Dual antagonists and uses thereof

Abstract

The present invention provides novel compounds having dual angiotensin II receptor and endothelin receptor antagonism represented by formula (I) and their use in the manufacture of medicines. [Case 1] TIFF2024539270000080.tif62161

Description

[Technical Field]

[0001] The present invention claims priority from an invention patent application filed in China on October 21, 2021, entitled "Dual Antagonists and Uses Thereof" and bearing application number 202111228856.0, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to novel compounds with dual angiotensin II receptor and endothelin receptor antagonism, and their use in the manufacture of medicaments. [Background technology]

[0003] Angiotensin II (Ang II) and endothelin-1 (ET-1) are two potent endogenous vasoactive peptides, both of which are thought to play a role in regulating vascular tone and pathological tissue remodeling associated with multiple diseases. Angiotensin II receptors include four subtypes: AT1, AT2, AT3, and AT4. AT1 and AT2 are the predominant subtypes, and AT1 mediates almost all physiological and pathological actions of angiotensin II receptors. Angiotensin II receptor antagonists (ARBs) are systemic antihypertensive drugs with advantages such as high affinity, selectivity, oral administration, long half-life, and good tolerability. Endothelin is a potent vasoactive peptide that promotes vasoconstriction and plays a crucial role in maintaining vascular stability. In the prior art, several different endothelin receptors (e.g., ETA, ETB1, ETB2, ETC, etc.) have been identified, among which ETA has been most studied, and its antagonists can be used to treat diseases such as hypertension, pulmonary hypertension, chronic kidney disease, and atherosclerosis.

[0004] Preclinical and early clinical data have shown that simultaneous blockade of angiotensin II and endothelin 1 at their respective receptors, AT1 and ETA, may provide improved treatment options for some cardiovascular diseases compared with the use of either mechanism alone. Dual angiotensin II and endothelin receptor antagonists have antagonistic effects on both angiotensin II and ETA receptors, and offer better therapeutic effects and a wider range of applications than single angiotensin II or ETA receptor antagonists, making them potential pharmaceuticals for the treatment of diseases such as hypertension or kidney disease. Although a series of dual angiotensin II and endothelin receptor antagonists have been disclosed in WO2000001389A1, CN101891735A, etc., there remains a need for the development of dual antagonist pharmaceuticals with better activity, higher selectivity, better water solubility, and fewer drug interactions. Summary of the Invention

[0005] The present invention provides a compound of Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] (Wherein, X is NR X1 or CR X2 R X3 is selected from Y is a chemical bond, NR Y1 or CR Y2 R Y3 is selected from R Y1 is hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered carbocyclyl), -C 0~4Alkylene-(4-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6- to 10-membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered aromatic heterocycle), R Y2 , R Y3 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered carbocyclyl), -C 0~4 Alkylene-(4-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6- to 10-membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered aromatic heterocycle), R X1 is hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered carbocyclyl), -C 0~4 Alkylene-(4-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6- to 10-membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered aromatic heterocycle), provided that alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further comprise one, two, three, or four independent R X11 may be substituted with Each R X11 are each independently hydrogen, halogen, cyano group, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR X12 , -C 0~4 Alkylene-SR X12 , -C 0~4 Alkylene-NR X12 R X13 Alternatively, two independent R X11 together with the bonded atoms [ka] Forming R X12 , R X13 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl, R X2 , R X3 together with the atom directly bonded thereto, form a 6- to 12-membered spiro ring, a 6- to 12-membered spiro hetero ring, a 6- to 12-membered fused ring, or a 6- to 12-membered fused hetero ring, provided that the spiro ring, spiro hetero ring, fused ring, or fused hetero ring further contains one, two, three, or four independent R X21 may be substituted with Each R X21 are each independently hydrogen, halogen, cyano group, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR X22 , -C 0~4Alkylene-SR X22 , -C 0~4 Alkylene-NR X22 R X23 Alternatively, two independent R X21 together with the atoms directly bonded to it [ka] Forming R X22 , R X23 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl, R 1 -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl, R 2 -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR 21 , -C 0~4 Alkylene-SR 21 , -C 0~4 Alkylene-NR 21 R 22 , -C 0~4 Alkylene-OC(O)R 21 , -C 0~4 Alkylene-S(O)R 21 , -C0~4 Alkylene-S(O)R 21 , -C 0~4 Alkylene-S(O)NR 21 R 22 , -C 0~4 Alkylene-S(O)NR 21 R 22 , -C 0~4 Alkylene-C(O)R 21 , -C 0~4 Alkylene-C(O)OR 21 , -C 0~4 Alkylene-C(O)NR 21 R 22 , -C 0~4 Alkylene-NR 21 C(O)R 22 , -C 0~4 Alkylene-NR 21 S(O)2R 22 , -C 0~4 Alkylene-NR 21 S(O)R 22 , -C 0~4 Alkylene-(3-10 membered carbocyclyl), -C 0~4 Alkylene-(4-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6- to 10-membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered aromatic heterocycle), R 21 , R 22 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered carbocyclyl), -C 0~4 Alkylene-(4-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6- to 10-membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered aromatic heterocycle), R 3 , R 4are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered carbocyclyl), -C 0~4 Alkylene-(4-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6- to 10-membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered aromatic heterocycle), provided that alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further comprise one, two, three, or four independent R 31 may be substituted with Each R 31 are each independently hydrogen, halogen, cyano group, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR 32 , -C 0~4 Alkylene-SR 32 , -C 0~4 Alkylene-NR 32 R 33 , -C 0~4 Alkylene-OC(O)R 32 , -C 0~4 Alkylene-S(O)R 32 , -C 0~4 Alkylene-S(O)R 32 , -C 0~4 Alkylene-S(O)NR 32 R 33 , -C 0~4 Alkylene-S(O)NR 32 R 33 , -C 0~4 Alkylene-C(O)R32 , -C 0~4 Alkylene-C(O)OR 32 , -C 0~4 Alkylene-C(O)NR 32 R 33 , -C 0~4 Alkylene-NR 32 C(O)R 33 , -C 0~4 Alkylene-NR 32 S(O)2R 33 , -C 0~4 Alkylene-NR 32 S(O)R 33 , -C 0~4 Alkylene-(3-10 membered carbocyclyl), -C 0~4 Alkylene-(4-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6- to 10-membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered aromatic heterocycle), or two independent R 31 together with the atoms directly bonded to it [ka] Forming R 32 , R 33 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl.

[0006] Furthermore, R 1 is selected from n-butyl.

[0007] Furthermore, R 2 -C 1~2 Alkylene-OR 21 , -C 1~2 Alkylene-SR 21 , -C 1~2 Alkylene-NR 21 R22 , -C 1~2 Alkylene-OC(O)R 21 , -C 1~2 Alkylene-S(O)R 21 , -C 1~2 Alkylene-S(O)R 21 , -C 1~2 Alkylene-S(O)NR 21 R 22 , -C 1~2 Alkylene-S(O)NR 21 R 22 , -C 1~2 Alkylene-C(O)R 21 , -C 1~2 Alkylene-C(O)OR 21 , -C 1~2 Alkylene-C(O)NR 21 R 22 , -C 1~2 Alkylene-NR 21 C(O)R 22 , -C 1~2 Alkylene-NR 21 S(O)2R 22 , -C 1~2 Alkylene-NR 21 S(O)R 22 is selected from R 21 , R 22 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~2 Alkylene-(3-10 membered carbocyclyl), -C 0~2 alkylene-(4- to 10-membered heterocycloalkyl).

[0008] Furthermore, R 2 teeth, [ka] is selected from R21 , R 22 are each independently hydrogen, -C 1~6 Alkyl, halogen substituted -C 1~6 Alkyl, -C 0~2 alkylene-(3- to 6-membered carbocyclyl).

[0009] More specifically, R 2 teeth, [ka] is selected from.

[0010] Furthermore, R 3 -C 0~2 Alkylene-(3-10 membered carbocyclyl), -C 0~2 Alkylene-(4-10 membered heterocycloalkyl), -C 0~2 Alkylene-(6- to 10-membered aromatic ring), -C 0~2 alkylene-(5- to 10-membered aromatic heterocycle), provided that alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further comprise one, two, three, or four independent R 31 may be substituted with Each R 31 are each independently hydrogen, halogen, cyano group, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl; or two independent R 31 together with the atoms directly bonded to it [ka] Forming R 4 is hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl.

[0011] Furthermore, R 3 is selected from 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 8-membered carbocyclyl, 9-membered carbocyclyl, 10-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 7-membered aromatic heterocycle, 8-membered aromatic heterocycle, 9-membered aromatic heterocycle, 8-membered aromatic heterocycle, with the proviso that the carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further be selected from one, two, three, or four independent R 31 may be substituted with R 4 is hydrogen, -C 1~6 alkyl.

[0012] More specifically, R 3 teeth, [ka] [ka] is selected from, where R 3 The ring selected as 31 may be substituted with.

[0013] Furthermore, specifically, R 3 teeth, [ka] [ka] is selected from.

[0014] Furthermore, X is NR X1 is selected from R X1 -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~2 Alkyl-(3- to 10-membered carbocyclyl), -C 0~2 Alkyl-(4-10 membered heterocycloalkyl), -C 0~2 Alkyl-(6- to 10-membered aromatic ring), -C 0~2 alkyl-(5- to 10-membered aromatic heterocycle).

[0015] Furthermore, R X1 -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 It is selected from alkynyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 8-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, benzene ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle.

