Bicyclo [2.1. 1] hexane derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly discloses a bicyclo [2.1. 1] hexane derivative as well as a preparation method and application thereof. The bicyclo [2.1. 1] hexane derivative is a compound as shown in a formula (I) or a formula (II), a pharmaceutically acceptable salt, a stereoisomer or an isotope label of the bicyclo [2.1. 1] hexane derivative, wherein R1 is optionally selected from C1-C6 alkyl groups, bromomethyl alkyl, benzyl alkyl, ester groups, acylamino and acyl groups; r2 is optionally selected from hydrogen, C1-C6 alkyl, benzyl alkyl, aryl, heteroaryl, alkenyl, halogen and silicon; r3 is optionally selected from hydrogen, C1-C6 alkyl, bromomethyl alkyl, benzyl alkyl, an ester group, an acylamino group, an acyl group, an amido group, a sulfenamide group, halogen and a carboxyl group; and R4 is optionally selected from C1-C6 alkyl, benzyl alkyl, aryl, heteroaryl and alkenyl. And the formula (II) can be obtained by carrying out half-pinacol intramolecular rearrangement on the formula (I). Tests prove that the compounds in the formula (I) and the formula (II) can be used for treating osteoarthritis diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to bicyclo[2.1.1]hexane derivatives, their preparation methods, and uses. Background Technology

[0002] Aromatic rings are the most commonly used structural fragments in commercially available small molecule drugs. However, undesirable "drug-like properties" such as poor metabolic stability and water solubility are often associated with benzene rings. In recent years, the concept of "escape from flatland"—replacing planar aromatic rings with three-dimensional saturated carbon rings—has attracted much attention in the field of new drug development. (Tsien J.; Hu C.; Merchant RR; Qin T.) Nat. Rev. Chem. 2024, 8 , 605–627; Dutta, S.; Lu, Y.-L.;Ercinger, JE; Shao, H.; Houk, KN; Glorius, F. et al. J. Am. Chem. Soc 2024, 146 , 5232–5241; Fu, Q.-Q.; Cao, S.-S.; Wang, J.-H.; Lv, X.-X.; Wang,H.; Jiang, Z.-Y. J. Am. Chem. Soc 2024, 146 , 8372–8380; Liu, Y.; Lin, S.; Li,Y.; Xue, J.-H.; Li, Q.-J.; Wang, H.-G. ACS Catal 2023, 13 , 5096–5103; Agasti, S.; Beltran, F.; Pye, E.; Kaltsoyannis, N.; Crisenza, GEM; Procter, DJ Nat. Chem. 2023, 15 , 535–541; Levterov, VV; Panasyuk, Y.; Pivnytska, VO; Mykhailiuk, PK Angew. Chem. Int. Ed 2020, 59(7161–7167). The three-dimensional saturated carbocyclic ring of bicyclic [2.1.1]hexane, as a bioisosteric isosteric group of aromatic rings, can replace planar aromatic rings in bioactive molecules. The introduction of bioisosteres brings new opportunities for improving the physicochemical properties, drug-like properties (ADME), and drug metabolism and pharmacokinetics (DMPK) properties of bioactive molecules. The most commonly used and efficient strategy for the synthesis of bicyclic [2.1.1]hexane to date mainly relies on [2+2] cycloaddition reactions, such as the intramolecular [2π+2π] cycloaddition reaction of 1,5-diene, and the intermolecular [2σ+2π] cycloaddition reaction between bicyclic [1.1.0]butane and unsaturated hydrocarbons (such as alkenes and alkynes). Cyclobutanone is readily available as a starting material, and the intramolecular cyclization of β-substituted cyclobutanone can provide a simple route for the synthesis of substituted bicyclic [2.1.1]hexane. However, this transformation process has not been fully explored, and reported methods are limited to the Barbier reaction and the Barluenga–Valdés coupling reaction. Nevertheless, transition metal-catalyzed cyclization of cyclobutanone to form bicyclo[2.1.1]hexane and derivatives of bicyclo[2.1.1]hexane have not been reported. Summary of the Invention

[0003] The purpose of this invention is to address the above-mentioned shortcomings of the prior art by providing a bicyclic [2.1.1]hexane derivative, its preparation method, and its uses. This bicyclic [2.1.1]hexane derivative is a novel bicyclic [2.1.1]hexane compound with good anti-inflammatory activity, and its preparation process is simple.

[0004] To achieve the above objectives, the present invention adopts the following technical solution: The first object of the present invention is to provide a compound of formula (I) or formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotope label thereof: , ; in, R1 can be selected from C1-C6 alkyl, bromomethylalkanes, benzylalkanes, ester groups, amide groups, or acyl groups; R2 can be selected from hydrogen, C1-C6 alkyl, benzyl alkyl, aryl, heteroaryl, alkenyl, halogen, or silyl. R3 can be selected from hydrogen, C1-C6 alkyl, bromomethylalkanes, benzylalkanes, ester groups, amide groups, acyl groups, amino groups, sulfinamide groups, halogens, and carboxyl groups; R4 can be selected from C1-C6 alkyl, benzyl alkyl, aryl, heteroaryl, or alkenyl groups.

[0005] A second object of the present invention is to provide a method for preparing a compound as shown in formula (I), comprising the following steps: S1. Additives and silane are added under the catalysis of a catalyst formed by the complexation of catalyst precursor and ligand, and the raw material shown in formula (III) reacts in a solvent. S2. After the reaction is complete, add water to quench the reaction. S3. Extract and concentrate the solvent, separate and purify to generate a bicyclic [2.1.1]hexane compound (I) containing a tertiary alcohol; the reaction equation is as follows: , Wherein, [Ni] represents the catalyst precursor nickel; Ligand represents the ligand; solvent represents the organic solvent; additive represents the additive; SiH represents silane; R 1 Choose from C1-C6 alkyl, bromomethylalkanes, benzylalkanes, ester groups, amide groups, and acyl groups; R 2 It can be selected from hydrogen, C1-C6 alkyl, benzyl alkyl, aryl, heteroaryl, alkenyl, halogen, and silyl.

[0006] Further, the catalyst precursor nickel comprises any one or more of Ni(OTs)2•6H2O, Ni(ClO4)2•6H2O, Ni(OAc)2•4H2O, Ni(BF4)2•6H2O, Ni(H2PO2)2•6H2O, NiCl2•glyme, Ni(OTf)2, Ni(dppp)Cl2, Ni(acac)2, NiCl2, NiCl2•DME, and Ni(COD)2; the ligand has the following structure or its enantiomers:

[0007] Furthermore, the mass ratio of the nickel element in the catalyst precursor to the mass of the raw material shown in formula (III) is 0.01:1 to 0.2:1; the molar ratio of the nickel element in the catalyst precursor to the ligand is 1:0.5 to 1:2; and the mass ratio of the additive to the silane is 0.3:1 to 2:1.

[0008] Further, the organic solvent includes any one or a mixture of methanol, ethanol, tert-butanol, isopropanol, hexafluoroisopropanol, ethyl acetate, anisole, toluene, 1,2-dichloroethane, chlorobenzene, acetonitrile, dimethylformamide, ethylene glycol dimethyl ether, diethyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, and 1,4-dioxane; The additives include any one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium fluoride, sodium acetate, potassium trifluoromethanesulfonate, potassium hydrogen sulfate, sodium bicarbonate, copper trifluoromethanesulfonate, zinc chloride, p-toluenesulfonic acid, tetrabutylammonium chloride, ammonium hexafluorophosphate, and cesium carbonate. The silanes referred to are dimethylethoxysilane, methyldiethoxysilane, trimethoxysilane, triethoxysilane, triisopropoxysilane, bistrimethylsiloxymethylsilane, and phenylsilane.

