Quinoline-4-carboxylic acid compound, preparation method therefor, and use thereof

Abstract

Disclosed in the present invention are a quinoline-4-carboxylic acid compound and the use thereof. Provided in the present invention are a compound represented by formula (I), an isotopically labeled compound thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, which can be used to prepare a drug for preventing and / or treating diseases caused by abnormal osteoclast activity.

Description

A class of quinoline-4-carboxylic acid compounds, their preparation methods and applications

[0001] This application claims priority to Chinese patent application 2025104902262, filed on April 18, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceuticals, specifically relating to a class of quinoline-4-carboxylic acid compounds, their preparation methods, and their use in pharmaceuticals for the prevention and / or treatment of diseases caused by abnormal osteoclast activity, or in dietary supplements for improving bone and joint movement function. Background Technology

[0003] Skeleton is a dynamically balanced tissue, encompassing bone formation dominated by osteoblasts and bone resorption dominated by osteoclasts. This dynamic cyclical process is called bone remodeling. Osteoclasts originate from bone marrow-derived macrophages (BMMs) and differentiate and activate into mature osteoclasts under the regulation of cytokines such as macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB (RANKL), thus performing the function of bone resorption. Overactivation of osteoclasts can disrupt bone homeostasis, leading to the development of various skeletal diseases, such as osteoporosis, rheumatoid arthritis, and osteoarthritis.

[0004] Most breast and prostate cancer bone metastases present as osteolytic defects. Metastatic cancer cells secrete large amounts of factors that stimulate osteoclast activation, promoting osteoclast bone resorption and disrupting the balance between bone formation and resorption, thus manifesting as osteolytic bone defects. Treatment can be achieved by inhibiting osteoclast activity and blocking pathological bone resorption. Currently, the main drugs used clinically to treat breast cancer bone metastases are bisphosphonates and RANKL antibodies, such as pamidronate disodium. Their mechanism is to inhibit osteoclast differentiation and promote apoptosis of osteoclasts and cancer cells. However, these drugs are inconvenient to administer and can cause osteonecrosis and inhibit bone formation. The RANKL inhibitor denosumab was launched in the United States in 2010 and approved for clinical trials in the treatment of osteoporosis and breast cancer bone metastases. However, the clinical application of antibody drugs is limited due to factors such as high cost.

[0005] Furthermore, osteoporosis patients exhibit significantly more osteoclast formation in their bone tissue than healthy individuals, leading to excessive bone resorption—a crucial pathological mechanism of osteoporosis. Although various medications exist to inhibit osteoclast formation, most have limited effectiveness and some exhibit significant side effects and adverse reactions. For instance, bisphosphonates have low bioavailability, are prone to gastrointestinal reactions, and long-term use can increase the risk of esophageal cancer and mandibular osteonecrosis; estrogens and selective estrogen receptor modulators are primarily targeted at postmenopausal women and carry an increased risk of deep vein thrombosis; and calcitonin analogs may cause allergic reactions.

[0006] Osteoclasts are the only bone-resorbing cells in the human body. Their bone resorption function plays a crucial role in maintaining bone metabolic homeostasis, helping to maintain the integrity of the skeletal system and mineral homeostasis, and is closely related to local or systemic bone metabolic diseases. Therefore, inhibiting osteoclast formation could ultimately be used to treat bone metabolism-related diseases. Summary of the Invention

[0007] This invention provides a quinoline-4-carboxylic acid compound and its application, specifically its use in the preparation of medicaments for the prevention and / or treatment of diseases caused by abnormal osteoclast activity.

[0008] The present invention provides a compound of formula (I), its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug thereof;

[0009] in,

[0010] R 1 R 2 R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, deuterated C1-C3 alkyl, -P(O)(CH3)2;

[0011] Ring A is a five-membered heteroaryl group that is unsubstituted or substituted with a methyl group; the five-membered heteroaryl group contains 1-2 heteroatoms selected from N, O, and S;

[0012] M is

[0013] R 5 The 5-6 membered heteroaryl group is selected from hydrogen, unsubstituted or substituted by one or more substituents selected from group A, and unsubstituted or substituted by one or more substituents selected from group A; the 5-6 membered heterocyclic group contains 1-2 heteroatoms selected from N, O, and S.

[0014] R 6 Selected from hydrogen or C1-C6 alkyl;

[0015] R 7 The 5-6 membered heteroaryl group is selected from phenyl groups that are unsubstituted or substituted by one or more substituents selected from group A, or from 5-6 membered heterocyclic groups that are unsubstituted or substituted by one or more substituents selected from group A; the 5-6 membered heterocyclic group contains 1-2 heteroatoms selected from N, O, and S.

[0016] R 8 The 5-6 membered heteroaryl group is selected from phenyl groups that are unsubstituted or substituted by one or more substituents selected from group A, or from 5-6 membered heterocyclic groups that are unsubstituted or substituted by one or more substituents selected from group A; the 5-6 membered heterocyclic group contains 1-2 heteroatoms selected from N, O, and S.

[0017] R 9 Selected from hydrogen or C1-C6 alkyl;

[0018] or R 8 and R 9 Together with the carbon atoms connected to them, they constitute an unsubstituted cyclohexyl group or a six-membered heterocyclic group, which is either unsubstituted or substituted by one or more substituents selected from group B; the six-membered heterocyclic group contains 1-2 heteroatoms selected from N, O, and S.

[0019] Group A substituents include: halogen, cyano, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy.

[0020] Group B substitutions include: halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -C(O)CH3.

[0021] Preferably, R 2 R is hydrogen or halogen. 1 R 3 R 4 All are hydrogen;

[0022] Preferably, R 1 R 2 R 3 R 4 Both are hydrogen.

