TWI874355B - Prodrug of nitroxoline and use thereof - Google Patents

Abstract

The present invention relates to the prodrug of nitroxoline and use thereof. Specifically, the present invention relates to a compound of formula (I) or the pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition comprising the same, as well as a use thereof in anti-infective and anti-tumor drugs. The compound of formula (I) has better pharmacokinetic parameters such as water solubility, blood concentration or half-life relative to nitroxoline. The compound of formula (I) can reduce the number of administrations, and has the possibility of being applied in other fields than the urinary tract field. The definition of each group in formula (I) is as defined in the description.

Description

Nitrate hydroxyquinoline prodrug and its use

The present invention relates to the field of medicine. Specifically, the present invention relates to a nitrohydroxyquinoline prodrug and its use.

Nitroxoline is a commercially available antibacterial drug that has long been used to treat urinary tract infections. Recent discoveries have shown that nitroxoline is also very effective in inhibiting angiogenesis and inhibiting the growth and invasion of cancer cells, and is currently being developed for anti-tumor use. Human pharmacokinetic studies have shown that nitroxoline can be rapidly absorbed into the blood circulation, but due to the severe first-pass effect of the liver on the drug, its biological half-life is very short (according to a single-arm, open, multi-center clinical phase II trial conducted in China by Jiangsu Yahong Pharmaceutical Technology Co., Ltd., its half-life is 1.22-1.44 hours), and frequent dosing is required. In order to maintain continuous drug exposure, nitroquinoline drugs are generally prescribed to be taken three times a day (TID) or four times a day (QID), which not only brings economic losses and is not conducive to patient compliance, but more seriously increases the drug's continued damage to the normal body. At the same time, because nitroquinoline has very low water solubility, it often needs to be made into a rapid-release preparation to improve solubility, which invisibly increases production costs.

Prodrug is a compound obtained by chemical modification of active drugs. It is converted into the original drug by enzymes in the body to exert its efficacy. Prodrugs are widely used in drug research and development. They have been successfully studied in many different drugs and have achieved good application results. The prodrug strategy can solve some defects of the parent drug (active agent) due to its own physical and chemical properties, such as: 1) eliminate the bad smell of the drug; 2) increase the blood drug concentration; 3) increase the fat solubility or water solubility of the drug; 4) prolong the duration of action of the drug; 5) change the route of drug administration, etc.

So far, there are no reports on the use of prodrug strategies to increase the biological half-life, exposure, and water solubility of nitroquinolines, thereby reducing the frequency of drug administration.

In view of the above defects, the inventors have designed a prodrug of the nitrohydroxyquinoline molecule, which is metabolized into nitrohydroxyquinoline after entering the body to exert its effect, and at the same time prolongs the half-life of nitrohydroxyquinoline in the body, so as to achieve the purpose of reducing the frequency of drug administration.

Due to the metabolic characteristics of nitroquinoline, which are low water solubility and short biological half-life, the general prescription requires that it be taken three or four times a day in antibacterial and anticancer applications. At the same time, since its main metabolic pathway is through renal metabolism and excretion through the urinary tract, the application of nitroquinoline is limited to areas other than urinary tract infection and bladder cancer.

The present invention provides a compound that can be used as a prodrug of nitroquinoline. Through screening and optimization of the compound structure, it is found that in animals, the compound has better pharmacokinetic parameters such as water solubility, blood concentration or biological half-life than nitroquinoline. The compound of the present invention can reduce the number of dosing times and expand the possibility of application in other fields besides the urinary tract field.

Therefore, the object of the present invention is to provide a compound represented by formula (I):

表示單鍵或雙鍵； R₁選自氫、C_1-6烷基、S或O；X選自O、N、S、-(CH₂)_n-、芳基、或雜環基；其中：當X選自N時，R₀和R₂各自獨立地選自氫、C_1-6烷基、芳基、或雜環基；當X選自芳基或雜環基時；R₀和R₂各自獨立地選自氫、鹵素、羥基、氰基、胺基、羧基、酯基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基，其中所述烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；當X選自O、S或-(CH₂)_n-時，R₂不存在；R₀選自C_1-6烷基、環烷基、 雜環基、-COR₁₁、-C(O)OR₁₂、

或

，所述C_1-6烷基、環烷 基、雜環基任選進一步被選自鹵素、胺基硝基、氰基、羥基、巰基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；其中： 當R₀選自

時，E選自O或NR₁₄；R₁₀、R₁₃、R₁₄各自獨立地選 自氫、C_1-6烷基、或芳基，所述C_1-6烷基或芳基任選進一步被選自鹵素、 羥基、巰基、羧基、酯基、烷基、烷氧基、環烷基、雜環基、芳基、芳基烷基、雜芳基、雜芳基烷基、-OR₁₂、-COR₁₁、-C(O)OR₁₂、 -OC(O)R₁₁、-OC(O)OR₁₂的一個或多個基團取代；當R₀選自

