LPAR2 targeting 4-methylquinoline derivative and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a 4-methylquinoline derivative as an LPAR2 inhibitor and application thereof, and provides a compound as shown in a formula (I) aiming at the problem of lack of LPAR2 targeted drugs in the prior art. In particular, in a mouse model with spinal cord injury, motor function recovery is significantly improved (BMS score is increased to 4.0), the invention also provides a pharmaceutical composition containing the compound and application of the pharmaceutical composition in prevention or treatment of LPAR2-related nervous system diseases (such as spinal cord injury, Alzheimer's disease and neuropathic pain), and the technical blank of target treatment drugs is filled.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to an LPAR2-targeting 4-methylquinoline derivative and its applications. Background Technology

[0002] Lysophosphatidic acid (LPA) is an important bioactive lipid molecule derived from cell membrane phospholipids. It can mediate various intracellular signaling pathways by activating its corresponding G protein-coupled receptors (GPCRs). The LPA receptor family includes six subtypes, LPAR1 to LPAR6. Among them, LPAR2 is an important member, widely expressed in multiple cell types of the central and peripheral nervous systems, and exhibits key functional activities in various neuropathological states.

[0003] Studies have found that LPAR2 activation plays a regulatory role in various neural processes and pathological mechanisms, such as neuronal cell death, glial cell activation, axonal retraction, neuropathic pain, and cognitive impairment. Existing in vitro and in vivo experimental data indicate that LPAR2 is closely related to secondary damage following central nervous system injury, particularly playing a promoting role in myelin degeneration after spinal cord injury. Animal experiments have shown that in transgenic models lacking LPAR2 expression, LPA injection-induced demyelination pathology was significantly alleviated, while motor function recovery after spinal cord injury was significantly improved, suggesting that LPAR2 may act as a key precipitating factor in this type of pathological state.

[0004] Despite the increasing depth of research into the LPA / LPAR signaling axis, particularly the increasingly clear role of LPAR2 in central nervous system diseases, effective small-molecule inhibitors targeting LPAR2 remain in the research stage. Currently, no LPAR2-specific drugs have been approved for marketing, and there is a lack of highly targeted and selective modulation methods with minimal side effects in clinical use. While some reported LPA receptor inhibitors, such as Ki16425, exhibit some inhibitory activity against LPAR1 and LPAR3, their inhibitory effects on LPAR2 still suffer from poor selectivity and efficacy, failing to meet the need for precise intervention of LPAR2 activity in specific disease states.

[0005] Furthermore, current research on LPAR2 antagonists suffers from limitations such as complex synthetic processes, poor drug-likeness, low bioavailability, and insufficient metabolic stability in vivo, restricting their feasibility in practical drug development. To address these issues, there is an urgent need to develop novel LPAR2 regulatory molecules with good targeting, a clear structural basis, significant biological activity, and excellent pharmacokinetic properties to advance precision intervention research for related diseases, particularly neurological disorders.

[0006] In summary, how to construct novel small molecule inhibitors with different structures to selectively inhibit LPAR2 activity has become one of the most pressing technical challenges in the field of medicinal chemistry, and it has significant theoretical research value and clinical application potential. Summary of the Invention

[0007] The first technical problem to be solved by the present invention is to provide an LPAR2-targeting 4-methylquinoline derivative to overcome the following defects in the prior art: currently known similar candidate compounds have limited inhibitory activity, poor selectivity, unstable structure, and low bioavailability in vivo, making it difficult to meet the requirements of high efficiency, safety and selectivity for clinical applications, especially limiting their application prospects in neurological diseases (such as spinal cord injury, postoperative cognitive impairment, Alzheimer's disease, etc.).

[0008] To overcome the shortcomings of the prior art, the present invention provides an LPAR2-targeting 4-methylquinoline derivative, the chemical formula of which is shown in formula (1) below:

[0009]

[0010] Where X is one of -NH-, -O-, -S-, and -CH2-, and Y is -(CH2). n - and n is an integer between 0 and 3;

[0011] R1 is selected from:

[0012] i: 5-10 membered monocyclic, bicyclic aryl, alicyclic, or

[0013] ii: 5-10 membered monocyclic or bicyclic heteroaryl or heterocyclic groups containing 1-4 heteroatoms selected from N, O and S;

[0014] The R1 ring may optionally be oxidized and optionally substituted with one or more substituents selected from:

[0015] i: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, amino, or

[0016] ii: A phenyl group that can be substituted with one or more halogens or C1-C3 alkyl groups, or

[0017] iii: 5-10 membered monocyclic or bicyclic heteroaryl or heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, which may be substituted with one or more halogens or C1-C3 alkyl groups;

[0018] R2 is a 5-7 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms selected from N, O, and S; the R2 ring may optionally be substituted by one or more substituents selected from:

[0019] i: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or

[0020] ii: Halogen, hydroxyl, amino, nitro, cyano, or

[0021] A phenyl group that can be substituted with one or more halogens or C1-C3 alkyl groups, or

[0022] A 5-10 member monocyclic or bicyclic heteroaryl or heterocyclic group containing 1-4 heteroatoms selected from N, O and S, which may be substituted with one or more halogens or C1-C3 alkyl groups.

[0023] As used herein, the terms “aryl,” “aryl ring,” and “aromatic ring” are used interchangeably to refer to monocyclic or bicyclic groups with a conjugated π-electron system, where all ring atoms are carbon atoms. The term “5-10 membered monocyclic or bicyclic aryl” refers to a monocyclic or bicyclic aryl group having 5-10 ring atoms, specifically a monocyclic or bicyclic aryl group having 6-10 ring atoms, examples of which include, but are not limited to, phenyl, naphthyl, etc.