[0023] Preferably, ring A is

[0024] Preferably, ring A is

[0025] Preferably,

[0026] M is

[0027] R 5 Selected from hydrogen, phenyl (unsubstituted or substituted by one or more substituents selected from group A), pyridyl (unsubstituted or substituted by one or more substituents selected from group A), and pyrazolyl (unsubstituted or substituted by one or more substituents selected from group A).

[0028] R 6 Selected from hydrogen, methyl, ethyl, or isopropyl;

[0029] R 7 Selected from phenyl groups that are unsubstituted or substituted by one or more substituents selected from group A, pyridyl groups that are unsubstituted or substituted by one or more substituents selected from group A, and pyrazolyl groups that are unsubstituted or substituted by one or more substituents selected from group A;

[0030] R 8 Selected from phenyl groups that are unsubstituted or substituted by one or more substituents selected from group A, pyridyl groups that are unsubstituted or substituted by one or more substituents selected from group A, and pyrazolyl groups that are unsubstituted or substituted by one or more substituents selected from group A;

[0031] R 9 From hydrogen, methyl, ethyl, or isopropyl;

[0032] or R 8 and R 9 Together with the carbon atoms connected to them, they constitute an unsubstituted cyclohexyl group or a six-membered heterocyclic group, which is either unsubstituted or substituted by one or more substituents selected from group B; the six-membered heterocyclic group contains 1-2 heteroatoms selected from N, O, and S.

[0033] Group A substituents include: halogen, cyano, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy.

[0034] Group B substitutions include: halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -C(O)CH3.

[0035] Preferably,

[0036] M is

[0037] R 6 and R 9 Selected from hydrogen, methyl, ethyl, or isopropyl;

[0038] m, n, p, and q are selected from 0, 1, 2, 3, 4, or 5;

[0039] R 5a R 7a R 8a and R 8b Selected from halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkoxy.

[0040] Preferably,

[0041] M is

[0042] m, n, p, and q are selected from 0, 1, or 2;

[0043] R 5a R 7a R 8a and R 8b Selected from halogen, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy.

[0044] Preferably, M is

[0045] Preferably, the compound of formula (I) is selected from the following compounds:

[0046] This invention also provides methods for preparing compounds of formula (I), their isotopic labels, enantiomers, diastereomers, solvates, or pharmaceutically acceptable salts thereof. These methods include the following:

[0047] Method 1:

[0048] Wherein, ring E is selected from phenyl (unsubstituted or substituted by one or more substituents selected from group A), pyridyl (unsubstituted or substituted by one or more substituents selected from group A), and pyrazolyl (unsubstituted or substituted by one or more substituents selected from group A); group A substituents are defined as described above.

[0049] Method 2:

[0050] Among them, R 7 The definitions of n and n are the same as described above.

[0051] Method 3:

[0052] Among them, R 7 The definitions of n and n are the same as described above.

[0053] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), an isotope label thereof, an enantiomer, a diastereomer, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

[0054] The present invention also provides the use of a compound of formula (I), an isotope label thereof, an enantiomer, a diastereomer, a solvate thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for treating bone metabolic diseases.

[0055] The bone metabolic diseases mentioned include osteoporosis, rheumatoid arthritis, psoriatic arthritis, bone metastasis of solid tumors, and tumors such as breast cancer.

[0056] The present invention also provides the use of compounds of formula (I), isotopic labels thereof, enantiomers, diastereomers, solvates thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, characterized in that the use is selected from the group consisting of:

[0057] (a) Pharmaceuticals or health products for the preparation of treatments for bone loss caused by metabolic diseases (preferably osteoporosis, rheumatoid arthritis); and / or

[0058] (b) Used in the preparation of medicines or health products for the prevention or treatment of bone and joint injuries; and / or

[0059] (c) Used to prepare drugs or health products that improve bone and joint movement function.

[0060] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0061] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0062] The term "solvate" refers to a substance formed by the combination of a compound and a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0063] The term "solvate of a pharmaceutically acceptable salt" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.). The amount of solvent can be stoichiometric or non-stoichiometric.

[0064] The "-" at the end of a group indicates that the group is attached to the rest of the molecule through that site. For example, CH3-C(=O)- refers to an acetyl group.

[0065] When the group valence bond has a wavy line At times, for example, in In the diagram, the wavy line indicates the connection point between the group and other parts of the molecule.

[0066] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0067] The term "alkyl" refers to a monovalent hydrocarbon group that has a specified number of carbon atoms (e.g., C1-C6), is straight-chain or branched, and has u. Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0068] The term "alkoxy" refers to the group R. X -O-,R X The definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0069] The term "heteroaryl" refers to a monocyclic, bicyclic, or fused polycyclic aromatic hydrocarbon group having a specified number of ring atoms (e.g., 5-10), containing at least one (e.g., 1-3) cyclic heteroatoms independently selected from N, O, and S (e.g., N), with the remaining ring atoms being carbon atoms; such as imidazolyl, pyridinyl, pyrrololyl, thiazolyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophene, pyrimidinyl, 1,2,4-triazolyl, benzoxazolyl, imidazopyridyl, triazolylpyridyl, benzofuranyl, pyrazolylpyrimidinyl, benzo-m-dioxacyclopentenyl, indolyl, quinolinyl, isoquinolinyl, etc.

[0070] The term "therapeutic effective dose" refers to the amount given to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0071] The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0072] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0073] The term "prevention" refers to reducing the risk of developing a disease.

[0074] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0075] The term "PG" indicates a protecting group, such as the Boc protecting group.

[0076] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0077] The reagents and raw materials used in this invention are all commercially available.

