Chiral 1, 4-diazabicyclo [3.1. 1] heptane derivative and synthesis and application thereof

Abstract

The invention discloses a chiral 1, 4-diazabicyclo [3.1. 1] heptane derivative as well as a synthesis method and application of the chiral 1, 4-diazabicyclo [3.1. 1] heptane derivative. According to the invention, a 1-azabicyclo [1.1. 0] butane derivative is taken as a raw material, under the catalytic action of a chiral iridium complex, the 1-azabicyclo [1.1. 1] butane derivative and an N-allyl carbonate derivative are subjected to [3 + 2] cycloaddition reaction, a series of chiral 1, 4-diazabicyclo [3.1. 1] heptane skeletons with diversified structures are constructed with high stereoselectivity, and the obtained product has the potential of further derivatization. The method has the advantages of easily available raw materials, mild reaction conditions, simplicity and convenience in operation, good functional group compatibility and the like.

Description

Technical Field

[0001] This invention relates to the field of synthetic chemistry, specifically to a class of chiral 1,4-diazabicyclo[3.1.1]heptane derivatives and their synthetic methods and applications. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] In recent years, the strategy of using a three-dimensional bicyclic framework as a bioisostere to replace aromatic rings has become a hot topic in the field of drug research. Nat . Rev. . Chemistry 2024, 8 , 605-627).

[0004] Chiral nitrogen-containing saturated bridged ring compounds are widely found in natural products and bioactive molecules, and are extremely important privileged skeletons in drug development. Among them, 1,4-diazabicyclo[3.1.1]heptane, as a highly strained nitrogen-bridged ring system, has a unique spatial configuration and rigid structure. This skeleton can effectively increase the three-dimensional properties of molecules, improve their metabolic stability and solubility, and therefore shows great potential in the screening of new drug candidates.

[0005] However, due to the significant geometric tension inherent in the bridge ring system [3.1.1], its construction is extremely challenging. Currently, methods for synthesizing this type of skeleton are very limited, and most suffer from the following shortcomings: 1) The synthesis steps are complicated: it usually requires multiple functional group conversions and complex protection / deprotection processes, resulting in a low overall yield.

[0006] 2) Low atom economy: Some methods rely on pre-functionalized precursors, resulting in a large number of chemical byproducts.

[0007] 3) Structural limitations: The currently obtained [3.1.1]bridged ring skeleton structures are limited, and 1,4-diazabicyclo[3.1.1]heptane has not been successfully synthesized, which seriously limits its further derivatization applications in medicinal chemistry.

[0008] 4) Difficulty in controlling enantioselectivity: Constructing a [3.1.1] bridged ring skeleton with high chiral purity in one step through catalytic asymmetric reaction remains a challenge in synthetic chemistry.

[0009] 1-Azabicyclo[1.1.0]butane, as a highly active electrophilic reagent, has been used in recent years to construct various azabicyclones, but there has been no report on its direct construction of the [3.1.1]heptane system via a chiral iridium (Ir)-catalyzed cycloaddition reaction with N-allyl carbonate.

[0010] Therefore, there is a need to develop a method that uses readily available raw materials, operates under mild reaction conditions, exhibits high enantioselectivity, and can efficiently construct structurally diverse chiral 1,4-diazabicyclic [3.1.1]heptane derivatives.

[0011] Furthermore, the resulting chiral 1,4-diazabicyclo[3.1.1]heptane can serve as a bioequivalence of pyrazines and can be used in the modification of drugs, active molecules, and natural products, providing a new chemical entity for drug development. In particular, it replaces the planar symmetric aza-aryl ring with a chiral three-dimensional bicyclic skeleton, and the introduction of chiral elements will bring new opportunities for drug development. Summary of the Invention

[0012] This invention provides a class of chiral 1,4-diazabicyclo[3.1.1]heptane derivatives, their synthesis methods, and applications. This invention uses a 1-diazabicyclo[1.1.0]butane derivative as a starting material, and under the catalysis of a chiral iridium complex, reacts with... N Allyl carbonate derivatives underwent a [3+2] cycloaddition reaction to construct a series of structurally diverse chiral 1,4-diazabicyclic [3.1.1]heptane skeletons with high stereoselectivity, and the resulting products have the potential for further derivatization. This invention has advantages such as readily available starting materials, mild reaction conditions, simple operation, and good functional group compatibility.

[0013] The specific technical solution is as follows: In a first aspect, the present invention provides a class of chiral 1,4-diazabicyclic [3.1.1]heptane derivatives having the structure shown in Formula 1 below: ; R 1 Selected from: hydrogen; hydroxyl; amino; substituted or unsubstituted C1-C20 alkyl (including straight-chain and branched); substituted or unsubstituted C1-C20 alkoxy (including straight-chain and branched); C1-C20 alkylamino (including straight-chain and branched); C1-C20 alkylthio (including straight-chain and branched); substituted or unsubstituted C6-C20 aryl (including phenyl, etc.); substituted or unsubstituted C3-C20 heteroaryl (including thiophene, etc.); 3- to 10-membered saturated or unsaturated heterocyclic groups having 1 to 4 heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur atoms; R 2Selected from: hydrogen; substituted or unsubstituted C1-C20 alkyl groups (including straight-chain and branched groups); substituted or unsubstituted C1-C20 alkoxy groups (including straight-chain and branched groups); C1-C20 alkylamino groups (including straight-chain and branched groups); C1-C20 alkylthio groups (including straight-chain and branched groups); substituted or unsubstituted C6-C20 aryl groups (including phenyl groups, etc.); substituted or unsubstituted C3-C20 heteroaryl groups (including thiophene groups, etc.); 3- to 10-membered saturated or unsaturated heterocyclic groups having 1 to 4 heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur atoms; acyl groups; ester groups; sulfonyl groups; R 1 R 2 Substitution in this context refers to the arbitrary substitution of one or more hydrogen atoms on a group by the following substituents: halogens (including fluorine, chlorine, bromine, iodine, etc.), cyano, nitro, C1~C6 alkyl (including tert-butyl (tBu), etc.), C1~C6 haloalkyl (including trifluoromethyl, etc.), C1~C6 alkoxy, amino, hydroxy, phenyl.

[0014] In a second aspect, the present invention provides a method for synthesizing the chiral 1,4-diazabicyclo[3.1.1]heptane derivative described in the first aspect, comprising: Using compound 2 as a starting material and compound 3 as a ternary synthon, under the catalysis of Lewis acid and chiral iridium complex, a solvent and a base were added to undergo a cycloaddition reaction to generate a chiral 1,4-diazabicyclo[3.1.1]heptane derivative; ; ; X is selected from: alkoxycarbonyl-OC(O)R 3 (e.g., tert-butyloxycarbonyl (Boc)); acyl-C(O)R 4 Dialkylphosphoryl-P(O)(OR) 5 )2; R 3 R 4 R 5 Each group is independently selected from C1-C6 alkyl groups (including straight-chain and branched-chain), C1-C6 haloalkyl groups, and substituted or unsubstituted C6-C20 aryl groups (including phenyl groups, etc.). Substitution refers to the arbitrary substitution of one or more hydrogen atoms on the group by the following substituents: halogen (including fluorine, chlorine, bromine, iodine, etc.), cyano, nitro, C1-C6 alkyl groups (including tert-butyl (tBu), etc.), C1-C6 haloalkyl groups (including trifluoromethyl groups, etc.), C1-C6 alkoxy groups, amino groups, hydroxyl groups, and phenyl groups.