[0016] More specifically, R X1 teeth, [ka] [ka] or [ka] is selected from.

[0017] Furthermore, the compound of formula I is represented by formula IIa. [ka] (Wherein m1 and m2 are each independently selected from 0, 1, 2, or 3; m3 is selected from 1, 2, 3, 4, or 5.

[0018] Furthermore, the compound of formula I is represented by formula IIb. [ka] (wherein n1 and n2 are each independently selected from 0, 1, 2, or 3; n3 is selected from 1, 2, 3, 4, or 5.

[0019] In some specific embodiments of the invention, the compound is specifically [ka] [ka] [ka] [ka] [ka] is.

[0020] The present invention also provides use of any of the above compounds, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of an angiotensin II receptor and endothelin receptor dual antagonist pharmaceutical.

[0021] The present invention also provides use of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical for treating cardiovascular and cerebrovascular diseases including hypertension, kidney diseases, and diabetes-related organ damage diseases.

[0022] The present invention also provides a pharmaceutical composition comprising a formulation prepared from any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0023] The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or vehicle.

[0024] The present invention also provides a method for treating a disease associated with angiotensin II receptors and endothelin receptors, comprising administering to a subject in need thereof an effective amount of any of the compounds of the present invention, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or any of the compositions described above, wherein the disease is preferably cardiovascular or cerebrovascular disease including hypertension, renal disease, or diabetes-related organ damage disease.

[0025] The present invention also provides a compound represented by formula IIIa or formula IIIb, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, m1, m2, m3, n1, n2, and n3 are defined as in the present invention above. R 1 -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6alkynyl, preferably n-butyl; m1 and m2 are each independently selected from 0, 1, 2, or 3; m3 is selected from 1, 2, 3, 4, or 5; n1 and n2 are each independently selected from 0, 1, 2, or 3; and n3 is selected from 1, 2, 3, 4, or 5. Preferred compounds represented by the above formula IIIa or IIIb are [ka] or [ka] is selected from.

[0026] The compounds and derivatives provided in the present invention can be named according to IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, Ohio) nomenclature.

[0027] Regarding the definition of terms used in the present invention, unless otherwise specified, the initial definition provided for a group or term in this text applies to this group or term described throughout the specification. For terms not specifically defined in this text, the meaning that a person skilled in the art can give based on the disclosure and context should be given.

[0028] "Substitution" refers to the replacement of a hydrogen atom in a molecule with another different atom or group, or the replacement of a lone electron pair on an atom in a molecule with another atom or group. For example, the replacement of a lone electron pair on an S atom with an O atom. [ka] or [ka] can be formed.

[0029] "Furthermore, optionally substituted" means that it may be "substituted," but does not mean that it must not be substituted; this term includes both substituted and unsubstituted cases.

[0030] The minimum and maximum carbon atom content in the hydrocarbon group is indicated by a prefix, e.g., the prefix C a~b Alkyl refers to any alkyl containing "a" to "b" carbon atoms. Thus, for example, C 1~6 Alkyl refers to alkyls containing 1 to 6 carbon atoms.

[0031] "Alkyl" refers to a saturated hydrocarbon chain having the specified number of atoms. Alkyl may be straight or branched. Representative branched alkyls have one, two, or three branches. Alkyl groups may be substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl may be part of another group, such as, for example, -O(C 1~6 alkyl).

[0032] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having the specified number of atoms. a ~ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene group" includes the following structure: [ka] Similarly, the term "dimethylbutylene" includes, for example, any one of the following structures: [ka] or [ka]

[0033] The -C0-4 alkylene of the present invention may be a C0 alkylene, a C1 alkylene (e.g., -CH2-), a C2 alkylene (e.g., -CH2CH2-, etc.), a C3 alkylene, or a C4 alkylene. C0 alkylene means that this group is absent and that the groups are bonded via a chemical bond. For example, A-C0 alkylene-B refers to AB, in which the A and B groups are directly bonded via a chemical bond.

[0034] The term "carbocyclyl" as used herein refers to a saturated or non-aromatic partially saturated cyclic group having a single ring or multiple rings (fused, bridged, spiro-bonded) with multiple carbon atoms and no heteroatoms. The term "carbocyclyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of monocarbocyclyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of fused carbocyclyl carbocyclyls include bicyclohexyl, bicyclopentyl, and bicyclooctyl. Two examples of such bicycloalkyl polycyclic structures are named below. [ka] bicyclohexyl group and [ka] Bicyclohexyl group. Illustrative examples of carbocyclyls in bridged carbocyclyl systems include: [ka] Examples of spirocarbocyclyl groups include adamantyl groups. [ka] The term "carbocyclyl" may also include partially saturated cyclic groups formed by the fusion of an aromatic ring and a non-aromatic ring, where the point of attachment may be at a non-aromatic or aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalen-5-yl and 5,6,7,8-tetrahydronaphthalen-5-yl.

[0035] The term "unsaturated" as used herein refers to the inclusion of a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond, or the like in a group or molecule.

[0036] "Alkenyl" refers to a straight or branched chain hydrocarbon group having at least one site of vinyl unsaturation (>C=C<). For example, C a-b Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0037] "Alkynyl" refers to a straight-chain monovalent hydrocarbon radical or a branched-chain monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include hydrocarbon radicals having one triple bond and one double bond. For example, C 2-6 Alkynyl is intended to include ethynyl, propynyl, and the like.

[0038] The term "heterocycloalkyl" as used herein refers to a saturated ring or non-aromatic partially saturated ring group having one or more rings (fused, bridged, spiro-bonded) containing at least one heteroatom. In this context, the heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. It generally refers to a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system of multiple ring atoms containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocycloalkyls in monoheterocycloalkyl systems include oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of heterocycloalkyls in fused heterocycloalkyl systems include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, and the like. Examples of heterocycloalkyls in bridged heterocycloalkyl systems include: [ka] Illustrative examples of heterocycloalkyls in spiroheterocycloalkyl systems include: [ka] Illustrative examples of partially saturated heterocycloalkyl include dihydrofuranyl, imidazolinyl, tetrahydropyridyl, or dihydropyranyl. The term "heterocycloalkyl" may also include partially saturated cyclic groups formed by the fusion of an aromatic ring containing at least one heteroatom with a non-aromatic ring, where the point of attachment may be at a non-aromatic carbon atom, an aromatic carbon atom, or a heteroatom, illustrative examples of which include: [ka] Examples include:

[0039] The term "aromatic ring" as used herein refers to an aromatic hydrocarbon group having multiple carbon atoms. An aryl group generally refers to a monocyclic, bicyclic, or tricyclic aryl group having multiple carbon atoms. The term "aryl group" as used herein may refer to an aromatic substituent of a single aromatic ring or condensed aromatic rings. Non-limiting examples include a phenyl group, a naphthyl group, or a tetrahydronaphthyl group.

[0040] The term "aromatic heterocycle" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom. It typically includes a monocyclic or bicyclic aromatic hydrocarbon ring of multiple ring members, with one or more heteroatoms selected from O, N, and S. Preferably, it contains one to three heteroatoms. Examples of heterocycloaryl groups include pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiapyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0041] "Halogen" as described in the present invention refers to fluorine, chlorine, bromine or iodine.

[0042] The term "halogen-substituted alkyl" as used herein means that one or more hydrogen atoms in the alkyl are substituted with halogen. For example, halogen-substituted C 1~4 Alkyl refers to an alkyl containing 1 to 4 carbon atoms in which a hydrogen atom is substituted with one or more halogen atoms. Further examples include monofluoromethyl, difluoromethyl, and trifluoromethyl groups.

[0043] The terms "-OR", "-NRR", etc. described in the present invention mean that the R group is bonded to an oxygen atom or a nitrogen atom via a single bond.

[0044] The oxygen atom in "-C(O)R", "-S(O)R" and the like described in the present invention is bonded to a carbon atom or a sulfur atom via a double bond.

[0045] In the "-C(O)R" and "-S(O)R" described in the present invention, the oxygen atom is bonded to the carbon atom or sulfur atom via a double bond, and the R group is bonded to the oxygen atom or sulfur atom via a single bond. For example, "-S(O)(NH)R" means that the oxygen atom and the nitrogen atom are bonded to the sulfur atom via a double bond, and the R group is bonded to the sulfur atom via a single bond.

[0046] Described in the present invention [ka] means that the oxygen atom or sulfur atom is bonded to the substitution site via a double bond.

[0047] In the description of the radicals of the present invention [ka] [ka] represents the position at which the group is substituted. For example, [ka] The tetrahydropyrrole ring is [ka] This means that the ring is fused to another ring in the structure at the position indicated by the arrow.

[0048] The term "chemical bond" as used herein refers to a single bond, for example, [ka] In the case where Y is selected from a chemical bond, the benzene ring and the sulfur atom of the sulfonyl group are directly bonded via a single bond.

[0049] In the description of the radicals of the present invention [ka] represents a single configuration of a chemical structure. For example, [ka] means that the cyclopropane moiety has a single configuration and the absolute configuration is undetermined.

[0050] The term "deuterated compound" as used herein refers to a molecule or group in which one or more hydrogen atoms have been replaced with deuterium atoms, with the proportion of deuterium atoms being greater than the abundance of deuterium in nature.

[0051] The term "pharmaceutically acceptable" means that a carrier, carrier, diluent, excipient, and / or formed salt is typically chemically or physically compatible with the other ingredients that make up the pharmaceutical dosage form and is physiologically compatible with the receptor.