[0009] Furthermore, the reaction temperature is 0℃-100℃; the reaction atmosphere is an inert atmosphere; and the reaction time is 1h-36h.

[0010] A third objective of this invention is to provide a method for preparing a compound as shown in formula (II), wherein the compound shown in formula (I) is subjected to intramolecular rearrangement of hemipinalol under acidic or alkaline conditions.

[0011] Further, the acid includes any one of acetic acid, hydrochloric acid, p-toluenesulfonic acid, or trifluoromethanesulfonic acid; the base includes sodium hydride, sodium hydroxide, potassium hydroxide, etc. N -bromosuccinimide, N -Chlorosilicate or N - Any one of iodosuccinimide.

[0012] A fourth object of the present invention is to provide a pharmaceutical composition comprising a compound represented by formula (I) and / or formula (II) above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotopic label thereof; and optionally one or more pharmaceutically acceptable excipients.

[0013] A fifth object of the present invention is to provide the use of the above-described compounds, their pharmaceutically acceptable salts, their stereoisomers, or isotopic labels, or the above-described pharmaceutical compositions in the preparation of medicaments for the treatment or prevention of osteoarthritis.

[0014] As used herein, the term "pharmaceutically acceptable salt" refers to acid or base addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0015] Pharmaceutically acceptable salts can be sulfates, pyrosulfates, bisulfates, sulfites, nitrates, borates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, etc., prepared from inorganic acids. Representative salts include hydrobromide, hydrochloride, sulfates, bisulfates, nitrates, borates, and phosphates. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, valerates, oleates, palmitates, stearates, laurates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates, glucono-p-ethyl, lactobionates, laurylsulfonates, and hydroxyethanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers salts of amino acids, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0016] This invention also includes isotopically labeled compounds (isotope variants) that are equivalent to those general formulas or specific compounds described in this application, but with one or more atoms replaced by atoms of different atomic masses or mass numbers than those commonly found in nature. Examples of isotopes that can be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of this invention containing the above-mentioned isotopes and / or other isotopes, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotopically labeled compounds of this invention, such as those incorporating radioactive isotopes (e.g., 3H and 14C), can be used for drug and / or substrate tissue distribution assays. Tritium (3H) and carbon-14 (14C) isotopes are particularly preferred because they are easy to prepare and detect. Additionally, substitution with heavier isotopes such as deuterium (2H) is preferred in some cases because it provides therapeutic benefits due to greater metabolic stability, such as prolonged in vivo half-life or reduced dosage requirements. Isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0017] Some compounds of this invention include one or more asymmetric centers and therefore can exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0018] Compared with existing technologies, the beneficial effects of the technical solution provided by this invention are as follows: (1) The present invention innovatively designs compounds of formula (I) or formula (II) to exhibit anti-inflammatory activity against osteoarthritis cells in vitro, showing significant effects in reducing cellular inflammatory expression. Moreover, the compounds have low cytotoxicity, more physiologically active sites, and the novelty of their molecular structure provides space for derivatization and modification, which can further optimize pharmacokinetic properties, enhance clinical translation potential, and provide new and effective means for the treatment of inflammatory diseases.

[0019] (2) The synthesis method provided by the present invention is expected to provide a more efficient synthesis strategy for the synthesis of bicyclo[2.1.1]hexane.

[0020] (3) The bicyclic [2.1.1]hexane of the skeleton of the present invention can be used as a bioisostere of the benzene ring to realize the substitution of the benzene ring in the development of new drugs. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this invention clearer, the specific embodiments of this invention are described in further detail below. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0022] The compounds in this invention are named systematically according to the "Nomenclature Principles of Organic Compounds" of the Chinese Chemical Society, maintaining the priority order of functional groups. The alkyne group is expressed as "prop-2-yn-1-yl" in a standard way. The positions of the substituents on the benzene ring are marked by ortho / meta / para. Complex substituents are named stepwise according to the priority of the substituent chain.

[0023] The preparation process route of the compound represented by formula (I) provided by this invention is as follows: Wherein, [Ni] is the catalyst precursor nickel; Ligand is the ligand; solvent is the organic solvent; additive is the additive; SiH is silane; R 1 Choose from alkyl (bromomethyl, benzyl, and C1-C6 alkyl), ester, amide, or acyl groups; R 2 It can be selected from hydrogen, alkyl (benzyl, C1-C6 alkyl), aryl (various electron-donating and electron-withdrawing substituted aryl, monosubstituted or polysubstituted aryl at various positions), heteroaryl (furan, thiophene, indole and substituted heteroaryl), alkenyl, halogen (fluorine, chlorine, bromine) and silyl.

[0024] The processes for preparing compounds of general formula (III) are all similar, and the compounds of formula (III) of this application can be obtained by choosing appropriate synthetic routes. No limitation is made in this invention. The preparation process given in this invention is as follows: Process (1)

[0025] General Method Step I: Under argon protection, substituted 3,3-dimethoxycyclobutane (1.0 equiv) and tetrahydrofuran were added to a Schlenk tube. Freshly prepared LDA (1 equiv, 1.0 M in THF) was slowly added dropwise at –78 °C, and the mixture was stirred at –78 °C for half an hour. Subsequently, 3-bromopropyne (1.1 equiv) was slowly added, and the reaction solution was stirred at –78 °C for another half hour, then slowly restored to room temperature and stirred overnight. After quenching, extraction, drying, filtration, vacuum distillation, and column chromatography, the intermediate methyl propargyl cyclobutyrate was obtained.

[0026] Step II: Under argon protection, cuprous iodide (7.5 mol%), palladium chloride (5 mol%), triphenylphosphine (10 mol%), and tetrahydrofuran (40 mL) were added to a Schlenk tube and stirred at room temperature for 30 minutes. Subsequently, the intermediate (1.0 equiv) and iodide R were added sequentially. 2 I (1.3 equiv) and triethylamine (2.5 equiv). The reaction solution was stirred at 40 °C. After 10 hours, the reaction was stopped and cooled to room temperature. After quenching, extraction, drying, filtration, vacuum distillation, and column chromatography, the crude coupling intermediate was obtained. The coupling intermediate was dissolved in acetonitrile, and 4 M hydrochloric acid aqueous solution was slowly added at 0 °C. The mixture was stirred overnight at 30 °C, extracted, dried, filtered, vacuum distilled, and column chromatography, and the alkynylcyclobutanone substrate was obtained.

[0027] Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14 Q15 Q16.

[0028] Process (2): Q17; Process (3): Q18; Process (4): Q19; Process (5): Q20; According to process (5), the following can also be prepared: Q21 Q22.

[0029] In exploring the preparation process, this invention investigated the reaction ligands, organic solvents used in the reaction, silanes, reaction additives, and reaction conditions, as detailed below: Using methyl 4-(3-(1-(methoxycarbonyl)-3-oxocyclobutyl)prop-1-yn-1-yl)benzoate as a standard substrate, nickel-catalyzed reaction was used to synthesize bicyclic [2.1.1]hexane compounds from ynylcyclobutanone.

[0030] (1) Screening of ligands The reaction process is as follows:

[0031] All ligands are commercially available, and their types are as follows:

[0032] The structure is shown in Table 1: Table 1. Ligand screening results.

[0033]

[0034] Where mol% refers to the relative molar amount, equiv represents the equivalent amount, the yield is the NMR yield, and condition 1 is the optimal reaction condition.