[0015] R in compound 2 1 R in the structure shown in Equation 1 1 They have the same meaning.

[0016] R in compound 3 2 R in the structure shown in Equation 1 2 They have the same meaning.

[0017] The Lewis acid preferably includes one or more of gallium trifluoromethanesulfonate (Ga(OTf)3), ytterbium trifluoromethanesulfonate (Yb(OTf)3), yttrium trifluoromethanesulfonate (Y(OTf)3), indium trifluoromethanesulfonate (In(OTf)3), scandium trifluoromethanesulfonate (Sc(OTf)3), europium trifluoromethanesulfonate (Eu(OTf)3), erbium trifluoromethanesulfonate (Er(OTf)3), dysprosium trifluoromethanesulfonate (Dy(OTf)3), boron trifluoride ether (BF3·OEt2), copper trifluoromethanesulfonate (Cu(OTf)2), silver trifluoromethanesulfonate (AgOTf), ferrous trifluoromethanesulfonate (Fe(OTf)2), zinc trifluoromethanesulfonate (Zn(OTf)2), zinc bromide (ZnBr2), and bismuth trifluoromethanesulfonate (Bi(OTf)3), and more preferably includes Dy(OTf)3.

[0018] The chiral iridium complex preferably includes one or more of [Ir]-A, [Ir]-B, [Ir]-C, [Ir]-D, [Ir]-E, [Ir]-F, [Ir]-G, [Ir]-H, and [Ir]-I, and more preferably includes [Ir]-E. ; Where: Ph represents phenyl; OTf represents trifluoromethanesulfonate group; ( R a )-BINOL represents 1,1'-bi-2-naphthol in the R configuration; R a )-8 H -BINOL represents the R configuration of 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol; 1-naphth represents 1-naphthyl; 2-OMePh represents 2-methoxyphenyl; 4-OMePh represents 4-methoxyphenyl; ( R a )-SPINOL represents the R-configuration of spirocyclic diol.

[0019] The solvent preferably includes one or more of tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, diethyl ether, dichloromethane, toluene, and acetonitrile, and more preferably includes tetrahydrofuran.

[0020] The alkali preferably includes N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), potassium carbonate (K2CO3), potassium phosphate (K3PO4), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium bis(trimethylsilyl)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), lithium diisopropylamino (LDA), and n-butyllithium ( n One or more of the following: -BuLi, cesium carbonate (Cs2CO3), 2,6-dimethylpyridine (2,6-Lutidine), sodium carbonate (Na2CO3), and sodium bicarbonate (NaHCO3), with DABCO being more preferred.

[0021] The preferred molar ratio of compound 2 to compound 3 is (5:1) to (1:5), for example, 1.2:1.

[0022] The molar ratio of compound 3 to the Lewis acid is preferably (1:0.01) to (1:0.5), for example, 1:0.1.

[0023] The molar ratio of compound 3 to the chiral iridium complex is preferably (1:0.01) to (1:0.5), for example, 1:0.04.

[0024] The molar ratio of compound 3 to the base is preferably (5:1) to (1:5), for example, 1:1.

[0025] The preferred cycloaddition reaction temperature is -10 to 50°C, such as 0°C, 25°C, etc., and more preferably 25°C.

[0026] The preferred cycloaddition reaction time is 2 to 24 hours, such as 4 hours or 12 hours.

[0027] After the cycloaddition reaction is completed, the product can be separated and characterized using conventional separation and purification methods to obtain the target product.

[0028] Thirdly, the present invention provides the application of the chiral 1,4-diazabicyclo[3.1.1]heptane derivative described in the first aspect in the preparation of antibacterial agents. Furthermore, the antibacterial agents target Mycobacterium tuberculosis, etc.

[0029] Fourthly, the present invention provides an antibacterial agent containing an effective amount of the chiral 1,4-diazabicyclo[3.1.1]heptane derivative described in the first aspect.

[0030] Fifthly, the present invention provides the use of the chiral 1,4-diazabicyclo[3.1.1]heptane derivative described in the first aspect for the preparation of medicaments for treating and / or preventing Mycobacterium tuberculosis infection.

[0031] This invention uses a 1-azabicyclo[1.1.0]butane derivative as a raw material, and under the catalysis of a Lewis acid and a chiral iridium complex, reacts with... N - An asymmetric cycloaddition reaction was carried out on allyl carbonate derivatives to synthesize a series of structurally diverse chiral 1,4-diazabicyclo[3.1.1]heptane derivatives with high yield and stereoselectivity. The products can be further derivatized.

[0032] Chiral aziridine [3.1.1]heptane is a novel compound and is considered a bioisostere of aziridine rings. It can be used to replace aziridine rings in drugs to study their biochemical activities. The raw materials of this invention are readily available, the operation is simple, and the reaction can efficiently and modularly synthesize chiral 1,4-diazabicyclo[3.1.1]heptane derivatives with potential biological activity.

[0033] Compared with the prior art, the beneficial effects of this invention are as follows: 1) 1-azabicyclo[1.1.0]butane derivatives are easy to prepare in large quantities and can be used to synthesize chiral 1,4-diazabicyclo[3.1.1]heptane derivatives of different types and structures.

[0034] 2) N -Allyl carbonate derivatives are easy to prepare in large quantities and can be conveniently used to construct a unique and bioactive 1,4-diazabicyclo[3.1.1]heptane skeleton.

[0035] 3) This invention utilizes 1-azabicyclo[1.1.0]butane derivatives to synthesize chiral 1,4-diazabicyclo[3.1.1]heptane derivatives with diverse structures using high stereoselectivity. The raw materials are readily available, the operation is simple, the yield of the target product is high, and it can be further derivatized.

[0036] 4) Mild synthesis conditions and high safety: Avoids the use of high temperature and high pressure conditions or strong corrosive reagents, suitable for industrial continuous synthesis.

[0037] 5) High potential for modular application: This reaction system can be flexibly applied to different substituents, and has broad substrate adaptability and platform potential.

[0038] In summary, this invention provides a chiral 1,4-diazabicyclo[3.1.1]heptane derivative with a well-defined structure, controllable configuration, efficient method, and derivatizable product, as well as its synthetic method, which has significant practical application value and industrial promotion prospects. Detailed Implementation

[0039] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Operating methods not specifically specified in the following embodiments are generally performed under conventional conditions or as recommended by the manufacturer.

[0040] All chemical reagents used below are available through existing technology or commercial means; for example, 1-azabicyclo[1.1.0]butane derivatives, N -Allyl carbonate derivatives can be synthesized according to methods reported in the literature (e.g. J. Am. Chem. Soc. 2025, 147, 33700-33710; ACS Catal. 2024, 14 (e.g., 17837-17849).

[0041] This invention utilizes a simple 1-azabicyclo[1.1.0]butane derivative (compound 2) and N Using an allyl carbonate derivative (compound 3) as a starting material, a cycloaddition reaction is carried out under the action of a Lewis acid and a chiral iridium complex. The reaction formula can be represented as follows: .

