4-carboxylic acid quinoline compounds, preparation method and application thereof

Abstract

The application discloses a 4-carboxylic acid quinoline compound and application. The application provides a compound as shown in formula (I), an isotope marker of the compound, a solvate of the compound, a pharmaceutically acceptable salt of the compound, a solvate of the pharmaceutically acceptable salt of the compound or a prodrug of the compound. The compound is

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a class of 4-carboxylic acid quinoline compounds, their preparation methods, and applications. Background Technology

[0002] 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.

[0003] 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.

[0004] 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.

[0005] 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

[0006] This invention provides a 4-carboxylic acid quinoline compound and its application, which has potential use in the preparation of therapeutic drugs for the prevention and / or treatment of diseases caused by abnormal osteoclast activity.

[0007] 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;

[0008]

[0009] in,

[0010] R 5 Selected from -COOH or -C(O)NH2;

[0011] R 1 R 2 R 3 R 4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, -NH2, -NH-(C1-C6 alkyl), -C(O)NH2, -C(O)NH-(C1-C6 alkyl), -P(O)(CH3)2, and cyclopropyl;

[0012] Ring A is selected from phenyl, 5-6 heteroaryl, and benzo5-6 heteroaryl; the 5-6 heteroaryl refers to a 5-6 heteroaryl containing 1-3 heteroatoms selected from N, O, and S;

[0013] R 6 It can be hydrogen, methyl, or cyano;

[0014] R 7 It can be hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or halo-C1-C6 alkyl;

[0015] Or R 6 With R 7 And the carbon atoms between them together form a C5-C6 ring;

[0016] m can be 0, 1, 2, or 3;

[0017] Each R 8It is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkyl, -C(O)NH2, -C(O)NH-(C1-C6 alkyl).

[0018] Preferably, R 1 R 2 R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, -P(O)(CH3)2, cyclopropyl;

[0019] Preferably, R 1 R 2 R 3 R 4 Each group is independently selected from hydrogen, halogen, cyano, -P(O)(CH3)2, and cyclopropyl;

[0020] Preferably, R 2 Selected from halogen, cyano, -P(O)(CH3)2, cyclopropyl, R 1 R 3 R 4 Both are hydrogen.

[0021] Preferably,

[0022] Ring A is selected from phenyl, 5-6 heteroaryl, and benzo5-6 heteroaryl; the 5-6 heteroaryl refers to a 5-6 heteroaryl containing 1-3 heteroatoms selected from N, O, and S;

[0023] R 7 It can be hydrogen, halogen, or methyl;

[0024] m is 0, 1, or 2;

[0025] Each R 8 It is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C1-C6 alkoxy-substituted C1-C6 alkyl.

[0026] Preferably, ring A is selected from phenyl,

[0027] Preferably, Selected from

[0028] Preferably, the compound of formula (I) is selected from the following structures:

[0029]

[0030] in,

[0031] R 1 R 2 R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, -P(O)(CH3)2, cyclopropyl;

[0032] R 5 It is -COOH or -C(O)NH2;

[0033] R 6 It can be hydrogen, methyl, or cyano;

[0034] R 8a R 8b and R 8c Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy;

[0035] R 8d Selected from H, C1-C6 alkyl, or C1-C6 alkoxy-substituted C1-C6 alkyl.

[0036] Preferably,

[0037] R 1 It is hydrogen;

[0038] R 2 Selected from halogen, cyano, -P(O)(CH3)2, cyclopropyl;

[0039] R 3 It is hydrogen;

[0040] R 4 It is hydrogen;

[0041] R 5 It is -COOH or -C(O)NH2;

[0042] R 6 It can be hydrogen, methyl, or cyano;

[0043] R 8a R 8b and R 8c Each is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, and halo-C1-C3 alkoxy;

[0044] R8d Ethyl groups substituted with H or methoxy groups;

[0045] Preferably,

[0046] R 1 It is hydrogen;

[0047] R 2 Selected from halogen, cyano, -P(O)(CH3)2, cyclopropyl;

[0048] R 3 It is hydrogen;

[0049] R 4 It is hydrogen;

[0050] R 5 It is -COOH or -C(O)NH2;

[0051] R 6 It can be hydrogen, methyl, or cyano;

[0052] R 8a for

[0053] R 8b It is hydrogen;

[0054] R 8c It is hydrogen or halogen;

[0055] R 8d Ethyl groups substituted with H or methoxy groups.

[0056] Preferably, the compound of formula (I) is selected from the following compounds:

[0057]

[0058]

[0059]

[0060]

[0061] 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:

[0062] Method 1:

[0063]

[0064] Method 2:

[0065]

[0066] Method 3:

[0067]

[0068] The definitions of each substituent are the same as those described above.

[0069] 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.