[0024] The terms "heteroaryl," "heteroaryl ring," and "heteroaryl ring" used in this invention are used interchangeably to refer to monocyclic or bicyclic groups in which the ring atoms are replaced by at least one heteroatom independently selected from N, O, and S. In the case of bicyclic heteroaryl groups, the two rings share adjacent ring atom pairs, which can be C-C or NC. The term "5-10-membered monocyclic or bicyclic heteroaryl" refers to monocyclic or bicyclic heteroaryl groups having 5-10 ring atoms; specific examples of 5-10-membered monocyclic heteroaryl groups include, but are not limited to: thiophene, furanyl, thiazolyl, isothiazolyl, imidazole, oxazolyl, pyrrole, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridinyl, etc.; 5-10-membered bicyclic heteroaryl groups... More specifically, it can be an 8-10 membered bicyclic heteroaryl group, and specific examples include, but are not limited to: benzisoxazolyl, indolyl, isoindolyl, benzimidazolyl, benzisothiazolyl, benzotriazolyl, benzooxazolyl, benzothiazolyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cyclolinyl, pyridinylpyrimidinyl, naphridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, etc.

[0025] The terms "alicyclic group," "cycloalkyl group," and "alicyclic group" used in this invention are used interchangeably to refer to cyclic aliphatic groups. In the case of bicyclic alicyclic groups, the two alicyclic rings can be bridged or spiked. The term "5-10 membered monocyclic or bicyclic alicyclic group" refers to monocyclic or bicyclic alicyclic groups having 5-10 ring atoms, examples of which include, but are not limited to: cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[4.2.0]octyl, bicyclo[3.3.1]nonyl, spiro[4.5]decyl, etc.

[0026] The terms "heterocyclic group" and "heterocycle" used in this invention are used interchangeably, referring to a monocyclic or bicyclic aliphatic group in which a ring atom is replaced by at least one heteroatom independently selected from N, O, and S. In the case of a bicyclic aliphatic group, one of the rings may have a conjugated π-electron system. Additionally, in the case of a bicyclic aliphatic group, the two aliphatic rings may be bridged or screwed together; in the case of bridging, the adjacent ring atom pairs shared by the two rings may be CC or NC. The term "5-10 membered monocyclic or bicyclic heterocyclic group" refers to a monocyclic or bicyclic heterocyclic group having 5-10 ring atoms, examples of which include, but are not limited to: pyrrolidinyl, tetrahydrofuranyl, oxazolyl, imidazoyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, azabicyclo[4.2.0]octyl, azabicyclo[3.3.1]nonyl, tetrahydrotriazolylpyridinyl, etc.

[0027] The term "alkyl" as used in this invention refers to an aliphatic hydrocarbon group, which may be a branched or straight-chain alkyl group. Depending on the structure, an alkyl group may be a monovalent or divalent group (i.e., an alkylene group). In this invention, an alkyl group may be an alkyl group having 1-6 carbon atoms, more preferably an alkyl group having 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, the terms methyl, ethyl, propyl, butyl, pentyl, hexyl, etc., as used in this invention. The term "alkyl" in this invention may include the alkyl group in all possible configurations and conformations. For example, "propyl" may include n-propyl and isopropyl.

[0028] The term "alkoxy" as used in this invention refers to -O-alkyl, wherein the alkyl group is as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc.

[0029] The term "substitution" as used in this invention refers to the substitution of any one or more hydrogen atoms on a particular atom by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable.

[0030] The term "oxo" as used in this invention refers to the substitution of two hydrogen atoms by an oxo group (i.e., =O).

[0031] Compared with existing technologies (related technologies), the LPAR2-targeting 4-methylquinoline derivative of this application has the following advantages: The compound of this invention uses a 4-methylquinoline structure as its core, and by introducing specific aryl or heteroaryl structures, it achieves highly selective inhibition of LPAR2. In particular, the introduction of heteroaryl groups such as pyrazine and pyridine substituted with R1 and R2 forms a stable coordination with the active site of the LPAR2 receptor, significantly enhancing the binding affinity. Furthermore, the diversified design of the X and Y linker groups modulates the molecular flexibility and spatial conformation, improving conformational adaptability to the receptor. Experimental results show that, compared with existing LPAR2 inhibitors, the compound of this invention exhibits stronger inhibitory activity (90-100% inhibition rate) in calcium ion mobilization experiments and significantly improves motor function recovery in an in vivo mouse model of spinal cord injury, increasing the BMS score from 2.3 to 4.0, demonstrating good pharmacodynamic performance. Therefore, compared with existing technologies, this invention has the following significant advantages and technical effects:

[0032] High activity and high selectivity: The inhibitory effect against LPAR2 is superior to that of existing control compounds;

[0033] High structural diversity and large optimization space: X, Y, R1, and R2 in the general formula have multiple combinations, which can not only realize a wide range of derivation and extension, but also facilitate subsequent structure-property relationship research.

[0034] Excellent in vivo activity: It showed significant neurological function recovery in an animal model of spinal cord injury;

[0035] It has the potential to be developed into a drug: the parent nucleus is stable, the synthesis process is feasible, and the pharmacokinetic properties are good, making it suitable for further development into an oral or injectable drug.

[0036] In summary, the 4-methylquinoline derivatives provided by this invention possess excellent LPAR2 inhibitory activity and good biological activity, and can serve as candidate lead compounds for the treatment of LPAR2-related diseases. They are particularly suitable for drug development for major diseases such as neurological damage, cognitive impairment, and neuropathic pain, and have broad application prospects and great clinical potential.

[0037] In one possible implementation, X is selected from -NH- and -O-; Y is selected from -CH2-, and n is 0 or 1.

