4-sulfamoylphenylpropanamide compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a 4-sulfamoylphenylpropanamide compound and the use thereof. Provided in the present invention are a compound as represented by formula (I), an isotopically labeled substance thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of the pharmaceutically acceptable salt thereof, or a prodrug thereof. The compound can promote ALP expression in osteoblasts, exhibit a relatively good activity for promoting osteoblast differentiation, and has potential therapeutic effects in promoting bone anabolism and treating bone-related diseases.

Description

A class of 4-aminosulfonylphenylpropionamide compounds, their preparation methods and applications

[0001] This application claims priority to Chinese patent application 2024115952006, filed on November 11, 2024. 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 4-aminosulfonylphenylpropionamide compounds, their preparation methods, and applications. Background Technology

[0003] Skeleton is a dynamically balanced tissue, involving bone formation dominated by osteoblasts and bone resorption dominated by osteoclasts. This dynamic cycle is called bone remodeling. Osteoblasts differentiate from bone marrow mesenchymal stem cells. Decreased osteoblast activity leads to an imbalance in bone homeostasis, resulting in the development of various skeletal diseases, such as osteoporosis, delayed bone growth, and slow fracture repair.

[0004] Most current treatments for bone repair work by inhibiting bone resorption to reduce bone loss, such as bisphosphonates and selective estrogen receptor modulators. While these anti-resorption drugs can effectively prevent further bone loss, simply using them cannot restore lost bone structure. Treatments that increase the number or activity of osteoblasts may be a more attractive approach to enhance bone formation and promote bone regeneration.

[0005] Currently available bone-promoting drugs include recombinant human parathyroid hormones such as hPTH(1-34) (teriparatide) and PTHrp (alotropin), and the osteoscin monoclonal antibody Evenity (romosozumab), all of which have been approved by the FDA. However, as hormonal drugs, clinical evidence suggests that long-term use of teriparatide and abalotropin carries a risk of inducing osteosarcoma, and their use is not recommended for patients with a history of radiation exposure or primary or secondary hyperparathyroidism. Evenity is a fully humanized monoclonal antibody that works by inhibiting the activity of osteoscin. In the ARCH trial, Evenity showed stronger efficacy compared to the existing anti-resorption drug alendronate, reducing both vertebral and non-vertebral fracture rates, but the Evenity group showed a certain risk of cardiovascular side effects. All of these drugs must be administered by injection. Therefore, there is an urgent need to find novel osteogenic anabolic drugs with oral potential for the treatment of related diseases. In the early stages of osteoblast differentiation, the activity of alkaline phosphatase (ALP), a marker protein, increases significantly. Therefore, detecting ALP activity levels can determine whether a compound promotes osteoblast differentiation. Currently, there are no reports on the promoting effects of 4-sulfonamide-phenylpropionamide compounds on osteoblast differentiation. The compound provided in this invention has a good effect on promoting ALP expression in osteoblasts, which is beneficial to osteoblast differentiation and mineralization. Summary of the Invention

[0006] This invention provides a 4-aminosulfonylphenylpropionamide compound and its application. This compound can promote the expression of ALP in osteoblasts and has good promoting activity on osteoblast differentiation, and has potential therapeutic effects in the treatment of bone and joint related diseases.

[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] in,

[0009] Each R 0 Each group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, and C3-C6 cycloalkyl.

[0010] X 1 Selected from N or CH;

[0011] X 2Selected from N or CR 2 ;

[0012] R 1 R 2 R 3 R 4 Each 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, -C(O)NH-(C1-C6 alkyl);

[0013] or R 1 R 2 Together with the C atoms between them, they constitute an unsubstituted or substituted phenyl group; group A substituents include: halogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl;

[0014] Ring A is selected from phenyl groups that are unsubstituted or substituted by one or more group B substituents, and 5-6-membered heteroaryl groups that are unsubstituted or substituted by one or more group B substituents; group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -NH2, -NH-(C1-C6 alkyl), -C(O)NH2, -C(O)NH-(C1-C6 alkyl); the 5-6-membered heteroaryl group refers to a 5-6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S.

[0015] As a preferred technical solution,

[0016] X 2 Selected from N or CR 2 ;

[0017] R 3 It is hydrogen;

[0018] R 4 It is hydrogen;

[0019] R 2 It is hydrogen;

[0020] R 1 It is hydrogen or -NH2;

[0021] or R 1 R 2 Together with the C atoms between them, they form an unsubstituted or halogenated phenyl group.