[0035] (2) Screening of organic solvents The reaction process is as follows:

[0036] The results of the organic solvent screening are shown in Table 2: Table 2. Results of organic solvent screening.

[0037]

[0038] Where mol% refers to the relative molar amount, equiv represents the equivalent amount, the yield is the NMR yield, and condition 1 is the optimal reaction condition.

[0039] (3) Screening of reactive silanes The reaction process is as follows:

[0040] The screening results for reactive silanes are shown in Table 3: Table 3. Screening results for reactive silanes.

[0041]

[0042] Where mol% refers to the relative molar amount, equiv represents the equivalent amount, the yield is the NMR yield, and condition 6 is the optimal reaction condition.

[0043] (4) Screening of mixed solvents Reaction process:

[0044] The screening results for mixed solvents are shown in Table 4.

[0045] Table 4. Screening results of mixed solvents.

[0046]

[0047] Where mol% refers to the relative molar amount, equiv represents the equivalent amount, the yield is the NMR yield, and condition 1 is the optimal reaction condition.

[0048] (5) Screening of mixed solvent ratio Reaction process:

[0049] The screening results for mixed solvents are shown in Table 5.

[0050] Table 5. Screening results of mixed solvents.

[0051]

[0052] Where mol% refers to the relative molar amount, equiv represents the equivalent amount, the yield is the NMR yield, and condition 5 is the optimal reaction condition.

[0053] (6) Screening of reaction temperature Reaction process:

[0054] The results of the reaction temperature screening are shown in Table 6.

[0055] Table 6. Results of the screening of reaction temperatures.

[0056]

[0057] Where mol% refers to the relative molar amount, equiv represents the equivalent amount, the yield is the NMR yield, and condition 4 is the optimal reaction condition.

[0058] (7) Screening of reaction additives Reaction process:

[0059] The results of the screening of reaction additives are shown in Table 7.

[0060] Table 7. Screening results of reaction additives.

[0061]

[0062] Where mol% refers to the relative molar amount, equiv represents the equivalent amount, the yield is the NMR yield, and condition 2 is the optimal reaction condition.

[0063] Based on the above research, the preparation method in this embodiment of the invention includes the following elements: Under argon protection, nickel p-toluenesulfonate hexahydrate (10.2 mg, 0.02 mmol, 10 mol%), ligand L1 (7.3 mg, 0.024 mmol, 12 mol%), methanol (0.6 mL), and 1,4-dioxane (1.2 mL) were added to a Schlenk tube. The mixture was stirred at 25 °C for half an hour. Subsequently, sodium dihydrogen phosphate (12.0 mg, 0.1 mmol, 0.5 equiv), bis(trimethylsiloxymethylsilane) (217 μL, 0.8 mmol, 4.0 equiv), starting materials: the compound shown in formula (III), methanol (0.6 mL), and 1,4-dioxane (1.6 mL) were added sequentially. After sealing the reaction tube, it was stirred at 70 °C. The reaction was stopped after 20 hours and cooled to 25 °C. The solvent was evaporated to dryness, and the remaining solid was purified by column chromatography using petroleum ether and ethyl acetate as elutions to obtain the target product compound (I).

