TRICYCLIC COMPOUND, AND PREPARATION METHOD THEREFOR AND MEDICAL USE THEREOF

Abstract

Disclosed are a tricyclic compound as represented by general formula (I), a pharmaceutical composition containing same, and a preparation method therefor and the medical use thereof. The compound can be used for preventing and treating a variety of diseases caused by toxic aldehydes.

##STR00001##

Claims

1. A compound of formula (I): ##STR00037## or a mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: A.sup.1 is selected from the group consisting of N and CR.sup.1; A.sup.2 is selected from the group consisting of N and CR.sup.2; ring A is selected from the group consisting of ##STR00038##  refers to the site attached to the phenyl moiety; R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R.sup.a, —O(O)CR.sup.a, —C(O)OR.sup.a, —C(O)NR.sup.aR.sup.b, —NHC(O)R.sup.a, —S(O).sub.mR.sup.a, —S(O).sub.mNR.sup.aR.sup.b and —NHS(O).sub.mR.sup.a; R.sup.3 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R.sup.a, —O(O)CR.sup.a, —C(O)OR.sup.a, —C(O)NR.sup.aR.sup.b, —NHC(O)R.sup.a, —S(O).sub.mR.sup.a, —S(O).sub.mNR.sup.aR.sup.b and —NHS(O).sub.mR.sup.a; X and Y are each independently selected from the group consisting of O and NR.sup.4; R.sup.4 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R.sup.a, —O(O)CR.sup.a, —C(O)OR.sup.a, —C(O)NR.sup.aR.sup.b, —NHC(O)R.sup.a, —S(O).sub.mR.sup.a, —S(O).sub.mNR.sup.aR.sup.b and —NHS(O).sub.mR.sup.a; R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester group, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or, R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester group, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sup.a and R.sup.b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester group, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or, R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl, wherein the nitrogen-containing heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is an integer from 0 to 2.

2. The compound of formula (I) according to claim 1, wherein: A.sup.1 is selected from CR.sup.1; and A.sup.2 is selected from the group consisting of N and CR.sup.2; R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and 5- to 6-membered heterocyclyl, and preferably hydrogen and C.sub.1-C.sub.6 alkyl.

3. The compound of formula (I) according to claim 1, wherein, ring A is selected from the group consisting of ##STR00039## R.sup.3 is selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkyl, 5- to 6-membered heterocyclyl, C.sub.6-C.sub.10 aryl and 5- to 10-membered heteroaryl, and preferably hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl and 5- to 6-membered heterocyclyl; R.sup.4 is selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkyl, 5- to 6-membered heterocyclyl, C.sub.6-C.sub.10 aryl and 5- to 10-membered heteroaryl, and preferably hydrogen, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 haloalkyl.

4. The compound of formula (I) according to claim 1, wherein, R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, thiol, C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl, and preferably hydroxy, thiol and C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally further substituted by one or more substituents selected from halogen; or, R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a C.sub.3-C.sub.6 cycloalkyl, wherein the C.sub.3-C.sub.6 cycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, thiol and C.sub.1-C.sub.6 alkyl.

5. The compound of formula (I) according to claim 1, wherein the compound is selected from the group consisting of: ##STR00040##

6. A method for preparing the compound of formula (I) according to claim 1, comprising the following step of: ##STR00041## reacting compound Ig with an alkyl Grignard reagent to obtain the compound of formula (I), wherein the alkyl Grignard reagent is preferably methylmagnesium chloride or methylmagnesium bromide; wherein A.sup.1, A.sup.2, ring A, R.sup.5 and R.sup.6 are as defined in claim 1.

7. A pharmaceutical composition comprising the compound of formula (I) according to claim 1 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. Use of the compound of formula (I) according to claim 1 in the preparation of a toxic aldehyde capture agent.

9. Use of the compound of formula (I) according to claim 1 in the preparation of medicaments for the prevention and/or treatment of diseases related to active carbonyl compound.

Description

DESCRIPTION OF THE DRAWINGS

[0104] FIG. 1 is a time-varying diagram of the capture reaction of the compounds of some examples of the present invention to nonenal.

[0105] FIG. 2 is a graph showing the results of the treatment score of the compound of Example 4 of the present invention in the C48/80-induced Wistar rat allergic conjunctivitis animal model.

DETAILED DESCRIPTION OF THE INVENTION

[0106] The compounds of the present invention and their preparation are further illustrated with reference to the following examples. These examples illustrate some methods for preparing or using said compounds. However, it should be understood that these examples are not intended to limit the scope of the present invention. Variations of the present invention now known or to be further developed are considered to fall within the scope of the present invention described and claimed herein.

[0107] The compound of the present invention is prepared by using convenient starting materials and general preparation procedures. The present invention provides typical or preferential reaction conditions, such as reaction temperature, duration, solvent, pressure and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. Optimal conditions may vary with the use of specific reactants or solvents, but under normal circumstances, reaction optimization steps and conditions can be determined.

[0108] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions. The protecting groups suitable for various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, “Protective Groups in Organic Synthesis” by T. W. Greene and G. M. Wuts (3rd edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protective groups.

[0109] The separation and purification of compounds and intermediates are carried out by appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high performance liquid chromatography or a combination of the above methods. The examples described in the present invention can be referred for the specific method of use. Of course, other similar separation and purification methods can also be used. They can be characterized using conventional methods (including physical constants and spectral data).

[0110] The structures of the compounds are identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (6) are given in 10.sup.−6 (ppm). NMR is determined by a Brukerdps300 machine. The solvents for determination are deuterated-dimethyl sulfoxide (DMSO-d.sub.6), deuterated-chloroform (CDCl.sub.3) and deuterated-methanol (CD.sub.3OD), and the internal standard is tetramethylsilane (TMS).

[0111] MS is determined by a LC(Waters 2695)/MS(Quattro Premier xE) mass spectrograph (manufacturer: Waters) (Photodiode Array Detector).

[0112] Preparative liquid chromatography is conducted on a 1c6000 high performance liquid chromatograph (manufacturer: Beijing Chuangxintongheng science and Technology Co., Ltd.).

[0113] Qingdao Haiyang Chemical GF254 silica gel plate is used for the thin-layer silica gel chromatography (TLC). The dimension of the silica gel plate used in TLC is 0.20 mm to 0.25 mm, and the dimension of the silica gel plate used in product purification (Prep-TLC) is 0.5 mm.

[0114] Qingdao Haiyang Chemical 100 to 200 mesh, 200 to 300 mesh and 300 to 400 mesh silica gel is generally used as a carrier for column chromatography.

[0115] The known starting materials of the present invention can be prepared by the known methods in the art, or can be purchased from Wanghua Mall, Beijing Ouhe Technology, Sigma, J&K Scientific, Yishiming, Shanghai Shuya Chemical, Innochem Science & Technology, Energy Chemical, Shanghai Bide Pharmatech and the like.

[0116] Unless otherwise stated, the reactions are carried out under a nitrogen atmosphere.

[0117] Argon atmosphere or nitrogen atmosphere means that a reaction flask is equipped with an argon or nitrogen balloon (about 1 L).

[0118] The reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, which includes for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, N-methylpyrrolidone (NMP), pyridine and the like. Unless otherwise specified in the examples, a solution means an aqueous solution.

[0119] The chemical reaction described in the present invention is generally carried out under normal pressure. The reaction temperature is between −78° C. and 200° C. The reaction duration and condition are, for example, between −78° C. and 200° C. under one atmospheric pressure, and completed within about 1 to 24 hours. If the reaction is conducted overnight, then the reaction duration is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20° C. to 30° C.

[0120] The progress of the reaction in the examples is monitored by thin layer chromatography (TLC). The developing systems used in the reactions include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone. The volume ratio of the solvent is adjusted depending on the polarity of the compound.

[0121] The eluent systems of column chromatography and the developing systems of TLC for the purification of the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or trifluoroacetic acid may be added for adjustment.

[0122] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the content described herein can be applied to the method of the present invention.

[0123] Abbreviations

[0124] NMR=nuclear magnetic resonance

[0125] Boc=tert-butoxycarbonyl

[0126] DIEA=diisopropylethylamine

[0127] DMF=N,N-dimethylformamide

[0128] DMSO=dimethyl sulfoxide

[0129] DCM=dichloromethane

[0130] EA=ethyl acetate

[0131] HPLC=high performance liquid chromatography

[0132] LC-MS=liquid chromatography-mass spectrometry

[0133] tol.=toluene

[0134] PE=petroleum ether

[0135] TBAF=tetrabutylammonium fluoride

[0136] TCDI=N,N′-thiocarbonyldiimidazole

[0137] THF=tetrahydrofuran

[0138] TMS=trimethylsilyl

[0139] TMSOTf=trimethylsilyl trifluoromethanesulfonic acid.

