LPAR1 antagonist and use thereof

Abstract

The present invention relates to a compound as represented by formula I and the use thereof in the preparation of a drug for preventing or treating LPAR-related diseases or symptoms.

Description

LPAR1 antagonists and their uses

[0001] Cross-reference of related applications

[0002] This application claims priority to two patent applications filed with the China National Intellectual Property Administration on December 27, 2024, entitled "LPAR1 antagonist and its use thereof" (application number CN202411951367.1) and November 5, 2025, entitled "LPAR1 antagonist and its use thereof" (application number CN202511612287.8), the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention disclosure relates to compounds that bind to lysophosphatidylcholine (LPA) receptors (such as LPAR1) and act as their antagonists. This disclosure also relates to the use of said compounds for the treatment and / or prevention of diseases and / or symptoms associated with one or more LPA receptors (e.g., LPAR1-related diseases or symptoms), particularly fibrosis-related diseases. Background Technology

[0004] Lysophosphatidic acid (LPA) is a class of bioactive phospholipids that can be synthesized from lysophosphatidylcholine (LPC), for example, through enzymatic autocrine motor factor production. A typical LPA contains glycerol, an ester-linked fatty acid at the sn-1 position, and a phosphate ester head group at the sn-3 position. LPAs with various fatty acids have been identified, including palmitoyl LPA (16:0), stearoyl LPA (18:0), oleoyl LPA (18:1), linoleoyl LPA (18:2), and arachidonicyl LPA (20:4). LPA is a structurally simple phospholipid composed of six LPA-specific GPCRs (LPAR1-6). It acts as a ligand for G protein-coupled receptors, activating various intracellular signaling pathways and regulating cellular activities such as proliferation, migration, and invasion. Studies have shown that the ATX-LPA-LPAR pathway is involved in various diseases, including tumor cell invasion and metastasis, nervous system development, rheumatoid arthritis, and fibrosis.

[0005] LPA exerts a wide range of cellular responses, such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis, through the rhodopsin-like G protein-coupled receptor (GPCR) family. Six LPA receptors have been characterized, and their tissue distribution and downstream signaling pathways have been found to differ. These six LPA receptors are generally referred to interchangeably as LPAR1-6 (gene) or LPA1-6 (protein). LPA receptor-mediated signaling has been shown to influence many biological processes, such as wound healing, immunity, oncogenesis, angiogenesis, and neurogenesis.

[0006] In vivo studies involving LPA receptor (LPAR)-deficient mice or certain tool compounds have demonstrated the potential of the LPA receptor as a drug target in a variety of diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease. In particular, the LPA receptor, expressed in alveolar epithelial cells, pulmonary vascular endothelial cells, and fibroblasts, mediates pulmonary fibrosis in multiple ways, most notably by inducing fibroblast activation, proliferation, and migration. LPAR expression differs in the lungs of humans and mice. Human lung tissue expresses LPAR1 and LPAR3 receptors, while mouse lung tissue expresses LPAR1, LPAR2, and LPAR3 receptors. Recently, LPAR1 antagonists have been investigated clinically in conjunction with fibrotic disease states such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.

[0007] Fibrosis-related diseases refer to conditions in which myofibroblasts over-secrete extracellular matrix (ECM) when normal organs or tissues are severely or repeatedly damaged, leading to the replacement of the injured area with fibrotic tissue. This causes the related organs to remodel, thicken, and harden. If fibrosis is not intervened in time, it can cause irreversible organ damage and even death. Fibrosis-related deaths account for 45% of all deaths.

[0008] There is currently no cure for idiopathic pulmonary fibrosis. Pirfenidone and nintedanib, two drugs approved in 2014 for the treatment of pulmonary fibrosis, are currently the most widely used for alleviating pulmonary fibrosis. They can only slow the decline in lung function; they cannot cure or reverse pulmonary fibrosis. Therefore, there remains a significant unmet clinical need. Summary of the Invention

[0009] The inventors accidentally discovered during their research that the compound represented by Formula I, or its stereoisomers, pharmaceutically acceptable salts, or solvates, can...

[0010] It is an effective LPAR1 antagonist that can effectively inhibit lysophosphatidyl receptor 1 (LPAR1).

[0011] Therefore, in a first aspect, a compound of Formula I or a stereoisomer thereof, a pharmaceutically acceptable salt or solvate is provided:

[0012] in,

[0013] X is selected from CH2, NHCO, NHCOCH2, O and S, preferably O or NHCO;

[0014] Y is selected from N and CH;

[0015] Q1, Q2, and Q3 are each independently selected from NH, N, CH2, and CH; and Q3 is optionally substituted with a methyl group;

[0016] R1 is selected from 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, 6-membered heteroaryl, spirocyclic, bridged cycloalkyl, cyano, and trifluoromethyl, wherein the 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, 6-membered heteroaryl, spirocyclic, and bridged cycloalkyl are optionally substituted by one, two, or three substituents selected from the following: methyl, trifluoromethyl, phenyl, fluorine, chlorine, cyano, ethynyl, carboxyl, chlorophenyl, hydroxyl, fluoromethyl, trifluoromethylmethyl, methoxy, aminoethyl, and pyridyl; wherein the 5- to 6-membered heterocycloalkyl contains one or two heteroatoms selected from O, N, and S, and the 6-membered heteroaryl is preferably pyrimidinyl or pyridinyl; R1 is preferably a cycloalkyl or a cycloalkyl substituted with a carboxyl group; the bridged ring is preferably bicyclo[1.1.1]pentane, and the spirocyclic ring is preferably spiro[2.3]heptane;

[0017] R2 is selected from C1-C3 alkyl and cycloalkyl, preferably methyl or ethyl, more preferably methyl;

[0018] R3 is selected from hydrogen and C1-C3 alkyl, preferably hydrogen or methyl, for example, R3 is attached to Q3;

[0019] A is selected from -CH2-NH-, -CH2-, -CH2-O-, CH2-O-CO-, -NH-COO-, -NHCOO-CH- and covalent bonds, with -CH2-NH- and -CH2-O- being preferred;

[0020] M1 is selected from -CH2-, -NH- and -N(CH3)-;

[0021] M 2、 M3 can be -NH-, -CH2-, or not exist independently;

[0022] Alternatively, M1, M2, and M3, together with the atoms they are attached to, form a 6-membered aryl or a 5-6-membered heteroaryl group, wherein the 6-membered aryl or 5-6-membered heteroaryl group is optionally substituted with one or two fluorine atoms; and the 6-membered aryl group is, for example, a phenyl group, and the 5-6-membered heteroaryl group is, for example, a phenyl group. Diazole, pyridinyl, or pyrimidinyl;

[0023] M4 is -CH2- or does not exist;

[0024] R4 is selected from C1-C3 alkyl groups such as methyl, ethyl, propyl or isopropyl, 3-5 membered cycloalkyl groups such as cyclopropyl, cyclobutyl or cyclopentyl, 3-5 membered cycloalkyl-CH2-, and methoxymethyl; R4 is preferably cyclobutyl or cyclobutylmethyl.

[0025] In some preferred embodiments, for formula I, wherein...

[0026] The structural part is

[0027] In some preferred embodiments, X is O or NHCO, more preferably O.

[0028] In some preferred embodiments, R1 in Formula I is a carboxyl-substituted cyclohexyl group, more preferably...

[0029] In some preferred embodiments, R4 in Formula I is a 3-5 membered cycloalkyl group, such as cyclopropyl, cyclobutyl or cyclopentyl, more preferably cyclobutyl.

[0030] In some preferred embodiments, for formula I, M1, M2, M3 together with the atoms they are attached to form phenyl groups. Diazolyl, pyridyl, or pyrimidinyl.

[0031] In some preferred embodiments, for formula I, wherein The structural part is

[0032] In some preferred embodiments, Y is N for Equation I.

[0033] In some preferred embodiments, the compound of formula I is selected from:

[0034] The compounds particularly preferred by this invention are the following compounds:

[0035] In another aspect, this application provides a pharmaceutical composition comprising a compound of formula I or a stereoisomer thereof as described in this invention, a pharmaceutically acceptable salt or solvate, and a pharmaceutically acceptable carrier.

[0036] On the other hand, this application provides the use of the Formula I compound of the present invention, or its pharmaceutically acceptable isomers, pharmaceutically acceptable salts, or solvates, in the preparation of medicaments for treating or preventing diseases or symptoms related to LPA receptors. The medicament may be an oral dosage form or an injectable dosage form. In some embodiments, the Formula I compound of the present invention, or its pharmaceutically acceptable isomers, pharmaceutically acceptable salts, or solvates, has significantly improved in vivo drug exposure levels; in some embodiments, the Formula I compound of the present invention, or its pharmaceutically acceptable isomers, pharmaceutically acceptable salts, or solvates, has significantly improved pulmonary drug exposure levels.

[0037] Preferably, the LPA receptor-related disease or symptom is selected from cancer, fibrosis, inflammation, pain, and cardiovascular disease; more preferably, the LPA receptor-related disease or symptom is fibrosis, such as pulmonary fibrosis.

[0038] On the other hand, this application provides compounds of Formula I or thereof, or pharmaceutically acceptable isomers, pharmaceutically acceptable salts or solvates thereof, for the treatment or prevention of diseases or symptoms associated with LPA receptors.

[0039] In another aspect, this application provides a method for treating or preventing diseases or symptoms related to LPA receptors, comprising administering to a subject in need a compound of formula I according to the invention or a pharmaceutically acceptable isomer thereof, a pharmaceutically acceptable salt or solvate, or a pharmaceutical composition according to the invention.

[0040] The present invention also relates to a pharmaceutical combination or kit comprising a compound of formula I or a stereoisomer thereof, a pharmaceutically acceptable salt or solvate, and another LPA receptor inhibitor.