[0022] As a preferred technical solution, each R 0Each group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, deuterated C1-C3 alkyl, halo-C1-C3 alkoxy, deuterated C1-C3 alkoxy, cyclopropyl, and isopropyl.

[0023] As a preferred technical solution, each R 0 Each is independently selected from halogen, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, and cyclopropyl.

[0024] As a preferred technical solution, ring A is selected from phenyl groups that are unsubstituted or substituted by one or more group B substituents, and 5-6 membered heteroaryl groups that are unsubstituted or substituted by one or more group B substituents; group B substituents include: halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -C(O)NH2, -C(O)NH-(C1-C6 alkyl); the 5-6 membered heteroaryl group refers to a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S.

[0025] As a preferred technical solution, ring A is selected from phenyl groups that are unsubstituted or substituted with one or more group B substituents. Unsubstituted or substituted by one or more group B substituents Unsubstituted or substituted by one or more group B substituents Unsubstituted or substituted by one or more group B substituents Unsubstituted or substituted by one or more group B substituents Unsubstituted or substituted by one or more group B substituents

[0026] Group B substituents include: halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -C(O)NH2, -C(O)NH-CH3.

[0027] As a preferred technical solution, ring A is selected from: More preferably, ring A is

[0028] As a preferred technical solution, Selected from

[0029] As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0030] in,

[0031] n is 0, 1, or 2;

[0032] Each R 0 Each is independently selected from halogen, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, isopropyl; R 1 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, -C(O)NH-(C1-C6 alkyl);

[0033] R a Selected from halogens, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, and deuterated C1-C6 alkyl groups;

[0034] R b Selected from hydrogen and methyl.

[0035] Preferably, the compound of formula (I) of the present invention is selected from the following compounds:

[0036] The present invention also provides a method for preparing compounds of formula (I), their isotopic labels, enantiomers, diastereomers, solvates, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0037] 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.

[0038] 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-related diseases.

[0039] The present invention also provides the use of compounds of formula (I), their isotopic labels, enantiomers, diastereomers, solvates or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for the treatment and / or prevention of bone-related diseases.

[0040] The bone-related diseases mentioned include osteoporosis, osteoarthritis, fractures, osteonecrosis, and alveolar bone loss.

[0041] The present invention also provides a method for treating and / or preventing bone-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.

[0042] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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).

[0053] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0054] The term "prevention" refers to reducing the risk of developing a disease.

[0055] 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.

[0056] The term "PG" indicates a protecting group, such as the Boc protecting group.

[0057] 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.

[0058] The reagents and raw materials used in this invention are all commercially available.

[0059] The positive and progressive effects of this invention are as follows: the compounds of this invention can promote the expression of ALP in osteoblasts and have good promoting activity on osteoblast differentiation, thus having potential therapeutic effects in the treatment of bone-related diseases. Attached Figure Description

[0060] Figure 1 is a bar chart showing the osteogenic induction ALP activity of the compounds of this invention against MC3T3-E1; in the figure, "JMG1-H" indicates that the dosage of compound JMG1 was 10. -6 mol / L, “JMG1-M” indicates that the dosage concentration of compound JMG1 is 10 mol / L. -8 mol / L, “JMG1-L” indicates that the administered concentration of compound JMG1 is 10 mol / L. -10 mol / L, and so on for other compounds. Detailed Implementation

[0061] 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.

[0062] Example 1:

[0063] Step 1: Compound 1 (2 g, 8.8 mmol), benzyl chloroformate (1.94 g, 11.4 mmol), and sodium bicarbonate (1.2 g, 11 mmol) in tetrahydrofuran / water (1:3, 20 mL) were stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate, concentrated, and eluted by column chromatography (20% ethyl acetate / petroleum ether) to give compound 2 (3.5 g), anhydrous oil. LCMS: 363.2 [M+1] + .

[0064] Step 2: Add 5 mL of 4N hydrochloric acid / 1,4-dioxane solution dropwise to 20 mL of tetrahydrofuran containing 3.5 g of compound 2, then stir at 50 °C for 3 hours and concentrate to obtain compound 3 (3 g, hydrochloride), a white solid.

[0065] Step 3: Under nitrogen protection, a 1,4-dioxane solution (40 mL) of compound 3 (1.2 g, 4.02 mmol), 4-chloropyridine hydrochloride (730 mg, 4.83 mmol), Pd2dba3 (360 mg, 0.4 mmol), Xantphos (462 mg, 0.8 mmol), and anhydrous tBuONa (1.0 g, 10.0 mmol) was stirred at 108 °C for 18 hours. After the reaction was complete as monitored by LCMS, the reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated and eluted by column chromatography (1–5% methanol / dichloromethane) to obtain compound 4 (580 mg), a yellow oil. LCMS: 321.2 [M+1] + .