[0042] The specific procedure of the example includes: under a nitrogen atmosphere, compound 2 (0.24 mmol) and compound 3 (0.20 mmol) were sequentially added to a Schlenk tube equipped with a magnetic stirrer. The tube was evacuated and backfilled with nitrogen five times. Then, anhydrous tetrahydrofuran (2.0 mL) was added via syringe. Then, Dy(OTf)3 (0.02 mmol) was added, and the mixture was stirred at 25°C until compound 3 was completely consumed. Then, [Ir]-E (0.008 mmol) was added, followed by the dropwise addition of DABCO (0.20 mmol, 1.0 equivalent). The mixture was stirred for 4 hours. After the reaction was complete, the mixture was quenched with water and extracted three times with ethyl acetate. The filtrates were separated, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2, v / v) to obtain the target product 1. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0043] Example 1: The specific procedure included: under a nitrogen atmosphere, compound 2a (38.2 mg, 0.24 mmol) and compound 3a (55.5 mg, 0.20 mmol) were sequentially added to a Schlenk tube equipped with a magnetic stirrer. The tube was evacuated and backfilled with nitrogen five times. Then, anhydrous tetrahydrofuran (2.0 mL) was added via syringe. Next, Dy(OTf)3 (0.004 mmol) was added, and the mixture was stirred at 25°C until compound 3a was completely consumed. Then, [Ir]-E (0.008 mmol) and DABCO (0.20 mmol, 1.0 equiv.) were added, and stirring continued for 4 hours. After the reaction was complete, the mixture was quenched with water and extracted three times with ethyl acetate. The separated filtrates were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting buffer: petroleum ether / ethyl acetate = 1 / 2, v / v) to obtain the target product 1a (50.9 mg, yield 80%, 95%). of (Enantiomer excess). The target product was confirmed by NMR spectroscopy and high-resolution mass spectrometry.

[0044] Example 2: The reaction procedure and operation were the same as in Example 1, except that compound 3b (52.7 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1b (47.5 mg, yield 78%, 95%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0045] Example 3: The reaction procedure and operation were the same as in Example 1, except that compound 3c (58.7 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1c (52.2 mg, yield 78%, 95%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0046] Example 4: The reaction procedure and operation were the same as in Example 1, except that compound 3d (68.4 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1d (59.8 mg, yield 78%, 95%) was obtained as a white solid. ofThe target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0047] Example 5: The reaction procedure and operation were the same as in Example 1, except that compound 3e (58.7 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1e (52.2 mg, yield 78%, 95%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0048] Example 6: The reaction procedure and operation were the same as in Example 1, except that compound 3f (68.4 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1f (70.5 mg, yield 92%, 96%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0049] Example 7: The reaction procedure and operation were the same as in Example 1, except that 3 g (59.6 mg, 0.20 mmol) of the compound was added to the reaction system. The reaction was stopped, and after post-treatment, 1 g (45.4 mg, yield 67%, 96%) of the target product was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0050] Example 8: The reaction procedure and operation were the same as in Example 2, except that compound 3h (56.3 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1h (61.3 mg, 95% yield) was obtained. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0051] Example 9: The reaction procedure and operation were the same as in Example 2, except that compound 3i (63.9 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1i (68.5 mg, 95% yield, 94%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0052] Example 10: The reaction procedure and operation were the same as in Example 2, except that compound 3j (67.9 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1j (72.3 mg, yield 95%, 94%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0053] Example 11: The reaction procedure and operation were the same as in Example 1, except that compound 2b (41.6 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1k (53.2 mg, yield 80%, 95%) was obtained as a white solid. of Tol represents 4-methylphenyl. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0054] Example 12: The reaction procedure and operation were the same as in Example 1, except that compound 2c (46.5 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1L (52.2 mg, yield 74%, 94%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0055] Example 13: The reaction procedure and operation were the same as in Example 1, except that compound 2d (45.4 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1m (57.8 mg, yield 83%, 95%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0056] Example 14: The reaction procedure and operation were the same as in Example 1, except that compound 2e (41.6 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1n (55.2 mg, yield 83%, 96%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0057] Example 15: The reaction procedure and operation were the same as in Example 1, except that compound 2f (57.1 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1o (68.3 mg, yield 86%, 94%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0058] Example 16: The reaction procedure and operation were the same as in Example 1, except that 2 g (42.5 mg, 0.24 mmol) of the compound was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1p (57.2 mg, yield 85%, 96%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0059] Example 17: The reaction procedure and operation were the same as in Example 1, except that compound 2h (54.5 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1q (68.0 mg, yield 88%, 98%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0060] Example 18: The reaction procedure and operation were the same as in Example 1, except that compound 2i (54.5 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1r (52.6 mg, yield 81%, 95%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0061] Example 19: The reaction procedure and operation were the same as in Example 1, except that compound 2j (45.4 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 1s (55.8 mg, yield 80%, 91%) was obtained as a white solid. of The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0062] Example 20: The reaction procedure and operation were the same as in Example 5, except that compound 2k (45.4 mg, 0.24 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, 1 t (54.7 mg, yield 75%, 91%) of the target product was obtained as a white solid. of PMP stands for p-methoxyphenyl. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0063] This invention uses a 1-azabicyclo[1.1.0]butane derivative as a raw material, and under the catalysis of a chiral iridium complex, reacts with... N - Cycloaddition reactions of allyl carbonate derivatives yielded a series of structurally diverse chiral 1,4-diazabicyclo[3.1.1]heptane derivatives with excellent chemoselectivity, and the products can be further derivatized. For example, hydrolysis yields carboxylic acid 4, and oxidative de-PMP reaction yields secondary amine 5, etc. The exemplary specific process includes: 1,4-diazabicyclo[3.1.1]heptane derivative 1s (69.7 mg, 0.20 mmol) was added to a reaction tube equipped with a magnetic stir bar, followed by anhydrous tetrahydrofuran (2.0 mL) and then lithium hydroxide monohydrate (0.8 mmol, 33.6 mg). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, ethyl acetate (3 mL) was added to extract the reaction solution. The organic phase was removed. The aqueous phase was acidified to pH=1 with 1N HCl. Extraction was performed with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to give target product 4 (49.6 mg, 96% yield). The target product was confirmed by NMR spectroscopy and high-resolution mass spectrometry. The exemplary specific process includes: 1,4-diazabicyclo[3.1.1]heptane derivative 1e (66.9 mg, 0.20 mmol) was added to a reaction tube equipped with a magnetic stir bar, followed by tetrahydrofuran (2.0 mL). Cerium ammonium nitrate (0.6 mmol, 91.3 mg) dissolved in 2.0 mL of water was then slowly added dropwise to the tetrahydrofuran solution of 1e at 0 °C. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, 1 M sodium hydroxide was added to adjust the pH to 10, and the mixture was stirred for 10 minutes. Extraction was performed with dichloromethane (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to give target product 5 (49.6 mg, 96% yield). The target product was confirmed by NMR spectroscopy and high-resolution mass spectrometry.