[0041] The kit of this invention can consist of a delivery system, a package, or a container box. The container box can be divided into multiple compartments to hold one or more containers, such as tubular bottles, test tubes, and the like, each containing a single component of the method described herein. Suitable containers include bottles, tubular bottles, syringes, and test tubes. The containers are made of acceptable materials such as glass or plastic. For example, the container may contain one or more compounds described herein, which may be present as pharmaceutical components or as mixtures with other components described herein. The container may have a sterile outlet (e.g., the container may be an intravenous infusion pack or bottle, with a stopper that can be punctured by a hypodermic needle). Such a kit may come with one compound and instructions, labeling, or operating instructions for use as described herein. A typical kit may include one or more containers, each containing one or more materials (such as reagents, concentrated stock solutions, and / or instruments) to suit commercial promotion and user needs for compound use. These materials include, but are not limited to, buffer solutions, diluents, filters, needles, syringes, delivery systems, packs, containers, bottles, and / or test tubes, accompanied by a list of contents and / or instructions for use. Instructions for use are also included with the inner packaging. The complete set of instructions must be included.

[0042] Terms and general definitions

[0043] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0044] Unless otherwise stated, the following definitions should be used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the 75th edition of the *Handbook of Chemistry and Physics*, 1994. Furthermore, general principles of organic chemistry can be found in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 1999, and *March's Advanced Organic Chemistry* (Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007), the entire contents of which are incorporated herein by reference.

[0045] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0046] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0047] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereo chemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0048] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0049] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0050] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called prototro pictautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0051] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be substituted at the same or different positions. The substituents mentioned therein may be, but are not limited to, =O, hydrogen, deuterium, cyano, nitro, halogen (preferably fluorine, chlorine, bromine and iodine), hydroxyl, mercapto, amino, alkyl (preferably C1-C4 alkyl), haloalkyl (preferably haloC1-C4 alkyl), alkoxy (preferably C1-C4 alkoxy), carboxyl, cycloalkyl (preferably C3-C5 cycloalkyl), cycloalkyloxy (preferably C3-C5 cycloalkyloxy), heterocyclic (preferably 3 to 6-membered heterocyclic containing 1, 2 or 3 heteroatoms selected from O, S and N), heterocyclic alkyl, heterocyclic oxy, aryl (preferably 6-10-membered aryl), arylalkyl (preferably 6-10-membered aryl C1-C4 alkyl), aryloxy (preferably 6-10-membered aryloxy), heteroaryl (preferably 6-10-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from O, S and N), heteroarylalkyl, heteroaryloxy, etc.

[0052] In this article, "one or more" means one, two, three or more.

[0053] In various parts of this specification, the substituents of the disclosed compounds are disclosed according to the type or range of groups. In particular, the invention includes every independent sub-combination of the members of these types and ranges. For example, the term "C1-C6 alkyl" specifically refers to an independently disclosed C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl.

[0054] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0055] As used in this invention, the term "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 1-6 carbon atoms; in other embodiments, the alkyl group contains 1-4 carbon atoms; and in still other embodiments, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0056] The term “halogenated C1-40 alkyl” means that a C1-40 alkyl group is replaced by one, two or more halogen atoms, and such examples include, but are not limited to, trifluoromethyl.

[0057] The term "cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon ring, preferably a monocyclic hydrocarbon ring. In some embodiments, the cycloalkyl group contains 3-6 carbon atoms, preferably 3-5 carbon atoms, or 3, 4, or 5 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl. In other embodiments, the cycloalkyl group contains 3-5 carbon atoms. The cycloalkyl group may optionally be substituted with one or more substituents described in this invention.

[0058] The term "heterocyclic group" refers to a saturated monocyclic or bicyclic hydrocarbon ring containing at least one heteroatom selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocyclic group is a 5- or 6-membered heterocyclic group. According to the invention, the heterocyclic group is non-aromatic. The heterocyclic group may optionally be substituted by one or more substituents described in this invention. Examples of heterocyclic groups include, but are not limited to, ethylene oxide, thiocyclobutyl, oxecyclopentyl, oxecyclohexyl, pyrrolidinyl, etc.

[0059] The term "halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0060] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic hydrocarbon ring that is monovalent or partially aromatic, preferably "C6-14 aryl," and particularly preferably a 6-membered aryl. Examples of aryl groups may include phenyl, naphthyl, or anthracene, especially phenyl. The aryl group may optionally be substituted by one or more substituents described in this invention.

[0061] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic system, wherein at least one ring contains one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, the heteroaryl group can be attached to the remainder of the molecule (e.g., the main structure in the general formula) through any reasonable site (such as C in CH or N in NH). Examples include, but are not limited to, furanyl, imidazolyl, etc.; and also include, but are not limited to, bicyclic, such as benzimidazolyl, benzofuranyl, etc. The heteroaryl group may optionally be substituted with one or more substituents described in this invention. Particularly preferred heteroaryls are 5- or 6-membered heteroaryls, which are optionally substituted with one or two fluorine atoms.Examples of heteroaromatic rings include, but are not limited to, acridine, azacyclic butyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, cenyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, imidazopyridyl, dihydroindole, indazinyl, indoleyl 3H-Indole, isobenzofuranyl, isochoryl, isoindazole, isodihydroindole, isoindole, isoquinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolopyridyl, oxazolyl, naphthalene-intercalated diazaphenyl, hydroxyindole, pyrimidinyl, phenanthidyl, phenanthrololinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperazine, piperidinyl, piperidone 4-piperidinone, piperin, pteridin, purinyl, pyranyl, pyrazinyl, pyrazolylalkyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridinium-imidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolylalkyl, pyrrololinyl, 2-pyrrolidone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quininecycloyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiaanthryl, thiazolyl Azolyl, thienyl, thiazopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indoleyl, isoindoleyl, dihydroindoleyl, 1H-inzolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromyl, 1,2,3,4-tetrahydroquinoxalinyl and 1,2,3,4-tetrahydroquinazolinyl.

[0062] The term "bridged ring" used in this article refers to polycyclic compounds that share two or more carbon atoms. They can be divided into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. The former consists of two alicyclic rings sharing two or more carbon atoms; the latter is a bridged ring composed of three or more rings.

[0063] The term "spirocycle" used in this article refers to a polycyclic ring in which single rings share a single carbon atom (called a spiro atom).

[0064] As used herein, the term "substitution" means the replacement of at least one hydrogen atom with a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. The cyclic double bond used herein refers to a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0065] The term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both the solution phase and the separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0066] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently selected" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can be independently selected from the same or different specific groups. More specifically, the descriptive phrase "...independently selected" can mean either that the specific options expressed by the same symbol in different groups do not affect each other, or that the specific options expressed by the same symbol in the same group do not affect each other.

[0067] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, etc.

[0068] The term "carrier" refers to a diluent, excipient, excipient, or matrix that is administered together with the compound. These drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Aqueous and aqueous solutions, saline solutions, and aqueous glucose and glycerol solutions are preferred as carriers, particularly injectable solutions. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences".

[0069] As used in this invention, "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates; organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbic acid salts, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, transbutenedioates, glucono-p-methyl, glycerol phosphates, gluconates, hemisulfates, heptahydrates, hexanoates, hydroiodates, 2-hydroxy-ethanesulfonates, lacturonates, lactates, laurates, lauryl sulfates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pyruvates, pectates, persulfates, 3-phenylpropionates, picrates, p-pentanoates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Salts obtained by reaction with suitable bases include alkali metals, alkaline earth metals, ammonium, and N+(C1-4 alkyl)4 salts. This invention also envisions the formation of quaternary ammonium salts from any compound containing an N-group. Water-soluble, oil-soluble, or dispersed products can be obtained via quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates, and aromatic sulfonates.

[0070] In this invention, a "solvent" refers to an association formed by one or more solvent molecules with a compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water. In this invention, solvates include hydrates.

[0071] In this invention, "ester" refers to an ester that is hydrolyzable in vivo, formed from a compound containing a hydroxyl or carboxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that, upon hydrolysis in a human or animal body, produces a parent alcohol or acid. The compounds of Formula I of this invention contain a carboxyl group and can form hydrolyzable esters in vivo with suitable groups, including, but not limited to, alkyl, arylalkyl, etc.

[0072] The term "nitrogen oxide" in this invention refers to an N-oxide formed by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen atoms in nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides.

[0073] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0074] Unless otherwise stated, any abbreviations for protecting groups, amino acids and other compounds used in this invention shall be those that are commonly used and recognized, or refer to the IUPAC-IUB Commission on Biochemical Nomenclature.

[0075] The bioactivity of the compounds of this invention can be assessed using any conventionally known method. Suitable detection methods are well known in the art. For example, the LPAR1 inhibitory activity, pharmacokinetic activity, and / or liver microsomal stability of the compounds of this invention can be detected by suitable conventional methods. The detection methods provided by this invention are presented by way of example only and do not limit the invention. The compounds of this invention are active in at least one of the detection methods provided by this invention.

[0076] The term "pharmaceutical composition" refers to a composition comprising the compounds of the present invention and at least one pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable medium or excipient commonly accepted in the art for delivering a bioactive agent to animals (specifically mammals), including (i.e.) adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. The pharmaceutical excipients described may be those widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipients may be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient in the composition. Pharmaceutically acceptable excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0077] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicates, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0078] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0079] The dosage form of the drug of this invention can be selected according to specific circumstances. A drug dosage form typically consists of a drug, excipients, and a container / sealing system. One or more excipients (also known as inactive ingredients) can be added to the compounds of this invention to improve or enhance the manufacture, stability, administration, and safety of the drug, and to provide a method for obtaining the desired drug release profile. Therefore, the type of excipient added to the drug can be determined by various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias. (See the United States Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); publications of the Center for Drug Evaluation and Research (CEDR) of the US Food and Drug Administration (www.fda.gov), such as the Inactive Ingredient Guide (1996); the Handbook of Pharmaceutical Additives (2002) by Ash; Synapse Information Resources, Inc. (Endicott NY); etc.)