[0078] The positive and progressive effects of this invention are that the compounds of this invention can be used to prepare drugs for the prevention and / or treatment of diseases caused by abnormal osteoclast activity. These diseases include osteoporosis, rheumatoid arthritis, periodontitis, tooth loss, Paget's disease, rickets, giant cell tumor of bone, myeloma bone disease, and bone destruction caused by cancer bone metastases. Attached Figure Description

[0079] Figure 1 shows the inhibitory effect of the compound of the present invention on the differentiation of osteoclast precursor cells in bone marrow;

[0080] Figures 2-4 show the effect of the compound of the present invention on osteoclast vesicle bubbling (4X). Detailed Implementation

[0081] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0082] Example 1:

[0083] Compound 1 (100 mg, 0.5 mmol), 3,4-difluorophenylboronic acid (95 mg, 0.6 mmol), PddppfCl2·CH2Cl2 (40 mg, 0.05 mmol), and potassium carbonate (180 mg, 1.3 mmol) in a 1,4-dioxane / water solution (9:1, 3 mL) were stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was concentrated and eluted by column chromatography (35–50% ethyl acetate / petroleum ether) to give compound 2 (30 mg), a yellow solid. LCMS: 221.3 [M+1] + .

[0084] 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (40 mg, 0.16 mmol) was refluxed in 1 mL of thionyl chloride for 1 hour, and the excess solvent was removed by concentration under reduced pressure to obtain acyl chloride. The above acyl chloride was dissolved in anhydrous dichloromethane (2.5 mL) and anhydrous tetrahydrofuran (2.5 mL), and compound 2 (30 mg, 0.14 mmol) and sodium hydrogen hydride (60%, 15 mg, 0.32 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS until complete, the solution was concentrated and eluted by column chromatography (1-5% methanol / dichloromethane). After concentration, the solution was further separated by reversed-phase chromatography (70-90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF1 (15 mg), a yellow solid.

[0085] LCMS: 456.5 [M+1] + .

[0086] 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),8.12(s,1H),8.09(d,J=8.6Hz,1H),8.01–7.9 1(m,1H),7.87–7.61(m,4H),7.40(d,J=3.3Hz,1H),6.45–6.38(m,1H),2.47(s,3H).

[0087] Example 2:

[0088] Compound 1 (100 mg, 0.5 mmol), 3-cyanobenzonic acid (90 mg, 0.6 mmol), PddppfCl2·CH2Cl2 (40 mg, 0.05 mmol), and potassium carbonate (180 mg, 1.3 mmol) in a 1,4-dioxane / water solution (9:1, 3 mL) were stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was concentrated and eluted by column chromatography (35–50% ethyl acetate / petroleum ether) to give compound 2 (40 mg), a yellow solid. LCMS: 210.3 [M+1] + .

[0089] 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (60 mg, 0.22 mmol) was refluxed in 1 mL of thionyl chloride for 1 hour, and the excess solvent was removed by concentration under reduced pressure to obtain acyl chloride. The acyl chloride was dissolved in 2.5 mL of anhydrous dichloromethane and 2.5 mL of anhydrous tetrahydrofuran, and compound 2 (40 mg, 0.19 mmol) and sodium hydrogen hydride (60%, 20 mg, 0.47 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS until complete, the solution was concentrated and eluted by column chromatography (1–5% methanol / dichloromethane). After concentration, the solution was further separated by reversed-phase chromatography (70–90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF2 (7 mg), a yellow solid.

[0090] LCMS: 445.3 [M+1] + .

[0091] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),8.23(d,J=7.8Hz,1H),8.11(s,1H),8.08(d,J=8.5Hz,1H),8.02(d,J=8.0Hz, 1H), 7.83 (t, J = 8.0Hz, 2H), 7.65 (t, J = 7.7Hz, 1H), 7.40 (d, J = 3.4Hz, 1H), 6.40 (dd, J = 3.3, 1.1Hz, 1H), 2.46 (s, 3H).

[0092] Example 3:

[0093] NBS (2.7 g, 15.3 mmol) was added to a DMF solution (20 mL) of compound 1 (1.5 g, 13.9 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined. The mixture was washed three times with supersaturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 2 (1.1 g) as a white solid. LCMS: 187.3 [M+1] + .

[0094] A solution of 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (340 mg, 1.34 mmol) in 5 mL of sulfoxide was refluxed for 1 hour, and the excess solvent was removed by concentration under reduced pressure to obtain an acyl chloride. The acyl chloride was dissolved in 10 mL of anhydrous dichloromethane and 10 mL of anhydrous tetrahydrofuran, and compound 2 (250 mg, 1.34 mmol) and sodium hydroxide (60%, 135 mg, 3.32 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was complete as monitored by LCMS, the solution was concentrated, eluted by column chromatography (1–5% methanol / dichloromethane), and concentrated to give the target product compound 3 (150 mg), a yellow solid. LCMS: 422.3 [M+1] + .

[0095] Compound 3 (40 mg, 0.1 mmol), 3-fluoro-4-methoxyphenylboronic acid (22 mg, 0.13 mmol), PddppfCl2·CH2Cl2 (10 mg, 0.01 mmol), and cesium carbonate (50 mg, 0.15 mmol) in a 1,4-dioxane / water solution (9:1, 2 mL) were stirred in a microwave at 150 °C for 1.5 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was concentrated and eluted by column chromatography (35–50% ethyl acetate / petroleum ether). Further separation by reversed-phase liquid chromatography yielded JMF3 (8 mg), a yellow solid.

[0096] LCMS: 468.5 [M+1] + .

[0097] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),8.10(d,J=8.0Hz,2H),7.86(d,J=7.7Hz,1H),7.75(d,J= 9.8Hz,2H),7.71–7.53(m,2H),7.46(s,1H),6.42(d,J=3.2Hz,1H),3.96(s,3H),2.48(s,3H).