[0038] In one possible implementation, R1 is selected from p-trifluoromethylphenyl, o-trifluoromethylphenyl, p-N,N-dimethylphenyl, p-N-methylphenyl, p-acetaminophenyl, 1-methylpiperidinyl, 2-trifluoromethyl-pyridin-4-yl, and 5-chlorothiophen-2-yl.

[0039] In one possible implementation, R2 is selected from pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 5,6-dimethyl-pyrazin-2-yl, and pyridin-3-yl.

[0040] The compounds of this invention can be formulated and / or used as pharmaceutically acceptable salts; said pharmaceutically acceptable salts can be inorganic acid salts or organic acid salts; said inorganic acid salts can be salts formed with hydrohalic acids, nitric acid, carbonic acid, sulfuric acid, phosphoric acid, etc.; said organic acid salts can be salts formed with malic acid, citric acid, fumaric acid, oxalic acid, lactic acid, camphor sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, etc.; said hydrohalic acid can be hydrofluoric acid, hydrobromic acid, hydroiodic acid, or hydrochloric acid. The pharmaceutically acceptable salts can be prepared by methods well known to those skilled in the art.

[0041] In one possible implementation, the chemical formula of the LPAR2-targeting 4-methylquinoline derivative is one of the following structural formulas:

[0042]

[0043]

[0044] The compounds of the present invention can be formulated and / or used as pharmaceutically acceptable prodrugs, which can readily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention; furthermore, the pharmaceutically acceptable prodrugs can be converted into the compounds of the present invention in the in vivo environment by chemical or biochemical methods.

[0045] When the compounds of the present invention have isomers such as optical isomers, stereoisomers, positional isomers, and rotational isomers, mixtures of any of the isomers are included within the scope of the compounds of the present invention; for example, when the compounds of the present invention have optical isomers, optical isomers separated from racemic mixtures are also included within the scope of the compounds of the present invention, each of which can be obtained as a separate compound by known synthetic and separation methods.

[0046] The compounds or salts thereof of the present invention may be amorphous or crystalline; in the case of crystals, both single crystals and polymorphs are included within the scope of the compounds or salts thereof of the present invention, which may be produced by crystallization by crystallization methods known per se in the art.

[0047] The compounds or salts thereof of the present invention may be in the form of solvates or non-solvents. For example, the compounds or salts thereof of the present invention may be in the form of hydrates, and any of these forms are included within the scope of the compounds or salts thereof of the present invention.

[0048] The compounds of the present invention or their salts may be made using isotopes (e.g.,2 H(D), 3 H, 13 C 14 C 35 S, 125 I) Forms of labeling; in the case of the above isotopic labeling, the isotopic atom may be an atom of a naturally occurring, but not most common, isotopic element; for example, the deuterium abundance level of the compound of the present invention or its salt is greater than the naturally occurring abundance of deuterium; any of the above forms are included within the scope of the compound of the present invention or its salt, and the preparation of isotopic labeled compounds, such as deuterated compounds, can be done by methods known per se in the art.

[0049] The second technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising the LPAR2-targeting 4-methylquinoline derivative and one or more excipients.

[0050] In the pharmaceutical composition of the present invention, an LPAR2-targeting 4-methylquinoline derivative or a pharmaceutically acceptable salt thereof is used according to the present invention, and the content of the drug is not limited. For example, the content of the pharmaceutically acceptable salt or prodrug of the LPAR2-targeting 4-methylquinoline derivative of the present invention may be 0.01-20 wt% or 0.01-5 wt%.

[0051] The excipients mentioned above can be conventional diluents, solubilizers, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorbent carriers, lubricants, flavoring agents, sweeteners, etc. in the pharmaceutical field.

[0052] The pharmaceutical compositions of the present invention can be formulated according to techniques known in the art. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ocular, ocular, rectal, vaginal, or transdermal administration. In the present invention, the pharmaceutical compositions are preferably in a form suitable for ocular administration.

[0053] The third technical problem to be solved by the present invention is to provide an application of the above-mentioned LPAR2-targeting 4-methylquinoline derivative, the application including the use of the above-mentioned LPAR2-targeting 4-methylquinoline derivative in the manufacture of a medicament for the prevention, relief or treatment of LPAR2-related diseases.

[0054] In one possible implementation, the dosage form of the above-mentioned drug can be various forms such as tablets, capsules, patches, ointments, emulsions, suspensions, gels, powders, granules, eye drops, oral solutions, and injections. Preferably, the dosage form of the drug is suitable for ocular application. These dosage forms can all be prepared according to conventional methods in the pharmaceutical field.

[0055] In one possible implementation, the disease is a neurological disorder, including spinal cord injury, neurological injury, cognitive impairment, postoperative cognitive impairment, Alzheimer's disease, and neuropathic pain.

[0056] The fourth technical problem to be solved by the present invention is to provide a method for preparing the above-mentioned LPAR2-targeting 4-methylquinoline derivative, the preparation method comprising the following steps:

[0057] S1: Synthesis of intermediate c

[0058] The quinolineamine compound shown in formula a and the carboxylic acid compound shown in formula b were reacted in DMF solvent at room temperature under the action of condensing agent HATU and base DIPEA to obtain the corresponding intermediate amide compound intermediate c.

[0059] S2: Synthesis of the target product

[0060] The target compound is prepared by reacting the intermediate amide compound c with one of the following two classes of compounds:

[0061] i: undergoes an amidation reaction with compounds containing substituted aryl amino structures represented by formula d; or

[0062] ii: It undergoes an etherification reaction with phenolic compounds containing substituted aryl groups as represented by formula e;

[0063] The reaction conditions were as follows: reaction in DMF in the presence of base K2CO3 at a reaction temperature of 40°C. After the reaction, the target compound was purified by washing with water, extraction, crystallization, or column chromatography. Among them, DIPEA is N,N-diisopropylethylamine, HATU is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and DMF is N,N-dimethylformamide.