時，Y選 自O、N或S，R₃選自

、

、環烷基、雜環基、芳基、雜芳基， 所述環烷基、雜環基、芳基、雜芳基任選被進一步被選自鹵素、羥基、巰基、羧基、酯基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、-OC(O)R₁₁的一個或多個基團取代；Z選自C、N或O；其中：當Z選自C時，R₄、R₅和R₆各自獨立地選自氫、鹵素、烷基、環烷基、雜環基、芳基、雜芳基、-OR₁₂、-SR₁₂、-C(O)R₁₁、-C(O)OR₁₂、-C(O)-(CH)_m-C(O)R₁₁、-OC(O)R₁₁、-NR^aR^b、-N(R^c)C(O)R^d、-C(O)N(R^a)(R^b)、-N(R^c)S(O)_pR^d、-S(O)_pN(R^a)(R^b)、-O(CH₂)_mO(CH₂)_qR₁₂、-N(R^c)C(O)-(CH)_m-N(R^c)C(O)R^d，其中所述烷基、環烷基、雜環基、芳基或雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、烷基、烷氧基、烯基、炔基、OR₁₂、SR₁₂、NR^aR^b、-COR₁₁、-C(O)OR₁₂、-OC(O)R₁₁、-N(R^c)C(O)R^d、-O(CH₂)_mO(CH₂)_qR₁₂、環烷基、雜環基、芳基、芳烷基、雜芳基、雜芳基烷基的一個或多個基團取代，所述芳基、芳烷基、雜芳基或雜芳烷基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、氧代基、烷基、烷氧基的一個或多個基團取代；或者R₄、R₅和R₆其中之一為氫，其餘兩者與Z一起形成環烷基或雜環基，所述環烷基或雜環基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、 巰基、烷基、烷氧基、烯基、炔基、-C(O)R₁₁、-C(O)OR₁₂、-OC(O)R₁₁、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；當Z選自N時，R₆不存在，R₄和R₅各自獨立地選自氫、鹵素、烷基、環烷基、雜環基、芳基、雜芳基、-OR₁₂、-SR₁₂、-C(O)R₁₁、-C(O)OR₁₂、-OC(O)R₁₁、-NR^aR^b、-N(R^c)C(O)R^d、-C(O)N(R^a)(R^b)、-N(R^c)S(O)_pR^d、-S(O)_pN(R^a)(R^b)、-O(CH₂)_mO(CH₂)_qR₁₂、-N(R^c)C(O)-(CH)_m-N(R^c)C(O)R^d，其中所述烷基、環烷基、雜環基、芳基、或雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、烷基、烷氧基、烯基、炔基、OR₁₂、SR₁₂、NR^aR^b、-C(O)R₁₁、-C(O)OR₁₂、-OC(O)R₁₁、-(CH)_m-OC(O)R₁₁、環烷基、雜環基、芳基、芳烷基、雜芳基、雜芳基烷基的一個或多個基團取代，或者R₄、R₅和Z一起形成環烷基或雜環基，所述環烷基或雜環基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、烷基、烷氧基、烯基、炔基、-C(O)R₁₁、-C(O)OR₁₂、-OC(O)R₁₁、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；當Z表示O時，R₅和R₆不存在，R₄選自C_1-6烷基、芳基或雜環基，其中所述C_1-6烷基、芳基或雜環基任選進一步被一個或多個-OH取代；或者當X選自O、N、S、或-(CH₂)_n-時，R₂不存在，R₁、X和R₀一起形成環烷基或雜環基，所述環烷基或雜環基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；R₁₁和R₁₂各自獨立地選自氫、鹵素、羥基、氰基、胺基、羧基、酯 基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基，其中所述烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、氧代基、烷基、烷氧基、-NR^aR^b、-OR^d、-N(R^c)C(O)R^d、-C(O)N(R^a)(R^b)、-N(R^c)S(O)_pR^d、-S(O)_pN(R^a)(R^b)、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；R^a和R^b各自獨立地選自氫、鹵素、羥基、氰基、胺基、羧基、酯基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基，其中所述胺基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；或者R^a和R^b與他們連接的原子一起形成雜環基，所述雜環基任選進一步被選自鹵素、胺基、硝基、氰基、氧代基、羥基、巰基、羧基、酯基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；R^c和R^d各自獨立地選自氫、鹵素、羥基、氰基、胺基、羧基、酯基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基，其中所述胺基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；n選自1至8的整數； m選自0至6的整數；p選自0、1或2；q選自0至6的整數。 or its meso form, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

represents a single bond or a double bond; R ₁ is selected from hydrogen, C _1-6 alkyl, S or O; X is selected from O, N, S, -(CH ₂ ) _n -, aryl, or heterocyclic group; wherein: when X is selected from N, R ₀ and R ₂ are each independently selected from hydrogen, C _1-6 alkyl, aryl, or heterocyclic group; when X is selected from aryl or heterocyclic group; R ₀ and R ₂ are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; when X is selected from O, S or -(CH ₂ ) _n -, R ₂ is absent; R ₀ is selected from C _1-6 alkyl, cycloalkyl, heterocyclic, -COR ₁₁ , -C(O)OR ₁₂ .