[0064] Example 1 In this embodiment, methyl (E)-3-benzyl-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 1. White solid (29.8 mg, 61% yield), R f = 0.5 (PE : EA = 3 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.41-7.29 (m, 4H), 7.24-7.17 (m, 1H), 6.34(t, J = 2.3 Hz, 1H), 3.75 (s, 3H), 2.92-2.86 (m, 2H), 2.27-2.18 (m, 3H), 2.03-1.96 (m, 2H). 13C NMR(100 MHz, CDCl3) δ 172.9, 142.3, 137.3, 128.7, 127.6,126.6, 115.7, 80.1, 52.2, 50.5, 39.9, 37.9.HRMS(ESI + ) m / z calc'd for C 15 H 17 O3[M+H] + : 245.1172, found 245.1166. Example 2 In this embodiment, (E)-3-benzyl-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 2. Colorless liquid (28.7 mg, 56% yield), R f = 0.3 (PE : EA = 5 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.43-7.29 (m, 4H), 7.25-7.17 (m, 1H), 6.34(t, J = 2.3 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.91-2.86 (m, 2H), 2.24-2.19 (m,2H), 2.10-1.88 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 C NMR(100 MHz, CDCl3) δ172.5, 142.5, 137.3, 128.7, 127.6, 126.6, 115.6, 80.1, 61.0, 50.4, 40.0,37.9, 14.4.HRMS(ESI + ) m / z calc'd for C 16 H 19 O3[M+H] + : 259.1329, found 259.1326. Example 3 In this embodiment, isopropyl (E)-3-benzyl-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 3. White solid (31.5 mg, 58% yield), R f = 0.4 (PE : EA = 5 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.44-7.27 (m, 4H), 7.25-7.09 (m, 1H), 6.35(t, J = 2.2 Hz, 1H), 5.07 (hept, J = 6.3 Hz, 1H), 3.02 (s, 1H), 2.89-2.81 (m,2H), 2.24-2.15 (m, 2H), 2.02-1.92 (m, 2H), 1.27 (d, J = 6.3 Hz, 6H). 13 C NMR(100MHz, CDCl3) δ 172.1, 142.6, 137.3, 128.6, 127.6, 126.5, 115.5, 80.0, 68.4,50.3, 40.2, 37.8, 21.9.HRMS(ESI + ) m / z calc'd for C 17 H 20 O3Na [M+Na] + : 295.1306, found 295.1297. Example 4 In this embodiment, (E)-3-benzyl-4-hydroxy-N,N-dimethylbicyclo[2.1.1]hexane-1-carboxamide was prepared, with the following structural formula: 4. Pale yellow solid (35.7 mg, 66% yield), R f = 0.1 (PE : EA = 1 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.39-7.28 (m, 4H), 7.23-7.16 (m, 1H), 6.38(t, J = 2.2 Hz, 1H), 2.99 (s, 6H), 2.91-2.86 (m, 2H), 2.49 (s, br, 1H), 2.21-2.14 (m, 2H), 2.12-2.07 (m, 2H). 13C NMR(100 MHz, CDCl3) δ 172.5, 142.5, 137.4,128.7, 127.6, 126.5, 115.7, 78.7, 50.7, 41.6, 38.9, 36.8.HRMS(ESI + ) m / z calc'dfor C 16 H 20 O2N [M+H] + : 258.1489, found 258.1489. Example 5 In this embodiment, (E)-(3-benzylidene-4-hydroxybicyclo[2.1.1]hexane-1-yl)(morpholino) methyl ketone was prepared, with the following structural formula: 5. White solid (40.5 mg, 67% yield), R f = 0.1 (PE : EA = 1 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.40-7.29 (m, 4H), 7.24-7.17 (m, 1H), 6.38(t, J = 2.3 Hz, 1H), 3.70 -3.46 (m, 8H), 2.93-2.75 (m, 2H), 2.26-2.14 (m, 3H), 2.10-2.04 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 171.2, 142.0, 137.2, 128.7, 127.6,126.7, 116.0, 78.7, 67.0, 50.7, 46.3, 42.7, 41.5, 39.2.HRMS(ESI + ) m / z calc'dfor C 18 H 21 O3NNa [M+Na] + : 322.1413, found 322.1410. Example 6 In this embodiment, (E)-4-(3-benzyl-4-hydroxybicyclo[2.1.1]hexane-1-formyl)piperazine-1-carboxylic acid tert-butyl ester was prepared, with the following structural formula: 6. White solid (48.4 mg, 61% yield), R f= 0.1 (PE : EA = 1 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.37-7.28 (m, 4H), 7.26-7.16 (m, 1H), 6.38(t, J = 2.1 Hz, 1H), 3.69 – 3.52 (m, 2H), 3.50-3.35 (m, 6H), 2.88-2.83 (m, 2H), 2.22-2.13 (m, 2H), 2.12-2.02 (m, 2H), 1.46 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ171.2, 154.7, 142.0, 137.2, 128.7, 127.6, 126.7, 116.0, 80.6, 78.7, 50.7,45.5, 42.2, 41.6, 39.2, 28.5.HRMS(ESI + ) m / z calc'd for C 23 H 30 O4N2Na [M+Na] + :421.2097, found 421.2093. Example 7 In this embodiment, (E)-3-benzyl-4-hydroxy-N-methoxy-N-methylbicyclo[2.1.1]hexane-1-carboxamide was prepared, with the following structural formula: 7. White solid (36.1 mg, 66% yield), R f = 0.2 (PE : EA = 1 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.40-7.29 (m, 4H), 7.23-7.16 (m, 1H), 6.35(t, J = 2.3 Hz, 1H), 3.66 (s, 3H), 3.24 (s, 3H), 2.97-2.91 (m, 2H), 2.81 (s,br, 1H), 2.22-2.14 (m, 2H), 2.11-2.04 (m, 2H). 13C NMR(100 MHz, CDCl3) δ 173.4,142.7, 137.4, 128.6, 127.6, 126.5, 115.3, 79.5, 61.5, 50.2, 40.9, 39.1,32.8.HRMS(ESI + ) m / z calc'd for C 16 H 20 O3N [M+H] + : 274.1438, found 274.1429. Example 8 In this embodiment, (E)-3-benzyl-4-hydroxy-N-phenylbicyclo[2.1.1]hexane-1-carboxamide was prepared, with the following structural formula: 8. Pale yellow solid (34.0 mg, 56% yield). R f = 0.2 (PE : EA = 3 : 1). 1 H NMR (400 MHz, CDCl3) δ 7.60 - 7.51 (m, 2H), 7.42 -7.29 (m, 7H), 7.23-7.17 (m, 1H), 7.17 -7.09 (m, 1H), 6.40 (t, J = 2.2 Hz, 1H), 3.09- 2.83 (m,2H), 2.58 (s, br, 1H), 2.25-2.18 (m, 2H), 2.10-2.06 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 170.5, 142.0, 137.5, 137.2, 129.2, 128.7, 127.7, 126.7, 124.9, 120.2, 116.0, 79.6, 50.1, 42.2, 38.5.HRMS(ESI + ) m / z calc'd for C 20 H 20 O2N [M+H] + :306.1489, found 306.1480. Example 9 In this embodiment, methyl (E)-4-hydroxy-3-(2-methylbenzyl)bicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 9. Colorless oily liquid (37.0 mg, 72% yield). R f = 0.3 (PE:EA = 5:1). 1 H NMR(400 MHz, CDCl3) δ 7.44 -7.37 (m, 1H), 7.21- 7.09 (m, 3H), 6.50(t, J = 2.4 Hz, 1H), 3.73 (s, 3H), 2.83- 2.70 (m, 2H), 2.51 (s, br, 1H), 2.35(s, 3H), 2.24 - 2.19 (m, 2H), 2.02- 1.96 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ173.0, 142.6, 136.0, 135.9, 130.4, 127.0, 126.7, 125.9, 113.2, 80.1, 52.1,50.3, 39.8, 37.3, 20.2.HRMS(ESI + ) m / z calc'd for C 16 H 19 O3[M+H] + : 259.1329, found259.1312. Example 10 In this embodiment, methyl (E)-4-hydroxy-3-(3-methylbenzyl)bicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 10. Colorless oily liquid (35.8 mg, 69% yield), R f = 0.3 (PE:EA =5:1). 1 H NMR(400 MHz, CDCl3) δ 7.25-7.16 (m, 3H), 7.05-7.00 (m, 1H), 6.31(t, J = 2.3 Hz, 1H), 3.76 (s, 3H), 2.94-2.83 (m, 2H), 2.40 (s, br, 1H), 2.35(s, 3H), 2.24-2.18 (m, 2H), 2.03-1.94 (m, 2H). 13C NMR(100 MHz, CDCl3) δ 173.0,142.1, 138.2, 137.2, 128.6, 128.4, 127.4, 124.7, 115.7, 80.1, 52.2, 50.4,39.9, 37.9, 21.7.HRMS(ESI + ) m / z calc'd for C 16 H 19 O3[M+H] + : 259.1329, found259.1328. Example 11 In this embodiment, methyl (E)-4-hydroxy-3-(4-methylbenzyl)bicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 11. White solid (35.5 mg, 68% yield), R f = 0.4 (PE:EA = 3:1). 1 H NMR(400 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.18-7.12 (m, 2H), 6.30(t, J = 2.3 Hz, 1H), 3.75 (s, 3H), 2.90-2.84 (m, 2H), 2.66 (s, br, 1H), 2.34(s, 3H), 2.24-2.16 (m, 2H), 2.03-1.93 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 172.9,141.2, 136.4, 134.4, 129.4, 127.6, 115.4, 80.1, 52.1, 50.5, 39.9, 37.9,21.3.HRMS(ESI + ) m / z calc'd for C 16 H 19 O3[M+H] + : 259.1329, found 259.1331. Example 12 In this embodiment, methyl (E)-3-(benzo[d][1,3]dioxacyclopentene-5-methylene)-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 12, white solid (35.9 mg, 62% yield), R f = 0.2 (PE:EA = 5:1). 