A dual antagonist and uses thereof

Abstract

Provided are novel compounds having both angiotensin II receptor and endothelin receptor dual antagonistic effects represented by formula (I) and their use in the preparation of medicaments.

Description

[0001] Citation of relevant applications

[0002] This invention claims priority to Chinese patent application No. 202111228856.0, filed on October 21, 2021, entitled "A dual antagonist and its use therein", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a class of novel compounds with dual antagonistic effects on angiotensin II receptors and endothelin receptors, and their use in the preparation of pharmaceuticals. Background Technology

[0004] Angiotensin II (AngII) and endothelin-1 (ET-1) are two potent endogenous vasoactive peptides believed to play roles in controlling vascular tone and pathological tissue remodeling associated with various diseases. There are four subtypes of angiotensin II receptors: AT1, AT2, AT3, and AT4. AT1 and AT2 are predominant, with AT1 receptors mediating almost all pathophysiological functions of angiotensin II receptors. Angiotensin II receptor antagonists, as systemic antihypertensive drugs, have demonstrated advantages such as high affinity, high selectivity, oral efficacy, long half-life, and good tolerability. Endothelin is a potent vasoconstrictive vasoactive peptide that plays a crucial role in maintaining vascular homeostasis. Current technologies have identified various endothelin receptors (such as ETA, ETB1, ETB2, and ETC), among which ETA has been the most extensively studied, and its antagonists can be used to treat hypertension, pulmonary hypertension, chronic kidney disease, and atherosclerosis.

[0005] Preclinical and initial clinical data suggest that simultaneous blockade of angiotensin II and endothelin 1 at their respective receptors AT1 and ETA may offer improved treatment options for several cardiovascular diseases compared to using either mechanism alone. Dual antagonists of angiotensin II and endothelin receptors exhibit antagonistic effects against both receptors, demonstrating better efficacy and broader applicability than single angiotensin II or ETA receptor antagonists, representing a potential class of drugs for conditions such as hypertension or kidney disease. While a series of dual antagonists of angiotensin II and endothelin receptors have been disclosed in publications such as WO2000001389A1 and CN101891735A, further development is needed to develop dual antagonist drugs with better activity, higher selectivity, better water solubility, and fewer drug-drug interactions. Summary of the Invention

[0006] This invention provides a compound of Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] X is selected from NR X1 or CR X2 R X3 ;

[0010] Y is selected from chemical bonds, NR Y1 or CR Y2 R Y3 ;

[0011] R Y1 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered aromatic heterocycles);

[0012] R Y2 R Y3 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered aromatic heterocycles);

[0013] R X1 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4Alkylene-(3- to 10-membered carbon cycloyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered aromatic heterocycle); wherein the alkylene, carbocyclic, heterocyclic, aromatic ring, or aromatic heterocycle may be optionally surrounded by one, two, three, or four independent R groups. X11 replace;

[0014] Each R X11 Each group is independently selected from hydrogen, halogen, cyano, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR X12 -C 0～4 Alkylene-SR X12 -C 0～4 Alkylene-NR X12 R X13 Or, two independent Rs X11 Formed together with the adjacent atoms

[0015] R X12 R X13 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0016] R X2 R X3 Together with the atoms directly bonded to it, it forms 6-12 membered spirocyclic rings, 6-12 membered spiroheterocyclic rings, 6-12 membered fused rings, and 6-12 membered fused heterocyclic rings; wherein, the spirocyclic ring, spiroheterocyclic ring, fused ring, and fused heterocyclic ring can be further optionally bonded by one, two, three, or four independent R atoms. X21 replace;

[0017] Each R X21 Each group is independently selected from hydrogen, halogen, cyano, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR X22 -C 0～4 Alkylene-SR X22 -C 0～4 Alkylene-NR X22 R X23 Or, two independent Rs X21 It forms together with the atoms directly connected to it.

[0018] R X22 R X23 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0019] R 1 Selected from -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0020] R 2 Selected from -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -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)2R 21 -C 0～4 Alkylene-S(O)R 21 -C 0～4 Alkylene-S(O)2NR 21 R 22 -C0～4 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 32 -C 0～4 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered aromatic heterocycles);

[0021] R 21 R 22 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered aromatic heterocycles);

[0022] R 3 R 4 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～4Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered aromatic heterocycle); wherein the alkylene, carbocyclic, heterocyclic, aromatic ring, or aromatic heterocycle may be optionally surrounded by one, two, three, or four independent R groups. 31 replace;

[0023] Each R 31 Each group is independently selected from hydrogen, halogen, cyano, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -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)2R 32 -C 0～4 Alkylene-S(O)R 32 -C 0～4 Alkylene-S(O)2NR 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)2R 33 -C 0～4 Alkylene-NR 32 S(O)R 33 -C 0～4 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～4Alkylene (4- to 10-membered heterocyclic alkyl), -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 It forms together with the atoms directly connected to it.

[0024] R 32 R 33 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkyne group.

[0025] Furthermore, R 1 Selected from n-butyl.

[0026] Furthermore,

[0027] R 2 Selected from -C 1～2 Alkylene-OR 21 -C 1～2 Alkylene-SR 21 -C 1～2 Alkylene-NR 21 R 22 -C 1～2 Alkylene-OC(O)R 21 -C 1～2 Alkylene-S(O)2R 21 -C 1～2 Alkylene-S(O)R 21 -C 1～2 Alkylene-S(O)2NR 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 32 -C 1～2 Alkylene-NR 21 C(O)R 22 -C 1～2 Alkylene-NR 21 S(O)2R22 -C 1～2 Alkylene-NR 21 S(O)R 32 ;

[0028] R 21 R 22 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～2 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～2 Alkylene-(4- to 10-membered heterocyclic alkyl).

[0029] Furthermore,

[0030] R 2 Selected from

[0031] R 21 R 22 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 6-membered carbon cyclo group).

[0032] To be more specific,

[0033] R 2 Selected from

[0034] Furthermore,

[0035] R 3 Selected from -C 0～2 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～2 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein the alkylene, carbocyclic, heterocyclic, aromatic ring, or aromatic heterocycle may be optionally surrounded by one, two, three, or four independent R groups. 31 replace;

[0036] Each R 31 Each group is independently selected from hydrogen, halogen, cyano, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkyne group; or, two independent R groups. 31 It forms together with the atoms directly connected to it.

[0037] R 4 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkyne group.

[0038] Furthermore,

[0039] R 3 Selected from 3-membered carbocyclic groups, 4-membered carbocyclic groups, 5-membered carbocyclic groups, 6-membered carbocyclic groups, 7-membered carbocyclic groups, 8-membered carbocyclic groups, 9-membered carbocyclic groups, 10-membered carbocyclic groups, 4-membered heterocyclic alkyl groups, 5-membered heterocyclic alkyl groups, 6-membered heterocyclic alkyl groups, 7-membered heterocyclic alkyl groups, 8-membered heterocyclic alkyl groups, 9-membered heterocyclic alkyl groups, 10-membered aromatic rings, 5-membered aromatic heterocycles, 6-membered aromatic heterocycles, 7-membered aromatic heterocycles, 8-membered aromatic heterocycles, 9-membered aromatic heterocycles, and 8-membered aromatic heterocycles; wherein the carbocyclic group, heterocyclic alkyl group, aromatic ring, and aromatic heterocycle may be further optionally separated by one, two, three, or four independent R groups. 31 replace;

[0040] R 4 Selected from hydrogen, -C 1～6 alkyl.