[0066] Step 4: Mix 10 mL of methanol solution of compound 4 (580 mg) and 5% Pd / C (50 mg) under hydrogen atmosphere at room temperature. After the reaction is complete as monitored by LCMS and TLC, filter with diatomaceous earth and concentrate the filtrate to obtain compound 5 (460 mg), which is used directly in the next step.

[0067] Step 5: Add 3 drops of glacial acetic acid to a methanol solution (5 mL) of compound 5 (100 mg, 0.49 mmol) and 3-cyanobenzaldehyde (84 mg, 0.63 mmol). Stir at room temperature for 20 minutes. Then add sodium cyanoborohydride (65 mg, 1 mmol) to the reaction solution. Continue stirring at room temperature for 3–6 hours. Quench with water, extract with ethyl acetate, concentrate, and elute by column chromatography (3–5% methanol / dichloromethane) to obtain compound 6 (40 mg) as a colorless oil. LCMS: 360.2 [M+1] + .

[0068] Step 6: A 2 mL solution of compound 6 (40 mg, 0.13 mmol), 3-(4-aminosulfonylphenyl)propionic acid (30 mg, 0.13 mmol), HATU (53 mg, 0.14 mmol), and DIPEA (45 mg, 0.32 mmol) in DMF was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the mixture was separated by reversed-phase liquid chromatography (40–55% acetonitrile / 0.1% TFA / water) to obtain the target compound JMG1 (14 mg), a white solid (hygroscopic).

[0069] LCMS: 532.3 [M+1] + ;

[0070] 1 H NMR(400MHz, DMSO-d6)δ8.20(d,J=7.0Hz,2H),7.83–7.68(m,4H),7.62–7.44(m,3H),7.39(d,J=8.2H z,1H),7.30(d,J=8.9Hz,2H),7.23–7.16(m,2H),4.61(d,J=32.7Hz,2H),4.20(d,J=13.4Hz,2H),3.31 (q,J=9.0,8.6Hz,2H),3.11(q,J=9.0,5.4Hz,2H),2.95(dt,J=23.5,7.4Hz,2H),2.86–2.63(m,2H),1 .78(t,J=15.4Hz,2H),1.69–1.50(m,1H),1.43(dt,J=22.2,7.5Hz,2H),1.14(q,J=11.4,10.8Hz,2H).

[0071] Example 2:

[0072] 3 drops of glacial acetic acid were added dropwise to a methanol solution (5 mL) of compound 5 (100 mg, 0.49 mmol) and 2-fluoro-3-chlorobenzaldehyde (100 mg, 0.63 mmol). After stirring at room temperature for 20 minutes, sodium cyanoborohydride (65 mg, 1 mmol) was added to the reaction solution. Stirring was continued at room temperature for 3–6 hours. The mixture was quenched with water, extracted with ethyl acetate, concentrated, and eluted by column chromatography (3–5% methanol / dichloromethane) to give compound 6 (40 mg) as a colorless oil. LCMS: 348.2 [M+1] + .

[0073] A solution of compound 6 (40 mg, 0.13 mmol), 3-(4-aminosulfonylphenyl)propionic acid (30 mg, 0.13 mmol), HATU (53 mg, 0.14 mmol), and DIPEA (45 mg, 0.32 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. After the reaction was monitored by LCMS to be complete, the target compound JMG2 (30 mg) was separated by reversed-phase liquid chromatography (40–55% acetonitrile / 0.1% TFA / water) as a white solid.

[0074] LCMS: 559.3 [M+1] + ;

[0075] 1 H NMR(400MHz, DMSO-d6)δ8.20(d,J=7.1Hz,2H),7.78–7.68(m,2H),7.58–7.44(m,2H),7.39(d,J=8.1Hz,1H), 7.35–7.25(m,2H),7.19(dq,J=7.0,4.3,3.7Hz,3H),7.11–6.99(m,1H),4.63(d,J=37.3Hz,2H),4.19(d,J=13 .5Hz,2H),3.36–3.25(m,2H),3.12(t,J=12.2Hz,2H),2.94(dt,J=13.8,7.3Hz,2H),2.75(dd,J=37.1,7.4Hz ,2H),1.77(d,J=11.8Hz,2H),1.68–1.52(m,1H),1.43(dt,J=34.6,7.2Hz,2H),1.14(q,J=13.8,12.5Hz,2H).