1 H NMR (400 MHz, CDCl3) δ 6.91 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.78(d, J = 8.0 Hz, 1H), 6.25 (t, J = 2.3 Hz, 1H), 5.95 (s, 2H), 3.75 (s, 3H), 2.92-2.75 (m, 2H), 2.70 (s, br, 1H), 2.25-2.14 (m, 2H), 2.05-1.88 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 172.9, 148.0, 146.3, 140.4, 131.7, 121.8, 115.3, 108.5,107.5, 101.1, 80.0, 52.2, 50.5, 39.9, 37.8.HRMS(ESI + ) m / z calc'd for C 16 H 17 O5[M+H] + : 289.1071, found 289.1068. Example 13 In this embodiment, methyl (E)-4-hydroxy-3-(4-methoxybenzyl)bicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 13, white solid (31.6 mg, 57% yield), R f = 0.3 (PE:EA = 3:1). 1 H NMR(400 MHz, CDCl3) δ 7.36-7.29 (m, 2H), 6.92-6.84 (m, 2H), 6.27(t, J = 2.3 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 2.88-2.82 (m, 2H), 2.24-2.17(m, 2H), 2.01-1.95 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.9, 158.4, 139.9,130.1, 128.8, 114.9, 114.1, 80.1, 55.4, 52.1, 50.5, 39.9, 37.7.HRMS (ESI + ) m / z calc'd for C 16 H 18 O4Na [M+Na] + : 297.1097, found 297.1085. Example 14 In this embodiment, (E)-3-(4-((N,4-dimethylphenyl)sulfonylamino)benzyl)-4-hydroxybicyclo[2.1.1]hexane-1-carboxylic acid was prepared, with the following structural formula: 14. White solid (44.2 mg, 50% yield), R f = 0.2 (PE:EA = 3:1). 1 H NMR (400 MHz, CDCl3) δ 7.47-7.40 (m, 2H), 7.32-7.27 (m, 2H), 7.27-7.21 (m, 2H), 7.10-7.00 (m, 2H), 6.32 (t, J = 2.3 Hz, 1H), 3.75 (s, 3H), 3.15(s, 3H), 2.91-2.80 (m, 2H), 2.42 (s, 3H), 2.31-2.17 (m, 2H), 2.01-1.96 (m,2H). 13 C NMR(100 MHz, CDCl3) δ 172.7, 143.7, 143.2, 139.8, 136.3, 133.6, 129.5,128.1, 128.0, 126.8, 114.9, 80.1, 52.2, 50.6, 39.9, 38.2, 37.9, 21.7.HRMS(ESI + ) m / z calc'd for C 23 H 26 O5NS [M+H] + : 428.1526, found 428.1507. Example 15 In this embodiment, methyl (E)-4-hydroxy-3-(4-(methoxycarbonyl)benzyl)bicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 15. White solid (37.7 mg, 62% yield), R f = 0.1 (PE : EA = 5 : 1). 1 H NMR(400 MHz, CDCl3) δ 8.13-7.75 (m, 2H), 7.55-7.34 (m, 2H), 6.41(t, J = 2.2 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 2.93-2.87 (m, 2H), 2.52 (s,br, 1H), 2.27-2.21 (m, 2H), 2.05-1.96 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 172.6,167.2, 145.5, 141.9, 130.0, 127.9, 127.4, 115.3, 80.2, 52.23, 52.22, 50.6,39.9, 38.0.HRMS (ESI + ) m / z calc'd for C 17 H 19 O5[M+H] + 303.1227 was found; 303.1230 was found. Example 16 In this embodiment, methyl (E)-3-(4-fluorobenzyl)-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 16, white solid (28.7 mg, 55% yield), R f = 0.3 (PE : EA = 5 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.39-7.30 (m, 2H), 7.06-6.95 (m, 2H), 6.31(t, J= 2.3 Hz, 1H), 3.75 (s, 3H), 2.87-2.78 (m, 2H), 2.36 (s, br, 1H), 2.26-2.18 (m, 2H), 2.01-1.95 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 172.8, 161.6 (d, J =246.2 Hz), 141.8 (d, J = 2.2 Hz), 133.4 (d, J = 3.3 Hz), 129.1 (d, J = 7.9 Hz), 115.5 (d, J = 21.4 Hz), 114.6, 80.0, 52.2, 50.5, 39.9, 37.7. 19 F NMR(376 MHz, CDCl3) δ -115.6 - -115.7 (m).HRMS(ESI + ) m / z calc'd for C 15 H 16 O3F [M+H] + : 263.1078, found 263.1090. Example 17 In this embodiment, methyl (E)-3-(4-chlorobenzyl)-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 17. White solid (33.0 mg, 59% yield), R f = 0.4 (PE : EA = 5 : 1). 1 H NMR (400 MHz, CDCl3) δ 7.34-7.27 (m, 4H), 6.31 (t, J = 2.2 Hz, 1H), 3.75 (s, 3H), 2.87-2.81 (m, 2H), 2.25-2.19 (m, 2H), 2.02-1.96 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 172.7, 143.0, 135.8, 132.2, 128.82, 128.80, 114.7, 80.1,52.2, 50.5, 39.9, 37.8.HRMS(ESI+ ) m / z calc'd for C 15 H 15 ClO3Na [M+Na] + : 301.0602, found 301.0607. Example 18 In this embodiment, methyl (E)-3-(4-bromobenzyl)-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 18, white solid (42.1 mg, 65% yield), R f = 0.4 (PE : EA = 5 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.49-7.41 (m, 2H), 7.26-7.21 (m, 2H), 6.29(t, J = 2.3 Hz, 1H), 3.75 (s, 3H), 2.86-2.80 (m, 2H), 2.25-2.18 (m, 2H), 2.02-1.96 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 172.7, 143.2, 136.2, 131.7, 129.2,120.3, 114.8, 80.1, 52.2, 50.5, 39.9, 37.8.HRMS(ESI + ) m / z calc'd for C 15 H 15 BrO3Na[M+Na] + : 345.0097, found 345.0099. Example 19 In this embodiment, methyl (E)-4-hydroxy-3-(4-(trifluoromethyl)benzyl)bicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 19, White solid (45.4 mg, 72% yield), R f = 0.2 (PE : EA = 5 : 1). 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.46 (d,J = 8.2 Hz, 2H), 6.41 (t, J = 2.2 Hz, 1H), 3.76 (s, 3H), 2.91-2.85 (m, 2H), 2.27 (s, br,1H), 2.26-2.23 (m, 2H), 2.04-1.99 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 172.6,145.2, 140.8 (q, J = 1.4 Hz), 128.4 (q, J = 32.4 Hz), 127.7, 125.6 (q, J = 3.8 Hz), 124.4 (q, J = 271.7 Hz), 114.9, 80.2, 52.3, 50.6, 39.9, 37.9. 19 F NMR (376 MHz, CDCl3) δ-62.40.HRMS (ESI + ) m / z calc'd for C 16 H 15 F3O3Na [M+Na] + : 335.0866, found335.0862. Example 20 In this embodiment, methyl (E)-3-(furan-2-methylene)-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 20, colorless oily liquid (9.6 mg, 28% yield), R f = 0.2 (PE : EA = 5 : 1). 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 1.8 Hz, 1H), 6.38 (dd, J = 3.3, 1.8Hz, 1H), 6.25 (t, J = 2.3 Hz, 1H), 6.20 (d, J= 3.3 Hz, 1H), 3.74 (s, 3H), 2.88-2.82 (m, 2H), 2.24-2.18 (m, 2H), 2.13 (s, br, 1H), 2.03-1.94 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 172.9, 153.3, 141.7, 141.5, 111.3, 106.9, 105.1, 79.8,52.1, 50.7, 39.8, 37.9.HRMS(ESI + ) m / z calc'd for C 13 H 15 O4[M+H] + : 235.0965, found235.0967. Example 21 In this embodiment, methyl (E)-4-hydroxy-3-(3-methylbut-2-ene-1-yl)bicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 21, colorless liquid (14.2 mg, 32% yield), R f = 0.4 (PE : EA = 5 : 1). 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 1.8 Hz, 1H), 6.38 (dd, J = 3.3, 1.8Hz, 1H), 6.25 (t, J = 2.3 Hz, 1H), 6.20 (d, J = 3.3 Hz, 1H), 3.74 (s, 3H), 2.88-2.82 (m, 2H), 2.24-2.18 (m, 2H), 2.13 (s, br, 1H), 2.03-1.94 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 172.9, 153.3, 141.7, 141.5, 111.3, 106.9, 105.1, 79.8,52.1, 50.7, 39.8, 37.9.HRMS(ESI + ) m / z calc'd for C 13 H 18O3Na [M+Na] + : 245.1148, found 245.1149. Example 22 In this embodiment, methyl (E)-4-hydroxy-3-(4-(1-methoxy-1-oxopropane-2-yl)benzyl)bicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 22, white solid (91.7 mg, 68% yield), R f = 0.2 (PE:EA = 5:1). 