[0080] The pharmaceutical compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate the processing of active molecules into formulations for pharmaceutical use.

[0081] The appropriate formulation depends on the desired route of administration. Routes of administration include intravenous injection, administration via mucosa or nose, and oral administration. For oral administration, compounds can be formulated into liquid or solid dosage forms and presented as immediate-release or controlled-release / sustained-release formulations. Suitable dosage forms for individual oral intake include tablets, pills, sugar-coated pills, hard-shell and soft-shell capsules, liquids, gels, syrups, ointments, suspensions, and emulsions.

[0082] Solid oral dosage forms can be obtained using excipients, including fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, flow aids, anti-adhesion agents, cation exchange resins, humectants, antioxidants, preservatives, colorants, and flavoring agents. These excipients can be synthetic or of natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silica, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth gum, hydrogenated vegetable oils, and waxes. Ethanol and water can be used as granulation aids. In some cases, tablets need to be coated with, for example, a taste-masking film, an acid-resistant film, or a delayed-release film. Natural and synthetic polymers are often combined with colorants, sugars, and organic solvents or water to coat tablets, resulting in sugar-coated pills. When capsules are preferred over tablets, their drug powders, suspensions, or solutions can be delivered in compatible hard-shell or soft-shell capsule forms.

[0083] The effective therapeutic dose can be estimated first using various methods well known in the art. The initial dose for animal studies can be based on the effective concentration established in cell culture assays. The appropriate dose range for individual humans can be determined, for example, using data obtained from animal studies and cell culture assays. In some embodiments, the compounds of the present invention can be prepared as oral formulations.

[0084] The appropriate formulation, route of administration, dosage, and dosing interval can be selected based on methods known in the art and taking into account the specific circumstances of the individual.

[0085] In the description of this specification, references to terms such as "some embodiments," "examples," or "a preferred embodiment," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0086] In the specification and claims, the given chemical formula or name shall cover all stereoisomers (including optical isomers) and racemic products containing such isomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this invention. Many geometric isomers such as C=C double bonds, C=N double bonds, ring systems, etc., may also be present in the compounds, and all such stable isomers are covered within this invention. This invention describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of this invention, which can be separated into mixtures of isomers or separate isomeric forms. The compounds of this invention can be separated in optically active or racemic forms. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. In the preparation of enantiomers or diastereomers, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the method conditions, the final products of this invention are obtained in free (neutral) or salt form. The free forms of these end products and their salts are all within the scope of this invention. If desired, one form of the compound can be converted to another. A free base or acid can be converted to a salt; a salt can be converted to a free compound or another salt; a mixture of isomers of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms, and their salts can exist in a variety of tautomeric forms, wherein hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all possible tautomeric forms are included within the scope of this invention.

[0087] Unless otherwise defined, when a substituent is labeled "optionally substituted," the substituent is selected from, for example, the following substituents: alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine group (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl. Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamide such as -SO2NH2, substituted sulfonamide, nitro, cyano, carboxyl, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or having two substituents selected from alkyl, aryl or arylalkyl on nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidine, heterocyclic, such as indolyl, imidazolyl, furanyl, thiophene, thiazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine, homopiperazine, etc., and substituted heterocyclic groups.

[0088] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0089] In this document, "LPA receptor-related diseases or symptoms" refers to diseases or conditions whose occurrence or development is related to LPA receptors. These LPA receptor-related diseases or symptoms can be selected from wound healing, cancer, fibrosis, pain, respiratory diseases, allergic diseases, chronic kidney disease, interstitial lung disease, neurological diseases, cardiovascular diseases, and inflammatory diseases. The fibrosis is preferably selected from pulmonary fibrosis, renal fibrosis, liver fibrosis, ocular fibrosis, myocardial fibrosis, and systemic sclerosis. The pulmonary fibrosis is, for example, idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD). Attached Figure Description

[0090] Figure 1 is a lung tissue staining diagram showing the effect of the compound of the present invention in alleviating bleomycin-induced pulmonary fibrosis in mice. Detailed Implementation

[0091] To better illustrate the technical means and effects of this disclosure, the following description, in conjunction with non-limiting examples, further describes the disclosure. The embodiments of this disclosure (including the descriptions provided in the embodiments) are intended to illustrate the implementation of this disclosure and are not intended to limit the scope of any claim. Based on this disclosure, those skilled in the art will understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of this disclosure, and the same or similar results can still be obtained.

[0092] Example 1

[0093] Reaction route:

[0094] Experimental procedure:

[0095] 1.

[0096] Compound DF301-S1 (30 g, 157.88 mmol) was dissolved in 1-methyl-2-pyrrolidone (200 mL), followed by the addition of 2-hydroxymethylpyrrolidone (18 g, 177.96 mmol) and potassium carbonate (43.64 g, 315.77 mmol) at 20-30 °C. The reaction solution was then heated to 130-140 °C and reacted for 6 hours. TLC (petroleum ether:ethyl acetate = 2:1, Rf) P1The result of 0.3 indicates that the starting material was completely consumed. The reaction mixture was cooled to room temperature, and water (1000 mL) was added. The aqueous phase was extracted with ethyl acetate (300 mL * 2), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. It was then purified by column chromatography (petroleum ether / ethyl acetate = 30:1 to 10:1). DF301-1 (41 g, yield: 95.77%) was obtained.

[0097] LCMS(ESI,m / z):[M+H] + =271.0

[0098] 2.

[0099] Compound DF301-1 (3 g, 11.06 mmol) and pyridine (3 g, 37.93 mmol) were dissolved in anhydrous dichloromethane (2250 mL), and then p-nitrobenzene chloroformate (3 g, 14.88 mmol) was added at 15–25 °C, and the reaction was allowed to proceed for 1 hour. TLC (petroleum ether:ethyl acetate = 1:1, Rf) P1 The result of 0.4 indicates that the raw materials have been completely consumed. 10 mL of tert-butyl methyl ether was added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure to obtain DF301-2 (4.1 g, yield: 84.94%).

[0100] LCMS(ESI,m / z):[M+H] + =436.04

[0101] 3.

[0102] Compound DF301-2 (3 g, 6.88 mmol) and N,N-diisopropylethylamine (3.00 g, 23.21 mmol) were dissolved in tetrahydrofuran (30 mL). (Cyclobutanemethyl)methylamine hydrochloride (426 g, 1.31 mol) was added under a nitrogen atmosphere, and the reaction was carried out at 15-25 °C for 1 hour. LCMS (EC20710-33-P1R1) monitoring revealed the formation of compound DF301-3. The reaction solution was concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 50:1 to 30:1) yielded DF301-3 (2.1 g, 77.05% yield).

[0103] LCMS(ESI,m / z):[M+H] + =396.12

[0104] 4.

[0105] Compound DF301-3 (0.8 g, 2.02 mmol), bis(diphenylphosphine)boronic acid ester (800 mg, 3.15 mmol), and potassium acetate (720.00 mg, 7.34 mmol) were dissolved in anhydrous dioxane (10 mL). 1,1-bis(diphenylphosphine)ferrocene palladium chloride (150 mg, 205.00 μmol) was added under a nitrogen atmosphere at 15–25 °C. The reaction solution was heated to 100–110 °C and reacted for 2 hours. LCMS (EC20710-40-P1R1) showed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure and purified by acid reversed-phase high-performance liquid chromatography (CD05-Phenomenex luna C18 150*40*10um; mobile phase: [water(HCl)-ACN]; gradient: 35%-65% B over 10min) to obtain DF301-4 (200mg, yield 27.43%).

[0106] LCMS(ESI,m / z):[M+H] + =362.22

[0107] 5.

[0108] Compound DF301-4 (200 mg, 553.64 μmol) was dissolved in water (1 mL) and tetrahydrofuran (1 mL), then sodium perborate monohydrate (110 mg, 1.10 mmol) was added at room temperature, and the mixture was heated to 60-70 °C and reacted for 1 hour. LCMS (EC20710-46-P1R1) showed that the starting material was completely consumed. Water (5 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (10 mL * 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was then purified by thin-layer chromatography (SiO2, petroleum ether:ethyl acetate = 1:1, Rf P1 =0.2) yielded DF301-5 (120mg, yield 65.01%).

[0109] LCMS(ESI,m / z):[M+H] + =334.21

[0110] 6.

[0111] Compound DF301-5 (200 mg, 1.07 mmol) and isopropyl(1S,3R)-3-hydroxycyclohexane-1-carboxylic acid (190 mg, 569.84 μmol) were dissolved in toluene (5 mL). Then, under nitrogen protection at room temperature, 1,1-azodicarboxylic acid dipiperidine (190 mg, 569.84 μmol) and tributylphosphine (200 mg, 988.55 μmol) were added, and the mixture was heated to 90-100 °C and reacted for 1 hour. LCMS (EC20710-53-P1R2) showed complete consumption of the starting materials. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by thin-layer chromatography (SiO2, petroleum ether:ethyl acetate = 3:1, Rf...). P1 =0.6) yielded DF301-6 (115mg, yield 40.23%).

[0112] LCMS(ESI,m / z):[M+H] + =502.32

[0113] 7.

[0114] Compound DF301-6 (110 mg, 219.27 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and then lithium hydroxide monohydrate (2 M, 438.55 μL) was added at room temperature. The mixture was heated to 60-70 °C and reacted for 1 hour. LCMS (EC20710-57-P1R2) showed that the starting material was completely consumed. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by neutral reversed-phase high-performance liquid chromatography (CD02-Waters Xbidge BEH C18 150*25*10 μm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 26%-56% B over 10 min) to obtain DF301 (40 mg, 83.62 μmol, yield 38.13%).