[0070] 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 or health product for the treatment of diseases caused by abnormal osteoclast activity.

[0071] Preferably, the diseases caused by abnormal osteoclast activity 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 metastasis.

[0072] Preferably, the application is selected from the group consisting of:

[0073] (a) Used in the preparation of pharmaceuticals or health products for the treatment of diseases caused by abnormal osteoclast activity; and / or

[0074] (b) Used in the preparation of pharmaceuticals or health products for the prevention and / or treatment of bone and joint injuries; and / or

[0075] (c) Used to prepare drugs or health products that improve bone and joint movement function.

[0076] The present invention also provides a method for treating and / or preventing bone and joint-related diseases, characterized in that it involves administering to a patient a therapeutically effective amount of a compound of formula (I), its isotopic label, enantiomer, diastereomer, solvate, or a pharmaceutically acceptable salt thereof.

[0077] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0078] The term "pharmaceuticalally 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0084] The term "alkyl" refers to a saturated monovalent hydrocarbon group that has a specified number of carbon atoms (e.g., C1-C6), is straight-chain or branched. 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.

[0085] 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.

[0086] 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.

[0087] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations 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).

[0088] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0089] The term "prevention" refers to reducing the risk of developing a disease.

[0090] 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.

[0091] The term "PG" stands for protecting group, such as the Boc protecting group.

[0092] 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.

[0093] The reagents and raw materials used in this invention are all commercially available.

[0094] 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

[0095] Figure 1 The compound of this invention has an inhibitory effect on the differentiation of osteoclast precursor cells in the bone marrow;

[0096] Figures 2-5 The effect of the compound of this invention on osteoclast vesicle bubbling (4X). Detailed Implementation

[0097] 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.

[0098] Example 1:

[0099]

[0100] Step 1: Anhydrous potassium carbonate (12.7 g, 92 mmol) and iodopropane (12.5 g, 7.35 mL, 73.5 mmol) were added sequentially to a DMF solution (60 mL) of compound 1 (5 g, 36.76 mmol). The solution was stirred at 80 °C for 5 hours. After the reaction was confirmed to be complete by TLC, the reaction solution was poured into water (500 mL), extracted three times with ethyl acetate, the organic phases were combined, concentrated, and eluted by column chromatography (20% ethyl acetate / petroleum ether) to obtain target compound 2 (6.6 g), a colorless oil. LCMS: 179.10 [M+1] + .

[0101] Step 2: Concentrated hydrochloric acid (2.13 g, 60 mmol) was added dropwise to a solution of compound 2 (1.78 g, 10 mmol) and compound 2A (2.26 g, 10 mmol) in glacial acetic acid (6 mL). The solution was stirred overnight at 105 °C. After cooling, water was added to dilute the reaction mixture. The precipitated solid was filtered, dried under vacuum, and the crude product was further purified by column chromatography (50–80% ethyl acetate / petroleum ether) to obtain target compound 3 (1 g), a red solid. LCMS: 385.03 [M+1] + .

[0102] Step 3: A DMF (1 mL) solution of compound 3 (30 mg, 0.08 mmol), ammonium chloride (5 mg, 0.09 mmol), HATU (45 mg, 0.12 mmol), and diisopropylethylamine (20 mg, 0.16 mmol) was stirred at room temperature for 0.5 hours. The reaction was monitored by LCMS until complete. The target compound JMD1 (30 mg) was obtained by reverse phase separation (60–90% acetonitrile / water) as a yellow solid.

[0103] LCMS: 385.03 [M+1] + .

[0104] 1H NMR (400MHz, DMSO-d6) δ8.50(d,J=2.2Hz,1H),8.43(brs,1H),8.29(d,J=8.9Hz,2H),8.22(s,1H),8.05(d,J=9. 0Hz,1H),8.02(s,1H),7.95(dd,J=9.0,2.3Hz,1H),7.23–7.02(m,2H),4.89–4.62(m,1H),1.35(d,J=6.0Hz,6H).

[0105] Example 2:

[0106]

[0107] Using 6-bromodihydroindole-2,3-dione (60 mg, 0.28 mmol) as the starting material, the synthesis procedure for compound JMD1 was followed in step 2:

[0108] JMD2 (25mg), yellow solid.

[0109] LCMS: 386.03 [M+1] + .

[0110] 1 H NMR(400MHz,DMSO-d6)δ8.73(d,J=8.4Hz,1H),8.38–8.24(m,3H),8.11(d,J=7.3Hz,1 H), 7.43 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 4.74 (m, 1H), 1.33 (d, J = 6.0 Hz, 6H).

[0111] Example 3:

[0112]

[0113] Using 7-bromodihydroindole-2,3-dione (60 mg, 0.28 mmol) as the starting material, following step 2 of the synthesis of compound JMD1, JMD3 (25 mg) was obtained as a yellow solid.