[0064] The chiral 1,4-diazabicyclo[3.1.1]heptane derivatives of this invention can be introduced into drug molecules as bioisosteres of aza-aryl rings. For example, they are used to synthesize a homologue 7 of pyrazinamide. The exemplary specific process includes: One ton (364.5 mg, 1 mmol) of 1,4-diazabicyclo[3.1.1]heptane derivative was added to a reaction tube equipped with a magnetic stir bar. Tetrahydrofuran (2.0 mL) was added, followed by the slow addition of cerium ammonium nitrate (3 mmol, 456.5 mg) dissolved in 2.0 mL of water at 0 °C to the 1 ton of tetrahydrofuran solution. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, 1 M sodium hydroxide was added to adjust the pH to 10, and the mixture was stirred for 10 minutes. The mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product containing compound 6 was obtained by rapid column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v). The crude product was directly loaded into a dry Schlenk tube. Anhydrous tetrahydrofuran (10.0 mL) was added to the reaction tube using a syringe. Trimethylsilanolate potassium (2 mmol, 256.5 mg) was slowly added at 0 °C. After 10 minutes, the reaction was allowed to proceed to room temperature for 2 hours. After the reaction was complete, the mixture was quenched with water, and the pH was adjusted to 9 with saturated sodium bicarbonate. The organic phase was extracted three times with water. The aqueous phases were combined, and the pH was adjusted to 3 with 2 M hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product and N,N'-carbonyldiimidazole (2 mmol, 324.3 mg) were loaded into a dry Schlenk tube and purged with nitrogen. 10.0 mL of anhydrous dichloromethane was added to the reaction tube using a syringe, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the temperature was lowered to 0 °C (ice-water bath), and NH₄OH was slowly added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1, v / v) to give the corresponding compound 7 as a white solid, with an overall yield of 41% (68.6 mg).

[0065] Further research showed that the minimum inhibitory concentration (MIC) of compound 7 against Mycobacterium tuberculosis was determined using the microbroth dilution method. Detection with resazurin chromogenic reagent showed that the MIC of compound 7 against Mycobacterium tuberculosis was ≤16 μg / mL, indicating that compound 7 has a certain inhibitory effect on Mycobacterium tuberculosis and could be considered a candidate drug molecule for lung diseases (such as pulmonary tuberculosis).

[0066] Reagents and equipment: Bacterial strain: Mycobacterium tuberculosis H37Ra (ATCC 25177).

[0067] Substrates: Compound 7 (25 µM), Pyrazinamide (25 µM).

[0068] Color developer: 0.02% sodium resazurin solution.

[0069] Culture medium: Middlebrook 7H9 broth, supplemented with 10% ADC enrichment broth and 0.5% glycerol. The pH was adjusted to 5.8 throughout the process.

[0070] Culture plate: 96-well transparent flat-bottomed microplate.

[0071] Reagent preparation: Compound 7 and the positive control Pyrazinamide were prepared into stock solutions using DMSO (dimethyl sulfoxide), and the final concentration gradient after dilution was 24~64 µg / mL; the negative control contained only the same proportion of DMSO without the drug.

[0072] Instruments and equipment: Biosafety cabinet (Class II A2 type), constant temperature incubator, McFarland turbidimeter, multichannel pipette.

[0073] Operating instructions: 1) Scrape logarithmic-phase H37Ra colonies from the slant. Suspend them in 7H9 (pH=5.8) containing glass beads, vortex to disperse, and collect the supernatant. Adjust the turbidity to 1.0 McFarland standard (approximately 3 × 10⁻⁶). 7 CFU / mL). Dilute 20-fold with the corresponding pH medium to obtain the working bacterial suspension (1.5 × 10⁻⁶ CFU / mL). 6 (CFU / mL) 2) Add compound 7 to the test wells, with final concentrations of 2, 4, 8, 16, 32, and 64 µg / mL; add the same concentration of Pyrazinamide to the positive control wells; and add no drug to the negative control wells.

[0074] 3) Add 100 μL of working bacterial solution to each well (final volume 200 μL, bacterial count approximately 7.5 × 10⁻⁶). 5 (CFU / mL), seal plate.

[0075] 4) Incubate at 37℃ for 10 days. When obvious bacterial sediment or turbidity appears at the bottom of the positive control well, perform color development. Add 30 μL of 0.02% resazurin to each well and continue incubation for 24-48 hours.

[0076] The experimental results are shown in Table 1 below.

[0077] Table 1 The minimum inhibitory concentration (MIC) of compound 7 against Mycobacterium tuberculosis was ≤16 μg / mL, which was comparable to that of the positive control Pyrazinamide, indicating that compound 7 has a certain inhibitory effect on Mycobacterium tuberculosis.

[0078] Typical compound characterization data: ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1a), white solid. (H NMR spectroscopy) 1 H NMR) (600MHz, CDCl3) δ 8.21 – 8.03 (m, 2H), 7.49 – 7.41 (m, 1H), 7.35 (d, J = 7.7 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 6.73 – 6.62 (m, 2H), 5.85 (d, J = 1.3 Hz, 1H),5.33 – 5.14 (m, 2H), 4.53 (d, J = 9.1 Hz, 1H), 4.06 (dd, J = 12.9, 9.4 Hz, 1H), 3.98 – 3.73 (m, 4H), 3.35 – 3.21 (m, 1H), 2.19 (s, 3H); Carbon NMR ( 13 C10 NMR (150 MHz, CDCl3) δ 198.4, 147.1, 137.2, 134.0, 133.4, 129.7(3)(2C), 129.6(6), 129.0(2C), 128.3(2C), 118.0(2C), 115.8, 74.8, 64.4, 61.0, 56.3, 50.6, 20.4; High-resolution mass spectrometry (HRMS) (electrospray ionization-time-of-flight (ESI-TOF), m / z): calcd for ... 21 H 22 N2ONa [M +Na] + : 341.1624, found: 341.1628; High Performance Liquid Chromatography (HPLC) (Chiralpak IC, n-hexane ( n (-hexane) / isopropanol (isopropanol) = 85 / 15, 1.0 mL / min, 254 nm) t R(Retention time) = 10.313 min (major), 17.105 min (minor); [α] D 25 = -171.0 ( c 0.05, CH2Cl2, 95% of ).

[0079] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1b), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 8.1, 1.4 Hz, 2H), 7.44 (d, J = 7.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 2H), 7.20 – 7.05 (m, 2H), 7.01 – 6.45 (m, 3H), 5.84 (ddd, J = 17.3,10.6, 5.0 Hz, 1H), 5.54 – 4.98 (m, 2H), 4.54 (d, J = 9.1 Hz, 1H), 4.25 – 4.01(m, 1H), 4.00 – 3.71 (m, 4H), 3.22 (dd, J = 9.1, 7.5 Hz, 1H); 13 C NMR (100MHz, CDCl3) δ 198.2, 149.3, 137.0, 133.9, 133.5, 129.2(2C), 129.0(2C), 128.3(2C), 120.2, 117.7(2C), 116.0, 74.6, 64.4, 61.0, 56.3, 50.3; HRMS (ESI-TOF,m / z): calcd for C 20 H 20 N2ONa [M + Na] + : 327.1468, found: 327.1470; HPLC(Chiralpak IC, n-hexane / isopropanol = 85 / 15, 1.0 mL / min, 254 nm) t R = 6.472min (major), 9.121min (minor); [α]D25 = -156.0 (c 0.05, CH2Cl2, 96%) of ).

[0080] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1c), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.17 – 7.97 (m, 2H), 7.49 – 7.38 (m, 1H), 7.32 (dd, J = 8.3, 7.2 Hz, 2H), 7.02 (d, J = 8.1 Hz, 1H), 6.44 – 6.17 (m, 3H), 5.83 (ddd, J = 17.3,10.6, 5.0 Hz, 1H), 5.41 – 5.15 (m, 2H), 4.54 (d, J = 9.1 Hz, 1H), 4.16 – 3.74(m, 5H), 3.68 (s, 3H), 3.21 (dd, J = 9.2, 7.5 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ198.1, 160.5, 150.7, 137.0, 133.9, 133.5, 129.9, 128.9(2C), 128.4(2C), 116.0, 110.2, 105.4, 103.9, 74.8, 64.4, 61.1, 56.4, 55.1, 50.1; HRMS(ESI-TOF, m / z): calcd for C 21 H 22 N₂O₂Na [M + Na] + : 357.1573, found: 357.1577;HPLC (Chiralpak IC, n -hexane / isopropanol = 85 / 15, 1.0 mL / min, 254 nm) t R =10.687 min (major), 13.507 min (minor); [α] D 25 = +88.0 ( c 0.05, CH2Cl2, 95% of ).