Example 1: Preparation of 2-(7-amino-[1,3]dioxolo[4,5-g]quinolin-6-yl)propan-2-ol (1)

[0140] ##STR00024##

Step 1: Preparation of 6-aminobenzo[d][1,3]dioxole-5-carbaldehyde (1a)

[0141] Iron powder (1.58 g, 28.2 mmol), ammonium chloride (200 mg, 3.60 mmol) were dissolved in a mixed solvent of ethanol (20 ml) and water (2 mL) at room temperature, followed by the addition of 6-nitrobenzo[d][1,3]dioxole-5-carbaldehyde (1.00 g, 5.13 mmol). The reaction solution was warmed up to 78° C., and stirred under reflux for 20 hours. The organic phase was extracted with 100 mL of ethyl acetate and 100 mL of water, and the aqueous phase was extracted once with 30 mL of ethyl acetate. The organic phases were combined, washed once with saturated sodium bicarbonate solution, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=10:1 to 4:1) to obtain 380 mg of the title compound as a yellow solid, yield: 44.9%.

[0142] LC-MS: m/z 165 [M+H].sup.+.

Step 2: Preparation of 1-(3-methoxy-2,3-dioxopropyl)pyridine-1-ammonium bromide (1b)

[0143] Pyridine (178 mg, 2.26 mmol) was dissolved in ethanol (10 mL) at room temperature, and then ethyl 3-bromo-2-oxopropanoate (400 mg, 2.05 mmol) was slowly added dropwise under a nitrogen atmosphere. The reaction solution was stirred at 65° C. for 2 hours, and used directly in the next step.

Step 3: Preparation of 1-(6-(ethoxycarbonyl)-[1,3]dioxolo[4,5-g]quinolin-7-yl)pyridine-1-ammonium bromide (1c)

[0144] The reaction solution of Step 2 was cooled to 18 to 22° C., to which 6-aminobenzo[d][1,3]dioxole-5-carbaldehyde (1a) (304 mg, 1.85 mmol) was added. The reaction solution was warmed up to 80° C. and stirred for 18 hours, which was used directly in the next step.

Step 4: Preparation of ethyl 7-amino-[1,3]dioxolo[4,5-g]quinoline-6-carboxylate (1d)

[0145] The reaction solution of Step 3 was cooled to 70° C., followed by the addition of morpholine (446 mg, 5.14 mmol). The mixture was stirred at 80° C. for 16 hours. The reaction solution was extracted with 50 mL of water and 50 mL of ethyl acetate, and the aqueous phase was extracted once with 20 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=8:1 to 2:1) to obtain 240 mg of the title compound as a yellow solid, yield: 45.0%.

[0146] LC-MS: m/z 260[M+H].sup.+.

Step 5: Preparation of 2-(7-amino-[1,3]dioxolo[4,5-g]quinolin-6-ylpropan-2-ol (1)

[0147] Ethyl 7-amino-[1,3]dioxolo[4,5-g]quinoline-6-carboxylate (1d) (190 mg, 0.730 mmol) was dissolved in tetrahydrofuran (19 mL) at room temperature. The solution was cooled to 0° C., to which methylmagnesium chloride (1.50 mL, 4.80 mmol) was slowly added dropwise under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 16 hours, and the reaction was quenched with water (10 mL). The reaction solution was extracted with water (30 mL) and ethyl acetate (30 mL), and the aqueous phase was extracted once with 20 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Daisogei 30 mm×250 mm, C18, 10 um, 100 Å, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-80%) to obtain 23 mg of the compound as a white solid. The compound was dissolved in 50 mL of ethyl acetate, and the pH was adjusted to about 10 to 11 with 10% aqueous ammonia solution. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 15 mg of the title compound as a yellow solid, yield: 8.34%.

[0148] LC-MS: m/z 247.28 [M+H].sup.+.

[0149] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.13 (s, 1H), 7.06 (s, 1H), 6.99 (s, 1H), 6.06 (s, 2H), 5.62 (s, 2H), 5.60 (s, 1H), 1.57 (s, 6H).

Example 2: Preparation of 2-(7-amino-2-methyloxazolo[5,4-g]quinolin-6-yl)propan-2-ol (2)

[0150] ##STR00025## ##STR00026##

Step 1: Preparation of 3-methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (2a)

[0151] 4-Amino-3-methoxybenzoic acid (5.00 g, 29.9 mmol) was dissolved in ethyl acetate (200 mL) at room temperature, to which a mixed solution of trifluoroacetic anhydride (5 mL, 35.9 mmol) and ethyl acetate (50 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residues were dissolved in ethyl acetate, and concentrated twice under reduced pressure to obtain 9.00 g of the crude title compound as a grey solid, which was used directly in the next step without purification.

Step 2: Preparation of 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid (2b)

[0152] 3-Methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (2a) (9.00 g, 34.2 mmol) was dissolved in concentrated sulfuric acid (96 mL) at room temperature, and the solution was cooled in an ice bath under stirring. A mixed solution of concentrated nitric acid (3.30 g) and concentrated sulfuric acid (24 mL) was added dropwise under cooling, and the temperature was kept below 10° C. After completion of the addition, the mixture was further stirred for 10 minutes. The reaction solution was added dropwise into ice water and filtered. The filter cake was rinsed with 200 mL of water, and dried under reduced pressure to obtain 7.20 g of the title compound as a light brown solid, yield: 68.3%.

Step 3: Preparation of 4-amino-5-hydroxy-2-nitrobenzoic acid (2c)

[0153] 5-Methoxy-2-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid (2b) (7.00 g, 22.7 mmol) was dissolved in 20% sodium hydroxide solution (50 mL) at room temperature, and the reaction solution was stirred under a nitrogen atmosphere at 100° C. for 16 hours. The reaction solution was cooled to room temperature, to which concentrated hydrochloric acid (21 mL) was added dropwise under ice bath cooling. The reaction solution was concentrated under reduced pressure, to which anhydrous ethanol (420 mL) was added. The solution was stirred for 0.5 hour and filtered. The filtrate was concentrated under reduced pressure to obtain 7.20 g of the crude title compound as a brown solid, which was used directly in the next step without purification.

Step 4: Preparation of methyl 4-amino-5-hydroxy-2-nitrobenzoate (2d)

[0154] 4-Amino-5-hydroxy-2-nitrobenzoic acid (2c) (7.20 g, 36.4 mmol) was dissolved in MeOH (477 mL) at room temperature, to which dioxane in hydrochloric acid (161 mL) was added and stirred at 64° C. for 16 hours. The reaction solution was concentrated under reduced pressure to obtain 6.80 g of the crude title compound as a black oily solid, which was used directly in the next step without purification.

Step 5: Preparation of methyl 2-methyl-5-nitrobenzo[d]oxazole-6-carboxylate (2e)

[0155] Methyl 4-amino-5-hydroxy-2-nitrobenzoate (2d) (5.00 g, 23.6 mmol) was dissolved in triethyl orthoacetate (25 mL) at room temperature, and the solution was stirred at room temperature for 16 hours followed by concentrating under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=10:1 to 3:1) to obtain 1.50 g of the title compound as a light yellow solid, yield: 27.0%.

Step 6: Preparation of methyl 5-amino-2-methylbenzo[d]oxazole-6-carboxylate (2f)

[0156] Methyl 2-methyl-5-nitrobenzo[d]oxazole-6-carboxylate (2e) (1.30 g, 5.51 mmol) was dissolved in MeOH (93 mL) at room temperature. Pd/C (195 mg) was added, and the reaction solution was stirred under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=10:1 to 3:1) to obtain 900 mg of the title compound as a light yellow solid, yield: 79.3%.

Step 7: Preparation of (5-amino-2-methylbenzo[d]oxazol-6-yl)methanol (2g)

[0157] Methyl 5-amino-2-methylbenzo[d]oxazole-6-carboxylate (2f) (800 mg, 3.88 mmol) was dissolved in THF (70 mL) at room temperature. Lithium aluminum hydride (5.84 mL) was added dropwise under a nitrogen atmosphere at 0° C., and the reaction solution was stirred for 30 minutes. 10 mL of water was added to the reaction solution to quench the reaction. The reaction solution was extracted with ethyl acetate (80 mL), and the organic phase was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 350 mg of the title compound as a dark yellow solid, yield: 50.7%.

Step 8: Preparation of 5-amino-2-methylbenzo[d]oxazole-6-carbaldehyde (2h)

[0158] (5-Amino-2-methylbenzo[d]oxazol-6-yl)methanol (2g) (340 mg, 1.91 mmol) was dissolved in DCM (10 mL) at room temperature. Manganese dioxide (3.32 g, 38.2 mmol) was added, and the reaction solution was stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 200 mg of the title compound as a dark yellow solid, yield: 59.5%.

Step 9: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridine-1-ammonium bromide (1b)

[0159] Pyridine (110 mg, 14.0 mmol) was dissolved in EtOH (10 mL) at room temperature, and then ethyl 3-bromo-2-oxopropanoate (246 mg, 1.26 mmol) was added under a nitrogen atmosphere. The reaction solution was stirred at 65° C. for 2 hours, which was used directly in the next step.