[0052] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed with the compounds or their stereoisomers, inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly by final separation and purification of the compounds. They can also be obtained by mixing the compounds or their stereoisomers with a certain amount of acid or base, as appropriate (e.g., equimolar amounts). These salts can be obtained by forming a precipitate in solution and collecting it by filtration, by evaporating the solvent, or by reacting in an aqueous medium and then lyophilizing.

[0053] In some embodiments, one or more compounds of the present invention can be used in combination. The compounds of the present invention can also be used in combination with any other active agent to manufacture a medicament or pharmaceutical composition for modulating cell function or treating disease. When a group of compounds is used, the compounds can be administered to a subject simultaneously, separately, or sequentially.

[0054] Based on the above content of the present invention, it is apparent that various other modifications, substitutions or changes can be made in consideration of the general technical knowledge and conventional means in this field, without departing from the above basic technical idea of ​​the present invention.

[0055] The above content of the present invention will be described in more detail below using examples as modes for carrying out the invention. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention. [Brief explanation of the drawings]

[0056] [Figure 1] FIG. 1 is a schematic diagram of the three-dimensional structure of the compound of Example 3 of the present invention obtained by single crystal X-ray diffraction. DETAILED DESCRIPTION OF THE INVENTION

[0057] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR chemical shifts (δ) are reported in units of 10-6 (ppm). NMR measurements were performed using nuclear magnetic resonance spectrometers (Bruker Avance III 400 and Bruker Avanceneo 600) with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as solvents, and tetramethylsilane (TMS) as an internal standard.

[0058] LC-MS measurements are performed using a Shimadzu liquid chromatography mass spectrometer (Shimadzu LC-MS 2020 (ESI)). HPLC measurements are performed using a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium-pressure preparative chromatography) is performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with 0.4mm to 0.5mm specifications used for thin-layer chromatography separation. Column chromatography typically uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0059] The known starting materials of the present invention can be synthesized using or according to methods known in the art, or purchased from companies such as Energy Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, J&K Scientific, etc.

[0060] In the examples, unless otherwise specified, reactions are carried out under a nitrogen atmosphere. In the examples, unless otherwise specified, solutions refer to aqueous solutions. In the examples, unless otherwise specified, reactions are at room temperature. In the examples, unless otherwise specified, M represents mol / L.

[0061] DIBAL-H: diisobutylaluminum hydride; DPPA: diphenylphosphoryl azide; DMF: dimethylformamide.

[0062] Example 1 [ka]

[0063] Step 1 Compound 1a (300 mg, 1.25 mmol) was dissolved in tetrahydrofuran (anhydrous) (5 mL). The mixture was cooled to -60 °C, and then a 1 M DIBAL-H / n-hexane solution (1.62 mL, 1.62 mmol) was added dropwise. The reaction mixture was warmed to room temperature and reacted for 2 h. After completion of the reaction was monitored by LC-MS, the reaction mixture was poured into dilute hydrochloric acid (2 M, 10 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 9:1) to give compound 1b (200 mg, 0.82 mmol, yield: 66%).

[0064] Step 2 Compound 1c (3.50 g, 10.57 mmol) was dissolved in 50 mL of anhydrous tetrahydrofuran, added with sodium hydride (60%, 592 mg, 14.80 mmol) at 0 °C, and stirred at this temperature for 30 minutes. Bromomethyl methyl ether (1.85 g, 14.80 mmol) was then added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into 50 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Compound 1d (3.20 g, 8.53 mmol, 81% yield) was obtained by column chromatography (petroleum ether:ethyl acetate = 4:1). MS-ESI calculated [M + Na] + The actual measured value was 397.0. 1 H NMR(400 MHz,DMSO-d6)δ7.98-7.96(m,1H),7.92-7.89(m,1H),7.61-7.54(m,2H),5.16(s,2H),3.39(s,3H),2.32(s,3H),1.85(s,3H).

[0065] Step 3 Compound 1d (300 mg, 0.80 mmol) was dissolved in 1,4-dioxane (9 mL). Nitrogen gas was bubbled through the reaction system for 5 minutes, and then bis(neopentylglycolato)diboron (304 mg, 1.35 mmol), Pd(dppf)Cl2 (29.0 mg, 0.040 mmol), and potassium acetate (157 mg, 1.60 mmol) were added. The reaction mixture was heated and refluxed for 3 hours. After completion of the reaction was monitored by LC-MS, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 1e (250 mg, 0.61 mmol, yield: 77%). 1 H NMR(400 MHz,DMSO-d6)δ7.70-7.52(m,4H),4.95(s,2H),3.66(s,4H),3.27(s,3H),3.27(s,3H),2.34(s,3H),1.81(s,3H).1.03(s,6H).

[0066] Step 4 Under nitrogen gas protection, compound 1e (500 mg, 1.18 mmol) was dissolved in a mixture of toluene (2 mL) and ethanol (1 mL), followed by the addition of tetrakis(triphenylphosphine)palladium (137 mg, 0.118 mmol) and sodium carbonate (377 mg, 3.56 mmol). The reaction mixture was heated to 85 °C and reacted for 3 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 7:3) to give compound 1f (225 mg, 0.49 mmol, 42% yield). MS-ESI calculated values ​​were [M + Na]. + The value was 481.1, and the actual measured value was 481.2. 1H NMR(400 MHz,DMSO-d6)δ10.09(s,1H),8.04-7.96(m,2H),7.84(dd,J=7.8,1.7Hz,1H),7.76 (td,J=7.5,1.4Hz,1H),7.66(td,J=7.8,1.4Hz,1H),7.37-7.29(m,2H),4.53(d,J= 11.0Hz,1H),4.39(d,J=11.0Hz,1H),4.24(d,J=12.9Hz,1H),4.13(d,J=12.8Hz,1H ),3.42-3.23(m,2H),3.20(s,3H),2.33(s,3H),1.79(s,3H),1.05(t,J=7.0Hz,3H).

[0067] Step 5 Compound 1f (200 mg, 0.436 mmol) was dissolved in methanol (2 mL) and cooled to 0 °C. Sodium borohydride (60%, 24.8 mg, 0.62 mmol) was added, and the reaction mixture was then warmed to room temperature and allowed to react for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was poured into dilute hydrochloric acid (0.5 M, 10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give 150 mg of compound 1g (150 mg, 0.326 mmol, 75% yield). MS-ESI calculated values ​​for [M+Na] were obtained. + The measured value was 483.2. 1 H NMR(400 MHz,Chloroform-d)δ8.00(dd,J=8.1,1.3Hz,1H),7.62-7.53(m,2H),7.45(td,J=7.6,1.4Hz,1H),7.37-7.27(m,3H),4.76(s,2H),4.37( dd,J=11.6,5.9Hz,2H),4.19(dd,J=18.0,11.6Hz,2H),3.50-3.27(m,2H),3.32(s,3H),2.30(s,3H),1.92(s,3H),1.12(t,J=7.0Hz,3H).

[0068] Step 6 Compound 1g (150 mg, 0.326 mmol) was dissolved in N,N-dimethylformamide (0.5 mL) at room temperature. The mixture was cooled to 0°C, and carbon tetrabromide (162 mg, 0.488 mmol) and triphenylphosphine (128 mg, 0.488 mmol) were added. The reaction was allowed to proceed at 0°C for 2 hours. After completion of the reaction was monitored by LC-MS, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 1h (122 mg, 0.233 mmol, yield: 71%). MS-ESI calculated value [M+Na] + The measured value was 547.1. 1 H NMR(400 MHz,Chloroform-d)δ8.00(dd,J=8.0,1.3Hz,1H),7.62-7.55(m,5H),7.49-7.41(m,2H),7.33-7.25(m,7H),4.56(s,2H) ,4.41-4.25(m,2H),4.22-4.12(m,2H),3.50-3.28(m,2H),3.31(s,3H),2.30(s,3H),1.92(s,3H),1.13(t,J=7.0Hz,3H).

[0069] Step 7 Compound 1i (200 mg, 2.08 mmol) was dissolved in isopropanol (0.2 mL) and then carefully added dropwise to a hydroxylamine solution (0.3 mL) containing ammonium chloride (145 mg, 2.71 mmol) and potassium cyanide (169 mg, 2.60 mmol). The reaction was allowed to react at room temperature for 16 hours. After completion of the reaction was monitored by TLC, water (10 mL) was added to the reaction mixture, the aqueous phase was extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 205 mg of compound 1j (205 mg, 1.68 mmol, 81% yield). 1 H NMR(400 MHz,Chloroform-d)δ3.00-2.27(m,6H),0.63-0.46(m,4H).

[0070] Step 8 Compound 1j (600 mg, 4.91 mmol) was dissolved in toluene (6 mL) and triethylamine (745 mg, 7.36 mmol) was added. At 15°C, pentanoic acid chloride (711 mg, 5.90 mmol) was slowly added, and the reaction mixture was incubated at 80°C for 2 hours. After the completion of the reaction was monitored by TLC, the reaction mixture was poured into water (8 mL) and diluted hydrochloric acid solution (0.2 M, 8 mL) was added. The organic phase was separated and washed with water (10 mL). The organic phase was concentrated to give 1k (820 mg crude product), which was used directly in the next step.