[0081] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1d), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.2, 1.3 Hz, 2H), 7.52 – 7.42 (m, 1H), 7.38 – 7.31 (m,2H), 7.01 – 6.72 (m, 3H), 6.57 (dd, J = 8.2, 2.4 Hz, 1H), 5.96 – 5.74 (m,1H), 5.49 – 5.10 (m, 2H), 4.55 (d, J = 9.2 Hz, 1H), 4.18 – 4.00 (m, 1H), 3.99– 3.69 (m, 4H), 3.17 (dd, J = 9.2, 7.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ197.7, 150.6, 136.7, 133.7(3), 133.6(7), 130.4, 128.9(2C), 128.5(2C), 123.2,123.0, 120.9, 116.3, 115.4, 74.5, 64.4, 61.0, 56.3, 50.2; HRMS (ESI-TOF, m / z): calcd for C 20 H 19 N2O 79 BrNa [M + Na] + : 405.0573, found: 405.0576; calcd forC 20 H 19 N2O 81 BrNa [M + Na] + : 407.0553, found: 407.0556; HPLC (Chiralpak IC, n -hexane / isopropanol = 85 / 15, 1.0 mL / min, 254 nm) t R = 13.391 min (major),19812 min (minor); [α] D 25= -108.0 ( c 0.05, CH2Cl2, 95% of ).

[0082] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1e), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.16 – 8.04 (m, 2H), 7.52 – 7.41 (m, 1H), 7.39 – 7.30 (m, 2H), 6.78– 6.59 (m, 4H), 6.02 – 5.48 (m, 1H), 5.35 – 5.07 (m, 2H), 4.44 (d, J = 9.1Hz, 1H), 4.03 – 3.73 (m, 5H), 3.67 (s, 3H), 3.28 – 3.10 (m, 1H); 13 C NMR (100MHz, CDCl3) δ 198.5, 154.0, 143.3, 137.3, 134.1, 133.4, 129.1(2C), 128.3(2C),120.2(2C), 115.8, 114.5(2C), 75.1, 64.4, 61.3, 55.8, 55.4, 51.1; HRMS (ESI-TOF, m / z): calcd for C 21 H 22 N₂O₂Na [M + Na] + : 357.1573, found: 357.1579; HPLC(Chiralpak IC, n -hexane / isopropanol = 85 / 15, 1.0 mL / min, 254 nm) t R = 13.299min (major), 17.634min (minor); [α] D 25 = +94.0 ( c 0.10, CH2Cl2, 96% of ).

[0083] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1f), white solid. 1H NMR (400 MHz,CDCl3) δ 8.06 (dd, J = 8.2, 1.4 Hz, 2H), 7.56 – 7.48 (m, 1H), 7.41 – 7.33 (m,2H), 7.26 – 7.18 (m, 2H), 6.69 – 6.52 (m, 2H), 5.85 (ddd, J = 17.3, 10.6, 5.5Hz, 1H), 5.37 – 5.15 (m, 2H), 4.55 (d, J = 9.2 Hz, 1H), 4.09 (dd, J = 13.1,9.4 Hz, 1H), 3.98 – 3.75 (m, 4H), 3.19 (t, J = 8.5 Hz, 1H); 13 C NMR (100 MHz,CDCl3) δ 197.9, 148.3, 136.8, 133.7, 132.0(2C), 128.9(2C), 128.4(2C), 119.2(2C), 116.2, 112.5, 100.0, 74.5, 64.3, 60.8, 56.2, 50.3; HRMS (ESI-TOF, m / z):calcd for C 20 H 19 N2O 79 BrNa [M + Na] + : 405.0573, found: 405.0571; calcd forC 20 H 19 N2O 81 BrNa [M + Na] + : 407.0553, found: 407.0552; HPLC (Chiralpak IC, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 7.983 min (major),11.694 min (minor); [α] D 25 = -152.0 ( c 0.05, CH2Cl2, 96% of )。

[0084] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1g), white solid. 1 H NMR (600 MHz, CDCl3) δ 8.04 – 7.85 (m, 2H), 7.47 – 7.34 (m, 1H), 7.30 – 7.22 (m, 2H), 7.01 – 6.86 (m, 2H), 6.66 – 6.44 (m, 2H), 5.77 (ddd, J = 17.3, 10.6, 5.4 Hz, 1H),5.36 – 4.93 (m, 2H), 4.47 (d, J = 9.1 Hz, 1H), 3.99 (dd, J = 12.8, 9.2 Hz,1H), 3.90 – 3.50 (m, 4H), 3.12 (t, J = 8.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ198.0, 147.9, 136.8, 133.7, 133.7, 129.2(2C), 128.9(2C), 128.4(2C), 125.2, 118.9(2C), 116.2 , 74.5 , 64.3 , 60.9 , 56.2 , 50.4; HRMS (ESI-TOF,m / z): calcd for C 20 H 19 N₂OClNa [M + Na] + : 361.1078, found: 361.1082; HPLC(Chiralpak IC, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 7.624min (minor), 8.243min (major); [α] D 25 = +121.0 ( c 0.10, CH2Cl2, 96% of ).

[0085] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1h), white solid. 1H NMR (400 MHz,CDCl3) δ 8.09 (d, J = 7.6 Hz, 2H), 7.54 – 7.44 (m, 1H), 7.39 – 7.33 (m, 2H),6.89 – 6.75 (m, 2H), 6.71 (dd, J = 9.0, 4.4 Hz, 2H), 5.85 (ddd, J = 16.7,10.6, 5.4 Hz, 1H), 5.38 – 5.04 (m, 2H), 4.51 (d, J = 9.2 Hz, 1H), 4.12 – 3.97(m, 1H), 3.99 – 3.87 (m, 2H), 3.87 – 3.61 (m, 2H), 3.22 (t, J = 8.5 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 198.1, 157.2 (d, J = 239.9 Hz), 145.7, 137.0,133.9, 133.5, 129.0(2C), 128.4(2C), 119.5 (d, J = 7.3 Hz)(2C), 116.0, 115.8(d, J = 22.5 Hz)(2C), 74.8, 64.3, 61.1, 56.0, 50.9; 19 F NMR (376 MHz, CDCl3) δ-125.65; HRMS (ESI-TOF, m / z): calcd for C 20 H 19 N2OFNa [M + Na] + : 345.1374,found: 345.1377; HPLC (Chiralpak IC, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 9.815 min (major), 16.555 min (minor); [α] D 25 = +107.0 ( c 0.10, CH2Cl2, 95% of )。

[0086] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1i), white solid. 1 H NMR δ 8.15 (d, J = 7.8 Hz, 2H), 7.58 – 7.43 (m, 1H), 7.39 – 7.32 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 5.84 (dd, J = 11.6, 5.9 Hz, 1H), 5.48 – 5.03(m, 2H), 4.52 (d, J = 9.1 Hz, 1H), 4.17 – 3.98 (m, 1H), 3.98 – 3.70 (m, 4H), 3.37 – 3.20 (m, 1H), 1.23 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 198.3, 146.9,142.9, 137.1, 134.0, 133.4, 129.1(2C), 128.3(2C), 126.0(2C), 117.6(2C),115.8, 74.8, 64.4, 60.9, 56.3, 50.4, 33.9, 31.4(3C); HRMS (ESI-TOF, m / z):calcd for C 24 H 28 N2ONa [M + Na] + : 383.2094, found: 383.2097; HPLC (Chiralpak IC, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 8.017 min (major),13.609 min (minor); [α] D 25 = -93.0 ( c 0.05, CH2Cl2, 96% of ).