[0114] LCMS: 386.03 [M+1] + .

[0115] 1H NMR (400MHz, DMSO-d6) δ8.73(d,J=9.0Hz,1H),8.31(s,1H),8.24(d,J=2.1Hz,1H),8.22–8.17(m, 2H), 7.71 (dd, J=9.0, 2.1Hz, 1H), 7.16–6.92 (m, 2H), 4.74 (p, J=6.0Hz, 1H), 1.33 (d, J=6.0Hz, 6H).

[0116] Example 4:

[0117]

[0118] Using 5,6-dichloro-1H-indole-2,3-dione (60 mg, 0.28 mmol) as the starting material, following step 2 of the synthesis of compound JMD1, JMD4 (25 mg) was obtained as a yellow solid.

[0119] LCMS: 376.03 [M+1] + .

[0120] 1 H NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.52(s,1H),8.38(s,1H),8.27–8.21(m,2H),7.16–7.08(m,2H),4.77(p,J=6.1Hz,1H),1.34(d,J=6.0Hz,6H).

[0121] Example 5:

[0122]

[0123] Step 1: Concentrated sulfuric acid (0.5 mL) was slowly added dropwise to ethanol (30 mL) containing compound 1 (2.5 g). The suspension was heated to reflux overnight. After the reaction was complete as monitored by LCMS, it was cooled to room temperature. The precipitated yellow solid was filtered and dried under vacuum to obtain target compound 2 (2.0 g, purity: 80%), which was used directly in the next step. LCMS: 414.04 [M+1]+.

[0124] Step 2: A DMF (5 mL) solution of compound 2 (90 mg, 0.22 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), Xantphos (27 mg, 0.044 mmol), dimethylphosphine oxide (50 mg, 0.64 mmol), and potassium phosphate (150 mg, 0.71 mmol) was stirred at 150 °C for 8 hours under N2 protection. After the reaction was complete as monitored by LCMS, water was added to the reaction solution, and the mixture was extracted with ethyl acetate, concentrated, and eluted by column chromatography (10–14% methanol / dichloromethane) to obtain target compound 3 (56 mg), a yellow solid, LCMS; 412.16 [M+1]+.

[0125] Step 3: The methanol / water (2 mL, 1:1) solution of compound 3 (56 mg, 0.14 mmol) and lithium hydroxide (20 mg, 0.47 mmol) was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the solution was concentrated and separated by reverse phase separation (60-80% acetonitrile / water) to obtain the target product JMD5 (38 mg), a yellow solid.

[0126] LCMS; 384.13[M+1]+.

[0127] 1 H NMR(400MHz, DMSO-d6)δ9.09(dd,J=13.3,1.6Hz,1H),8.50(s,1H),8.38–8.27(m,2H),8.22(dd,J=8.6,2.7Hz,1H),8.12 (td,J=9.1,1.7Hz,1H),7.22–7.01(m,2H),4.77(hept,J=6.1Hz,1H),1.77(d,J=13.4Hz,6H),1.35(s,3H),1.33(s,3H).

[0128] Example 6:

[0129]

[0130] Step 1: A toluene / water (5 mL, 4:1) solution of compound 2 (70 mg, 0.17 mmol), Pd(OAc)2 (8 mg, 0.017 mmol), tricyclohexylphosphine (20 mg, 0.034 mmol), cyclopropylboronic acid (45 mg, 0.51 mmol), and potassium phosphate (185 mg, 0.85 mmol) was reacted overnight at 110 °C under N2 protection. After the reaction was complete as monitored by LCMS, water was added to the reaction solution, and the mixture was extracted with ethyl acetate, concentrated, and eluted by column chromatography (10–15% ethyl acetate / petroleum ether) to obtain target compound 3 (54 mg), a yellow solid, LCMS; 376.18 [M+1]+.

[0131] Step 2: The methanol / water (2 mL, 1:1) solution of compound 3 (54 mg, 0.14 mmol) and lithium hydroxide (13 mg, 0.31 mmol) was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the solution was concentrated and separated by reverse phase separation (60-80% acetonitrile / water) to obtain the target product JMD6 (55 mg), a yellow solid.

[0132] LCMS; 348.13 [M+1] + .

[0133] 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=2.6Hz,2H),8.27–8.13(m,2H),8.02(d,J=8.7Hz,1H),7.51(dd,J=8.8,2.1Hz,1H),7.14–7 .00(m,2H),4.75(p,J=6.0Hz,1H),2.18(td,J=8.5,4.3Hz,1H),1.33(d,J=6.0Hz,5H),1.14–1.06(m,2H),0.87–0.79(m,2H).