[0076] Example 3:

[0077] 3 drops of glacial acetic acid were added dropwise to a methanol solution (5 mL) of compound 5 (100 mg, 0.49 mmol) and 3-chloro-4-methoxybenzaldehyde (107 mg, 0.63 mmol). After stirring at room temperature for 20 minutes, sodium cyanoborohydride (65 mg, 1 mmol) was added to the reaction solution. Stirring was continued at room temperature for 3–6 hours. The mixture was quenched with water, extracted with ethyl acetate, concentrated, and eluted by column chromatography (3–5% methanol / dichloromethane) to give compound 6 (52 mg) as a colorless oil. LCMS: 360.2 [M+1] + .

[0078] A solution of compound 6 (52 mg, 0.15 mmol), 3-(4-aminosulfonylphenyl)propionic acid (30 mg, 0.13 mmol), HATU (53 mg, 0.14 mmol), and DIPEA (45 mg, 0.32 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the target compound JMG3 (24 mg) was obtained by reversed-phase liquid chromatography (40–55% acetonitrile / 0.1% TFA / water) as a white solid.

[0079] LCMS: 571.2 [M+1] + ;

[0080] 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=7.2Hz,2H),7.78–7.68(m,2H),7.47(d,J=8.2Hz,1H),7.43–7.34(m,2H),7.30(s,1 H),7.18–7.16(m,1H),6.97(dd,J=16.4,1.9Hz,1H),6.72(ddd,J=17.8,8.1,1.9Hz,1H),4.55(d,J=22.2Hz,2H),4.19( d,J=13.4Hz,2H),3.81(d,J=3.4Hz,3H),3.37–3.21(m,1H),3.10(td,J=11.7,11.0,4.9Hz,2H),2.95(d,J=25.5Hz,3H ),2.82–2.64(m,3H),1.88–1.72(m,2H),1.59(d,J=20.4Hz,1H),1.42(dq,J=14.9,7.2Hz,2H),1.14(q,J=10.9Hz,2H).

[0081] Example 4:

[0082] 3 drops of glacial acetic acid were added dropwise to a methanol solution (5 mL) of compound 5 (100 mg, 0.49 mmol) and thiazolium-5-carboxaldehyde (72 mg, 0.63 mmol). After stirring at room temperature for 20 minutes, sodium cyanoborohydride (65 mg, 1 mmol) was added to the reaction solution. Stirring was continued at room temperature for 3–6 hours. The mixture was quenched with water, extracted with ethyl acetate, concentrated, and eluted by column chromatography (3–5% methanol / dichloromethane) to give compound 6 (62 mg) as a colorless oil. LCMS: 303.2 [M+1] + .

[0083] A solution of compound 6 (62 mg, 0.20 mmol), 3-(4-aminosulfonylphenyl)propionic acid (48 mg, 0.21 mmol), HATU (83 mg, 0.22 mmol), and DIPEA (70 mg, 0.5 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the target compound JMG4 (23 mg) was obtained by reversed-phase liquid chromatography (40–55% acetonitrile / 0.1% TFA / water) as a white solid.

[0084] LCMS: 514.2 [M+1] + ;

[0085] 1 H NMR(400MHz, DMSO-d6)δ9.02(d,J=27.6Hz,1H),8.16–8.08(m,2H),7.85(d,J=2.4Hz,1H), 7.73(d,J=8.1Hz,2H),7.43(dd,J=13.1,8.2Hz,2H),7.30(d,J=3.0Hz,2H),6.87–6.75(m,2 H),4.75(d,J=55.6Hz,2H),3.99–3.79(m,2H),3.34–3.25(m,2H),2.93(q,J=7.2Hz,2H),2 .83–2.65(m,4H),1.70(t,J=14.0Hz,2H),1.43(dd,J=14.9,6.5Hz,3H),1.19–1.09(m,2H).

[0086] Examples 5 and 6:

[0087] Step 1: Add 3 drops of glacial acetic acid to a methanol solution (5 mL) of compound 1 (120 mg, 0.53 mmol) and thiazolium-5-carboxaldehyde (80 mg, 0.63 mmol). Stir at room temperature for 20 minutes. Then add sodium cyanoborohydride (106 mg, 1 mmol) to the reaction solution. Continue stirring at room temperature for 3–6 hours. Quench with water, extract with ethyl acetate, concentrate, and elute by column chromatography (3–5% methanol / dichloromethane) to obtain compound 2 (170 mg), a colorless oil. LCMS: 303.2 [M+1] + .