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.32 (t, J = 2.3 Hz, 1H), 3.71 (q, J = 7.0 Hz, 1H), 2.89-2.83 (m, 2H), 2.24-2.18 (m, 2H), 2.02-1.92 (m, 2H), 1.49 (d, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 175.1, 172.8, 142.4, 138.8, 136.3, 127.9, 127.8, 115.2, 79.6, 46.5, 44.8, 44.8, 43.2, 18.1.HRMS (ESI + ) m / z calc'd for C 19 H 23 O5[M+H] + : 303.1227, found 303.1229. Example 23 In this embodiment, (E)-2-benzylidene-4-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[2.1.1]hexane-1-ol was prepared, with the following structural formula: 23, colorless oily liquid (38.0 mg, 58% yield), R f = 0.3 (PE:EA = 5:1). 1H NMR (400 MHz, CDCl3) δ 7.46-7.37 (m, 2H), 7.37-7.30 (m, 2H), 7.23-7.15 (m, 1H), 6.31 (t, J = 2.2 Hz, 1H), 3.78 (s, 2H), 2.65 (brs, 1H), 2.61-2.49(m, 2H), 1.86-1.77 (m, 2H), 1.77-1.65 (m, 2H), 0.93 (s, 9H), 0.08 (s, 6H). 13 CNMR(100 MHz, CDCl3) δ 145.3, 137.9, 128.6, 127.5, 126.2, 114.5, 80.7, 64.5,48.3, 40.0, 38.1, 26.1, 18.5,-5.2.HRMS(ESI + ) m / z calc'd for C 20 H 30 O2SiNa [M+Na] + :353.1907, found 353.1906. Example 24 In this embodiment, (E)-2-benzyl-4-(bromomethyl)bicyclo[2.1.1]hexane-1-ol was prepared, with the following structural formula: 24. Colorless oily liquid (39.3 mg, 68% yield), R f = 0.3 (PE : EA = 5 : 1). 1 H NMR(400 MHz, CDCl3) δ 7.45-7.29 (m, 4H), 7.25 -7.16 (m, 1H), 6.33(t, J = 2.3 Hz, 1H), 3.75 -3.54 (m, 2H), 2.86-2.70 (brs, 1H), 2.70-2.54 (m,2H), 1.91-1.76 (m, 4H). 13 C NMR(100 MHz, CDCl3) δ 144.3, 137.4, 128.6, 127.6,126.5, 115.1, 79.8, 50.0, 39.3, 39.1, 36.4.HRMS(ESI + ) m / z calc'd for C 14 H 16 BrO [M+H] + : 279.0379, found 279.0372. Example 25 In this embodiment, (E)-2-benzyl-4-methylbicyclo[2.1.1]hexane-1-ol was prepared, with the following structural formula: 25, white solid (24.3 mg, 58% yield), R f = 0.4 (PE : EA = 5 : 1). 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.3 Hz, 2H), 7.36-7.28 (m, 2H),7.22 -7.15 (m, 1H), 6.27 (t, J = 2.3 Hz, 1H), 2.59-2.50 (brs, 1H), 2.51-2.47(m, 2H), 1.75-1.70 (m, 2H), 1.70-1.65 (m, 2H), 1.31 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 146.6, 138.0, 128.5, 127.5, 126.1, 114.1, 80.4, 52.0, 42.6, 34.3,19.2.HRMS (ESI + ) m / z calc'd for C 14 H 17 O [M+H] + : 201.1274, found 201.1267. Example 26 In this embodiment, methyl (E)-4-((1-hydroxy-4-(methoxycarbonyl)bicyclo[2.1.1]hexane-2-ylidene)methyl)furan-2-carboxylate was prepared, with the following structural formula: 26, white solid (29.2 mg, 50% yield), R f = 0.2 (PE : EA = 3 : 1). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.26 (s, 1H), 6.17 (t, J = 2.3Hz, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 2.75 -2.70 (m, 2H), 2.27-2.17 (m, 2H), 2.03 -1.93 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 172.6, 159.3, 144.9, 143.5,143.4, 125.0, 117.1, 104.7, 79.8, 52.22, 52.17, 50.7, 39.8, 37.4.HRMS (ESI + ) m / z calc'd for C 15 H 17 O6[M+H] + : 293.1020, found 293.1012. Example 27 In this embodiment, methyl (E)-4-((1-hydroxy-4-(methoxycarbonyl)bicyclo[2.1.1]hexane-2-ylidene)methyl)thiophene-2-carboxylate was prepared, with the following structural formula: 27, white solid (37.6 mg, 61% yield), R f = 0.3 (PE:EA = 3:1). 1 H NMR(400 MHz, (CD3)2CO) δ 7.83 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 6.44 (t, J = 2.2 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 2.80-2.75 (m, 2H), 2.19-2.12 (m, 2H), 1.93-1.85 (m, 2H). 13 C NMR(100 MHz, (CD3)2CO) δ 172.9,162.9, 145.4, 141.0, 134.2, 133.5, 128.7, 109.9, 80.3, 52.4, 52.0, 51.2,40.7, 38.3.HRMS(ESI+ ) m / z calc'd for C 15 H 17 O5S [M+H] + : 309.0791, found 309.0789. Example 28 In this embodiment, (E)-4-hydroxy-3-((1-p-toluenesulfonyl-1H-indol-3-yl)methylene)bicyclo[2.1.1]hexane-1-carboxylic acid methyl ester was prepared, with the following structural formula: 28, pale yellow solid (52.4 mg, 60% yield), R f = 0.2 (PE : EA = 3 : 1). 1 H NMR (400 MHz, CDCl3) δ 8.02-7.95 (m, 1H), 7.77 (d, J = 8.5 Hz, 2H),7.65 – 7.60 (m, 1H), 7.53 (s, 1H), 7.35-7.30 (m, 1H), 7.28-7.24 (m, 1H), 7.21(d, J = 8.1 Hz, 2H), 6.46 (t, J = 2.4 Hz, 1H), 3.79 (s, 3H), 2.81-2.75 (m, 2H), 2.33 (s, 3H), 2.30-2.23 (m, 2H), 2.09-2.00 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ172.7, 145.1, 143.8, 135.3, 134.8, 130.5, 130.0, 126.9, 125.1, 123.4, 121.5,119.5, 119.4, 113.7, 104.4, 80.0, 52.2, 51.0, 39.9, 38.2, 21.7.HRMS(ESI + ) m / z calc'd for C 24 H 24 O5NS [M+H] + : 438.1370, found 438.1366. Example 29 In this embodiment, (E)-N-(3-bromo-5-(trifluoromethyl)phenyl)-3-ethylidene-4-hydroxybicyclo[2.1.1]hexane-1-carboxamide was prepared, with the following structural formula: 29, white solid (29.2 mg, 75% yield), R f = 0.3 (PE : EA = 3 : 1). 1 H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 1.9, 1.8 Hz, 1H), 7.75 (d, J = 1.8Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.41 (brs, 1H), 5.37 (qt, J = 6.7, 2.2 Hz,1H), 2.58-2.52 (m, 2H), 2.30 (brs, 1H), 2.17-2.11 (m, 2H), 1.99-1.92 (m, 2H),1.66 (dt, J = 6.7, 1.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.0, 139.9, 139.3,132.9 (q, J = 33.3 Hz), 125.9, 124.3 (q, J = 3.9 Hz), 123.2, 123.0 (q, J = 272.9Hz), 115.4 (q, J = 3.9 Hz), 109.9, 78.9, 49.7, 41.9, 35.7, 13.6. 19 F NMR (376 MHz, CDCl3) δ –62.95.HRMS (ESI + ) m / z calc'd for C 16 H 16 BrF3O2N [M+H] + : 390.0311, found390.0314. Example 30 In this embodiment, methyl (E)-3-(2-(benzyloxy)ethylidene)-4-hydroxybicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 30, colorless liquid (26.5 mg, 45% yield), R f = 0.2 (PE : EA = 5 : 1). 1 H NMR (400 MHz, CDCl3) δ 7.37-7.33 (m, 4H), 7.31-7.27 (m, 1H), 5.60-5.49 (m, 1H), 4.52 (s, 2H), 4.05 (d, J = 6.8 Hz, 2H), 3.71 (s, 3H), 3.09-2.69(brs, 1H), 2.53-2.46 (m, 2H), 2.17-2.10 (m, 2H), 1.90-1.83 (m, 2H). 13 C NMR(100MHz, CDCl3) δ 172.9, 145.0, 138.4, 128.5, 127.9, 127.8, 111.5, 79.3, 72.3,67.3, 52.1, 49.8, 39.6, 35.3.HRMS(ESI + ) m / z calc'd for C 17 H 20 O4Na [M+Na] + :311.1254, found 311.1250. Example 31 In this embodiment, methyl (E)-4-hydroxy-3-pentylenebicyclo[2.1.1]hexane-1-carboxylate was prepared, with the following structural formula: 31, colorless liquid (17.7 mg, 38% yield), R f = 0.3 (PE : EA = 5 : 1). 1 H NMR (400 MHz, CDCl3) δ 5.25 (tt, J = 7.3, 2.3 Hz, 1H), 3.71 (s, 3H),2.73-2.57 (brs, 1H), 2.45 (s, 2H), 2.16-2.07 (m, 2H), 2.07-1.96 (m, 2H),1.87-1.81 (m, 2H), 1.40-1.27 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.3, 139.9, 114.8, 79.2, 52.0, 50.0, 39.6, 35.3, 31.9, 28.1, 22.4,14.1.HRMS (ESI + ) m / z calc'd for C 13 H 20 O3Na [M+Na] + : 247.1305, found 247.1307. Example 32 In this embodiment, methyl(E)-4-hydroxy-3-((trimethylsilyl)methylene)bicyclo[2.1.1]hexanecarboxylate was prepared, and its structural formula is as follows: 32, colorless liquid (16.3 mg, 34% yield), R f = 0.3 (PE : EA = 5 : 1). 1 H NMR (400 MHz, CDCl3) δ 5.70-5.65 (m, 1H), 4.28 (s, 1H), 3.63 (s,3H), 2.78 (d, J = 12.3 Hz, 2H), 2.49 (d, J = 12.3 Hz, 2H), 0.08 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 175.4, 161.4, 127.7, 79.3, 51.9, 47.1, 45.6, 42.2, 0.1.HRMS (ESI + ) m / z calc'd for C 12 H 21 O3Si [M+H] + : 241.1254, found 241.1259. Example 33 Preparation of the compound shown in formula (II).