or

, the C _1-6 alkyl, cycloalkyl, heterocyclic group is optionally further substituted by one or more groups selected from halogen, aminonitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; wherein: when R ₀ is selected from

when E is selected from O or NR ₁₄ ; R ₁₀ , R ₁₃ , R ₁₄ are each independently selected from hydrogen, C _1-6 alkyl, or aryl, wherein the C _1-6 alkyl or aryl is optionally further substituted by one or more groups selected from halogen, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR ₁₂ , -COR ₁₁ , -C(O)OR ₁₂ , -OC(O)R ₁₁ , -OC(O)OR ₁₂ ; when R ₀ is selected from

When Y is selected from O, N or S, R ₃ is selected from

,

, cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, -OC(O)R ₁₁ ; Z is selected from C, N or O; wherein: when Z is selected from C, R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -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(CH ₂ ) _m O(CH ₂ ) _q R ₁₂ , -N(R ^c )C(O)-(CH) _m -N(R ^c )C(O)R ^d , wherein the alkyl, cycloalkyl, heterocyclo, aryl or heteroaryl is optionally further selected from halogen, amine, nitro, cyano, hydroxyl, oxalyl, alkyl, alkoxy, alkenyl, alkynyl, OR ₁₂ , SR ₁₂ , NR ^a R ^b , -COR ₁₁ , -C(O)OR ₁₂ R 11 , -OC(O)R ₁₁ , -N(R ^c )C(O)R ^d , -O(CH ₂ ) _m O(CH ₂ ) _q R ₁₂ , cycloalkyl, heterocyclo, aryl, aralkyl, heteroaryl, heteroarylalkyl, wherein the aryl, aralkyl, heteroaryl or heteroaralkyl is optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy; or R ₄ , R ₅ and R ₆ is hydrogen, and the remaining two together with Z form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, -C(O)R ₁₁ , -C(O)OR ₁₂ , -OC(O)R ₁₁ , cycloalkyl, heterocyclic group, aryl, heteroaryl; when Z is selected from N, R ₆ is absent, and R ₄ and R ₅ are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -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(CH ₂ ) _m O(CH ₂ ) _q R ₁₂ , -N(R ^c )C(O)-(CH) _m -N(R ^c )C(O)R ^d , wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from halogen, amine, nitro, cyano, hydroxyl, oxalyl, alkyl, alkoxy, alkenyl, alkynyl, OR ₁₂ , SR ₁₂ , NR ^a R ^b , -C(O)R ₁₁ , -C(O)OR ₁₂ wherein R ₄ , R 5 _{and Z} together form _a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, oxirane, alkyl, alkoxy, alkenyl, alkynyl, -C(O)R ₁₁ , -C(O)OR _{12 ,} -OC(O)R _{11 ,} cycloalkyl, heterocyclic group, aryl, heteroaryl; when Z represents O, R ₅ and R ₆ are absent, and R ₄ is selected from C wherein _{the C 1-6 alkyl} , aryl or heterocyclic group is optionally further substituted by one or more -OH groups; or when X is selected from O, N, S or -(CH ₂ ) _n -, R ₂ is absent, R ₁ , X and R ₀ together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, -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 ), alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl group; Ra and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, ^aryl , heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or Ra and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; ^b together with the atoms to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R ^c and R ^d are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; n is selected from an integer from 1 to 8; m is selected from an integer from 0 to 6; p is selected from 0, 1 or 2; q is selected from an integer from 0 to 6.

In a preferred embodiment, the compound represented by formula (I) according to the present invention is a compound represented by the following formula (II):

wherein R ₁ is selected from hydrogen or C _1-6 alkyl; R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -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(CH ₂ ) _m O(CH ₂ ) _q R ₁₂ , -N(R ^c )C(O)-(CH) _m -N(R ^c )C(O)R ^d , wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally further selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, OR ₁₂ , SR ₁₂ , NR ^a R ^b , -COR ₁₁ , -C(O)OR ₁₂ , -OC(O)R ₁₁ , -N(R ^c )C(O)R ^d , -O(CH ₂ ) _m O(CH ₂ ) _q R ₁₂ R 4 , R 5 and R 6 are hydrogen, and the other two together with Z form a cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, -C(O)R _{11 ,} -C(O ₎ OR _{12 ,} -OC(O)R ₁₁ R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, -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) _pN ( ^Ra )( ^Rb ), alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; ^Ra and ^Rb are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or R ^{R a} and R ^b together with the atoms to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R ^c and R ^d are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; m is selected from an integer from 0 to 6; p is selected from 0, 1 or 2; q is selected from an integer from 0 to 6.