[0064] The chemical formula of the quinolineamine compound is: The chemical formula of the carboxylic acid compound is:

[0065] R2-COOH; the chemical formula of the intermediate amide compound is: The chemical formula of the compound containing the substituted arylamino structure is: The chemical formula of the phenolic compound containing the substituted aryl group structure is R2-OH.

[0066] In one possible implementation, the chemical reaction formula of the preparation method is as follows:

[0067]

[0068] RT represents room temperature. Attached Figure Description

[0069] Figure 1 The graph shows the changes in BMS motor function scores over time in the LPAR2-targeting 4-methylquinoline derivative treatment group and the control group. Detailed Implementation

[0070] First, those skilled in the art should understand that these embodiments are merely used to explain the technical principles of the embodiments of this application and are not intended to limit the scope of protection of the embodiments of this application. Those skilled in the art can make adjustments as needed to adapt to specific application scenarios.

[0071] In the embodiments of this invention, all reagents used are conventional reagents unless otherwise specified; all synthesis methods are conventional methods unless otherwise specified. Column chromatography was performed using 100-200 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. MS analysis was performed using a WatersUPLC-Mass Spectrometer.

[0072] The abbreviations used in the synthesis steps in the following embodiments of the present invention are explained as follows:

[0073] Table 1: Explanation of abbreviations in this invention:

[0074]

[0075]

[0076] This invention provides an LPAR2-targeting 4-methylquinoline derivative, the chemical formula of which is shown in formula (1) below:

[0077]

[0078] Where X is one of -NH-, -O-, -S-, and -CH2-, and Y is -(CH2). n - and n is an integer between 0 and 3;

[0079] R1 is selected from:

[0080] i: 5-10 membered monocyclic, bicyclic aryl, alicyclic, or

[0081] ii: 5-10 membered monocyclic or bicyclic heteroaryl or heterocyclic groups containing 1-4 heteroatoms selected from N, O and S;

[0082] The R1 ring may optionally be oxidized and optionally substituted with one or more substituents selected from:

[0083] i: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, amino, or

[0084] ii: A phenyl group that can be substituted with one or more halogens or C1-C3 alkyl groups, or

[0085] iii: 5-10 membered monocyclic or bicyclic heteroaryl or heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, which may be substituted with one or more halogens or C1-C3 alkyl groups;

[0086] R2 is a 5-7 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms selected from N, O, and S; the R2 ring may optionally be substituted by one or more substituents selected from:

[0087] i: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or

[0088] ii: Halogen, hydroxyl, amino, nitro, cyano, or

[0089] A phenyl group that can be substituted with one or more halogens or C1-C3 alkyl groups, or

[0090] A 5-10 member monocyclic or bicyclic heteroaryl or heterocyclic group containing 1-4 heteroatoms selected from N, O and S, which may be substituted with one or more halogens or C1-C3 alkyl groups.

[0091] As a preferred embodiment, X is selected from -NH- and -O-; Y is selected from -CH2-, and n is 0 or 1.

[0092] As a preferred embodiment, R1 is selected from p-trifluoromethylphenyl, o-trifluoromethylphenyl, p-N,N-dimethylphenyl, p-N-methylphenyl, p-acetaminophenyl, 1-methylpiperidinyl, 2-trifluoromethyl-pyridin-4-yl, and 5-chlorothiophen-2-yl.

[0093] As a preferred embodiment, R2 is selected from pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 5,6-dimethyl-pyrazin-2-yl, and pyridin-3-yl.

[0094] As a preferred embodiment, the chemical formula of the LPAR2-targeting 4-methylquinoline derivative is one of the following 13 structural formulas:

[0095] Table 2: LPAR2-targeting 4-methylquinoline derivative compounds 1-13 and their structural formulas:

[0096]

[0097]

[0098] The compounds of the present invention can effectively inhibit the activity of LPAR2. Compared with the known LPAR2 inhibitor Ki16425, the compounds of the present invention have a stronger inhibitory effect. Therefore, the compounds of the present invention can potentially be used for the prevention, relief or treatment of LPAR2-related diseases.

[0099] The following is the chemical formula of the inhibitor Ki16425:

[0100]

[0101] The present invention provides a pharmaceutical composition comprising the LPAR2-targeting 4-methylquinoline derivative and one or more excipients.

[0102] The present invention provides an application of the LPAR2-targeting 4-methylquinoline derivative, the application including the use of the LPAR2-targeting 4-methylquinoline derivative in the manufacture of medicaments for the prevention, relief or treatment of LPAR2-related diseases.

[0103] In embodiments of the present invention, when the application of the LPAR2-targeted 4-methylquinoline derivative according to the present invention is used in pharmaceuticals, the dosage of the drug administered for the treatment of a patient depends on many factors, such as the specific dosing regimen, the type and severity of the disease or condition, the uniqueness of the patient or host requiring treatment (e.g., weight), and the specific surrounding circumstances, including, for example, the specific drug already used, the route of administration, the condition being treated, and the patient being treated. The dosage can be conventionally determined by methods known in the art. Typically, for therapeutic use, the dosage is in the range of 0.0004-500 mg / kg body weight / day, for example, about 0.02-30 mg / kg body weight / day. This required dosage can be conveniently expressed as a single dose, or administered simultaneously (or over a short period of time), or in fractions at appropriate intervals, such as two, three, four, or more doses per day. Those skilled in the art will understand that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0104] As a preferred embodiment, the disease is a neurological disease, including spinal cord injury, nervous system injury, cognitive impairment, postoperative cognitive impairment, Alzheimer's disease, and neuropathic pain.