[0134] Example 7:

[0135]

[0136] Step 2: A 2 mL NMP solution of compound 2 (200 mg, 0.48 mmol), cuprous cyanide (86 mg, 0.97 mmol), and cuprous iodide (1.8 mg, 0.01 mmol) was reacted at 120 °C for 5 hours. After the reaction was complete as monitored by LCMS, water was added to the reaction solution, followed by extraction with ethyl acetate, concentration, and elution by column chromatography (20–50% ethyl acetate / petroleum ether) to obtain target compound 3 (75 mg), a yellow solid. LCMS: 361.18 [M+1] + .

[0137] Step 3: The methanol / water (2 mL, 1:1) solution of compound 3 (75 mg, 0.21 mmol) and lithium hydroxide (21 mg, 0.51 mmol) was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the solution was concentrated and separated by reverse phase separation (60-80% acetonitrile / water) to obtain the target product JMD8 (18 mg), a yellow solid.

[0138] LCMS; 333.12[M+1]+.

[0139] 1H NMR(400MHz,DMSO-d6)δ9.15(d,J=1.8Hz,1H),8.56(s,1H),8.33–8.27(m,2H),8.23(d,J=8.7Hz,1H ), 8.10 (dd, J = 8.7, 1.9 Hz, 1H), 7.11 ( d, J = 8.9 Hz, 2H), 4.76 ( p, J = 6.0 Hz, 1H), 1.33 ( d, J = 6.0 Hz, 6H).

[0140] Example 8:

[0141]

[0142] Step 1: A 25 mL solution of compound 1 (5 g, 22 mmol) and malonic acid (6.9 g, 66 mmol) in glacial acetic acid was stirred overnight at 120 °C. After the reaction was complete as monitored by LCMS, the solvent was removed by vacuum distillation, the pH was adjusted to 8 with water, and insoluble impurities were removed by filtration. The filtrate was then adjusted to pH 1 with dilute hydrochloric acid. The precipitated solid was filtered and dried under vacuum to obtain target compound 2 (3.2 g). LCMS: 268.12 [M+1]+.

[0143] Step 2: Concentrated sulfuric acid (0.5 mL) was slowly added dropwise to ethanol (30 mL) containing compound 2 (3.2 g). The suspension was heated to reflux overnight. After the reaction was complete as monitored by LCMS, it was cooled to room temperature. The precipitated yellow solid was filtered and dried under vacuum to obtain target compound 3 (3.0 g, purity: 80%), which was used directly in the next step. LCMS: 296.12 [M+1]+.

[0144] Step 3: A 10 mL solution of compound 3 (3.0 g, 10 mmol) in phosphorus oxychloride was stirred at 100 °C for 30 min, cooled to room temperature, the solvent was removed under reduced pressure, ice water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain target compound 4 (2.8 g), which was used directly in the next step. LCMS: 314.12 [M+1]+.

[0145] Step 4: A solution of compound 4 (150 mg, 0.48 mmol), 4-trifluoromethoxyphenylboronic acid (98 mg, 0.48 mmol), Pd(PPh3)4 (55 mg, 0.05 mmol), and potassium carbonate (132 mg, 0.96 mmol) in 1,4-dioxane (5 mL) / water (1 mL) was reacted at 80 °C for 1 hour under N2 protection. After cooling, the solution was concentrated and eluted by column chromatography (5–10% ethyl acetate / petroleum ether) to give target compound 5 (150 mg), LCMS: 440.12 [M+1]+.

[0146] Step 5: The methanol / water (3 mL, 1:1) solution of compound 5 (150 mg, 0.34 mmol) and lithium hydroxide (50 mg, 1.2 mmol) was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the solution was concentrated and separated by reverse phase separation (60-80% acetonitrile / water) to obtain the target product JMD10 (58 mg), a yellow solid.

[0147] LCMS; 412.12[M+1]+.

[0148] 1 H NMR(400MHz,DMSO-d6)δ9.11(d,J=2.4Hz,1H),8.36(d,J=8.8Hz,2H),8.24(s, 1H), 7.97 (d, J = 9.0Hz, 1H), 7.83 (dd, J = 8.9, 2.2Hz, 1H), 7.53 (d, J = 8.3Hz, 2H).

[0149] Example 9:

[0150]

[0151] Using 2-fluoropyridine-3-boronic acid as a starting material, and following steps 4 and 5 of the synthetic route for compound JMD10, compound JMD11 (32 mg) was obtained as a yellow solid.

[0152] LCMS; 347.14 [M+1] + .

[0153] 1 H NMR(400MHz, DMSO-d6)δ9.03(d,J=2.2Hz,1H),8.67(ddd,J=9.9,7.5,2.0Hz,1H),8.47(d,J=1.9Hz,1H),8.43 (dt,J=4.8,1.6Hz,1H),8.14(d,J=9.0Hz,1H),8.04(dd,J=9.0,2.2Hz,1H),7.61(ddd,J=7.2,4.8,2.0Hz,1H).