In a further preferred embodiment of the present invention, according to the compound of formula (II) described in the present invention, R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, alkyl, aryl, heteroaryl, -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(CH ₂ ) _m O(CH ₂ ) _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 optionally further selected from halogen, hydroxyl, alkyl, OR ₁₂ , SR ₁₂ , NR ^a R ^b , -COR ₁₁ , -C(O)OR ₁₂ , }-O(O)CR ₁₁ , -N(R ^c )C(O)R ^d , -O(CH ₂ ) _m O(CH ₂ ) _q R ₁₂ wherein the aryl, aralkyl, heteroaryl or heteroarylalkyl is optionally substituted by one or more groups selected from halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further selected from halogen, amine, hydroxyl, alkyl, alkoxy, -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 ), cycloalkyl, heterocyclic, aryl, heteroaryl; ^Ra and R R a and ^{R b} are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; or R ^a and R ^b together with the atoms to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R ^c and R ^d are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; m is selected from an integer from 0 to 6; p is selected from 0, 1 or 2; q is selected from an integer from 0 to 6.

In a further preferred embodiment of the present invention, according to the compound of formula (II) described in the present invention, R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, alkyl, aryl, heteroaryl, -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 is optionally further selected from halogen, hydroxyl, alkyl, OR ₁₂ , SR ₁₂ , NR ^a R ^b , -COR ₁₁ , -C(O)OR ₁₂ , -O(O)CR ₁₁ , -N(R ^c )C(O)R ^d _{R 11 and} R _{12 are} each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further selected from halogen, amine, hydroxyl, alkyl, -OR ^d , -N(R ^c )C(O ₎ ^R _d ^R and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; or R and R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, ^aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; ^b together with the atoms to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R ^c and R ^d is each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; m is selected from an integer from 0 to 6; q is selected from an integer from 0 to 6.

In a further preferred embodiment of the present invention, according to the compound of formula (II) described in the present invention, one of R ₄ , R ₅ and R ₆ is hydrogen, and the other two together with the carbon atom to which they are connected form a cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, oxirane, alkyl, alkoxy, alkenyl, alkynyl, -C(O)R ₁₁ , -C(O)OR ₁₂ , -OC(O)R ₁₁ , cycloalkyl, heterocyclic group, aryl, heteroaryl; R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, -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 ), alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, hydroxyaryl, heteroaryl; Ra and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, ^aryl , heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or ^Ra and R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; ^b together with the atoms to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R ^c and R ^d is each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; p is selected from 0, 1 or 2.

In a further preferred embodiment of the present invention, according to the compound of formula (II) described in the present invention, one of R ₄ , R ₅ and R ₆ is hydrogen, and the other two together with the carbon atom to which they are connected form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from -C(O)R ₁₁ , -C(O)OR ₁₂ ; R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further selected from halogen, hydroxyl, alkyl, -OR ^d , -N(R ^c )C(O)R R ^c and R ^d are each independently selected from hydrogen, alkyl, alkoxy, aryl, heteroaryl, wherein the ^alkyl , alkoxy, aryl and heteroaryl are optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl.

In another preferred embodiment of the present invention, the compound represented by formula (I) according to the present invention is a compound represented by the following formula (III):

wherein R ₁ is selected from hydrogen or C _1-6 alkyl; R ₄ and R ₅ are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -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(CH ₂ ) _m O(CH ₂ ) _q R ₁₂ , -N(R ^c )C(O)-(CH) _m -N(R ^c )C(O)R ^d wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, oxirane, alkyl, alkoxy, alkenyl, alkynyl, OR ₁₂ , SR ₁₂ , NR ^a R ^b , -C(O)R ₁₁ , -C(O)OR ₁₂ , -O(O)CR ₁₁ , -(CH) _m -OC(O)R ₁₁ , cycloalkyl, heterocyclic, aryl, aralkyl, heteroaryl, heteroarylalkyl, or R ₄ , R R ₁₁ and R 12 are taken together to form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, -C(O)R ₁₁ , -C(O)OR ₁₂ , -O(O)CR ₁₁ , cycloalkyl, heterocyclic group, aryl, heteroaryl; R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, -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 ), alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl group; Ra and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, ^aryl , heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or Ra and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; ^b together with the atoms to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R ^c and R ^d are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; m is selected from an integer from 0 to 6; p is selected from 0, 1 or 2; q is selected from an integer from 0 to 6.