Step 10: Preparation of 1-((6-methoxycarbonyl)-2-methyloxazolo[5,4-g]quinolin-7-yl)pyridin-1-ammonium bromide (2i)

[0160] The reaction solution of Step 9 was cooled to 18 to 22° C., followed by the addition of 5-amino-2-methylbenzo[d]oxazole-6-carbaldehyde (2h) (200 mg, 1.14 mmol) and pyridine (230 mg, 2.91 mmol). The reaction solution was stirred under a nitrogen atmosphere at 80° C. for 9 hours, which was used directly in the next step.

Step 11: Preparation of ethyl 7-amino-2-methyloxazolo[5,4-g]quinoline-6-carboxylate (2j)

[0161] The reaction solution of Step 10 was cooled to 70° C., followed by the addition of morpholine (275 mg, 3.16 mmol). The reaction solution was warmed up to 80° C., and stirring under a nitrogen atmosphere at 80° C. for 4 hours. 50 mL of water was added to the reaction solution, and extracted with 50 mL of dichloromethane. The aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/ethyl acetate=10:1 to 2:1) to obtain 80 mg of the title compound as a brown yellow solid, yield: 23.4%.

Step 12: Preparation of 2-(7-amino-2-methyloxazolo[5,4-g]quinolin-6-yl)propan-2-ol (2)

[0162] Methylmagnesium chloride (3N, 0.57 mL, 1.70 mmol) was added dropwise to THF (6 mL) under a nitrogen atmosphere at 0° C. Ethyl 7-amino-2-methyloxazolo[5,4-g]quinoline-6-carboxylate (2j) (70.0 mg, 0.258 mmol) dissolved in THF (4 mL) was added, and the reaction solution was stirred at room temperature for 30 minutes. 5 mL of water was added to quench the reaction. 15 mL of water was added to the reaction solution, and extracted with 20 mL of ethyl acetate. The aqueous phase was extracted twice with 15 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Daisogei 30 mm×250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile/water, gradient: 10%-60%) to obtain 8.00 mg of the title compound as a light yellow solid, yield: 12.1%.

[0163] LC-MS: m/z 258.25 [M+H].sup.+.

[0164] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.89 (s, 1H), 7.73 (s, 1H), 7.31 (s, 1H), 5.92 (s, 2H), 5.75 (s, 1H), 2.51 (s, 3H), 1.62 (s, 6H).

Example 3: Preparation of 2-(7-amino-2-morpholinooxazolo[5,4-g]quinolin-6-yl)propan-2-ol (3)

[0165] ##STR00027## ##STR00028##

Step 1: Preparation of 3-methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (3a)

[0166] 4-Amino-3-methoxybenzoic acid (5.00 g, 29.9 mmol) was dissolved in ethyl acetate (200 mL) at room temperature, to which a mixed solution of trifluoroacetic anhydride (5 mL, 35.9 mmol) and ethyl acetate (50 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residues were dissolved in ethyl acetate, and concentrated twice under reduced pressure to obtain 9.00 g of the crude title compound as a grey solid, which was used directly in the next step without purification.

Step 2: Preparation of 5-methoxy-2-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid (3b)

[0167] 3-Methoxy-4-(2,2,2-trifluoroacetamido)benzoic acid (3a) (9.00 g, 34.2 mmol) was dissolved in concentrated sulfuric acid (96 mL) at room temperature, and the solution was cooled in an ice bath under stirring. A mixed solution of concentrated nitric acid (3.30 g) and concentrated sulfuric acid (24 mL) was added dropwise under cooling with keeping the temperature below 10° C. After completion of the addition, the mixture was further stirred for 10 minutes. The reaction solution was added dropwise into ice water and filtered. The filter cake was rinsed with 200 mL of water, and dried under reduced pressure to obtain 7.20 g of the title compound as a light brown solid, yield: 68.3%.

Step 3: Preparation of 4-amino-5-hydroxy-2-nitrobenzoic acid (3c)

[0168] 5-Methoxy-2-nitro-4-(2,2,2-trifluoroacetamido)benzoic acid (3b) (7.00 g, 22.7 mmol) was dissolved in 20% sodium hydroxide solution (50 mL) at room temperature, and the reaction solution was stirred under a nitrogen atmosphere at 100° C. for 16 hours. The reaction solution was cooled to room temperature, to which concentrated hydrochloric acid (21 mL) was added dropwise under ice bath cooling. The reaction solution was concentrated under reduced pressure, to which anhydrous ethanol (420 mL) was added. The solution was stirred for 0.5 hour and filtered. The filtrate was concentrated under reduced pressure to obtain 7.20 g of the crude title compound as a brown solid, which was used directly in the next step without purification.

Step 4: Preparation of methyl 4-amino-5-hydroxy-2-nitrobenzoate (3d)

[0169] 4-Amino-5-hydroxy-2-nitrobenzoic acid (3c) (7.20 g, 36.4 mmol) was dissolved in MeOH (477 mL) at room temperature, to which dioxane in hydrochloric acid (161 mL) was added and stirred at 64° C. for 24 hours. The reaction solution was concentrated under reduced pressure to obtain 6.20 g of the crude title compound as a black oily solid, which was used directly in the next step without purification.

Step 5: Preparation of methyl 5-nitro-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxylate (3e)

[0170] Methyl 4-amino-5-hydroxy-2-nitrobenzoate (3d) (6.20 g, 29.2 mmol) was dissolved in ethanol (75 mL) at room temperature, to which carbon disulfide (24 mL) and potassium hydroxide (1.97 g, 35.1 mmol) were added. The reaction solution was stirred at 80° C. for 16 hours, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=10:1 to 3:1) to obtain 9.00 g of the crude title compound as a brown black solid, which was used directly in the next step without purification.

Step 6: Preparation of methyl 2-morpholino-5-nitrobenzo[d]oxazole-6-carboxylate (3f)

[0171] Methyl 5-nitro-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxylate (3e) (9.00 g, 35.4 mmol) was dissolved in DMF (150 mL) at room temperature, to which morpholine (6.17 g, 70.9 mmol) and DIEA (9.21 g, 70.9 mmol) were added. The reaction solution was stirred at 80° C. for 0.5 hour, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=10:1 to 1:1) to obtain 600 mg of the title compound as a light yellow solid, yield: 5.52%.

Step 7: Preparation of methyl 5-amino-2-morpholino-benzo[d]oxazole-6-carboxylate (3g)

[0172] Methyl 2-morpholino-5-nitrobenzo[d]oxazole-6-carboxylate (3f) (600 mg, 1.95 mmol) was dissolved in ethanol (20 mL) and water (2 mL) (ethanol: water=10:1) at room temperature, to which iron powder (602 mg, 10.8 mmol) and ammonium chloride (73.2 mg, 1.37 mmol) were added. The reaction solution was stirred at 78° C. for 4 hours, and extracted with 50 mL of ethyl acetate. The aqueous phase was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=10:1 to 1:1) to obtain 400 mg of the title compound as a light yellow solid, yield: 74.1%.

Step 8: Preparation of (5-amino-2-morpholino-benzo[d]oxazol-6-yl)methanol (3h)

[0173] Methyl 5-amino-2-morpholino-benzo[d]oxazole-6-carboxylate (3g) (800 mg, 3.88 mmol) was dissolved in THF (70 mL) at room temperature. LiAlH.sub.4 (5.84 mL) was added dropwise under a nitrogen atmosphere at 0° C., and the reaction solution was stirred for 30 minutes. 10 mL of water was added to the reaction solution to quench the reaction. The reaction solution was extracted with ethyl acetate (80 mL), and the organic phase was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 350 mg of the title compound as a dark yellow solid, yield: 50.7%.

Step 9: Preparation of 5-amino-2-morpholino-benzo[d]oxazole-6-carbaldehyde (3i)

[0174] (5-Amino-2-morpholino-benzo[d]oxazol-6-yl)methanol (3h) (340 mg, 1.91 mmol) was dissolved in DCM (10 mL) at room temperature. Manganese dioxide (3.32 g, 38.2 mmol) was added, and the reaction solution was stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 200 mg of the title compound as a dark yellow solid, yield: 59.5%.

Step 10: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridine-1-ammonium bromide (1b)

[0175] Pyridine (110 mg, 14.0 mmol) was dissolved in EtOH (10 mL) at room temperature, and then ethyl 3-bromo-2-oxopropanoate (246 mg, 1.26 mmol) was added under a nitrogen atmosphere. The reaction solution was stirred at 65° C. for 2 hours, which was then used directly in the next step.

Step 11: Preparation of 1-(6-(ethoxycarbonyl)-2-morpholinooxazolo[5,4-g]quinoline-7-yl)pyridine-1-ammonium bromide (3j)

[0176] The reaction solution of Step 10 was cooled to 18 to 22° C., followed by the addition of 5-amino-2-morpholino-benzo[d]oxazole-6-carbaldehyde (3i) (249 mg, 1.01 mmol) and pyridine (183 mg, 2.32 mmol). The reaction solution was stirred under a nitrogen atmosphere at 80° C. for 9 hours, which was then used directly in the next step.