[0154] Example 10:

[0155]

[0156] Using 3,4-difluorophenylboronic acid as a starting material, compound JMD12 (47 mg) was obtained as a yellow solid by following steps 4 and 5 of the synthetic route of compound JMD10.

[0157] LCMS; 365.14[M+1]+.

[0158] 1 H NMR (400MHz, DMSO-d6) δ9.08(d,J=2.3Hz,1H),8.28(ddd,J=12.3,8.0,2.2Hz,1H),8.23(s,1H),8. 16–8.05(m,1H),7.97(d,J=9.0Hz,1H),7.83(dd,J=9.0,2.4Hz,1H),7.60(dt,J=10.6,8.5Hz,1H).

[0159] Example 11:

[0160]

[0161] Using 3-methoxy-4-fluorophenylboronic acid as a starting material, and following steps 4 and 5 of the synthetic route for compound JMD10, compound JMD13 (25 mg) was obtained as a yellow solid.

[0162] LCMS; 376.14[M+1]+.

[0163] 1 H NMR (400MHz, DMSO-d6) δ8.90(d,J=2.2Hz,1H),8.55(s,1H),8.11(d,J=8.9Hz,1H),8.05(dd,J=8.4,2.2Hz,1H ), 7.98 (dd, J = 9.0, 2.3Hz, 1H), 7.88 (ddd, J = 8.5, 4.4, 2.1Hz, 1H), 7.40 (dd, J = 11.2, 8.5Hz, 1H), 4.01 (s, 3H).

[0164] Example 12:

[0165]

[0166] Using benzofuran-5-boronic acid as a raw material, and following steps 4 and 5 of the synthetic route for compound JMD10, the target compound JMD14 (13 mg) was obtained as a yellow solid.

[0167] LCMS; 368.14[M+1]+.

[0168] 1H NMR(400MHz, DMSO-d6)δ8.95(d,J=2.2Hz,1H),8.63–8.59(m,2H),8.30(dd,J=8.7,1.9Hz,1H) ,8.16–8.06(m,2H),7.99(dd,J=9.0,2.3Hz,1H),7.78(d,J=8.7Hz,1H),7.12(d,J=2.2Hz,1H).

[0169] Example 13:

[0170]

[0171] Using 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrazole as the starting material, compound JMD16 (20 mg) was obtained as a yellow solid by following steps 4 and 5 of the synthetic route of compound JMD10.

[0172] LCMS; 332.14[M+1]+.

[0173] 1 H NMR (400MHz, DMSO-d6) δ8.85 (d, J = 2.1 Hz, 1H), 8.59 (s, 1H), 8.24 (d, J = 16.0 Hz, 2H), 7.98–7.84 (m, 2H), 4.0 (t, 2H), 3.67 (t, 2H), 3.35 (s, 3H).

[0174] Example 14:

[0175]

[0176] Using 3-isopropoxyphenylboronic acid as a starting material, the target compound JMD17 (15 mg) was obtained as a yellow solid by following steps 4 and 5 of the synthetic route of compound JMD10.

[0177] LCMS; 386.14[M+1]+.

[0178] 1 H NMR (400MHz, DMSO-d6) δ8.93(d,J=2.2Hz,1H),8.51(s,1H),8.11(d,J=9.0Hz,1H),7.98(dd,J=9.0,2.3Hz,1H),7. 81 (dd, J = 8.2, 1.7 Hz, 2H), 7.48 (t, J = 8.1 Hz, 1H), 7.15–7.06 (m, 1H), 4.77 (p, J = 6.0 Hz, 1H), 1.33 (d, J = 6.0 Hz, 6H).

[0179] Example 15:

[0180]

[0181] Using 2-fluoro-4-trifluoromethylphenylboronic acid as a starting material, the target compound JMD18 (22 mg) was obtained as a yellow solid by following steps 4 and 5 of the synthetic route of compound JMD10.

[0182] LCMS; 414.14[M+1]+.

[0183] 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=2.2Hz,1H),8.44(d,J=2.1Hz,1H),8.31(t,J=7.9Hz,1H),8.15(d, J=9.0Hz, 1H), 8.04 (dd, J=9.0, 2.2Hz, 1H), 7.92 (dd, J=11.2, 1.8Hz, 1H), 7.80 (dd, J=8.3, 1.8Hz, 1H).

[0184] Example 16:

[0185]

[0186] Using N-isopropylindole-5-boronic acid as a starting material, the target compound JMD19 (35 mg) was obtained as a yellow solid by following steps 4 and 5 of the synthetic route of compound JMD10.

[0187] LCMS; 409.14[M+1]+.