In a further preferred embodiment of the present invention, according to the compound of formula (III) described in the present invention, _R4 and _R5 are each independently selected from hydrogen, alkyl, aryl, heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally further substituted by one or more groups selected from halogen, hydroxyl, hydroxyl, alkyl, -C(O) _R11 , -C(O) _OR12 , -O(O) _CR11 , -(CH) _m -OC(O) _R11 , aryl, heteroaryl; _R11 and _R12 are each independently selected from hydrogen, alkyl, wherein the alkyl is optionally further substituted by one or more groups selected from halogen, ^-ORd , -N( ^Rc )C(O) ^Rd ; ^Rc and R ^d are each independently selected from hydrogen, alkyl, aryl, heteroaryl, wherein the alkyl, aryl and heteroaryl are optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; m is selected from an integer from 0 to 6; p is selected from 0, 1 or 2.

In another preferred embodiment of the present invention, the compound represented by formula (I) according to the present invention is a compound represented by the following formula (IV),

wherein R ₁ is selected from hydrogen or C _1-6 alkyl; A is selected from C, O or N; R ₇ and R ₈ are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy; R ₉ is selected from hydrogen, halogen, amine, hydroxyl, alkyl, alkoxy, -C(O)R ₁₁ , -C(O)OR ₁₂ , -OC(O)R ₁₁ , cycloalkyl, heterocyclic; R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, -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 ), alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl group; Ra and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, ^aryl , heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or Ra and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; ^b together with the atoms to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R ^c and R ^d is each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; p is selected from 0, 1 or 2.

In another preferred embodiment of the present invention, the compound represented by formula (I) according to the present invention is a compound represented by the following formula (V),

wherein E is selected from O or NR ₁₄ ; R ₁₀ , R ₁₃ , R ₁₄ are each independently selected from hydrogen, C _1-6 alkyl, or aryl, wherein the C _1-6 alkyl or aryl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR ₁₂ , -COR ₁₁ , -C(O)OR ₁₂ , -OC(O)R ₁₁ , -OC(O)OR ₁₂ ; R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, -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 ), alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl group; Ra and ^R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, ^aryl , heteroaryl group, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl group are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl group; or Ra and R are each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, ^aryl , heteroaryl group; ^b together with the atoms to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R ^c and R ^d is each independently selected from hydrogen, halogen, hydroxyl, cyano, amine, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkynyl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; p is selected from 0, 1 or 2.

In a further preferred embodiment of the present invention, according to the compound of formula (V) described in the present invention, R ₁₀ , R ₁₃ , R ₁₄ are each independently selected from hydrogen or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, hydroxyl, alkyl, alkoxy, aryl, heteroaryl, -OR ₁₂ , -COR ₁₁ , -C(O)OR ₁₂ , -OC(O)OR ₁₁ ; R ₁₁ and R ₁₂ are each independently selected from alkyl, aryl, and heteroaryl, wherein the alkyl, aryl, and heteroaryl are optionally further substituted by one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkoxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl.

Typical compounds of the present invention include but are not limited to the following compounds:

Or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

The present invention further relates to a method for preparing the compound represented by formula (II) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Compound IIc is reacted with nitrohydroxyquinoline in a solvent in the presence of a base to undergo a nucleophilic reaction to obtain a compound represented by the general formula (II); wherein the base is preferably selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, and pyridine; the solvent is preferably selected from dichloromethane, N,N-dimethylformamide, tetrahydrofuran, and tert-butyl alcohol methyl ether; R ₁ , R ₄ , R ₅ and R ₆ are as defined in the general formula (II).

The present invention further relates to a method for preparing the compound represented by formula (III) according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Compound IIIc and nitrohydroxyquinoline undergo a nucleophilic reaction in a solvent in the presence of a base to obtain a compound represented by the general formula (III); wherein the base is preferably selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, and pyridine; the solvent is preferably selected from dichloromethane, N,N-dimethylformamide, tetrahydrofuran, and tert-butyl alcohol methyl ether; _R4 and _R5 are as defined in the general formula (III).

The present invention further relates to a method for preparing a compound represented by formula (II') or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

(II') comprising the following steps:

Compound II'b and compound II'c are subjected to a nucleophilic reaction in the presence of a base in a solvent to obtain a compound of formula (II'); wherein the base is preferably potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine; the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran and tert-butyl alcohol methyl ether; R ₄ , R ₅ and R ₆ are as defined in the general formula (II).

The present invention further relates to a method for preparing a compound represented by formula (V') or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

It includes the following steps:

Compound V'd and compound II'b undergo a nucleophilic reaction in the presence of a base in a solvent to obtain a compound represented by formula (V'); wherein the base is preferably potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether; R ₁₀ and R ₁₃ are as defined in the general formula (V).

