Nitroxoline prodrugs and uses thereof

Abstract

The present invention provides nitroxoline prodrugs and uses thereof, specifically, the compound of formula (I) or a pharmaceutically acceptable salt thereof, a method for preparing the same, compositions containing the same, and the use of the same in the manufacture of anti-infective and anti-tumor drugs, where the definitions of each group in formula (I) are as defined in the specification. The compound of formula (I) has good water solubility for nitroxoline and pharmacokinetic parameters such as plasma concentration and half-life. The compound of formula (I) reduces the frequency of administration and is expected to be applicable to fields other than the urinary tract field.

Description

[Technical field]

[0001] The present invention relates to the pharmaceutical field. In particular, the present invention relates to nitroxoline prodrugs and their uses. [Background technology]

[0002] Nitroxoline has long been used as a commercially available antibacterial drug to treat urinary tract infections. Recent discoveries have revealed that nitroxoline is also very effective in inhibiting angiogenesis and inhibiting the proliferation and invasion of cancer cells, and is currently being developed as an antitumor drug. Human pharmacokinetic studies have shown that nitroxoline is rapidly absorbed into the blood circulation, but due to the severe first-pass effect on the drug in the liver, its biological half-life is very short (an open-label, single-arm, multi-center clinical phase II study conducted by Jiangsu Yahong Pharmaceutical Technology Co., Ltd. in China showed that its half-life is 1.22-1.44 hours), and it needs to be administered frequently. In order to maintain continuous drug exposure, the general prescription for nitroxoline drugs requires taking them three times daily (TID) or four times daily (QID), which not only brings economic losses but also is unfavorable to patient compliance, and more seriously, increases the persistent harm of the drug to normal living organisms. On the other hand, nitroxoline has low water solubility and therefore requires immediate release formulations to increase its solubility, thereby substantially increasing production costs.

[0003] A prodrug is a compound obtained by chemically modifying an active drug, which is converted into the original drug by the action of enzymes in the body to exert its medicinal effects. Prodrugs are widely used in drug research and development, and have already been successfully researched on a variety of drugs, with good application effects. The prodrug strategy can solve some of the shortcomings caused by the physicochemical properties of the active agent itself, such as 1) eliminating the bad odor of the drug, 2) increasing the blood concentration, 3) improving the lipid solubility or water solubility of the drug, 4) extending the duration of action of the drug, and 5) changing the dosage of the drug.

[0004] To date, there have been no reports of using a prodrug strategy to increase the biological half-life, exposure and water solubility of nitroxoline and reduce the frequency of drug administration.

[0005] In response to the above-mentioned drawbacks, the present inventors have designed a prodrug of a nitroxoline molecule that is metabolized to nitroxoline upon entry into the body and exerts its effect, thereby extending the half-life of nitroxoline in the body and reducing the frequency of administration. Summary of the Invention [Problem to be solved by the invention]

[0006] Nitroxoline has metabolic characteristics of low water solubility and short biological half-life, so that when used for antibacterial and anticancer applications, it needs to be taken three or four times a day in general prescriptions. In addition, its main metabolic pathway is metabolism via the kidney and excretion via the urinary tract, limiting the application of nitroxoline to fields other than urinary tract infection and bladder cancer.

[0007] The present invention provides a compound useful as a prodrug of nitroxoline. As a result of screening and optimization of the compound structure, this compound has good pharmacokinetic parameters such as water solubility, plasma concentration and biological half-life compared to nitroxoline in animals. The compound of the present invention can reduce the number of administrations and is expected to be applied to fields other than the urinary tract field. [Means for solving the problem]

[0008] It is therefore an object of the present invention to provide a compound of formula (I) or in the form of its meso form, racemate, enantiomeric form, diastereomeric form or mixtures thereof, or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, [ka] represents a single bond or a double bond, R1 is hydrogen, C 1-6 alkyl group, S or O; X is O, N, S, -(CH2) n -, an aryl group, or a heterocyclic group; Where: When X is selected from N, R0 and R2 are each independently hydrogen, C 1-6 selected from an alkyl group, an aryl group, or a heterocyclic group; When X is selected from an aryl group or a heterocyclic group, R0 and R2 are each independently selected from a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen atom, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; X is O, S or -(CH2) n -, R2 is absent and R0 is C 1-6 Alkyl group, cycloalkyl group, heterocyclic group, -COR 11 , -C(O)OR 12 , [ka] and C is selected from 1-6 The alkyl group, the cycloalkyl group, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Where: R0 is [ka] When selected from, E is O or NR 14 Selected from R 10 , R 13 , R 14 are each independently hydrogen, C 1-6 An alkyl group or an aryl group, 1-6 The alkyl or aryl group may further include a halogen, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, -OR 12 , -COR 11 , -C(O)OR 12 , -OC(O)R 11 , -OC(O)OR 12 and R0 is optionally substituted with one or more groups selected from [ka] When selected from the group consisting of, Y is selected from O, N or S, and R3 is [ka] A cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OC(O)R 11 and Z is selected from C, N or O; Where: When Z is selected from C, R4, R5 and R6 each independently represent a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 12 , -SR 12 , -C(O)R 11 , -C(O)OR 12, -C(O)-(CH) m -C(O)R 11 , -OC(O)R 11 , -NR a R b , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), -O(CH2) m O(CH2) q R 12 , -N(R c )C(O)-(CH) m -N(R c )C(O)R d wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further selected from the group consisting of halogen, amino group, nitro group, cyano group, hydroxy group, mercapto group, alkyl group, alkoxy group, alkenyl group, alkynyl group, OR 12 , S.R. 12 , N.R. a R b , -COR 11 , -C(O)OR 12 , -OC(O)R 11 , -N(R c )C(O)R d , -O(CH2) m O(CH2) q R 12 , a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group, and the aryl group, arylalkyl group, heteroaryl group, or heteroarylalkyl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, and an alkoxy group, or Among R4, R5 and R6, one is hydrogen, and the remaining two together with Z form a cycloalkyl group or a heterocyclic group, and the cycloalkyl group or the heterocyclic group may further include a halogen atom, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, -C(O)R 11 , -C(O)OR 12 , -OC(O)R 11 may be substituted by one or more groups selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; When Z is selected from N, R6 is absent, and R4 and R5 are each independently hydrogen, halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 12 , -SR 12 , -C(O)R 11 , -C(O)OR 12 , -OC(O)R 11 , -NR a R b , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), -O(CH2) m O(CH2) q R 12 , -N(R c )C(O)-(CH) m -N(R c )C(O)R d wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is further selected from the group consisting of halogen, amino group, nitro group, cyano group, hydroxy group, mercapto group, alkyl group, alkoxy group, alkenyl group, alkynyl group, OR 12 , S.R. 12 , N.R. a R b , -C(O)R 11 , -C(O)OR 12, -OC(O)R 11 , -(CH) m -OC(O)R 11 , a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, or R4 and R5 together with Z form a cycloalkyl group or a heterocyclic group, and the cycloalkyl group or the heterocyclic group may further include a halogen atom, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, -C(O)R 11 , -C(O)OR 12 , -OC(O)R 11 may be substituted by one or more groups selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; When Z represents O, R5 and R6 are absent and R4 is C 1-6 An alkyl group, an aryl group, or a heterocyclic group, 1-6 The alkyl, aryl or heterocyclic group may be further substituted by one or more -OH groups; or X is O, N, S, or -(CH2) n -, R2 is not present, and R1, X and R0 together form a cycloalkyl group or a heterocyclic group, which may be further substituted by one or more groups selected from halogen, amino group, nitro group, cyano group, hydroxy group, mercapto group, carboxy group, ester group, oxo group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; R 11 and R 12are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, -NR a R b , -OR d , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, R a and R b are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R a and R bform a heterocyclic group together with the atom to which they are linked, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R c and R d are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; n is an integer selected from 1 to 8; m is an integer selected from 0 to 6; p is selected from 0, 1 or 2; q is selected from integers of 0 to 6.

[0009] In one preferred embodiment, the compound represented by formula (I) of the present invention is a compound represented by formula (II): [ka] (In the formula, R1 is hydrogen or C 1-6 selected from alkyl groups, R4, R5, and R6 each independently represent a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 12 , -SR 12 , -C(O)R 11 , -C(O)OR 12, -C(O)-(CH) m -C(O)R 11 , -OC(O)R 11 , -NR a R b , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), -O(CH2) m O(CH2) q R 12 , -N(R c )C(O)-(CH) m -N(R c )C(O)R d wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is further selected from the group consisting of halogen, amino group, nitro group, cyano group, hydroxy group, mercapto group, alkyl group, alkoxy group, alkenyl group, alkynyl group, OR 12 , S.R. 12 , N.R. a R b , -COR 11 , -C(O)OR 12 , -OC(O)R 11 , -N(R c )C(O)R d , -O(CH2) m O(CH2) q R 12 , a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group, and the aryl group, arylalkyl group, heteroaryl group, or heteroarylalkyl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, and an alkoxy group, or Among R4, R5 and R6, one is hydrogen, and the remaining two together with Z form a cycloalkyl group or a heterocyclic group, and the cycloalkyl group or the heterocyclic group may further include a halogen atom, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, -C(O)R 11 , -C(O)OR 12 , -OC(O)R 11 may be substituted by one or more groups selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 11 and R 12 are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, -NR a R b , -OR d , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, R a and R bare each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R a and R b form a heterocyclic group together with the atom to which they are linked, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R c and R d are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are each optionally substituted with one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; m is an integer selected from 0 to 6; p is selected from 0, 1 or 2; q is selected from integers of 0 to 6.

[0010] In a further preferred embodiment of the present invention, in the compound represented by formula (II) of the present invention, R4, R5 and R6 each independently represent a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, -OR 12 , -SR 12 , -C(O)R 11 , -C(O)OR 12 , -C(O)-(CH) m -C(O)R 11 , -OC(O)R 11 , -(CH) m -N(R c )C(O)R 11 , -NR a R b , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), -O(CH2) m O(CH2) q R 12 , -N(R c )C(O)-(CH) m -N(R c )C(O)R d wherein the alkyl, aryl or heteroaryl group is further selected from the group consisting of a halogen, a hydroxyl group, an alkyl group, an OR 12 , S.R. 12 , N.R. a R b , -COR 11 , -C(O)OR 12 , -O(O)CR 11 , -N(R c )C(O)R d , -O(CH2) m O(CH2) q R 12, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group, and the aryl group, arylalkyl group, heteroaryl group, and heteroarylalkyl group may be further substituted by one or more groups selected from a halogen, a hydroxy group, a mercapto group, an alkyl group, and an alkoxy group; R 11 and R 12 are each independently selected from hydrogen, halogen, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, an amino group, a hydroxy group, an alkyl group, an alkoxy group, -NR a R b , -OR d , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, R a and R bare each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R a and R b form a heterocyclic group together with the atom to which they are linked, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R c and R d are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; m is an integer selected from 0 to 6; p is selected from 0, 1 or 2; q is selected from integers of 0 to 6.

[0011] In a further preferred embodiment of the present invention, in the compound represented by formula (II) of the present invention, R4, R5 and R6 each independently represent a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, -OR 12 , -SR 12 , -C(O)R 11 , -C(O)OR 12 , -C(O)-(CH) m -C(O)R 11 , -OC(O)R 11 , -(CH) m -N(R c )C(O)R 11 wherein the alkyl, aryl or heteroaryl group is further selected from the group consisting of a halogen, a hydroxyl group, an alkyl group, an OR 12 , S.R. 12 , N.R. a R b , -COR 11 , -C(O)OR 12 , -O(O)CR 11 , -N(R c )C(O)R d , -O(CH2) m O(CH2) q R 12 , a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, and the aryl group, arylalkyl group, heteroaryl group, or heteroarylalkyl group may be further substituted by one or more groups selected from a halogen and a hydroxy group; R 11 and R 12 are each independently selected from hydrogen, halogen, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, an amino group, a hydroxy group, an alkyl group, -OR d , -N(R c )C(O)R dmay be substituted by one or more groups selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R a and R b are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R a and R b form a heterocyclic group together with the atom to which they are linked, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R c and R d are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; m is an integer selected from 0 to 6; q is selected from integers of 0 to 6.

[0012] In a further preferred embodiment of the present invention, in the compound represented by formula (II) of the present invention, Among R4, R5 and R6, one is hydrogen, and the remaining two together with the carbon atom to which they are connected form a cycloalkyl group or a heterocyclic group, and the cycloalkyl group or the heterocyclic group may further include a halogen atom, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, -C(O)R 11 , -C(O)OR 12 , -OC(O)R 11 may be substituted by one or more groups selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 11 and R 12 are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, -NR a R b , -OR d , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a hydroxyaryl group, and a heteroaryl group, R a and R b are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R a and R b form a heterocyclic group together with the atom to which they are linked, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R c and R d are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; p is selected from 0, 1 or 2.

[0013] In a further preferred embodiment of the present invention, in the compound represented by formula (II) of the present invention, Among R4, R5 and R6, one is hydrogen, and the remaining two form a cycloalkyl group or a heterocyclic group together with the carbon atom to which they are linked, and the cycloalkyl group or the heterocyclic group further includes -C(O)R 11 , -C(O)OR 12 may be substituted with one or more groups selected from R 11 and R 12 are each independently selected from hydrogen, halogen, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, a hydroxy group, an alkyl group, -OR d , -N(R c )C(O)R d , an aryl group, a hydroxyaryl group, or a heteroaryl group; R c and R d are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, an aryl group, and a heteroaryl group, and the alkyl group, alkoxy group, aryl group, and heteroaryl group are optionally substituted with one or more groups selected from a halogen atom, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0014] In another preferred embodiment of the present invention, the compound represented by formula (I) of the present invention is a compound represented by formula (III): [ka] (In the formula, R1 is hydrogen or C 1-6 selected from alkyl groups, R4 and R5 each independently represent a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 12 , -SR 12 , -C(O)R 11 , -C(O)OR 12 , -OC(O)R 11 , -NR a R b , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), -O(CH2) m O(CH2) q R 12 , -N(R c )C(O)-(CH) m -N(R c )C(O)R d wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is further selected from the group consisting of halogen, amino group, nitro group, cyano group, hydroxy group, mercapto group, alkyl group, alkoxy group, alkenyl group, alkynyl group, OR 12 , S.R. 12 , N.R. a R b , -C(O)R 11 , -C(O)OR 12 , -O(O)CR 11 , -(CH) m -OC(O)R 11 , a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, or R4 and R5 together with the N atom form a heterocyclic group, and the heterocyclic group can further include a halogen atom, an amino group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, -C(O)R 11 , -C(O)OR 12, -O(O)CR 11 may be substituted by one or more groups selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 11 and R 12 are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, -NR a R b , -OR d , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, R a and R bare each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R a and R b form a heterocyclic group together with the atom to which they are linked, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R c and R d are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; m is an integer selected from 0 to 6; p is selected from 0, 1 or 2; q is selected from integers of 0 to 6.

[0015] In a further preferred embodiment of the present invention, in the compound represented by formula (III) of the present invention, R4 and R5 are each independently selected from hydrogen, an alkyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the aryl group, or the heteroaryl group is further selected from halogen, a hydroxyl group, a mercapto group, an alkyl group, a -C(O)R 11 , -C(O)OR 12 , -O(O)CR 11 , -(CH) m -OC(O)R 11 may be substituted by one or more groups selected from the group consisting of an aryl group and a heteroaryl group; R 11 and R 12 are each independently selected from hydrogen and an alkyl group, wherein the alkyl group is further selected from halogen, -OR d , -N(R c )C(O)R d may be substituted with one or more groups selected from R c and R d are each independently selected from hydrogen, an alkyl group, an aryl group, and a heteroaryl group, and the alkyl group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; m is an integer selected from 0 to 6; p is selected from 0, 1 or 2.

[0016] In another preferred embodiment of the present invention, the compound represented by formula (I) of the present invention is a compound represented by formula (IV): [ka] (In the formula, R1 is hydrogen or C 1-6selected from alkyl groups, A is selected from C, O or N; R7 and R8 are each independently selected from hydrogen, halogen, a hydroxyl group, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group; R9 is hydrogen, halogen, amino group, hydroxyl group, mercapto group, alkyl group, alkoxy group, -C(O)R 11 , -C(O)OR 12 , -OC(O)R 11 , a cycloalkyl group, or a heterocyclic group; R 11 and R 12 are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, -NR a R b , -OR d , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O) p N(R a )(R b ), an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, R a and R bare each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R a and R b form a heterocyclic group together with the atom to which they are linked, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R c and R d are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; p is selected from 0, 1, or 2.

[0017] In another preferred embodiment of the present invention, the compound represented by formula (I) of the present invention is a compound represented by formula (V): [ka] (In the formula, E is O or NR 14 Selected from R 10 , R 13 , R 14 are each independently hydrogen, C 1-6 An alkyl group or an aryl group, 1-6 The alkyl or aryl group may further include a halogen, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, -OR 12 , -COR 11 , -C(O)OR 12 , -OC(O)R 11 , -OC(O)OR 12 may be substituted by one or more substituents selected from R 11 and R 12 are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are further selected from halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, -NR a R b , -OR d , -N(R c )C(O)R d , -C(O)N(R a )(R b ), -N(R c )S(O) p R d , -S(O)p N(R a )(R b ), an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, R a and R b are each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R a and R b form a heterocyclic group together with the atom to which they are linked, and the heterocyclic group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R c and R dare each independently selected from hydrogen, halogen, a hydroxy group, a cyano group, an amino group, a carboxy group, an ester group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and wherein the amino group, the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted by one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; p is selected from 0, 1, or 2.

[0018] In a further preferred embodiment of the present invention, in the compound represented by formula (V) of the present invention, R 10 , R 13 , R 14 are each independently hydrogen or C 1-6 alkyl group, 1-6 The alkyl group may further include a halogen, a hydroxy group, a mercapto group, an alkyl group, an alkoxy group, an aryl group, a heteroaryl group, -OR 12 , -COR 11 , -C(O)OR 12 , -OC(O)OR 11 may be substituted by one or more substituents selected from R 11 and R 12 are each independently selected from an alkyl group, an aryl group, and a heteroaryl group, and the alkyl group, aryl group, and heteroaryl group may be further substituted with one or more groups selected from a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxy group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0019] Representative examples of the compounds of the present invention include, but are not limited to, the following compounds, or their meso, racemic, enantiomeric, diastereomeric, or mixture forms, or pharma- ceutically acceptable salts: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17]

[0020] The present invention further relates to a method for producing the compound represented by formula (II) according to the present invention, or a meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, the method comprising the steps of: [ka] The method includes a step of subjecting compound IIc and nitroxoline to a nucleophilic reaction in a solvent in the presence of an alkali to obtain a compound represented by general formula (II), The alkali is preferably selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, and pyridine, and the solvent is preferably selected from dichloromethane, N,N-dimethylformamide, tetrahydrofuran, and t-butanol methyl ether; R1, R4, R5 and R6 are as defined in general formula (II).