[0188] 1 H NMR (400MHz, DMSO-d6) δ8.96(d,J=2.3Hz,1H),8.51(d,J=2.1Hz,2H),8.13(dd,J=8.7,1.8Hz,1H),8.05(d,J=8.9Hz,1H),7.90(dd,J =9.0, 2.3Hz, 1H), 7.67 (d, J = 8.8Hz, 1H), 7.58 (d, J = 3.2Hz, 1H), 6.64 (d, J = 3.2Hz, 1H), 4.82 (q, J = 6.7Hz, 1H), 1.50 (d, J = 6.7Hz, 6H).

[0189] Example 17:

[0190]

[0191] Using indole-5-boronic acid as a starting material, the target compound JMD25 (30 mg) was obtained as a yellow solid by following steps 4 and 5 of the synthetic route of compound JMD10.

[0192] LCMS; 367.14[M+1]+.

[0193] 1 H NMR (400MHz, DMSO-d6) δ11.37(s,1H),8.94(d,J=2.2Hz,1H),8.61(s,1H),8.55(d,J=1.7Hz,1H),8.14–8.0 8 (m, 2H), 7.97 (dd, J = 9.0, 2.3Hz, 1H), 7.58 (d, J = 8.5Hz, 1H), 7.46 (t, J = 2.7Hz, 1H), 6.63 (t, J = 2.5Hz, 1H).

[0194] Example 18:

[0195]

[0196] Step 1: NaH (60%, 370 mg, 9.24 mmol) was added to a 20 mL THF solution of acetonitrile (5 mL) at 0 °C. The mixture was stirred at this temperature for 30 min. Then, compound 1 (1.2 g, 6.2 mmol) was added to the above solution. The reaction system was brought to room temperature and stirred for 4 hours. The mixture was quenched with water, extracted with ethyl acetate, concentrated, and eluted by column chromatography (25% ethyl acetate / petroleum ether) to obtain target compound 2 (580 mg), a yellow oily substance. LCMS: 204.12 [M+1]+.

[0197] Step 2: Compound 2 (110 mg, 0.49 mmol), 5-bromodihydroindole-2,3-dione (100 mg, 0.49 mmol) and KOH (84 mg, 1.5 mmol) were refluxed in ethanol / water (3 mL / 0.5 mL) for 48 hours, cooled to room temperature, concentrated, and the pH was adjusted to 1 with dilute hydrochloric acid. The precipitated solid was filtered, and the filter cake was further separated by reverse phase separation (60-80% acetonitrile / water) to obtain the target compound JMD20 (10 mg) as a yellow solid.

[0198] LCMS; 411.14[M+1]+.

[0199] 1H NMR(400MHz, DMSO-d6)δ8.22(d,J=2.1Hz,1H),8.06–7.97(m,2H),7.89–7.83(m,2H),7.26(s ,1H),7.12(dd,J=9.2,2.5Hz,3H),7.00(s,1H),4.74(q,J=6.0Hz,1H),1.34(d,J=6.0Hz,6H).

[0200] Example 19:

[0201]

[0202] Step 1: At 0°C, a tetrahydrofuran solution of magnesium ethyl bromide (2.0 M, 9.0 mmol, 4.5 mL) was slowly added dropwise to a tetrahydrofuran solution of compound 1 (1.28 g, 7.8 mmol) (10 mL). The mixture was slowly heated to room temperature and stirred for 2 hours. The solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil (1.46 g), which was used directly in the next step. LCMS: 217.14 [M+23]+.

[0203] Step 2: At 0°C, PCC (3.23 g, 15 mmol) was added to a dichloromethane solution of compound 2 (1.46 g, 7.5 mmol) and silica gel (3 g). The mixture was stirred for 30 min, filtered, and the filter cake was directly concentrated to obtain the target compound, which was used directly in the next step. LCMS: 193.12 [M+1]+.

[0204] Step 3: Compound 3 (500 mg, 2.6 mmol), 5-bromodihydroindole-2,3-dione (490 mg, 2.17 mmol) and KOH (364 mg, 6.5 mmol) were refluxed in ethanol / water (5 mL / 1 mL) for 48 hours, cooled to room temperature, concentrated, and the pH was adjusted to 1 with dilute hydrochloric acid. The precipitated solid was filtered, and the filter cake was further separated by reverse phase separation (60-80% acetonitrile / water) to obtain the target compound JMD20 (30 mg) as a yellow solid.

[0205] LCMS; 400.14[M+1]+.

[0206] 1H NMR (400MHz, DMSO-d6) δ7.96(d,J=8.9Hz,1H),7.93(d,J=2.1Hz,1H),7.87(dd,J=8.9,2.2Hz,1H) ,7.60–7.51(m,2H),7.08–6.99(m,2H),4.73(p,J=6.0Hz,1H),2.41(s,3H),1.33(d,J=6.0Hz,6H).