[0071] Step 9 Compound 1k (820 mg, crude product from the previous step) was dissolved in methanol (5 mL) at 20 °C, and potassium hydroxide (172 mg, 3.07 mmol) and aqueous hydrogen peroxide (30%, 2 mL, 4.91 mmol) were added. The reaction mixture was incubated at 50 °C for 30 min, then cooled to room temperature. Potassium hydroxide (689 mg, 12.28 mmol) was added again, and the mixture was heated to 70 °C and incubated for 2 h. After completion of the reaction was monitored by LC-MS and TLC, solid ammonium chloride (100 mg) was added to neutralize the mixture. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 7:3) to give compound 1l (203 mg, 0.984 mmol, 20% yield for two steps). MS-ESI calculated value is [M+H] + The measured value was 207.3, and the actual value was 207.2. 1 H NMR(400 MHz,Chloroform-d)δ2.64-2.56(m,2H),2.55-2.41(m,4H),1.68(p,J=7.5Hz,2H),1.51-1.34(m,3H),0.95(t,J=7.3Hz,3H),0.66-0.51(m,4H).

[0072] Step 10 Compound 1l (50 mg, 0.242 mmol) was dissolved in N,N-dimethylformamide (2 mL), cooled to 0 °C, and sodium hydride (60%, 12.2 mg, 0.51 mmol) was carefully added and stirred for 30 min. Next, intermediate 1h (114 mg, 0.218 mmol) in N,N-dimethylformamide (0.5 mL) was added to the mixture, and the mixture was allowed to warm to room temperature and react for 5 h. After monitoring the completion of the reaction by LC-MS, the mixture was poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give 80 mg of compound 1m (80 mg, 0.123 mmol, 51% yield). MS-ESI calculated values ​​of [M+H] were obtained. + The calculated value was 649.8, and the actual measured value was 649.4. 1 H NMR(400 MHz,DMSO-d6)δ7.93(dd,J=8.1,1.3Hz,1H),7.73-7.67(m,1H),7.61-7.55(m,1H),7.31-7.25 (m,2H),7.14-7.08(m,2H),4.75(s,2H),4.29(d,J=11Hz,1H),4.19-4.13(m,2H),4.05(d,J=12 .9Hz,1H),3.31-3.15(m,2H),3.17(s,3H),2.48-2.34(m,6H),2.31(s,3H),1.79(s,3H),1.59 -1.51(m,2H),1.35-1.27(m,2H),1.0(t,J=7Hz,3H),0.84(t,J=4.4Hz,3H),0.63-0.49(m,4H).

[0073] Step 11 Compound 1m (70 mg, 0.108 mmol) was dissolved in a mixture of ethanol (3 mL) and hydrochloric acid (6 M, 3 mL) and reacted at 75 °C for 3 hours. After the reaction was completed, the pH of the system was adjusted to 8 with sodium hydroxide solution (5 M), then adjusted to 5 with dilute hydrochloric acid (0.5 M), extracted with ethyl acetate (20 mL * 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 1 (37 mg, 0.061 mmol, yield: 56%, HPLC purity: 98.6%). MS-ESI calculated values ​​of [M+H] + The measured value was 605.8, and the actual value was 605.4. 1 H NMR(400 MHz,DMSO-d6)δ10.48(s,1H),8.08-8.03(m,1H),7.68-7.58(m,2H),7.23-7.15(m,2H) ,7.02(dd,J=1.6,1.6Hz,1H),6.93(d,J=7.8Hz,1H),4.72(s,2H),4.00(s,2H),3.25-3. 14(m,2H),2.49-2.46(m,2H),2.42-2.35(m,4H),2.2(s,3H),1.66(s,3H),1.6-1.5(m,2 H),1.35-1.26(m,2H),0.99(t,J=6.9Hz,3H),0.83(t,J=7.2Hz,3H),0.62-0.49(m,4H).

[0074] Example 2 [ka]

[0075] Step 1 At 25°C, compound 2b (350 mg, 3.22 mmol) was dissolved in 1 mL of water, and hydrochloric acid solution (0.5 N, 0.35 mL) was added dropwise to the system. After stirring for 5 minutes, an aqueous solution (1 mL) of compound 2a (460 mg, 3.53 mmol) was added dropwise to the system. After stirring for 4 hours, ethanol was added to the reaction system until the system became clear, and the reaction solution was frozen at 4°C for 16 hours. The system was subjected to LC-MS to monitor the completion of the reaction. After extraction with ethyl acetate (15 mL * 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2c (500 mg), which was used directly in the next step. MS-ESI calculated value is [M+H] + The value was 185.1, and the actual measured value was 185.2.

[0076] Step 2 To a toluene solution (6 mL) of compound 2c (500 mg, crude product obtained in the previous step) at room temperature, triethylamine (1.5 mL, 10.8 mmol) and DPPA (710 mg, 2.58 mmol) were added, and the mixture was refluxed at 120 °C for 1 hour. After the completion of the reaction was monitored by LC-MS, the mixture was poured into water (8 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After further purification by column chromatography (water / acetonitrile), compound 2d (398 mg, 2.20 mmol, total yield for both steps: 68%) was obtained. MS-ESI calculated [M+H] + The measured value was 182.1. 1 H NMR(600 MHz,Chloroform-d)δ11.67(s,1H),3.12(tt,J=7.1,3.7Hz,1H),2.51(t,J=7.8Hz,2H), 1.65(p,J=7.7Hz,2H),1.38(h,J=7.4Hz,2H),1.04(q,J=3.9Hz,2H),1.02-0.91(m,5H).

[0077] Step 3 In an ice bath, sodium hydride (60%, 12 mg, 0.50 mmol) was added to a solution of compound 2d (30 mg, 0.166 mmol) in DMF (2 mL). The mixture was allowed to react at 25 ° C for 30 minutes, after which a solution of compound 1h (80 mg, 0.153 mmol) in DMF (0.5 mL) was added dropwise to the reaction mixture and stirred for 5 hours. After the completion of the reaction was monitored by LC-MS, the mixture was poured into saturated ammonium chloride (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL), the organic phase was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 2e (80 mg, 0.128 mmol, yield: 84%). 1 H NMR(600 MHz,DMSO-d6)δ7.93(dd,J=8.1,1.2Hz,1H),7.71(td,J=7.6,1.3Hz,1H),7.59(td,J=7.8,1.4Hz,1H),7.33( d,J=1.7Hz,1H),7.28(dd,J=7.6,1.4Hz,1H),7.17-7.09(m,2H),4.87(s,2H),4.31(d,J=11.0Hz,1H),4.20-4 .14(m,2H),4.06(d,J=12.9Hz,1H),3.34-3.11(m,3H),3.17(s,3H),2.44-2.38(m,2H),2.31(s,3H),1.79(s ,3H),1.51-1.42(m,2H),1.33-1.21(m,2H),1.01(t,J=7.0Hz,3H),0.94-0.85(m,4H),0.83(t,J=6.0Hz,3H).

[0078] Step 4 65 mg of compound 2e (65 mg, 0.104 mmol) was dissolved in ethanol (3 mL), and hydrochloric acid solution (6 M, 3 mL) was added. The reaction mixture was incubated at 75 °C for 5 h. After LC-MS showed approximately 85% of the target product, the pH of the mixture was adjusted to 8 with sodium hydroxide solution (5 M), and then further adjusted to 8 with hydrochloric acid solution (0.5 M). The aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 7:3) to give the final compound 2 (37 mg, 0.064 mmol, yield: 62%, HPLC purity: 97.4%). MS-ESI calculated values ​​of [M+H] were + The calculated value was 580.3, and the actual measured value was 580.2. 1 H NMR(600 MHz,DMSO-d6)δ10.50(s,1H),8.05(dd,J=8.0,1.5Hz,1H),7.68-7.58(m,2H),7.27(d,J=1.8Hz,1H ),7.19(dd,J=7.4,1.6Hz,1H),7.07(dd,J=7.8,1.9Hz,1H),6.94(d,J=7.8Hz,1H),4.84(s,2H),4.0 1(q,J=12.9Hz,2H),3.28-3.12(m,3H),2.43(t,J=7.7Hz,2H),2.20(s,3H),1.67(s,3H),1.47(q,J= 7.7Hz,2H),1.37-1.21(m,2H),1.00(t,J=7.0Hz,3H),0.89(d,J=5.4Hz,4H),0.83(t,J=7.3Hz,3H).

[0079] Example 3 [ka]

[0080] Step 1 At 0 °C, diiodomethane (24.5 g, 91.5 mmol) was carefully added dropwise to a solution of diethylzinc in dichloromethane (166 mL, 1 M, 166 mmol) and stirred for 30 minutes. Compound 3a (7.0 g, 83.3 mmol) was then added and the reaction was continued for 3 hours. After completion of the reaction was monitored by TLC, saturated aqueous ammonium chloride (100 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 3b (2.0 g, 20.4 mmol, yield: 24%). 1 H NMR(400 MHz,Chloroform-d)δ4.38(tt,J=6.6,0.9Hz,1H),2.16-2.04(m,2H),1.72(d,J=12Hz,2H),1.42(s,1H),1.34-1.22(m,2H),0.58-0.43(m,2H).

[0081] Step 2 Compound 3b (200 mg, 2.0 mmol) was dissolved in dichloromethane (12 mL) and cooled to 0°C. Dess-Martin periodinane (951 mg, 2.2 mmol) was added, and the reaction mixture was warmed to room temperature and reacted for 3 hours. After completion of the reaction was monitored by TLC, the reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 3c (70 mg, 0.73 mmol, yield: 36%). 1 H NMR(400 MHz,Chloroform-d)δ2.66-2.50(m,2H),2.22-2.10(d,J=20Hz,2H),1.54(dtd, J=8.0,4.0,1.6Hz,2H),0.91(tdt,J=7.8,5.8,1.9Hz,1H),0.01--0.03(m,1H).