[0021] The present invention relates to a method for producing the compound represented by the formula (III) according to the present invention, or a meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutical acceptable salt thereof, the method comprising the steps of: [ka] The method includes a step of subjecting compound IIIc and nitroxoline to a nucleophilic reaction in a solvent in the presence of an alkali to obtain a compound represented by general formula (III), The alkali is preferably selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, and pyridine, and the solvent is preferably selected from dichloromethane, N,N-dimethylformamide, tetrahydrofuran, and t-butanol methyl ether; R4 and R5 are as defined in general formula (III).

[0022] The present invention further relates to a process for preparing a compound of formula (II') or its meso, racemic, enantiomeric, diastereomeric or mixtures thereof, or a pharma- ceutical acceptable salt thereof, comprising the steps of: [ka] The method includes the steps of: reacting compound II'b with compound II'c in a solvent in the presence of an alkali to obtain a compound of formula (II'), [ka] The alkali is preferably potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, or pyridine, and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, or t-butanol methyl ether; R4, R5 and R6 are as defined in general formula (II).

[0023] The present invention further relates to a process for preparing a compound of formula (V') or its meso, racemic, enantiomeric, diastereomeric or mixtures thereof, or a pharma- ceutical acceptable salt thereof, comprising the steps of: [ka] The method includes the above step of subjecting compound V'd and compound II'b to a nucleophilic reaction in a solvent in the presence of an alkali to obtain a compound represented by formula (V'), The alkali is preferably potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, triethylamine, or pyridine, and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, or t-butanol methyl ether; R 10 and R 13is as defined in general formula (V).

[0024] The present invention further relates to a process for preparing a compound of formula (V″) or its meso, racemic, enantiomeric, diastereomeric or mixtures thereof, or a pharma- ceutical acceptable salt thereof, comprising the steps of: [ka] The method includes the steps of: reacting compound V″a with nitroxoline in the presence of an alkali in a solvent to obtain a compound represented by formula (V″); [ka] The alkali is preferably potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, triethylamine, or pyridine, and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, or t-butanol methyl ether; R 10 and R 13 is as defined in general formula (V).

[0025] The present invention further relates to a pharmaceutical composition comprising as an active ingredient a compound represented by the general formula (I) according to the present invention, or a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0026] The present invention further relates to the use of the compound represented by the general formula (I) according to the present invention, or in the form of a racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the manufacture of an anti-infective and anti-tumor drug, wherein the tumor may be bladder cancer, prostate cancer, or kidney cancer.

[0027] The pharma- ceutically acceptable salt of the compound represented by general formula (I) of the present invention may be an acid addition salt or an alkali addition salt.The acid may be an inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; an organic acid, including but not limited to citric acid, maleic acid, oxalic acid, formic acid, acetic acid, propionic acid, valeric acid, glycolic acid, benzoic acid, fumaric acid, trifluoroacetic acid, succinic acid, tartaric acid, lactic acid, glutamic acid, aspartic acid, salicylic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, and p-benzenesulfonic acid. The alkali may be an inorganic alkali, including but not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; an organic alkali, including but not limited to ammonium hydroxide, triethylamine, N,N-dibenzylethylenediamine, cloprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucosamine, procaine, N-benzylphenethylamine, arginine or lysine; an alkali metal salt, including but not limited to lithium, potassium and sodium salts; an alkaline earth metal salt, including but not limited to barium, calcium and magnesium salts; a transition metal salt, including but not limited to zinc salts; or another metal salt, including but not limited to sodium hydrogen phosphate and disodium hydrogen phosphate.

[0028] Another aspect of the present invention is to prepare the compound of formula (I) or its pharma- ceutical acceptable salt into a clinically usable pharmaceutical composition.Depending on clinical indications, routes and modes of administration, the pharmaceutical preparations include, but are not limited to, oral preparations such as tablets, gels, soft / hard capsules, emulsions, dispersible powders, granules, water / oil suspension emulsions, etc.; injections including intravenous injections, intramuscular injections, intraperitoneal injections, rectal suppositories, and intracranial injections, which may be aqueous or oily solutions; topical preparations including creams, ointments, gels, water / oil solutions and clathrate preparations; inhalation preparations including fine powders, liquid aerosols and various forms suitable for implantation in the body.

[0029] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, troches, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method for preparing pharmaceutical compositions known in the art, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutical preparations with good appearance and milder taste. Tablets contain the active ingredient and non-toxic pharmaceutical excipients suitable for mixing to prepare tablets. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques to provide a sustained release action over a longer period by masking the taste of the drug or by delaying disintegration and absorption in the gastrointestinal tract For example, water-soluble taste-masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate, etc. may be used.

[0030] Oral formulations can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol, or an oil solvent such as peanut oil, liquid paraffin, or olive oil.

[0031] Aqueous suspensions contain the active substance and a mixing excipient suitable for producing an aqueous suspension, such as suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or humectants, such as naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearic acid esters, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexylitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with meta-esters derived from fatty acids and hexylitol anhydrides, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartane.

[0032] Oil suspensions can be prepared by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oil suspensions may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. In addition, the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding an antioxidant such as butyl ether or alpha-tocopherol.

[0033] Dispersible powders and granules suitable for preparing a water suspension can provide the active ingredient and a dispersing or wetting agent for mixing, a suspending agent, or one or more preservatives by adding water. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavorings, and coloring agents can also be added. These compositions are preserved by the addition of an antioxidant, for example ascorbic acid.

[0034] The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil, peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, esters or metaesters derived from fatty acids and hexylitol anhydrides, such as sorbitan monooleate, and condensation products of said metaesters with ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavorings, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners, such as glycerin, propylene glycol, sorbitol, or sucrose, may be used. Such preparations may also contain emollients, preservatives, coloring agents, and antioxidants.

[0035] The pharmaceutical compositions of the invention may be in the form of a sterile injectable aqueous solution. Acceptable solvents and vehicles that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. A mixture of water and glycerin is then treated with the oil solution to form the microemulsion. The injectable solution or microemulsion can be injected into the patient's bloodstream by localized large-volume injection. Alternatively, the solutions and microemulsions are preferably administered to maintain a constant circulating concentration of the compound of the invention. A continuous intravenous drug delivery device can be used to maintain this concentration.

[0036] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be prepared by known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic, non-gastrointestinally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, it is easy to use sterile fixed oils as a solvent or suspending medium. For this purpose, any formulated fixed oil may be used, including synthetic glycerin mono- or diesters. In addition, fatty acids such as oleic acid may also be injectable.

[0037] The compound of the present invention can be administered in the form of suppositories for rectal administration.These pharmaceutical compositions can be prepared by mixing with suitable non-irritating excipients that are solid at normal temperature but liquid in the rectum, and therefore melt in the rectum to release the drug.Such materials include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0038] As known to those skilled in the art, the dosage of a drug depends on several factors, including but not limited to the activity of the specific compound used, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the food and drink of the patient, the administration time, the administration method, the excretion rate, the combination of drugs, etc., and the optimal treatment method, such as the treatment pattern, the daily dose of the compound of the present invention or the type of medicinal salt, can be verified based on conventional treatment protocols.

[0039] The present invention contains the compound represented by general formula (I) and its pharma- ceutically acceptable salt, hydrate or solvate as an active ingredient, which can be mixed with a pharma- ceutically acceptable carrier or excipient to prepare a composition and prepare it into a clinically acceptable dosage form. The derivative of the present invention can be used in combination with other active ingredients, so long as it does not cause other undesirable effects such as allergic reactions. The compound of the present invention can be used as the sole active ingredient or in combination with other treatments and other drugs. The combination treatment can be achieved by administering each treatment component simultaneously, separately or successively.

[0040] Unless stated to the contrary, terms used in the specification and claims have the following definitions.

[0041] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, and more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, Examples of such groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted on any available point of attachment, and the substituent may be preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, or formate groups.

[0042] The term "alkenyl group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. An alkenyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0043] The term "alkynyl group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, etc. An alkynyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0044] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spiro, fused, and bridged ring cycloalkyl groups.

[0045] The term "spirocycloalkyl group" refers to a polycyclic group in which one carbon atom (called a spiro atom) is shared between 5-20 membered monocyclic rings, which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl groups, bisspirocycloalkyl groups, and polyspirocycloalkyl groups, and are preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, they are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include the following: [ka]

[0046] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that it comprises, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, and is preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered biscycloalkyl group. Non-limiting examples of fused cycloalkyl groups include the following: [ka]

[0047] The term "bridged cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of rings that it comprises, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, and is preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include the following: [ka]

[0048] The cycloalkyl ring may be fused onto an aryl group, a heteroaryl group, or a heterocycloalkyl ring, where the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, or formate groups.

[0049] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, in which one or more of the ring atoms is nitrogen, oxygen, or S(O). m(where m is an integer of 0 to 2), but does not include the ring moiety -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, most preferably contains 4 to 10 ring atoms, of which 1 to 3 are heteroatoms, and most preferably contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyridinepyranyl, etc., preferably 1,2,5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

[0050] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group having 5- to 20-membered rings sharing one atom (called a spiro atom) between the rings, where one or more of the ring atoms is nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of spiro atoms shared between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a bisspiro heterocyclic group, or a polyspiro heterocyclic group, and is preferably a monospiro heterocyclic group or a bisspiro heterocyclic group. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include the following: [ka]

[0051] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members in which each individual ring in the system shares an adjacent pair of atoms with every other ring in the system, where one or more of the rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and where one or more of the ring atoms is nitrogen, oxygen, or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, and preferably, it is a bicyclic or tricyclic, more preferably, a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include the following. [ka]

[0052] The term "bridged heterocyclic group" refers to a 5-14 membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly linked, and may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and in which one or more of the ring atoms is not nitrogen, oxygen, or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, and is preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include the following. [ka]

[0053] The heterocyclic ring can be fused onto an aryl group, a heteroaryl group, or a cycloalkyl ring, where the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include the following: [ka]

[0054] The heterocyclic group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, or formate groups.

[0055] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6-14 members, such as phenyl and naphthyl groups. More preferably, phenyl. The aryl ring can be fused onto a heteroaryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, non-limiting examples of which include: [ka]

[0056] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxy groups, or formate groups.

[0057] The term "heteroaryl group" refers to a heteroaryl family containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5-10 membered and contains 1-3 heteroatoms, more preferably 5 or 6 membered and contains 1-2 heteroatoms, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl, more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused onto an aryl, heterocyclic or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include: [ka]

[0058] The heteroaryl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxy groups, or formate groups.

[0059] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy groups. An alkoxy group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or formate groups.

[0060] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where alkyl group is as defined above.

[0061] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0062] The term "hydroxy" refers to an --OH group.

[0063] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0064] The term "amino group" refers to --NH.sub.2.

[0065] The term "cyano" refers to -CN.

[0066] The term "nitro group" refers to --NO.sub.2.

[0067] The term "oxo" refers to =O.

[0068] The term "carboxy" refers to -C(O)OH.

[0069] The term "mercapto" refers to -SH.

[0070] The term "ester group" refers to a -C(O)O(alkyl group) or a -C(O)O(cycloalkyl group), where alkyl and cycloalkyl groups are defined above.

[0071] The term "acyl group" refers to a compound containing a -C(O)R group, where R is an alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group.

[0072] "May" or "may" means that the subsequently described event or circumstance can occur but does not have to occur, and the description includes cases where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may be present but is not required to be present, and the description includes cases where the heterocyclic group is substituted by an alkyl group and cases where the heterocyclic group is not substituted by an alkyl group.

[0073] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are each independently replaced by the corresponding number of substituents. Needless to say, the substituents are only present at their possible chemical positions, and the skilled person can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, amino groups or hydroxy groups with free hydrogen may be unstable when they are attached to carbon atoms with unsaturated (e.g., ethylenic) bonds.

[0074] By "pharmaceutical composition" is meant a mixture of one or more of the compounds described herein or physiological / pharmaceutical salts or prodrugs thereof with other chemical components, as well as other components such as physiological / pharmaceutical carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, facilitate absorption of the active ingredient, and exert biological activity.

[0075] The term "pharmaceutical salt" refers to a salt of a compound that is safe and effective when used in a mammalian body and that possesses the desired biological activity.

[0076] Methods for synthesizing the compounds of the present invention In order to achieve the object of the present invention, the present invention uses the following synthesis scheme to prepare the compound of general formula (I) of the present invention.

[0077] When the compound represented by formula (I) is a compound represented by formula (II), the compound represented by formula (II) is synthesized according to the following scheme 1. [ka]

[0078] Step 1: An acyl chloride compound IIa and an aldehyde compound IIb are subjected to an insertion reaction in the presence of an alkali and zinc chloride in a solvent to obtain a compound IIc, wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc.

[0079] Step 2: Compound IIc is reacted with nitroxoline in the presence of an alkali in a solvent to obtain a compound of formula (II), wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc.

[0080] When R1 in the compound represented by formula (II) is hydrogen, the compound represented by formula (II') can be synthesized according to the following scheme 2. [ka]

[0081] Step 1: The sulfonyl chloride compound II'a and nitroxoline are reacted nucleophilically in the presence of an alkali in a solvent to obtain compound II'b, wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc.

[0082] Step 2: Compound II'b and compound II'c are subjected to a nucleophilic reaction in the presence of an alkali in a solvent to obtain a compound of formula (II'), wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc.

[0083] When the compound represented by formula (I) is a compound represented by formula (III), the compound represented by formula (III) is synthesized according to the following scheme 3. [ka]

[0084] Step 1: Amino compound IIIa and chloromethoxy acyl chloride compound IIIb are subjected to an amide condensation reaction in a solvent in the presence of an alkali to obtain compound IIIc, wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc.

[0085] Step 2: Compound IIIc is reacted with nitroxoline in the presence of an alkali in a solvent to obtain a compound of formula (III), wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydrogen carbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc.

[0086] When the compound represented by formula (I) is a compound represented by formula (V') or formula (V''), the compound represented by formula (V') or formula (V'') is synthesized according to the following schemes 4 and 5. [ka]

[0087] Step 1: Amino compound V'a, phenoxy phosphoryl chloride compound V'b, and hydroxy compound V'c are condensed in a solvent in the presence of an alkali to obtain compound V'd, wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc.

[0088] Step 2: Compound V'd and compound II'b are subjected to a nucleophilic reaction in the presence of an alkali in a solvent to obtain a compound represented by formula (V'), wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc. [ka]

[0089] Compound V″a and nitroxoline are subjected to a nucleophilic reaction in the presence of an alkali in a solvent to obtain a compound represented by formula (V″), wherein the alkali is preferably an inorganic or organic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, t-butanol methyl ether, etc.

[0090] R1, R4, R5, R6, R 10 and R 13 is as defined in general formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0091] The present invention will now be further described with reference to the following examples, which should not be construed as limiting the scope of the invention.

[0092] The present invention will be further described below with reference to embodiments, which should not be construed as limiting the scope of the invention.

[0093] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6The NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer, with deuterated dimethylsulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as solvents, and with tetramethylsilane (TMS) as the internal standard.

[0094] A liquid chromatograph mass spectrometer (Thermo, Ultimate3000 / MSQ) is used for MS measurements.

[0095] A high pressure liquid chromatograph (Agilent 1260 Infinity, Gemini C18 250×4.6 mm, 5 u column) is used for HPLC measurements.

[0096] Thin layer chromatography (TLC) uses silica gel plates HSGF245 manufactured by Yantai Huanghai, thin layer chromatography analysis products use 0.15mm~0.2mm specifications, thin layer chromatography separation purification products use 0.9mm~1.0mm specifications.

[0097] Column chromatography generally uses 200-300 mesh silica gel made by Yantai Huanghai as the carrier.

[0098] The known starting materials of the present invention can be synthesized using methods known in the art, or can be purchased from Shanghai Darui Fine Chemicals Co., Ltd., Shanghai Taitan Technology Co., Ltd., Shanghai Runjie Chemical Reagents Co., Ltd., TCI, Aldrich Chemical Company. Experimental methods without specific conditions specified in the examples generally follow the usual conditions or the conditions suggested by the manufacturers of raw materials or products. Reagents without specific origins are ordinary reagents purchased on the market.

[0099] Unless otherwise specified in the examples, the reactions can be carried out under either an argon or nitrogen atmosphere, where argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0100] Unless otherwise specified in the examples, solutions refer to aqueous solutions.

[0101] Unless otherwise specified in the examples, the reaction temperature is room temperature, ie, 20°C to 30°C.

[0102] Example 1: Synthesis of (5-nitroquinolin-8-yloxy)methyl acetate (1) [ka] Step 1: Preparation of 5-nitro-8-chloromethyloxyquinoline (1a) At room temperature, aqueous sodium hydrogen carbonate solution (60 mL, 3.5 mol / L) and tetrabutyl ammonium hydrogen sulfate (TBAHS) (1.78 g, 5.24 mmol) were added to a solution of nitroxoline (10.00 g, 52.59 mmol) in dichloromethane (DCM) (100 mL) and stirred for 20 minutes. Chloromethyl chlorosulfonate (10.42 g, 63.15 mmol) was added dropwise to the reaction system and stirred at room temperature for 16 hours. The reaction solution was filtered, and the organic phase was washed with potassium carbonate solution and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 5-nitro-8-chloromethyloxyquinoline (2.5 g, yield 20%). Step 2: Preparation of (5-nitroquinolin-8-yloxy)methyl acetate (1) Acetic acid (38 mg, 0.63 mmol), potassium carbonate (104 mg, 0.75 mmol), and sodium iodide (9 mg, 0.06 mmol) were added to N,N-dimethylformamide (3 mL) at room temperature and stirred uniformly. The reaction system was heated to 60°C and stirred for 10 minutes, after which 5-nitro-8-chloromethyloxyquinoline (150 mg, 0.63 mmol) was added and stirred for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed with a saturated saline solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography fractionation plate (eluent: 5% methanol / 95% dichloromethane) to obtain (5-nitroquinolin-8-yloxy)methyl acetate (145 mg, yield 88%). 1 H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.17 (s, 2H), 2.16 (s, 3H). MS calculation: 262.2; MS measurement: 263.1 [M+H] + .

[0103] Example 2: Synthesis of (5-nitroquinolin-8-yloxy)methyl propionate (2) [ka] (5-nitroquinolin-8-yloxy)methylpropionate (2) was obtained in the same manner as in Example 1, except that propionic acid was used instead of acetic acid in step 2. 1H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.19 (s, 2H), 2.44 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H). MS calculation: 276.2;MS measurement: 277.1 [M+H] + .

[0104] Example 3: Synthesis of (5-nitroquinolin-8-yloxy)methyl isobutyrate (3) [ka] (5-nitroquinolin-8-yloxy)methyl isobutyrate (3) was obtained in the same manner as in Example 1, except that isobutyric acid was used instead of acetic acid in Step 2. 1 H NMR (400 MHz, CDCl3) δ 9.20 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.19 (s, 2H), 2.64 (hept, J = 7.0 Hz, 1H), 1.19 (d, J = 7.0 Hz, 6H). MS calculation: 290.3;MS actual measurement: 291.1 [M+H] + .