[0098] Example 4:

[0099] Step 1: Under ice bath conditions, ethyl magnesium bromide (3.4 M tetrahydrofuran solution, 13.5 mL, 45.6 mmol) was slowly added dropwise to an anhydrous tetrahydrofuran solution (50 mL) of compound 1 (5 g, 38 mmol). The mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete as monitored by TLC, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain target compound 2 (4.3 g), a yellow oil, which was used directly in the next step. LCMS: 146.2 [M-18] + .

[0100] Step 2: Under ice bath conditions, pyridinium chlorochromate (PCC, 10.75 g, 52 mmol) was added in portions to a solution of compound 2A (4.3 g) and silica gel (100–200 mesh, 12.8 g) in 150 mL of dichloromethane. The mixture was stirred for 0.5 hours. After the reaction was complete as monitored by TLC, the reaction solution was subjected to rapid column chromatography (rapid elution with dichloromethane) to obtain target compound 3 (3.1 g), a yellow oily substance. LCMS: 163.2 [M+1] + .

[0101] Step 3: An ethanol solution (50 mL) of compound 3 (3.1 g, 19.1 mmol), sulfur powder (620 mg, 19.1 mmol), and malononitrile (1.26 g, 19.1 mmol) was stirred at room temperature for 0.5 hours. Diethylamine (2.92 g, 40 mmol) was slowly added dropwise. The mixture was stirred at 60 °C for another 2 hours, concentrated, and eluted by column chromatography (25–35% ethyl acetate / petroleum ether) to give target compound 4 (800 mg), a yellow solid. LCMS: 243.2 [M+1] + .

[0102] Step 4: The sulfoxide solution of compound JMD-16 (110 mg, 0.33 mmol) in 2 mL of dichlorosulfoxide was refluxed for 1 hour, and the excess solvent was removed by vacuum concentration to obtain acyl chloride. The above acyl chloride was dissolved in anhydrous dichloromethane (2.5 mL) and anhydrous tetrahydrofuran (2.5 mL), and compound 4 (80 mg, 0.3 mmol) and sodium hydroxide (60%, 30 mg, 0.75 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS to be complete, it was concentrated and eluted by column chromatography (1-5% methanol / dichloromethane). After concentration, the target product JMF7 (32 mg) was further separated by reversed-phase chromatography (70-90% acetonitrile / 0.1% TFA / water) as a yellow solid.

[0103] LCMS: 556.6, 558.6 [M+1] + .

[0104] 1 H NMR (400MHz, DMSO-d6) δ12.57(s,1H),8.58(s,1H),8.26(s,1H),8.19(s,1H),8.13(d,J=2.1Hz,1H),8.02–7.90(m,2H),7 .27(d,J=7.8Hz,1H),7.19(d,J=1.9Hz,1H),7.13(dd,J=7.6,2.0Hz,1H),3.95(s,3H),2.35(s,3H),2.29(d,J=2.1Hz,6H).

[0105] Example 5:

[0106] Compound 1 (200 mg, 1.08 mmol), N-methylpyrazole-4-pyrrolidone borate (255 mg, 1.23 mmol), PddppfCl2·CH2Cl2 (81 mg, 0.1 mmol), and potassium carbonate (350 mg, 2.5 mmol) in a 1,4-dioxane / water solution (5 mL, 9:1) were stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was concentrated and eluted by column chromatography (35–50% ethyl acetate / petroleum ether) to give compound 2 (80 mg), a yellow solid. LCMS: 189.3 [M+1] + .

[0107] A solution of 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (120 mg, 0.48 mmol) in 2 mL of thionyl chloride was refluxed for 1 hour, and the excess solvent was removed by concentration under reduced pressure to obtain an acyl chloride. The acyl chloride was dissolved in anhydrous dichloromethane (2.5 mL) and anhydrous tetrahydrofuran (2.5 mL), and compound 2 (80 mg, 0.41 mmol) and sodium hydrogen hydride (60%, 36 mg, 0.9 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS until complete, the solution was concentrated and eluted by column chromatography (1–5% methanol / dichloromethane). After concentration, the solution was further separated by reversed-phase chromatography (70–90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF13 (13 mg), a yellow solid.

[0108] LCMS: 424.6 [M+1] + .

[0109] 1H NMR(400MHz,DMSO-d6)δ8.41(s,2H),8.18(s,1H),8.12–8.06(m,1H),7.95(s,1H),7.85–7.74(m,2H),7.61(s,1H) ,7.58(ddd,J=8.2,6.8,1.2Hz,1H),7.32(d,J=3.3Hz,1H),6.38(dd,J=3.3,1.1Hz,1H),3.78(s,3H),2.43(s,3H).

[0110] Example 6:

[0111] A solution of compound 1 (100 mg, 0.93 mmol), iodoisopropane (200 mg, 1.20 mmol), and potassium carbonate (280 mg, 2 mmol) in N,N-dimethylformamide (5 mL) was stirred at 60 °C for 18 hours. After the reaction was complete as monitored by TLC, a large amount of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed three times with supersaturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered to obtain compound 2 (170 mg), a yellow solid. LCMS: 151.2 [M+1] + .

[0112] 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (120 mg, 0.48 mmol) was refluxed in 2 mL of thionyl chloride for 1 hour, and the excess solvent was removed by concentration under reduced pressure to obtain acyl chloride. The acyl chloride was dissolved in anhydrous dichloromethane (2.5 mL) and anhydrous tetrahydrofuran (2.5 mL), and compound 2 (60 mg, 0.41 mmol) and sodium hydrogen (60%, 36 mg, 0.9 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS until complete, the solution was concentrated and eluted by column chromatography (1–5% methanol / dichloromethane). After concentration, the solution was further separated by reversed-phase chromatography (70–90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF14 (37 mg), a yellow solid.