Step 12: Preparation of ethyl 7-amino-2-morpholinooxazolo[5,4-g]quinoline-6-carboxylate (3k)

[0177] The reaction solution of Step 11 was cooled to 70° C., followed by the addition of morpholine (487 mg, 5.60 mmol). The reaction solution was warmed up to 80° C., and stirring under a nitrogen atmosphere at 80° C. for 4 hours. 50 mL of water was added to the reaction solution which was then extracted with 50 mL of dichloromethane. The aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/ethyl acetate=10:1 to 2:1) to obtain 210 mg of the title compound as a brown yellow solid, yield: 27.4%.

Step 13: Preparation of 2-(7-amino-2-morpholinooxazolo[5,4-g]quinolin-6-yl)propan-2-ol (3)

[0178] Methylmagnesium chloride (3N, 0.97 mL, 2.92 mmol) was added dropwise to THF (10 mL) under a nitrogen atmosphere at 0° C. Ethyl 7-amino-2-morpholinooxazolo[5,4-g]quinoline-6-carboxylate (10k) (100 mg, 0.292 mmol) dissolved in THF (10 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. 5 mL of water was added to quench the reaction. 15 mL of water was added to the reaction solution, and extracted with 40 mL of dichloromethane. The aqueous phase was extracted with 30 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Daisogei 30 mm×250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile/water, gradient: 10%-50%) to obtain 8.00 mg of the title compound as a white solid, yield: 8.35%.

[0179] LC-MS: m/z 329.23 [M+H].sup.+.

[0180] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.52 (s, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 5.69 (s, 3H), 3.75˜ 3.72 (m, 4H), 3.65˜ 3.62 (m, 4H), 1.61 (s, 6H).

Example 4: Preparation of 2-(7-aminonaphtho[2,3-d][1,3]dioxol-6-yl)propan-2-ol (4)

[0181] ##STR00029##

Step 1: Preparation of 1,4,6,7-tetrabromonaphthalene-2,3-diol (4a)

[0182] Naphthalene-2,3-diol (3.00 g, 18.7 mmol) was added to acetic acid (30 mL) at room temperature, to which bromine (393 mg, 3.61 mmol) was added. The reaction solution was warmed up to 120° C. and stirred for 45 minutes. The reaction solution was cooled to room temperature, and poured into ice water. The solution was extracted with ethyl acetate, and concentrated under reduced pressure. The residues were recrystallized from acetic acid to obtain 6.00 g of the title compound as a yellow solid, yield: 67.0%.

[0183] LC-MS: m/z 475.2 [M+H].sup.+.

Step 2: Preparation of 6,7-dibromonaphthalene-2,3-diol (4b)

[0184] 1,4,6,7-Tetrabromonaphthalene-2,3-diol (4a) (500 mg, 1.10 mmol) was added to acetic acid (10 mL) at room temperature, followed by the addition of stannous chloride (2.00 g, 8.80 mmol). The reaction solution was warmed up to 120° C. and stirred for 45 minutes. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residues were recrystallized from toluene to obtain 300 mg of the crude title compound as a white solid, which was used directly in the next step without purification.

[0185] LC-MS: m/z 316.1 [M+H].sup.+.

Step 3: Preparation of 6,7-dibromonaphtho[2,3-d][1,3]dioxole (4c)

[0186] 6,7-Dibromonaphthalene-2,3-diol (4b) (160 mg, 0.500 mmol) and dibromomethane (175 mg, 1.01 mmol) were added to N,N-dimethylformamide (10 mL) at room temperature, to which cesium carbonate (50.0 mg, 0.185 mmol) was added. The reaction solution was warmed up to 100° C. and stirred for 50 minutes. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent: EA/PE=1:1) to obtain 20.0 mg of the title compound as a white solid, yield: 12.0%.

[0187] LC-MS: m/z 331 [M+H].sup.+.

Step 4: Preparation of N-(7-bromonaphtho[2,3-d][1,3]dioxol-6-yl)-1,1-diphenylmethanimine (4d)

[0188] 6,7-Dibromonaphtho[2,3-d][1,3]dioxole (4c) (30.0 mg, 0.0900 mmol), dibenzylidimide (16.0 mg, 0.0900 mmol), sodium tert-butoxide (35.0 mg, 0.360 mmol), tris(dibenzylideneacetone)dipalladium (8.30 mg, 0.00900 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (11.0 mg, 0.0190 mmol) were added to anhydrous toluene (10 mL) at room temperature. The system was heated to 100° C. under a nitrogen atmosphere and stirred for 1 hour. The reaction solution was cooled to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were extracted with ethyl acetate, and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent: PE/EA=1:5) to obtain 50.0 mg of the title compound as a light yellow oil, yield: 64.0%.

[0189] LC-MS: m/z 431.6 [M+H].sup.+.

Step 5: Preparation of methyl 7-((diphenylmethylene)amino)naphtho[2,3-d][1,3]dioxole-6-carboxylate (4e)

[0190] N-(7-Bromonaphtho[2,3-d][1,3]dioxol-6-yl)-1,1-diphenylmethanimine (4d) (50.0 mg, 0.120 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (8.50 mg, 0.0110 mmol) and triethylamine (47.0 mg, 0.470 mmol) were added to methanol (5 mL) at room temperature. The system was heated to 120° C. under a carbon monoxide atmosphere and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were extracted with ethyl acetate, and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent: PE/EA=1:2) to obtain 30.0 mg of the title compound as a light yellow oil, yield: 62.0%.

[0191] LC-MS: m/z 409.7 [M+H].sup.+.

Step 6: Preparation of methyl 7-aminonaphtho[2,3-d][1,3]dioxole-6-carboxylate (4f)

[0192] Methyl 7-((diphenylmethylene)amino)naphtho[2,3-d][1,3]dioxole-6-carboxylate (4e) (30.0 mg, 0.0700 mmol) was added to tetrahydrofuran (5 mL) and 3M hydrochloric acid (1 mL) at room temperature. The reaction system was stirred at room temperature for 16 hours, and concentrated under reduced pressure. The residues were extracted with ethyl acetate, and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent: PE/EA=2:1) to obtain 15.0 mg of the title compound as a light yellow oil, yield: 83.0%.

[0193] LC-MS: m/z 245.9 [M+H].sup.+.

Step 7: Preparation of 2-(7-aminonaphtho[2,3-d][1,3]dioxol-6-yl)propan-2-ol (4)

[0194] Methylmagnesium bromide (3 mol/L, 1.20 mL) was added to anhydrous tetrahydrofuran (10 mL) at room temperature. Methyl 7-aminonaphtho[2,3-d][1,3]dioxole-6-carboxylate (12f) (50 mg, 0.2 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise under a nitrogen atmosphere at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Gemini-C18 150×21.2 mm, 5 um, mobile phase: acetonitrile/water, gradient: 10%-90%) to obtain 49.0 mg of the title compound as a white solid, yield: 50.1%.

[0195] LC-MS: m/z 246.1 [M+H].sup.+.

[0196] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.48 (s, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 6.86 (s, 1H), 5.94 (s, 2H), 1.71 (s, 6H).

Example 5: Preparation of 2-(7-amino-3-methyl-3H-imidazo[4,5-g]quinolin-6-yl)propan-2-ol (5)

[0197] ##STR00030## ##STR00031##

Step 1: Preparation of methyl benzimidazole-5-carboxylate (5a)

[0198] Benzimidazole-5-carboxylic acid (5.00 g, 30.9 mmol) was dissolved in MeOH (30 mL), followed by the addition of HCl (30 mL, 4 N in dioxane) and stirring at 65° C. overnight. The reaction solution was concentrated under reduced pressure and used directly in the next step.

Step 2: Preparation of methyl 6-nitro-1H-benzo[d]imidazole-5-carboxylate (5b)

[0199] Concentrated sulfuric acid (100 mL) was added to concentrated nitric acid (100 mL) at 0° C., and methyl benzimidazole-5-carboxylate (5a) (5.00 g, 28.4 mmol) was added in batches. The reaction solution was stirring at room temperature overnight. The reaction solution was added dropwise to ice water and filtered. The filter cake was rinsed with 200 mL of water and dried under reduced pressure to obtain 5.00 g of the title compound as a yellow solid, yield: 79.6%.

Step 3: Preparation of methyl 1-methyl-6-nitro-1H-benzo[d]imidazole-5-carboxylate (5c)

[0200] Methyl 6-nitro-1H-benzo[d]imidazole-5-carboxylate (5b) (5.00 g, 22.6 mmol), iodomethane (3.53 g, 24.8 mmol) and potassium carbonate (9.37 g, 67.9 mmol) were dissolved in DMF (100 mL) at room temperature and stirred overnight. 100 mL of water was added to the reaction solution which was then extracted with 100 mL of ethyl acetate. The aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: ethyl acetate) to obtain 3.00 g of the title compound as a yellow solid, yield: 56.4%.