[0041] To be more specific,

[0042] R 3 Selected from Among them, R 3 The selected rings can be further arbitrarily selected by one, two, three or four independent Rs. 31 replace.

[0043] To be more specific,

[0044] R 3 Selected from

[0045] Furthermore,

[0046] X is selected from NR X1 ;

[0047] R X1 Selected from -C 1～6Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～2 Alkyl-(3- to 10-membered carbon cycloyl), -C 0～2 Alkyl-(4- to 10-membered heterocyclic alkyl), -C 0～2 Alkyl-(6- to 10-membered aromatic rings), -C 0～2 Alkyl-(5-10 membered aromatic heterocycles).

[0048] Furthermore,

[0049] R X1 Selected from -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne group, 3-membered carbon cycloyl group, 4-membered carbon cycloyl group, 5-membered carbon cycloyl group, 6-membered carbon cycloyl group, 7-membered carbon cycloyl group, 8-membered carbon cycloyl group, 4-membered heterocyclic alkyl group, 5-membered heterocyclic alkyl group, 6-membered heterocyclic alkyl group, 7-membered heterocyclic alkyl group, 8-membered heterocyclic alkyl group, benzene ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle.

[0050] To be more specific,

[0051] R X1 Selected from

[0052] Furthermore, the compounds of formula I are shown in formula IIa:

[0053]

[0054] in,

[0055] m1 and m2 are each independently selected from 0, 1, 2 or 3;

[0056] m3 is selected from 1, 2, 3, 4 or 5.

[0057] Furthermore, the compounds of formula I are as shown in formula IIb:

[0058]

[0059] in,

[0060] n1 and n2 are independently selected from 0, 1, 2 or 3 respectively;

[0061] n3 is selected from 1, 2, 3, 4 or 5.

[0062] In some specific embodiments of the present invention, the compound is specifically:

[0063]

[0064]

[0065]

[0066]

[0067] The present invention also provides the use of any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, in the preparation of angiotensin II receptor and endothelin receptor dual antagonist drugs.

[0068] The present invention also provides the use of any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, in the preparation of medicaments for treating diseases related to cardiovascular and cerebrovascular diseases, including hypertension, kidney diseases, and diabetes-related organ damage.

[0069] The present invention also provides a pharmaceutical composition comprising any of the above-mentioned compounds, or their deuterated compounds, stereoisomers, or pharmaceutically acceptable salts thereof, as preparations.

[0070] The aforementioned pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and mediators.

[0071] The present invention also provides a method for treating conditions related to angiotensin II receptor and endothelin receptor, the method comprising administering to a subject in need an effective amount of any of the compounds described above, or their deuterated compounds, stereoisomers, or pharmaceutically acceptable salts thereof, or any of the above combinations thereof; preferably, the conditions include cardiovascular and cerebrovascular diseases including hypertension, kidney diseases, and diseases related to organ damage associated with diabetes.

[0072] The present invention also provides compounds represented by formula IIIa or IIIb, or their deuterated compounds, stereoisomers, or pharmaceutically acceptable salts thereof:

[0073] Wherein m1, m2, m3, n1, n2, and n3 are defined as described above in this invention; R 1 Selected from -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6The alkynyl group is preferably selected from n-butyl; m1 and m2 are independently selected from 0, 1, 2, or 3, respectively; m3 is selected from 1, 2, 3, 4, or 5; n1 and n2 are independently selected from 0, 1, 2, or 3, respectively; n3 is selected from 1, 2, 3, 4, or 5. Preferably, the compounds represented by formula IIIa or IIIb are selected from...

[0074] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0075] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0076] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups; or the replacement of lone pairs of electrons in an atom by other atoms or groups, for example, the lone pair of electrons on a sulfur atom can be replaced by an oxygen atom to form a hydrogen atom.

[0077] "Optionally replaceable" means that "replacement" may but does not have to occur, and this statement includes situations in which it may or may not occur.

[0078] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups indicate any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, C 1～6 Alkyl groups are alkyl groups containing 1 to 6 carbon atoms.

[0079] "alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally 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 groups may also be part of other groups, such as -O(C) 1～6 alkyl).

[0080] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of member atoms. C 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" can be exemplified by the following structures: Similarly, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0081] The present invention -C 0～4 The alkylene group can be C0 alkylene, C1 alkylene (e.g., -CH2-), C2 alkylene (e.g., -CH2CH2-), C3 alkylene, or C4 alkylene; C0 alkylene refers to the absence of a group here, which is connected by a chemical bond. For example, A-C0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.

[0082] In this invention, "carbocyclic group" refers to a saturated or non-aromatic partially saturated cyclic group having a single ring or multiple rings (fused, bridged, spirofused) with multiple carbon atoms and no cyclic heteroatoms. The term "carbocyclic group" includes cycloalkenyl groups, such as cyclohexenyl. Examples of monocarbonyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of carbocyclic groups in fused carbocyclic systems include dicyclohexyl, dicyclopentyl, dicyclooctyl, etc. Two such dicycloalkyl polycyclic structures are exemplified and named below: Dicyclohexyl and Dicyclohexyl. Examples of carbocyclic groups in bridged carbocyclic systems include... adamantyl groups, etc. Examples of carbocyclic groups in spirocyclocyclic systems include... The term "carbocyclic group" also includes partially saturated cyclic groups formed by the fusion of an aromatic ring and a non-aromatic ring, the linking site of which can be located on a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphth-5-yl and 5,6,7,8-tetrahydronaphth-5-yl.

[0083] In this invention, unsaturation refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc., in groups or molecules.

[0084] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one vinyl unsaturated site (>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, etc.

[0085] "Alynyl" refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, C 2-6 The term "alkynyl" is intended to include ethynyl, propynyl, etc.

[0086] In this invention, "heterocyclic alkyl" refers to a saturated ring or a non-aromatic partially saturated ring containing at least one heteroatom and having a single or multiple rings (fused, bridged, spirofused); wherein the heteroatom refers to nitrogen, oxygen, sulfur, etc. It typically represents a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system containing 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocyclic alkyl groups in monoheterocyclic alkyl systems include oxobutyl, aziridine, pyrrolidine, 2-oxo-pyrrolidine-3-yl, tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolidine, imidazoalkyl, thiazoalkyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine-heptyl, diaziridine-heptyl, homopiperazinyl, or oxaza-heptanyl, etc. Examples of heterocyclic alkyl groups in fused heterocyclic alkyl systems include 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, etc. Examples of heterocyclic alkyl groups in bridged heterocyclic alkyl systems include... Examples of heterocyclic alkyl groups in spiroheterocyclic alkyl systems include Examples of partially saturated heterocyclic alkyl groups include dihydrofuranyl, imidazolinyl, tetrahydropyridyl, or dihydropyranyl. The term "heterocyclic alkyl" also includes partially saturated cyclic groups formed by the fusion of an aromatic ring containing at least one heteroatom with a non-aromatic ring, the linking site of which may be located on a non-aromatic carbon atom, an aromatic carbon atom, or a heteroatom, examples of which include...