[0113] LCMS: 386.2 [M+1] + .

[0114] 1H NMR (400MHz, DMSO-d6) δ11.46(s,1H),8.68(s,1H),8.19(d,J=8.3Hz,1H),8.09(t,J=4.2Hz,2H),7.88–7.79(m,1H),7.65(dd,J =8.2, 6.7Hz, 1H), 7.41 (d, J = 3.3Hz, 1H), 6.41 (dd, J = 3.3, 1.2Hz, 1H), 4.57 (p, J = 6.6Hz, 1H), 2.47 (s, 3H), 1.48 (d, J = 6.6Hz, 6H).

[0115] Example 7:

[0116] Compound 1 (200 mg, 1.08 mmol), pyridine-3-boronic acid (160 mg, 1.23 mmol), PddppfCl2·CH2Cl2 (81 mg, 0.1 mmol), and potassium carbonate (350 mg, 2.5 mmol) in a 1,4-dioxane / water solution (5 mL, 9:1) were stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was concentrated and eluted by column chromatography (35–50% ethyl acetate / petroleum ether) to give compound 2 (90 mg), a yellow solid. LCMS: 186.3 [M+1] + .

[0117] 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (120 mg, 0.48 mmol) was refluxed in 2 mL of thionyl chloride for 1 hour, and the excess solvent was removed by concentration under reduced pressure to obtain acyl chloride. The acyl chloride was dissolved in anhydrous dichloromethane (2.5 mL) and anhydrous tetrahydrofuran (2.5 mL), and compound 2 (90 mg, 0.51 mmol) and sodium hydrogen hydride (60%, 36 mg, 0.9 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS until complete, the solution was concentrated and eluted by column chromatography (1–5% methanol / dichloromethane). After concentration, the solution was further separated by reversed-phase chromatography (70–90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF15 (19 mg), a yellow solid.

[0118] LCMS:421.3[M+1] + .

[0119] 1H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.78(s,1H),8.31(d,J=8.0Hz,1H),8.20(d,J=8.4Hz,1H),8.15–8.08(m ,2H),7.86(ddd,J=8.4,6.8,1.4Hz,1H),7.75–7.62(m,2H),7.43(d,J=3.3Hz,1H),6.42(s,1H),2.48(s,3H).

[0120] Example 8:

[0121] An ethanolic solution (20 mL) of compound 3 (1.4 g, 10 mmol), sulfur powder (320 mg, 10 mmol), and malononitrile (660 mg, 10 mmol) was stirred at room temperature for 0.5 h. Diethylamine (1.5 g, 20 mmol) was slowly added dropwise. The mixture was stirred at 60 °C for another 2 h, concentrated, and eluted by column chromatography (25–35% ethyl acetate / petroleum ether) to give target compound 4 (1.2 g), a yellow solid. LCMS: 193.2 [M+1] + .

[0122] Compound 2 (120 mg, 0.48 mmol) was refluxed in 2 mL of thionyl chloride for 1 hour, and the excess solvent was removed by concentration under reduced pressure to obtain acyl chloride. The acyl chloride was dissolved in 2.5 mL of anhydrous dichloromethane and 2.5 mL of anhydrous tetrahydrofuran, and compound 4 (100 mg, 0.51 mmol) and sodium hydroxide (60%, 36 mg, 0.9 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS until complete, the solution was concentrated and eluted by column chromatography (1–5% methanol / dichloromethane). After concentration, the solution was further separated by reversed-phase chromatography (70–90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF8 (32 mg), a yellow solid.

[0123] LCMS: 428.5 [M+1] + .

[0124] 1H NMR (400MHz, DMSO-d6) δ12.50(s,1H),8.12–8.06(m,2H),7.93(dd,J=8.4,1.3Hz,1H),7.82(d dd,J=8.5,6.9,1.4Hz,1H),7.62(ddd,J=8.2,6.9,1.3Hz,1H),7.39(d,J=3.3Hz,1H),6.39(dd ,J=3.3,1.2Hz,1H),2.80(dd,J=16.3,5.0Hz,1H),2.70–2.54(m,3H),2.45(s,3H),2.35–2.20 (m,1H),2.01–1.81(m,2H),1.42(dtd,J=13.0,10.8,10.3,5.9Hz,1H),1.07(d,J=6.5Hz,3H).

[0125] Example 9:

[0126] An ethanolic solution (20 mL) of compound 3 (1.4 g, 10 mmol), sulfur powder (320 mg, 10 mmol), and malononitrile (660 mg, 10 mmol) was stirred at room temperature for 0.5 h. Diethylamine (1.5 g, 20 mmol) was slowly added dropwise. The mixture was stirred at 60 °C for 2 h, concentrated, and eluted by column chromatography (25–35% ethyl acetate / petroleum ether) to give target compound 4 (1.2 g), a yellow solid. LCMS: 222.2 [M+1] + .

[0127] Compound 2 (120 mg, 0.48 mmol) was refluxed in 2 mL of thionyl chloride for 1 hour, and the excess solvent was removed by concentration under reduced pressure to obtain acyl chloride. The acyl chloride was dissolved in 2.5 mL of anhydrous dichloromethane and 2.5 mL of anhydrous tetrahydrofuran, and compound 4A (110 mg, 0.51 mmol) and sodium hydroxide (60%, 36 mg, 0.9 mmol) were added. The solution was stirred at room temperature for 3 hours. After the reaction was monitored by LCMS until complete, the solution was concentrated and eluted by column chromatography (1–5% methanol / dichloromethane). After concentration, the solution was further separated by reversed-phase chromatography (70–90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF9 (22 mg), a yellow solid.