[0105] The present invention also provides a method for preparing the LPAR2-targeted 4-methylquinoline derivative, the method comprising the following steps:

[0106] S1: Synthesis of intermediate c

[0107] The quinolineamine compound shown in formula a and the carboxylic acid compound shown in formula b were reacted in DMF solvent at room temperature under the action of condensing agent HATU and base DIPEA to obtain the corresponding intermediate amide compound intermediate c.

[0108] S2: Synthesis of the target product

[0109] The target compound is prepared by reacting the intermediate amide compound c with one of the following two classes of compounds:

[0110] i: undergoes an amidation reaction with compounds containing substituted aryl amino structures represented by formula d; or

[0111] ii: It undergoes an etherification reaction with phenolic compounds containing substituted aryl groups as represented by formula e;

[0112] The reaction conditions were as follows: reaction in DMF in the presence of base K2CO3 at a reaction temperature of 40°C. After the reaction, the target compound was purified by washing with water, extraction, crystallization, or column chromatography. Among them, DIPEA is N,N-diisopropylethylamine, HATU is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and DMF is N,N-dimethylformamide.

[0113] The chemical formula of the quinolineamine compound is: The chemical formula of the carboxylic acid compound is:

[0114] R2-COOH; the chemical formula of the intermediate amide compound is: The chemical formula of the compound containing the substituted arylamino structure is: The chemical formula of the phenolic compound containing the substituted aryl group structure is R2-OH.

[0115] As a preferred embodiment, the chemical reaction formula of the preparation method is as follows:

[0116]

[0117] RT represents room temperature.

[0118] The compounds of the present invention can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art. The synthesis of the compounds disclosed in the present invention can utilize reactions known in the art, and these reactions can be modified by reagents and reaction conditions deemed appropriate by those skilled in the art to introduce various parts of the molecules provided in the present invention.

[0119] If necessary, the reaction products can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. These products can be characterized using conventional methods, including physical constants and spectral data.

[0120] The following specific embodiments, combined with specific data and operating methods, are provided to further elaborate on the above-mentioned technical solutions and contents of the present invention, and to provide specific preparation methods for compounds 1-13. In the following embodiments, Examples 1-13 correspond sequentially to compounds 1-13 in Table 2:

[0121] Example 1:

[0122] Synthesis of N-[4-methyl-2-({4-(trifluoromethyl)phenyl}amino)quinoline-6-yl]pyrazine-2-carboxamide (Compound 1)

[0123] S1: Synthesis of intermediate compound 1c:

[0124] 1b (pyrazine 2-formate, 0.250 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.300 mmol) were added to a three-necked flask and dissolved in N,N-dimethylacetamide (2 mL). Then, N,N-diisopropylethylamine (0.300 mmol) was added. The reaction apparatus was purged three times with argon gas, and the reaction was carried out at room temperature for 30 min. Then, compound a (0.300 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was quenched by slowly adding an aqueous solution (2.00 mL), washed with saturated sodium chloride solution (2.00 mL), extracted with ethyl acetate (8.00 mL), concentrated the organic phase, and then purified by silica gel column chromatography (dichloromethane:methanol = 60:1–40:1) to give compound 2c (white solid, yield 88%).

[0125] S2: Synthesis of Compound 1:

[0126] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 1d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 1 (white solid, yield 78%). ESI-MS: m / z = 424 [M+1] + .

[0127] Example 2:

[0128] Synthesis of N-[4-methyl-2-({2-(trifluoromethyl)phenyl}amino)quinoline-6-yl]pyrazine-2-carboxamide (compound 2)

[0129] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0130] S2: Synthesis of Compound 2:

[0131] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 2d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to obtain compound 2 (white solid, yield 79%). ESI-MS: m / z = 424 [M+1] + .

[0132] Example 3:

[0133] Synthesis of N-[2-({4-(dimethylamino)phenyl}amino)-4-methylquinoline-6-yl]pyrazine-2-carboxamide (compound 3)

[0134] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0135] S2: Synthesis of Compound 3:

[0136] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 3d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h, and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 3 (white solid, yield 81%). ESI-MS: m / z = 399 [M+1] + .

[0137] Example 4:

[0138] Synthesis of O-[4-methyl-2-({4-(methylamino)phenyl}amino)quinoline-6-yl]pyrazine-2-carboxamide (compound 4)

[0139] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0140] S2: Synthesis of Compound 4:

[0141] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 4d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 4 (white solid, yield 83%). ESI-MS: m / z = 385 [M+1] + .

[0142] Example 5:

[0143] Synthesis of N-[2-({4-acetamidophenyl}amino)-4-methylquinoline-6-yl]pyrazine-2-carboxamide (compound 5)

[0144] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0145] S2: Synthesis of Compound 5:

[0146] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 5d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h, and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 5 (white solid, yield 86%). ESI-MS: m / z = 385 [M+1] + .

[0147] Example 6:

[0148] Synthesis of O-[4-methyl-2-({1-methylpiperidin-4-yl}amino)quinoline-6-yl]pyrazine-2-carboxamide (compound 6)

[0149] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0150] S2: Synthesis of Compound 6:

[0151] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 6d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the mixture was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 6 (white solid, yield 82%). ESI-MS: m / z = 377 [M+1] + .

[0152] Example 7:

[0153] Synthesis of N-[4-methyl-2-({6-(trifluoromethyl)pyridin-3-yl}amino)quinoline-6-yl]pyrazin-2-carboxamide (compound 7)

[0154] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0155] S2: Synthesis of Compound 7:

[0156] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 7d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 7 (white solid, yield 77%). ESI-MS: m / z = 425 [M+1] + .