[0088] Step 2: A 2 mL solution of compound 2 (170 mg, 0.49 mmol), 3-(4-aminosulfonylphenyl)propionic acid (120 mg, 0.52 mmol), HATU (205 mg, 0.53 mmol), and DIPEA (170 mg, 1.3 mmol) in DMF was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the reaction solution was poured into water, extracted with ethyl acetate, and the combined organic phases were washed three times with supersaturated brine. The solution was concentrated and eluted by column chromatography (1–3% methanol / dichloromethane) to obtain compound 3 (253 mg) as a colorless oil. LCMS: 555.2 [M+1] + .

[0089] Step 3: Add 1 mL of 4N hydrochloric acid / 1,4-dioxane solution dropwise to 4 mL of tetrahydrofuran containing compound 2 (250 mg, 0.45 mmol), then stir at 50 °C for 3 hours and concentrate to obtain compound 4 (200 mg, hydrochloride), a white solid.

[0090] Step 4: A solution of compound 4 (80 mg, 0.18 mmol), 4-chloro-2-aminopyridine (30 mg, 0.21 mmol), and DIPEA (80 mg) in isopropanol (3 mL) was sealed in a tube and stirred overnight at 120 °C. After the reaction was monitored by LCMS until complete, the solvent was removed by concentration, and compound JMG5 (10 mg) was obtained by reversed-phase liquid chromatography as a white solid.

[0091] LCMS: 547.2 [M+1] + ;

[0092] 1H NMR(400MHz, DMSO-d6)δ7.82–7.67(m,4H),7.58(d,J=6.2Hz,1H),7.56–7.51(m,1H),7.50–7.45(m,2 H),7.38(d,J=8.3Hz,1H),7.30(d,J=7.8Hz,2H),6.12(dd,J=6.4,2.9Hz,1H),5.83(t,J=2.5Hz,1H),5 .43(s,2H),4.75–4.46(m,2H),3.71(d,J=12.8Hz,2H),3.34–3.25(m,2H),3.00–2.88(m,2H),2.80(t ,J=7.3Hz,1H),2.75–2.62(m,2H),1.65(t,J=13.9Hz,2H),1.52–1.32(m,2H),1.13(d,J=11.7Hz,3H).

[0093] Using 2-amino-4-chloropyrimidine as a starting material, and following the synthetic route of compound JMG5, compound JMG6 (12 mg) was obtained as a white solid.

[0094] LCMS: 548.2 [M+1] + ;

[0095] 1 H NMR (400MHz, DMSO-d6) δ7.83–7.68(m,5H),7.63–7.50(m,2H),7.47(d,J=8.3Hz,1H),7. 38(d,J=8.2Hz,1H),7.30(d,J=7.8Hz,2H),6.24(d,J=15.2Hz,2H),6.10(t,J=5.8Hz,1H ),4.67–4.52(m,2H),4.29(d,J=12.2Hz,2H),3.34–3.25(m,2H),2.94(dt,J=22.4,7.5H z,2H),2.87–2.63(m,4H),1.66(t,J=14.2Hz,2H),1.61–1.33(m,3H),1.14–0.93(m,2H).

[0096] Example 7:

[0097] Step 1: A solution of compound 1 (800 mg, 3.5 mmol), 4,7-dichloroquinoline (690 mg, 3.5 mmol), and DIPEA (1.2 g, 10 mmol) in isopropanol (20 mL) was refluxed overnight at 85 °C (with the tube sealed). After the reaction was complete as monitored by LCMS, the solvent was removed by vacuum distillation. The residue was separated by reversed-phase chromatography (30–40% acetonitrile / 0.1% NH4HCO3 / water) to give compound 2 (580 mg), a yellow oily substance. LCMS: 391.2 [M+1] + .

[0098] Step 2: Add 3 mL of 4N hydrochloric acid / 1,4-dioxane solution dropwise to 4 mL of tetrahydrofuran containing compound 2 (580 mg, 1.45 mmol), then stir at 50 °C for 3 hours and concentrate to obtain compound 3 (400 mg, hydrochloride), a white solid.

[0099] Step 3: Add 3 drops of glacial acetic acid to a methanol solution (3 mL) of compound 3 (80 mg, 0.28 mmol) and N-methylpyrrole-2-carboxaldehyde (35 mg, 0.3 mmol). After stirring at room temperature for 20 minutes, add sodium cyanoborohydride (40 mg, 0.48 mmol) to the reaction solution. Continue stirring at room temperature for 3–6 hours, quench with water, extract with ethyl acetate, concentrate, and elute by column chromatography (3–5% methanol / dichloromethane) to obtain compound 4 (34 mg), a colorless oil. LCMS: 384.2 [M+1] + .