[0082] Step 3 Compound 3c (890 mg, 9.26 mmol) was dissolved in isopropanol (2 mL) and carefully added dropwise to an aqueous ammonia solution (3 mL) containing ammonium chloride (644 mg, 12.04 mmol) and potassium cyanide (754 mg, 11.58 mmol). The reaction was allowed to proceed at room temperature for 16 hours. After completion of the reaction was monitored by TLC, water (15 mL) was added to the reaction mixture, the aqueous phase was extracted with dichloromethane (20 mL), the organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to give compound 3d (800 mg, 6.55 mmol, 71% yield), which contains two isomers.

[0083] Step 4 Compound 3d (400 mg, 3.27 mmol) was dissolved in toluene (5 mL) and triethylamine (497 mg, 4.91 mmol) was added. Pentanoic acid chloride (474 ​​mg, 3.93 mmol) was carefully added at 15 °C, and the reaction mixture was reacted at 80 °C for 2 hours. After the completion of the reaction was monitored by TLC, the reaction mixture was poured into water (8 mL), diluted hydrochloric acid solution (0.2 M, 8 mL) was added, and the organic phase was separated. The organic phase was washed with water (10 mL), separated, and concentrated under reduced pressure to obtain crude compound 3e (610 mg), which was directly used in the next reaction.

[0084] Step 5 Crude compound 3e (610 mg) was dissolved in methanol (6 mL) at 20°C, and potassium hydroxide (332 mg, 5.92 mmol) and 30% hydrogen peroxide (1.5 mL) were added. The reaction mixture was reacted at 50°C for 30 minutes, cooled to room temperature, and potassium hydroxide (332 mg, 5.92 mmol) was added again. The reaction mixture was heated to 70°C and reacted for 2 hours. After monitoring the completion of the reaction by LC-MS and TLC, solid ammonium chloride (1.2 g) was added to the reaction mixture and stirred. The mixture was diluted with methanol and then concentrated. Water (20 mL) was added to the concentrate, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 7:3) to obtain two isomers, 3f-1 and 3f-2 (ratio approximately 1:1), totaling 504 mg, 2.44 mmol, total yield for the two steps: 75%). The relative configurations of the two isomers were confirmed by single-crystal X-ray diffraction experiments in Example 3. 3f-1 was used in Examples 3, 5, and 7.

[0085] 3f-1Rf=0.3 (ethyl acetate:petroleum ether=7:3). 1 H NMR(400 MHz,Chloroform-d)δ2.48-2.36(t,J=8Hz,2H),2.25(ddt,J=14.0,4.1,1.2Hz,2H),1.92(d,J=13.8Hz,2H),1.71-1 .58(m,2H),1.55-1.45(m,2H),1.43-1.32(m,2H),0.98-0.85(t,J=8Hz,3H),0.96-0.85(m,1H),0.69-0.59(m,1H).

[0086] 3f-2Rf=0.5 (ethyl acetate:petroleum ether=7:3). 1H NMR(400 MHz,Chloroform-d)δ2.45-2.35(t,J=8Hz,2H),2.29(ddd,J=13.1,3.1,1.5Hz,2H),1.79(d,J=12Hz,2H),1.67-1.56(m,2H),1. 52-1.43(m,2H),1.37(dq,J=14.6,7.4Hz,2H),0.99(q,J=4.3Hz,14H),0.92(t,J=7.3Hz,3H),0.47(tdt,J=8.2,4.8,1.1Hz,1H).

[0087] Step 6 Compound 3f-1 (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (2 mL) and cooled to 0 °C. Sodium hydride (60%, 12 mg, 0.31 mmol) was added and stirred for 30 min. Compound 1h (114 mg, 0.22 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise and the reaction continued for 5 h. After completion of the reaction was monitored by LC-MS, the system was poured into saturated ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 3g (110 mg, 0.17 mmol, yield: 71%). 1H NMR(400 MHz,DMSO-d6)δ7.93(dd,J=8.0,1.3Hz,1H),7.71(td,J=7.5,1.4Hz,1H),7.59(td,J=7.7,1.4Hz,1H),7.30(dd,J=7.6,1.4Hz,1H ),7.25(d,J=1.7Hz,1H),7.17-7.07(m,2H),4.71(s,2H),4.28(d,J=11.1Hz,1H),4.22-4.11(m,2H),4.07(d,J=13.0Hz,1H),3.31 -3.21(m,2H),3.18(s,3H),2.37-2.26(m,5H),2.18(d,J=3.7Hz,2H),1.85(dd,J=13.6,1.5Hz,2H),1.81(d,J=0.8Hz,3H),1.57-1 .44(m,4H),1.36-1.26(m,2H),1.05-0.96(m,1H),1.02-1.05(t,J=7.3Hz,3H)0.83(t,J=7.3Hz,3H),0.55(td,J=8.2,4.3Hz,1H).

[0088] Step 7 Compound 3g (50 mg, 0.08 mmol) was dissolved in a mixture of 95% ethanol (3 mL) and 6 M hydrochloric acid (3 mL) and reacted at 75 °C for 3 hours. LC-MS showed that 80% of the product was produced. After the reaction was complete, the pH of the system was adjusted to 8 with 5 M sodium hydroxide solution, then to 5 with 0.5 M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase medium-pressure preparative separation (water / acetonitrile system) and further purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the final compound 3 (30 mg, 0.05 mmol, yield: 63%, HPLC purity: 97.3%). MS-ESI calculated values ​​of [M+H] were + The calculated value was 605.3, and the actual measured value was 605.2. 1H NMR(400 MHz,DMSO-d6)δ10.48(s,1H),8.09-8.03(m,1H),7.63(pd,J=7.4,1.6Hz,2H),7.24-7.13(m,2H),7.0 5-6.87(m,2H),4.68(s,2H),4.00(s,2H),3.28-3.13(m,2H),2.32(t,J=7.4Hz,2H),2.23-2.16(m,2H) ,2.21(s,3H),1.86(dd,J=13.6,1.5Hz,2H),1.67(s,3H),1.54-1.43(m,4H),1.27(dt,J=14.1,7.2Hz, 3H),1.07(q,J=4.1Hz,1H),1.02(t,J=7.0Hz,3H),0.82(t,J=7.4Hz,3H),0.55(td,J=8.2,4.3Hz,1H).

[0089] Single crystal growth method for final product 3 in Example 3: 20 mg of solid was weighed and placed in an ampoule containing a mixture of 1 ml of ethyl acetate and 2 ml of n-hexane. Cotton was placed in the bottle's neck to slow the evaporation rate. The mixture was left to stand at room temperature to evaporate the solvent, and crystals were obtained after two days. The experimental parameters and results obtained by X-ray single crystal diffraction analysis are as follows. Analysis revealed that the configuration of compound 3 is as shown in Figure 1, which is consistent with that of final product 3 in Example 3.

[0090] TIFF0007735563000048.tif167169

[0091] Example 4 [ka]

[0092] Step 1 Compound 3f-2 (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (2 mL) and cooled to 0 °C. Sodium hydride (60%, 12 mg, 0.31 mmol) was added and stirred for 30 minutes. Compound 1h (114 mg, 0.22 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise and the reaction was continued for 5 hours. After completion of the reaction was monitored by LC-MS, the system was poured into saturated ammonium chloride (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 4a (85.0 mg, 0.13 mmol, 54% yield). MS-ESI calculated [M+H] + The measured value was 649.3.

[0093] Step 2 Compound 4a (85 mg, 0.13 mmol) was dissolved in a mixture of 95% ethanol (3 mL) and 6 M hydrochloric acid (3 mL) and reacted at 75 °C for 3 hours. LC-MS showed that 80% of the product was produced. After the reaction was complete, the pH of the system was adjusted to 8 with 5 M sodium hydroxide solution, then to 5 with 0.5 M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (ammonium bicarbonate / acetonitrile system) and then by normal-phase column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 4 (53 mg, 0.09 mmol, yield: 69%). MS-ESI calculated values ​​of [M+H] were + The calculated value was 605.3, and the actual measured value was 605.2. 1H NMR(400 MHz,DMSO-d6)δ10.49(s,1H),8.06(dd,J=8.1,1.3Hz,1H),7.63(td,J=7.4,1.6Hz,2H),7.19(dd,J=7.3,1.7Hz,1H ),7.14(d,J=1.7Hz,1H),6.98(dd,J=7.9,1.8Hz,1H),6.94(d,J=7.8Hz,1H),4.73(s,2H),4.00(s,2H),3.28-3.13( m,2H),2.33(t,J=7.4Hz,2H),2.23(s,1H),2.21(s,3H),1.72(d,J=12.9Hz,2H),1.67(s,3H),1.54-1.44(m,4H),1 .32-1.21(m,3H),1.12(q,J=4.1Hz,1H),1.02(t,J=7.0Hz,3H),0.82(t,J=7.3Hz,3H),0.42(td,J=8.0,4.1Hz,1H).

[0094] Example 5 [ka]

[0095] Step 1 Compound 1d (1.00 g, 2.66 mmol), bis(neopentylglycolato)diboron (910 mg, 4.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (110 mg, 0.14 mmol), and potassium acetate (520 mg, 5.31 mmol) were added in this order to a three-necked flask. After purging the air and introducing nitrogen gas using a Schlenk line, dioxane (20 mL) was added and the reaction mixture was heated to reflux with stirring for 3 hours. After completion of the reaction was monitored by LC-MS, the mixture was filtered through diatomaceous earth and concentrated to dryness. The crude product was purified by reverse-phase medium-pressure preparative separation (water / acetonitrile) to give compound 5a (360 mg, 1.06 mmol, 40% yield). 1H NMR(600 MHz,Chloroform-d)δ7.86(d,J=8.0Hz,1H),7.70(d,J=7.4Hz,1H),7.60(td,J=7.5,1.2H z,1H),7.51(td,J=7.7,1.5Hz,1H),5.02(s,2H),3.25(s,3H),2.36(s,3H),1.98(s,3H).