[0157] Example 8:

[0158] Synthesis of O-[2-({5-chlorothiophene-2-yl}amino)-4-methylquinoline-6-yl]pyrazine-2-carboxamide (compound 8)

[0159] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0160] S2: Synthesis of Compound 8:

[0161] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 8d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 8 (white solid, yield 72%). ESI-MS: m / z = 396 [M+1] + .

[0162] Example 9:

[0163] Synthesis of N-[2-({4-(dimethylamino)benzyl}amino)-4-methylquinoline-6-yl]pyrazine-2-carboxamide (compound 9)

[0164] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0165] S2: Synthesis of Compound 9:

[0166] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 9d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 9 (white solid, yield 77%). ESI-MS: m / z = 413 [M+1] + .

[0167] Example 10:

[0168] Synthesis of O-[2-(4-(dimethylamino)phenoxy)-4-methylquinoline-6-yl]pyrazine-2-carboxamide (compound 10)

[0169] S1: The synthesis method of the intermediate compound 1c is the same as that in Example 1;

[0170] S2: Synthesis of Compound 10:

[0171] Intermediate compound 1c (4.45 mmol) was dissolved in DMF (12 mL), followed by the addition of e (5.34 mmol) and K₂CO₃ (8.90 mmol) sequentially. The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the crude solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 10 (white solid, yield 76%). ESI-MS: m / z = 400 [M+1] + .

[0172] Example 11:

[0173] Synthesis of N-[2-({4-(dimethylamino)phenyl}amino)-4-methylquinoline-6-yl]-5-methylpyrazine-2-carboxamide (compound 11)

[0174] S1: Synthesis of intermediate 2c:

[0175] 2b (5-methyl-2-carboxylic acid pyrazine, 0.250 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.300 mmol) were added to a three-necked flask and dissolved in N,N-dimethylacetamide (2 mL). Then, N,N-diisopropylethylamine (0.300 mmol) was added. The reaction apparatus was purged three times with argon gas, and the reaction was carried out at room temperature for 30 min. Then, compound a (0.300 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, an aqueous solution (2.00 mL) was slowly added to quench the reaction. The mixture was washed with saturated sodium chloride solution (2.00 mL), extracted with ethyl acetate (8.00 mL), concentrated the organic phase, and then purified by silica gel column chromatography (dichloromethane:methanol = 60:1–40:1) to give compound 2c (white solid, yield 92%).

[0176] S2: Synthesis of Compound 11:

[0177] Compound 2c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 3d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 11 (white solid, 80% yield). ESI-MS: m / z = 413 [M+1]+ .

[0178] Example 12:

[0179] Synthesis of N-[2-({4-(dimethylamino)phenyl}amino)-4-methylquinoline-6-yl]-5,6-dimethylpyrazine-2-carboxamide (compound 12)

[0180] S1: Synthesis of intermediate 3c:

[0181] Add 3b (5,6-dimethyl-2-carboxylic acid pyrazine, 0.250 mmol) and 2-(7-azobenzotriazine) to a three-necked flask.

[0182] Compound 3c (0.300 mmol) was dissolved in N,N-dimethylacetamide (2 mL), followed by the addition of N,N-diisopropylethylamine (0.300 mmol). The reaction apparatus was purged three times with argon gas, and the reaction was carried out at room temperature for 30 min. Then, compound a (0.300 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was quenched by the slow addition of aqueous solution (2.00 mL), washed with saturated sodium chloride solution (2.00 mL), extracted with ethyl acetate (8.00 mL), concentrated, and then purified by silica gel column chromatography (dichloromethane:methanol = 60:1–40:1) to give compound 3c (white solid, yield 91%).

[0183] S2: Synthesis of Compound 12:

[0184] Compound 3c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 3d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 12 (white solid, yield 88%). ESI-MS: m / z = 427 [M+1] + .

[0185] Example 13:

[0186] Synthesis of N-[2-({4-(dimethylamino)phenyl}amino)-4-methylquinoline-6-yl]nicotinamide (compound 13)

[0187] S1: Synthesis of intermediate 4c:

[0188] 4b (3-pyridinecarboxylic acid, 0.250 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.300 mmol) were added to a three-necked flask and dissolved in N,N-dimethylacetamide (2 mL). Then, N,N-diisopropylethylamine (0.300 mmol) was added. The reaction apparatus was purged three times with argon gas, and the reaction was carried out at room temperature for 30 min. Then, compound a (0.300 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was quenched by slowly adding an aqueous solution (2.00 mL), washed with saturated sodium chloride solution (2.00 mL), extracted with ethyl acetate (8.00 mL), concentrated the organic phase, and then purified by silica gel column chromatography (dichloromethane:methanol = 60:1–40:1) to give compound 4c (white solid, 90% yield).

[0189] S2: Synthesis of Compound 13:

[0190] Compound 4c (4.45 mmol) was dissolved in DMF (12 mL), followed by the sequential addition of 3d (5.34 mmol) and K₂CO₃ (8.90 mmol). The reaction was carried out at 40 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 15 mL of purified water was added to precipitate the solid. The mixture was stirred for 1 h and filtered to obtain a crude gray solid. A mixed solvent of PE:EA = 7:1 (5.0 mL) was added to the crude solid, and the mixture was stirred at room temperature for 3 h. After filtration, the solid was purified by silica gel column chromatography (dichloromethane:methanol = 80:1–30:1) to give compound 13 (white solid, yield 85%). ESI-MS: m / z = 398 [M+1] + .