[0087] In this invention, "aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aryl groups having multiple carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0088] In this invention, "aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; where the heteroatom refers to nitrogen, oxygen, sulfur, etc. Typically, it refers to aromatic monocyclic or bicyclic hydrocarbons containing multiple ring atoms, one or more of which are selected from O, N, and S heteroatoms. Preferably, it has one to three heteroatoms. Examples of heterocyclic aryl groups include: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiophene, benzofuranyl, benzothiophene, benzopyranyl, benzothiapyranyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazole, thiophene, oxadiazolyl, benzimidazole, benzothiazolyl, and benzoxazolyl.

[0089] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0090] In this invention, "halogen-substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted by a halogen; for example, halogen-substituted C 1～4 Alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which one or more hydrogen atoms are replaced by one or more halogen atoms; examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0091] In this invention, "-OR", "-NRR", etc., refer to the R group being connected to an oxygen atom or a nitrogen atom by a single bond.

[0092] In this invention, the oxygen atom in “-C(O)R”, “-S(O)2R”, etc., is connected to a carbon atom or a sulfur atom by a double bond.

[0093] In this invention, the oxygen atom in “-C(O)R”, “-S(O)2R”, etc., is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond; for example, “-S(O)(NH)R” means that the oxygen atom and nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.

[0094] The invention described This refers to oxygen and sulfur atoms being connected to substitution sites via double bonds.

[0095] The "---" in the description of the functional groups in this invention It is used to describe the position of group substitution. For example This refers to the fusion of the tetrahydropyrrole ring with other rings in the structure through the "---" position.

[0096] In this invention description, "chemical bond" refers to a single bond, for example... When Y is selected from chemical bonds, the sulfur atoms of the benzene ring and the sulfonyl group are directly connected by single bonds.

[0097] In the description of the functional groups of this invention It is a single stereoconfiguration used to represent chemical structures; for example This indicates that the cyclopropane moiety has a single stereoconfiguration, and the absolute configuration is uncertain.

[0098] The "deuterated compound" of this invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0099] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0100] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkyl ammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds, or their stereoisomers, with an appropriate (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium.

[0101] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0102] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0103] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0104] Figure 1 This is a schematic diagram of the three-dimensional structure of the compound of Example 3 of the present invention obtained by X-ray single-crystal diffraction analysis. Detailed Implementation

[0105] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AvanceIII 400 and a Bruker Avanceneo 600 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0106] LC-MS was performed using a Shimadzu LC-MS 2020 (ESI) system. HPLC was performed using a Shimadzu LC-20A system. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography (TLC) used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a thickness of 0.4 mm to 0.5 mm for product separation and purification. Column chromatography generally used Yantai Huanghai 200–300 mesh silica gel as the support.

[0107] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0108] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Unless otherwise specified in the examples, M is moles per liter.

[0109] DIBAL-H: diisobutylaluminum hydride; DPPA: diphenyl azidophosphate; DMF: dimethylformamide.

[0110] Example 1

[0111]

[0112] Step 1

[0113] Compound 1a (300 mg, 1.25 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). The system was cooled to -60 °C, and then DIBAL-H n-hexane solution (1 M, 1.62 mL, 1.62 mmol) was added dropwise. The reaction system was heated to room temperature and reacted for 2 hours. After the reaction was completed by LC-MS monitoring, the reaction mixture was poured into dilute hydrochloric acid (2 M, 10 mL). The mixture was extracted with ethyl acetate (20 mL * 3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 9:1) to give compound 1b (200 mg, 0.82 mmol, yield: 66%).

[0114] Step 2

[0115] Compound 1c (3.50 g, 10.57 mmol) was dissolved in 50 mL of anhydrous tetrahydrofuran. Sodium hydride (60%, 592 mg, 14.80 mmol) was added at 0 °C, and the mixture was stirred at this temperature for 30 min. Then, bromomethyl methoxyether (1.85 g, 14.80 mmol) was added, and the reaction mixture was brought to room temperature and stirred for 16 h. The reaction mixture was poured into 50 mL of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 1d (3.20 g, 8.53 mmol, yield: 81%). MS-ESI calculated value [M+Na] + 397.0, measured value 397.0. 1 H NMR (400MHz, 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).

[0116] Step 3

[0117] Compound 1d (300 mg, 0.80 mmol) was dissolved in 1,4-dioxane (9 mL). Nitrogen gas was bubbled into the reaction system for 5 minutes, followed by the addition of neopentyl glycol diboronate (304 mg, 1.35 mmol), Pd(dppf)Cl2 (29.0 mg, 0.040 mmol), and potassium acetate (157 mg, 1.60 mmol). The reaction system was refluxed for 3 hours. After the reaction was completed as monitored by LC-MS, the system 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 (400MHz, 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).

[0118] Step 4

[0119] Under nitrogen protection, compound 1e (500 mg, 1.18 mmol) was dissolved in a mixed solution 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), and 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, yield: 42%). MS-ESI calculated value [M+Na] + 481.1, measured value 481.2. 1 H NMR (400MHz, 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, 1 H), 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).

[0120] Step 5

[0121] Compound 1f (200 mg, 0.436 mmol) was dissolved in methanol (2 mL), cooled to 0 °C, and sodium borohydride (60%, 24.8 mg, 0.62 mmol) was added. The reaction system was then heated to room temperature and reacted for 2 hours. After the reaction was complete as detected by LC-MS, the reaction mixture was poured into dilute hydrochloric acid solution (0.5 M, 10 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 4:1) to give 1 g of 150 mg compound (150 mg, 0.326 mmol, yield: 75%). MS-ESI calculated value [M + Na] + 483.2, measured value 483.2. 1H NMR (400MHz, 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).

[0122] Step 6

[0123] At room temperature, 1 g (150 mg, 0.326 mmol) of the compound was dissolved in N,N-dimethylformamide (0.5 mL). The solution was cooled to 0 °C, and carbon tetrabromide (162 mg, 0.488 mmol) and triphenylphosphine (128 mg, 0.488 mmol) were added. The reaction mixture was reacted at 0 °C for 2 hours. After the reaction was complete as detected by LC-MS, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 1 h (122 mg, 0.233 mmol, yield: 71%). MS-ESI calculated value [M+Na] + 547.1, measured value 547.1. 1 H NMR (400MHz, 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).

[0124] Step 7

[0125] Compound 1i (200 mg, 2.08 mmol) was dissolved in isopropanol (0.2 mL). This solution was 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 system was allowed to react at room temperature for 16 hours. After the reaction was complete as detected by TLC, the system was poured into water (10 mL), and 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, yield: 81%). 1 H NMR (400MHz, Chloroform-d) δ3.00-2.27 (m, 6H), 0.63-0.46 (m, 4H).