[0115] LCMS(ESI,m / z):[M+H] + =460.27

[0116] 1H NMR (400MHz, CDCl3) δppm 7.27(d,J=8.00Hz,1H)6.34(d,J=8.00Hz,1H)4.96-4.66(m,1H)4.35-4.20(m,3H)3.93-3.91(m,1H)3.49-3.47(m,1H)3.25 (s,3H)2.88(s,3H)2.87(d,J=16.7Hz,1H)2.73(m,1H)2.56(m,1H)2.36-2.33(m,3H).2.01–1.70(m,16H)1.49–1.42(m,2H).

[0117] Example 2

[0118] Reaction route:

[0119] Experimental procedure:

[0120] 1:

[0121] DF-B59-S1 (1 g, 7.93 mmol) was added to anhydrous tetrahydrofuran (10 mL), and the mixture was cooled to 5-15 °C. A 1 M, 27.8 mL solution of borane tetrahydrofuran was added dropwise, and the reaction mixture was heated to 65-70 °C and reacted at 65-70 °C for 4 hours. TLC (petroleum ether: ethyl acetate = 1:1) showed that compound DF-B59-S1 was completely consumed. Methanol (10 mL) and 2 M hydrochloric acid (2 mL) were added dropwise at 0-10 °C, and the mixture was stirred at 15-25 °C for 1 hour, then concentrated under reduced pressure. The crude compound DF-B59-1 (800 mg) was obtained by silica gel column chromatography.

[0122] LCMS(ESI,m / z):[M+H] + =113.1

[0123] 2:

[0124] Compounds DF-B59-1 (605 mg, 5.39 mmol), DF-B59-S2 (1.00 g, 3.60 mmol), cesium carbonate (1.52 g, 4.67 mmol), and cuprous iodide (68.5 mg, 360 μmol) were dissolved in dimethyl sulfoxide (10 mL). The reaction solution was heated to 140–145 °C and then reacted at 140–145 °C for 12 hours. LC-MS showed that compound DF-B59-S2 was completely consumed. The reaction solution was diluted with water (50 mL), the aqueous phase was extracted with ethyl acetate (25 mL * 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by silica gel column chromatography to obtain compound DF-B59-2 (200 mg, crude).

[0125] LCMS(ESI,m / z):[M+H] + =310.1

[0126] 3:

[0127] Compound DF-B59-2 (200 mg, 646 μmol) and pyridine (Py) (153 mg, 1.94 mmol) were dissolved in anhydrous dichloromethane (2.00 mL), followed by the addition of p-nitrobenzene chloroformic acid (169 mg, 840 μmol). The reaction was carried out at 15–25 °C for 1 hour. LC-MS showed complete consumption of compound DF-B59-2. Concentration under reduced pressure yielded compound DF-B59-3 (307 mg, crude product).

[0128] LCMS(ESI,m / z):[M+H] + =475.2

[0129] 4:

[0130] Compound DF-B59-3 (307 mg, 647 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and N,N-diisopropylethylamine (284 mg, 2.20 mmol) and (cyclobutanemethyl)methylamine hydrochloride (114 mg, 841 μmol) were added. The reaction was carried out at 15–25 °C for 0.5 h. LC-MS showed that compound DF-B59-3 was completely consumed. The solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 2), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by thin-layer chromatography to give compound DF-B59-4 (270 mg, crude product).

[0131] LCMS(ESI,m / z):[M+H] + =435.3

[0132] 5:

[0133] Palladium on carbon (61.2 mg, 57.5 μmol, 10% purity) was dissolved in methanol (5 mL) under an argon atmosphere. Compound DF-B59-4 (250 mg, 575 μmol) was added, and the argon atmosphere was replaced three times with hydrogen. The reaction was carried out under a hydrogen atmosphere (15 Psi) at 25-30 °C with stirring for 2 hours. LCMS (EC19808-514-P1R1) showed that compound DF-B59-4 was completely consumed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. DF-B59-5 (140 mg, crude product) was obtained by silica gel column chromatography.

[0134] LCMS(ESI,m / z):[M+H] + =345.2

[0135] 6:

[0136] Compound DF-B59-5 (130 mg, 377 μmol) and isopropyl(1S,3R)-3-hydroxycyclohexane-1-carboxylic acid (140.60 mg, 754.92 μmol) were dissolved in anhydrous toluene (2 mL), purged three times with nitrogen, and heated to 90-95 °C. Then, tributylphosphine (267 mg, 1.32 mmol) and 1,1-azodicarbonylpiperidine (333 mg, 1.32 mmol) were added, and the reaction was stirred at 90-95 °C for 2 hours. LC-MS showed that compound DF-B59-5 was completely consumed. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL * 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. DF-B59-6 (190 mg, crude product) was obtained by silica gel column chromatography.

[0137] LCMS(ESI,m / z):[M+H] + =513.4

[0138] 7:

[0139] Compound DF-B59-6 (190 mg, 371 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (2 M, 834 μL) was added. The reaction was carried out at 50-55 °C for 1 hour. LC-MS showed that compound DF-B59-6 was completely consumed. The pH of the reaction solution was adjusted to 7-8 with hydrochloric acid (0.50 M), and the solution was concentrated under reduced pressure. The solution was purified by reversed-phase high-performance liquid chromatography (column: CD20-Waters Xbidge BEH C18 250*25*10 μm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 19%-49% B over 15 min) to give compound DF-B59 (46.26 mg, yield: 26.5%).

[0140] LCMS(ESI,m / z):[M+H] + =471.2

[0141] 1 H NMR(400MHz,DMSO-d6)δppm 7.71-7.28(m,3H)5.50-5.30(m,2H)4.73(s,1H)3.17(d,J=5.50Hz,1H)2.87(d,J=6.50 Hz,1H)2.79-2.53(m,3H)2.45(s,1H)2.36(s,3H)2.28-2.01(m,4H)1.97-1.28(m,14H).

[0142] Example 3

[0143] Reaction route:

[0144] Experimental procedure:

[0145] 1:

[0146] Compound DF-B60-S1 (17.6 g, 179 mmol, 1.00 eq) was dissolved in DMSO (500 mL). NaN3 (23.0 g, 353 mmol, 1.97 eq) was slowly added in portions at 25 °C. The reaction mixture was reacted at 50 °C for 0.5 h, then heated to 80 °C and reacted for another 0.5 h. TLC (petroleum ether / ethyl acetate = 20:1) confirmed the complete reaction of starting material DF-B60-S1, and the formation of compound DF-B60-1. A 7% NaClO aqueous solution (100 mL) was slowly added to the reaction mixture at 25 °C, and the mixture was stirred at 25 °C for 0.5 h. The pH of the system was then adjusted to 2–3 with hydrochloric acid (3.00 M). The mixture was then extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was pulped and purified at 25°C, filtered and washed, and dried to obtain the product, yielding compound DF-B60-1 (13.5 g, yield: 53.3%).

[0147] LCMS(ESI,m / z):[M+H] + =142.1

[0148] 2:

[0149] Compounds DF-B60-1 (7.00 g, 49.6 mmol, 1.00 eq), DF-B60-S2 (12.3 g, 64.5 mmol, 1.30 eq), and K2CO3 (13.7 g, 99.2 mmol, 2.00 eq) were dissolved in DMF (100 mL), and the reaction mixture was reacted at 125 °C for 2 hours. LC-MS monitoring revealed the formation of compound DF-B60-2. The reaction mixture was diluted with H2O (300 mL) at 25 °C, extracted with EtOAc (500 mL * 2), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure, precipitating a solid. The solid was then dried after filtration to obtain the product. Compound DF-B60-2 (3.33 g, yield: 41.6%) was obtained.

[0150] LCMS(ESI,m / z):[M+H] + =310.9

[0151] 3:

[0152] Compound DF-B60-2 (2.83 g, 9.10 mmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (50.0 mL), and N2 was replaced three times. The system was cooled to 0–5 °C, and LiBH4 (2.00 M, 6.82 mL, 1.50 eq) was added dropwise. The reaction solution was reacted at 25 °C for 7 hours. LC-MS showed that compound DF-B60-2 was completely consumed, and compound DF-B60-3 was detected. Saturated NH4Cl aqueous solution (30.0 mL) was slowly added dropwise to the reaction solution at 0 °C, and the mixture was concentrated to obtain the crude product. The crude product was dissolved in MeOH (20.0 mL), filtered, and the filtrate was concentrated to obtain the product. Compound DF-B60-3 (2.33 g, yield: 41.6%) was obtained.

[0153] LCMS(ESI,m / z):[M+H] + =282.9

[0154] 4:

[0155] Compounds DF-B60-3 (1.00 g, 3.53 mmol, 1.00 eq), DF-B40-S3 (1.42 g, 7.06 mmol, 2.00 eq), and pyridine (838 mg, 10.6 mmol, 3.00 eq) were dissolved in dichloromethane (50.0 mL). After purging with nitrogen three times, the system was reacted at 25 °C for 1 hour. LC-MS showed complete consumption of compound DF-B60-3, and monitoring revealed the formation of compound DF-B60-4. The reaction solution was diluted with water (5.00 mL), extracted with DCM (5.00 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography yielded compound DF-B60-4 (1.45 g, 91.6% yield).

[0156] LCMS(ESI,m / z):[M+H] + =450.0

[0157] 5:

[0158] Compound DF-B60-4 (1.45 g, 3.23 mmol, 1.00 eq) was dissolved in DCM (50.0 mL), and DF-B40-5 (570 mg, 4.21 mmol, 1.30 eq, HCl) and DIEA (1.25 g, 9.70 mmol, 1.69 mL, 3.00 eq) were added. The reaction was carried out at 25 °C for 1 hour. TLC (petroleum ether / ethyl acetate = 3:1) confirmed that the starting material DF-B60-4 had completely reacted and compound DF-B60-6 was formed. The reaction solution was diluted with water (20.0 mL) dropwise, and then extracted with DCM (20.0 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by silica gel column chromatography to give compound DF-B60-6 (1.17 g, yield 88.6%).