[0191] The compounds 1-13 obtained by the present invention were evaluated and tested, with Ki16425 as a comparison object, specifically including:

[0192] Test Example 1: Calcium Ion Mobilization Experiment to Evaluate Receptor LPAR2 Inhibitory Activity

[0193] Experimental methods:

[0194] Changes in intracellular calcium ion levels were detected using the fluorescent calcium-sensitive dye Fluo-4NW (obtained from Invitrogen). RH7777 cells (obtained from ATCC) were seeded in 96-well (Corning) plates with a black transparent bottom coated with poly-D-lysine or collagen at a density of 50,000 cells / well and cultured overnight.

[0195] Replace with 100 μL of Fluo-4NW dye loading solution containing 2.5 μM probenecid, incubate at 37°C for 30 minutes, and then let stand at room temperature for 30 minutes;

[0196] Then add 20 μL of the 6× concentration of the test compound (dissolved in the detection buffer), immediately monitor the fluorescence signal for 120 seconds, then add 10 μM LPA (18:1, 1-oleoyl-sn-glycerol-3-phosphate) and continue monitoring for 120 seconds.

[0197] Detection parameters:

[0198] Fluorescence changes were recorded using a FluoStarOptima microplate reader (obtained from BMG Labtech) (excitation wavelength 494 nm, emission wavelength 525 nm); calcium transient increase was determined by calculating the difference between the maximum signal after LPAR2 (1 μM) stimulation and the baseline; antagonistic activity was expressed as the percentage by which the compound inhibited the increase in calcium signal induced by LPAR2 (LPAR2 alone was set as 100%); positive controls were included in each experiment (10 μM LPA and 10 μM ionomycin); the LPAR2 receptor inhibitory activity of all final compounds was assessed at a concentration of 1 μM as described above, and the data were obtained from three independent experiments.

[0199] The test results are shown in Table 3 below:

[0200] Table 3: Inhibition rate of compounds 1-13 in the examples against LPAR2 at a concentration of 1 μM

[0201]

[0202] In Table 3, "+++" indicates an inhibition rate of 80-90%, and "++++" indicates an inhibition rate of 90-100%. The results show that the compounds of this invention can effectively inhibit LPAR2 activity, and compared with the known LPAR2 inhibitor Ki16425, the compounds of this invention have a stronger inhibitory effect; therefore, the compounds of this invention, as effective LPAR2 inhibitors, are expected to be used for the prevention, relief, or treatment of LPAR2-related diseases.

[0203] Test Example 2: In vivo efficacy test

[0204] Adult female C57Bl / 6J mice aged 10-12 weeks (obtained from Shanghai Xipu Bikai Experimental Animal Co., Ltd.) were selected and housed for one week to acclimatize to their environment. They were then divided into a drug administration group and a model control group, with 6 mice in each group. The mice were anesthetized by intramuscular injection of a mixture of ketamine and toluenethiazide (90:10 mg / kg), and a laminectomy was performed at the 11th thoracic vertebra. The exposed spinal cord was then impinged with an Infinite Horizon impactor (Harvard, IH-0400) at a force of 60,000 dynes. Only mice with spinal cord tissue displacement between 450 and 550 micrometers were selected. One hour after injury, mice were administered a compound (30 mg / kg) intraperitoneally, followed by daily injections for 10 consecutive days. Motor function was assessed using the Basso Mouse Scale (BMS), the gold standard for motor assessment after spinal cord injury, ranging from 0 (no movement) to 9 (completely normal motor behavior). Two uninformed observers rated the mice's motor performance on a 9-point scale. Results were obtained from six independent measurements and are expressed as mean ± standard deviation. ** indicates P < 0.01, *** indicates P < 0.001. P-values ​​were obtained through one-way ANOVA followed by a Sidak t-test, and compared with the model group. The test results are as follows: Figure 1 As shown, Figure 1 The graphs showing the changes in BMS motor function scores over time in the LPAR2-targeted 4-methylquinoline derivative treatment group and the control group of the present invention can be seen from... Figure 1 It was found that the compounds of the present invention significantly improved the recovery of motor function after spinal cord injury in LPAR2 wild-type mice. Compared with the model control group, intraperitoneal administration of the compounds of the present invention for 10 consecutive days resulted in a significant improvement in the recovery of motor function after spinal cord injury in mice: from day 35 after modeling, the motor skills of the injured mice in the treatment group were significantly improved, and at the treatment endpoint (day 50 after injury), the mice treated with solvent were able to put their hind paws on the ground, but did not have a weight-bearing gait (BMS score of 2.33), in contrast, the mice in the treatment group occasionally or frequently exhibited a gait (BMS score of 4.00).

[0205] The test examples above further demonstrate that the LPAR2-targeting 4-methylquinoline derivative provided by this invention not only has excellent LPAR2 inhibitory activity in vitro, but also exhibits good neuroprotective effects and significant functional recovery effects in in vivo animal models. In particular, in the spinal cord injury model, the motor function recovery of the treated group was significantly better than that of the control group, verifying that it has a clear intervention potential for LPAR2-mediated secondary neurological injury.

[0206] Based on the pathogenic role of the LPAR2 receptor in various neurological diseases (including spinal cord injury, neuropathic pain, and cognitive impairment), this invention constructs and screens a class of derivatives with 4-methylquinoline as the parent nucleus. Through rational structural design (introducing specific aryl or heteroaryl fragments at specific sites in the compound), the compounds of this invention achieve selective recognition and effective binding of LPAR2 at the molecular level, inhibiting its downstream signaling pathways, thereby achieving a series of neuroprotective effects such as blocking the release of inflammatory factors, inhibiting glial cell activation, and slowing down demyelination.