[0096] Step 2 Compound 5b (3.00 g, 10.79 mmol) was dissolved in tetrahydrofuran (anhydrous) (30 mL), and methylamine tetrahydrofuran solution (2 M, 50 mL, 100 mmol) was added to the mixture, followed by stirring at room temperature for 30 minutes. After completion of the reaction was monitored by LC-MS, the reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (160 mL * 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 5c (2.50 g, 10.96 mmol, crude yield: 102%). MS-ESI calculated values ​​of [M+H] + The measured value was 228.0 and the actual value was 228.2.

[0097] Step 3 Compound 5c (2.50 g, 10.96 mmol) was dissolved in tetrahydrofuran (anhydrous) (80 mL) and cooled to 0 °C. Triethylamine (6.80 g, 67.20 mmol) and 3,3-dimethylbutyryl chloride (3.00 g, 22.29 mmol) were added in that order and stirred for 30 minutes while maintaining the temperature. After monitoring the completion of the reaction by LC-MS, the reaction mixture was poured into ice water (80 mL) and extracted with ethyl acetate (160 mL). The organic phase was separated, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:2) to give compound 5d (2.70 g, 8.28 mmol, 76% yield). MS-ESI calculated values ​​of [M+H] were: + The measured value was 326.1, and the actual value was 325.8.

[0098] Step 4 Compound 5d (500 mg, 1.53 mmol) and compound 5a (690 mg, 2.03 mmol) were dissolved in a mixture of toluene (10 mL), water (4 mL), and ethanol (5 mL). Nitrogen gas was bubbled through the mixture for 10 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium (90.0 mg, 0.08 mmol) and sodium carbonate (500 mg, 4.72 mol), in that order. The mixture was stirred at 85 °C for 3 hours. After completion of the reaction was monitored by LC-MS, the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2.5:1) to give compound 5e (102 mg, 0.19 mmol, 12% yield). MS-ESI calculated [M+H] + The calculated value was 542.2, and the actual measured value was 542.1.

[0099] Step 5 Compound 5e (102 mg, 0.19 mmol) was dissolved in methanol (5 mL) and cooled to -40 °C. Sodium borohydride (5.0 mg, 0.13 mmol) was added and stirred for 1 h while maintaining the temperature. After monitoring the completion of the reaction by LC-MS, the system was poured into dilute hydrochloric acid (0.5 M, 15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 5f (91 mg, 0.17 mmol, 89% yield). MS-ESI calculated value [M+H] + The measured value was 544.2.

[0100] Step 6 Compound 5f (91 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (anhydrous) (5 mL) at 0 °C, and carbon tetrabromide (169 mg, 0.51 mmol) and triphenylphosphine (134 mg, 0.51 mmol) were added in this order. The mixture was stirred for 2 hours while maintaining the temperature. After the completion of the reaction was monitored by LC-MS, the system was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether: ethyl acetate = 9:1) to obtain compound 5g (75 mg, 0.12 mmol, yield: 71%). The calculated MS-ESI value was [M+H]. + The calculated value was 606.2, and the actual measured value was 606.1.

[0101] Step 7 Compound 3f-1 (24.0 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL) (anhydrous) at 0 °C, and sodium hydride (60%, 10.6 mg, 0.26 mmol) was added. After stirring for 30 min, a solution of compound 5g (70 mg, 0.12 mmol) in N,N-dimethylformamide (0.5 mL) was added to the mixture. After stirring at room temperature for 3 h and monitoring the completion of the reaction by LC-MS, the mixture was poured into saturated ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 5h (65 mg, 0.09 mmol, yield: 75%). MS-ESI calculated values ​​of [M+H] were obtained. + The measured value was 732.4.

[0102] Step 8 Compound 5h (60 mg, 0.08 mmol) was dissolved in a mixture of ethanol (6 mL) and hydrochloric acid (6 M, 5 mL) and stirred at 75 °C for 3 hours. After monitoring the completion of the reaction by LC-MS, the pH of the system was adjusted to 8 with sodium hydroxide solution (5 M), then adjusted to 5 with dilute hydrochloric acid (0.5 M), extracted with ethyl acetate (20 mL * 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by preparative chromatography (water, acetonitrile) to give compound 5 (30 mg, 0.04 mmol, yield: 50%, HPLC purity: 98.2%). MS-ESI calculated values ​​of [M+H] + The measured value was 688.4. 1 H NMR(600 MHz,DMSO-d6)δ10.63(s,1H),8.13-7.98(m,1H),7.76-7.54(m,2H),7.24(t,J=8.1Hz,1H) ,7.12-6.88(m,2H),6.83-6.65(m,1H),4.78-4.54(m,2H),4.40-3.99(m,2H),2.80-2.59( m,3H),2.35-2.10(m,8H),1.97-1.87(m,1H),1.87-1.79(m,2H),1.77-1.68(m,3H),1.59- 1.37(m,4H),1.32-1.17(m,2H),1.14-1.02(m,1H),1.01-0.75(m,12H),0.61-0.48(m,1H).

[0103] Example 6 [ka]

[0104] Step 1 Compound 3f-2 (26.0 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (anhydrous) (1.2 mL) at 0 °C, sodium hydride (60%, 11.2 mg, 0.28 mmol) was added, and the mixture was stirred for 30 min. Then, a solution of compound 5g (75 mg, 0.12 mmol) in N,N-dimethylformamide (0.7 mL) was added to the mixture. After stirring at room temperature for 3 h and monitoring the completion of the reaction by LC-MS, the mixture was poured into saturated ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 6a (67 mg, 0.09 mmol, yield: 69%). The calculated MS-ESI value for [M+H] was 0.09 mg. + The calculated value was 732.4, and the actual measured value was 732.3.

[0105] Step 2 Compound 6a (65 mg, 0.09 mmol) was dissolved in a mixture of ethanol (5 mL) and hydrochloric acid (6 M, 5 mL) and stirred at 75 °C for 3 hours. After monitoring the completion of the reaction by LC-MS, the pH of the system was adjusted to 8 with sodium hydroxide solution (5 M), then adjusted to 5 with dilute hydrochloric acid (0.5 M), extracted with ethyl acetate (20 mL * 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by preparative chromatography (ammonium bicarbonate:acetonitrile) to give compound 6 (37 mg, 0.05 mmol, yield: 56%, HPLC purity: 99.0%). MS-ESI calculated value [M+H] + The measured value was 688.4. 1H NMR(600 MHz,Methanol-d4)δ8.35-7.98(m,1H),7.73-7.39(m,2H),7.23-7.10(m,1H),7.1 0-6.96(m,2H),6.94-6.72(m,1H),4.82-4.70(m,2H),4.62-4.14(m,2H),2.95-2.7 2(m,3H),2.51-2.24(m,5H),2.24-1.93(m,4H),1.87-1.77(m,2H),1.75-1.66(m, 3H),1.61-1.46(m,4H),1.42-1.25(m,2H),1.11-0.80(m,13H),0.61-0.33(m,1H).

[0106] Example 7 [ka]

[0107] Step 1 Under nitrogen gas protection, compound 1b (30 g, 0.12 mol), bis(pinacolato)diboron (32.9 g, 0.13 mol), potassium acetate (24.2 g, 0.25 mol), and [1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex] (5.0 g, 6.22 mmol) were added to a dioxane solution (800 mL) in this order and refluxed for 16 h. After completion of the reaction was monitored by TLC, the mixture was filtered through diatomaceous earth to remove solids, concentrated under reduced pressure to remove dioxane, transferred to water (400 mL), extracted with ethyl acetate (300 mL*3), and the combined organic phases were washed with saturated brine (300 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 7a (56 g).

[0108] Step 2 Under nitrogen gas protection, compound 7b (980 mg, 10.00 mmol) was dissolved in dichloromethane (15 mL) and cooled to 0 °C. N-chlorosuccinimide (1.46 g, 10.93 mmol) was slowly added to the system and the reaction was continued at this temperature for 2 hours. Sodium hydroxide solution (1 M, 10 mL) was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (15 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 7c (712 mg, 5.37 mmol, yield: 54%). MS-ESI [M+H] + The actual measured value was 133.1.

[0109] Step 3 Compound 7c (500 mg, 3.77 mmol), 2-bromobenzenesulfonyl chloride (962 mg, 3.76 mmol), and 4-dimethylaminopyridine (62.0 mg, 0.51 mmol) were added to pyridine (15 mL) in this order at 0 °C. The mixture was stirred for 10 min, then heated to 40 °C and reacted for 12 h. After completion of the reaction was monitored by LC-MS, the system was transferred to an ice bath, the pH was adjusted to 6 with glacial hydrochloric acid (1 M), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 7d (1.3 g, 3.70 mmol, 98% yield). MS-ESI [M+H] + The actual measured value was 351.1.