[0100] Step 4: A 2 mL solution of compound 4 (34 mg, 0.09 mmol), 3-(4-aminosulfonylphenyl)propionic acid (23 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), and DIPEA (40 mg, 0.25 mmol) in DMF was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the mixture was separated by reversed-phase liquid chromatography (40–55% acetonitrile / 0.1% TFA / water) to obtain the target compound JMG7 (7 mg), a white solid.

[0101] LCMS: 595.2 [M+1] + ;

[0102] 1H NMR (400MHz, DMSO-d6) δ8.79–8.69(m,1H),8.09–7.97(m,2H),7.74(dd,J=8.3,3.8Hz,2H),7.58(dd ,J=9.0,2.3Hz,1H),7.46(dd,J=20.5,8.1Hz,2H),7.30(d,J=4.4Hz,2H),7.01(dd,J=12.4,5.0Hz,1H ),6.71(q,J=3.4,2.4Hz,1H),6.09–5.83(m,2H),4.59(d,J=11.8Hz,2H),3.51(s,1H),3.39(s,2H), 3.20-3.12(m,4H),2.97(dt,J=14.6,7.3Hz,2H),2.89–2.74(m,3H),2.65(s,4H),2.45–2.31(m,2H).

[0103] Example 8:

[0104] Step 1: A solution of compound 1 (500 mg, 2.2 mmol), 4-chloropyridine hydrochloride (650 mg, 2.2 mmol), and DIPEA (1.2 g, 10 mmol) in isopropanol (20 mL) was refluxed overnight at 85 °C (with the tube sealed). After the reaction was complete as monitored by LCMS, the solvent was removed by vacuum distillation. The residue was separated by reversed-phase chromatography (20–30% acetonitrile / 0.1% NH4HCO3 / water) to give compound 2 (200 mg), a yellow oil. LCMS: 307.2 [M+1] + .

[0105] Step 2: Under ice bath conditions, thionyl chloride (3 mL) was added dropwise to dichloromethane (10 mL) containing compound 3A (1 g, 5.9 mmol). The solution was refluxed for 3 hours and concentrated to obtain crude compound 3 (900 mg), which was used directly in the next step.

[0106] Step 3: Under ice bath conditions, sodium hydroxide (60%, 40 mg, 0.85 mmol) was added to anhydrous DMF (3 ml) containing compound 2 (200 mg, 0.65 mmol). After stirring for 30 minutes, compound 3 (122 mg, 0.65 mmol) was added. The mixture was slowly heated and stirred at room temperature for 3 hours. The mixture was then quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed three times with supersaturated brine. The mixture was concentrated and eluted by column chromatography (50% ethyl acetate / petroleum ether) to obtain compound 4 (300 mg). LCMS: 459.2 [M+1] + .

[0107] Step 4: Add 1.2 mL of 4N hydrochloric acid / 1,4-dioxane solution dropwise to 4 mL of tetrahydrofuran (300 mg, 0.65 mmol) of compound 2, then stir at 50 °C for 3 hours and concentrate to obtain compound 5 (200 mg, hydrochloride), a white solid.

[0108] Step 5: A DMF solution (5 mL) of compound 5 (200 mg, 0.56 mmol), 3-(4-aminosulfonylphenyl)propionic acid (127 mg, 0.56 mmol), HATU (208 mg, 0.58 mmol), and DIPEA (170 mg, 1.3 mmol) was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LCMS, the reaction solution was poured into water, extracted with ethyl acetate, and the combined organic phases were washed three times with supersaturated brine. The solution was concentrated and eluted by column chromatography (1–3% methanol / dichloromethane) to obtain target compound 7 (300 mg) as a colorless oil. LCMS: 570.2 [M+1] + .

[0109] Step 6: The isopropanol (2 mL) solution of compound 7 (60 mg, 0.11 mmol) and methylamine hydrochloride (70 mg, 1.1 mmol) was sealed in a tube (86 °C) and refluxed overnight. After the reaction was monitored by LCMS to be complete, the solvent was removed by concentration. The residue was separated by reversed-phase liquid chromatography (30-40% acetonitrile / 0.1% NH4CO3 / water) to obtain compound JMG8 (21 mg), a white solid.