[0207] Therefore, this invention achieves highly efficient inhibition of LPAR2 by constructing a 4-methylquinoline derivative with specific structural features, thus providing a novel and well-defined small-molecule intervention for neurological diseases. Compared with existing non-specific LPA receptor antagonists, the compounds of this invention have the following technical advantages:

[0208] Higher selectivity: Specifically targets LPAR2, reducing adverse reactions caused by other LPA subtypes;

[0209] Large space for structural optimization: Based on general formula (I), multi-point modifications can be made, which facilitates subsequent structural optimization;

[0210] Significant efficacy and long-lasting effects: It has demonstrated significant and sustained therapeutic effects in animal experiments;

[0211] Strong drug development potential: It possesses good physicochemical properties and biocompatibility, making it suitable for development into oral or injectable formulations.

[0212] In summary, this invention provides a novel, highly active, and promising class of LPAR2 inhibitors, offering important chemical entities and theoretical foundations for drug development in neurological diseases, and possessing extremely high industrialization value and social application significance.

[0213] In the description of this application, the references to terms such as "an embodiment," "some embodiments," "in this embodiment," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. 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 a suitable manner in any 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.

[0214] The above description is merely a specific embodiment of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. An LPAR2-targeting 4-methylquinoline derivative, characterized in that, The chemical formula of the LPAR2-targeting 4-methylquinoline derivative is shown in formula (1) below: Where X is one of -NH-, -O-, -S-, and -CH2-, and Y is -(CH2). n - and n is an integer between 0 and 3; R1 is selected from: i: 5-10 membered monocyclic, bicyclic aryl, alicyclic, or ii: 5-10 membered monocyclic or bicyclic heteroaryl or heterocyclic groups containing 1-4 heteroatoms selected from N, O and S; The R1 ring may optionally be oxidized and optionally substituted with one or more substituents selected from: i: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, amino, or ii: A phenyl group that can be substituted with one or more halogens or C1-C3 alkyl groups, or iii: 5-10 membered monocyclic or bicyclic heteroaryl or heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, which may be substituted with one or more halogens or C1-C3 alkyl groups; R2 is a 5-7 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms selected from N, O, and S; the R2 ring may optionally be substituted by one or more substituents selected from: i: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or ii: Halogen, hydroxyl, amino, nitro, cyano, or A phenyl group that can be substituted with one or more halogens or C1-C3 alkyl groups, or A 5-10 member monocyclic or bicyclic heteroaryl or heterocyclic group containing 1-4 heteroatoms selected from N, O and S, which may be substituted with one or more halogens or C1-C3 alkyl groups.

2. The LPAR2-targeting 4-methylquinoline derivative according to claim 1, characterized in that, X is selected from -NH- and -O-; Y is selected from -CH2-, and n is 0 or 1.

3. The LPAR2-targeting 4-methylquinoline derivative according to claim 1, characterized in that, R1 is selected from p-trifluoromethylphenyl, o-trifluoromethylphenyl, p-N,N-dimethylphenyl, p-N-methylphenyl, p-acetaminophenyl, 1-methylpiperidinyl, 2-trifluoromethyl-pyridin-4-yl, and 5-chlorothiophen-2-yl.

4. The LPAR2-targeting 4-methylquinoline derivative according to claim 1, characterized in that, R2 is selected from pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 5,6-dimethyl-pyrazin-2-yl, and pyridin-3-yl.

5. The LPAR2-targeting 4-methylquinoline derivative according to claim 1, characterized in that, The chemical formula of the LPAR2-targeting 4-methylquinoline derivative is one of the following structural formulas:

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any one of the LPAR2-targeting 4-methylquinoline derivatives according to claims 1-5 and one or more excipients.

7. The application of the LPAR2-targeting 4-methylquinoline derivative according to any one of claims 1-5, characterized in that, The applications include the use of the LPAR2-targeting 4-methylquinoline derivative in the manufacture of medicaments for the prevention, relief or treatment of LPAR2-related diseases.

8. The application of the LPAR2-targeting 4-methylquinoline derivative according to claim 7, characterized in that, The disease in question is a neurological disorder, which includes spinal cord injury, neurological injury, cognitive impairment, postoperative cognitive impairment, Alzheimer's disease, and neuropathic pain.

9. A method for preparing the LPAR2-targeting 4-methylquinoline derivative of claim 1, characterized in that, The preparation method includes the following steps: S1: Synthesis of intermediate c The quinolineamine compound shown in formula a and the carboxylic acid compound shown in formula b were reacted in DMF solvent at room temperature under the action of condensing agent HATU and base DIPEA to obtain the corresponding intermediate amide compound intermediate c. S2: Synthesis of the target product The target compound is prepared by reacting the intermediate amide compound c with one of the following two classes of compounds: i: undergoes an amidation reaction with compounds containing substituted aryl amino structures represented by formula d; or ii: It undergoes an etherification reaction with phenolic compounds containing substituted aryl groups as represented by formula e; The reaction conditions were as follows: reaction in DMF in the presence of base K2CO3 at a reaction temperature of 40°C. After the reaction, the target compound was purified by washing with water, extraction, crystallization, or column chromatography. Among them, DIPEA is N,N-diisopropylethylamine, HATU is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and DMF is N,N-dimethylformamide. The chemical formula of the quinolineamine compound is: The chemical formula of the carboxylic acid compound is: R2-COOH; the chemical formula of the intermediate amide compound is: The chemical formula of the compound containing the substituted arylamino structure is: The chemical formula of the phenolic compound containing the substituted aryl group structure is R2-OH.

10. The method for preparing the LPAR2-targeted 4-methylquinoline derivative according to claim 9, characterized in that, The chemical reaction formula for the preparation method is as follows: RT represents room temperature.

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