[0207] Example 20:

[0208]

[0209] Step 1: A DMF (10 mL) solution of compound 1 (1.0 g, 6.2 mmol), iodopropane (2.1 g, 12.3 mmol), and potassium carbonate (2.15 g, 15 mmol) was stirred at 80 °C for 5 hours. After cooling, the solvent was removed under reduced pressure. Ethyl acetate was added to dissolve the compound, and the mixture was washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (1.2 g), which was used directly in the next step. LCMS: 205.14 [M+1]+.

[0210] Step 2: Compound 2 (200 mg, 0.97 mmol), 5-bromodihydroindole-2,3-dione (220 mg, 0.97 mmol), and KOH (168 mg, 3.0 mmol) were refluxed in ethanol / water (5 mL / 1 mL) for 48 hours, cooled to room temperature, concentrated, and the pH was adjusted to 1 with dilute hydrochloric acid. The precipitated solid was filtered, and the filter cake was further separated by reverse phase separation (60-80% acetonitrile / water) to obtain the target compound JMD22 (96 mg), a yellow solid.

[0211] LCMS; 412.14[M+1]+.

[0212] 1 H NMR (400MHz, DMSO-d6) δ8.36(d,J=8.7Hz,1H),8.00(d,J=8.9Hz,1H),7.94(d,J=2.2Hz,1H),7.88(dd,J=8.9,2.2Hz,1H),6.99(dd,J= 8.7, 2.6Hz, 1H), 6.92 (d, J = 2.5Hz, 1H), 4.75 (p, J = 6.0Hz, 1H), 3.09 (dd, J = 8.5, 5.4Hz, 2H), 3.01–2.93 (m, 2H), 1.33 (d, J = 6.0Hz, 6H).

[0213] Example 21:

[0214]

[0215] Step 1: A DMF (10 mL) solution of compound 1 (1.0 g, 6.2 mmol), iodopropane (2.1 g, 12.3 mmol), and potassium carbonate (2.15 g, 15 mmol) was stirred at 80 °C for 5 hours. After cooling, the solvent was removed under reduced pressure. Ethyl acetate was added to dissolve the compound, and the mixture was washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (1.2 g), which was used directly in the next step. LCMS: 205.14 [M+1]+.

[0216] Step 2: Compound 2 (300 mg, 1.57 mmol), 5-bromodihydroindole-2,3-dione (360 mg, 1.57 mmol) and KOH (268 mg, 4.7 mmol) were refluxed in ethanol / water (3 mL / 3 mL) for 48 hours, cooled to room temperature, concentrated, and the pH was adjusted to 1 with dilute hydrochloric acid. The precipitated solid was filtered, and the filter cake was further separated by reverse phase separation (60-80% acetonitrile / water) to obtain the target compound JMD23 (66 mg), a yellow solid.

[0217] LCMS; 398.14[M+1]+.

[0218] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=2.2Hz,1H),8.05(t,J=9.2Hz,2H),7.90(dd,J=8.9,2.3Hz,1H),7.29( d, J=2.2Hz, 1H), 7.09 (dd, J=8.5, 2.3Hz, 1H), 4.79 (p, J=6.0Hz, 1H), 4.28 (s, 2H), 1.35 (d, J=6.0Hz, 6H).

[0219] Example 22:

[0220]

[0221] Following the synthetic route of compound JMD6, compound JMD24 (52 mg) was obtained as a yellow solid.

[0222] LCMS; 348.14[M+1]+.

[0223] 1¹H NMR (400MHz, DMSO-d⁶) δ 8.40 (s, 1H), 8.34 (dd, J = 8.5, 1.3Hz, 1H), 8.31–8.27 (m, 2H), 7.53 (dd, J = 8.5, 7.3Hz, 1H), 7.27 (dd, J = 7.3, 1.3Hz, 1H), 7.10 (d, J = 8.8Hz, 2H), 4.74 (p, J = 6.0Hz, 1H), 3.36 (ddd, J = 8.6, 7.0, 4.2Hz, 1H), 1.32 (d, J = 6.0Hz, 6H), 1.19–1.13 (m, 2H), 0.95–0.82 (m, 2H). Bioassay

[0224] Biochemical activity experiments:

[0225] Example 23:

[0226] 1. Main experimental materials and instruments

[0227] 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.

[0228] 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.

[0229] Instruments: Thermo Scientific CO2 incubator, Olympus inverted microscope, Tecan microplate reader, GE Biacore T200.

[0230] 2. Experimental methods:

[0231] 1) Preparation of test cells

[0232] 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 M-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 M-CSF and 50 ng / mL RANKL) was added for 5-6 days to obtain mature osteoclasts.