[0110] LCMS: 555.4 [M+1] + ;

[0111] 1 HNMR(400MHz,DMSO-d6)δ8.34(d,J=7.2Hz,2H),8.03(br s,1H),7.83(t,J=5.7Hz,1H),7.75–7.68(m,3H),7.43–7.34(m,2H),7.20(d,J=7.3Hz,2H),6.50(s,1H),5.33(s,2H),3.65–3.58( m, 4H), 3.17 (q, J = 6.3Hz, 2H), 2.88 (t, J = 7.6Hz, 2H), 2.70 (d, J = 4.2Hz, 2H), 2.49–2.44 (m, 5H), 2.42–2.32 (dt, J = 18.7, 7.0Hz, 4H).

[0112] Example 9:

[0113] Following the synthetic route of JMG7, JMG9 (14 mg) was synthesized as a white solid.

[0114] LCMS: 593.4 [M+1] + ;

[0115] 1 H NMR(400MHz,DMSO-d6)δ8.72(dd,J=5.0,1.8Hz,1H),8.62–8.45(m,1H),8.06–7.98(m,2H),7.83 –7.68(m,3H),7.57(dd,J=8.9,2.3Hz,1H),7.53–7.46(m,1H),7.39(d,J=8.2Hz,1H),7.35–7.25 (dd,J=9.7,4.5Hz,3.5H),7.13(d,J=7.9Hz,0.5H),7.00(dd,J=14.9,5.1Hz,1H),4.70(d,J=28. 4Hz, 2H), 3.52 (dt, J = 13.1, 6.9Hz, 2H), 3.20–3.10 (m, 4H), 3.04–2.85 (m, 4H), 2.77–2.64 (m, 5H).

[0116] Example 10:

[0117] Following the synthetic route of JMG7, JMG10 (7 mg) was synthesized as a white solid.

[0118] LCMS: 617.4 [M+1] + ;

[0119] 1 H NMR(400MHz,DMSO-d6)δ8.76–8.70(m,1H),8.08–7.95(m,2H),7.82–7.69(m ,4H),7.63–7.47(m,4H),7.41–7.25(m,3H),7.00(dd,J=16.7,5.1Hz,1H),4. 69(d,J=35.9Hz,2H),3.55–3.46(m,2H),3.20–3.10(m,4H),2.99(d,J=7.0H z, 1H), 2.92 (d, J = 4.2Hz, 2H), 2.72-2.64 (m, 4H), 1.28 (q, J = 6.2, 5.5Hz, 2H).

[0120] Example 11: In vitro activity test of 4-aminosulfonylphenylpropionamide compounds

[0121] (1) Experimental materials and instruments

[0122] Reagents: α-MEM medium, PBS, and trypsin were purchased from Gibco; fetal bovine serum (FBS) was purchased from Procell; vitamin C and sodium β-glycerophosphate, which are osteogenic induction components, were purchased from Peiyu and Aladdin, respectively; ALP detection kit and penicillin-streptomycin were purchased from Beyotime.

[0123] Cells: MC3T3-E1, purchased from IMMOCELL, cultured in complete α-MEM medium, i.e., α-MEM + 10% FBS + 1% penicillin and streptomycin.

[0124] Instruments: CO2 incubator and biosafety cabinet, microplate reader purchased from Thermofisher, USA, constant temperature water bath purchased from BKMAMLAB, China, inverted microscope purchased from Mingmei, China, centrifuge purchased from Xiangyi, China, pipette purchased from Dalong, China.

[0125] (2) Cell preparation and culture

[0126] Thaw cryovials containing 1 mL of cell suspension rapidly by shaking in a 37°C water bath. Add 4 mL of complete α-MEM medium and mix thoroughly. Centrifuge at 1000 rpm for 3 min, discard the supernatant, add 1-2 mL of complete α-MEM medium, and mix well by pipetting. Then, transfer all cell suspensions to culture dishes containing an appropriate amount of complete α-MEM medium and incubate overnight. Change the medium the next day and check the cell density.

[0127] (3) Detection of osteoblast calcification in vitro and compound-induced osteoblast formation

[0128] After the cells were expanded to a sufficient quantity, they were seeded into 96-well plates. When the cell density reached 60-100%, the blank control group (BK group) was cultured in complete α-MEM medium without osteogenic induction components, the negative control group (NC group) was cultured in complete α-MEM medium containing osteogenic induction components, and the other groups were cultured in media containing three concentrations (10T) of each compound. -6 mol / L, 10 -8 mol / L, 10 -10 The culture medium was filled with complete α-MEM medium containing osteogenic induction components (mol / L), and the medium was changed every 2-3 days. ALP activity was detected on day 7.