[0126] Step 8

[0127] Compound 1j (600 mg, 4.91 mmol) was dissolved in toluene (6 mL), and triethylamine (745 mg, 7.36 mmol) was added. Vanoyl chloride (711 mg, 5.90 mmol) was slowly added at 15 °C, and the reaction mixture was reacted at 80 °C for 2 hours. After the reaction was complete as detected by TLC, the reaction mixture was poured into water (8 mL), and dilute hydrochloric acid solution (0.2 M, 8 mL) was added. The organic phase was separated, washed with water (10 mL), and concentrated to give 1k (820 mg crude product), which was used directly in the next step.

[0128] Step 9

[0129] Compound 1k (820 mg, crude product obtained in the previous step) was dissolved in methanol (5 mL) at 20 °C, and potassium hydroxide (172 mg, 3.07 mmol) and hydrogen peroxide (30%, 2 mL, 4.91 mmol) were added. The reaction system was reacted at 50 °C for 30 minutes, cooled to room temperature, and potassium hydroxide (689 mg, 12.28 mmol) was added again. The reaction system was then heated to 70 °C and reacted for 2 hours. After the reaction was complete, solid ammonium chloride (100 mg) was added to the reaction system for neutralization. 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, two-step yield: 20%). MS-ESI calculated value [M+H] + 207.3, measured value 207.2. 1H NMR (400MHz, 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).

[0130] Step 10

[0131] Compound 1L (50 mg, 0.242 mmol) was dissolved in N,N-dimethylformamide (2 mL). The system was cooled to 0 °C, and sodium hydride (60%, 12.2 mg, 0.51 mmol) was carefully added, followed by stirring for 30 minutes. Then, a solution of intermediate 1H (114 mg, 0.218 mmol) in N,N-dimethylformamide (0.5 mL) was added, and the system was allowed to return to room temperature and reacted for 5 hours. After the reaction was complete as monitored by LC-MS, the system was poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), and 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 = 4:1) to give 80 mg of compound 1M (80 mg, 0.123 mmol, yield: 51%). MS-ESI calculated value [M+H] + 649.8, measured value 649.4. 1 H NMR (400MHz, 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).

[0132] Step 11

[0133] Compound 1 (70 mg, 0.108 mmol) was dissolved in a mixed solution of ethanol (3 mL) and hydrochloric acid (6 M, 3 mL) and reacted at 75 °C for 3 hours. After the reaction was complete, the pH of the system was adjusted to 8 with sodium hydroxide solution (5 M), and then adjusted to 5 with dilute hydrochloric acid (0.5 M). The mixture was 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 value [M+H] + 605.8, measured value 605.4. 1 H NMR (400MHz, 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 , 2H), 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).

[0134] Example 2

[0135]

[0136] Step 1

[0137] At 25°C, compound 2b (350 mg, 3.22 mmol) was dissolved in 1 mL of water. Hydrochloric acid solution (0.5 N, 0.35 mL) was added dropwise to the system, and the mixture was stirred continuously for 5 minutes. Then, an aqueous solution of compound 2a (460 mg, 3.53 mmol) (1 mL) was added dropwise to the system. After stirring for 4 hours, ethanol was added to the reaction system until the solution became clear, and the reaction mixture was frozen at 4°C for 16 hours. The system was monitored by LC-MS. After the reaction was complete, 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 to obtain compound 2c (500 mg), which was used directly in the next step.

[0138] MS-ESI calculated value [M+H] + 185.1, measured value 185.2.

[0139] Step 2

[0140] At room temperature, triethylamine (1.5 mL, 10.8 mmol) and DPPA (710 mg, 2.58 mmol) were added to a toluene solution (6 mL) of compound 2c (500 mg, the crude product obtained in the previous step), and the system was refluxed at 120 °C for 1 hour. After the reaction was monitored by LC-MS, the system was poured into water (8 mL) and extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (water / acetonitrile) to obtain compound 2d (398 mg, 2.20 mmol, overall yield of two steps: 68%). MS-ESI calculated value [M+H] + 182.1, measured value 182.1. 1 H NMR (600MHz, 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).

[0141] Step 3

[0142] Under ice bath conditions, sodium hydride (60%, 12 mg, 0.50 mmol) was added to a 2 mL DMF solution of compound 2d (30 mg, 0.166 mmol). After reacting at 25 °C for 30 minutes, a 0.5 mL DMF solution of compound 1h (80 mg, 0.153 mmol) was added dropwise to the reaction system, and stirring was continued for 5 hours. After the reaction was completed as monitored by LC-MS, the system 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%). 1H NMR (600MHz, 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).

[0143] Step 4

[0144] 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 system was reacted at 75 °C for 5 h. When approximately 85% of the target compound was detected by LC-MS, the pH of the system was adjusted to 8 with sodium hydroxide solution (5 M), and then adjusted to 90% with hydrochloric acid solution (0.5 M). The aqueous phase was extracted with ethyl acetate (20 mL), and the organic phase was washed with saturated brine. The solution was 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 value [M+H] + 580.3, measured value 580.2. 1H NMR (600MHz, 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=1.8 Hz, 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), 4.01 (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).

[0145] Example 3

[0146]

[0147] Step 1

[0148] At 0 °C, diiodomethane (24.5 g, 91.5 mmol) was carefully added dropwise to a dichloromethane solution of diethylzinc (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 the reaction was completed by TLC monitoring, saturated ammonium chloride aqueous solution (100 mL) was added to quench the reaction. The system was extracted with dichloromethane (200 mL * 2), 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 (400MHz, 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).

[0149] Step 2

[0150] Compound 3b (200 mg, 2.0 mmol) was dissolved in dichloromethane (12 mL), the system was cooled to 0 °C, and Dysmart oxidant (951 mg, 2.2 mmol) was added. The reaction was then brought to room temperature and allowed to proceed for 3 hours. After the reaction was completed as monitored by TLC, the reaction system was filtered, 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 (400MHz, 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).

[0151] Step 3

[0152] Compound 3c (890 mg, 9.26 mmol) was dissolved in isopropanol (2 mL) and carefully added dropwise to an ammonia solution (3 mL) containing ammonium chloride (644 mg, 12.04 mmol) and potassium cyanide (754 mg, 11.58 mmol). The reaction system was allowed to react at room temperature for 16 hours. After the reaction was completed by TLC, water (15 mL) was added to the reaction system, and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to give compound 3d, containing two isomers (800 mg, 6.55 mmol, yield: 71%).

[0153] Step 4

[0154] Compound 3d (400 mg, 3.27 mmol) was dissolved in toluene (5 mL), and triethylamine (497 mg, 4.91 mmol) was added. Vanoyl chloride (474 ​​mg, 3.93 mmol) was carefully added at 15 °C, and the reaction mixture was incubated at 80 °C for 2 hours. After the reaction was complete as detected by TLC, the reaction mixture was poured into water (8 mL), and dilute hydrochloric acid solution (0.2 M, 8 mL) was added. The organic phase was separated, washed with water (10 mL), separated, and concentrated under reduced pressure to obtain crude compound 3e (610 mg), which was then directly used for the next reaction.