[0087] ( R)-1,4-diazabicyclo[3.1.1]heptane derivative (1j), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 8.3 Hz, 3H), 7.43 – 7.33 (m,6H), 7.28-7.22 (m, 1H), 6.83 (d, J = 8.3 Hz, 2H), 5.88 (ddd, J = 16.5, 10.6,5.0 Hz, 1H), 5.41 – 5.02 (m, 2H), 4.60 (d, J = 9.1 Hz, 1H), 4.28 – 4.07 (m,1H), 4.03 – 3.78 (m, 4H), 3.27 (t, J = 8.3 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ198.2, 148.6, 140.5, 137.0, 133.9, 133.6, 132.9, 129.0(2C), 128.7(2C), 128.4(2C), 127.8(2C), 126.6, 126.5(2C), 117.9(2C), 116.1, 74.7, 64.4, 61.0, 56.4,50.3; HRMS (ESI-TOF, m / z): calcd for C 26 H 24 N2O [M + H] + : 403.1781, found:403.1786; HPLC (Chiralpak IC, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254nm) t R = 7.819 min (major), 9.304 min (minor); [α] D 25 = +267.0 ( c 0.10, CH2Cl2, 94% of ).

[0088] ( R)-1,4-diazabicyclo[3.1.1]heptane derivative (1k), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.33 – 7.26 (m, 1H), 7.27 –7.17 (m, 1H), 6.96 (d, J = 8.1 Hz, 2H), 6.68 (d, J = 8.1 Hz, 2H), 5.85 (ddd, J = 16.5, 10.6, 5.1 Hz, 1H), 5.36 – 5.12 (m, 2H), 4.51 (d, J = 9.1 Hz, 1H), 4.05 (dd, J = 12.0, 8.8 Hz, 1H), 3.87 (ddt, J = 26.1, 17.2, 8.6 Hz, 4H), 3.23(t, J = 8.3 Hz, 1H), 2.34 (s, 3H), 2.19 (s, 3H).); 13 C NMR (100 MHz, CDCl3) δ198.5, 147.1, 138.1, 137.2, 134.3, 134.0, 129.7(2C), 129.6, 129.5, 128.1,126.4, 118.1(2C), 115.8, 74.8, 64.4, 61.0, 56.3, 50.5, 21.4, 20.4; HRMS (ESI-TOF, m / z): calcd for C 22 H 24 N2ONa [M + Na] + : 355.1781, found: 355.1786; HPLC(Chiralpak IC, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 7.624min (major), 13.972min (minor); [α] D 25 = -71.0 ( c 0.05, CH2Cl2, 95% of ).

[0089] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1l), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.46 – 7.37 (m,1H), 7.34 – 7.21 (m, 1H), 6.94 (d, J = 8.1 Hz, 2H), 6.63 (d, J = 8.0 Hz, 2H), 5.82 (ddd, J = 16.5, 10.6, 5.1 Hz, 1H), 5.39 – 5.08 (m, 2H), 4.49 (d, J = 9.1Hz, 1H), 4.10 – 3.93 (m, 1H), 3.92 – 3.73 (m, 4H), 3.20 (t, J = 8.4 Hz, 1H), 2.18 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 197.2, 147.0, 137.1, 135.6, 134.6,133.5, 130.2, 130.0(2C), 129.8, 129.2, 127.2, 118.2(2C), 116.1, 74.8, 64.4,61.0, 56.2, 50.7, 20.5; HRMS (ESI-TOF, m / z): calcd for C 21 H 21 N2ONa [M + Na] + :375.1235, found: 375.1238; HPLC (Chiralpak IC, n -hexane / isopropanol = 70 / 30,1.0 mL / min, 254 nm) t R = 6.624 min (major), 11.682 min (minor); [α] D 25 = -109.0 ( c0.05, CH2Cl2, 94% of ).

[0090] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1m), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.21 – 8.05 (m, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.84 – 6.74 (m, 2H), 6.72 – 6.53 (m, 2H), 5.83 (ddd, J = 17.4, 10.6, 5.0 Hz, 1H), 5.46 – 5.03 (m,2H), 4.50 (d, J = 9.1 Hz, 1H), 4.13 – 3.68 (m, 8H), 3.20 (t, J = 8.3 Hz, 1H), 2.16 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 196.7, 163.8, 147.2, 137.2, 131.6(2C), 129.8(2C), 129.7, 127.1, 118.1(2C), 116.0, 113.7 (2C), 74.7, 64.5,61.2, 56.3, 55.5, 50.7, 20.5; HRMS (ESI-TOF, m / z): calcd for C 22 H 24 N₂O₂Na [M +Na] + : 371.1730, found: 371.1735; HPLC (Chiralpak IC, n -hexane / isopropanol =70 / 30, 1.0 mL / min, 254 nm) t R = 7.024 min (major), 10.644 min (minor); [α] D 25 = +55 ( c 0.05, CH2Cl2, 95% of ).

[0091] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1n), white solid.1 H NMR (400 MHz,CDCl3) δ 8.02 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.2Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 5.83 (ddd, J = 16.6, 10.6, 5.4 Hz, 1H),5.32 – 5.11 (m, 2H), 4.49 (d, J = 9.1 Hz, 1H), 4.19 – 3.97 (m, 1H), 3.84(tdd, J = 35.6, 12.1, 7.2 Hz, 4H), 3.20 (t, J = 8.4 Hz, 1H), 2.31 (s, 3H),2.16 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.0, 147.2, 144.4, 137.3, 131.5,129.8(2C), 129.6, 129.3(2C), 129.2(2C), 118.0(2C), 115.9, 74.8, 64.5, 61.1,56.4, 50.6, 21.8, 20.5; HRMS (ESI-TOF, m / z): calcd for C 22 H 24 N2ONa [M + Na] + :355.1781, found: 355.1784; HPLC (Chiralpak IC, n -hexane / isopropanol = 70 / 30,1.0 mL / min, 254 nm) t R = 6.224 min (major), 10.779 min (minor); [α] D 25 = -146.0 ( c 0.05, CH2Cl2, 95% of )。

[0092] ( R)-1,4-diazabicyclo[3.1.1]heptane derivative (1o), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.1Hz, 2H), 6.62 (d, J = 8.1 Hz, 2H), 5.82 (ddd, J = 16.4, 10.6, 5.1 Hz, 1H),5.39 – 4.99 (m, 2H), 4.49 (d, J = 9.2 Hz, 1H), 4.10 – 3.70 (m, 5H), 3.19 (t, J = 8.4 Hz, 1H), 2.17 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 197.7, 166.8, 145.0,137.1, 132.8 (2C), 130.8, 129.6, 129.4(2C), 118.5(2C), 115.7, 115.6(2C),74.8, 64.4, 60.6, 56.5, 50.8, 20.5; HRMS (ESI-TOF, m / z): calcd forC 21 H 21 N2O 79 BrNa [M + Na] + : 419.0729, found: 419.0734; calcd for C 21 H 21 N2O 81 BrNa [M+ Na] + : 421.0709, found: 421.0711; HPLC (Chiralpak IC, n -hexane / isopropanol =70 / 30, 1.0 mL / min, 254 nm) t R = 6.834 min (major), 13.332 min (minor); [α] D 25 = -134.0 ( c0.05, CH2Cl2, 96% of ).