The present invention further relates to a method for preparing a compound represented by formula (V") or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

It includes the following steps:

Compound V"a reacts with nitrohydroxyquinoline in the presence of a base in a solvent to undergo a nucleophilic reaction to obtain a compound represented by formula (V"); wherein the base is preferably potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine; and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether; R ₁₀ and R ₁₃ are as defined in the general formula (V).

The present invention further relates to a pharmaceutical composition, which contains the compound represented by the general formula (I) according to the present invention, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

The present invention further relates to the use of the compound represented by the general formula (I) according to the present invention, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of anti-infection and anti-tumor drugs, wherein the tumor may be bladder cancer, prostate cancer or kidney cancer.

The pharmaceutically acceptable salt of the compound represented by the general formula (I) of the present invention may be an acid addition salt or a base addition salt. The acid may be an inorganic acid, including but not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; or may be 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, glutamine, aspartic acid, salicylic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. The base may be an inorganic base, including but not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; or an organic base, including but not limited to ammonium hydroxide, triethylamine, N,N-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, , N-benzylphenethylamine, arginine or lysine; or it may be an alkali metal salt, including but not limited to: lithium, potassium and sodium salts; or it may be an alkali earth metal salt, including but not limited to: barium, calcium and magnesium salts; or it may be a transition metal salt, including but not limited to zinc salts; or other metal salts, including but not limited to: sodium hydrogen phosphate and disodium hydrogen phosphate.

In another aspect of the present invention, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is prepared into a pharmaceutical composition that can be used clinically. According to clinical indications, routes and methods of administration, its pharmaceutical preparations include but are not limited to oral preparations such as tablets, gels, soft/hard capsules, emulsions, dispersible powders, granules, and water/oil suspensions; injections include intravenous injections, intramuscular injections, intraperitoneal injections, rectal suppositories, and intracranial injections, which can be aqueous solutions or oil solutions; topical preparations include creams, ointments, gels, water/oil solutions, and inclusion preparations; inhalation preparations include fine powders, liquid aerosols, and various preparations suitable for implantation in the body.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, 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 known method for preparing pharmaceutical compositions in the art, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and a non-toxic pharmaceutically acceptable excipient suitable for preparing tablets for mixing. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time. For example, water-soluble taste-masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate may be used.

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

The aqueous suspension contains the active substance and a suitable excipient for mixing in order to prepare an aqueous suspension. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing agents or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, for example heptadecaethyleneoxy cetyl alcohol. cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension 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 sweeteners, such as sucrose, saccharin or aspartame.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickener such as beeswax, hard wax or cetyl alcohol. Sweeteners and flavoring agents as described above may be added to provide a palatable preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water may provide the active ingredient and a dispersant or wetting agent, a suspending agent or one or more preservatives for mixing. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives, colorants and antioxidants.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation 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. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used.

The pharmaceutical composition of the present invention may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension may be prepared according to known techniques using appropriate dispersants or wetting agents and suspending agents as described above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils may be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used to prepare injections.

The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will melt there to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the following factors: 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 diet of the patient, the time of administration, the method of administration, the rate of excretion, the combination of drugs, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound of the present invention or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

The present invention may contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compound of the present invention can be used as the only active ingredient, or it can be used in combination with other treatments and other drugs. Combination therapy is achieved by administering each treatment component simultaneously, separately or successively.

Unless otherwise stated, the terms used in the specification and application have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-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, 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 having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-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. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, oxalyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or formate.

The term "alkenyl" 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 vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "alkynyl" 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. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, oxirane, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused-ring, and bridged-ring cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between monocyclic rings of 5 to 20 members, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members. According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, preferably monospirocycloalkyl and dispirocycloalkyl. More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to a full carbon polycyclic group with 5 to 20 members, each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, and more preferably 5-member/5-member or 5-member/6-member bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

The term "bridged cycloalkyl" refers to a full carbon polycyclic group with 5 to 20 members, any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, oxalyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or formate.

The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; most preferably, it contains 4 to 10 ring atoms, wherein 1 to 3 are heteroatoms; and most preferably, it contains 5 to 7 ring atoms, wherein 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, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, the spiro heterocyclic group is divided into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiro heterocyclic group and a double spiro 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 monospiroheterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, the number of members is 6 to 14, and more preferably, 7 to 10. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

和

等。 The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heterocyclic ring, non-limiting examples of which include:

and

wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, oxalyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or formate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or formate.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclo or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or formate.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, oxalyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or formate.

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

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

The term "hydroxy" refers to the -OH group.

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

The term "amine" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" refers to =O.

The term "carboxyl" refers to -C(O)OH.

The term "巰基" refers to -SH.

The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

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

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person in the art can determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

"Drug composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the drug composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

Synthesis method of the compound of the present invention

In order to achieve the purpose of the present invention, the present invention adopts the following synthesis scheme to prepare the compound of general formula (I) of the present invention.