[0110] Step 4 Compound 7d (1.3 g, 3.70 mmol) was dissolved in N,N-dimethylformamide (10 mL) at -15°C, and sodium hydride (60%, 171 mg, 4.28 mmol) was added in portions. After stirring for 5 minutes, the mixture was warmed to room temperature and reacted for 30 minutes. Next, the system was cooled to -15°C, and bromomethyl methyl ether (600 mg, 4.80 mmol) was added dropwise. After stirring for 5 minutes, the mixture was allowed to warm naturally and reacted for 30 minutes. The completion of the reaction was confirmed by LC-MS. The reaction mixture was transferred to an ice bath, and cold water (40 mL) was added to quench the reaction. The pH was adjusted to 7 with 0.5 M hydrochloric acid, and the mixture was extracted with ethyl acetate (15 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 7e (777 mg, 1.96 mmol, yield: 53%). MS-ESI [M+H] + The actual measured value was 394.9.

[0111] Step 5 Under nitrogen gas protection, compound 7e (300 mg, 0.76 mmol), compound 7a (220 mg, 0.76 mmol), tetrakis(triphenylphosphine)palladium (114 mg, 0.099 mmol), and sodium carbonate (402 mg, 3.79 mmol) were added, in this order, to a mixture of toluene (15 mL), water (15 mL), and ethanol (15 mL). The reaction mixture was incubated at 85°C for 2 hours. After completion of the reaction was monitored by LC-MS, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 7f (255 mg, 0.53 mmol, yield: 70%). MS-ESI [M+H] + The actual measured value was 479.0.

[0112] Step 6 Compound 7f (235 mg, 0.49 mmol) was dissolved in methanol (5 mL) at 0 °C, and sodium borohydride (29.8 mg, 0.79 mmol) was added. After 5 minutes, the system was heated to 25 °C and reacted for 1 hour. The system was transferred to an ice bath, and ice water (30 mL) was added. The pH was adjusted to 7 with hydrochloric acid (1 M), and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 7g (237 mg), which was used directly in the next step. MS-ESI [M+H] + The actual measured value was 481.0.

[0113] Step 7 Compound 7g (237 mg), carbon tetrabromide (243 mg, 0.73 mmol), and triphenylphosphine (194 mg, 0.74 mmol) were added to N,N-dimethylformamide (5 mL) in this order at 0 °C, and the reaction was continued for 2 h while maintaining this temperature. After complete reaction was confirmed by LC-MS, ice water (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 7h (172 mg, 0.32 mmol, 65% yield for both steps). MS-ESI [M+H] + The actual measured value was 543.3.

[0114] Step 8 At 0 ° C, compound 3f-1 (25.0 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (anhydrous) (2 mL), sodium hydride (60%, 5.34 mg, 0.13 mmol) was added, and the mixture was stirred for 5 minutes, then warmed to room temperature and stirred for 30 minutes. The mixture was then transferred to an ice bath, and a solution of compound 7h (55 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was slowly added dropwise to the reaction mixture. After 5 minutes, the mixture was warmed to room temperature and reacted for 1 hour. After LC-MS showed that the raw materials had completely reacted, ice water (30 mL) was added to the mixture, and the pH was adjusted to 7 with hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (3 x 10 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 7i (67.0 mg, 0.10 mmol, yield: 100%). MS-ESI [M+H] + The actual measured value was 669.1.

[0115] Step 9 Compound 7i (67.0 mg, 0.10 mmol) was dissolved in absolute ethanol (2.5 mL), hydrochloric acid (6N, 2.5 mL) was added, and the mixture was heated at 40 °C for 1 h. After completion of the reaction was monitored by LC-MS, the system was transferred to an ice bath, the pH was adjusted to 7 with solid sodium bicarbonate, and extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by reverse-phase chromatography (ammonium bicarbonate / acetonitrile system) to give compound 7 (31 mg, 0.05 mmol, 50% yield). MS-ESI [M+H] + The actual measured value was 625.2. 1H NMR(600 MHz,Chloroform-d)δ8.28(dd,J=8.0,1.4Hz,1H),7.62(td,J=7.5,1.4Hz,1H),7.57(td,J=7.8,1.5Hz,1H),7.35(d,J=2.0Hz,1H),7.25(dd ,J=7.5,1.4Hz,1H),7.10(d,J=7.7Hz,1H),7.05(dd,J=7.8,1.9Hz,1H),4.69(d,J=2.3Hz,2H),4.16(d,J=12.4Hz,1H),4.08(d,J=12.3Hz,1 H),3.33(ttd,J=9.4,7.0,2.3Hz,2H),2.34(d,J=9.0Hz,6H),2.31(d,J=4.0Hz,1H),1.98(dd,J=13.8,2.4Hz,2H),1.65(tt,J=9.1,6.9Hz,2 H),1.58-1.52(m,2H),1.42-1.31(m,2H),1.09(t,J=7.0Hz,3H),1.06(q,J=4.3Hz,1H),0.91(t,J=7.4Hz,3H),0.66(td,J=8.2,4.7Hz,1H).

[0116] The effects of the compounds of the present invention will be explained below using test examples.

[0117] Test Example 1: Calcium flux assay using AT1

[0118] Test materials: a) Cell line: AT1 / HEK293; b) Media: F12, Invitrogen (Cat#11765-047); FBS, Corning (Cat# 35-076-CV); Geneticin, Invitrogen (Cat#10131); c) Reagents: Fluo-4 Direct, (Invitrogen,Cat# F10471); d) Equipment: 384 well Poly-D-Lysine protein coating plate, Greiner#781946; Vi-cell XR Cell Viability Analyzer, Beckman Coulter; Incubator,Thermo;

[0119] Test Method: For the agonist (angiotensin II) master plate, the agonist solution was diluted from 1 mM to 200 μM in test buffer. For the antagonist (Losartan) and compound plates, the antagonist and test compound were gradient diluted 1:4 with DMSO to obtain 10 concentration points. Then, 900 nL of the compound solution was transferred to the master plate and 30 μL of test buffer was added. a) The cell plate was removed from the incubator and 20 μL of 2X Fluo-4 Direct was pipetted into the 384-well cell culture plate. b) The cell plate was incubated at 37°C in a 5% CO2 environment for 50 minutes, followed by incubation at room temperature for 10 minutes. c) The cell plate was removed from the incubator and placed in the FLIPR. The compound plate and tipbox were placed in the FLIPR. d) For EC80 plates: 1) The operation was performed on FLIPRTETRA. 2) 10 μL of compound was transferred from the EC80 master plate to the cell plate. 3) The fluorescent signal was read. 4) The read signals were calculated, and the EC80 value of each cell line was calculated using FLIPR. 5) For compound plate concentrations, solutions were prepared at concentrations that were 6 times the EC80 concentration of the reference agonist. e) For compound plates: 1) The operation was performed on FLIPRTETRA. 2) 10 μL of compound was transferred to the cell plate. 3) The fluorescent signal was read. 4) 10 μL of a solution containing 6 times the EC80 concentration of the reference agonist was transferred. 5) The fluorescent signal was read. f) Data were analyzed using Prism.

[0120] Table 1 (AT1 activity IC 50+ represents 100 nM to 1 μM, ++ represents 10 nM to 100 nM, and +++ represents 1 nM to 10 nM. Specific activities are shown in the third column of Table 1. [Table 1]

[0121] Test Example 2: Calcium flux assay using ETa

[0122] Test materials: a) Cell line: ETa / HEK293; b) Media: DMEM, Invitrogen (Cat#11960); Geneticin, Invitrogen(Cat# 10131); c) Reagents: Fluo-4 Direct, (Invitrogen, Cat# F10471); d) Equipment: 384 well Poly-D-Lysine protein coating plate, Greiner #781946; Vi-cell XR Cell Viability Analyzer, Beckman Coulter; Incubator, Thermo.

[0123] Test Method: For the agonist used, endothelin-1 (ET-1) master plate, the agonist was diluted from 50 μM to 15 μM in the buffer used in the test. For the antagonist (BQ123, Am J Physiol. 1994 Apr;266(4 Pt 2):H1327-31.) and compound plates, the antagonist and test compound were diluted 1:4 with DMSO to obtain 10 concentration points. 900 nL of compound was then transferred to the master plate, and 30 μL of test buffer was added. a) Remove cell lines from the incubator and gently pipette 20 μL of 2X Fluo-4 Direct™ Buffer into a 384-well cell culture plate. b) The cell plate was incubated at 37°C in a 5% CO2 environment for 50 minutes, followed by incubation at room temperature for 10 minutes. c) The cell plate was removed from the incubator and placed in the FLIPR. The compound plate and tipbox were placed in the FLIPR. d) EC80 plate 1) The operation was performed on FLIPRTETRA. 2) 10 μL of compound was transferred from the EC80 master plate to the cell plate. 3) The fluorescent signal was read. 4) The read signals were calculated, and the EC80 value of each cell line was calculated using FLIPR. 5) For compound plate concentrations, solutions were prepared at concentrations that were 6 times the EC80 concentration of the reference agonist. e) For compound plates: 1) The operation was performed on FLIPRTETRA. 2) 10 μL of compound was transferred to the cell plate. 3) The fluorescent signal was read. 4) 10 μL of a solution at a concentration six times the EC80 concentration of the reference agonist was transferred to the cell plate. 5) The fluorescent signal was read. f) Data were analyzed using Prism.

[0124] Table 2 (ETa activity IC 50 + represents 100 nM to 1 μM, ++ represents 10 nM to 100 nM, and +++ represents 1 nM to 10 nM. Specific activities are shown in the third column of Table 2. [Table 2]

[0125] Test Example 3: Water Solubility Test This measurement is performed in accordance with the high-performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Four Parts General Rules 0512). Chromatographic conditions for HPLC-UV method: Mobile phase: 0.02M KH2PO4 aqueous solution - acetonitrile (90:10), gradient elution; Chromatographic column: C 18; Measurement wavelength: 210 nm. Calculations were made using the peak area using the external standard method.