[0093] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1p), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 8.8, 5.6 Hz, 2H), 7.05 – 6.84 (m, 4H), 6.67 – 6.36 (m,2H), 5.82 (ddd, J = 17.4, 10.6, 5.1 Hz, 1H), 5.31 – 5.04 (m, 2H), 4.50 (d, J = 9.1 Hz, 1H), 4.01 (dd, J = 11.9, 8.7 Hz, 1H), 3.95 – 3.62 (m, 4H), 3.37 –3.03 (m, 1H), 2.17 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 196.7, 165.8 (d, J =255.7 Hz), 147.0, 137.1, 131.8 (d, J = 9.1 Hz)(2C), 130.4 (d, J = 2.9 Hz),129.9, 129.8(2C), 118.0(2C), 115.9, 115.5 (d, J = 21.8 Hz)(2C), 74.6, 64.3,60.9, 56.1, 50.6, 20.4; 19 F NMR (376 MHz, CDCl3) δ -115.65; HRMS (ESI-TOF, m / z): calcd for C 21 H 21 N₂OFNa [M + Na] + : 359.1530, found: 359.1530; HPLC(Chiralpak IC, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R= 9.554min (major), 13.786min (minor); [α] D 25 = -132.0 ( c 0.05, CH2Cl2, 96% of ).

[0094] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1q), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.2Hz, 2H), 6.69 – 6.52 (m, 2H), 5.83 (ddd, J = 17.3, 10.6, 5.4 Hz, 1H), 5.32 –5.12 (m, 2H), 4.52 (d, J = 9.1 Hz, 1H), 4.23 – 3.96 (m, 1H), 3.96 – 3.73 (m,4H), 3.22 (t, J = 8.4 Hz, 1H), 2.17 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 197.7,146.9, 137.1, 136.8, 134.5 (q, J = 32.4 Hz), 130.2, 130.0(2C), 129.4(2C),125.5 (q, J = 3.6 Hz)(2C), 123.6 (q, J = 272.9 Hz), 118.1(2C), 116.1, 74.9,64.5, 60.9, 56.3, 50.7, 20.5; 19 F NMR (376 MHz, CDCl3) δ -63.27; HRMS (ESI-TOF, m / z): calcd for C 22 H 21 N2OF3Na [M + Na] +: 409.1498, found: 409.1495; HPLC(Chiralpak IC, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 7.624min (major), 14.732min (minor); [α] D 25 = -84.0 ( c 0.05, CH2Cl2, 98% of ).

[0095] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1r), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.19 – 7.76 (m, 1H), 7.48 (dd, J = 4.9, 1.3 Hz, 1H), 7.01 – 6.90 (m,3H), 6.67 (d, J = 8.4 Hz, 2H), 5.80 (ddd, J = 17.2, 10.6, 5.0 Hz, 1H), 5.30 –5.03 (m, 2H), 4.52 (d, J = 9.1 Hz, 1H), 4.00 (d, J = 13.7 Hz, 1H), 3.92 –3.63 (m, 4H), 3.15 (t, J = 8.4 Hz, 1H), 2.19 (s, 3H); 13 C NMR (100 MHz, CDCl3)δ 190.6, 147.0, 137.3, 137.1, 134.8, 134.2, 130.0(2C), 129.8, 127.6, 117.7(2C), 116.0, 74.1, 64.4, 59.8, 56.6, 50.7, 20.5; HRMS (ESI-TOF, m / z): calcdfor C 19 H 20 N2OSNa [M + Na] + : 347.1189, found: 347.1185; HPLC (Chiralpak IC, n-hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 9.634 min (major),12.562 min (minor); [α] D 25 = -77.0 ( c 0.05, CH2Cl2, 95% of ).

[0096] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1s), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.0 Hz, 3H), 7.13 – 7.03 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 8.1 Hz, 2H), 5.74 (ddd, J = 16.6, 10.6, 5.4 Hz, 1H), 5.24 –4.99 (m, 4H), 4.40 (d, J = 9.0 Hz, 1H), 4.00 – 3.70 (m, 4H), 3.60 (t, J = 8.7Hz, 1H), 3.10 (t, J = 8.4 Hz, 1H), 2.25 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ170.0, 146.9, 137.0, 135.4, 129.9(2C), 129.7, 128.5(2C), 128.3(3C), 117.5(2C), 115.9, 68.7, 67.0, 64.3, 61.0, 54.6, 51.3, 20.5; HRMS (ESI-TOF, m / z):calcd for C 22 H 24 N₂O₂Na [M + Na] + : 376.1672, found: 376.1670; HPLC (ChiralpakIG, n-hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 7.624 min (major),9.682 min (minor); [α] D 25 = -155.0 ( c 0.05, CH2Cl2, 91% of ).

[0097] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (1t), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.0 Hz, 3H), 7.11 – 7.00(m, 2H), 6.79 (d, J = 8.0 Hz, 2H), 6.51 (d, J = 8.1 Hz, 2H), 5.78(ddd, J = 16.6, 10.6, 5.4 Hz, 1H), 5.22 –4.97 (m, 4H), 4.34 (d, J = 9.0 Hz, 1H), 3.94– 3.65 (m 4H), 3.67 (s, 3H), 3.55(t, J = 8.6 Hz, 1H), 3.10 (t, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ172.6, 147.7, 138.5, 135.8, 128.9(2C), 129.4, 127.7(2C), 126.7, 125.3(2C),115.5(2C), 113.9, 68.7, 67.0, 64.3, 61.0, 55.3, 54.6, 51.3; HRMS (ESI-TOF, m / z): calcd for C 22 H 24 N₂O₃Na [M + Na] + : 387.1679, found: 387.1670; HPLC(Chiralpak IG, n-hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 9.644min (major), 14.699min (minor); [α] D 25 = -109.0 ( c 0.05, CH2Cl2, 92% of ).

[0098] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (4), white solid. 1 H NMR of (400 MHz, CDCl3) δ 7.08 – 6.81 (m, 2H), 6.74 – 6.63 (m, 2H), 6.01 (ddd, J = 16.4, 10.1,6.2 Hz, 1H), 5.42 – 4.94 (m, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.55– 3.41 (m5H), 3.10 (t, J = 8.4 Hz, 1H) 2.33 (d, J = 1.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.4, 145.5, 140.3(2C), 133.7, 130.8(2C), 119.4, 118.1, 64.9, 60.7,54.7, 52.1, 50.0, 20.8; HRMS (ESI-TOF, m / z): calcd for C 15 H 18 N₂O₂Na [M + Na] + :281.1260, found: 281.1263; HPLC (Chiralpak AD, n -hexane / isopropanol = 70 / 30,1.0 mL / min, 254 nm) t R = 15.249 min (major), 21.112 min (minor); [α] D 25 = -69( c 0.10, CH2Cl2, 93% of ).