[0105] Example 4: Synthesis of (5-nitroquinolin-8-yloxy)methyl pivalate (4) [ka] (5-Nitroquinolin-8-yloxy)methyl pivalate (3) was obtained in the same manner as in Example 1, except that pivalic acid was used instead of acetic acid in Step 2. 1 H NMR (400 MHz, CDCl3) δ 9.20 (dd, J = 8.9, 1.6 Hz, 1H), 9.08 (dd, J = 4.1, 1.6 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.19 (s, 2H), 1.22 (s, 9H). MS calculation: 304.3;MS measurement: 305.1 [M+H] + .

[0106] Example 5: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-ethylbutyrate (5) [ka] Potassium carbonate (9.59g, 69.41mmol) was added batchwise to a solution of nitroxoline (6.00g, 35.55mmol) and 2-ethylbutyrate-1-chloromethyl 10.00g, 60.74mmol in N,N-dimethylformamide (100mL) at room temperature. The reaction was stirred at 60°C for 16 hours. Water was added to quench the reaction, and the mixture was extracted with dichloromethane (100mLx3). The organic phase was washed with 1M hydrochloric acid, 1M aqueous sodium bicarbonate, and saturated saline, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% n-hexane / 95% ethyl acetate) to give (5-nitroquinolin-8-yloxy)methyl 2-ethylbutyrate (1.4g, 14% yield). 1H NMR (400 MHz, CD3OD): δ 9.17-9.14 (m, 1H), 8.97-8.95 (m, 1H), 8.55 (d, J = 8.8 Hz, 1H), 7.84-7.81 (m, 1H), 7.58 (d, J = 8.8 Hz, 1H), 6.21 (s, 2H), 2.34-2.27 (m, 1H), 1.67-1.47 (m, 4H), 0.815 (t, J = 7.2 Hz, 6H). MS calculation: 318.1;MS measurement: 319.1 [M+H] + .

[0107] Example 6: Synthesis of (5-nitroquinolin-8-yloxy)methyl 4-methylpiperazine-1-carboxylate (6) [ka] Step 1: Preparation of 4-methylpiperazine-1-chloromethylformate (6a) 1-Methylpiperazine (1g, 10mmol) was dissolved in dichloromethane (30mL), and triethylamine (1.21g, 12mmol) and chloromethyl chloroformate (1.29g, 10mmol) were added dropwise in an ice-water bath. The reaction solution was stirred at 0°C for 30 minutes, then heated to 25°C and stirred for 16 hours. After quenching the reaction with water (50mL), the reaction solution was extracted with dichloromethane (100mLx3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-methylpiperazine-1-chloromethyl formate (1.7g, 89% yield). Step 2: Preparation of (5-nitroquinolin-8-yloxy)methyl 4-methylpiperazine-1-carboxylate (6) Nitroxoline (600mg, 3.16mmol) and 4-methylpiperazine-1-chloromethylformate (915mg, 4.74mmol) were dissolved in N,N-dimethylformamide (15mL), and then potassium carbonate (870mg, 6.31mmol) and sodium iodide (45mg, 0.32mmol) were added at 0℃. The reaction solution was stirred at 60℃ for 4 hours. The reaction solution was cooled to room temperature, quenched with water, and extracted with dichloromethane (100mLx3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% methanol / 95% dichloromethane) to give (5-nitroquinolin-8-yloxy)methyl 4-methylpiperazine-1-carboxylate (150mg, 14% yield) as a yellow solid product. 1 H NMR (400 MHz, CDCl3) δ: 9.20 (dd, J = 8.8, 1.6 Hz, 1H), 9.06 (dd, J = 4.0, 1.2 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.8, 4.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.21 (s, 2H), 3.52 (dd, J =10.0, 4.8 Hz, 4H), 2.39 (t, J = 4.8 Hz, 2H), 2.32 (t, J = 4.8 Hz, 2H), 2.28 (s, 3H). MS calculation: 346.13;MS measurement: 347.1 [M+H] + .

[0108] Example 7: Synthesis of (5-nitroquinolin-8-yloxy)methylmorpholine-4-carboxylate (7) Except for using morpholine instead of 1-methylpiperazine in Step 1, the same procedure as in Example 6 was followed to obtain (5-nitroquinolin-8-yloxy)methylmorpholine-4-carboxylate. 1H NMR (400 MHz, CDCl3) δ: 9.20-9.18 (s, 1H), 9.07-9.06 (s, 1H),8.50 (d, J = 8.8 Hz, 1H), 7.73-7.70 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.22 (s, 2H), 3.68 (s, 2H), 3.61 (s, 2H), 3.50 (s, 4H). MS calculation: 333;MS actual measurement: 334[M+H] + .

[0109] Example 8: Synthesis of 4-((5-nitroquinolin-8-yloxy)methoxy)-4-oxobutyric acid (8) [ka] Step 1: Preparation of t-butyl(((5-nitroquinolin-8-yl)oxy)methyl)succinate (8a) 8-(Chloromethoxy)-5-nitroquinoline (400mg, 1.68mmol) and 4-(t-butoxy)-4-oxobutyric acid (584mg, 3.36mmol) were dissolved in DMF (10mL), and potassium carbonate (463mg, 3.36mmol) was added. The reaction solution was stirred at 25°C for 3 hours. After the reaction was quenched with water (100mL), the reaction solution was extracted with ethyl acetate (20mLx2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain 310mg of t-butyl(((5-nitroquinolin-8-yl)oxy)methyl)succinate as the product. Step 2: Preparation of 4-((5-nitroquinolin-8-yloxy)methoxy)-4-oxobutyric acid (8) t-Butyl (((5-nitroquinolin-8-yl)oxy)methyl)succinate (230 mg, 0.718 mmol) was added to 10 mL of HCl / dioxane and stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain the product 4-((5-nitroquinolin-8-yloxy)methoxy)-4-oxobutyric acid (128 mg, 65% yield) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d6) δ: 12.3 (br, 1H).9.05 (d, J = 2.8 Hz, 1H), 9.00 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.8, 4.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 6.14 (s, 2H), 2.60~2.65 (m, 2 Hz, 4H), 2.50~2.55 (m, 2H). MS calculation: 320.26;MS measurement: 321.1 [M+H] + .

[0110] Example 9: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-(pyridin-3-yl)acetate (9) [ka] 5-Nitro-8-chloromethyloxyquinoline (1a) (250 mg, 1.05 mmol) was dissolved in DMF (10 mL), 3-pyridineacetic acid (186 mg, 1.05 mmol) and triethylamine (510 mg, 5.25 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:1 to 0:1) to obtain the product ((5-nitroquinolin-8-yl)oxy)methyl 2-(pyridin-3-yl)acetate (90 mg, 26% yield) as a green solid with a purity of 97%. 1 H NMR (400 MHz,DMSO-d6) δ: 8.95~9.10 (d, 2H), 8.47~8.54 (d, 2H), 7.33~7.89 (m,4H), 7.54 (d, J = 8.4 Hz, 1H),6.18 (s, 2H), 3.89 (s,2H), 4.72~4.75 (m, 2H). MS calculation: 339.31;MS actual measurement: 340.1[M+H] + .

[0111] Example 10: Synthesis of (5-nitroquinolin-8-yloxy)methyl 8-hydroxycaprylate [ka] At room temperature, 8-hydroxycaprylic acid (201 mg, 1.25 mmol), potassium carbonate (209 mg, 1.51 mmol), and sodium iodide (19 mg, 0.13 mmol) were added to N,N-dimethylformamide (6 mL) and stirred uniformly. The reaction system was heated to 60°C and stirred for 10 minutes, after which 5-nitro-8-chloromethyloxyquinoline (1a) (300 mg, 1.26 mmol) was added and stirred for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed with a saturated saline solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (rinsing with dichloromethane) to obtain (5-nitroquinolin-8-yloxy)methyl 8-hydroxycaprylate (200 mg, yield 44%). 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (dd, J = 4.1, 1.6 Hz, 1H), 9.00 (dd, J = 8.9, 1.6 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.9, 4.1 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 6.14 (s, 2H), 3.30 (t, J = 6.6 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.56 - 1.45 (m, 2H), 1.35 - 1.24 (m, 2H), 1.15 (s, 6H). MS calculation: 362.4;MS actual measurement: 363.3[M+H] + .

[0112] Example 11: Synthesis of methyl (5-nitroquinolin-8-yloxy)methyl adipate (11) [ka] Methyl (5-nitroquinolin-8-yloxy)methyl adipate (11) was obtained in the same manner as in Example 10, except that monomethyl adipate was used instead of 8-hydroxycaprylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (dd, J = 4.1, 1.6 Hz, 1H), 9.99 (dd, J = 8.9, 1.5 Hz, 1H), 9.55 (d, J = 8.8 Hz, 1H), 8.86 (dd, J = 8.9, 4.1 Hz, 1H), 8.54 (d, J = 8.9 Hz, 1H), 7.13 (s, 2H), 4.53 (s, 3H), 4.32 (s, 4H), 3.42 (t, J = 7.0 Hz, 2H), 3.25 (t, J = 7.1 Hz, 2H). MS calculation: 362.3;MS actual measurement: 363.3[M+H] + .

[0113] Example 12: Synthesis of (5-nitroquinolin-8-yloxy)methyl 7-(t-butoxycarbonylamino)enanthate (12) [ka] Except for using 7-(t-butoxycarbonyl-amino)-enanthic acid (purchased from Darui Chemical Co., Ltd.) instead of 8-hydroxycaprylic acid, the same preparation method as in Example 10 was used to obtain (5-nitroquinolin-8-yloxy)methyl 7-(t-butoxycarbonylamino)enanthate. 1H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.18 (s, 2H), 4.47 (s, 1H), 3.07 (d, J = 6.4 Hz, 2H), 2.40 (t, J = 7.5 Hz, 2H), 1.69 - 1.60 (m, 2H), 1.42 (d, J = 10.2 Hz, 11H), 1.35 - 1.25 (m, 4H). MS calculation: 447.5;MS actual measurement: 448.4[M+H] + .

[0114] Example 13: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)-3-phenylpropionate (13) [ka] (S)-(5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)-3-phenylpropionate (13) was obtained in the same manner as in Example 10, except that t-butoxycarbonyl-L-phenylalanine was used instead of 8-hydroxycaprylic acid. 1H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.5 Hz, 1H), 9.08 (dd, J = 4.1, 1.5 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.20 - 7.03 (m, 6H), 6.17 (dd, J = 63.5, 6.5 Hz, 2H), 4.95 (d, J = 7.7 Hz, 1H), 4.62 (dd, J = 13.8, 6.8 Hz, 1H), 3.06 (d, J = 6.3 Hz, 2H), 1.40 (s, 9H). MS calculation: 467.5;MS actual measurement: 468.3[M+H] + .

[0115] Example 14: Synthesis of (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-acetylaminosuccinate (14) [ka] [ka] Step 1: Preparation of (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)succinate (14a) N-(t-butoxycarbonyl-L)-S-methyl-L-cysteine ​​(590 mg, 2.5 mmol), potassium carbonate (580 mg, 4.2 mmol), and potassium iodine (83 mg, 0.5 mmol) were added to N,N-dimethylformamide (5 mL) and stirred uniformly. The reaction system was heated to 60°C and stirred for 10 minutes, after which 5-nitro-8-chloromethoxyquinoline (1a) (500 mg, 2.1 mmol) was added and stirred for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography preparative plate (developing agent: 5% methanol / 95% dichloromethane) to give (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)succinate (200 mg, yield 33%). Step 2: Preparation of (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-aminosuccinate (14b) Trifluoroacetic acid (5 mL) was added dropwise to a solution of (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)succinate (200 mg, 0.46 mmol) in dichloromethane (5 mL) at room temperature. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain crude (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-aminosuccinate (220 mg, yield 99%). Step 3: Preparation of S-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-acetylaminosuccinate (14) (S)-4-Methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-aminosuccinate (200 mg, 0.68 mmol) and acetyl chloride (80 mg, 1.0 mmol) were dissolved in dichloromethane (10 mL), triethylamine (140 mg, 2.0 mmol) was slowly added dropwise under ice-water bath conditions, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The reaction solution was added to dichloromethane (100 mL), washed once with water, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (178 mg, 57% yield). 1 H-NMR (400 Hz, CDCl3) δ: 9.20 (dd, J = 8.8, 1.6 Hz, 1H), 9.10 (dd, J = 4, 1.6 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 8.8 Hz, 4.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8 Hz, 1H), 6.23-6.27 (m, 2H), 4.94-4.98 (m, 1H), 3.61 (s, 3H), 3.03-3.09 (m, 1H), 3.85-2.90 (m, 1H), 2.03 (s, 3H).

[0116] Example 15: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-acetylamino-4-methylvalerylamino)acetate (15) [ka] [ka] Step 1: Preparation of (5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)acetate (15a) Potassium carbonate (0.65g, 4.2mmol) was added to a solution of Boc-glycine (700mg, 4.1mmol) and 5-nitro-8-(chloromethoxy)quinoline (1a) (500mg, 2.1mmol) in N,N-dimethylformamide (10mL) at room temperature. The reaction was allowed to proceed for 2 hours at room temperature, followed by extraction with 30mL of water and dichloromethane (20mLx2). The organic phase was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain 600mg of the product as a white solid with a yield of 75.7% and a purity of 95%. Step 2: Preparation of (5-nitroquinolin-8-yloxy)methyl 2-aminoacetate hydrochloride (15b) At room temperature, (5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)acetate (600 mg, 1.59 mmol) was added to 10 mL of HCl / dioxane solution and stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain 600 mg of product as a white solid with a purity of 97%. Step 3: Preparation of ((S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-(t-butoxycarbonylamino)-4-methylvalerylamino)acetate (15c) At room temperature, (5-nitroquinolin-8-yloxy)methyl 2-aminoacetate hydrochloride (500 mg, 1.6 mmol) and Boc-L-leucine (553 mg, 2.4 mmol) were added to 10 mL of DMF, the temperature was lowered to 0°C, 1-hydroxy-benzo-triazole (HOBt) (342 mmol, 2.4 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (480 mg, 2.4 mmol), and TEA (500 mg, 4.8 mmol) were added in sequence, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15:1) to obtain 80 mg of the product with a purity of 97%. Step 4: Preparation of (S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-amino-4-methylvalerylamino)acetate hydrochloride (15d) ((S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-(t-butoxycarbonylamino)-4-methylvalerylamino)acetate (80 mg, 0.16 mmol) was added to 10 mL of HCl / dioxane (4 M) and stirred for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain 70 mg of the product as a white solid with a purity of 95%. Step 5: Preparation of (S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-acetylamino-4-methylvalerylamino)acetate (15) (S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-amino-4-methylvalerylamino)acetate hydrochloride (70 mg, 0.16 mmol) was added to 10 mL of dichloromethane, cooled in an ice bath, acetyl chloride (39 mg, 0.48 mmol) was added, and then TEA (80 mg, 0.8 mmol) was slowly added and stirred at 10° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain the product (S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-acetylamino-4-methylvalerylamino)acetate (40 mg, 57% yield). Pale yellow solid, 97% pure. 1 H-NMR (400 MHz, DMSO-d6) δ: 9.05 (dd, J = 4.4 Hz,1.4Hz,1H), 9.00 (dd, J = 8.8 Hz,1.6Hz,1H), 8.55 (d, J=8.8 Hz, 1H), 8.41(t,J=6Hz,1H), 8.00(d,J=8.8Hz,1H), 7.88(dd, J = 8.8 Hz, 4.0Hz,1H), 7.54 (d, J=8.8 Hz, 1H), 6.14-6.18 (m, 2H), 4.26-4.32 (m, 1H), 3.85-3.99 (m, 2H), 1.825 (s,3H),1.52-1.58 (m, 1H),1.35-1.39(m, 2H) ,0.81 (d, J=6.8Hz,3H), 0.78 (d, J=6.4Hz,3H). MS calculation: 432.16;MS measurement: 433.2 [M+H]+.

[0117] Example 16: Synthesis of (R)-(5-nitroquinolin-8-yloxy)methyl 2-acetylamino-3-(methylthio)propionate (16) [ka] [ka] Step 1: Preparation of (R)-(5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)-3-(methylthio)propionate (16a) At room temperature, N-(t-butoxycarbonyl)-S-methyl-L-cysteine ​​(590 mg, 2.5 mmol), potassium carbonate (580 mg, 4.2 mmol), and potassium iodine (83 mg, 0.5 mmol) were added to N,N-dimethylformamide (5 mL) and stirred uniformly. The reaction system was heated to 60°C and stirred for 10 minutes, after which 5-nitro-8-chloromethoxyquinoline (1a) (500 mg, 2.1 mmol) was added and reacted for 1 hour with stirring. The reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography preparative plate (eluent: 5% methanol / 95% dichloromethane) to give (R)-(5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)-3-(methylthio)propionate (300 mg, yield 33%). Step 2: Preparation of (R)-(5-nitroquinolin-8-yloxy)methyl 2-amino-3-(methylthio)propionate (16b) Trifluoroacetic acid (2 mL) was added dropwise to a solution of (R)-(5-nitroquinolin-8-yloxy)methyl 2-(t-butoxycarbonylamino)-3-(methylthio)propionate (200 mg, 0.46 mmol) in dichloromethane (5 mL) at room temperature. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain (R)-(5-nitroquinolin-8-yloxy)methyl 2-amino-3-(methylthio)propionate (150 mg, yield 99%). Step 3: Preparation of (R)-(5-nitroquinolin-8-yloxy)methyl 2-acetylamino-3-(methylthio)propionate (16) At 0°C, (R)-(5-nitroquinolin-8-yloxy)methyl 2-amino-3-(methylthio)propionate (200mg, 0.68mmol) and acetyl chloride (80mg, 1.0mmol) were dissolved in dichloromethane (10mL), triethylamine (140mg, 2.0mmol) was slowly added dropwise in an ice-water bath, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The reaction solution was added to dichloromethane (100mL), washed once with water, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reversed-phase high-performance liquid chromatography (column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0 mL / min) to obtain the product (R)-(5-nitroquinolin-8-yloxy)methyl 2-acetylamino-3-(methylthio)propionate (178 mg, yield 57%). 1 H-NMR (400 Hz, CDCl3) δ: 9.37-9.41 (m, 1H), 9.17-9.19 (m, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 8.8, 4.4 Hz, 1H), 7.48(d, J = 8.8 Hz, 1H), 6.56 (d, J = 6.8 Hz, 1H), 6.19-6.24 (m, 2H), 4.83-4.88 (m, 1H), 2.90-3.0 (m, 2H), 2.10 (s, 3H), 2.06 (s, 3H). MS calculation: 379.39;MS measurement: 380.1 [M+H] + .

[0118] Example 17: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-(N-methylacetylamino)acetate (17) [ka] (5-nitroquinolin-8-yloxy)methyl 2-(N-methylacetylamino)acetate was obtained in the same manner as in Example 16, except that N-(t-butoxycarbonyl)-N-methylglycine was used instead of N-(t-butoxycarbonyl)-S-methyl-L-cysteine ​​in step 1. 1 H-NMR (400Hz, CDCl3) δ: 9.23 (d, J = 8.8 Hz, 1H), 9.11 (d, J = 2.8 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 8.8, 4.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.21 (s, 2H), 4.20 (s, 2H), 3.11(s, 3H), 2.16 (s, 3H). MS calculation: 333.30;MS actual measurement: 334.1 [M+H] + .