[0126] [Table 3]

[0127] Conclusion: Most of the specific compounds prepared in this invention have better water solubility than the control compounds under various test conditions.

[0128] Test Example 4: Inhibitory effect on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4)

[0129] Six specific probe substrates for six CYP isozymes were used: α-naphthoflavone (CYP1A2), sulfaphenazole (CYP2C9), ticlopidine (CYP2C19), quinidine (CYP2D6), ketoconazole (CYP3A4), and montelukast (CYP2C8). Each sample was incubated with recombinant liver enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP2C8 and the test compound, and the reaction was initiated by adding nicotinamide adenine dinucleotide phosphate (NADP+), D-glucose-6-phosphate (G6P), and glucose-6-phosphate dehydrogenase (G6DHP). After the reaction was completed, the corresponding half-maximal inhibitory concentrations (IC) were determined by fluorescence detection (Ex 490 nm / Em 520 nm). 50 ) was calculated.

[0130] [Table 4]

[0131] Conclusion: Spencentan exhibited inhibitory effects on CYP3A4 and CYP2C8 without the risk of inhibiting the activity of human hepatic microsomal cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, and CYP2D6. The compound of Example 3 exhibited inhibitory effects on CYP3A4 only without the risk of inhibiting the activity of human hepatic microsomal cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP2C8. The compound of Example 7 was found to exhibit no risk of inhibiting the activity of any of the human hepatic microsomal cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2C8.

[0132] Based on the above data, the compounds of Examples 3 and 7 are predicted to have a lower DDI (drug interaction) risk in clinical use.

[0133] Test Example 5: In vivo pharmacokinetics test in rats

[0134] Experimental animals: SD rats, 6 to 8 weeks old. Six animals were used for each example compound.

[0135] Preparation of pharmaceutical solutions: All test example compounds were formulated to a 1 mg / mL solution in a solution system of 5% DMSO + 20% Solutol HS15 + 75% (20% HP-β-CD in water).

[0136] Administration and grouping: Group 1 was administered orally by gavage (PO, 3 SD rats, 10 mg / kg, fasted overnight before administration and fed 4 hours after administration), and Group 2 was administered intravenously via the dorsum of the foot (IV, 3 SD rats, 1 mg / kg, food ad libitum).

[0137] Blood collection and processing: Blood samples were collected from the jugular vein at 7 to 8 time points: 0.083 (intravenous administration group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours. Blood samples were centrifuged (2000 g, 4°C, 5 minutes) to obtain plasma. Samples were stored at -70°C until analysis.

[0138] Analytical equipment and conditions: LC-MS / MS-33 (Triple Quad 6500+); MS: positive, ESI; Mobile phase: Mobile phase A: H2O-0.025% FA-1 mM NH4OAc, Mobile phase B: MeOH-0.025% FA-1 mM NH4OAc; Flow rate: 0.60 mL / min; Chromatographic column: ACQUITY UPLC-BEH C 18 (2.1 × 50 mm, 1.7 μm); column temperature: 60°C.

[0139] Table 5: Oral (PO) Pharmacokinetic Parameters [Table 5]

[0140] Conclusion: After oral administration of the compounds of Examples 3 and 7 of the present application, the oral administration group was able to obtain higher in vivo exposure and higher oral bioavailability, and it was found that the compounds of Examples 3 and 7 have better pharmacokinetic properties than the control compound.

[0141] The above is merely a more preferred embodiment of the present invention, and the scope of the present invention is not limited to the above embodiment. Any equivalent modifications or changes made by a person skilled in the art based on the disclosure of the present invention should be included in the scope of the claims.

Claims

Claim 1: Formula I, Formula IIa, or Formula IIb: 【Chemical 1】 (Wherein, X is NR Ｘ１ and Y is a chemical bond; R Ｘ１ is -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ alkylene-(3- to 10-membered carbocyclyl), -C ０～４ alkylene-(4- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), —C ０～４ alkylene-(5- to 10-membered aromatic heterocycle), provided that alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further comprise one, two, three, or four independent R Ｘ１１ may be substituted with Each R Ｘ１１ are each independently hydrogen, halogen, a cyano group, or —C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR Ｘ１２ , -C ０～４ Alkylene-SR Ｘ１２ , -C ０～４ Alkylene -NR Ｘ１２ R Ｘ１３ or two independent R Ｘ１１ together with the atoms directly bonded to it 【Chemistry 2】 Forming R Ｘ１２ , R Ｘ１３ are each independently hydrogen, —C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, R １ is -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, R ２ Below: 【Chemistry 3】 and R ３ , R ４ are each independently hydrogen, —C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ alkylene-(3- to 10-membered carbocyclyl), -C ０～４ alkylene-(4- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), —C ０～４ alkylene-(5- to 10-membered aromatic heterocycle), provided that the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further comprise one, two, three, or four independent R ３１ may be substituted with Each R ３１ are each independently hydrogen, halogen, a cyano group, or —C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR ３２ , -C ０～４ Alkylene-SR ３２ , -C ０～４ Alkylene -NR ３２ R ３３ , -C ０～４ Alkylene -OC(O)R ３２ , -C ０～４ Alkylene-S(O) ２ R ３２ , -C ０～４ Alkylene-S(O)R ３２ , -C ０～４ Alkylene-S(O) ２ NR ３２ R ３３ , -C ０～４ Alkylene-S(O)NR ３２ R ３３ , -C ０～４ Alkylene -C(O)R ３２ , -C ０～４ Alkylene -C(O)OR ３２ , -C ０～４ Alkylene-C(O)NR ３２ R ３３ , -C ０～４ Alkylene -NR ３２ C(O)R ３３ , -C ０～４ Alkylene -NR ３２ S (O) ２ R ３３ , -C ０～４ Alkylene -NR ３２ S(O)R ３３ , -C ０～４ alkylene-(3- to 10-membered carbocyclyl), -C ０～４ alkylene-(4- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), —C ０～４ alkylene-(5- to 10-membered aromatic heterocycle), or two independent R ３１ together with the atoms directly bonded to it 【Chemistry 4】 Forming R ３２ , R ３３ are each independently hydrogen, —C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, m1 and m2 are each independently selected from 1, 2, or 3; m3 is selected from 1, 2, 3, 4, or 5; n1 and n2 are each independently selected from 1, 2, or 3, and n3 is selected from 2, 3, 4, or 5. or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

2. R １ is selected from n-butyl, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. R ３ is -C ０～２ alkylene-(3- to 10-membered carbocyclyl), -C ０～２ alkylene-(4- to 10-membered heterocycloalkyl), —C ０～２ alkylene-(6- to 10-membered aromatic ring), —C ０～２ alkylene-(5- to 10-membered aromatic heterocycle), provided that alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further comprise one, two, three, or four independent R ３１ may be substituted with Each R ３１ are each independently hydrogen, halogen, a cyano group, or —C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl; or two independent R ３１ together with the atoms directly bonded to it 【Chemistry 5】 Forming R ４ is hydrogen, -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ 2. The compound of claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkynyl, ...

4. R ３ is selected from 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 8-membered carbocyclyl, 9-membered carbocyclyl, 10-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 7-membered aromatic heterocycle, 8-membered aromatic heterocycle, 9-membered aromatic heterocycle, 8-membered aromatic heterocycle, with the proviso that the carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further be selected from one, two, three, or four independent R ３１ may be substituted with R ４ is hydrogen, -C １～６ 4. The compound of claim 3, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl, aryl, arylsulfonyl ...

5. R ３ teeth, 【Chemistry 6】 【Chemistry 7】 is selected from, where R ３ The ring selected as ３１ 5. The compound according to claim 4, wherein the compound is optionally substituted with:

6. R ３ teeth, 【Chemistry 8】 【Chemistry 9】 6. The compound according to claim 5, wherein the compound is selected from the group consisting of:

7. X is NR Ｘ１ is selected from R Ｘ１ is -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～２ Alkyl-(3- to 10-membered carbocyclyl), -C ０～２ alkyl-(4- to 10-membered heterocycloalkyl), —C ０～２ Alkyl-(6- to 10-membered aromatic ring), —C ０～２ The compound according to claim 1, wherein the compound is selected from alkyl-(5- to 10-membered aromatic heterocycle), or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. R Ｘ１ is -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ The compound according to claim 7, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from alkynyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 8-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, benzene ring, 5-membered aromatic heterocycle, and 6-membered aromatic heterocycle.

9. R Ｘ１ teeth, 【Chemistry 10】 【Chemistry 11】 or 【Chemistry 12】 9. The compound of claim 8, wherein the compound is selected from the group consisting of:

10. The following: 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. 10. A pharmaceutical composition comprising a formulation prepared from the compound of claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

12. 12. The pharmaceutical composition of claim 11, further comprising a pharmaceutically acceptable carrier, excipient, or vehicle.

13. A compound represented by formula IIIa or IIIb, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 16】 (In the formula, R １ is -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl or halogen-substituted —C ２～６ alkynyl, m1 and m2 are each independently selected from 1, 2, or 3, m3 is selected from 1, 2, 3, 4, or 5, n1 and n2 are each independently selected from 1, 2, or 3, and n3 is selected from 2, 3, 4, or 5.

14. The compound according to claim 13, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is n-butyl.

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