[0159] LCMS(ESI,m / z):[M+H] + =410.1

[0160] 6:

[0161] Compounds DF-B60-6 (1.17 g, 2.87 mmol, 1.00 eq), B2pin2 (1.09 g, 4.30 mmol, 1.50 eq), Pd(dppf)Cl2 (210 mg, 287 μmol, 0.10 eq), and KOAc (1.12 g, 11.5 mmol, 4.00 eq) were dissolved in dioxane (20 mL) and reacted at 100 °C for 1 hour. LC-MS showed complete consumption of compound DF-B60-6, and monitoring revealed the formation of compound DF-B60-7. Concentration under reduced pressure yielded compound DF-B60-7 (1.30 g, crude product).

[0162] LCMS(ESI,m / z):[M+H] + =456.2

[0163] 7:

[0164] Compound DF-B60-7 (1.30 g, 2.85 mmol, 1.00 eq) was dissolved in THF (20.0 mL) and H₂O (10.0 mL), and NaBO₃ (598 mg, 6.00 mmol, 2.10 eq) was added. The reaction mixture was reacted at 60 °C for 0.5 h. LCMS showed that compound DF-B60-7 was completely consumed, and compound DF-B60-8 was detected to form. The reaction mixture was diluted with water (20.0 mL), and then extracted with EtOAc (20.0 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography to give compound DF-B60-8 (1.21 g).

[0165] LCMS(ESI,m / z):[M+H] + =346.0

[0166] 8:

[0167] Compound DF-B60-8 (200 mg, 579 μmol, 1.00 eq) was dissolved in THF (8.00 mL), and DF-B60-9 (162 mg, 869 μmol, 1.50 eq), PPh3 (380 mg, 1.45 mmol, 2.50 eq), and DBAD (333 mg, 1.45 mmol, 2.50 eq) were added. The reaction was carried out at 25 °C for 3 hours. LCMS showed that compound DF-B60-8 was completely consumed, and compound DF-B60-10 was detected as formed. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound DF-B60-10 (180 mg, yield 60.5%).

[0168] LCMS(ESI,m / z):[M+H] + =514.3

[0169] 9:

[0170] Compound DF-B60-10 (180 mg, 350 μmol, 1.00 eq) was dissolved in MeOH (5.00 mL) and THF (5.00 mL), and lithium hydroxide monohydrate (2.00 M in H2O, 0.80 mL, 4.50 eq) was added. The reaction solution was reacted at 40 °C for 3.5 hours. LC-MS showed that compound DF-B60-10 was completely consumed, and monitoring revealed the formation of compound DF-B60. The pH of the reaction solution was adjusted to 7–8 with hydrochloric acid (1.00 M), and then concentrated under reduced pressure. The compound DF-B60 was purified by neutral reversed-phase high-performance liquid chromatography (column: CD02-Waters Xbidge BEH C18 150*25*10um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 19%-49% B over 10min). After purification, the organic phase was concentrated, and the aqueous phase was lyophilized to obtain the product, yielding compound DF-B60 (63.98mg, yield: 38.7%).

[0171] LCMS(ESI,m / z):[M+H] + =472.2

[0172] H NMR: (400MHz, CDCl3) δ7.75(d,J=8.4Hz,1H),7.28(d,J=8.4Hz,1H),5.27(s,2H),4.68(m,1H),3.24-3.34(m,2H),2.88( d,J=16.4Hz,3H),2.58(s,3H),2.49-2.53(m,1H),2.44(s,3H),2.13-2.16(m,1H),1.84-2.01(m,7H),1.63-1.78(m,7H).

[0173] Example 5

[0174] Reaction route:

[0175] Experimental procedure:

[0176] 1:

[0177] Compound DF-B72-S2 (5.00 g, 39.7 mmol) was added to anhydrous tetrahydrofuran (50.0 mL), and the reaction was cooled to 0 °C. Borane tetrahydrofuran (1 M, 138 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for half an hour, followed by a reaction at 70 °C for 4 hours. Thin-layer chromatography (ethyl acetate: petroleum ether = 1:1) was used to monitor the completeness of the reaction. Methanol (40.0 mL) and hydrochloric acid (2 M, 20.0 mL) were slowly added dropwise to the reaction solution at 0–10 °C. The mixture was extracted with ethyl acetate (50.0 mL * 3), and the organic phase was directly concentrated to give compound DF-B72-7 (4.00 g, yield: 89.9%).

[0178] LCMS(ESI,m / z):[M+H] + =113.1

[0179] 2:

[0180] Compounds DF-B72-S1 (4.90 g, 17.6 mmol), DF-B72-7 (2.96 g, 26.4 mmol), cuprous iodide (335 mg, 1.76 mmol), and cesium carbonate (2.96 g, 26.4 mmol) were dissolved in dimethyl sulfoxide (40.0 mL) and reacted at 140 °C for 12 hours. Thin-layer chromatography and LCMS monitoring revealed the formation of compound DF-B72-1. The reaction solution was cooled to room temperature, and water (20.0 mL) was added. Extraction was performed at 25 °C with ethyl acetate (10.0 mL x 3), followed by washing with brine (20.0 mL x 1). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound DF-B72-1 (600 mg, yield: 10.3%).

[0181] LCMS(ESI,m / z):[M+H] + =310.3

[0182] 3:

[0183] Compounds DF-B72-1 (200 mg, 646 μmol), DF-B72-S3 (169 mg, 840 μmol), and pyridine (153 mg, 1.94 mmol) were added to anhydrous dichloromethane (5.00 mL) and the reaction mixture was heated to 25 °C and reacted for 4 hours. LCMS monitoring revealed the formation of compound DF-B72-2. The reaction mixture was concentrated under reduced pressure to obtain compound DF-B72-2 (3000 mg, crude product), which was directly used in the next step.

[0184] LCMS(ESI,m / z):[M+H] + =475.1

[0185] 4:

[0186] Compounds DF-B72-2 (300 mg, 632 μmol), DIEA (278 mg, 2.15 mmol), and DF-B72-S4 (60.1 mg, 822 μmol) were added to anhydrous tetrahydrofuran (5.00 mL) and reacted at 25 °C for 1 hour. LC-MS monitoring revealed the formation of compound DF-B72-3. The reaction solution was extracted with ethyl acetate (10.0 mL * 3) at room temperature, washed with brine (20.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thin-layer chromatography (TLC) purification yielded compound DF-B72-3 (200 mg, yield: 77.5%).

[0187] LCMS(ESI,m / z):[M+H] + =409.1

[0188] 5:

[0189] The hydrogenation flask was cleaned and dried, and placed in an argon atmosphere. Linde catalyst (101 mg, 48.9 μmol, 10.0%) was added. After wetting the catalyst with methanol, compound DF-B72-3 (200 mg, 489 μmol) was added to replace the hydrogen three times. The reaction was carried out at 25°C under hydrogen (15 Psi) for 4 hours. Thin-layer chromatography and LCMS showed complete consumption of the starting material. The reaction mixture was filtered with diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to obtain compound DF-B72-4 (150 mg, yield: 96.2%).

[0190] LCMS(ESI,m / z):[M+H] + =319.1

[0191] 6:

[0192] Compounds DF-B72-4 (140 mg, 440 μmol) and DF-B72-5 (164 mg, 879 μmol) were dissolved in anhydrous toluene (3.00 mL). The system was heated to 95 °C under a nitrogen atmosphere, and 1,1-azodicarbonylpiperidine (388 mg, 1.54 mmol) and tributylphosphine (311 mg, 1.54 mmol) were added. The reaction was carried out at 95 °C for 2 hours. The formation of compound DF-B7-6 was detected by thin-layer chromatography and LCMS. The reaction solution was cooled to room temperature, and water (10.0 mL) was added. The mixture was extracted with ethyl acetate (20.0 mL * 2), and the organic phase was concentrated under reduced pressure. After separation and purification by thin-layer chromatography, compound DF-B72-6 (200 mg, yield: 93.4%) was obtained.

[0193] LCMS(ESI,m / z):[M+H] + =487.3

[0194] 7:

[0195] Compound DF-B72 (110 mg, 411 μmol) was added to anhydrous methanol (1.00 mL), followed by the addition of lithium hydroxide monohydrate (2 M, 822 μL). The system was heated to 25 °C and reacted for 1 hour. LC-MS showed complete consumption of the starting material. After removing the methanol, water (5.00 mL) was added, and the pH of the solution was adjusted to 7 with hydrochloric acid (0.5 M). The organic phase was then concentrated directly under reduced pressure using ethyl acetate (10.0 mL * 3). The solution was purified by neutral reversed-phase high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18 150*25*7 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 11.0 min) to obtain compound DF-B72 (57.48 mg, yield: 31.3%).

[0196] LCMS(ESI,m / z):[M+H] + =455.22

[0197] 1 H NMR: (400MHz, CHLOROFORM-d) δ = 7.52 (d, J = 8.8Hz, 1H), 7.48-7.45 (m, 1H), 7.27-7.23 (m, 1H), 5.50 (br d,J=8.0Hz,2H),4.68-4.62(m,1H),3.26-3.15(m,1H),2.94(br d,J=4.8Hz,1H),2.91-2.77(m,3H),2.69-2.61(m,2H),2.45(s,3H),2.16(s,3H),1.97-1.88(m,3H ),1.80-1.71(m,1H),1.69-1.60(m,3H),1.57-1.46(m,1H),1.30-1.24(m,1H),0.90-0.62(m,3H).

[0198] Example 6

[0199] Reaction route:

[0200] Experimental procedure:

[0201] 1.