[0119] Example 18: Synthesis of (S)-2-(5-nitroquinolin-8-yloxy)methyl 1-propylpyrrolidine-1,2-dicarboxylate (18) [ka] [ka] Step 1: Preparation of 1-(t-butyl) 2-(((5-nitroquinolin-8-yl)oxy)methyl)(S)-pyrrole-1,2-carbonate diester (18a) At room temperature, 5-nitro-8-(chloromethoxy)quinoline (1a) (1.5g, 6.3mmol) and L-Boc proline (2.02g, 9.4mmol) were dissolved in 15mL of DMF, and potassium carbonate (1.73g, 12.6mmol) was added. The mixture was reacted at room temperature for 3 hours, 70mL of water was added, and the mixture was extracted with ethyl acetate (50mLx2). The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain the product 1-(t-butyl) 2-(((5-nitroquinolin-8-yl)oxy)methyl)(S)-pyrrole-1,2-carbonate diester (2.8g, 106% yield). Step 2: Preparation of ((5-nitroquinolin-8-yl)oxy)methyl L-proline ester hydrochloride (18b) At 0° C., 1-(t-butyl) 2-(((5-nitroquinolin-8-yl)oxy)methyl)(S)-pyrrole-1,2-carbonate diester (2.8 g, 6.71 mmol) was added to 30 mL of HCl / dioxane and stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain the product ((5-nitroquinolin-8-yl)oxy)methyl L-proline ester hydrochloride (2.3 g, 97% yield). Step 3: Preparation of (S)-2-(5-nitroquinolin-8-yloxy)methyl 1-propylpyrrolidine-1,2-dicarboxylate (18) At room temperature, ((5-nitroquinolin-8-yl)oxy)methyl L-proline ester hydrochloride (150 mg, 0.424 mmol) was added to 10 mL of DCM, cooled to 0-5°C in an ice bath, propyl chloroformate (104 mg, 0.85 mmol) was added, and then TEA (170 mg, 1.7 mmol) was slowly added. After the addition was completed, the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain the product (S)-2-(5-nitroquinolin-8-yloxy)methyl 1-propylpyrrolidine-1,2-dicarboxylate (70 mg, 40% yield). 1H-NMR (400 MHz, DMSO-d6): δ 9.05~9.06 (m, 1H), 9.01 (dd, J=8.8,1.6Hz,1H), 8.56 (dd, J = 8.8, 4.8Hz, 1H), 7.87 (d, J = 8.8, 4.0Hz, 1H), 7.55 (dd, J = 8.8,2.2Hz, 1H), 6.14~6.15 (m,2H), 4.29-4.31 (m, 1H), 3.88-3.81 (m, 1H),3.47-3.59 (m, 1H), 3.40-3.45 (m, 2H), 1.75-1.95(m, 3H), 1.51~1.45(m, 1H), 0.83-0.85(m, 2H) 0.50-0.51(m, 2H). MS calculated: 403.39 MS observed: 426.1 [M+Na + ].

[0120] Example 19: Synthesis of (S)-2-(5-nitroquinolin-8-yloxy)methyl 1-acetylpyrrolidine-2-carboxylate (19) [ka] (S)-2-(5-nitroquinolin-8-yloxy)methyl 1-acetylpyrrolidine-2-carboxylate was obtained in the same manner as in Example 18, except that acetyl chloride was used instead of propyl chloroformate in Step 3. 1 H-NMR (400 MHz, DMSO-d6): δ:9.05 (dd, J = 4.0 Hz,1.2Hz,1H), 9.00 (dd, J = 8.8 Hz,1.2Hz,1H), 8.55 (d, J=8.8 Hz, 1H), 7.88(dd, J = 4.0 Hz,8.8Hz,1H),7.55 (d, J=8.8 Hz, 1H), 6.11-6.24 (m, 2H), 4.34-4.31 (m, 1H), 3.55-3.35 (m, 2H) ,2.34-2.27 (m, 1H), 2.19-1.79(m, 3H) ,1.94 (s, 3H). MS calculation: 359.3; MS measurement: 360.2 [M+H] + .

[0121] Example 20: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate (20) [ka] Except for using isobutyryl chloride instead of propyl chloroformate in step 3, the same procedure as in Example 18 was followed to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate. 1 H-NMR (400 MHz, DMSO-d6): δ:9.05 (d, J = 4.0 Hz,1H), 9.00 (d, J = 8.8 Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 7.89-7.86 (dd, J = 4.0 Hz,8.8Hz,1H),7.55 (d, J=8.8 Hz, 1H), 6.24-6.11 (m, 2H), 4.36-4.33 (m, 1H), 3.59-3.68 (m, 2H), 2.51-2.66(m, 1H), 2.14~2.19(m, 1H),1.92-1.85(m, 2H), 1.83-1.78(m, 1H) ,0.95 (d, J=6.8 Hz .3H), 0.89 (d, J=6.8 Hz .3H). MS calculation: 387.3; MS measurement: 388.2 [M+H] + .

[0122] Example 21: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-pivaloylpyrrolidine-2-carboxylate (21) [ka] Except for using pivaloyl chloride instead of propyl chloroformate in Step 3, the same procedure as in Example 18 was followed to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-pivaloylpyrrolidine-2-carboxylate. 1 H-NMR (400 MHz, DMSO-d6): δ:9.05 (m,1H), 9.00 (m, 1H), 8.56 (d, J=8.0 Hz, 1H), 7.88(d, J = 5.2Hz,1H),7.55 (d, J=7.6 Hz, 1H), 6.24-6.11 (m, 2H), 4.35 (m, 1H), 3.66 (m, 2H), 2.08(m, 1H), 1.88(m, 2H), 1.70(m, 1H), 1.09 (s, 9H). MS calculation: 401.4; MS measurement: 402.2 [M+H] + .

[0123] Example 22: Synthesis of (R)-2-(5-nitroquinolin-8-yloxy)methyl 1-acetylpyrrolidine-2-carboxylate (22) [ka] (R)-2-(5-nitroquinolin-8-yloxy)methyl 1-acetylpyrrolidine-2-carboxylate was obtained in the same manner as in Example 19, except that D-Boc proline was used instead of L-Boc proline in step 1. 1 H-NMR (400 MHz, DMSO-d6): δ: 9.05 (dd, J = 4.0 Hz,1.2Hz,1H), 9.00 (dd, J = 8.8 Hz,1.2Hz,1H), 8.56(d, J=8.8 Hz, 1H), 7.88 (dd, J = 4.0 Hz,8.8Hz,1H),7.55 (d, J=8.8 Hz, 1H), 6.15 (m, 2H), 4.34-4.31 (m, 1H), 3.55-3.34 (m, 2H) ,2.18-2.14 (m, 1H), 1.91-1.78(m, 3H) ,1.94 (s, 3H). MS calculated: 359.3; MS measured: 360.2 [M+H] + .

[0124] Example 23: Synthesis of (R)-(5-nitroquinolin-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate (23) [ka] Except for using isobutyryl chloride instead of propyl chloroformate in step 3, the same procedure as in Example 22 was followed to obtain (R)-(5-nitroquinolin-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate. 1 H-NMR (400 MHz, DMSO-d6): δ:9.05 (d, J = 2.8 Hz,1H), 9.00 (d, J = 8.4 Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 7.88 (dd, J = 4.0 Hz,8.8Hz,1H),7.55 (d, J=8.8 Hz, 1H), 6.19 (d, J=6.4 Hz, 1H), 6.11 (d, J=6.4 Hz,1H), 4.36-4.33 (m, 1H), 3.58-3.55 (m, 2H), 2.70-2.63(m, 1H), 2.19-2.14(m, 1H), 1.92-1.87(m, 2H), 1.82-1.77(m, 1H), 0.95 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H). MS calculated: 387.3; MS measured: 388.2 [M+H] + .

[0125] Example 24: Synthesis of (R)-(5-nitroquinolin-8-yloxy)methyl 1-pivaloylpyrrolidine-2-carboxylate (24) [ka] Except for using pivaloyl chloride instead of propyl chloroformate in Step 3, the same procedure as in Example 22 was followed to obtain (R)-(5-nitroquinolin-8-yloxy)methyl 1-pivaloylpyrrolidine-2-carboxylate. 1 H-NMR (400 MHz, DMSO-d6): δ:9.06 (dd, J = 4.0 Hz,1.2Hz,1H), 9.00 (dd, J = 8.8 Hz,1.2Hz,1H), 8.55 (d, J=8.8 Hz, 1H), 7.88 (dd, J = 4.0 Hz,8.8Hz,1H),7.55 (d, J=8.8 Hz, 1H), 6.19 (d, J=6.8 Hz, 1H), 6.11 (d, J=6.8 Hz,1H), 4.36-4.33 (m, 1H), 3.67-3.64 (m, 2H) ,2.11-2.04 (m, 1H), 1.90-1.85(m, 2H), 1.72-1.67(m, 1H),1.09(s, 9H). MS calculation: 401.2; MS measurement: 402.2 [M+H] + .

[0126] Example 25: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-pyridineformylpyrrolidine-2-carboxylate (25): [ka] [ka] At room temperature, ((5-nitroquinolin-8-yl)oxy)methyl L-proline ester hydrochloride (18b) (150 mg, 0.43 mmol) was added to anhydrous dichloromethane (15 mL), cooled in an ice bath, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (121.4 mg, 0.636 mmol), 1-hydroxy-benzo-triazole (HOBt) (86 mg, 0.636 mmol), and 2-picolinic acid (78.22 mg, 0.636 mmol) were added in sequence, and the mixture was stirred at 0 to 20 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:1 to 0:1) to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-pyridineformylpyrrolidine-2-carboxylate (30 mg, yield 17%). 1 H-NMR (400 MHz, DMSO-d6): δ:9.01~9.07 (m, 2H), 8.67~8.74 (m, 2H), 8.39~8.51 (m, 1H), 7.86~7.90 (m,1H), 7.30~7.60 (m,3H), 6.02~6.28 (m, 2H), 4.52-4.58 (m, 1H), 3.50-3.58 (m, 2H), 2.29-2.33 (m, 1H), 1.79-1.96 (m, 3H). MS calculation: 422.4; MS measurement: 423.2 [M+H] + .

[0127] Example 26: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-nicotinylpyrrolidine-2-carboxylate (26) [ka] (S)-(5-nitroquinolin-8-yloxy)methyl 1-nicotinylpyrrolidine-2-carboxylate was obtained in the same manner as in Example 25, except that 3-picolinic acid was used instead of 2-picolinic acid. 1H-NMR (400 MHz, DMSO-d6): δ:8.98~9.06 (m, 2H), 8.67~8.74 (m, 2H), 8.39~8.51 (m, 1H), 7.86~7.90 (m,2H), 7.54~7.59 (m,2H), 6.17~6.28 (m, 2H), 4.52-4.58 (m, 1H), 3.40-3.48 (m, 2H), 2.29-2.33 (m, 1H), 1.79-1.96 (m, 3H). MS calculation: 422.4; MS measurement: 423.1 [M+H] + .

[0128] Example 27: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-isonicotinylpyrrolidine-2-carboxylate (27) [ka] (S)-(5-nitroquinolin-8-yloxy)methyl 1-isonicotinylpyrrolidine-2-carboxylate was obtained in the same manner as in Example 25, except that 4-picolinic acid was used instead of 2-picolinic acid. 1 H-NMR (400 MHz, DMSO-d6): δ:8.98~9.07 (m, 2H), 8.67~8.74 (m, 2H), 8.39~8.51 (m, 1H), 7.86~7.90(m,1H), 7.30~7.60 (m,3H), 6.02~6.28 (m, 2H), 4.52-4.58 (m, 1H), 3.40-3.48 (m, 2H), 2.29-2.33 (m, 1H), 1.79-1.96 (m, 3H). MS calculation: 422.4; MS measurement: 423.1 [M+H] + .

[0129] Example 28: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-((S)-2-acetylamino-3-(4-hydroxyphenyl)propionyl)pyrrolidine-2-carboxylate (28) [ka] [ka] ((5-nitroquinolin-8-yl)oxy)methyl L-proline ester hydrochloride (18b) (300 mg, 0.85 mmol) was added to anhydrous DMF (10 mL) and cooled in an ice bath. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (484 mg, 1.27 mmol), triethylamine (260 mg, 2.55 mmol), and N-acetyl-L-tyrosine (189 mg, 0.85 mmol) were added in that order. The mixture was stirred at 0-20°C for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:1 to 0:1) to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-((S)-2-acetylamino-3-(4-hydroxyphenyl)propionyl)pyrrolidine-2-carboxylate (100 mg, yield 22.5%). 1 H-NMR (400 MHz, DMSO-d6): δ:9.19(s,1H), 9.04~9.05(m,1H),8.98~9.07 (m, 2H), 8.48~8.55 (m, 1H), 8.19~8.24 (m, 1H), 7.86~7.90(m,1H), 7.52~7.56(m,1H), 6.95~6.97(m,2H), 6.61~6.65(m,2H), 6.02~6.28(m,2H), 4.53-4.57 (m, 1H), 4.37-4.40 (m, 1H), 3.65-3.70 (m, 1H), 3.41-3.47(m,1H) , 2.61-2.67(m,1H), 2.41-2.47(m,1H), 2.11-2.18(m,1H), 1.80-1.81(m,3H), 1.72(s,3H). MS calculation: 522.51; MS measurement: 523.2 [M+H] + .

[0130] Example 29: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-((2S,3R)-2-(t-butoxycarbonylamino)-3-hydroxybutyryl)pyrrolidine-2-carboxylate (29) [ka] Except for using N-Boc-L-threonine instead of N-acetyl-L-tyrosine, (S)-(5-nitroquinolin-8-yloxy)methyl 1-((2S,3R)-2-(t-butoxycarbonylamino)-3-hydroxybutyryl)pyrrolidine-2-carboxylate was obtained in the same manner as in Example 28. 1 H-NMR (400 MHz, DMSO-d6): δ:8.98~9.07 (m, 2H), 8.77(br,1H)8.54~8.56 (m, 1H), 8.19~8.24 (m, 1H), 7.86~7.90 (m,1H), 7.52~7.56 (m,1H), 615~6.16 (m,2H), 4.37-4.41 (m, 1H), 4.06-4.07 (m, 1H) ,3.65-3.70 (m, 3H), 2.16-2.20 (m,1H) , 1.78-1.90 (m,3H) ,1.36 (s,9H), 0.84(d,J = 8Hz, 3H). MS calculation: 518.52; MS measurement: 519.2 [M+H] + .

[0131] Example 30: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-((S)-2-acetylamino-3-hydroxypropionyl)pyrrolidine-2-carboxylate (30) [ka] [ka] (S)-(5-nitroquinolin-8-yloxy)methyl 1-((S)-2-acetylamino-3-hydroxypropionyl)pyrrolidine-2-carboxylate was obtained in the same manner as in Example 28, except that N-acetyl-L-serine was used instead of N-acetyl-L-tyrosine. 1 H-NMR (400 MHz, DMSO-d6): δ: 8.98~9.07 (m, 2H), 8.48~8.55 (m, 1H), 8.19~8.24 (m, 1H), 7.86~7.90(m,1H),7.52~7.56(m,1H), 6.02~6.28(m, 2H), 4.85-4.95 (m, 1H), 4.40-4.60 (m, 2H), 3.65-3.70 (m, 3H), 1.80-2.01(m, 7H). MS calculation: 446.42; MS measurement: 447.1 [M+H] + .

[0132] Example 31: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-methoxyacetate (31) [ka] The same procedure as in Example 1 was followed except that methoxyacetic acid was used instead of acetic acid in step 2, to obtain (5-nitroquinolin-8-yloxy)methyl 2-methoxyacetate. 1 H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.26 (s, 2H), 4.12 (s, 2H), 3.45 (s, 3H). MS calculation: 292.2;MS measurement: 293.1[M+H] + .

[0133] Example 32: Synthesis of (5-nitroquinolin-8-yloxy)methylcyclobutaneformate (32) [ka] [ka] Except for using cyclobutyl formate instead of acetic acid in step 2, the same procedure as in Example 1 was followed to obtain (5-nitroquinolin-8-yloxy)methylcyclobutane formate. 1 H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.5 Hz, 1H), 9.07 (dd, J = 4.1, 1.5 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.9, 4.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.18 (s, 2H), 3.22 (p, J = 8.3 Hz, 1H), 2.37 - 2.16 (m, 4H), 2.06 - 1.84 (m, 2H). MS calculation: 302.3;MS actual measurement: 303.1[M+H] + .

[0134] Example 33: Synthesis of (5-nitroquinolin-8-yloxy)methyl tetrahydrofuran-3-carboxylate (33) [ka] Except for using 3-tetrahydrofuranformic acid instead of acetic acid in step 2, the same procedure as in Example 1 was followed to obtain (5-nitroquinolin-8-yloxy)methyl tetrahydrofuran-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.5 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.21 (q, J = 6.5 Hz, 2H), 4.01 - 3.91 (m, 2H), 3.84 (qd, J = 14.9, 8.3 Hz, 2H), 3.18 (ddt, J = 8.9, 7.8, 5.9Hz, 1H), 2.28 - 2.09 (m, 2H). MS calculation: 318.3;MS measurement: 319.1[M+H] + .

[0135] Example 34: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-acetoxybenzoate (34) [ka] (5-Nitroquinolin-8-yloxy)methyl 2-acetoxybenzoate was obtained in the same manner as in Example 1, except that o-acetylsalicylic acid was used instead of acetic acid in step 2. 1 H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 9.17 (s, 1H), 8.55 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.47 (s, 1H), 7.31 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.40 (s, 2H), 2.31 (s, 3H). MS calculation: 382.3;MS measurement: 383.1[M+H] + .

[0136] Example 35: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-(2,4-dichlorophenoxy)acetate (35) [ka] Except for using sodium 2,4-dichlorophenoxyacetate (purchased from Darui Chemical Co., Ltd.) instead of acetic acid in step 2, the same production method as in Example 1 was used to obtain (5-nitroquinolin-8-yloxy)methyl 2-(2,4-dichlorophenoxy)acetate. 1 H NMR (400 MHz, CDCl3) δ 9.18 (dd, J = 8.9, 1.5 Hz, 1H), 9.06 (dd, J = 4.1, 1.5 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.5 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.26 (s, 2H), 4.79 (s, 2H). MS calculation: 423.2;MS actual measurement: 423.0[M+H] + .

[0137] Example 36: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-morpholine acetate (36) [ka] Except for using 4-morpholineacetic acid instead of acetic acid in step 2, the same procedure as in Example 1 was followed to obtain (5-nitroquinolin-8-yloxy)methyl 2-morpholine acetate. 1H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.23 (s, 2H), 3.77 - 3.68 (m, 4H), 3.31 (s, 2H), 2.63 - 2.53 (m, 4H). MS calculation: 347.3;MS actual measurement: 348.2[M+H] + .