When the compound represented by formula (I) is a compound represented by formula (II), the compound represented by formula (II) is synthesized by the following scheme 1:

Step 1: The acyl chloride compound IIa and the aldehyde compound IIb undergo insertion reaction in a solvent in the presence of an alkali and zinc chloride to obtain compound IIc; 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, tert-butyl alcohol methyl ether, etc.

Step 2: Compound IIc reacts with nitrohydroxyquinoline in a solvent in the presence of a base to produce a compound of formula (II); wherein the base is preferably an inorganic or organic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether, etc.

When R ₁ in the compound represented by formula (II) is hydrogen, the compound represented by formula (II') can also be synthesized by the following scheme 2:

Step 1: Sulfonyl chloride compound II'a reacts with nitrohydroxyquinoline in a solvent in the presence of a base to obtain compound II'b; wherein the base is preferably an inorganic or organic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether, etc.

Step 2: Compound II'b and compound II'c react with each other in a solvent in the presence of a base to obtain a compound of formula (II'); wherein the base is preferably an inorganic or organic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether, etc.

When the compound represented by formula (I) is a compound represented by formula (III), the compound represented by formula (III) is synthesized by the following scheme 3:

Step 1: The amino compound IIIa and the chloromethoxy acyl chloride compound IIIb undergo an amide condensation reaction in the presence of a base in a solvent to obtain compound IIIc; wherein the base is preferably an inorganic or organic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether, etc.

Step 2: Compound IIIc reacts with nitrohydroxyquinoline in a solvent in the presence of a base to produce a compound of formula (III); wherein the base is preferably an inorganic or organic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether, etc.

When the compound represented by formula (I) is a compound represented by formula (V') or formula (V"), the compounds represented by formula (V') or formula (V") are synthesized by the following schemes 4 and 5:

Step 1: The amino compound V'a undergoes a condensation reaction with the phenoxyphosphonic acid chloride compound V'b and the hydroxy compound V'c in the presence of a base in a solvent to obtain a compound V'd; wherein the base is preferably an inorganic or organic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether, etc.

Step 2: Compound V'd and compound II'b undergo a nucleophilic reaction in a solvent in the presence of a base to obtain a compound represented by formula (V'); wherein the base is preferably an inorganic or organic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether, etc.

Compound V"a reacts with nitrohydroxyquinoline in a solvent in the presence of a base to produce a compound represented by formula (V"); wherein the base is preferably an inorganic or organic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, etc., and the solvent is preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, tert-butyl alcohol methyl ether, etc.

R ₁ , R ₄ , R ₅ , R ₆ , R ₁₀ and R ₁₃ are as defined in the general formula (I).

Specific implementation methods

The present invention is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present invention.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

MS was determined using a liquid chromatography-mass spectrometer (Thermo, Ultimate3000/MSQ).

HPLC determination was performed using a high pressure liquid chromatograph (Agilent 1260 Infinity, Gemini C18 250×4.6mm, 5u column).

Thin layer chromatography (TLC) uses Yantai Huanghai silica plate HSGF245. The specifications used for TLC analysis products are 0.15mm~0.2mm, and the specifications used for TLC separation and purification products are 0.9mm~1.0mm.

Column chromatography generally uses Yantai Huanghai 200~300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by methods known in the art, or purchased from Shanghai Darui Fine Chemicals Co., Ltd., Shanghai Titan Technology Co., Ltd., Shanghai Runjie Chemical Reagent Co., Ltd., TCI, Aldrich Chemical Company. The experimental methods without specific conditions in the embodiments are usually carried out under conventional conditions or under conditions recommended by the raw material or commodity manufacturers. Reagents without specific sources are conventional reagents purchased on the market.

Unless otherwise specified in the embodiments, the reactions can be carried out in an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.

Unless otherwise specified in the examples, the solution refers to an aqueous solution.

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

Example 1: Synthesis of (5-nitroquinolin-8-yloxy)methyl acetate ( 1 )

Step 1: Preparation of 5-nitro-8-chloromethyloxyquinoline (1a)

At room temperature, add sodium bicarbonate aqueous solution (60mL, 3.5mol/L) and tetrabutylammonium hydrogen sulfate (TBAHS) (1.78g, 5.24mmol) to a solution of nitrohydroxyquinoline (10.00g, 52.59mmol) in dichloromethane (DCM) (100mL) and stir for 20 minutes. Add chloromethyl chlorosulfonate (10.42g, 63.15mmol) dropwise to the reaction system and stir at room temperature for 16 hours. Filter the reaction solution, wash the organic phase with potassium carbonate solution and saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure after filtration. 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)

At room temperature, add acetic acid (38 mg, 0.63 mmol), potassium carbonate (104 mg, 0.75 mmol), sodium iodide (9 mg, 0.06 mmol) to N,N-dimethylformamide (3 mL) and stir to mix. Heat the reaction system to 60°C, stir for 10 minutes, add 5-nitro-8-chloromethyloxyquinoline (150 mg, 0.63 mmol), and stir for 1 hour. Add water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated salt solution, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (eluent: 5% methanol/95% dichloromethane) to obtain (5-nitroquinolin-8-yloxy)methyl acetate (145 mg, yield 88%).