[0128] LCMS: 457.6 [M+1] + .

[0129] 1H NMR (400MHz, DMSO-d6) δ12.68(d,J=9.9Hz,1H),8.11(s,1H),8.09(d,J=8.4Hz ,1H),7.93(dd,J=8.4,1.4Hz,1H),7.82(ddd,J=8.3,6.9,1.4Hz,1H),7.67–7. 58(m,1H),7.39(d,J=3.3Hz,1H),6.39(d,J=3.3Hz,1H),4.66(d,J=20.7Hz,2H ),3.81–3.72(m,2H),2.78–2.58(m,2H),2.45(s,3H),2.11(d,J=14.0Hz,3H).

[0130] Example 10:

[0131] Step 1: Under ice bath conditions, ethyl magnesium bromide (3.4 M tetrahydrofuran solution, 8 mL, 26.2 mmol) was slowly added dropwise to an anhydrous tetrahydrofuran solution (25 mL) of compound 1A (3.15 g, 22.2 mmol). The mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete as monitored by TLC, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain target compound 2A (3.5 g), a yellow oil, which was used directly in the next step. LCMS: 154 [M-18] + .

[0132] Step 2: Under ice bath conditions, pyridinium chlorochromate (PCC, 9.55 g, 44.4 mmol) was added in portions to a solution of compound 2A (3.5 g) and silica gel (100–200 mesh, 9 g) in 100 mL of dichloromethane. The mixture was stirred for 0.5 hours. After the reaction was complete as monitored by TLC, the reaction solution was subjected to rapid column chromatography (rapid elution with dichloromethane) to obtain the target compound 3A (2.8 g), a yellow oily substance. LCMS: 171.2 [M+1] + .

[0133] Step 3: An ethanol solution (20 mL) of compound 3A (2.8 g, 17 mmol), sulfur powder (540 mg, 17 mmol), and malononitrile (1.12 g, 17 mmol) was stirred at room temperature for 0.5 hours. Diethylamine (2.5 g, 34 mmol) was slowly added dropwise. The mixture was stirred at 60 °C for 2 hours, concentrated, and eluted by column chromatography (25–35% ethyl acetate / petroleum ether) to give target compound 4A (360 mg), a yellow solid. LCMS: 251.2 [M+1] + .

[0134] Step 4: Reflux a solution of compound 2 (120 mg, 0.48 mmol) in 2 mL of thionyl chloride for 1 hour, concentrate under reduced pressure to remove excess solvent, and obtain acyl chloride; dissolve the above acyl chloride in anhydrous dichloromethane (2.5 mL) and anhydrous tetrahydrofuran (2.5 mL), add compound 4A (125 mg, 0.51 mmol) and sodium hydroxide (60%, 36 mg, 0.9 mmol), stir the above solution at room temperature for 3 hours, monitor the reaction for completeness by LCMS, concentrate, elute by column chromatography (1-5% methanol / dichloromethane), concentrate, and further separate by reversed-phase chromatography (70-90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF10 (50 mg), a yellow solid.

[0135] LCMS: 486.4 [M+1] + .

[0136] 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.14(s,1H),8.11(d,J=8.4Hz,1H),7.97(dd,J=8.3,1.4Hz,1H),7.85(ddd,J=8.4,6 .8,1.4Hz,1H),7.72–7.55(m,3H),7.42(d,J=3.3Hz,1H),7.35–7.29(m,1H),6.44–6.39(m,1H),2.47(s,3H),2.39(s,3H).

[0137] Example 11:

[0138] Compound JMF11 (40 mg) was synthesized from 3,4-dichlorobenzaldehyde using the same method as JMF10. It was a yellow solid.

[0139] LCMS: 518.4 [M+1] + .

[0140] 1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),8.14(s,1H),8.13–8.09(m,1H),7.97 (dd,J=8.3,1.4Hz,1H),7.88–7.83(m,1H),7.81(d,J=8.3Hz,1H),7.76(d,J= 2.1Hz,1H),7.65(ddd,J=8.3,6.9,1.3Hz,1H),7.47(dd,J=8.3,2.1Hz,1H),7 .42(d,J=3.4Hz,1H), 6.41(dd,J=3.3,1.1Hz,1H), 2.46(s,3H), 2.39(s,3H).

[0141] Example 12:

[0142] Step 1: A solution of pyridine-2-carboxaldehyde (500 mg, 4.67 mmol), hydroxylamine hydrochloride (680 mg, 9.81 mmol), and sodium carbonate (400 mg, 3.73 mmol) in ethanol / water (5 mL + 5 mL) was stirred at room temperature for 3 hours. After the reaction was complete as monitored by LCMS, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give crude compound 2 (500 mg), which was used directly in the next step. LCMS: 123.5 [M+1] + .

[0143] Step 2: Add NCS (700 mg, 5.61 mmol) to 10 mL of DMF containing crude compound 2, stir at room temperature for 8 hours, pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, wash three times with supersaturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain crude compound 3 (450 mg), which can be used directly in the next step. LCMS: 157.2 [M+1] + .

[0144] Step 3: Under nitrogen protection, a solution (10 mL) of anhydrous tetrahydrofuran containing malononitrile (320 mg, 4.8 mmol) and sodium ethoxide (410 mg, 6 mmol) was stirred for 0.5 hours in an ice bath. Then, a solution (5 mL) of anhydrous tetrahydrofuran containing compound 3 (450 mg) was added to the solution, and the mixture was slowly brought to room temperature and stirred for another 8 hours. After the reaction was monitored by LCMS until complete, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 3), concentrated, and eluted by column chromatography (20–30% ethyl acetate / petroleum ether) to give compound 4 (146 mg) as a yellow solid. LCMS: 187.2 [M+1] + .