[0138] Example 37: Synthesis of (R)-(5-nitroquinolin-8-yloxy)methyl 2-hydroxy-2-phenylacetate (37) [ka] At room temperature, (S)-mandelic acid (64 mg, 0.42 mmol), triethylamine (51 mg, 0.50 mmol), and pyridine (33 mg, 0.42 mmol) were added to N,N-dimethylformamide (1 mL) and stirred uniformly. The reaction system was heated to 35°C and stirred for 10 minutes, after which 5-nitro-8-chloromethoxyquinoline (1a) (100 mg, 0.42 mmol) was added and stirred for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography fractionation plate (developing agent: 5% methanol / 95% dichloromethane) to obtain (R)-(5-nitroquinolin-8-yloxy)methyl 2-hydroxy-2-phenylacetate (50 mg, yield 34%). 1H NMR (400 MHz, CDCl3) δ 9.14 (dd, J = 8.9, 1.6 Hz, 1H), 9.03 (dd, J = 4.1, 1.6 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.9, 4.1 Hz, 1H), 7.35 (dd, J = 7.1, 2.4 Hz, 2H), 7.25 (dd, J = 5.2, 1.9 Hz, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.18 (dd, J = 31.0, 6.4 Hz, 2H), 5.24 (s, 1H), 3.39 (s, 1H). MS calculation: 354.3;MS actual measurement: 355.1[M+H] + .

[0139] Example 38: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 2-hydroxy-2-phenylacetate (38) [ka] (S)-(5-nitroquinolin-8-yloxy)methyl 2-hydroxy-2-phenylacetate was obtained in the same manner as in Example 37, except that (R)-mandelic acid was used instead of (S)-mandelic acid. 1 H NMR (400 MHz, CDCl3) δ 9.14 (dd, J = 8.9, 1.6 Hz, 1H), 9.03 (dd, J = 4.1, 1.6 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.9, 4.1 Hz, 1H), 7.35 (dd, J = 7.1, 2.4 Hz, 2H), 7.25 (dd, J = 5.2, 1.9 Hz, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.18 (dd, J = 31.1, 6.4 Hz, 2H), 5.24 (s, 1H), 3.40 (s, 1H). MS calculation: 354.3;MS actual measurement: 355.1[M+H] + .

[0140] Example 39: Synthesis of (5-nitroquinolin-8-yloxy)methyl butyrate (39) [ka] (5-nitroquinolin-8-yloxy)methyl butyrate was obtained in the same manner as in Example 1, except that n-butyric acid was used instead of acetic acid in step 2. 1 H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.18 (s, 2H), 2.39 (t, J = 7.4 Hz, 2H), 1.69 (dt, J = 14.8, 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). MS calculation: 290.3;MS actual measurement: 291.1[M+H] + .

[0141] Example 40: Synthesis of (5-nitroquinolin-8-yloxy)methyl n-hexanoate (40) [ka] (5-nitroquinolin-8-yloxy)methyl n-hexanoate was obtained in the same manner as in Example 1, except that n-hexanoic acid was used instead of acetic acid in step 2. 1H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.9, 4.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.18 (s, 2H), 2.40 (t, J = 7.5 Hz, 2H), 1.68 - 1.60 (m, 2H), 1.33 - 1.22 (m, 4H), 0.91 - 0.79 (m, 3H). MS calculation: 318.3;MS actual measurement: 319.2[M+H] + .

[0142] Example 41: Synthesis of (5-nitroquinolin-8-yloxy)methyl n-caprylate (41) [ka] (5-nitroquinolin-8-yloxy)methyl n-caprylate was obtained in the same manner as in Example 1, except that n-caprylic acid was used instead of acetic acid in step 2. 1 H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 4.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.18 (s, 2H), 2.40 (t, J = 7.5 Hz, 2H), 1.64 (dd, J = 14.6, 7.4 Hz, 2H), 1.32 - 1.16 (m, 8H), 0.84 (t, J = 7.0 Hz, 3H). MS calculation: 346.4;MS measurement: 347.2[M+H] + .

[0143] Example 42: Synthesis of (5-nitroquinolin-8-yloxy)methyl n-decanoate (42) [ka] (5-nitroquinolin-8-yloxy)methyl n-decanoate was obtained in the same manner as in Example 1, except that n-capric acid was used instead of acetic acid in step 2. 1 H NMR (400 MHz, CDCl3) δ 9.20 (dd, J = 8.9, 1.6 Hz, 1H), 9.07 (dd, J = 4.1, 1.6 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.9, 4.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.18 (s, 2H), 2.40 (t, J = 7.5 Hz, 2H), 1.63 (dt, J = 15.2, 7.5 Hz, 2H), 1.32 - 1.17 (m, 12H), 0.86 (t, J = 6.9 Hz, 3H). MS calculation: 374.4;MS actual measurement: 375.2[M+H] + .

[0144] Example 43: Synthesis of (5-nitroquinolin-8-yloxy)methyl dodecanoate (43) [ka] (5-nitroquinolin-8-yloxy)methyl dodecanoate was obtained in the same manner as in Example 1, except that lauric acid was used instead of acetic acid in step 2. 1H-NMR (400 Hz, CDCl3) δ: 9.22 (dd, J = 8.8, 1.2 Hz, 1H), 9.10 (dd, J = 4.0, 1.6 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 8.8 Hz, 4.0 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 6.20 (s, 2H), 2.41 (t, J = 3.6 Hz, 2H), 1.61-1.68 (m, 2H), 1.23-1.25 (m, 12H), 0.87-0.91 (m, 3H), 0.05-0.09 (4H). MS calculation: 402.49;MS actual measurement: 403.3 [M+H] + .

[0145] Example 44: Synthesis of 6-(5-nitroquinolin-8-yloxy)-tetrahydropyran-2-one (44) [ka] Step 1: Preparation of 2-((5-nitroquinolin-8-yl)oxo)cyclopentan-1-one (44a) At room temperature, sodium methanol (170 mg, 3.15 mmol) and potassium iodine (87 mg, 0.52 mmol) were added to a solution of nitroxoline (500 mg, 2.63 mmol) in N-methylpyrrolidone (12.5 mL). The reaction system was heated to 60°C and stirred for 15 minutes, after which 2-chlorocyclopentanone (623 mg, 5.25 mmol) was added and reacted for 7 hours with stirring. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed with a saturated saline solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by a silica gel column with 50% petroleum ether / 50% ethyl acetate to obtain 2-(5-nitroquinoline-8-oxy)-cyclopentanone (240 mg, yield 34%). Step 2: Preparation of 6-(5-nitroquinolin-8-yloxy)-tetrahydropyran-2-one (44) Sodium bicarbonate (56 mg, 0.67 mmol) was added to a solution of 2-(5-nitroquinoline-8-oxy)-cyclopentanone (44a) (140 mg, 0.51 mmol) in dichloromethane (2 mL) at room temperature. The reaction system was cooled to 0°C, m-chloroperoxybenzoic acid (m-CPBA) (purity: 85%, 136 mg, 0.67 mmol) was added, and the mixture was allowed to naturally warm to room temperature and stirred for 16 hours. The reaction was quenched by adding water, extracted with dichloromethane, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography fractionation plate (developing agent: 5% methanol / 95% dichloromethane) to obtain 6-(5-nitroquinolin-8-yloxy)-tetrahydropyran-2-one (94 mg, yield 63%). 1 H NMR (400 MHz, CDCl3) δ 9.17 (dd, J = 8.9, 1.5 Hz, 1H), 9.04 (dd, J = 4.1, 1.5 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.9, 4.1 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.39 (t, J = 3.3 Hz, 1H), 2.89 - 2.63 (m, 2H), 2.56 - 2.44 (m, 2H), 2.37 - 1.97 (m, 2H). MS calculation: 288.3;MS measurement: 289.1[M+H] + .

[0146] Example 45: Synthesis of ((5-nitroquinolin-8-yl)oxy)methyl 2-(2-(2-methoxyethoxy)ethoxy)acetate (45) [ka] Except for using 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (purchased from Darui Chemical Co., Ltd.) instead of acetic acid in step 2, the same procedure as in Example 1 was followed to obtain ((5-nitroquinolin-8-yl)oxy)methyl 2-(2-(2-methoxyethoxy)ethoxy)acetate. 1 H-NMR (400 Hz, CDCl3) δ: 9.20 (dd, J = 6.0 Hz, 1H), 9.08 (d, J = 2.8 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 8.8 Hz, 4.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.26 (s, 2H), 4.27 (s, 2H), 3.75-3.76 (m, 2H), 3.69-3.70 (m, 2H), 3.63-3.65 (m, 2H), 3.53-3.55 (m, 2H), 3.37 (s,3H). MS calculation: 380.35;MS measurement: 381.1 [M+H] + .

[0147] Example 46: Synthesis of bis(5-nitroquinolin-8-yloxy)-methyl adipate (46) [ka] At room temperature, adipic acid (300 mg, 2.05 mmol), potassium carbonate (680 mg, 4.92 mmol), and sodium iodide (62 mg, 0.41 mmol) were added to N,N-dimethylformamide (20 mL) and stirred uniformly. The reaction system was heated to 60°C and stirred for 10 minutes, after which 5-nitro-8-chloromethoxyquinoline (1a) (980 mg, 4.11 mmol) was added and stirred for 2 hours. The reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography fractionation plate (developing agent: 5% methanol / 95% dichloromethane) to obtain bis(5-nitroquinolin-8-yloxy)-methyl adipate (78 mg, yield 7%). 1H NMR (400 MHz, CDCl3) δ 9.18 (dd, J = 8.9, 1.6 Hz, 2H), 9.06 (dd, J = 4.1, 1.6 Hz, 2H), 8.49 (d, J = 8.8 Hz, 2H), 7.71 (dd, J = 8.9, 4.1 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.16 (s, 4H), 2.41 (s, 4H), 1.68 (t, J = 3.2 Hz, 4H). MS calculation: 550.5;MS measurement: 551.3[M+H] + .

[0148] Example 47: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl acetate (47) [ka] Step 1: Preparation of acid-1-chloroethyl ester (47a) At 0°C, acetyl chloride (1.00g, 12.74mmol) was slowly added to a solution of acetaldehyde (0.56g, 12.71mmol) and zinc chloride (0.17g, 1.25mmol) in dichloromethane (20mL), and the reaction solution was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 16 hours. Water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain acetic acid-1-chloroethyl ester (1.39g) as a crude product. Step 2: Preparation of 1-(5-nitroquinolin-8-yloxy)ethyl acetate (47) At room temperature, sodium methanol (68 mg, 1.26 mmol) and potassium iodine (17 mg, 0.10 mmol) were added to a solution of nitroxoline (200 mg, 1.05 mmol) in N-methylpyrrolidone (5 mL). The reaction system was heated to 60°C and stirred for 15 minutes, after which acetic acid-1-chloroethyl ester (193 mg, 1.57 mmol) was added and stirred for 16 hours. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography separation plate (developing agent: 5% methanol / 95% dichloromethane) to obtain 1-(5-nitroquinolin-8-yloxy)ethyl acetate (124 mg, yield 43%). 1H NMR (400 MHz, CDCl3) δ 9.18 (dd, J = 8.9, 1.6 Hz, 1H), 9.08 (dd, J = 4.1, 1.6 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.9, 4.1 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.97 (q, J = 5.3 Hz, 1H), 2.10 (s, 3H), 1.87 (d, J = 5.3 Hz, 3H). MS calculated: 276.2;MS measured: 277.1 [M+H] + .

[0149] Example 48: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl propionate (48) [ka] The same procedure as in Example 47 was followed except that propionyl chloride was used instead of acetyl chloride in Step 1, to obtain 1-(5-nitroquinolin-8-yloxy)ethyl propionate. 1H NMR (400 MHz, CDCl3) δ 9.18 (dd, J = 8.9, 1.5 Hz, 1H), 9.08 (dd, J = 4.1, 1.5 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.9, 4.1 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 6.99 (q, J = 5.2 Hz, 1H), 2.38 (q, J = 7.5 Hz, 2H), 1.87 (d, J = 5.3 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H). MS calculation: 290.3;MS measurement: 291.1 [M+H] + .

[0150] Example 49: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl isobutyrate (49) [ka] The same procedure as in Example 47 was followed except that isobutyryl chloride was used instead of acetyl chloride in Step 1, to obtain 1-(5-nitroquinolin-8-yloxy)ethyl isobutyrate. 1 H NMR (400 MHz, CDCl3) δ 9.18 (dd, J = 8.9, 1.2 Hz, 1H), 9.08 (dd, J = 3.9, 1.1 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.9, 4.1 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.98 (q, J = 5.2 Hz, 1H), 2.64 - 2.51 (m, 1H), 1.87 (d, J = 5.2 Hz, 3H), 1.14 (dd, J = 14.4, 7.0 Hz, 6H). MS calculation: 304.3;MS measurement: 305.2 [M+H] + .

[0151] Example 50: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl pivalate (50) [ka] Except for using pivaloyl chloride instead of acetyl chloride in Step 1, the same procedure as in Example 47 was followed to obtain 1-(5-nitroquinolin-8-yloxy)ethyl pivalate. 1 H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 8.9, 1.5 Hz, 1H), 9.08 (dd, J = 4.1, 1.5 Hz, 1H), 8.45 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.9, 4.1 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.96 (q, J = 5.2 Hz, 1H), 1.88 (d, J = 5.2 Hz, 3H), 1.17 (s, 9H). MS calculation: 318.3;MS measurement: 319.2 [M+H] + .

[0152] Example 51: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl 2-ethylbutyrate (51) [ka] 1-(5-nitroquinolin-8-yloxy)ethyl 2-ethylbutyrate was obtained in the same manner as in Example 47, except that 2-ethylbutyryl chloride was used instead of acetyl chloride in Step 1. 1H NMR (400 MHz, CDCl3) δ: 9.20-9.17 (m, 1H), 9.08-9.07 (m, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.72-7.68 (m, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.03-7.01 (m, 1H), 2.25-2.11 (m, 1H), 1.88 (d, J = 5.2 Hz, 3H), 1.60-1.49 (m, 4H), 0.88-0.81 (m, 6H). MS calculation: 332;MS actual measurement: 333[M+H] + .

[0153] Example 52: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2,3-dihydroxypropyl(methyl)carbamate (52) [ka] Step 1: Preparation of chloromethyl 2,3-dihydroxypropyl(methyl)carbamate (52a) N-methyl-2,3-dihydroxypropylamine (1g, 10mmol) was dissolved in a mixed solvent of acetonitrile (40mL) and methanol (8mL), and triethylamine (1.15g, 11.4mmol) and chloromethyl chloroformate (1.35g, 10.48mmol) were slowly added dropwise in an ice-water bath, and the reaction solution was stirred at 0°C for 30 minutes, then heated to 25°C and stirred for 16 hours. The reaction solution was quenched with water (50mL), extracted with dichloromethane (100mLx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain chloromethyl 2,3-dihydroxypropyl(methyl)carbamate (1.7g, 89% yield) as the product. Step 2: Preparation of (5-nitroquinolin-8-yloxy)methyl 2,3-dihydroxypropyl(methyl)carbamate (52) Nitroxoline (600mg, 3.16mmol) and chloromethyl 2,3-dihydroxypropyl(methyl)carbamate (940mg, 4.7mmol) were dissolved in N,N-dimethylformamide (15mL), then potassium carbonate (871mg, 6.31mmol) and sodium iodide (47mg, 0.32mmol) were added at 0℃, and the reaction solution was stirred at 60℃ for 4 hours. The reaction was allowed to warm to room temperature, quenched with water, extracted with dichloromethane (100mLx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% methanol / 95% dichloromethane) to give the product (5-nitroquinolin-8-yloxy)methyl 2,3-dihydroxypropyl(methyl)carbamate (300mg, 27% yield). 1 H NMR (400 MHz, CDCl3) δ: 9.20-9.18 (m, 1H), 9.06 (dd, J = 4.0, 1.2 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.73-7.70 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.21-6.13 (m, 2H), 3.88 (s, 1H), 3.67-3.40 (m, 4H), 3.04-2.95 (m, 5H). MS calculation: 351.11;MS measurement: 352.1 [M+H] + .

[0154] Example 53: Synthesis of methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)acetate (53) [ka] Step 1: Preparation of methyl 2-(2,4-dimethoxybenzylamino)acetate (53a) At 0°C, 2,4-dimethoxybenzaldehyde (720mg, 4.34mmol) and sodium borohydride acetate (1.38g, 6.51mmol) were added slowly in sequence to a solution of triethylamine (658mg, 6.51mmol) and 2-amino-methyl acetate hydrochloride (1.00g, 6.51mmol) in dichloromethane (40mL). The reaction solution was stirred at 60°C for 2 hours and then cooled to room temperature. Water was added to quench the reaction, and the reaction solution was extracted with dichloromethane (100mLx3). The organic phase was washed with 1M hydrochloric acid, 1M aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% methanol / 95% dichloromethane) to give 2-(2,4-dimethoxybenzylamino)methyl acetate (1.1g, yield 95%). MS[M+H] + : 240.0. Step 2: Preparation of methyl 2-(((chloromethoxy)formyl)(2,4-dimethoxybenzyl)amino)acetate (53b) At 0°C, chloromethyl chloroformate (595mg, 4.60mmol) was slowly added dropwise to a solution of methyl 2-(2,4-dimethoxybenzylamino)acetate (1.0g, 4.39mmol) and triethylamine (485mg, 4.80mmol) in dichloromethane (20mL). The reaction solution was stirred at 50°C for 2 hours and then cooled to room temperature. Water was added to quench the reaction, and the reaction solution was then extracted with dichloromethane (100mLx3). The organic phase was washed with 1M hydrochloric acid, 1M aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% n-hexane / 95% ethyl acetate) to give methyl 2-(((chloromethoxy)formyl)(2,4-dimethoxybenzyl)amino)acetate (1.00g, yield 69%). MS[M+H] + :332.1. Step 3: Preparation of methyl 2-((2,4-dimethoxybenzyl)(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)acetate (53c) At room temperature, 2-(((chloromethoxy)formyl)(2,4-dimethoxybenzyl)amino)methyl acetate (1.05g, 2.79mmol) was added to a solution of nitroxoline (360mg, 1.9mmol), potassium carbonate (385mg, 2.79mmol), and sodium iodide (30mg, 0.19mmol) in N,N-dimethylformamide (15mL). The reaction solution was stirred at 50°C for 2 hours and then cooled to room temperature. Water was added to quench the reaction, and the reaction solution was then extracted with dichloromethane (100mLx3). The organic phase was washed with 1M hydrochloric acid, 1M aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% n-hexane / 95% ethyl acetate) to give methyl 2-((2,4-dimethoxybenzyl)(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)acetate (440 mg, yield 48%). MS[M+H] + :486.0. Step 4: Preparation of methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)acetate (53) Trifluoroacetic acid (8 mL) was added dropwise to a dichloromethane (8 mL) solution of 2-((2,4-dimethoxybenzyl)(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)methyl acetate (440 mg, 0.91 mmol) at room temperature. After stirring the reaction solution at room temperature for 2 hours, water was added to quench the reaction, and the reaction solution was then extracted with dichloromethane (100 mL x 3). The organic phase was washed with 1 M hydrochloric acid, 1 M aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50% n-hexane / 50% ethyl acetate) to give 2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)methyl acetate (200 mg, yield 67%). 1H NMR (400 MHz, CDCl3) δ: 9.18 (dd, J = 8.8, 1.6 Hz, 1H), 9.06 (dd, J = 4.0, 1.6 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.4, 4.4 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 6.18 (s, 2H), 5.41 (s, 1H), 4.01 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H). MS calculation: 335.08;MS measurement: 336.1 [M+H] + .

