operating steps

[0527] 1. Aspirate 1 μl of the compound from the dilution plate into each well of the 96-well test plate (the concentration of the test compound in the reaction will be diluted 100-fold). Add 1 μL of DMSO to the control wells.

[0528] 2. Prepare 10 mL of membrane solution containing 5 μg / μL.

[0529] 3. Use a pipette to add the membrane solution from step 2 to the compound test plate, adding 89 μL to each well.

[0530] 4. Dilute the 50 μCi / mL isotope-labeled Vasopressin stock solution to a final concentration of 10-fold with analytical buffer, and add 10 μL / well to the reaction plate using a pipette. The final concentrations of isotope-labeled Vasopressin in the V1a, V1b, and V2 receptor experiments are 1.5 nM, 0.75 nM, and 1 nM, respectively.

[0531] 5. Incubate the prepared test plate at 30℃ for 60 minutes.

[0532] 6. Collect the membrane complex into a 0.5% PEI pre-coated GF / B plate using Cell Harvester, and wash three times with 2 ml of elution buffer pre-cooled at 4°C.

[0533] Dry at 7.37℃ for 2 hours. Measure the content of isotopically labeled Vasopressin bound to the receptor using a liquid scintillation / luminescence counter.

[0534] 8. Process the read data using Prism 5, and fit the following equation to obtain the dose-response curve of the compound, as well as the IC50 value of the compound competitively inhibiting the binding of the isotope label Vasopressin to the receptor.

[0535] Y = Bottom + (Top - Bottom) / (1 + 10^((X - LogIC50))), where: Y is the liquid scintillation meter reading, and X is the logarithmic value of the compound concentration. The affinity Ki for the compound to competitively bind to the receptor is calculated using the IC50 value: Ki = IC50 / (1 + ([L] / Kd)), where [L] is the concentration of isotopically labeled Vasopressin in the experiment, and Kd is the dissociation constant between the isotopically labeled Vasopressin and the receptor.

[0536] The results of the two repeated experiments are shown in Table 4. Vasopressin's binding Ki to the three receptors is close to that reported in the literature. Neither compound 10A nor control 1 binds to the V1b receptor (IC50>10uM). The binding affinity to V2R is higher than that to V1a, and they have different degrees of V1a / V2 selectivity.

[0537] Table 4: Binding affinity of the test compounds to V1a, V1b, and V2 receptors

[0538]

Claims

1. The compound shown in formula (III) or its pharmacologically acceptable salt, ， in, One of X1 and X2 is selected from O or NR. A Another one is selected from C(R) A )2; X3 is selected from C(R) A )2; T1 and T2 are independently selected from N and C(R) respectively. T ); Y1 and Y2 are independently selected from N and C(R) respectively. Y ); R1, R2, R3, R A R T R Y Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs; R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, or 5-6 heteroaryl groups are optionally surrounded by 1, 2, or 3 R groups. 4a replace; R, R 4a Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkylamino group may be optionally substituted with 1, 2 or 3 R's; R' is selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 alkyl; m1, m2, m3, m4, and n are each independently selected from 0, 1, or 2; The C 1-6 Heteroalkyl or 5-6-membered heteroaryl groups contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

2. The compound shown in formula (IV) or a pharmacologically acceptable salt thereof, ， in, T1 and T2 are independently selected from O, N, and C(R) respectively. T ); Y1 and Y2 are independently selected from N and C(R) respectively. Y ); R1, R2, R3, R A R T R Y Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs; R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, phenyl, or 5-6 heteroaryl groups are optionally surrounded by 1, 2, or 3 R groups. 4a replace; R, R 4a Each of the following is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkylamino group may be optionally substituted with 1, 2 or 3 R's; R' is selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 alkyl; m2, m3, and n are each independently selected from 0, 1, or 2; The C 1-6 Heteroalkyl or 5-6-membered heteroaryl groups contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

3. The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof, wherein, R4 is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CF3. , , , , Cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, thienyl, and thiazolyl.

4. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein, Selected from aziridine, oxadiidine, pyrroleyl, tetrahydrofuranyl, cyclobutane, cyclopentaneyl, and cyclohexaneyl, wherein the aziridine, oxadiidine, pyrroleyl, tetrahydrofuranyl, cyclobutane, cyclopentaneyl, or cyclohexaneyl is optionally prefixed with one or two R's. A replace.

5. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein, Selected from , , , , and .

6. The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof, wherein, Selected from phenyl and pyridyl, wherein the phenyl or pyridyl group is optionally substituted with 1, 2 or 3 R3 groups.

7. The compound according to claim 6 or a pharmacologically acceptable salt thereof, wherein, Selected from and .

8. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein, Selected from , , and .

9. A compound of the following formula or a pharmacologically acceptable salt thereof, selected from... 。 10. A compound of the following formula or a pharmacologically acceptable salt thereof, selected from... 。 11. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 in the preparation of a medicament for the prevention or treatment of hypertension, Reye's syndrome, dysmenorrhea, premature birth, adrenocorticotropic hormone-releasing hormone secretion disorder, adrenal hyperplasia, depression, chronic congestive heart failure, cirrhosis, antidiuretic hormone secretion disorder syndrome, hyponatremia caused by chronic heart failure, cirrhosis or antidiuretic hormone secretion disorder, or polycystic kidney disease.

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