[0065]

[0066] The preparation method of the compound shown in formula (II) includes the following steps: Reactant formula (I) (1.0 equiv) and 10 mL of acetonitrile are added to a flask. Trifluoromethanesulfonic acid (10.0 equiv) is added at 0 °C and the mixture is stirred at 30 °C for 2 hours. After the reaction is complete, the solvent is removed by vacuum distillation. The remaining oily substance is subjected to column chromatography with petroleum ether and ethyl acetate as the developing solvent to obtain the target product formula (II). Add reactant (I) (1.0 equiv) and 5 mL to a flask. N,N -Dimethylformamide. Sodium hydride (2.0 equiv, 60%, dispersion in Paraffin Liquid) was added at 0 °C and stirred at 0 °C for 0.5 hours. The mixture was quenched, extracted, dried, filtered, distilled under reduced pressure, and separated by column chromatography to obtain the target product (II). Add formula (I) (1.0 equiv) and 5 mL of acetonitrile to a flask. At 30 °C, add... N - Bromosuccinimide (1.05 equiv) was stirred at 30 °C for 5 minutes. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain the target product (II).

[0067] Reference Example: Preparation of methyl 4-benzyl-3-oxobicyclo[2.1.1]hexane-1-carboxylate, the structural formula of which is as follows: 33, white solid (29.2 mg, 75% yield), R f = 0.3 (PE : EA = 3 : 1). 1 H NMR (400 MHz, CDCl3) δ 7.33-7.26 (m, 2H), 7.25-7.19 (m, 1H), 7.16-7.08 (m, 2H), 3.69 (s, 3H), 2.91 (s, 2H), 2.50 (t, J = 2.8 Hz, 2H), 2.18-2.07(m, 2H), 1.85-1.76 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 210.2, 171.6, 138.0,129.6, 128.6, 126.5, 63.4, 52.2, 44.9, 44.8, 44.3, 33.3.HRMS(ESI + ) m / z calc'dfor C 15H 16 O3Na [M+Na] + : 267.0992, found 267.0990. The structure and physical properties of the reference example compound (Reference Example 1) obtained by a process similar to that described above, and the compounds obtained by a similar process (Examples 33 to 52) are shown in Table 8 below.

[0068] Table 8. Compounds of formula (II).

[0069]

[0070] The present invention also discovered that the compound of formula (II) of the present invention can be further reacted to prepare bicyclic [2.1.1]hexane derivatives in good yield: 48; 1 H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.25-7.19 (m, 1H), 7.15-7.08 (m, 2H), 2.92 (s, 2H), 2.52 (t, J = 2.9 Hz, 2H), 2.19-2.11 (m, 2H), 1.84(dd, J = 4.8, 2.2 Hz, 2H). 13 C NMR(100 MHz, CDCl3) δ 209.8, 176.3, 137.8, 129.6,128.6, 126.6, 63.5, 44.9, 44.6, 44.0, 33.3.HRMS (ESI + ) m / z calc'd for C 14 H 14 O3Na[M+Na] + : 253.0835, found 253.0830. 49; 1H NMR(400 MHz, CDCl3) δ 7.31-7.24 (m, 3H), 7.23-7.17 (m, 1H), 7.15-7.09 (m, 2H), 5.75 (s, 1H), 2.93 (s, 2H), 2.55 (t, J = 2.9 Hz, 2H), 2.13-2.06(m, 2H), 1.99 (dd, J = 4.5, 2.0 Hz, 2H), 1.93 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ210.2, 170.3, 138.4, 129.6, 128.5, 126.4, 61.4, 53.6, 46.7, 45.8, 32.7,23.7.HRMS(ESI + ) m / z calc’d for C 15 H 17 NO2Na [M+Na] + : 266.1151, found 266.1152. 50; 1 H NMR(400 MHz, CDCl3) δ 7.31-7.26 (m, 2H), 7.24-7.17 (m, 1H), 7.16-7.11 (m, 2H), 2.87 (s, 2H), 2.69-2.64 (m, 1H), 2.26-2.18 (m, 2H), 1.96-1.80(m, 2H), 1.57-1.47 (m, 2H). 13 C NMR(100 MHz, CDCl3) δ 214.3, 139.0, 129.7,128.4, 126.2, 66.0, 43.0, 42.7, 33.9, 31.5.HRMS(ESI + ) m / z calc’d for C 13 H 14 ONa [M+Na] + : 209.0937, found 209.0933. 51; 1H NMR (400 MHz, CDCl3) δ 7.34-7.27 (m, 2H), 7.23 (d, J = 7.4 Hz, 1H), 7.16-7.05 (m, 2H), 2.93 (s, 2H), 2.71-2.57 (m, 2H), 2.32-2.25 (m, 2H), 2.18-2.07 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 208.2, 137.5, 129.4, 128.6, 126.6, 64.4, 51.9, 50.8, 45.6, 32.6. HRMS (ESI + ) m / z calc'd for C 13 H 13 BrONa [M+Na] + :287.0042, found 287.0040. 52; 1 H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 3H), 7.27-7.19 (m, 2H), 7.14-7.07 (m, 2H), 2.92 (s, 2H), 2.73-2.66 (m, 2H), 2.46-2.35 (m, 2H), 2.23-2.07(m, 2H). 13 C NMR(100 MHz, CDCl3) δ 209.1, 137.7, 129.6, 128.7, 126.7, 67.2,53.6, 53.4, 32.9, 16.1.HRMS(ESI + ) m / z calc'd for C 13 H 13 IONa [M+Na] + : 334.9903, found 334.9900. In vitro cellular anti-inflammatory activity of compounds 1-52 in osteoarthritis was investigated.