[0155] Example 54: Synthesis of methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)butyrate (54) [ka] Methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)butyrate was obtained in the same manner as in the preparation method of Example 53, except that methyl 2-aminobutyrate was used instead of methyl 2-aminoacetate hydrochloride in Step 1. 1 H NMR (400 MHz, CDCl3): δ 9.19 (dd, J = 8.8, 1.6 Hz, 1H), 9.06 (s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.17 (d, J = 7.6 Hz, 2H), 5.43 (d, J = 8.0 Hz, 1H), 4.36 (d, J = 5.6 Hz, 1H), 3.75 (s, 3H), 1.90 (s, 1H), 1.72 (d, J = 7.2 Hz, 1H), 0.90 (d, J = 7.4 Hz, 3H). MS calculated: 363; MS observed: 364.

[0156] Example 55: Synthesis of methyl 3-methyl-2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)valerate (55) [ka] Methyl 3-methyl-2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)valerate was obtained in the same manner as in the preparation method of Example 53, except that methyl 2-amino-3-methylvalerate hydrochloride was used instead of methyl 2-amino-acetate hydrochloride in Step 1. 1 H NMR (400 MHz, CDCl3) δ: 9.19 (dd, J = 9.2, 1.2 Hz, 1H), 9.06 (dd, J = 4.0, 1.6 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 9.2, 4.4 Hz, 1H), 7.40 (dd, J =8.8, 1.2 Hz, 1H), 6.18-6.16 (m, 2H), 5.38 (m, 1H), 4.45 (dd, J = 9.2, 4.0 Hz, 1H), 3.74 (s, 3H), 1.99-1.87 (m, 1H), 1.43-1.37 (m, 1H), 1.21-1.14 (m, 1H), 0.95-0.89 (m, 4H), 0.84-0.82 (d, J = 8.8 Hz, 2H). MS calculation: 391.14;MS actual measurement: 392.1 [M+H] + .

[0157] Example 56: Synthesis of methyl 3-methyl-2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)valerate (56) [ka] Step 1: Preparation of methyl N-benzyl-2-amino-3-methylvalerate (56a) Methyl 2-amino-3-methylvalerate hydrochloride (4.0 g, 21.9 mmol) and sodium borohydride acetate were added at 0°C. (The mixture (9.2 g, 43.4 mmol) was slowly added successively to a solution of benzaldehyde (1.6 g, 14.7 mmol) and triethylamine (2.2 g, 21.9 mmol) in dichloromethane (80 mL). The reaction mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (20 mL), and the reaction mixture was extracted with dichloromethane (150 mL×3). The organic phases were combined, dried, and concentrated under reduced pressure to obtain crude product methyl N-benzyl-2-amino-3-methylvalerate (4.2 g, 100% yield). MS[M+H] + :236.0. Step 2: Preparation of methyl N-methyl-N-benzyl-2-amino-3-methylvalerate (56b) At 0°C, 37% aqueous formaldehyde (5.4g, 179mmol), sodium cyanoborohydride (2.5g, 39.4mmol), and acetic acid (2mL) were added sequentially to a solution of methyl N-benzyl-2-amino-3-methylvalerate (4.2g, 17.9mmol) in acetonitrile (100mL). The reaction was stirred at room temperature for 16 hours and then quenched with saturated aqueous sodium bicarbonate (100mL). The reaction was extracted with dichloromethane (150mLx3), and the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% methanol / 95% dichloromethane) to give methyl N-methyl-N-benzyl-2-amino-3-methylvalerate (4.2g, 93% yield). MS[M+H] + :250.0. Step 3: Preparation of methyl N-methyl-N-Boc-2-amino-3-methylvalerate (56c) Methyl N-methyl-N-benzyl-2-amino-3-methylvalerate (4.2 g, 16.8 mmol), Pd / C (900 mg), and Boc2O (10 mL) were added to methanol (30 mL). The reaction mixture was stirred at 50° C. for 16 hours under a hydrogen atmosphere. The solid was removed by filtration, and the mixture was concentrated under reduced pressure to obtain crude product methyl N-methyl-N-Boc-2-amino-3-methylvalerate (5.2 g, 100% yield). MS[M+H] + :260.0. Step 4: Preparation of methyl N-methyl-2-amino-3-methylvalerate (56d) A solution of 5 M hydrochloric acid in 1,4 dioxane (10 mL) was added to a solution of N-methyl-N-Boc-2-amino-3-methyl methyl valerate (5.2 g, 20 mmol) in tetrahydrofuran (50 mL) at 0° C. The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure to give N-methyl-2-amino-3-methyl methyl valerate (3.2 g, 82% yield). MS[M+H] + :160.0. Step 5: Preparation of methyl N-methyl-N-chloromethoxyformyl-2-amino-3-methylvalerate (56e) At 0°C, chloromethyl chloroformate (0.48mL, 5.37mmol) was slowly added dropwise to a solution of methyl N-methyl-2-amino-3-methylvalerate (1g, 5.12mmol) and triethylamine (1.8mL, 12.8mmol) in dichloromethane (30mL). The reaction solution was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 16 hours. After quenching the reaction with water (25mL), the reaction solution was extracted with dichloromethane (100mLx3), the organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude N-methyl-N-chloromethoxyformyl-2-amino-3-methylvalerate (638mg, 49% yield). MS[M+H] + :252.0. Step 6: Preparation of methyl 3-methyl-2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)valerate (56) At room temperature, methyl N-methyl-N-chloromethoxyformyl-2-amino-3-methylvalerate (638 mg, 2.53 mmol) was slowly added dropwise to a solution of nitroxoline (350 mg, 2.63 mmol), potassium carbonate (464 mg, 3.36 mmol), and sodium iodide (27 mg, 0.18 mmol) in N,N-dimethylformamide (10 mL). The reaction solution was stirred at 60° C. for 2 hours. After quenching the reaction with water (25 mL), the reaction solution was extracted with dichloromethane (100 mL×3), the organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% methanol / 95% dichloromethane) to give methyl 3-methyl-2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)valerate (70 mg, 10% yield). 1 H NMR (400 MHz, CDCl3) δ 9.20 (d, J = 8.8 Hz, 1H), 9.07 - 9.06 (m, 1H), 8.50 (dd, J = 8.8, 3.2 Hz, 1H), 7.72 (dd, J = 8.8, 4.0 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.25 - 6.21 (m, 2H), 4.61 - 4.30 (m, 1H), 3.71 - 3.58 (m, 3H), 2.94 - 2.89 (m, 3H), 1.98 (br s, 1H), 1.39 - 1.34 (m, 1H), 0.95 - 0.75 (m, 7H). MS calculation: 405.15;MS measurement: 406.1 [M+H] + .

[0158] Example 57: Synthesis of methyl 2-(methyl((5-nitroquinolin-8-yloxy)formyl)amino)acetate (57) [ka] At 0°C, triphosgene (296.8mg, 1mmol) and pyridine (790mg, 10mmol) were added batchwise to dichloromethane (6mL). After stirring the reaction solution at room temperature for 20 minutes, a solution of N-methyl-2-aminoacetate methyl (124mg, 1.2mmol) in acetonitrile (2mL) was slowly added dropwise to the reaction solution and stirred at room temperature for 1 hour. After removing the solvent under reduced pressure, pyridine (2mL) was added and nitroxoline (190mg, 1mmol) was added batchwise. The reaction solution was heated at 110°C for 2 hours in a microwave. The reaction was quenched by adding water, and the reaction solution was extracted with dichloromethane (100mLx3). The organic phase was washed with 1M hydrochloric acid, 1M aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% n-hexane / 95% ethyl acetate) to give methyl 2-(methyl((5-nitroquinolin-8-yloxy)formyl)amino)acetate (100 mg, yield 31%). 1 H NMR (400 MHz, CDCl3) δ: 9.10-9.04 (m, 2H), 8.47-8.43 (m, 1H), 7.68-7.60 (m, 2H), 4.30 (d, J = 84.8 Hz, 2H), 3.82 (d, J = 13.6 Hz, 3H), 3.27 (d, J = 88.0 Hz, 3H). MS calculation: 319.08;MS actual measurement: 320.0 [M+H] + .

[0159] Example 58: Synthesis of (S)-2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)-3-phenylpropionate methyl (58) [ka] Methyl (S)-2-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)-3-phenylpropionate was obtained in the same manner as in Example 53, except that L-phenylalanine methyl ester was used instead of methyl 2-aminoacetate hydrochloride in Step 1. 1 H-NMR (400 Hz, CDCl3) δ: 9.35 (dd, J = 8.8, 1.6 Hz, 1H), 9.15 (dd, J = 4.4, 1.6 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 8.8 Hz, 4.4Hz, 1H), 7.56 (br, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.25-7.17 (m, 3H), 7.04-7.18 (m, 2H), 6.10 (s, 2H), 4.51-4.68 (m, 1H), 3.72 (s, 3H), 2.95-3.18 (m, 2H). MS calculation: 425.40;MS measurement: 426.3 [M+H] + .

[0160] Example 59: Synthesis of (2S,6R)-(5-nitroquinolin-8-yloxy)methyl 2,6-dimethylmorpholine-4-formate (59) [ka] Step 1: Preparation of N-chloromethoxyformyl-(2S,6R)-2,6-dimethylmorpholine (59a) At 0°C, (2S,6R)-2,6-dimethylmorpholine (0.46g, 4mmol) was dissolved in dichloromethane (10mL), triethylamine (1.1mL, 8mmol) and chloromethyl chloroformate (0.6g, 4.6mmol) were slowly added dropwise in succession, and the mixture was stirred for 30 minutes, then warmed to room temperature and stirred for 4 hours. After quenching with water (50mL), the mixture was extracted with dichloromethane (100mLx3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product N-chloromethoxyformyl-(2S,6R)-2,6-dimethylmorpholine (0.5g, 60% yield). Step 2: Preparation of (2S,6R)-(5-nitroquinolin-8-yloxy)methyl 2,6-dimethylmorpholine-4-formate (59) At room temperature, nitroxoline (0.6 g, 3.1 mmol) and N-chloromethoxyformyl-(2S,6R)-2,6-dimethylmorpholine (0.5 g, 2.4 mmol) were dissolved in N,N-dimethylformamide (10 mL), then potassium carbonate (0.7 g, 5.0 mmol) and potassium iodine (83 mg, 0.5 mmol) were added and the reaction was stirred at 60° C. for 4 hours. After cooling the reaction to room temperature, the reaction was quenched with water and extracted with dichloromethane (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by reversed-phase high-performance liquid chromatography (column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0 mL / min) to obtain (2S,6R)-(5-nitroquinolin-8-yloxy)methyl 2,6-dimethylmorpholine-4-formate (90 mg, yield 11%). 1 H-NMR (400 Hz, CDCl3) δ: 9.23 (dd, J = 8.8, 1.2 Hz, 1H), 9.10 (d, J = 3.2 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 8.8 Hz, 4.0 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8 Hz, 1H), 6.20-6.24 (m, 2H), 4.02 (d, J = 12.8 Hz, 1H), 3.87 (d, J = 12.8 Hz, 1H), 3.50-3.60 (m, 2H), 2.52-2.64 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 6.0 Hz,3H). MS calculation: : 361.35;MS actual measurement: 362.3 [M+H] + .

[0161] Example 60: Synthesis of (5-nitroquinolin-8-yloxy)methyl 1,4'-bipiperidine-1'-formate (60) [ka] Except for using 4-piperidinylpiperidine instead of (2S,6R)-2,6-dimethylmorpholine in Step 1, the same procedure as in the preparation method of Example 59 was followed to obtain (5-nitroquinolin-8-yloxy)methyl 1,4'-bipiperidine-1'-formate. 1 H-NMR (400 Hz, CDCl3) δ: 9.25-9.27 (m, 1H), 9.12-9.13 (m, 1H), 8.53-8.55 (m, 1H), 7.75-7.78 (m, 1H), 7.42-7.44 (m, 1H), 6.21-6.22 (s, 2H), 3.53-4.03 (m, 8H), 2.52-2.64 (m, 2H), 1.08-1.20 (m,9H). MS calculation: 414.46; MS measurement: 415.3 [M+H] + .

[0162] Example 61: Synthesis of methyl 4-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)butyrate (61) [ka] Methyl 4-(((5-nitroquinolin-8-yloxy)methoxy)formylamino)butyrate was obtained in the same manner as in the preparation method of Example 53, except that methyl 4-aminobutyrate hydrochloride was used instead of methyl 2-aminoacetate hydrochloride in Step 1. 1 H-NMR (400 Hz, CDCl3) δ: 9.23 (dd, J = 8.8, 0.8 Hz, 1H), 9.22 (dd, J = 4.4, 3.6 Hz, 1H), 8.60 (d, J = 9.2 Hz, 1H), 7.91 (dd, J = 8.8, 4.4Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 6.11 (s, 2H), 5.27 (s, 1H), 3.67 (s, 3H), 3.25-3.30 (m, 2H), 2.36-2.39(m, 2H), 1.82-1.86 (m, 2H). MS calculation: 363.33;MS measurement: 364.3 [M+H] + .

[0163] Example 62: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-methylmorpholine-4-formate (62) [ka] (5-nitroquinolin-8-yloxy)methyl 2-methylmorpholine-4-formate was obtained in the same manner as in the preparation method of Example 59, except that 2-methylmorpholine was used instead of (2S,6R)-2,6-dimethylmorpholine in Step 1. 1 H-NMR (400 Hz, CDCl3) δ: 9.37-9.39 (m, 1H), 9.18-9.19 (m, 1H), 8.59 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.8 Hz, 4.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.15-6.22 (s, 2H), 3.88-4.03 (m, 3H), 3.51-3.59 (m, 2H), 2.98-3.10 (m, 1H), 2.62-2.69 (m, 1H), 1.18-1.20 (m, 3H). MS calculation: 347.33;MS measurement: 338.3 [M+H] + .

[0164] Example 63: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-hydroxyethyl(methyl)carbamate (63) [ka] Step 1: Preparation of N-[2-(t-butyldimethylsiloxy)ethyl]methylamine (63a) At 0°C, N-methyl-2-hydroxyethylamine (3.5g, 46.6mmol) and t-butyldimethylchlorosilane (7.7g, 51.2mmol) were dissolved in dichloromethane (100mL), and triethylamine (13mL, 93mmol) was slowly added dropwise. The reaction solution was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred overnight. The reaction solution was concentrated to dryness, dissolved in methyl t-butyl ether (200mL), washed with 1M aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain N-[2-(t-butyldimethylsiloxy)ethyl]methylamine (6g, yield 68%) as the product. Step 2: Preparation of N-(chloromethoxyformyl)-N-[2-(t-butyldimethylsiloxy)ethyl]methylamine (63b) At 0°C, N-[2-(t-butyldimethylsiloxy)ethyl]methylamine (3g, 15.8mmol) was dissolved in dichloromethane (80mL), and triethylamine (4.5mL, 31.6mmol) and chloromethyl chloroformate (2.6g, 20.6mmol) were slowly added dropwise in sequence. The reaction solution was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred overnight. After quenching with water (100mL), it was extracted with dichloromethane (200mLx3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain N-(chloromethoxyformyl)-N-[2-(t-butyldimethylsiloxy)ethyl]methylamine (2g, 29% yield). Step 3: Preparation of (5-nitroquinolin-8-yloxy)methyl 2-(t-butyldimethylsiloxy)ethyl(methyl)carbamate (63c) Nitroxoline (1.75g, 9.2mmol) and N-(chloromethoxyformyl)-N-[2-(t-butyldimethylsiloxy)ethyl]methylamine (2.0g, 7.1mmol) were dissolved in N,N-dimethylformamide (10mL) at room temperature, then potassium carbonate (2g, 14.2mmol) and potassium iodine (230mg, 1.4mmol) were added, and the reaction solution was stirred at 60°C for 4 hours. After the reaction solution was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane (200mLx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% methanol / 95% dichloromethane) to give (5-nitroquinolin-8-yloxy)methyl 2-(t-butyldimethylsiloxy)ethyl (methyl)carbamate (500 mg, 16.2% yield). Step 4: Preparation of (5-nitroquinolin-8-yloxy)methyl 2-hydroxyethyl(methyl)carbamate (63) At room temperature, (5-nitroquinolin-8-yloxy)methyl 2-(t-butyldimethylsiloxy)ethyl(methyl)carbamate (0.5g, 1.1mmol) and tetrabutylammonium fluoride (TBAF) (0.35g, 1.3mmol) were dissolved in dichloromethane (20mL) and stirred for 4 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was separated by reversed-phase high-performance liquid chromatography (column: Eclipse XDB-C18 (21.2mm x 250mm, 7μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0mL / min) to obtain the product (5-nitroquinolin-8-yloxy)methyl 2-hydroxyethyl(methyl)carbamate (0.2g, yield 29%).

[0165] Example 64: Synthesis of 2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)ethyl acetate (64) [ka] At 0°C, (5-nitroquinolin-8-yloxy)methyl 2-hydroxyethyl(methyl)carbamate (320mg, 1.0mmol) and acetyl chloride (100mg, 1.2mmol) were dissolved in dichloromethane (10mL), and pyridine (160mg, 2.0mmol) was slowly added dropwise. The temperature was raised to room temperature and the mixture was stirred for 2 hours. After cooling to room temperature, the reaction was quenched with water, extracted with dichloromethane (100mLx3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reversed-phase high-performance liquid chromatography (column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0 mL / min) to obtain the product 2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)ethyl acetate. 1 H-NMR (400 Hz, CDCl3) δ: 9.21 (d, J = 8.0 Hz, 1H), 9.08 (d, J = 4 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.22 (s, 2H), 4.13-4.25 (m, 2H), 3.53-3.58 (m, 2H), 3.00 (s, 3H), 2.00 (s, 3H). MS calculation: 363.33;MS measurement: 364.1 [M+H] + .