[0145] Step 4: Reflux a solution of 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (100 mg, 0.40 mmol) in 2 mL of thionyl chloride for 1 hour, concentrate under reduced pressure to remove excess solvent, and obtain acyl chloride; dissolve the above acyl chloride in anhydrous dichloromethane (2.5 mL) and anhydrous tetrahydrofuran (2.5 mL), add compound 4 (75 mg, 0.40 mmol) and sodium hydrogen (60%, 32 mg, 0.8 mmol), stir the above solution at room temperature for 3 hours, monitor the reaction for completeness by LCMS, concentrate, elute by column chromatography (1-5% methanol / dichloromethane), concentrate, and further separate by reversed-phase chromatography (70-90% acetonitrile / 0.1% TFA / water) to obtain the target product JMF16 (14 mg), a yellow solid.

[0146] LCMS: 422.5 [M+1] + .

[0147] 1 H NMR (400MHz, DMSO-d6) δ8.86(d,J=4.9Hz,1H),8.29(s,1H),8.21(d,J=8.3Hz,1H),8.16–8.04(m,3H),7.87(ddd,J= 8.4, 6.9, 1.4Hz, 1H), 7.69 (ddt, J=8.9, 4.9, 1.6Hz, 2H), 7.42 (d, J=3.4Hz, 1H), 6.43 (d, J=3.3Hz, 1H), 2.48 (s, 3H).

[0148] Example 13:

[0149] Using 3,4-difluorobenzaldehyde as a raw material, and referring to the synthesis method of compound JMF16, the target compound JMF17 (15 mg) was obtained as a yellow solid.

[0150] LCMS: 457.2 [M+1] + .

[0151] 1 H NMR(400MHz,DMSO-d6)δ8.09–8.03(m,1H),7.95–7.90(m,1H),7.89–7.72(m,2H),7.68 –7.35(m,3H),7.34(s,1H),7.21(s,1H),7.08(s,1H),6.40-6.35(m,1H),2.44(s,3H).

[0152] Example 14:

[0153] Using 4-isopropoxybenzaldehyde as a raw material, and referring to the synthesis method of compound JMF16, the target compound JMF18 (12 mg) was obtained as a yellow solid.

[0154] LCMS: 479.5 [M+1] + .

[0155] 1 H NMR (400MHz, DMSO-d6) δ8.12–8.01(m,1H),8.00–7.89(m,2H),7.88–7.72(m,2H),7.54(d,J=22.3Hz,1H),7.41(d,J=8.1Hz,1 H),7.09(dd,J=20.7,8.3Hz,2H),6.86(d,J=8.4Hz,1H),6.40(s,1H),4.89–4.54(m,1H),2.46(s,3H),1.28(d,J=6.0Hz,6H).

[0156] Example 15:

[0157] Using 3-cyanobenzaldehyde as a raw material, and referring to the synthesis method of compound JMF16, the target compound JMF20 (25 mg) was obtained as a yellow solid.

[0158] LCMS: 446.2 [M+1] + .

[0159] 1 H NMR (400MHz, DMSO-d6) δ8.38–8.35(m,1H),8.30(s,1H),8.27–8.15(m,4H),8.13(d,J=8.5Hz,1H),7.96–7.8 2(m,2H),7.69(ddd,J=8.3,6.8,1.3Hz,1H),7.41(d,J=3.4Hz,1H),6.44(dd,J=3.4,1.2Hz,1H),2.48(s,3H).

[0160] Bioevaluation

[0161] Biochemical activity experiments:

[0162] Example 16:

[0163] 1. Main experimental materials and instruments

[0164] Materials: Fetal bovine serum, α-MEM medium, and penicillin / streptomycin were purchased from Gibco; DMSO, MTT, and TRAP staining kits were purchased from Sigma; cytokines such as mM-CSF, mRANKL, hRNAK, and hRNAKL were purchased from Peprotech; cell lysis buffer was purchased from Promega; PBS was purchased from Wisent; and 4-week-old C57BL / 6 mice were purchased from Slack.

[0165] Cells: Bone marrow osteoclast precursor cells, obtained from femoral and tibial medullary cavity cells of C57BL / 6 mice under normal culture conditions, cultured in complete α-MEM medium, i.e., α-MEM + 10% fetal bovine serum + 1% penicillin / streptomycin.

[0166] Instruments: Thermo Scientific CO2 incubator, Olympus inverted microscope, Tecan microplate reader, GE Biacore T200.

[0167] 2. Experimental methods:

[0168] 1) Preparation of test cells

[0169] C57BL / 6 mice were euthanized by cervical dislocation, disinfected by immersion in 75% alcohol, and under aseptic conditions, the long bones of the hind limbs (femur and tibia) were dissected, and attached soft tissue was removed. The surface of the bone marrow cavity was repeatedly flushed with complete culture medium to completely remove the cells. The cell suspension was filtered through a cell strainer, and after quantitative analysis, the cells were seeded into 10cm cell culture dishes and cultured overnight under 5% CO2 and saturated humidity. The next day, the supernatant of non-adherent cells was collected by centrifugation and replaced with fresh complete proliferation medium (complete medium supplemented with 30 ng / mL LM-CSF) for two more days to obtain bone marrow osteoclast precursor cells. Two days later, the bone marrow osteoclast precursor cells were seeded into well plates at a certain concentration and induction medium (complete medium supplemented with 30 ng / mL LM-CSF and 50 ng / mL RANKL) was added, and the cells were cultured for 5-6 days to obtain mature osteoclasts.