[0071] This experiment used the C28 / I2 human chondrocyte cell line to establish an in vitro osteoarthritis (OA)-like inflammation model. Cells were stimulated with interleukin-1β (IL-1β) (10 ng / mL) for 24 hours to simulate the OA-related inflammatory microenvironment. The experiment consisted of four groups: The control group (control) received no treatment and was used to reflect the baseline state of normal chondrocytes. Inflammation group (IL-1β), with only IL-1β added to verify the successful construction of the inflammation model; Example treatment group (IL-1β + Example, 20 μM) was given with the addition of compounds of formula (I) and (II) synthesized in this invention to evaluate their anti-inflammatory effects on the basis of inflammatory stimulation; All drugs were diluted with serum-free medium and administered to cells. After 24 hours of treatment, the mRNA expression levels of inflammatory factors IL-6 and TNF-α were detected by real-time quantitative PCR (RT-qPCR). The results showed that IL-1β treatment significantly induced an increase in the gene expression of these two inflammatory factors, demonstrating the effectiveness of the model construction. The in vitro cellular anti-inflammatory activity of the example groups (compounds 1-52) in osteoarthritis is shown in Table 9.

[0072] Table 9. In vitro cellular anti-inflammatory activity data for osteoarthritis.

[0073]

[0074] As shown in Table 9, the compounds of formula (I) and formula (II) prepared in this invention all exhibit the ability to inhibit the upregulation of mRNA expression levels of inflammation-related factors IL-6 and TNF-α. In particular, compounds 5, 6, 22, 29, 35, 41, and 48 showed significant anti-inflammatory activity in an in vitro chondrocyte inflammation model. The compounds of formula (I) and formula (II) prepared in this invention can be used to treat or prevent osteoarthritis and have the potential application prospects as anti-osteoarthritis drugs.

[0075] Furthermore, the compound of formula (I) prepared by this invention can be used as an intermediate for the compound of formula (II) to prepare the compound of formula (II). The preparation method is simple and conducive to large-scale industrial production, providing a reliable source of intermediate raw materials with stable yield for the subsequent industrial production of the compound of formula (II).

[0076] Where there is no conflict, the above embodiments and features described herein can be combined with each other.

[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound represented by Formula (I) or Formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotopically-labeled material thereof: wherein, including the following steps: 、 ； S1, adding an additive and a silane under the catalysis of a catalyst formed by complexing a catalyst precursor and a ligand, and reacting a raw material represented by Formula (III) in a solvent; R 1 optionally selected from C1-C6alkyl, bromomethylalkane, benzylalkane, ester, amide, acyl; R 2 optionally selected from hydrogen, C1-C6alkyl, benzylalk, aryl, heteroaryl, alkenyl, halogen, silicon group; R 3 optionally selected from hydrogen, C1-C6alkyl, bromomethylalkane, benzylalkane, ester, amide, acyl, amine, sulfoximine, halogen, carboxyl; R 4 optionally selected from C1-C6alkyl, benzylalk, aryl, heteroaryl, alkenyl.

2. A process for the preparation of a compound of formula (I) ###0002### (I) characterized in that, S2, after the reaction is completed, quenching the reaction by adding water; S3, extracting and concentrating the solvent, and separating and purifying to obtain a bicyclo[2.1.1]hexane compound represented by Formula (I) containing a tertiary alcohol; and a reaction equation thereof is as follows: The catalyst precursor containing nickel includes any one or more of Ni (OTs) 2·6H 2O, Ni (ClO 4) 2·6H 2O, Ni (OAc) 2·4H 2O, Ni (BF 4) 2·6H 2O, Ni (H 2PO 2) 2·6H 2O, NiCl 2·glyme, Ni (OTf) 2, Ni (dppp) Cl 2, Ni (acac) 2, NiCl 2, NiCl 2·DME and Ni (COD) 2; and the ligand has the following structure or an enantiomer thereof: The ratio of the mass of the catalyst precursor containing the metal element nickel to the mass of the raw material represented by Formula III is 0.01:1-0.2:1; the molar ratio of the catalyst precursor containing the metal element nickel to the ligand is 1:0.5-1:2; and the mass ratio of the additive to the silane is 0.3:1-2:

1. ， wherein [Ni] is a catalyst precursor nickel; Ligand is a ligand; solvent is an organic solvent; additive is an additive; SiH is a silane; R 1 optionally selected from C1-C6alkyl, bromomethylalkane, benzylalkane, ester, amide, acyl; R 2 optionally selected from hydrogen, C1-C6alkyl, benzylalkane, aryl, heteroaryl, alkenyl, halogen, silyl.

3. The preparation method according to claim 2, characterized in that, The organic solvent includes any one or more of a mixed solution of methanol, ethanol, tert-butyl alcohol, isopropyl alcohol, hexafluoroisopropyl alcohol, ethyl acetate, anisole, toluene, 1, 2-dichloroethane, chlorobenzene, acetonitrile, dimethylformamide, ethylene glycol dimethyl ether, diethyl ether, cyclopentyl methyl ether, 2-methyl tetrahydrofuran, tetrahydrofuran and 1, 4-dioxane; 。 4. The production method according to claim 3, characterized by, The additive includes any one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium fluoride, sodium acetate, potassium trifluoromethanesulfonate, potassium hydrogen sulfate, sodium bicarbonate, copper trifluoromethanesulfonate, zinc chloride, p-toluenesulfonic acid, tetrabutylammonium chloride, hexafluorophosphonium amine and cesium carbonate; 5. The preparation method according to claim 4, characterized in that, The silane refers to dimethylethoxysilane, methyldiethoxysilane, trimethoxysilane, triethoxysilane, triisopropoxysilane, bis-trimethylsilyloxymethylsilane and phenylsilane. The temperature of the reaction is 0-100℃; the reaction atmosphere is inert atmosphere; and the reaction time is 1-36 h. The compound represented by Formula (I) is subjected to hemipinacol intramolecular rearrangement under the condition of an acid or a base.

6. The production method according to claim 5, characterized by, The compound represented by Formula (I) and / or Formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotopically-labeled material thereof; and optionally one or more pharmaceutically acceptable excipients.

7. A process for the preparation of a compound of formula (II) ###0005### (II) characterized in that, 10.Use of the compound represented by Formula (I) or Formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or an isotopically-labeled material thereof, or the pharmaceutical composition of claim 9, in the preparation of a drug for treating or preventing osteoarthritis.

8. The preparation method according to claim 7, characterized in that, The acid includes any one of acetic acid, hydrochloric acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid; the base includes sodium hydride, sodium hydroxide, potassium hydroxide, N - bromosuccinimide, N - chlorosuccinimide or N - iodosuccinimide.

9. A pharmaceutical composition, characterized by, ​ ​

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