[0166] Example 65: Synthesis of (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methylacetylamino)acetate (65) [ka] Step 1: Preparation of (2-(methylamino)pyridin-3-yl)methyl 2-(t-butoxycarbonyl(methyl)amino)acetate (65a) 2-Methylamino-3-pyridinemethanol (2.8g, 20.3mmol), N-(t-butoxycarbonyl)-N-methylglycine (5g, 26.4mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (5.1g, 26.4mmol) and 4-dimethylaminopyridine (DMAP) (250mg, 2mmol) were added to dichloromethane (100mL) at room temperature and stirred overnight. The reaction was quenched by adding water, extracted with ethyl acetate (100mLx3), and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography preparative plate (eluent: 5% methanol / 95% dichloromethane) to give (2-(methylamino)pyridin-3-yl)methyl 2-(t-butoxycarbonyl(methyl)amino)acetate (3 g, yield 49%). Step 2: Preparation of (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(t-butoxycarbonyl(methyl)amino)acetate (65b) At 0°C, (2-(methylamino)pyridin-3-yl)methyl 2-(t-butoxycarbonyl(methyl)amino)acetate (3.4g, 11mmol) was dissolved in dichloromethane (80mL), and N,N-diisopropylethylamine (2.8g, 22mmol) and chloromethyl chloroformate (2.1g, 16.5mmol) were slowly added dropwise in sequence. The reaction solution was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred overnight. After quenching with water (100mL), it was extracted with dichloromethane (200mLx3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(t-butoxycarbonyl(methyl)amino)acetate (4g, 91% yield). Step 3: Preparation of (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(methylamino)acetate (65c) At room temperature, (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(t-butoxycarbonyl(methyl)amino)acetate (1.7g, 5.6mmol) was dissolved in dichloromethane (50mL), and hydrochloric acid dioxane (4.5mL, 18mmol) was slowly added dropwise and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the product (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(methylamino)acetate (1.27g, yield 99%). Step 4: Preparation of (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(N-methylacetylamino)acetate (65d) At 0°C, (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(methylamino)acetate (1g, 3.3mmol) and acetyl chloride (390mg, 5.0mmol) were dissolved in dichloromethane (50mL), triethylamine (0.7mL, 6.6mmol) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 2 hours. After cooling the reaction to room temperature, the reaction was quenched with water, extracted with dichloromethane (100mLx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(N-methylacetylamino)acetate (1.0g, yield 91%). Step 5: Preparation of (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methylacetylamino)acetate (65) Nitroxoline (1.5g, 7.9mmol) and (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(N-methylacetylamino)acetate (2.7g, 7.9mmol) were dissolved in N,N-dimethylformamide (10mL) at room temperature, then potassium carbonate (2.2g, 16.0mmol) and potassium iodine (270mg, 1.6mmol) were added, and the reaction solution was stirred at 60°C for 4 hours. After the reaction solution was cooled to room temperature, the reaction was quenched with water and extracted with dichloromethane (200mLx3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reversed-phase high performance liquid chromatography (column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0 mL / min) to obtain the product (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methylacetylamino)acetate (500 mg, yield 13%). 1 H-NMR (400 Hz, CDCl3) δ: 9.05-9.18 (m, 2H), 8.32-8.57 (m, 2H), 7.79-7.83 (m, 2H), 7.29-7.32 (m, 2H), 6.06-6.30 (m, 2H), 5.00-5.11 (m, 2H), 4.01-4.06 (m, 2H), 3.34 (s,3H), 3.00 (s,3H), 2.13 (s,3H). MS calculation: 497.46;MS measurement: 498.2 [M+H] + .

[0167] Example 66: Synthesis of (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methyl t-butyrylamino)acetate (66) [ka] Except for using pivaloyl chloride instead of acetyl chloride in step 4, (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methyl t-butyrylamino)acetate was obtained in the same manner as in Example 65. 1 H-NMR (400Hz, CDCl3) δ: 9.05-9.18 (m, 2H), 8.32-8.57 (m, 2H), 7.79-7.83 (m, 2H), 7.29-7.32 (m, 2H), 6.06-6.30 (m, 2H), 5.04-5.12 (m, 2H), 4.01-4.06 (m, 2H), 3.340 (s, 3H), 3.00 (s, 3H), 1.31 (s,9H). MS calculation: 539.55;MS measurement: 540.2 [M+H] + .

[0168] Example 67: Synthesis of (5-nitroquinolin-8-yloxy)methylpiperidine 1-formate (67) [ka] Except for using piperidine hydrochloride instead of 1-methylpiperazine in Step 1, the same procedure as in Example 6 was followed to obtain (5-nitroquinolin-8-yloxy)methylpiperidine 1-formate. 1 H-NMR (400 Hz, CDCl3) δ: 9.23 (dd, J = 8.8, 1.6 Hz, 1H), 9.09 (dd, J = 4.0, 1.6 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 8.8 Hz, 4.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.22 (s, 2H), 3.42-3.47 (m, 4H), 1.35-1.63 (m, 6H). MS calculation: 331.33;MS measurement: 332.3 [M+H] + .

[0169] Example 68: Synthesis of 3-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)propyl acetate (68) [ka] Step 1: Preparation of t-butyl (3-hydroxypropyl)methylcarbamate (68a) At room temperature, triethylamine (1.36 g, 13.44 mmol) was added to a solution of 3-methylamino-1-propanol (1.00 g, 11.22 mmol) in methanol (10 mL) and stirred until clear. Di-t-butyl dicarbonate (2.94 g, 13.47 mmol) was added dropwise and stirred for 16 hours. The reaction was concentrated under reduced pressure, diluted with dichloromethane, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude t-butyl (3-hydroxypropyl) methylcarbamate (2.20 g). Step 2: Preparation of 3-(methylamino)propyl acetate (68b) At room temperature, triethylamine (0.64 g, 6.32 mmol) was added to a solution of t-butyl (3-hydroxypropyl) methylcarbamate (1.00 g, 5.28 mmol) in dichloromethane (5 mL), and the mixture was stirred until clear. The reaction system was cooled to 0°C, acetyl chloride (0.50 g, 6.37 mmol) was added dropwise, and the mixture was allowed to naturally warm to room temperature and stirred for 1 hour. The reaction solution was filtered, rinsed with dichloromethane, and the filtrate was concentrated to obtain a solid crude product. At 0°C, a solution of hydrogen chloride in dioxane (3.3 mL, 4 M) was added dropwise to the crude product, and the mixture was stirred for 16 hours. The reaction solution was concentrated to obtain a crude product of 3-(methylamino)propyl acetate. Step 3: Preparation of 3-(((chloromethoxy)carbonyl)(methyl)amino)propyl acetate (68c) The crude 3-(methylamino)propyl acetate was clarified with dichloromethane (8 mL), and triethylamine (1.07 g, 10.57 mmol) and chloromethyl chloroformate (0.68 g, 5.27 mmol) were added to the solution at 0° C., and the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by adding water, extracted with dichloromethane, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 83% petroleum ether / 17% ethyl acetate) to give 3-(((chloromethoxy)carbonyl)(methyl)amino)propyl acetate (400 mg, 34% yield). Step 4: Preparation of 3-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)propyl acetate (68) At room temperature, nitroxoline (340 mg, 1.79 mmol), potassium carbonate (297 mg, 2.15 mmol), and sodium iodide (27 mg, 0.18 mmol) were added to N,N-dimethylformamide (8 mL) and stirred uniformly. The reaction system was heated to 60°C and stirred for 15 minutes, after which 3-(((chloromethoxy)carbonyl)(methyl)amino)propyl acetate (400 mg, 1.79 mmol) was added and stirred for 16 hours. The reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography fractionation plate (developing agent: 5% methanol / 95% dichloromethane) to obtain 3-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)propyl acetate (196 mg, yield 29%). 1H NMR (400 MHz, CDCl3) δ 9.20 (dd, J = 8.8, 2.4 Hz, 1H), 9.07 (d, J = 1.4 Hz, 1H), 8.64 - 8.46 (m, 1H), 7.81 - 7.66 (m, 1H), 7.52 - 7.38 (m, 1H), 6.21 (s, 2H), 4.05 (dd, J = 28.3, 3.6 Hz, 2H), 3.38 (dd, J = 14.3, 7.2 Hz, 2H), 3.02 - 2.89 (m, 3H), 2.03 (dd, J = 17.5, 3.7 Hz, 3H), 1.86 (d, J = 24.3 Hz, 2H). MS calculation: 377.3;MS measurement: 378.2[M+H] + .

[0170] Example 69: Synthesis of 4-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)butyl acetate (69) [ka] Except for using 4-methylamino-1-butanol instead of 3-methylamino-1-propanol in Step 1, the same procedure as in Example 68 was followed to obtain 4-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)butyl acetate. 1H NMR (400 MHz, CDCl3) δ 9.18 (dd, J = 8.9, 1.3 Hz, 1H), 9.06 (d, J = 4.0 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.9, 4.1 Hz, 1H), 7.42 (dd, J = 8.8, 3.9 Hz, 1H), 6.20 (d, J = 4.7 Hz, 2H), 4.04 (dd, J = 27.3, 21.6 Hz, 2H), 3.36 - 3.22 (m, 2H), 2.96 - 2.86 (m, 3H), 2.01 (d, J = 19.7 Hz, 3H), 1.64 - 1.57 (m, 2H), 1.53 (s, 2H). MS calculation: 391.4;MS actual measurement: 392.2[M+H] + .

[0171] Examples 70 and 71: Synthesis of di-t-butyl(5-nitroquinolin-8-yloxy)methyl phosphate (70) and (5-nitroquinolin-8-yloxy)methyl dihydrophosphate (71) [ka] Step 1: Preparation of di-t-butyl(5-nitroquinolin-8-yloxy)methyl phosphate (70) Potassium carbonate (1.45g, 10.52mmol) was added to a solution of nitroxoline (1.0g, 5.26mmol) and di-t-butyl chloromethyl phosphate (2.04g, 7.89mmol) in N,N-dimethylformamide (17mL) at room temperature. The reaction solution was stirred at 60°C for 2 hours. The reaction was quenched by adding water, extracted with dichloromethane (100mLx3), and the organic phase was washed with 1M hydrochloric acid, 1M aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% n-hexane / 95% ethyl acetate) to give di-t-butyl (5-nitroquinolin-8-yloxy)methyl phosphate (570mg, yield: 26%). MS[M+H] + :413.3. Step 2: Preparation of (5-nitroquinolin-8-yloxy)methyl dihydrophosphate (71) At room temperature, trifluoroacetic acid (7 ml) was slowly added dropwise to a solution of di-t-butyl (5-nitroquinolin-8-yloxy)methyl phosphate (520 mg, 1.18 mmol) in dichloromethane (7 ml). The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure. After adjusting the pH to 7 with saturated sodium bicarbonate solution, the solid was precipitated and filtered to obtain the crude product. The crude product was purified by preparative liquid chromatography (Agilent 1260 preparative liquid chromatography: acetonitrile / water gradient 95 / 5-50 / 50) to obtain the product (5-nitroquinolin-8-yloxy)methyl dihydrophosphate (100.24 mg, yield: 24%). 1 H NMR (400 MHz, D2O): δ 8.97-8.94 (m, 1H), 8.76-8.75 (m, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.69-7.65 (m, 1H), 7.38 (d, J = 9.2 Hz, 1H), 5.76 (d, J = 11.2 Hz, 1H). MS calculation: 300.0;MS actual measurement: 301.0 [M+H] + .

[0172] Example 72: Synthesis of (hydroxy((5-nitroquinolin-8-yloxy)methoxy)phosphoryloxy)methyl isopropyl carboxylate (72) [ka] Step 1: Preparation of (hydroxy((5-nitroquinolin-8-yloxy)methoxy)phosphoryloxy)methyl isopropyl carboxylate (72) (5-nitroquinolin-8-yloxy)methyl dihydrophosphate hydrochloride (672 mg, 2 mmol, see Example 71 for synthesis steps), chloromethyl isopropyl carbonate (1.22 g, 8 mmol), and triethylamine (1.01 g, 10 mmol) were added to 20 mL of DMF and stirred at 50° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by pre-HPLC (Agilent 1260 preparative liquid chromatography: acetonitrile / water gradient 95 / 5-50 / 50) to obtain (hydroxy((5-nitroquinolin-8-yloxy)methoxy)phosphoryloxy)methyl isopropyl carboxylate (121 mg, yield 14.5%). 1 H-NMR (400 MHz, DMSO-d6) δ: 9.05 (d, J = 2.8 Hz, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 8.4, 4.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 5.91~5.94 (m, 2H), 5.45~5.49 (m, 2H), 4.72~4.75 (m, 2H), 1.18 (d, J=6.0Hz, 6H). MS calculation: 416.28; MS measurement: 417.1[M+H] + .

[0173] Example 73: Synthesis of (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphorylamino)propionate (73) [ka] Step 1: Preparation of (2S)-methyl 2-(benzyloxy(phenoxy)phosphorylamino)propionate (73a) At room temperature, benzyl alcohol (2g, 18.49mmol) and phenyl dichlorophosphate (4.29g, 20.34mmol) were added to 40mL dichloromethane, the reaction solution was cooled to 0-5℃ in an ice bath, triethylamine (7.47g, 73.96mmol) was slowly added, and then L-alanine methyl ester hydrochloride (2.84, 20.34mmol) was added, stirred for 20 minutes, and then stirred at room temperature for 5 hours. The reaction solution was washed with 20mLx2 water, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain (2S)-methyl 2-(benzyloxy(phenoxy)phosphorylamino)propionate (4.2g, yield: 65.6%). Step 2: Preparation of (2S)-methyl 2-(hydroxy(phenoxy)phosphorylamino)propionate (73b) At room temperature, (2S)-methyl 2-(benzyloxy(phenoxy)phosphorylamino)propionate (2.5 g, 7.16 mmol) was dissolved in 25 mL of tetrahydrofuran, and 500 mg of wet Pd / C was added. The reaction solution was stirred at room temperature for 8 hours under a hydrogen atmosphere. Next, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain (2S)-methyl 2-(hydroxy(phenoxy)phosphorylamino)propionate (1.5 g, yield: 81%). Step 3: Preparation of (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphorylamino)propionate (73) At room temperature, (2S)-methyl 2-(hydroxy(phenoxy)phosphorylamino)propionate (1.5g, 5.79mmol) and 5-nitro-8-(chloromethoxy)quinoline (1a) (921mg, 3.86mmol) were dissolved in 20mL of DMF, followed by addition of catalytic amounts of KI (10mg) and potassium carbonate (1.6g, 11.58mmol) and stirring at room temperature for 6 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=40:1) to obtain (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphorylamino)propionate (160mg, yield: 8.9%). 1 H-NMR (400 MHz, DMSO-d6): δ 9.05~9.06 (m, 1H), 8.99~9.01 (m, 1H), 8.54 (dd, J = 8.4, 3.2Hz, 1H), 7.87 (dd, J = 8.8 Hz, 4.0Hz, 1H), 7.50~7.55 (m, 1H), 7.25 ~ 7.30 (m, 2H), 7.09~7.18 (m,3H), 6.29~6.35 (m,1H), 6.03~6.11 (m,2H), 5.60 (br,1H), 3.88~3.97 (m, 1H), 3.54 (d,J = 10Hz, 3H), 1.18~1.21 (m,3H). MS calculation: 461.37;MS measurement: 462.2 [M+H] + .

[0174] Example 74: Synthesis of (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphorylamino)-3-phenylpropionate (74) [ka] Except for using L-phenylalanine methyl ester hydrochloride instead of L-alanine methyl ester hydrochloride in step 1, the same procedure as in Example 73 was followed to obtain (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphorylamino)-3-phenylpropionate. 1 H-NMR (400 MHz, DMSO-d6): δ 9.03 (d,J=4Hz, 1H), 8.99 (dd, J = 8.8, 1.2Hz, 1H), 8.52 (dd,J = 8.4, 6.4 Hz, 1H), 7.87 (dd,J = 6.4Hz, 1.6Hz, 1H), 7.50~7.55 (m, 1H), 7.10~7.29 (m,6H), 7.00~709 (m, 2H), 6.98~6.99 (m, 2H), 6.40~6.51 (m,1H), 5.85~5.95 (m,2H), 3.98~4.02 (m, 1H), 3.54 (s, 3H), 2.95~3.01 (m, 1H), 2.75~2.85 (m, 1H). MS calculation: 537.46;MS measurement: 538.3 [M+H] + .

[0175] Example 75: Synthesis of (2S)-isopropyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphorylamino)propionate (75) [ka] (2S)-Isopropyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphorylamino)propionate was obtained in the same manner as in the preparation method of Example 73, except that L-alanine isopropyl hydrochloride was used instead of L-alanine methyl ester hydrochloride in Step 1. 1H-NMR (400 MHz, DMSO-d6): δ 9.05~9.06 (m, 1H), 8.99~9.01 (m, 1H), 8.54(dd,J=8.4,3.2Hz,1H), 7.87 (dd,J=8.8Hz,4.0Hz,1H), 7.50~7.55(m,1H), 7.25~7.30 (m,2H), 7.09~7.18(m,3H), 6.29~6.35(m,1H), 6.03~6.11(m,2H), 4.85~4.95 (m,1H), 3.88~3.97(m,1H), 1.18~1.21(m,9H). MS calculation: 489.42;MS measurement: 490.3 [M+H] + .

[0176] Example 76: Synthesis of (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl(5-nitroquinolin-8-yloxy)methyl hydrogenphosphate (76) [ka] Step 1: Preparation of dibenzyl (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl phosphate (76a) At 0°C, sodium hydride (purity: 60%, 0.42g, 10.5mmol) was added to a solution of 6-cyclohexyl-4-methyl-pyridin-1-hydroxy-2-one (purchased from Darui Chemical Co., Ltd.) (2.00g, 9.65mmol) in N,N-dimethylformamide (30mL), and the mixture was stirred for 30 minutes, after which dibenzyl (chloromethyl) phosphate (4.10g, 12.55mmol) was added, the mixture was allowed to warm to room temperature, and the mixture was stirred for 5 hours. The reaction was quenched by adding an aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 75% petroleum ether / 25% ethyl acetate) to give dibenzyl (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl phosphate (1.58 g, 33% yield). Step 2: Preparation of (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl dihydrophosphate (76b) At room temperature, 10% palladium carbon (0.20 g) was added to a solution of dibenzyl (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl phosphate (1.58 g, 3.18 mmol) in tetrahydrofuran (16 mL). The mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered and rinsed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl dihydrophosphate (0.35 g, yield 35%). Step 3: Preparation of (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl(5-nitroquinolin-8-yloxy)methyl hydrogenphosphate (76) At room temperature, (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl dihydrophosphate (350 mg, 1.10 mmol), potassium carbonate (305 mg, 2.21 mmol), and sodium iodide (28 mg, 0.19 mmol) were added to N,N-dimethylformamide (7 mL) and stirred uniformly. The reaction system was heated to 40°C and stirred for 10 minutes, after which 5-nitro-8-chloromethoxyquinoline (1a) (448 mg, 1.88 mmol) was added and stirred for 4 hours. The reaction was quenched by the addition of water, impurities were back-extracted with ethyl acetate, and the aqueous phase was lyophilized and then purified by preparative liquid chromatography (Agilent 1260 preparative liquid chromatography: acetonitrile / water gradient 95 / 5-50 / 50) in a reversed phase system of 95% water / 5% acetonitrile to give (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl(5-nitroquinolin-8-yloxy)hydrogen methyl phosphate (66 mg, 12% yield). 1H NMR (400 MHz, CDCl3) δ 9.65 (d, J = 7.6 Hz, 1H), 9.21 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 6.36 (s, 1H), 6.07 (s, 1H), 6.00 (d, J = 15.2 Hz, 2H), 5.73 (d, J = 12.0 Hz, 2H), 2.15 (s, 3H), 1.94 (d, J = 10.2 Hz, 2H), 1.79 (d, J = 11.8 Hz, 2H), 1.75 - 1.68 (m, 1H), 1.47 - 1.13 (m, 6H). MS calculation: 519.4;MS actual measurement: 520.2[M+H] + .