[0155] Step 5

[0156] At 20°C, the crude compound 3e (610 mg) was dissolved in methanol (6 mL), and potassium hydroxide (332 mg, 5.92 mmol) and 30% hydrogen peroxide (1.5 mL) were added. The reaction system 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 system was then heated to 70°C and reacted for 2 hours. After the reaction was completed by LC-MS and TLC, solid ammonium chloride (1.2 g) was added to the reaction system and stirred. The mixture was then diluted with methanol and concentrated. Water (20 mL) was added to the concentrate, and the aqueous phase was extracted with ethyl acetate (30 mL). After separating the organic phase, the concentrate 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). Two isomers, 3f-1 and 3f-2 (ratio approximately 1:1), were obtained, totaling 504 mg and 2.44 mmol. The overall yield of the two steps was 75%. The relative configurations of the two isomers were confirmed by single-crystal diffraction experiments in Example 3. 3f-1 was used in Examples 3, 5, and 7.

[0157] 3f-1 Rf=0.3 (ethyl acetate∶petroleum ether=7∶3). 1 H NMR (400MHz, 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).

[0158] 3f-2 Rf = 0.5 (ethyl acetate: petroleum ether = 7:3). 1 H NMR (400MHz, 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).

[0159] Step 6

[0160] Compound 3f-1 (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (2 mL). After cooling to 0 °C, sodium hydride (60%, 12 mg, 0.31 mmol) was added, and the mixture was stirred for 30 minutes. Then, a solution of 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 the reaction was completed as monitored by LC-MS, the system was poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (10 mL * 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 3 g of compound (110 mg, 0.17 mmol, yield: 71%). 1 H NMR (400MHz, 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, 1.4 Hz, 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).

[0161] Step 7

[0162] 3 g (50 mg, 0.08 mmol) of the compound was dissolved in a mixed solution of 95% ethanol (3 mL) and 6 M hydrochloric acid (3 mL), and reacted at 75 °C for 3 hours. LC-MS detected 80% product formation. After the reaction was complete, the pH of the system was adjusted to 8 with 5 M sodium hydroxide solution, and then adjusted 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 medium-pressure preparation (water, acetonitrile system), followed by column chromatography purification (petroleum ether:ethyl acetate = 1:1) to give the final compound 3 (30 mg, 0.05 mmol, yield: 63%, HPLC purity: 97.3%). MS-ESI calculated value [M+H] + 605.3, measured value 605.2. 1 H NMR (400MHz, 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 ), 7.05-6.87(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, 7.2H z, 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).

[0163] Example 3: Single crystal growth method of final product 3: Weigh 20 mg of solid and place it in an ampoule containing a mixed solution of 1 mL ethyl acetate and 2 mL n-hexane. Place cotton wool at the mouth of the ampoule to slow down the evaporation rate. Allow the solvent to evaporate at room temperature, and crystals are obtained after 2 days. The experimental parameters and results obtained by X-ray single crystal diffraction analysis are as follows; the configuration of compound 3 is as follows. Figure 1 As shown, it is consistent with the final product 3 of Example 3.

[0164]

[0165] Example 4

[0166]

[0167] Step 1

[0168] Compound 3f-2 (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (2 mL). After cooling to 0 °C, sodium hydride (60%, 12 mg, 0.31 mmol) was added, and the mixture was stirred for 30 minutes. Then, a solution of 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 the reaction was completed as monitored by LC-MS, the system was poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (3 x 10 mL), and the organic phases were combined. The mixture was 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, yield: 54%). MS-ESI calculated value [M+H] + 649.3, measured value 649.3.

[0169] Step 2

[0170] Compound 4a (85 mg, 0.13 mmol) was dissolved in a mixture of 95% ethanol (3 mL) and hydrochloric acid (6 M, 3 mL) and reacted at 75 °C for 3 hours. LC-MS detected 80% product formation. After the reaction was complete, the pH was adjusted to 8 with 5 M sodium hydroxide solution, and 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) followed 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 value [M+H] + 605.3, measured value 605.2. 1H NMR (400MHz, 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, 1.7 Hz, 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).

[0171] Example 5

[0172]

[0173] Step 1

[0174] Compound 1d (1.00 g, 2.66 mmol), neopentyl glycol diborate (910 mg, 4.03 mmol), 1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (110 mg, 0.14 mmol), and potassium acetate (520 mg, 5.31 mmol) were added sequentially to a three-necked flask. After purging with nitrogen using a double-row tube, dioxane (20 mL) was added, and the reaction was heated and refluxed with stirring for 3 hours. After the reaction was completed as monitored by LC-MS, the system was filtered through diatomaceous earth and concentrated directly to dryness. The crude product was purified by reverse medium-pressure preparation (water, acetonitrile system) to obtain compound 5a (360 mg, 1.06 mmol, yield: 40%). 1 H NMR (600MHz, Chloroform-d) δ786 (d, J=8.0Hz, 1H), 7.70 (d, J=7.4Hz, 1H), 7.60 (td, J=7.5, 1 .2Hz, 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).

[0175] Step 2

[0176] Compound 5b (3.00 g, 10.79 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). A methylamine tetrahydrofuran solution (2 M, 50 mL, 100 mmol) was added to the system, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete as monitored by LC-MS, the reaction mixture was poured into water (80 mL), extracted with ethyl acetate (160 mL * 3), and the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 5c (2.50 g, 10.96 mmol, crude yield: 102%). MS-ESI calculated [M+H] + 228.0, measured value 228.2.

[0177] Step 3

[0178] Compound 5c (2.50 g, 10.96 mmol) was dissolved in anhydrous tetrahydrofuran (80 mL), cooled to 0 °C, and then triethylamine (6.80 g, 67.20 mmol) and 3,3-dimethylbutyryl chloride (3.00 g, 22.29 mmol) were added sequentially. The mixture was stirred at this temperature for 30 minutes. After the reaction was completed as monitored by LC-MS, the reaction solution was poured into ice water (80 mL), extracted with ethyl acetate (160 mL), and the separated organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:2) to give compound 5d (2.70 g, 8.28 mmol, yield: 76%). MS-ESI calculated value [M+H] + 326.1, measured value 325.8.

[0179] Step 4

[0180] Compound 5d (500 mg, 1.53 mmol) and compound 5a (690 mg, 2.03 mmol) were dissolved in a mixed solution of toluene (10 mL), water (4 mL), and ethanol (5 mL). Nitrogen gas was bubbled through the system for 10 minutes, followed by the sequential addition of tetrakis(triphenylphosphine)palladium (90.0 mg, 0.08 mmol) and sodium carbonate (500 mg, 4.72 mol). The system was stirred at 85 °C for 3 hours. After the reaction was completed as 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 crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2.5:1) to give compound 5e (102 mg, 0.19 mmol, yield: 12%). MS-ESI calculated value [M+H] + 542.2, measured value 542.1.