[0099] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (5), white solid. 1 H NMR (400 MHz, CDCl3) δ 8.26 – 7.81 (m, 2H), 7.74 – 7.26 (m, 3H), 6.08 (ddd, J = 16.5, 10.3,6.1 Hz, 1H), 5.35 – 4.90 (m, 2H), 4.01 (d, J = 11.4 Hz, 1H), 3.66– 3.40 (m5H), 3.10 (t, J = 8.4 Hz, 1H), 1.43 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 189.0,141.4, 140.7, 132.5, 129.4(2C), 128.2(2C), 118.6, 67.4, 64.2, 62.8, 62.3,40.8; HRMS (ESI-TOF, m / z): calcd for C 14 H 16 N2ONa [M + Na] + : 251.1155, found:251.1158; HPLC (Chiralpak AD, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254nm) t R = 12.559 min (major), 17.873 min (minor); [α] D 25 = +133 ( c 0.10, CH2Cl2, 95% of ).

[0100] ( R )-1,4-diazabicyclo[3.1.1]heptane derivative (6), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.97 – 6.99 (m, 5H), 5.88 (ddd, J= 16.5, 10.2, 6.1 Hz, 1H), 5.29 –4.71 (m, 4H), 4.40 (d, J = 9.0 Hz, 1H), 3.94– 3.65 (m 4H), 3.55 (t, J = 8.6Hz, 1H), 3.10 (t, J = 8.4 Hz, 1H), 1.77 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ173.3, 140.7, 135.4, 128.3(2C), 128.2(2C), 128.0, 118.6, 68.8, 67.3, 64.1,61.0, 54.6, 51.4; HRMS (ESI-TOF, m / z): calcd for C 15 H 18 N₂O₂Na [M + Na] + :281.1260, found: 281.1264. HPLC (Chiralpak AD, n -hexane / isopropanol = 70 / 30,1.0 mL / min, 254 nm) t R = 11.577 min (major), 15.866 min (minor); [α] D 25 = +11( c 0.10, CH2Cl2, 92% of ).

[0101] Homologue of Pyrazinamide (7), white solid. 1 H NMR (400 MHz, CDCl3) δ 6.06 – 5.78(m, 3H), 5.31 – 4.76 (m, 2H), 3.85 (d, J = 11.2 Hz, 2H), 3.55 (d, J = 11.2Hz, 2H), 3.39 – 2.58 (m, 3H), 1.77(s, 1H); 13C NMR (100 MHz, CDCl3) δ 173.8,140.7, 118.6, 64.6, 62.3, 58.5, 56,5, 43.6. HRMS (ESI-TOF, m / z): calcd forC8H 13 N3ONa [M + Na] + : 190.0951, found: 190.0956; HPLC (Chiralpak AD, n -hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm) t R = 14.897 min (major), 19.753 min(minor); [α] D 25 = +133 ( c 0.10, CH2Cl2, 92% of ).

[0102] Furthermore, it should be understood that after reading the above description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A chiral 1,4-diazabicyclo[3.1.1]heptane derivative, characterized in that, It has the structure shown in Equation 1: ； R 1 Selected from: hydrogen; hydroxyl; amino; substituted or unsubstituted C1-C20 alkyl; substituted or unsubstituted C1-C20 alkoxy; C1-C20 alkylamino; C1-C20 alkylthio; substituted or unsubstituted C6-C20 aryl; substituted or unsubstituted C3-C20 heteroaryl; 3- to 10-membered saturated or unsaturated heterocyclic groups having 1 to 4 heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur atoms; R 2 Selected from: hydrogen; substituted or unsubstituted C1-C20 alkyl; substituted or unsubstituted C1-C20 alkoxy; C1-C20 alkylamino; C1-C20 alkylthio; substituted or unsubstituted C6-C20 aryl; substituted or unsubstituted C3-C20 heteroaryl; 3- to 10-membered saturated or unsaturated heterocyclic groups having 1 to 4 heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur atoms; acyl; ester; sulfonyl; R 1 R 2 Substitution in this context refers to the arbitrary substitution of one or more hydrogen atoms on a group by the following substituents: halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, hydroxy, and phenyl.

2. The chiral 1,4-diazabicyclo[[] according to claim 1] 3.1.1] A method for synthesizing heptane derivatives, characterized in that, include: Using compound 2 as a starting material and compound 3 as a ternary synthon, under the catalysis of Lewis acid and chiral iridium complex, a solvent and a base were added to undergo a cycloaddition reaction to generate a chiral 1,4-diazabicyclo[3.1.1]heptane derivative; ； ； X is selected from: alkoxycarbonyl-OC(O)R 3 ; Acyl-C(O)R 4 Dialkylphosphoryl-P(O)(OR) 5 )2; R 3 R 4 R 5 Each group is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, substituted or unsubstituted C6-C20 aryl groups, wherein substitution refers to one or more hydrogen atoms on the group being substituted by any of the following substituents: halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, hydroxy, phenyl.

3. The synthesis method according to claim 2, wherein the Lewis acid comprises one or more of gallium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, indium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, europium trifluoromethanesulfonate, erbium trifluoromethanesulfonate, dysprosium trifluoromethanesulfonate, boron trifluoride ether, copper trifluoromethanesulfonate, silver trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, zinc trifluoromethanesulfonate, zinc bromide, and bismuth trifluoromethanesulfonate; The chiral iridium complex includes one or more of [Ir]-A, [Ir]-B, [Ir]-C, [Ir]-D, [Ir]-E, [Ir]-F, [Ir]-G, [Ir]-H, and [Ir]-I: ， Where: Ph represents phenyl; OTf represents trifluoromethanesulfonate group; ( R a )-BINOL represents 1,1'-bi-2-naphthol in the R configuration; R a )-8 H -BINOL represents the R configuration of 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol; 1-naphth represents 1-naphthyl; 2-OMePh represents 2-methoxyphenyl; 4-OMePh represents 4-methoxyphenyl; ( R a )-SPINOL represents the R-configuration of spirocyclic diol; The solvent includes one or more of tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, diethyl ether, dichloromethane, toluene, and acetonitrile. The base includes one or more of N,N-diisopropylethylamine, triethylamine, 1,4-diazabicyclo[2.2.2]octane, potassium carbonate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino, lithium n-butyllithium, cesium carbonate, 2,6-dimethylpyridine, sodium carbonate, and sodium bicarbonate.

4. The synthesis method according to claim 2, characterized in that, The molar ratio of compound 2 to compound 3 is (5:1) to (1:5); The molar ratio of compound 3 to the Lewis acid is (1:0.01) to (1:0.5); The molar ratio of compound 3 to the chiral iridium complex is (1:0.01) to (1:0.5); The molar ratio of compound 3 to the base is (5:1) to (1:5).

5. The synthesis method according to claim 2, characterized in that, The cycloaddition reaction temperature is -10~50℃; The cycloaddition reaction takes 2 to 24 hours.

6. The application of the chiral 1,4-diazabicyclo[3.1.1]heptane derivative according to claim 1 in the preparation of antibacterial agents.

7. The application according to claim 6, characterized in that, The antibacterial agent targets Mycobacterium tuberculosis.

8. An antibacterial agent, characterized in that, Contains an effective amount of the chiral 1,4-diazabicyclo[3.1.1]heptane derivative of claim 1.

9. The chiral 1,4-diazabicyclo[[] according to claim 1] 3.1.1] The use of heptane derivatives in the preparation of drugs for the treatment and / or prevention of Mycobacterium tuberculosis infection.

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