[0233] 2) The effect of the compounds of the present invention on osteoclast formation

[0234] 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 JMD 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. Cells were washed with PBS, fixed with 4% paraformaldehyde for 10 minutes, and then washed again with PBS. TRAP staining solution was prepared according to the TRAP staining kit, added to the fixed cells, and incubated at 37°C for approximately 1 hour. The cells were observed and photographed under an inverted microscope, and osteoclast-like cells with >3 nuclei were counted.

[0235] 2. Experimental Results:

[0236] The compounds in the embodiments of this invention exhibit good inhibitory effects on osteoclast formation. The results are shown in Table 1 and... Figure 1-3 .

[0237] Table 1. Inhibitory effect of this series of compounds on bone marrow osteoclast precursor cell differentiation (inhibition rate: %)

[0238]

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 5 Selected from -COOH or -C(O)NH2; R 1 R 2 R 3 R 4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, -NH2, -NH-(C1-C6 alkyl), -C(O)NH2, -CO)NH-(C1-C6 alkyl), -P(O)(CH3)2, and cyclopropyl. Ring A is selected from phenyl, 5-6 heteroaryl, and benzo5-6 heteroaryl; the 5-6 heteroaryl refers to a 5-6 heteroaryl containing 1-3 heteroatoms selected from N, O, and S; R 6 It can be hydrogen, methyl, or cyano; R 7 It can be hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or halo-C1-C6 alkyl; Or R 6 With R 7 And the carbon atoms between them together form a C5-C6 ring; m can be 0, 1, 2, or 3; Each R 8 It is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkyl, -C(O)NH2, -C(O)NH-(C1-C6 alkyl).

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 1 R 2 R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, -P(O)(CH3)2, cyclopropyl; Preferably, R 1 R 2 R 3 R 4 Each group is independently selected from hydrogen, halogen, cyano, -P(O)(CH3)2, and cyclopropyl. Preferably, R 2 Selected from halogen, cyano, -P(O)(CH3)2, cyclopropyl, R 1 R 3 R 4 Both are hydrogen.

3. 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: Ring A is selected from phenyl, 5-6 heteroaryl, and benzo5-6 heteroaryl; the 5-6 heteroaryl refers to a 5-6 heteroaryl containing 1-3 heteroatoms selected from N, O, and S; R 7 It can be hydrogen, halogen, or methyl; m is 0, 1, or 2; Each R 8 It is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C1-C6 alkoxy-substituted C1-C6 alkyl.

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: Ring A is selected from phenyl, 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: Selected from 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, Compounds of formula (I) are selected from the following structures: in, R 1 R 2 R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, -P(O)(CH3)2, cyclopropyl; R 5 It is -COOH or -C(O)NH2; R 6 It can be hydrogen, methyl, or cyano; R 8a R 8b and R 8c Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy; preferably, R 8a for R 8b For hydrogen, R 8c It is hydrogen or halogen; R 8d Selected from H, C1-C6 alkyl, or C1-C6 alkoxy-substituted C1-C6 alkyl.

7. A compound of formula (I) as claimed in claim 6, its isotopic label, its solvate, its pharmaceutically acceptable salt, a solvate of its pharmaceutically acceptable salt, or a prodrug thereof, characterized in that: R 1 It is hydrogen; R 2 Selected from halogen, cyano, -P(O)(CH3)2, cyclopropyl; R 3 It is hydrogen; R 4 It is hydrogen; R 5 It is -COOH or -C(O)NH2; R 6 It can be hydrogen, methyl, or cyano; R 8a R 8b and R 8c Each is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, and halo-C1-C3 alkoxy; R 8d Ethyl groups substituted with H or methoxy groups; Preferably, R 1 It is hydrogen; R 2 Selected from halogen, cyano, -P(O)(CH3)2, cyclopropyl; R 3 It is hydrogen; R 4 It is hydrogen; R 5 It is -COOH or -C(O)NH2; R 6 It can be hydrogen, methyl, or cyano; R 8a for R 8b It is hydrogen; R 8c It is hydrogen or halogen; R 8d Ethyl groups substituted with H or methoxy groups.

8. 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, The compound of formula (I) is selected from the following compounds:

9. A pharmaceutical composition comprising a compound of formula (I) as claimed 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. The use of a compound of formula (I) as described in any one of claims 1-8, its isotopic label, enantiomer, diastereomer, solvate or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9 in the preparation of a medicament or health product for the prevention and / or treatment of diseases caused by abnormal osteoclast activity; Preferably, the diseases caused by abnormal osteoclast activity 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 metastasis. Preferably, the application is selected from the group consisting of: (a) Used in the preparation of pharmaceuticals or health products for the treatment of diseases caused by abnormal osteoclast activity; and / or (b) Used in the preparation of pharmaceuticals or health products for the prevention and / 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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