[0181] Step 5

[0182] A solution of compound 5e (102 mg, 0.19 mmol) was dissolved in methanol (5 mL), cooled to -40 °C, and sodium borohydride (5.0 mg, 0.13 mmol) was added. The mixture was stirred for 1 hour while maintaining the temperature. After the reaction was complete as monitored by LC-MS, the mixture was poured into dilute hydrochloric acid (0.5 M, 15 mL), 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 crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 5f (91 mg, 0.17 mmol, yield: 89%). MS-ESI calculated value [M+H] + 544.2, measured value 544.2.

[0183] Step 6

[0184] Compound 5f (91 mg, 0.17 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) at 0 °C, followed by the sequential addition of carbon tetrabromide (169 mg, 0.51 mmol) and triphenylphosphine (134 mg, 0.51 mmol). The mixture was stirred at this temperature for 2 hours. After the reaction was completed as monitored by LC-MS, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 9:1) to give 5 g of compound (75 mg, 0.12 mmol, yield: 71%). MS-ESI calculated value [M+H] + 606.2, measured value 606.1.

[0185] Step 7

[0186] At 0 °C, compound 3f-1 (24.0 mg, 0.12 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), and sodium hydride (60%, 10.6 mg, 0.26 mmol) was added. After stirring for 30 minutes, a solution of 5 g (70 mg, 0.12 mmol) of compound 3f-1 in N,N-dimethylformamide (0.5 mL) was added to the system. The mixture was stirred at room temperature for 3 hours. After the reaction was complete as monitored by LC-MS, the system was poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), and the separated organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The 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 value [M+H] + 732.4, measured value 732.4.

[0187] Step 8

[0188] Compound 5 (60 mg, 0.08 mmol) was dissolved in a mixed solution of ethanol (6 mL) and hydrochloric acid (6 M, 5 mL) and stirred at 75 °C for 3 hours. After the reaction was completed as monitored by LC-MS, the pH of the system was adjusted to 8 with sodium hydroxide solution (5 M), and then adjusted to 5 with dilute hydrochloric acid (0.5 M). The mixture was 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 crude product was then prepared by preparative chromatography (water, acetonitrile) to give compound 5 (30 mg, 0.04 mmol, yield: 50%, HPLC purity: 98.2%). MS-ESI calculated value [M+H] + 688.4, measured value 688.4. 1 H NMR (600MHz, DMSO-d6) δ1063 (s, 1H), 8.13-7.98 (m, 1H), 7.76-7.54 (m, 2H), 7.24 (t, J=8.1H z, 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).

[0189] Example 6

[0190]

[0191] Step 1

[0192] At 0 °C, compound 3f-2 (26.0 mg, 0.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.2 mL), and sodium hydride (60%, 11.2 mg, 0.28 mmol) was added. After stirring for 30 minutes, a solution of 5 g (75 mg, 0.12 mmol) of compound 3f-2 in N,N-dimethylformamide (0.7 mL) was added to the system. The mixture was stirred at room temperature for 3 hours. After the reaction was complete as monitored by LC-MS, the system was poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), and the separated organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 6a (67 mg, 0.09 mmol, yield: 69%). MS-ESI calculated value [M+H]+ 732.4, measured value 732.3.

[0193] Step 2

[0194] 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 the reaction was completed as monitored by LC-MS, the pH of the system was adjusted to 8 with sodium hydroxide solution (5 M), and then adjusted to 5 with dilute hydrochloric acid (0.5 M). The mixture was 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 crude product was prepared 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] + 688.4, measured value 688.4. 1 H NMR (600MHz, Methanol-d4) δ8.35-7.98(m, 1H), 7.73-7.39(m, 2H), 7.23-7.10(m, 1H ), 7.10-6.96(m, 2H), 6.94-6.72(m, 1H), 4.82-4.70(m, 2H), 4.62-4.14(m, 2H), 2.95 -2.72(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).

[0195] Example 7

[0196]

[0197] Step 1

[0198] Under nitrogen protection, compound 1b (30 g, 0.12 mol), pinacol diborate (32.9 g, 0.13 mol), potassium acetate (24.2 g, 0.25 mol), and [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (5.0 g, 6.22 mmol) were sequentially added to a dioxane solution (800 mL), and the mixture was refluxed for 16 hours. After the reaction was complete as monitored by TLC, the solid was removed by diatomaceous earth filtration, and the dioxane was removed by concentration under reduced pressure. The mixture was then transferred to water (400 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 7a (56 g).

[0199] Step 2

[0200] Under nitrogen 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. The reaction was quenched by adding sodium hydroxide solution (1 M, 10 mL), 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 measured value is 133.1.

[0201] Step 3

[0202] At 0 °C, 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 sequentially added to pyridine (15 mL), stirred for 10 min, and then heated to 40 °C for 12 h. After the reaction was complete as detected by LC-MS, the system was transferred to an ice bath, the pH was adjusted to 6 with glacial hydrochloric acid (1 M), 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 to give compound 7d (1.3 g, 3.70 mmol, yield: 98%). MS-ESI [M+H] + The measured value is 351.1.

[0203] Step 4

[0204] Compound 7d (1.3 g, 3.70 mmol) was dissolved in N,N-dimethylformamide (10 mL) at -15 °C. Sodium hydride (60%, 171 mg, 4.28 mmol) was added dropwise, and the mixture was stirred for 5 minutes before being allowed to rise to room temperature for 30 minutes. The system was then transferred to -15 °C, and bromomethyl methyl ether (600 mg, 4.80 mmol) was added dropwise. The mixture was stirred for 5 minutes before being allowed to rise naturally for 30 minutes. The reaction was confirmed by LC-MS. The reaction mixture was then transferred to an ice bath, quenched with cold water (40 mL), and the pH was adjusted to 7 with hydrochloric acid (0.5 M). The mixture was extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The mixture was 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 measured value is 394.9.

[0205] Step 5

[0206] Under nitrogen protection, compound 7e (300 mg, 0.76 mmol), compound 7a (220 mg, 0.76 mmol), tetraphenylphosphine palladium (114 mg, 0.099 mmol), and sodium carbonate (402 mg, 3.79 mmol) were sequentially added to a mixed solution of toluene (15 mL), water (15 mL), and ethanol (15 mL). The system was reacted at 85 °C for 2 hours. After the reaction was completed as detected by LC-MS, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and the 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 measured value is 479.0.

[0207] Step 6

[0208] 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 transferred to 25 °C and reacted for 1 hour. The system was then transferred to an ice bath, and ice water (30 mL) was added. The pH was adjusted to 7 with hydrochloric acid (1 M), and the mixture was 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 give 7 g (237 mg) of crude product, which was used directly in the next reaction. MS-ESI [M+H] + The measured value is 481.0.

[0209] Step 7

[0210] At 0°C, 7 g (237 mg) of compound, carbon tetrabromide (243 mg, 0.73 mmol), and triphenylphosphine (194 mg, 0.74 mmol) were sequentially added to anhydrous N,N-dimethylformamide (5 mL), and the reaction was continued at this temperature for 2 hours. After the starting material was confirmed to have reacted completely by LC-MS, ice water (30 mL) was added to the system, followed by extraction 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 pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 7h (172 mg, 0.32 mmol, two-step yield: 65%). MS-ESI [M+H] + The measured value is 543.3.