[0129] (4) ALP activity detection

[0130] Cells were washed with PBS and then lysed with cell lysis buffer. After lysis, the supernatant was mixed with substrate and buffer in a new well plate (100 μL / well) and incubated at 37°C for 10 min.

[0131] The standard stock solution volumes per 100 μl of standard were 4, 8, 16, 24, 32, and 40 μL, respectively.

[0132] Add 100 μL of reaction stop solution to each well to terminate the reaction.

[0133] OD values ​​were measured at 405 nm. One unit of enzyme activity (U) is defined as the amount of ALP required per minute to hydrolyze the para-nitrophenyl phosphate chromogenic substrate to produce 1 μmol of p-nitrophenol in diethanolamine (DEA) buffer at pH 9.8 and 37°C.

[0134] ALP calculation: Based on the definition of enzyme activity, the ALP activity in the sample is calculated and corrected by the ratio of lysis volume to the volume of substrate involved in the reaction.

[0135] (5) Experimental Results

[0136] When comparing each compound with the NC group (3 concentrations, Dunnett's test), the following compounds showed statistically significant differences at all three concentrations:

[0137] JMG1-H, JMG1-M, JMG1-L(****P JMG1-H <0.0001, ***P JMG1-M <0.001, ****P JMG1-L <0.0001);

[0138] JMG7-H, JMG7-M, JMG7-L(****P JMG7-H <0.0001, ***P JMG7-M <0.001, **P JMG7-L <0.01);

[0139] JMG8-H, JMG8-M, JMG8-L(*P) JMG8-H <0.05, *P JMG8-M <0.05, *P JMG8-L <0.05);

[0140] JMG9-H, JMG9-M, JMG9-L (*P) JMG9-H <0.05, *P JMG9-M <0.05, *P JMG9-L <0.05);

[0141] JMG10-H, JMG10-M, JMG10-L(*P JMG8-H <0.05, **P JMG8-M <0.01, **P JMG8-L <0.01).

[0142] This series of compounds significantly promoted osteoblast formation. The results are shown in Figure 1.

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, n is 0, 1, or 2; Each R 0 Each group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkoxy, and C3-C6 cycloalkyl. X 1 Selected from N or CH; X 2 Selected from N or CR 2 ; R 1 R 2 R 3 R 4 Each 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, -C(O)NH-(C1-C6 alkyl); Or R 1 R 2 Together with the C atoms between them, they constitute an unsubstituted or substituted phenyl group; group A substituents include: halogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl; Ring A is selected from phenyl groups that are unsubstituted or substituted by one or more group B substituents, and 5-6-membered heteroaryl groups that are unsubstituted or substituted by one or more group B substituents; group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -NH2, -NH-(C1-C6 alkyl), -C(O)NH2, -C(O)NH-(C1-C6 alkyl); the 5-6-membered heteroaryl group refers to a 5-6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S.

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: X 2 Selected from N or CR 2 ; R 3 It is hydrogen; R 4 It is hydrogen; R 2 It is hydrogen; R 1 It is hydrogen or -NH2; Or R 1 R 2 Together with the C atoms between them, they form an unsubstituted or halogenated phenyl group.

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 groups that are unsubstituted or substituted by one or more group B substituents, and 5-6 membered heteroaryl groups that are unsubstituted or substituted by one or more group B substituents; group B substituents include: halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -C(O)NH2, -C(O)NH-(C1-C6 alkyl); the 5-6 membered heteroaryl group refers to a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S.

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 groups that are unsubstituted or substituted with one or more group B substituents. Unsubstituted or substituted by one or more group B substituents Unsubstituted or substituted by one or more group B substituents Unsubstituted or substituted by one or more group B substituents Unsubstituted or substituted by one or more group B substituents Unsubstituted or substituted by one or more group B substituents Group B substituents include: halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, -C(O)NH2, -C(O)NH-CH3; Preferably, ring A is selected from: More preferably, ring A is 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, n is 0, 1, or 2; Each R 0 Each is independently selected from halogen, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, isopropyl; R 1 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, -C(O)NH-(C1-C6 alkyl); R a Selected from halogens, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, and deuterated C1-C6 alkyl groups; R b Selected from hydrogen and methyl.

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

8. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-7, an isotopic label thereof, an enantiomer, a diastereomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

9. The use of a compound of formula (I) as claimed in any one of claims 1-7, its isotopic label, enantiomer, diastereomer, solvate or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating and / or preventing bone and joint-related diseases.

10. The application as described in claim 9, wherein the bone and joint related diseases are osteoporosis, osteoarthritis, fractures, osteonecrosis, and alveolar bone loss.

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