[0170] 2) The effect of the compounds of the present invention on osteoclast formation

[0171] Bone marrow osteoclast precursor cells were seeded at a concentration of 5000 cells / well in 96-well plates (100 μL per well) and cultured overnight. The next day, the JMF series of compounds were diluted with complete medium containing M-CSF and IRANKL and added to the cells to a final concentration of 4 μmol / L (100 μL per well). Control wells were treated with an equal volume of medium and the corresponding proportion of DMSO. After 2 days of cell culture, the medium was replaced with fresh medium containing the drug. After 4 days, osteoclasts fused and formed vesicular structures. After washing the cells with PBS, they were fixed with 4% paraformaldehyde for 10 minutes, followed by washing with PBS. TRAP staining solution was prepared according to the TRAP staining kit and added to the fixed cells. The cells were incubated at 37°C for approximately 1 hour, observed and photographed under an inverted microscope, and counted as osteoclast-like cells with >3 nuclei.

[0172] 2. Experimental Results:

[0173] The compounds in the embodiments of this invention have a good inhibitory effect on osteoclast formation. The results are shown in Figures 1-4.

[0174] Table 1. Inhibitory effect of this series of compounds on bone marrow osteoclast precursor cell differentiation (inhibition rate: %)

Claims

1. A compound of formula (I), its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug thereof, characterized in that: in, R 1 , R 2 , R 3 , R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, deuterated C1-C3 alkyl, -P(O)(CH3)2; Ring A is a five-membered heteroaryl group that is unsubstituted or substituted with a methyl group; the five-membered heteroaryl group contains 1-2 heteroatoms selected from N, O, and S; M is R 5 selected from the group consisting of hydrogen, phenyl which is unsubstituted or substituted by one or more substituents selected from group A, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group A; said 5-6 membered heteroaryl contains 1-2 heteroatoms selected from N, O, S; R 6 selected from hydrogen or Ci-C6alkyl; R 7 selected from the group consisting of phenyl, 5-6 membered heteroaryl; said phenyl, 5-6 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from the group A; said 5-6 membered heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, S; R 8 selected from the group consisting of phenyl, 5-6 membered heteroaryl; said phenyl, 5-6 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from the group A; said 5-6 membered heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, S; R 9 selected from hydrogen or Ci-C6alkyl; or R 8 and R 9 and the carbon atom linking them together form a cyclohexyl group, unsubstituted or substituted by one or more substituents selected from group B, a six-membered heterocyclic group, unsubstituted or substituted by one or more substituents selected from group B; said six-membered heterocyclic group containing 1-2 heteroatoms selected from N, O, S; Group A substituents include: halogen, cyano, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy. Group B substitutions include: halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -C(O)CH3.

2. A compound of formula (I), its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug as described in claim 1, characterized in that: R 2 is hydrogen or halogen, R 1 , R 3 , R 4 are each hydrogen; Preferably, R 1 , R 2 , R 3 , R 4 are each hydrogen.

3. A compound of formula (I), its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug as described in claim 1, characterized in that: Ring A is Preferably, ring A is 4. A compound of formula (I) as claimed in claim 1, its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug thereof, characterized in that: M is R 5 selected from the group consisting of hydrogen, phenyl which is unsubstituted or substituted by one or more substituents selected from group A, pyridyl which is unsubstituted or substituted by one or more substituents selected from group A, pyrazolyl which is unsubstituted or substituted by one or more substituents selected from group A; R 6 selected from hydrogen, methyl, ethyl or isopropyl; R 7 selected from the group consisting of phenyl, which is unsubstituted or substituted by one or more substituents selected from group A, pyridyl, which is unsubstituted or substituted by one or more substituents selected from group A, pyrazolyl, which is unsubstituted or substituted by one or more substituents selected from group A; R 8 selected from the group consisting of phenyl, which is unsubstituted or substituted by one or more substituents selected from group A, pyridyl, which is unsubstituted or substituted by one or more substituents selected from group A, pyrazolyl, which is unsubstituted or substituted by one or more substituents selected from group A; R 9 from hydrogen, methyl, ethyl or isopropyl; or R 8 and R 9 and the carbon atoms linking them together form a cyclohexyl group, unsubstituted or substituted by one or more substituents selected from group B, a six-membered heterocyclic group, unsubstituted or substituted by one or more substituents selected from group B; said six-membered heterocyclic group containing 1-2 heteroatoms selected from N, O, S; Group A substituents include: halogen, cyano, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy. Group B substitutions include: halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -C(O)CH3.

5. A compound of formula (I) as claimed in claim 1, its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug thereof, characterized in that: M is R 6 and R 9 is selected from hydrogen, methyl, ethyl or isopropyl; m, n, p, and q are selected from 0, 1, 2, 3, 4, or 5; R 5a , R 7a , R 8a and R 8b are selected from halogen, cyano, hydroxy, Ci-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy.

6. A compound of formula (I) as claimed in claim 1, its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug thereof, characterized in that: M is m, n, p, and q are selected from 0, 1, or 2; R 5a , R 7a , R 8a and R 8b are selected from halogen, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy.

7. A compound of formula (I) as claimed in claim 1, its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug thereof, characterized in that: M is 8. The compound of claim 1, an isotopically-labeled version thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, according to Formula (I), wherein, The compound of formula (I) is selected from the following compounds: ​ 9. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-8, an isotopic label thereof, an enantiomer, a diastereomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

10. Use of a compound of any one of claims 1-8, an isotopically-labeled, enantiomer, diastereomer, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, wherein, The intended use is selected from the following group: (a) Pharmaceuticals or health products for the preparation of treatments for bone loss caused by metabolic diseases (preferably osteoporosis, rheumatoid arthritis); and / or (b) Used in the preparation of medicines or health products for the prevention or treatment of bone and joint injuries; and / or (c) Used to prepare drugs or health products that improve bone and joint movement function.

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