[0211] Step 8

[0212] At 0°C, compound 3f-1 (25.0 mg, 0.12 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and sodium hydride (60%, 5.34 mg, 0.13 mmol) was added. After stirring for 5 minutes, the mixture was brought to room temperature and stirred for 30 minutes. The system was then transferred to an ice bath, and a solution of N,N-dimethylformamide (2 mL) containing compound 7h (55 mg, 0.10 mmol) was slowly added dropwise to the reaction mixture. After 5 minutes, the mixture was brought to room temperature and reacted for 1 hour. After the starting material was confirmed to have completely reacted by LC-MS, ice water (30 mL) was added to the system, and the pH was adjusted to 7 with hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (3 x 10 mL), and 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 measured value is 669.1.

[0213] Step 9

[0214] Compound 7i (67.0 mg, 0.10 mmol) was dissolved in anhydrous ethanol (2.5 mL), and hydrochloric acid (6 N, 2.5 mL) was added. The mixture was heated at 40 °C for 1 hour. After the reaction was complete as detected by LC-MS, the system was transferred to an ice bath, the pH was adjusted to 7 with sodium bicarbonate solids, and the mixture was 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, yield 50%). MS-ESI [M+H] + The measured value is 625.2. 1H NMR (600MHz, Chloroform-d) δ828 (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=2.3 Hz, 2H), 4.16 (d, J=12.4Hz, 1H), 4.08 (d, J=12.3Hz, 1H), 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, 2H), 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).

[0215] The technical effects of the compounds of the present invention are illustrated below through experimental examples.

[0216] Experimental Example 1: AT1 Calcium Flow Experiment

[0217] Test materials: a) Cell line: AT1 / HEK293; b) Medium: F12, Invitrogen (Cat#11765-047); FBS, Coming (Cat#35-076-CV); Geneticin, Invitrogen (Caf#10131); c) Reagent: Fluo-4Direct (Invitrogen, Cat#F10471); d) Instruments: 384well Poly-D-Lysine protein coating plate, Greiner#781946; Vi-cell XR Cell Viability Analyzer, Beckman Coulter; Incubator, Thermo.

[0218] Test method:

[0219] For the agonist (angiotensin II) master plate: the agonist solution was diluted from 1 mM to 200 μM with test buffer. For the antagonist (Losartan) and compound plates: the antagonist and the test compound were serially diluted with DMSO at a ratio of 1:4 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.

[0220] a) Remove the cell culture plate from the incubator and add 20 μL of 2X Fluo-4 Direct to the 384-well cell culture plate using a pipette.

[0221] b) Incubate the cell plate at 37°C for 50 minutes in a 5% CO2 environment, then incubate at room temperature for 10 minutes.

[0222] c) Remove the cell plate from the incubator and place it in the FLIPR. Place the compound plate and tip box into the FLIPR.

[0223] d) For EC80 boards:

[0224] 1) Perform the operation on FLIPRTETRA.

[0225] 2) Transfer 10 μL of the compound from the EC80 mother plate to the cell plate.

[0226] 3) Read the fluorescence signal.

[0227] 4) Calculate the read signals and use FLIPR to calculate the EC80 value for each cell line.

[0228] 5) For the concentration of the compound plate, prepare a solution with a concentration 6 times that of the reference agonist EC80.

[0229] e) For compound plates:

[0230] 1) Perform the operation on FLIPRTETRA.

[0231] 2) Transfer 10 μL of the compound to the cell plate.

[0232] 3) Read the fluorescence signal.

[0233] 4) Transfer 10 μL of a solution with a concentration 6 times that of the reference agonist EC80.

[0234] 5) Read the fluorescence signal.

[0235] f) Analyze the data using Prism.

[0236] Table 1 (AT1 active 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 column 3 of Table 1.

[0237] Example 1 +++ 2.90nM Example 2 +++ 6.14nM Example 3 +++ 1.97nM Example 4 +++ 4.78 nM Example 5 ++ 26.82nM Example 6 + 257.6 nM Example 7 +++ 3.55nM Sparsentan +++ 9.79nM Losartan +++ 1.86nM

[0238] Experimental Example 2: ETa Calcium Flow Experiment

[0239] Test materials: a) Cell line: ETa / HEK293; b) Medium: DMEM, Invitrogen (Cat#11960); Geneticin, Invitrogen (Cat#10131); c) Reagent: Fluo-4 Direct (Invitrogen, Cat#F10471); d) Instruments: 384well Poly-D-Lysine protein coating plate, Greiner#781946; Vi-cell XRCell Viability Analyzer, Beckman Coulter; Incubator, Thermo.

[0240] Test method:

[0241] For the endothelin-1 (ET-1) agonist master plate used: dilute the agonist from 50 μM to 15 μM with the test buffer.

[0242] For the antagonist (BQ123, Am J Physiol. 1994 Apr; 266(4 Pt 2): H1327-31.) and the compound plate: the antagonist and the analyte were serially diluted with DMSO at a ratio of 1:4 to obtain 10 concentration points. Then, 900 nmL of the compound was transferred to the master plate and 30 μL of test buffer was added.

[0243] a) Take the cell line from the incubator and gently add 20 μL of 2X Fluo-4 Direct™ buffer to a 384-well cell culture plate using a pipette.

[0244] b) Incubate the cell plate at 37°C for 50 minutes in a 5% CO2 environment, then incubate at room temperature for 10 minutes.

[0245] c) Remove the cell plate from the incubator and place it in the FLIPR. Place the compound plate and tip box into the FLIPR.

[0246] d) For EC80 boards:

[0247] 1) Perform the operation on FLIPRTETRA.

[0248] 2) Transfer 10 μL of the compound from the EC80 mother plate to the cell plate.

[0249] 3) Read the fluorescence signal.

[0250] 4) Calculate the read signals and use FLIPR to calculate the EC80 value for each cell line.

[0251] 5) For the concentration of the compound plate, prepare a solution with a concentration 6 times that of the reference agonist EC80.

[0252] e) For compound plates:

[0253] 1) Perform the operation on FLIPRTETRA.

[0254] 2) Transfer 10 μL of the compound to the cell plate.

[0255] 3) Read the fluorescence signal.

[0256] 4) Transfer 10 μL of a solution with a concentration 6 times that of the reference agonist EC80 to the cell plate.

[0257] 5) Read the fluorescence signal.

[0258] f) Analyze the data using Prism.

[0259] 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 column 3 of Table 2.

[0260] Example 1 ++ 24.60 nM Example 2 ++ 23.55nM Example 3 ++ 10.53nM Example 4 + 131.60 nM Example 5 ++ 14.83 nM Example 6 ++ 17.58nM Example 7 ++ 24.29 nM Sparsentan ++ 80.81 nM BQ123 +++ 2.56nM

[0261] Experiment 3: Water Solubility Test

[0262] This detection is performed using high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512):

[0263] HPLC-UV chromatographic conditions: mobile phase: 0.02M KH₂PO₄ aqueous solution-acetonitrile (90:10), gradient elution; chromatographic column: C₂O₃. 18 Detection wavelength: 210nm. Calculation was performed using the external standard method based on peak area.