Step 4: Preparation of methyl 6-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (5d)

[0201] Methyl 1-methyl-6-nitro-1H-benzo[d]imidazole-5-carboxylate (5c) (1.50 g, 6.38 mmol) was dissolved in MeOH (100 mL) at room temperature. Pd/C (200 mg) was added, and the reaction solution was stirred under a hydrogen atmosphere for 48 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=40:1) to obtain 750 mg of the title compound as a yellow solid, yield: 57.3%.

Step 5: Preparation of (6-amino-1-methyl-1H-benzo[d]imidazol-5-yl)methanol (5e)

[0202] Methyl 6-amino-1-methyl-1H-benzo[d]imidazole-5-carboxylate (5d) (650 mg, 3.17 mmol) was dissolved in THF (25 mL) at room temperature. LiAlH.sub.4 (4.7 mL) was added dropwise under a nitrogen atmosphere at 0° C., and the reaction solution was stirred for 2 hours. 10 mL of methanol was added to the reaction solution, and the solution was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=10:1) to obtain 450 mg of the title compound as a yellow solid, yield: 80.2%.

Step 6: Preparation of 6-amino-1-methyl-1H-benzo[d]imidazole-5-carbaldehyde (5f)

[0203] (6-Amino-1-methyl-1H-benzo[d]imidazol-5-yl)methanol (5e) (450 mg, 2.54 mmol) was dissolved in DCM (20 mL) at room temperature. Manganese dioxide (4.42 g, 50.8 mmol) was added, and the reaction solution was stirred for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1) to obtain 220 mg of the title compound as a yellow solid, yield: 49.4%.

Step 7: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridine-1-ammonium bromide (1b)

[0204] Pyridine (70.8 mg, 0.896 mmol) was dissolved in EtOH (5 mL) at room temperature, and then ethyl 3-bromo-2-oxopropanoate (190 mg, 0.974 mmol) was added under a nitrogen atmosphere. The reaction solution was stirred at 65° C. for 2 hours, which was then used directly in the next step.

Step 8: Preparation of 1-(6-ethoxycarbonyl)-3-methyl-3H-imidazo[4,5-g]quinolin-7-yl)pyridin-1-ammonium bromide (5g)

[0205] The reaction solution of Step 7 was cooled to 18 to 22° C., followed by the addition of 6-amino-1-methyl-1H-benzo[d]imidazole-5-carbaldehyde (5f) (140 mg, 0.800 mmol) and pyridine (145 mg, 1.84 mmol). The reaction solution was stirred under a nitrogen atmosphere at 80° C. overnight, which was then used directly in the next step.

Step 9: Preparation of ethyl 7-amino-3-methyl-3H-imidazo[4,5-g]quinoline-6-carboxylate (5h)

[0206] The reaction solution of Step 8 was cooled to 70° C., followed by the addition of morpholine (111 mg, 1.28 mmol). The reaction solution was warmed up to 80° C., and stirring under a nitrogen atmosphere at 80° C. for 48 hours. 50 mL of water was added to the reaction solution which was then extracted with 50 mL of dichloromethane. The aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1) to obtain 110 mg of the title compound as a yellow solid, yield: 32.4%.

Step 10: Preparation of 2-(7-amino-3-methyl-3H-imidazo[4,5-g]quinolin-6-yl)propan-2-ol (5)

[0207] Methylmagnesium chloride (3N, 0.8 mL, 2.40 mmol) was added dropwise to THF (5 mL) under a nitrogen atmosphere at 0° C. Ethyl 7-amino-3-methyl-3H-imidazo[4,5-g]quinoline-6-carboxylate (13h) (100 mg, 0.370 mmol) dissolved in THF (5 mL) was added, and the reaction solution was stirred at room temperature for 3 hours. 50 mL of water was added to the reaction solution, and extracted with 50 mL of dichloromethane. The aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Daisogei 30 mm×250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 10%-60%) to obtain 44.25 mg of the title compound as a yellow solid, yield: 46.7%.

[0208] LC-MS: m/z 256.8 [M+H].sup.+.

[0209] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.33 (s, 1H), 7.97 (s, 1H), 8.04 (s, 1H), 7.41 (s, 1H), 3.85 (s, 3H), 1.76 (s, 6H).

Example 6: Preparation of 2-(8-amino-2,3-dihydronaphtho[2,3-b][1,4]dioxin-7-yl)propan-2-ol (6)

[0210] ##STR00032##

Step 1: Preparation of 7,8-dibromo-2,3-dihydronaphtho[2,3-b][1,4]dioxine (6a)

[0211] 6,7-Dibromonaphthalene-2,3-diol (4b) (1.00 g, 3.10 mmol) and potassium carbonate (1.75 g, 12.6 mmol) were added to acetonitrile (200 mL) at room temperature. The reaction solution was warmed up to 85° C. and stirred for 10 minutes, to which dibromoethane (0.600 g, 3.10 mmol) was added dropwise and stirred for 1 hour. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: EA/PE=3:1) to obtain 110 mg of the crude title compound as a yellow solid.

Step 2: Preparation of N-(8-bromo-2,3-dihydronaphtho[2,3-b][1,4]dioxin-7-yl)-1,1-diphenylmethanimine (6b)

[0212] 7,8-Dibromo-2,3-dihydronaphtho[2,3-b][1,4]dioxine (6a) (90.0 mg, 0.260 mmol), dibenzylidimide (47.0 mg, 0.260 mmol), sodium tert-butoxide (50.0 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium (9.60 mg, 0.0100 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (12.0 mg, 0.0200 mmol) were added to anhydrous toluene (10 mL) at room temperature. The system was heated to 100° C. under a nitrogen atmosphere and stirred for 1 hour. The reaction solution was cooled to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were added to ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: EA/PE=5:1) to obtain 29.0 mg of the crude title compound as a light yellow oil.

[0213] LC-MS: m/z 444.6 [M+H].sup.+.

Step 3: Preparation of methyl 8-((diphenylmethylene)amino)-2,3-dihydronaphtho[2,3-b][1,4]dioxine-7-carboxylate (6c)

[0214] N-(8-Bromo-2,3-dihydronaphtho[1,3-b][1,4]dioxin-7-yl)-1,1-diphenylmethanimine (6b) (29.0 mg, 0.0600 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (4.70 mg, 0.00600 mmol) and triethylamine (26.0 mg, 0.26 mmol) were added to methanol (5 mL) at room temperature. The system was then heated to 120° C. under a carbon monoxide atmosphere and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were added to ethyl acetate, and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: EA/PE=2:1) to obtain 28.0 mg of the crude title compound as a light yellow oil.

[0215] LC-MS: m/z 424.1 [M+H].sup.+.

Step 4: Preparation of methyl 8-amino-1,3-dihydronaphtho[2,3-b][1,4]dioxine-7-carboxylate (6d)

[0216] Methyl 8-((diphenylmethylene)amino)-2,3-dihydronaphtho[2,3-b][1,4]dioxine-7-carboxylate (6c) (28.0 mg, 0.0700 mmol) was added to tetrahydrofuran (5 mL) and 3M hydrochloric acid (1 mL) at room temperature. The system was stirred at room temperature for 16 hours, and concentrated under reduced pressure. The residues were added to ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: EA/PE=2:1) to obtain 25.0 mg of the crude title compound as a light yellow oil.

[0217] LC-MS: m/z 260.2 [M+H].sup.+.

Step 5: Preparation of 2-(8-amino-2,3-dihydronaphtho[2,3-b][1,4]dioxin-7-yl)propan-2-ol (6)

[0218] Methylmagnesium bromide (3 mol/L, 1.20 mL) was added to anhydrous tetrahydrofuran (10 mL) at room temperature. A solution of methyl 8-amino-1,3-dihydronaphtho[2,3-b][1,4]dioxine-7-carboxylate (19d) (48.0 mg, 0.190 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise under a nitrogen atmosphere at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Gemini-C18 150×21.2 mm, 5 um, mobile phase: acetonitrile/water, gradient: 10%-90%) to obtain 10.1 mg of the title compound as a white solid, yield: 21%.

[0219] LC-MS: m/z 259.1 [M+H].sup.+.

[0220] .sup.1H NMR (300 MHz, CD3OD) δ 7.42 (s, 1H), 7.05 (s, 1H), 6.89 (s, 1H), 6.84 (s, 1H), 4.25 (s, 4H), 1.69 (s, 6H).

Example 7: Preparation of 2-(7-amino-2-morpholinooxazolo[4,5-g]quinolin-6-yl)propan-2-ol (7)

[0221] ##STR00033## ##STR00034##

Step 1: Preparation of methyl 3-amino-4-hydroxybenzoate (7a)

[0222] 3-Amino-4-hydroxybenzoic acid (10.0 g, 65.4 mmol) was dissolved in methanol (500 mL) at room temperature, to which acetyl chloride (15.4 g, 196 mmol) was slowly added dropwise. The reaction solution was stirred at 72° C. for 16 hours, and concentrated under reduced pressure to obtain 11.0 g of the crude title compound as a light green solid.