[0202] Compound 7 (10 g, 67.1 mmol) and ferric acetylacetone (1.19 g, 3.36 mmol) were dissolved in tetrahydrofuran (90 mL). The reaction system was cooled to -70 to -65 °C, and compound 8 (0.5 M, 100 mL) was added under a nitrogen atmosphere. The reaction was stirred at -70 to -65 °C for 1 hour. The formation of compound 2 was detected by thin-layer chromatography (petroleum ether / ethyl acetate = 20 / 1). The reaction solution was cooled to 0-5 °C and quenched with saturated ammonium chloride aqueous solution (80 mL). Extraction was performed with ethyl acetate (80 mL x 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 2 (3.00 g, crude product) was obtained by column chromatography.

[0203] LCMS:(ESI,m / z):[M+H] + =168.06

[0204] 2.

[0205] Compound 1 (150 mg, 485 μmol) and compound 2 (102 mg, 606 μmol) were dissolved in tetrahydrofuran (2.00 mL). The reaction solution was cooled to 0–5 °C, and a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 975 μL) was added at this temperature. The reaction was carried out at 25–30 °C for 1 hour. LC-MS monitoring revealed the formation of compound 3, and incomplete consumption of compound 1. The reaction solution was cooled to 0–5 °C and quenched with saturated ammonium chloride aqueous solution (30 mL). Extraction was performed with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by thin-layer chromatography to give compound 3 (100 mg, yield: 46.7%).

[0206] LCMS:(ESI,m / z):[M+H] + =441.22

[0207] 3.

[0208] Compound 3 (80 mg, 181 μmol) was dissolved in methanol (5.00 mL), and Lindela catalyst (37.4 mg, 18.1 μmol, 10% purity) was added at room temperature. Hydrogen gas was bubbled into the reaction solution and purged three times. The reaction was carried out under a hydrogen atmosphere at 25 °C (15 psi) for 1 hour. LC-MS was used to monitor complete consumption of the starting material. The reaction solution was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography to obtain compound 4 (0.06 g, crude product).

[0209] LCMS:(ESI,m / z):[M+H] + =351.17

[0210] 4.

[0211] Compound 4 (50.0 mg, 143 μmol) and compound 5 (100 mg, 294 μmol) were dissolved in N,N-dimethylformamide (3.00 mL), and potassium carbonate (40.0 mg, 289 μmol) was added. The mixture was then heated to 105 °C and reacted for 12 hours. LCMS was used to monitor complete consumption of the starting materials. 10 mL of H₂O was added to the reaction mixture, followed by extraction with ethyl acetate (10.0 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain compound 6 (0.065 g, crude product).

[0212] LCMS:(ESI,m / z):[M+H] + =519.28

[0213] 5.

[0214] Compound 6 (60.0 mg, 115 μmol) was dissolved in methanol (1.00 mL) and tetrahydrofuran (1.00 mL), and lithium hydroxide monohydrate aqueous solution (2.0 M, 429 μL) was added. The mixture was heated to 60 °C and reacted for 1 hour. LC-MS monitoring showed that the starting material was completely consumed. The pH of the system was adjusted to 6-7 with hydrochloric acid (1 M), and the crude product was concentrated under reduced pressure. The crude product was purified by neutral reversed-phase high-performance liquid chromatography (column: CD). 07 -Daisogel SP-100-8-ODS-PK 150*25*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 23%-53% B over 10.0min), to obtain compound DF-B73 (20.0mg, yield: 36.3%, purity: 99.9%).

[0215] LCMS:(ESI,m / z):[M+H] + =477.24

[0216] 1H NMR: (400MHz, MeOD), 8.35 (d, J=5.2Hz, 1H), 7.51-7.47 (m, 3H), 6.95 (d, J=4.8Hz, 1H), 5.85 (s, 2H), 4.74 (s, 1H), 3.61-3.53 (m, 1H), 2.77 –2.73(m,1H),2.41–2.22(m,4H),2.19(s,3H),2.14(s,3H),2.06–1.90(m,2H),1.89-1.75(m,4H),1.74-1.60(m,3H),1.47-1.25(m,1H).

[0217] Example 7

[0218] Reaction route:

[0219] Experimental procedure:

[0220] 1:

[0221] Compounds DF-B72-1 (300 mg, 970 μmol, 1.00 eq) and DF-B74-S1 (231 mg, 1.45 mmol, 1.50 eq) were dissolved in THF (5.00 mL). tBuOK (1.00 M in THF, 1.94 mL, 2.00 eq) was slowly added dropwise at 0–5 °C, and the reaction mixture was reacted at 25 °C for 1 hour. LC-MS showed complete consumption of the starting materials. A saturated NH4Cl aqueous solution (10.0 mL) was added to the reaction mixture at 25 °C, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by thin-layer chromatography to give compound DF-B74-1 (100 mg, yield: 23.6%).

[0222] LCMS(ESI,m / z):[M+H] + =432.2

[0223] 2:

[0224] Compound DF-B74-1 (100 mg, 232 μmol, 1.00 eq) was dissolved in MeOH (5.00 mL). Lindlar catalyst (95.7 mg, 46.4 μmol, 10.0% purity, 0.20 eq) was added at 25 °C. The reaction mixture was reacted at 25 °C for 1 hour under a hydrogen atmosphere (15 psi). LC-MS showed complete consumption of the starting material. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH (50.0 mL). The organic phases were combined and concentrated under reduced pressure to give compound DF-B74-2 (62.0 mg, yield: 78.4%).

[0225] LCMS:(ESI,m / z):[M+H] + =342.1

[0226] 3:

[0227] Compounds DF-B74-2 (52.0 mg, 152 μmol, 1.00 eq), DF-B74-S2 (77.8 mg, 229 μmol, 1.50 eq), and K2CO3 (42.1 mg, 305 μmol, 2.00 eq) were dissolved in DMF (3.00 mL), and the reaction mixture was reacted at 100 °C for 8 hours. LC-MS showed complete consumption of the starting materials. Water (5.00 mL) was added to the reaction mixture at 25 °C, and the mixture was extracted with ethyl acetate (5.00 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product compound DF-B74-3 (54.0 mg, yield: 67.0%) was obtained by separation and purification using thin-layer chromatography.

[0228] LCMS:(ESI,m / z):[M+H] + =510.4

[0229] 4:

[0230] Compound DF-B74-3 (54.0 mg, 106 μmol, 1.00 eq) was dissolved in MeOH (2.00 mL) and THF (2.00 mL). Lithium hydroxide (238 μL, 2.00 M in H2O, 4.5 eq) was added at 25 °C, and the reaction mixture was reacted at 40 °C for 1 hour. LC-MS showed complete consumption of the starting material and formation of compound DF-B74. The pH of the reaction mixture was adjusted to 7–8 with hydrochloric acid (2.00 M), and then concentrated under reduced pressure. The mixture was purified by neutral reversed-phase high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18 150*25*7 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 13%–43% Bover 11.0 min) to obtain compound DF-B74 (12.63 mg, yield: 25.4%).

[0231] LCMS(ESI,m / z):[M+H] + =468.2

[0232] 1 H NMR: (400MHz, CDCl3) δ8.48(d,J=5.2Hz,1H),7.56(d,J=8.8Hz,1H),7.48(s,1H),7.22(d,J=8.8Hz,1H),7.09(d,J=4.8Hz,1H ),5.84(s,2H),4.61(s,1H),4.43(s,2H),3.47(s,3H),2.76-2.84(m,1H),2.19(s,6H),1.86-2.08(m,4H),1.61-1.71(m,4H).

[0233] Example 9

[0234] Reaction route:

[0235] Experimental procedure:

[0236] 1.

[0237] Compound 1 (0.30 g, 970 μmol) and diphenyl azidophosphate (810 mg, 2.94 mmol, 635 μL) were dissolved in tetrahydrofuran (3.00 mL). 1,8-diazabicyclo[5.4.0]undecane-7-ene (885 mg, 5.81 mmol, 876 μL) was added at room temperature. The reaction mixture was heated to 70 °C and reacted for 1 hour. Thin-layer chromatography confirmed complete consumption of the starting material. The reaction mixture was used directly in the next step to obtain compound 2 in 3 mL of tetrahydrofuran solution (0.32 g, crude product).

[0238] LCMS:(ESI,m / z):[M+H] + =334.15

[0239] 2.

[0240] Compound 2 (0.32 g, 957 μmol) and compound 2 (102 mg, 606 μmol) were dissolved in tetrahydrofuran (4.00 mL) and water (1.00 mL). Triphenylphosphine (1.26 g, 4.79 mmol) was added at room temperature, and the reaction mixture was reacted at 25–30 °C for 1 hour. LC-MS monitoring confirmed complete consumption of the starting materials. Aqueous solution (30 mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 3 (290 mg, crude product) was obtained by separation and purification using thin-layer chromatography.

[0241] LCMS:(ESI,m / z):[M+H] + =308.16

[0242] 3.

[0243] Compound 3 (0.26 g, 843.12 μmol) and compound 2 (102 mg, 606 μmol) were dissolved in 1,4-dioxane (3.00 mL). N,N-diisopropylethylamine (327 mg, 2.53 mmol, 441 μL) was added at room temperature. The reaction mixture was heated to 105 °C and reacted for 1 hour. Compound 4 was detected by LC-MS. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by thin-layer chromatography to give compound 4 (60 mg, yield: 16.2%).

[0244] LCMS:(ESI,m / z):[M+H] + =440.23

[0245] 4.

[0246] Compound 4 (55 mg, 125 μmol) was dissolved in methanol (5.00 mL), and Lindela catalyst (78 mg, 37.8 μmol, 10% purity) was added at room temperature. Hydrogen gas was bubbled into the reaction solution and purged three times. The reaction was carried out under a hydrogen atmosphere at 25 °C (15 psi) for 1 hour. LC-MS was used to monitor complete consumption of the starting material. The reaction solution was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain compound 5 (0.04 g, crude product).