[0177] Example 77: Synthesis of 4-methyl-5-((5-nitroquinolin-8-yloxy)methyl)-1,3-dioxazol-2-one (77) [ka] Potassium iodide (83mg, 0.5mmol) and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (1.8g, 12mmol) were added batchwise to a solution of nitroxoline (1.9g, 10mmol) and potassium carbonate (2.7g, 20mmol) in N,N-dimethylformamide (10mL) at 60℃, and the reaction was stirred for 2 hours. The reaction was quenched by adding water, extracted with dichloromethane (100mLx3), and the organic phase was washed with 1M hydrochloric acid, 1M aqueous sodium bicarbonate, and saturated saline, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by reversed-phase high-performance liquid chromatography (column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0 mL / min) to obtain 4-methyl-5-((5-nitroquinolin-8-yloxy)methyl)-1,3-dioxazol-2-one (0.6 g, yield 20%). 1H-NMR (400 Hz, CDCl3) δ: 9.23 (dd, J = 8.8, 1.6 Hz, 1H), 9.09 (dd, J = 4.0, 1.6 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 8.8, 4.0 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 5.22 (s, 2H), 2.26 (s, 3H). MS calculation: 302.24;MS actual measurement: 303.1 [M+H] + .

[0178] Example 78: Synthesis of 5-nitroquinolin-8-yl dimethylcarbamate (78) [ka] At 0°C, pyridine (790mg, 10mmol) was slowly added to a solution of triphosgene (296.75mg, 1mmol) in dichloromethane (6mL). After stirring at room temperature for 20 minutes, a solution of dimethylamine in tetrahydrofuran (0.53mL, 1.07mmol) was added. After stirring the reaction solution for 1 hour, the solvent was removed under reduced pressure, pyridine (1mL) and nitroxoline (190mg, 1mmol) were added in sequence, and the reaction solution was stirred at 110°C for 3 hours. The reaction was quenched by adding water, extracted with dichloromethane (100mLx3), and the organic phase was washed with 1M hydrochloric acid, 1M aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% n-hexane / 95% ethyl acetate) to give 5-nitroquinolin-8-yl dimethylcarbamate (80 mg, yield 31%). 1H NMR (400 MHz, DMSO-d6) δ: 9.09 (dd, J = 4.0, 1.2 Hz, 1H), 8.93 (dd, J = 9.2, 1.6 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.8, 4.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 3.21 (s, 3H), 2.96 (s, 3H). MS calculation: 261.07;MS actual measurement: 262.0 [M+H] + .

[0179] Example 79: Synthesis of bis(5-nitroquinolin-8-yl)sebacate (79) [ka] Nitroxoline (332 mg, 1.76 mmol) and pyridine (417 mg, 5.28 mmol) were added batchwise to a solution of sebacoyl chloride (200 mg, 0.84 mmol) in dichloromethane (6 mL) at 0°C. The reaction was stirred at room temperature for 2 hours, and then water was added to quench the reaction. The reaction was extracted with dichloromethane (100 mL x 3), and the organic phase was washed with 1 M hydrochloric acid, 1 M aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% n-hexane / 95% ethyl acetate) to give bis(5-nitroquinolin-8-yl) sebacate (100 mg, yield 22%). 1 H NMR (400 MHz, DMSO-d6) δ: 9.05 (dd, J = 4.4, 1.6 Hz, 2H), 8.92 (dd, J = 8.4, 1.6 Hz, 2H), 8.52 (d, J = 8.8 Hz, 2H), 7.85 (dd, J = 9.2, 4.4 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 1.76 (d, J = 7.2 Hz, 4H), 1.52-1.41 (m, 8H). MS calculation: 546.18;MS actual measurement: 547.2 [M+H] + .

[0180] Test Example 1: Measurement of water solubility of the compound of the present invention The compound of formula (I) of the present invention can release the active ingredient nitroxoline after being introduced into the human body, and nitroxoline simultaneously inhibits methionine aminopeptidase MetAP2 and silencing information regulator 2-related enzyme in vascular endothelial cells, exerting a synergistic effect of inhibiting tumor angiogenesis. Nitroxoline also has the effect of suppressing the proliferation of tumor cells. In addition, the released active ingredient nitroxoline inhibits bacterial methionine aminopeptidase MetAP, thereby exerting a bacteriostatic effect. The present inventors first investigated the water solubility of nitroquinoline and nitroquinoline prodrugs. Experimental equipment: 96-hole filter plate (MSHVN4510 or MSHVN4550, Millipore); electronic digital vortex mixer (MS3 Digital, IKA); water circulation type multi-purpose vacuum pump (SHB-III, Zhengzhou Great Wall Science and Technology Trading Co., Ltd.); balance (XSLT05, Mettler Toledo); comfortable mixer (Eppendorf AG 22331 Hamburg, Eppendorf); liquid chromatography (LC-30AD, Shimadzu); mass spectrometry (API4000, Applied Biosystems, USA); sampler (Anylytics A)GSystem, CTC). Nitroquinoline was synthesized by Kaimon Huishu Co., Ltd. according to the method disclosed in Journal of Heterocyclic Chemistry, 1971, vol. 8, p. 821. Experimental procedure: 500 μL of phosphate buffer (pH = 1.2, 4.5, 6.8 or 7.4) was placed in a glass bottle, 2 mg of compound powder was added, the stopper was inserted, and the bottle was placed in a mixer (VORTEX-GENIE2) and mixed at room temperature for 24 hours. After that, the bottle was vacuum filtered, and the filtrate was treated, and the compound concentration was measured by LC / MS / MS. The solubility results for the compounds of the present invention are shown in Table 1. [Table 2-1] [Table 2-2] Conclusion: By optimizing the structure of the prodrug molecule, the water solubility of the prodrug molecule can be significantly increased compared to nitroxoline. For example, the water solubility of compounds 18, 20, 23, 30, 52, 65, 66, 70, and 72 is improved by several times. The water solubility of the water-permeable compound does not change with the change in pH value. This feature is particularly important in the development of drug formulations. Test Example 2: Measurement of liver microsome and plasma stability of the compound of the present invention The compound of formula (I) of the present invention is expected to be decomposed into nitroxoline in vivo and to exert an anticancer effect. Since liver microsomal enzymes and plasma metabolic enzymes are important means of compound metabolism in the body, in vitro experiments were performed to measure the stability of the compound of the present invention in liver microsomes and plasma. 1. Measurement of liver microsome stability Experimental equipment: thermostatic oscillator (SHA-B, Kuohua); centrifuge (5810R, Eppendorf); mass spectrometer (API4000, Applied Biosystems, USA); liquid chromatography (LC-30AD, Shimadzu); sampler (CTC A does not apply to Lytics AG System, CTC). Experimental procedure: 25 μg / mL alamethicin (Aldrich Reagents), 5 mM magnesium chloride, and 0.5 mg / mL microsomes (XENOTECH) were added to 100 mM phosphate buffer to prepare a reaction solution without coenzymes. Then, 1 mM reduced nicotinamide adenine dinucleotide phosphate (Aldrich Reagents) and 5 mM uridine diphosphate glucuronic acid (Aldrich Reagents) were added to a portion of the solution to prepare a reaction solution containing coenzymes. Then, the working solution of the compound of the present invention was added to the two reaction solutions to make the final concentration of the compound 2 μM. Immediately after mixing, 50 μL of the solution was taken out as a 0-minute sample, and the remaining samples were incubated at 37° C. for 30 minutes, after which 50 μL was taken out. Proteins were immediately precipitated from all the samples taken out, and the samples were centrifuged to take the supernatant, and the compound concentrations were measured by LC / MS / MS. The microsomal stability results for compounds of the invention are shown in Table 2. [Table 3-1] [Table 3-2] [Table 3-3] Conclusion: By optimizing the structure of the prodrug molecules, different types of microsome-stable compounds can be obtained, and the microsome-stability of compounds 6, 7, 52, and 53 indicates that such compounds may have a longer half-life in the body. Another type of compound with microsome-stability indicates that the compound can be rapidly converted to nitroxoline once it enters the body, reducing the possibility of unwanted biological toxicity. After analyzing the two types, both have advantages and characteristics for development as drugs. 2.Plasma stability measurement Experimental equipment: thermostatic oscillator (SHA-B, Kuohua); centrifuge (5810R, Eppendorf); mass spectrometer (API4000, Applied Biosystems, USA); liquid chromatography (LC-30AD, Shimadzu); sampler (CTC A does not apply to Lytics AG System, CTC). Experimental animals: human (lot number: BRH1343165), rat (lot number: RAT336728), mouse (lot number: MSE280000), dog (lot number: BGL99137), and monkey (lot number: PH-Monkey-20180821) plasma were obtained from Shanghai Sishin Biotechnology Co., Ltd. Experimental procedure: The compound of the present invention was dissolved in an organic solvent to make a working solution of 1 mM, and then 3 μL was taken and added to 597 μL of pre-incubated human or rat plasma, and mixed uniformly. Then, 50 μL was quickly taken as the 0-minute sample, and the remaining samples were incubated at 37°C, and 50 μL was taken at 15, 30, 60, and 120 minutes. After taking all the samples, protein was precipitated immediately, and the supernatant was taken by centrifugation, and the compound concentration was measured by LC / MS / MS. The plasma stability results for the compounds of the present invention are shown in Table 3. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] Conclusion: By optimizing the structure of the prodrug molecule, different types of plasma-stable compounds can be obtained, and the plasma stability of compounds 6, 7, 52, 53, 54, 55, 56, 57, 58, 59, 62, 70, 75, etc. indicates that such compounds may have a longer half-life in the body. Another type of plasma-unstable compound indicates that the compound will be rapidly converted to nitroxoline once it enters the body, reducing the possibility of unwanted biological toxicity. After analyzing the two types, it was found that both have advantages and characteristics for development as drugs.

[0181] Test Example 3: Pharmacokinetic measurement of the compound of the present invention in rats Nitroxoline mainly undergoes biphasic metabolism through the liver, and has a fast metabolic rate, so its half-life in the body is short. The present invention modifies its structure and prepares 13 kinds of compounds of formula (I) by chemical synthesis. In this study, nitroxoline and compound of formula (I) were administered to rats intravenously or orally once, respectively, and the concentration change of compound nitroxoline in rat plasma was studied, thereby evaluating the pharmacokinetic behavior of nitroxoline and compound of formula (I) in rats. 1. Experimental Equipment Tandem quadrupole mass spectrometer (API4000, Applied Biosystems, USA), liquid chromatography (1200, Agilent), autosampler (CTC A not applicable for lyst HTC PAL, Applied Biosystems, USA A not applicable for lyst v1.6.2), low-temperature refrigerated centrifuge (1-15PK, Sigma), vortex oscillator (VX-III, Beijing Tajin Technology Co., Ltd.). 2. Pharmacokinetic experiments Male SD rats (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., Experimental Animal Production Permit Number: SCXK(Kyoto)2016-0006, Experimental Animal Qualification Certificate Number: 11400700325643), 3 rats per group, weight 180-250g, age 6-7 weeks, fasted overnight before administration, drinking water ad libitum, fed 4 hours after administration. The test compound was placed in an EP tube, and DMSO 1.017mL, solutol 2.035mL, and sterile water for injection (volume ratio of the three was 1:2:17, v:v:v) were added, and the mixture was sonicated for 20 minutes to dissolve sufficiently (compound concentration: 0.005mmol / mL). The intravenous dose was 0.01mmol / kg, and the oral dose was 0.1mmol / kg. Before administration (0 hours) and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, 28, 32, and 48 hours after administration (sampling points were adjusted depending on the situation), 0.3 ml of whole blood was collected from the orbital venous plexus, placed in a centrifuge tube containing EDTA-K2 (Aldrich Reagents) anticoagulant, and placed on crushed ice after collection. Within 0.5 hours, the tube was centrifuged at 5000 rpm for 5 minutes to separate all the plasma, placed in another clean centrifuge tube, and added stabilizing solution at a ratio of 100:3 (plasma / stabilizing solution, v / v), and placed in a refrigerator at -20°C for preparation for measurement. Preparation of the stabilizing solution: 200 mg of vitamin C (Aldrich) was dissolved in 8 mL of physiological saline, and then 2 mL of formic acid was added and thoroughly mixed. 3. Measuring Sample Concentration Calibration curve: A series of calibration curve working solutions was prepared, and 5 μL was added to 50 μL of blank rat plasma, and 150 μL of internal standard working solution (containing 2 ng / mL of diphenhydramine (Aldrich Reagents) in acetonitrile) was added, followed by vortex shaking for 1 minute. Centrifugation was performed for 10 minutes at 4°C and 12,000 rpm, and 100 μL of the supernatant was collected in a sampling tube, and 10 μL was injected into a liquid chromatograph mass spectrometer for measurement. Measurement sample: 50μL of the sample plasma was mixed with 5μL of the diluted working solution, then 150μL of the internal standard working solution (containing diphenhydramine 2ng / mL in acetonitrile) was added and vortex-shaken for 1 minute. The mixture was centrifuged for 10 minutes at 4℃ and 12000 rpm, and 100μL of the supernatant was collected in a sampling tube, and 10μL was injected into a liquid chromatograph mass spectrometer for measurement. Pharmacokinetic parameters were calculated using the WinNonlin V6.2 non-ventricular model. The measurement results are shown in Tables 4 to 45. [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17]

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

[0182] Test Example 4: Pharmacokinetic measurement of the compound of the present invention in dogs Nitroxin is mainly metabolized through the liver via phase II metabolism and has a fast metabolism rate, so its half-life in the body is short. In the present invention, its structure was modified, and 13 types of compounds of formula (I) were produced by chemical synthesis. This test examined the concentration changes of the compound nitroxin in canine plasma after single intravenous or oral administration of nitroxin and the compounds of formula (I) respectively, and thereby evaluated the pharmacokinetic behaviors of nitroxin and the compounds of formula (I) in the body. 1. Experimental equipment Tandem quadrupole mass spectrometer (API5500, Applied Biosystems, USA), liquid chromatography (1200, Agilent), autosampler (CTC A is not applicable to Lytics HTC PAL), and A of Applied Biosystems, USA is not applicable to Lyst v1.6.2. 2. Pharmacokinetic experiment Male beagle dogs (Beijing Marshal Biotechnology Co., Ltd., experimental animal production license number: SCXK (Jing) 2016-0001, experimental animal quality certification number: 11400600001728), 3 dogs in each group, body weight 10 - 13 kg, 20 - 22 months old, fasted overnight before administration, free access to water, fed 4 hours after administration. The compound to be measured was placed in an EP tube, DMSO, solutol, and sterile injection water (the volume ratio of the three was 1:2:17, v:v:v) were added, and ultrasonic treatment was performed for more than 20 minutes to dissolve it sufficiently (the compound formulation concentration was: 0.005 mmol / mL). The intravenous administration dose was 0.01 mmol / kg, and the oral administration dose was 0.1 mmol / kg. Before administration (0 hour) and at 0.0833, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 hours after administration (the sampling points were adjusted according to the situation), 0.3 ml of whole blood was collected from the jugular vein and placed in a centrifuge tube containing EDTA-K2 (Aldrich reagent) anticoagulant. After collection, it was placed in crushed ice and centrifuged at 1530 g for 10 minutes within 0.5 hour to separate all the plasma, which was placed in another clean centrifuge tube and put into a -20°C refrigerator for measurement preparation. 3. Measurement of sample concentration A series of calibration curve solutions were prepared. 10 μL of the calibration curve solution and 1000 μL of the internal standard working solution (acetonitrile solution containing verapamil 5 ng / mL (Aldrich), glibenurea 50 ng / mL (Aldrich), and diclofenac 50 ng / mL (Aldrich)) were added to each sample, and the mixture was vortex-shaken for 5 minutes. The mixture was centrifuged at 4°C and 3700 rpm for 10 minutes, and 60 μL of the supernatant was placed in a sampling tube and mixed with 120 μL of water. 10 μL was then injected into the vortex-shaker for measurement. Pharmacokinetic parameters were calculated using the WinNonlin V6.2 non-ventricular model. The measurement results are shown in the following Tables 46 to 52. [Table 47] [Table 48] [Table 49] [Table 50] [Table 51] [Table 52] [Table 53] Conclusion: As evident from the data, the prodrug molecules compounds 5, 20, and 51 were better absorbed in beagle dogs than nitroxoline, suggesting that the prodrug molecules could effectively reduce the dose of the drug molecules.

Claims

1. A compound represented by the following formula (II), or its meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof: embedded image 【Chemistry 1】 (In the formula, R １ is hydrogen and C １－６ alkyl groups, R ４ , R ５ and R ６ are each independently hydrogen, C １ -C １２ selected from the group consisting of alkyl groups and -O-C 1 -C 6 alkyl groups; or R ４ , R ５ and R ６ Of these, one is hydrogen and the other two are C together with carbon. ３ -C ６ A cycloalkyl group or a 5- to 7-membered heterocyclic group is formed, ３ -C ６ The cycloalkyl group or the 5- to 7-membered heterocyclic group is further substituted with one or more groups selected from the group consisting of -C(O)R11; R11 is C １ -C ６ is an alkyl group.

2. R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl groups; R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen and a C 1 -C 6 alkyl group; or one of R 4 , R 5 and R 6 is hydrogen and the remaining two together with the carbon form a pyrrolidinyl group, said pyrrolidinyl group being further substituted with one or more substituents selected from the group consisting of -C(O)R 11 ; R １１ is C １ -C ６ 2. A compound of formula (II) according to claim 1, which is an alkyl group, or a meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

3. R 1 is hydrogen; R ４ , R ５ and R ６ one of which is hydrogen and the remaining two together with the carbon form a pyrrolidinyl group, said pyrrolidinyl group being further substituted with one or more groups selected from the group consisting of -C(O)R11; The compound of formula (II) according to claim 2, wherein R 11 is a C 1 -C 6 alkyl group, or a meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

4. A compound selected from the group consisting of the following, or its meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof: 【Chemistry 2-1】 【Chemistry 2-2】

5. A method for producing a compound represented by formula (II) according to claim 1, or a meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, comprising the steps of: 【Chemistry 3】 The method includes the steps of: reacting compound IIc with nitroxoline in a solvent in the presence of an alkali to obtain a compound represented by general formula (II), 【Chemistry 4】 R １ , R ４ , R ５ and R ６ is as defined in claim 1.

6. 6. The method according to claim 5, wherein the alkali is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, and pyridine, and the solvent is selected from the group consisting of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, and t-butanol methyl ether.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the manufacture of an anti-infective or anti-tumor drug.

9. The use according to claim 8, wherein the tumor is selected from the group consisting of bladder cancer, prostate cancer, and kidney cancer.

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