Step 2: Preparation of methyl 2-thioxo-2,3-dihydrobenzo[d]oxazole-5-carboxylate (7b)

[0223] Methyl 3-amino-4-hydroxybenzoate (7a) (3.00 g, 18.0 mmol) was dissolved in TCDI (3.84 g, 21.6 mmol) at room temperature, and stirred at 30° C. for 16 hours. A few drops of concentrated hydrochloric acid was added to the reaction solution to adjust it to weakly acidic. The solution was extracted with 60 mL of ethyl acetate, and the aqueous phase was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.00 g of the crude title product as a light orange solid.

Step 3: Preparation of methyl 2-morpholinobenzo[d]oxazole-5-carboxylate (7c)

[0224] Methyl 2-thioxo-2,3-dihydrobenzo[d]oxazole-5-carboxylate (7b) (3.00 g, 14.4 mmol) was dissolved in DMF (40 mL) at room temperature, to which morpholine (2.50 g, 28.7 mmol) and DIPEA (5.56 g, 43.1 mmol) were added. The reaction solution was stirred at 110° C. for 2 hours. 30 mL of ice water was added to the reaction solution which was then extracted with 80 mL of ethyl acetate. The aqueous phase was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 3.00 g of the title product as a light yellow solid, yield: 79.5%.

Step 4: Preparation of methyl 2-morpholino-6-nitrobenzo[d]oxazole-5-carboxylate (7d)

[0225] Methyl 2-morpholinobenzo[d]oxazole-5-carboxylate (7c) (2.00 g, 7.63 mmol) was dissolved in concentrated sulfuric acid (25 mL) at 0° C., to which concentrated nitric acid (15 mL) was slowly added dropwise. The reaction solution was stirred in an ice bath for 10 minutes. 30 mL of ice water was added to the reaction solution. The solution was extracted with 40 mL of ethyl acetate, and the aqueous phase was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=2:1) to obtain 1.40 g of the title product as a yellow solid, yield: 59.8%.

Step 5: Preparation of methyl 6-amino-2-morpholinobenzo[d]oxazole-5-carboxylate (7e)

[0226] Methyl 2-morpholino-6-nitrobenzo[d]oxazole-5-carboxylate (7d) (1.40 g, 4.56 mmol) was dissolved in ethanol (30 mL) and water (3 mL) (ethanol: water=10:1) at room temperature, to which iron powder (1.41 g, 25.1 mmol) and ammonium chloride (171 mg, 3.19 mmol) were added. The reaction solution was stirred at 78° C. for 16 hours. The reaction solution was extracted with 50 mL of ethyl acetate, and the aqueous phase was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: DCM/EA=1:1) to obtain 1.10 g of the title product as a light yellow solid, yield: 87.1%.

Step 6: Preparation of (6-amino-2-morpholinobenzo[d]oxazol-5-yl)methanol (7f)

[0227] Methyl 6-amino-2-morpholinobenzo[d]oxazole-5-carboxylate (7e) (1.10 g, 3.97 mmol) was dissolved in THF (30 mL) at room temperature. LiAlH.sub.4 (6.00 mL, 5.96 mmol) was added dropwise under a nitrogen atmosphere at 0° C., and the reaction solution was stirred in an ice bath for 1.5 hours. 5 mL of water was added to the reaction solution to quench the reaction. The solution was extracted with ethyl acetate (50 mL), and the aqueous phase was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=10:1) to obtain 800 mg of the title product as a brown solid, yield: 80.9%.

Step 7: Preparation of 6-amino-2-morpholinobenzo[d]oxazole-5-carbaldehyde (7g)

[0228] (6-Amino-2-morpholinobenzo[d]oxazol-5-yl)methanol (7f) (550 mg, 2.21 mmol) was dissolved in DCM (45 mL) at room temperature. Manganese dioxide (3.84 g, 44.2 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=10:1) to obtain 400 mg of the title product as a brown solid, yield: 73.3%.

Step 8: Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridine-1-ammonium bromide (1b)

[0229] Pyridine (157 mg, 1.98 mmol) was dissolved in EtOH (30 mL) at room temperature, and then ethyl 3-bromo-2-oxopropanoate (351 mg, 1.80 mmol) was added under a nitrogen atmosphere. The reaction solution was stirred at 65° C. for 2 hours, which was used directly in the next step.

Step 9: Preparation of 1-(6-(ethoxycarbonyl)-2-morpholinooxazolo[4,5-g]quinoline-7-yl)pyridine-1 (7h)

[0230] The reaction solution of the above step was cooled to 18 to 22° C., followed by the addition of 6-amino-2-morpholinobenzo[d]oxazole-5-acetaldehyde (400 mg, 1.62 mmol) and pyridine (327 mg, 4.14 mmol). The reaction solution was stirred under a nitrogen atmosphere at 80° C. for 16 hours, which was used directly in the next step.

Step 10: Preparation of ethyl 7-amino-2-morpholinooxazolo[4,5-g]quinoline-6-carboxylate (7j)

[0231] The reaction solution of the previous step was cooled to 70° C., followed by the addition of morpholine (392 mg, 4.50 mmol). The reaction solution was warmed up to 80° C., and stirring under a nitrogen atmosphere for 4 hours. 30 mL of water was added to the reaction solution, and extracted with 40 mL of dichloromethane. The aqueous phase was extracted twice with 30 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: dichloromethane/ethyl acetate=2:1) to obtain 126 mg of the title compound as a yellow solid, yield: 22.7%.

Step 11: Preparation of 2-(7-amino-2-morpholinooxazolo[4,5-g]quinolin-6-yl)propan-2-ol (7)

[0232] Methylmagnesium chloride (3N, 0.78 mL, 2.34 mmol) was added dropwise to THF (10 mL) under a nitrogen atmosphere at 0° C., followed by the addition of ethyl 7-amino-2-morpholinooxazolo[4,5-g]quinoline-6-carboxylate (80 mg, 0.234 mmol) dissolved in THF (10 mL). The reaction solution was stirred at room temperature for 2 hours, and 5 mL of water was added to quench the reaction. 15 mL of water was added to the reaction solution which was then extracted with 30 mL of ethyl acetate. The aqueous phase was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Daisogei 30 mm×250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile/water, gradient: 10%-50%) to obtain 16.0 mg of the title compound as a white solid, yield: 20.8%.

[0233] LC-MS: m/z 329.00 [M+H].sup.+.

[0234] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.59 (s, 1H), 7.31 (s, 1H), 7.22 (s, 1H), 5.69˜5.66 (s, 3H), 3.75˜3.72 (m, 4H), 3.66˜3.64 (m, 4H), 1.60 (s, 6H).

Example 8: Preparation of 2-(14-amino-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecin-13-yl) propan-2-ol (8)

[0235] ##STR00035##

Step 1: Preparation of 13,14-dibromo-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecine (8a)

[0236] 6,7-Dibromonaphthalene-2,3-diol (4b) (1.60 g, 5.00 mmol) and 1,2-bis(2-bromoethoxy)ethane (9.25 g, 10.1 mmol) were added to N,N-dimethylformamide (50 mL) at room temperature. Potassium carbonate (2.77 g, 20.2 mmol) was added, and the reaction solution was warmed up to 120° C. and stirred for 24 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent: EA/PE=1:1) to obtain 590 mg of the title compound as a white solid, yield: 27.1%.

Step 2: Preparation of N-(14-bromo-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecin-13-yl)-1,1-diphenylmethanimine (8b)

[0237] 13,14-Dibromo-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecine (8a) (300 mg, 0.700 mmol), dibenzylidimide (139 mg, 0.735 mmol), sodium tert-butoxide (80.4 mg, 0.837 mmol), tris(dibenzylideneacetone)dipalladium (63.6 mg, 0.0696 mmol) and 1,1′-binaphthyl-2,2′-bis(diphenylphosphino) (64.8 mg, 0.105 mmol) were added to anhydrous toluene (30 mL) at room temperature. The system was heated to 80° C. under a nitrogen atmosphere and stirred for 24 hours. The reaction solution was cooled to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were added to ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent: EA) to obtain 360 mg of the title compound as a light yellow oil, yield: 97.1%.

[0238] LC-MS: m/z 532.1 [M+H].sup.+.

Step 3: Preparation of 14-bromo-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecin-13-amine (8c)

[0239] N-(14-Bromo-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecin-13-yl)-1,1-diphenylmethanimine (8b) (300 mg, 0.565 mmol) was added to tetrahydrofuran (50 mL) and 3M hydrochloric acid (10 mL) at room temperature. The system was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residues were added to ethyl acetate and washed with saturated sodium carbonate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent: EA) to obtain 150 mg of the title compound as a light yellow oil, yield: 72.3%.

[0240] LC-MS: m/z 368.2 [M+H].sup.+.