[0247] LCMS:(ESI,m / z):[M+H] + =350.19

[0248] 5.

[0249] Compound 5 (40 mg, 114 μmol) and compound 7 (60.00 mg, 176 μmol) were dissolved in N,N-dimethylformamide (1.00 mL), and potassium carbonate (40.00 mg, 289 μmol) was added. The mixture was then heated to 105 °C and reacted for 5 hours. Compound 6 was detected by LCMS. 10 mL of H2O was added to the reaction solution, and the mixture was extracted with ethyl acetate (10.0 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain compound 6 (0.04 g, crude product).

[0250] LCMS:(ESI,m / z):[M+H] + =518.30

[0251] 6.

[0252] Compound 6 (0.04 g, 77.12 μmol) was dissolved in methanol (1.00 mL) and tetrahydrofuran (1.00 mL), and lithium hydroxide monohydrate aqueous solution (2 M, 310 μL) was added. The mixture was heated to 60 °C and reacted for 1 hour. LC-MS showed complete consumption of the starting material. The pH of the system was adjusted to 6-7 with hydrochloric acid (1 M), and the crude product was concentrated under reduced pressure. The crude product was purified by neutral reversed-phase high-performance liquid chromatography (column: CD). 07 -Daisogel SP-100-8-ODS-PK 150*25*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 26%-56% B over 10.0min), to obtain compound DF-B77 (16.0mg, yield: 43.5%, purity: 99.9%).

[0253] LCMS:(ESI,m / z):[M+H] + =476.25

[0254] 1 H NMR: (400MHz, MeOD), 8.11(d,J=4.4Hz,1H),7.53(s,2H),7.44(s,1H),6.51(d,J=5.2Hz,1H),4.81-4.79(m,1H),4.78(s,2H),3.52-3.44(m,1 H),2.79–2.73(m,1H),2.71(s,3H),2.49–2.27(m,4H),2.25(s,3H)2.2 3-2.05(m,2H),2.03–1.85(m,4H),1.83-1.61(m,4H),1.49-1.27(m,1H)

[0255] Comparative Example 1

[0256] Reaction route:

[0257] Experimental procedure:

[0258] 1.

[0259] Compound (4-(5-hydroxy-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate (344 mg, 1.0 mmol) and isopropyl(1S,3R)-3-hydroxycyclohexane-1-carboxylic acid (186 mg, 1.0 mmol) were dissolved in toluene (5 mL). Then, 1,1-azodicarboxylic acid dipiperidine (190 mg, 570 μmol) and tributylphosphine (200 mg, 1.0 mmol) were added under nitrogen protection at room temperature. The mixture was heated to 90-100 °C and reacted for 1 hour. TLC showed that the starting materials were completely consumed. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3:2, Rf = 0.6) to give isopropyl (1S, 3S)-3-((6-(5-(((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid ester (206 mg, yield 40.2%).

[0260] LCMS(ESI,m / z):[M+H] + =513.32

[0261] 2.

[0262] Isopropyl (1S,3S)-3-((6-(5-(((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid ester (105 mg, 0.2 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and then lithium hydroxide monohydrate (2 M, 438.55 μL) was added at room temperature. The mixture was heated to 60-70 °C and reacted for 1 hour. TLC showed that the starting material was completely consumed. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by neutral reversed-phase high-performance liquid chromatography (CD02-Waters Xbidge BEH C18 150*25*10um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 26%-56% B over 10min) to obtain (1S,3S)-3-((6-(5-(((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (45mg, yield 48.2%).

[0263] LCMS(ESI,m / z):[M+H] + =471.25

[0264] 1 H NMR(400MHz,DMSO-d6)δppm 7.75-7.35(m,3H)5.50-5.30(m,2H)4.73(s,1H)3.17(d,J=5.50Hz,1H)2.87(d,J=6.50 Hz,1H)2.79-2.53(m,3H)2.45(s,1H)2.38(s,3H)2.28-2.01(m,4H)1.97-1.28(m,14H).

[0265] Comparative Example 2

[0266] Reaction route:

[0267] Experimental Operation

[0268] 1.

[0269] Compound 6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-ol (350 mg, 1.0 mmol) and isopropyl(1S,3R)-3-hydroxycyclohexane-1-carboxylic acid (186 mg, 1.0 mmol) were dissolved in toluene (5 mL). Then, 1,1-azodicarboxylic acid dipiperidine (190 mg, 570 μmol) and tributylphosphine (200 mg, 1.0 mmol) were added under nitrogen protection at room temperature. The mixture was heated to 90-100 °C and reacted for 1 hour. TLC showed that the starting materials were completely consumed. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3:1, Rf = 0.5) to obtain (1S,3S)-3-((6-(5-((((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)isopropylcyclohexane-1-carboxylate (178 mg, yield 34.2%).

[0270] LCMS(ESI,m / z):[M+H] + =521.15

[0271] 2.

[0272] (1S,3S)-3-((6-(5-((((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)isopropylcyclohexane-1-carboxylate (104 mg, 0.2 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and then lithium hydroxide monohydrate (2 M, 438.55 μL) was added at room temperature. The mixture was heated to 60-70 °C and reacted for 1 hour. TLC showed that the starting material was completely consumed. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by neutral reversed-phase high-performance liquid chromatography (CD02-Waters Xbidge BEH C18 150*25*10um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 26%-56% B over 10min) to obtain (1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (42 mg, yield 49.3%).

[0273] LCMS(ESI,m / z):[M+H] + =479.25

[0274] 1 H NMR: (400MHz, DMSO-d6), 8.25 (s, 1H), 7.45-7.25 (m, 2H), 6.95 (d, J = 4.8Hz, 1H), 5.85 (s, 2H), 4.74 (s, 1H), 3.61-3.53 (m, 1H), 2.77–2 .73(m,1H),2.41–2.22(m,4H),2.19(s,3H),2.14(s,3H),2.06–1.90(m,2H),1.89-1.75(m,4H),1.74-1.60(m,3H),1.47-1.25(m,1H)

[0275] Comparative Example 3

[0276] Reaction route:

[0277] Experimental procedure:

[0278] 1.

[0279] Compound 6-(5-(((4-cyclobutylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-ol (350 mg, 1.0 mmol) and isopropyl(1S,3R)-3-hydroxycyclohexane-1-carboxylic acid (186 mg, 1.0 mmol) were dissolved in toluene (5 mL). Then, 1,1-azodicarboxylate dipiperidine (190 mg, 570 μmol) and tributylphosphine (200 mg, 1.0 mmol) were added under nitrogen protection at room temperature. The mixture was heated to 90-100 °C and reacted for 1 hour. TLC showed that the starting materials were completely consumed. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3:1, Rf = 0.5) to obtain (1S, 3S)-3-((6-(5-(((((4-cyclobutylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester (140 mg, yield 27.0%).

[0280] LCMS(ESI,m / z):[M+H] + =520.35

[0281] 2.

[0282] (1S,3S)-3-((6-(5-(((((4-cyclobutylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester (95 mg, 0.2 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and then lithium hydroxide monohydrate (2 M, 438.55 μL) was added at room temperature. The temperature was raised to 60-70 °C, and the reaction was carried out for 1 hour. TLC showed that the starting material was completely consumed. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by neutral reversed-phase high-performance liquid chromatography (CD02-Waters Xbidge BEH C18 150*25*10 μm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 26%-56% B over (1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (37 mg, yield 38.8%) was obtained after 10 min.

[0283] LCMS(ESI,m / z):[M+H] + =478.15

[0284] 1 H NMR: (400MHz, DMSO-d6), 8.25 (s, 1H), 7.45-7.25 (m, 2H), 6.95 (d, J=4.8Hz, 1H), 5.75 (s, 2H), 4.74 (s, 1H), 3.61-3.53 (m, 1H), 2.77–2 .73(m,1H),2.41–2.22(m,4H),2.19(s,3H),2.14(s,3H),2.06–1.90(m,2H),1.89-1.75(m,4H),1.74-1.60(m,3H),1.47-1.25(m,1H)

[0285] Table 1. MS Data Table for Example

[0286] -----------------

[0287] Bioactivity experimental data

[0288] 1. FLIPR calcium flow experiment

[0289] Experimental materials

[0290] Table 2. Reagent Sources and Batch Numbers

[0291] Experimental methods

[0292] Cell lines stably expressing the LPAR1 receptor were incubated with different concentrations of the test compound. Intracellular calcium production was measured using the FLIPR calcium flux assay. 2+ The levels of the test substance were varied to study its ability to act on the LPAR1 target and the corresponding concentration-effect curves were calculated.

[0293] Experimental steps

[0294] 1. Digest and collect cells, count them, and then seed the cells in black-bottomed 384-well plates and culture overnight.

[0295] 2. Prepare the Assay Buffer according to the FLIPR Calcium 6 Assay Kit instructions, and dilute Component A with the Assay Buffer to 1× loading buffer for later use.

[0296] 3. Invert the plate and centrifuge to remove the culture medium from the 384-well plate. Immediately add 35 μL of 1× loading buffer to the corresponding experimental wells. After centrifugation, incubate at 37°C in the dark for 2 hours.

[0297] 4. Prepare 10× positive compound and test substance intermediate solution, and transfer 5 μL to the corresponding 384-well plate. After centrifugation, incubate at 37°C in the dark for 30 minutes.

[0298] 5. Prepare 5× agonist intermediate solution and transfer 20 μL / well to the corresponding 384 source plate.

[0299] 6. After the test compound has been incubated, 10 μL of the agonist prepared in step 5 is added to each well using a FLIPR instrument. Data is collected at wavelengths of 515 nm to 575 nm, and the IC50 and Kb values ​​are calculated according to the kit instructions. The Kb value reflects the degree of binding between the compound and the receptor; the lower the value, the higher the affinity.