[0264] Table 3:

[0265]

[0266] Conclusion: The specific compounds prepared by this invention have better water solubility than the reference compounds under various test conditions in most cases.

[0267] Experimental Example 4: Inhibition of the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4)

[0268] Six specific probe substrates representing six CYP isoenzymes—α-Naphthoflavone (CYP1A2), Sulphaphenazole (CYP2C9), Ticlopidine (CYP2C19), Quinidine (CYP2D6), Ketoconazole (CYP3A4), and Montelukast (CYP2C8)—were co-incubated with recombinant hepatic drug-metabolizing enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP2C8, as well as the test compound. Nicotinamide adenine dinucleotide phosphate (NADP+), D-glucose-6-phosphate (G6P), and glucose-6-phosphate dehydrogenase (G6DHP) were added to initiate the reaction. After the reaction, the corresponding half-inhibitory concentrations (IC50) were calculated using fluorescence detection (Ex 490 nm / Em 520 nm). 50 ).

[0269] Table 4:

[0270]

[0271] Conclusion: Sparsentan poses no risk of inhibiting the activities of human liver microsomal cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, and CYP2D6, but inhibits CYP3A4 and CYP2C8. The compound in Example 3 poses no risk of inhibiting the activities of human liver microsomal cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP2C8, but inhibits CYP3A4 only. The compound in Example 7 poses no risk of inhibiting the activities of human liver microsomal cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP2C8.

[0272] The data above suggest that the compounds in Examples 3 and 7 have a lower risk of drug-drug interaction (DDI) in clinical use.

[0273] Experimental Example 5: Pharmacokinetic Test in Rats

[0274] Experimental animals: SD rats, 6–8 weeks old. Six animals were used for each compound in each example.

[0275] Drug solution preparation: All compounds in the test examples were prepared into 1 mg / mL solutions. The solution system consisted of 5% DMSO + 20% Solutol HS15 + 75% (20% HP-β-CD aqueous solution).

[0276] Dosage groups: Group 1 was administered orally by gavage (PO, 3 SD rats, 10 mg / kg, fasted overnight before administration, fed 4 hours after administration); Group 2 was administered via dorsal paw vein injection (IV, 3 SD rats, 1 mg / kg, free access to food).

[0277] Blood collection time and processing method: Blood was collected via the jugular vein at 7–8 time points: 0.083 (intravenous injection group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours. Blood samples were centrifuged (2000g, 4℃, 5 minutes) to obtain plasma. Samples were stored at -70℃ before analysis.

[0278] Analytical instruments and conditions: LC-MS / MS-33 (Triple Quad 6500+); MS: positive, ESI; Mobile phase: Mobile phase A: H2O-0.025% FA-1mM NH4OAc, Mobile phase B: MeOH-0.025% FA-1mM NH4OAc; Flow rate: 0.60 mL / min; Column: ACQUITY UPLC-BEH C 18 (2.1×50mm, 1.7μm); Column temperature: 60℃.

[0279] Table 5: Oral (PO) Pharmacokinetic Parameters

[0280]

[0281] Conclusion: The oral gavage administration groups of the compounds of Example 3 and Example 7 of this application achieved higher in vivo exposure and higher oral bioavailability after oral administration, indicating that the compounds of Example 3 and Example 7 have better pharmacokinetic properties than the reference compound.

[0282] The above description is only a preferred embodiment of the present invention. The scope of protection of the present invention is not limited to the above embodiments. Any equivalent modifications or changes made by those skilled in the art based on the content disclosed in the present invention should be included within the scope of protection set forth in the claims.

Claims

1. Compounds of formula IIa or IIb, or their deuterated compounds, stereoisomers, or pharmaceutically acceptable salts thereof: in, R 1 Selected from -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; R 2 Selected from -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -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)2R 21 -C 0~4 Alkylene-S(O)R 21 -C 0~4 Alkylene-S(O)2NR 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 ; R 21 R 22 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; R 3 Selected from , , , , , Among them, R 3 The selected rings can be further arbitrarily selected by one, two, three or four independent Rs. 31 replace; R 4 Selected from hydrogen, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; Each R 31 Each group is independently selected from hydrogen, halogen, cyano, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -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)2R 32 -C 0~4 Alkylene-S(O)R 32 -C 0~4 Alkylene-S(O)2NR 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)2R 33 -C 0~4 Alkylene-NR 32 S(O)R 33 ; R 32 R 33 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group; m1 is selected from 0, 1, 2 or 3; m2 is selected from 1, 2 or 3; m3 is selected from 1, 2, 3, 4 or 5; n1 and n2 are independently selected from 0, 1, 2 or 3 respectively; n3 is selected from 1, 2, 3, 4 or 5.

2. The compound according to claim 1, or its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: R 1 Selected from n-butyl.

3. The compound according to claim 1, or its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: R 2 Selected from -C 1~2 Alkylene-OR 21 -C 1~2 Alkylene-SR 21 -C 1~2 Alkylene-NR 21 R 22 -C 1~2 Alkylene-OC(O)R 21 -C 1~2 Alkylene-S(O)2R 21 -C 1~2 Alkylene-S(O)R 21 -C 1~2 Alkylene-S(O)2NR 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 ; R 21 R 22 Selected independently from hydrogen and -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 Alkyne group.

4. The compound according to claim 3, or its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: R 2 Selected from , , ; R 21 R 22 Selected independently from hydrogen and -C 1~6 Alkyl, halogen-substituted -C 1~6 alkyl.

5. The compound according to claim 4, or its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The R 2 Selected from , .

6. The compound according to claim 1, or its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: R 4 Selected from hydrogen, -C 1~6 alkyl.

7. The compound according to claim 1, or its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: R 3 Selected from , , , , .

8. The compound according to claim 1, or its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The compound is specifically: 、 、 、 、 、 、 、 、 、 、 、 、 。 9. Use of the compound of any one of claims 1 to 8, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a dual antagonist medicament for angiotensin II receptor and endothelin receptor.

10. The use according to claim 9, characterized in that, The drug is used to treat cardiovascular and cerebrovascular diseases, kidney diseases, and diseases related to organ damage associated with diabetes.

11. The use according to claim 10, characterized in that, The drug is used to treat hypertension.

12. A pharmaceutical composition comprising a formulation prepared from the compound of any one of claims 1 to 8, a deuterated compound thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 12, further comprising pharmaceutically acceptable excipients and carriers.

14. A compound represented by formula IIIa or IIIb, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: , where R 1 Selected from -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl or halogen-substituted -C 2~6 Alkyne group; m1 is selected from 0, 1, 2 or 3; m2 is selected from 1, 2 or 3; m3 is selected from 1, 2, 3, 4 or 5; n1 and n2 are independently selected from 0, 1, 2 or 3; n3 is selected from 1, 2, 3, 4 or 5.

15. The compound according to claim 14, or its deuterated compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: R 1 Selected from n-butyl.

Images