Step 4: Preparation of methyl 14-amino-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecine-13-carboxylate (8d)

[0241] 14-Bromo-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecin-13-amine (8c) (50.0 mg, 0.144 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (8.50 mg, 0.0144 mmol) and triethylamine (47.0 mg, 0.470 mmol) were added to methanol (5 mL) at room temperature. The system was heated to 120° C. under a carbon monoxide atmosphere and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were extracted with ethyl acetate, and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (eluent: PE/EA=1:2) to obtain 30.0 mg of the title compound as a light yellow oil, yield: 62.0%.

[0242] LC-MS: m/z 409.7 [M+H].sup.+.

Step 5: Preparation of 2-(14-amino-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecin-13-yl) propan-2-ol (8)

[0243] Methylmagnesium chloride (3 mol/L, 1.20 mL) was added to anhydrous tetrahydrofuran (10 mL) at room temperature. A solution of methyl 14-amino-2,3,5,6,8,9-hexahydronaphtho[2,3-b][1,4,7,10]tetraoxacyclododecine-13-carboxylate (50 mg, 0.2 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise under a nitrogen atmosphere at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Gemini-C18 150×21.2 mm, 5 um, mobile phase: acetonitrile/water, gradient: 10%-90%) to obtain 30.0 mg of the title compound as a white solid, yield: 60.0%.

[0244] LC-MS: m/z 330.0 [M-17].sup.+.

[0245] .sup.1H NMR (400 MHz, DMSO) δ 7.65 (s, 1H), 7.31 (s, 1H), 6.98 (s, 1H), 6.78 (s, 1H), 5.54 (s, 2H), 5.35 (s, 1H), 4.14-4.09 (m, 4H), 3.78-3.66 (m, 8H), 1.59 (s, 6H).

Example 9: Preparation of 1-(7-aminonaphtho[2,3-d][1,3]dioxol-6-yl)cyclopropan-1-ol (9)

[0246] ##STR00036##

Step 1: Preparation of N-(7-(1-ethoxyvinyl)naphtho[2,3-d][1,3]dioxol-6-yl)-1,1-diphenylmethanimine (9a)

[0247] N-(7-Bromonaphtho[2,3-d][1,3]dioxol-6-yl)-1,1-diphenylmethanimine (4d) (4.86 g, 11.3 mmol), tributyl(1-ethoxyvinyl)stannane (6.14 g, 17 mmol) and bis(triphenylphosphine)palladium chloride (795 mg, 1.13 mmol) were added to N,N-dimethylformamide (50 mL) at room temperature. The system was heated to 100° C. under a nitrogen atmosphere and stirred for 18 hours. The reaction solution was cooled to room temperature, to which 100 mL of saturated potassium fluoride solution was added and stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 4.77 g of the crude title compound as a dark brown oil.

[0248] LC-MS: m/z 422.1 [M+H].sup.+.

Step 2: Preparation of 1-(7-aminonaphtho[2,3-d][1,3]dioxol-6-yl)ethan-1-one (9b)

[0249] N-(7-(1-Ethoxyvinyl)naphtho[2,3-d][1,3]dioxol-6-yl)-1,1-diphenylmethanimine (9a) (4.77 g, 11.3 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature, followed by the addition of hydrochloric acid (3M, 50 mL). The reaction system was stirred at room temperature for 6 hours and concentrated under reduced pressure. The residues were adjusted to pH=7-8 with saturated sodium carbonate solution. The resulting solid was filtered, rinsed and dried to obtain 2.09 g of the title compound as a light yellow solid, yield: 80.1%.

[0250] LC-MS: m/z 230.0 [M+H].sup.+.

Step 3: Preparation of 1-(7-(dibenzylamino)naphtho[2,3-d][1,3]dioxol-6-yl)ethan-1-one (9c)

[0251] 1-(7-Aminonaphtho[2,3-d][1,3]dioxol-6-yl)ethan-1-one (9b) (1.00 g, 4.37 mmol), benzyl bromide (2.24 g, 13.1 mmol) and potassium carbonate (3.02 g, 21.85 mmol) were added to acetonitrile (30 mL) at room temperature. The system was stirred at 80° C. for 10 hours and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/DCM=1:1) to obtain 1.16 g of a yellow solid, yield: 64.8%.

[0252] LC-MS: m/z 410.1 [M+H].sup.+.

Step 4: Preparation of N,N-dibenzyl-7-(1-((trimethylsilyl)oxy)vinyl)naphtho[2,3-d][1,3]dioxol-6-amine (9d)

[0253] 1-(7-(Dibenzylamino)naphtho[2,3-d][1,3]dioxol-6-yl)ethan-1-one (9c) (500 mg, 1.22 mmol) and triethylamine (370 mg, 3.67 mmol) were added to dichloromethane (8 mL) at room temperature. The mixture was cooled to 0° C., and trimethylsilyl trifluoromethanesulfonic acid (489 mg, 2.20 mmol) was added dropwise. The reaction system was stirred at room temperature for 18 hours, and then quenched by saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 588 mg of the crude title compound as a yellow oil, which was used directly in the next step.

Step 5: Preparation of N,N-dibenzyl-7-(1-((trimethylsilyl)oxy)cyclopropyl)naphtho[2,3-d][1,3]dioxol-6-amine (9e)

[0254] N,N-Dibenzyl-7-(1-((trimethylsilyl)oxy)vinyl)naphtho[2,3-d][1,3]dioxol-6-amine (9d) (588 mg, 1.222 mmol) and diiodomethane (655 mg, 2.444 mmol) were added to dichloromethane (10 mL) at room temperature. The mixture was cooled to 0° C., and diethylzinc (1M, 1.833 mL, 1.833 mmol) was added dropwise. The reaction system was stirred at room temperature for 18 hours, and then quenched by saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/DCM=1:1) to obtain 30 mg of the title compound. Yield: 5%.

[0255] LC-MS: m/z 495.8 [M+H].sup.+.

Step 6: Preparation of 7-(1-((trimethylsilyl)oxy)cyclopropyl)naphtho[2,3-d][1,3]dioxol-6-amine (9f)

[0256] N,N-Dibenzyl-7-(1-((trimethylsilyl)oxy)cyclopropyl)naphtho[2,3-d][1,3]dioxol-6-amine (9e) (120 mg, 0.242 mmol) and Pd/C (120 mg) were added to ethyl acetate (6 mL) at room temperature. The reaction solution was stirred under a hydrogen atmosphere at room temperature for 48 hours. The reaction solution was filtered and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (mobile phase: PE/EA=10:1) to obtain 21.0 mg of the title compound as a light yellow solid, yield: 27.5%.

[0257] LC-MS: m/z 316.0 [M+H].sup.+.

Step 7: Preparation of 1-(7-aminonaphtho[2,3-d][1,3]dioxol-6-yl)cyclopropan-1-ol (9)

[0258] 7-(1-((Trimethylsilyl)oxy)cyclopropyl)naphtho[2,3-d][1,3]dioxol-6-amine (21.0 mg, 0.0670 mmol) was added to anhydrous tetrahydrofuran (3 mL) at room temperature. Tetrabutylammonium fluoride (1 M, 0.2 mL, 0.200 mmol) was slowly added dropwise under a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 5 minutes. After completion of the reaction, ethyl acetate was added to the reaction solution, and the solution was washed twice with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residues were purified by preparative liquid chromatography (column model: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: acetonitrile/water, gradient: 20%-55%) to obtain 9.00 mg of the title compound as a yellow solid, yield: 55.3%.

[0259] LC-MS: m/z 244.1 [M+H].sup.+.

[0260] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.40 (s, 1H), 7.08 (s, 1H), 6.94 (s, 1H), 6.82 (s, 1H), 5.99 (s, 2H), 5.81 (s, 1H), 5.14 (s, 2H), 0.96-0.94 (m, 2H), 0.84-0.81 (m, 2H).

Biological Assay

Test Example 1: Test of the Determination of Aldehyde Capture Rate

[0261] In the aldehyde capture test disclosed in the present invention, the stable lipid metabolite, nonenal, was used as the model aldehyde to react with the compound of the Example. The specific protocol was as follows.

[0262] 0.05 mM of the compounds of the Examples of the present invention were precisely weighed respectively and dissolved in 1.2 mL of a mixed solution (v/v=1:1) of triolein (Aladdin, G105172-5g) and linoleic acid (Aladdin, L100442-25g), respectively. 2.5 mL of PBS (Solarbio) solution containing 20% Captisol® (Aladdin, C125030-25g) was added, and the solution was stirred at room temperature overnight. After the example compound was completely dissolved, 0.025 mM nonenal (Sigma, 255653-5G) was added, and the solution was stirred vigorously at room temperature. 200 μL of the sample was added to 800 μL of acetonitrile (Fisher, A995) at 0, 45, 90, 180, 225 and 465 minutes, respectively. The solution was mixed vigorously by vortex for 2 minutes, and centrifuged at a low speed of 1000 r/min for 3 minutes. The supernatant was transferred to an injection vial. The nonenal in the reaction mixture was analyzed quantitatively by high performance liquid chromatography. The adduct resulted from the example compound of the present invention and nonenal was analyzed qualitatively by high performance liquid chromatography-mass spectrometry.