[0300] Table 3. IC50 and Kb values ​​of the compounds Note: BMS-986278 is a prior art compound with the following structural formula:

[0301] As can be seen from the above results, compared with existing compounds, the compounds of the present invention exhibit better LPAR1 inhibitory activity and receptor binding affinity.

[0302] 2. Rat Pharmacokinetic Studies

[0303] To investigate the pharmacokinetic characteristics of the compound of the present invention in rats after oral administration, the following experiments were conducted.

[0304]

Experimental Reagents

[0305] Acetonitrile, methanol, isopropanol, formic acid, PEG400, DMSO.

[0306] [Experimental Samples]

[0307] Storage conditions: Dry and sealed at 0-5℃.

[0308] Compound BMS-986278: Purity 98.1%

[0309] Compound B73: Purity 96.8%

[0310] Laboratory animals

[0311] Male SD rats, 3 rats per group.

[0312] [Dosage Regimen]

[0313] The tail vein group received medication via tail vein, while the gavage group received medication via gavage.

[0314] Table 4 Grouping and Dosage

[0315]

Experimental Methods

[0316] (1) Drug administration and sampling in rats: All animals were administered drugs via tail vein / gavage at a dose of 10 mL / kg. Blood samples of 0.2 mL were collected from the test animals at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after drug administration. The samples were added to disposable anticoagulant tubes, centrifuged at 3500 rpm for 10 min, and the supernatant was collected and stored at -20℃ for later analysis.

[0317] (2) The plasma sample processing method is as follows: Take 50 μL of plasma sample into a 1.5 mL centrifuge tube, add 400 μL of internal standard working solution (5 ng / mL diazepam acetonitrile solution), vortex for 5 min, centrifuge at 12000 rpm for 10 min, take the supernatant, add it to the vial for LC-MS / MS analysis, and record the chromatogram.

[0318]

Experimental Results

[0319] Compared to compound BMS-986278, B73 showed significantly increased in vivo drug exposure levels. Relevant data are shown in Tables 5 and 6.

[0320] Table 5

[0321] Considering the different drug dosages, dose corrections were applied to exposure-related parameters such as Cmax and AUC.

[0322] Table 6

[0323] Considering the different drug dosages, dose corrections were applied to exposure-related parameters such as Cmax and AUC.

[0324] 3. Lung tissue distribution test of single-dose gavage administration in mice

[0325] To investigate the distribution of the compound of the present invention in the lung tissue of mice after oral administration, the following study was conducted.

[0326]

Experimental Reagents

[0327] Acetonitrile, methanol, isopropanol, formic acid, PEG400, DMSO.

[0328] [Experimental Samples]

[0329] Storage conditions: Dry and sealed at 0-5℃.

[0330] Compound BMS-986278: Purity 99.7%

[0331] Compound B73: 100% purity

[0332] Laboratory animals

[0333] Male C57 mice, 50 mice per group.

[0334] [Dosage Regimen]

[0335] Administer the medication via gavage.

[0336] Table 7 Grouping and Dosage

[0337]

Experimental Methods

[0338] Animals were administered the drug via gavage at a dose of 10 mL / kg. At 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration, blood was collected from the eyeballs of the test animals until death. Whole blood was added to disposable anticoagulant tubes and centrifuged at 3500 rpm for 10 min at 4°C. The supernatant was collected and stored at -20°C for later analysis. After blood collection, lung tissue was harvested from the mice. The tissue was shredded, accurately weighed, and mixed with physiological saline (mass-to-volume ratio 1:3). The mixture was then homogenized using a homogenizer (the program consisted of four cycles of homogenization at 6500 rpm for 30 s, followed by a 20 s pause). The homogenate was stored at -20°C for later analysis.

[0339]

Experimental Results

[0340] Compared to compound BMS-986278, B73 showed a significantly increased pulmonary drug exposure level. Relevant data are shown in Table 8.

[0341] Table 8

[0342] 4. Bleomycin-induced pulmonary fibrosis in mice

[0343] To investigate the effects of the compounds of this invention on a mouse model of pulmonary fibrosis, the following studies were conducted.

[0344]

Experimental Reagents

[0345] Bleomycin sulfate (MCE), sulfobutyl-β-cyclodextrin (McClene).

[0346] [Experimental Samples]

[0347] Storage conditions: Dry and sealed at 0-5℃.

[0348] Compound BMS-986278: Purity 99.7%

[0349] Compound B73: 100% purity

[0350] Laboratory animals

[0351] Male C57 mouse.

[0352] [Dosage Regimen]

[0353] The drugs were administered by gavage, and the grouping and dosage are shown in Table 9.

[0354] Table 9 Grouping and Dosage

[0355]

Experimental Methods

[0356] Animals were anesthetized with isoflurane and underwent a single tracheal injection. The sham-operated group received saline, while the other groups received bleomycin sulfate. Seven days after tracheal injection modeling, the test drug was administered twice daily for 14 consecutive days. The sham-operated and model groups received the corresponding volume of solvent. Animals were administered the drug via gavage at a dose of 10 mL / kg. Lung function was assessed after drug administration; the lungs were fixed with fixative solution and Masson staining was performed to assess fibrosis.

[0357]

Experimental Results

[0358] Compared to compound BMS-986278, B73 improved lung function at a lower dose, and pathological staining showed a significant reduction in the degree of pulmonary fibrosis. Relevant data are shown in Table 10 and Figure 1.

[0359] Table 10 Lung function results

Claims

1. The compound represented by Formula I or its stereoisomers, pharmaceutically acceptable salts or solvates: in, X is selected from CH2, NHCO, NHCOCH2, O and S, preferably O or NHCO; Y is selected from N and CH; Q1, Q2, and Q3 are each independently selected from NH, N, CH2, and CH; and Q3 is optionally substituted with a methyl group; R1 is selected from 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, 6-membered heteroaryl, spirocyclic, bridged cycloalkyl, cyano, and trifluoromethyl, wherein the 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, 6-membered heteroaryl, spirocyclic, and bridged cycloalkyl are optionally substituted by one, two, or three substituents selected from the following: methyl, trifluoromethyl, phenyl, fluorine, chlorine, cyano, ethynyl, carboxyl, chlorophenyl, hydroxyl, fluoromethyl, trifluoromethylmethyl, methoxy, aminoethyl, and pyridyl; wherein the 5- to 6-membered heterocycloalkyl contains one or two heteroatoms selected from O, N, and S, and the 6-membered heteroaryl is preferably pyrimidinyl or pyridinyl; R1 is preferably a cycloalkyl or a cycloalkyl substituted with a carboxyl group; the bridged ring is preferably bicyclo[1.1.1]pentane, and the spirocyclic ring is preferably spiro[2.3]heptane; R2 is selected from C1-C3 alkyl and cycloalkyl, preferably methyl or ethyl, more preferably methyl; R3 is selected from hydrogen and C1-C3 alkyl, preferably hydrogen or methyl, for example, R3 is attached to Q3; A is selected from -CH2-NH-, -CH2-, -CH2-O-, CH2-O-CO-, -NH-COO-, -NHCOO-CH- and covalent bonds, with -CH2-NH- and -CH2-O- being preferred; M1 is selected from -CH2-, -NH- and -N(CH3)-; M 2、 M3 can be -NH-, -CH2-, or not exist independently; Alternatively, M1, M2, and M3, together with the atoms they are attached to, form a 6-membered aryl or a 5-6-membered heteroaryl group, wherein the 6-membered aryl or 5-6-membered heteroaryl group is optionally substituted with one or two fluorine atoms; and the 6-membered aryl group is, for example, a phenyl group, and the 5-6-membered heteroaryl group is, for example, a phenyl group. Diazole, pyridinyl, or pyrimidinyl; M4 is -CH2- or does not exist; R4 is selected from C1-C3 alkyl groups such as methyl, ethyl, propyl or isopropyl, 3-5 membered cycloalkyl groups such as cyclopropyl, cyclobutyl or cyclopentyl, 3-5 membered cycloalkyl-CH2-, and methoxymethyl; R4 is preferably cyclobutyl or cyclobutylmethyl.

2. The compound or its stereoisomer, pharmaceutically acceptable salt or solvate according to claim 1, wherein... The structural part is 3. The compound or its stereoisomer, pharmaceutically acceptable salt or solvate according to claim 1 or 2, wherein X is O or NHCO, preferably O.

4. The compound or its stereoisomer, pharmaceutically acceptable salt, solvate, hydrate or metabolite according to any one of claims 1 to 3, wherein R1 is a carboxyl-substituted cyclohexyl group, preferably 5. The compound or its stereoisomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 4, wherein R4 is cyclobutyl.

6. The compound or its stereoisomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 5, wherein M1, M2, M3 together with the atoms to which they are attached form a phenyl group. Diazolyl, pyridyl, or pyrimidinyl.

7. The compound or its stereoisomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 6, wherein... The structural part is 8. The compound or its stereoisomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 7, wherein Y is N.

9. The compound or its stereoisomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 8, wherein the compound is selected from:

10. A pharmaceutical composition comprising the compound or a stereoisomer thereof according to any one of claims 1 to 9, a pharmaceutically acceptable salt or solvate, and a pharmaceutically acceptable carrier.

11. Use of the compound or its stereoisomer, pharmaceutically acceptable salt or solvate according to any one of claims 1-9 in the preparation of a medicament for treating or preventing diseases or symptoms associated with LPA receptors.

12. The use according to claim 11, wherein the disease or symptom associated with the LPA receptor is selected from wound healing, cancer, fibrosis, pain, respiratory diseases, allergic diseases, chronic kidney disease, interstitial lung disease, nervous system diseases, cardiovascular diseases, and inflammatory diseases.

13. The use according to claim 11, wherein the disease or symptom associated with the LPA receptor is fibrosis, such as pulmonary fibrosis.

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