[0263] Liquid chromatograph: Waters I Class;

[0264] Column: ACQUITY UPLC HSS T3 1.8 μm;

[0265] Column temperature: 40° C.;

[0266] Liquid chromatography condition: mobile phase A: acetonitrile containing 0.1% formic acid; B: water containing 0.1% formic acid;

[0267] Flow rate: 0.4 mL/mL;

[0268] Injection volume: 0.5 mL.

[0269] Gradient of the mobile phases:

TABLE-US-00002 Time (min) A % 0 10 0.5 10 2.5 95 3.4 95 3.5 10 4.0 10

[0270] In the developed detection method, the retention time of the model aldehyde nonenal was 2.42 minutes.

[0271] Mass spectrometry conditions:

[0272] Mass spectrometer: Waters TQ-S micro

[0273] Ion source: ESI.sup.+

[0274] Capillary voltage: 0.5 kV

[0275] Cone voltage: 10V

[0276] Source temperature: 150° C.

[0277] Degassing temperature: 500° C., degassing flow: 1000 L/Hr

[0278] SIM mode

[0279] m/z: 247.30 [M.sub.Example 1+H].sup.+, 369.30 [M.sub.adduct 1+H].sup.+

[0280] The variation of nonenal and some example compounds over reaction time is shown in FIG. 1. The aldehyde consumption behavior of the example compounds of the present invention is shown in Table 1 below.

TABLE-US-00003 TABLE 1 Aldehyde consumption behavior of the example compounds of the present invention at different time points 225 minutes 465 minutes Aldehyde Aldehyde consumption consumption Examples (100%) Capture rate .sup.a (100%) Capture rate .sup.a Example 1 10.73 −0.05 18.43 −0.04 Example 2 11.99 −0.06 12.11 −0.03 Example 3 35.38 −0.17 43.67 −0.10 Example 4 52.65 −0.25 66.62 −0.14 Example 5 20.02 −0.08 36.01 −0.08 Example 6 16.48 −0.07 22.01 −0.05 Example 7 7.12 −0.03 8.34 −0.01 Example 8 19.78 −0.07 19.82 −0.04 Example 9 15.43 −0.06 16.60 −0.03 .sup.a Aldehyde capture rate is represented by the slope of the capture curve per unit time, and the higher the absolute value of the slope, the higher the capture rate.

[0281] It can be seen from FIG. 1 and the above Table 1 that the compounds of the present invention have aldehyde capture ability.

Test Example 2: Therapeutic Effect of the Compound of the Present Invention in Uveitis Animal Model

[0282] Female lewis rats were used as the research subjects. Lewis rats (Vital River) were randomly divided into groups (4 animals per group, a total of 8 eyes). The groups are as follows: normal control group, model control group, and example administration group. The inflammation model was established in these groups except for the normal control group.

[0283] Formulation of Eye Drops:

[0284] (1) Formulation of drug vehicle stock solution: 2090 mg of Na.sub.2HPO.sub.4.12H.sub.2O (Xilong Scientific, 9009012-01-09), 19 mg of NaH.sub.2PO.sub.4.2H.sub.2O (Xilong Scientific, 9009013-01-09) and 9500 mg of β-cyclodextrin (Sigma, E1930253) were precisely weighed and dissolved in 30 mL sterile water for injection (Beijing CR Double-Crane), followed by the addition of 10 mL of PEG-400 (Solarbio, 222U011). The solution was mixed well, and made up to 50 mL with water for injection.

[0285] (2) Formulation of drug solution: 10 mg of the compound of Example 4 of the present invention was weighed and dissolved in 1 mL of the vehicle stock solution, and the resulting solution was made up to 2 mL with water for injection. The content of each substance is as follows: Na.sub.2HPO.sub.4.12H.sub.2O 0.83%, NaH.sub.2PO.sub.4.2H.sub.2O 0.017%, ρ-cyclodextrin 9.5%, PEG-400 5.0%, active compound 0.5%.

[0286] (3) The pH value of the formulated drug solution was determined by pH test paper. If the pH value was not within 7.3±0.05, then it was adjusted to this range with 1 N HCl or 1 N NaOH. The solution was filtered through a 0.22 m sterile filter (Merck, Millex), and stored at 4° C.

[0287] Handling of the Animal Model:

[0288] The animal model was a noninfectious uveitis animal model established by intraperitoneal injection of lipopolysaccharide (derived from Escherichia coli, 055:B5, Sigma, L2880-100MG, injection dose: 2 mg/kg). At the same time of modeling, drug administration was carried out according to the above grouping situation. The normal control group was administered with normal saline, the model control group was administered with blank vehicle, and the example administration group was administered with the eye drops formulated above. The drug was administered by eye instillation to both eyes of each animal, and the eye instillation dose was 20 μL/eye. After the completion of eye instillation, the eyelids were closed for 20 seconds to prevent the loss of the drug. The administration was repeated at 3, 6 and 23 hours after modeling. When the illness was severe (24 hours after modeling), the animals were anesthetized by intraperitoneal injection of 3.5% chloral hydrate. The ocular inflammation of the animals in each group was examined with a slit lamp microscope (Jiangxi Jiangfeng, LYL-S), and evaluated according to the McDonald-Shadduck scoring system (GB/T 28538-2012).

[0289] The animals were sacrificed, and the bilateral eyeballs were enucleated. The eyeball was subjected to corneal puncture. The aqueous humor of each eyeball was collected by a capillary, placed in a 1.5 mL centrifuge tube, and centrifuged at 1000 r/min. Quantitative analysis of total protein in aqueous humor was performed on the supernatant by a BCA protein quantification kit (Beyotime, P0010).

[0290] The effect of the compound of Example 4 of the present invention on the ocular inflammation score and protein concentration in aqueous humor of the ocular inflammation model rats are shown in Table 2 below.

TABLE-US-00004 TABLE 2 Ocular inflammation score and protein concentration in aqueous humor of the model rats after treatment (mean ± standard deviation) Protein concentration in aqueous Group of the animals Ocular score humor (μg/mL) Normal control group 4.5 ± 1.4 623.8 ± 83.3 Model control group 23.0 ± 2.8  1664.1 ± 215.6 Example 4 group   8.4 ± 2.8***   840.6 ± 449.7*** ***P < 0.001, V.S. model control group

[0291] It can be seen from the above Table 2 that in the ocular inflammation animal model, the treatment with the compound of Example 4 of the present invention can effectively reduce the ocular inflammation model score and significantly reduce the protein concentration in the aqueous humor, showing a therapeutic effect.

Test Example 3: Therapeutic Effect of the Compound of the Present Invention on Allergic Conjunctivitis Animal Model

[0292] C48/80 is a polymer formed by the condensation of N-methyl-p-methoxyphenethylamine with formaldehyde, which acts directly on G protein and induces mast cell degranulation. After degranulation, the mast cell releases active substances such as histamine and kinin, which can cause acute type I allergic reactions such as telangiectasia and enhanced permeability. It can cause allergic conjunctivitis if applied topically to the ocular surface.

[0293] Female Wistar rats were used as the research subjects. Wistar rats (Vital River) were randomly divided into groups (5 animals per group, a total of 10 eyes). The groups are as follows: normal control group, model control group, positive drug group, and example administration group. The inflammation model was established in these groups except for the normal control group. Emedastine Difumarate Eye Drops (Emadine®, Alcon, H20181192) was used as the positive drug. Model establishment, administration and evaluation processes are as follows.

[0294] The animal was subjected to inhalation anesthesia (isoflurane, Hebei Yipin pharmaceutical Co., Ltd., C002151205; anesthesia parameters: flow rate: 1.0 L/min, oxygen pressure: 0.1 MPa, solubility: 4.5%, anesthesia time: 5 minutes). The animal was grabbed with one hand and kept ventral side up. 10 μL of C48/80 solution (Sigma, C2313-100MG, 200 mg/mL, formulated with 0.9% saline) was added dropwise to the corneal surface of both eyes of the animal by a 10 μL pipette. The upper and lower eyelids were gently closed for 10 seconds to prevent the loss of the drug.

[0295] After 10 minutes of stimulation, different drug treatments were carried out according to the group settings. Both eyes of the same animal were subjected to the same drug treatment (10 μL per eye). The eyelids were closed for 10 seconds by the same method. Ophthalmological examination was performed 20 minutes after administration by a handheld slit lamp microscope (Jiangxi Jiangfeng, LYL-S). The clinical score was evaluated individually on the eyes of each animal according to the McDonald-Shadduck scoring system (GB/T 28538-2012).

[0296] The results are shown in FIG. 2. According to the evaluation principle of the McDonald-Shadduck scoring system, the score value is positively correlated with the severity of ocular inflammation. The compound of Example 4 of the present invention has a good therapeutic effect on the allergic conjunctivitis in Wistar rats induced by C48/80.