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.6Hz,1H),9.07(dd, J =4.1,1.6Hz,1H),8.51(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.36(d, J =8.8Hz,1H),6.17(s,2H),2.16(s,3H).

MS calculated: 262.2; MS found: 263.1 [M+H] ⁺ .

Example 2: Synthesis of (5-nitroquinolin-8-yloxy)methyl propionate (2)

The preparation method is the same as that of Example 1, except that propionic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl propionate (2).

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.6Hz,1H),9.07 (dd, J =4.1,1.6Hz,1H),8.50(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.37(d, J =8.8Hz,1H),6.19(s,2H),2.44(q, J =7.5Hz,2H),1.17(t, J =7.5Hz,3H).

MS calculated: 276.2; MS found: 277.1 [M+H] ⁺ .

Example 3: Synthesis of (5-nitroquinolin-8-yloxy)methyl isobutyrate (3)

The preparation method is the same as that of Example 1, except that isobutyric acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl isobutyrate (3).

¹ H NMR (400MHz, CDCl ₃ )δ 9.20(dd, J =8.9,1.6Hz,1H),9.07(dd, J =4.1,1.6Hz,1H),8.51(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.37(d, J =8.8Hz,1H),6.19(s,2H),2.64(hept, J =7.0Hz,1H),1.19(d, J =7.0Hz,6H).

MS calculated: 290.3; MS found: 291.1 [M+H] ⁺ .

Example 4: Synthesis of (5-nitroquinolin-8-yloxy)methyl pivalate (4)

The preparation method is the same as that of Example 1, except that pivalic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl pivalate (3).

¹ H NMR(400MHz, CDCl ₃ )δ 9.20(dd, J =8.9,1.6Hz,1H),9.08(dd, J =4.1,1.6Hz,1H),8.51(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.37(d, J =8.8Hz,1H),6.19(s,2H),1.22(s,9H).

MS calculated: 304.3; MS found: 305.1 [M+H] ⁺ .

Example 5: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-ethylbutyrate ( 5 )

Potassium carbonate (9.59 g, 69.41 mmol) was added in portions to a solution of nitrohydroxyquinoline (6.00 g, 35.55 mmol) and 1-chloromethyl 2-ethylbutyrate (10.00 g, 60.74 mmol) in N,N-dimethylformamide (100 mL) at room temperature. The reaction solution was stirred at 60 °C for 16 hours. The reaction was quenched by adding water, extracted with dichloromethane (100 mL x 3), and the organic phase was washed with 1 M hydrochloric acid, 1 M sodium bicarbonate aqueous solution and saturated brine. 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 obtain (5-nitroquinolin-8-yloxy)methyl 2-ethylbutyrate (1.4 g, yield 14%).

¹ H NMR (400MHz, CD ₃ OD): δ 9.17-9.14(m,1H),8.97-8.95(m,1H),8.55(d, J =8.8Hz,1H),7.84-7.81(m,1H),7.58(d, J =8.8Hz,1H),6.21(s,2H),2.34-2.27(m,1H),1.67-1.47(m,4H),0.815(t, J = 7.2Hz,6H).

MS calculated: 318.1; MS found: 319.1 [M+H] ⁺ .

Example 6: Synthesis of (5-nitroquinolin-8-yloxy)methyl 4-methylpiperazine-1-carboxylate ( 6 )

Step 1: Preparation of chloromethyl 4-methylpiperazine-1-carboxylate (6a)

Dissolve 1-methylpiperazine (1g, 10mmol) in dichloromethane (30mL), slowly add triethylamine (1.21g, 12mmol) and chloromethyl chloroformate (1.29g, 10mmol) in an ice-water bath. Stir the reaction solution at 0℃ for 30 minutes and then raise the temperature to 25℃ and stir for 16 hours. After quenching the reaction with water (50mL), extract the reaction solution with dichloromethane (100mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 4-methylpiperazine-1-carboxylic acid chloromethyl ester (1.7g, yield 89%).

Step 2: Preparation of (5-nitroquinolin-8-yloxy)methyl 4-methylpiperazine-1-carboxylate ( 6 )

Nitrohydroxyquinoline (600 mg, 3.16 mmol) and 4-methylpiperazine-1-carboxylic acid chloromethyl ester (915 mg, 4.74 mmol) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of potassium carbonate (870 mg, 6.31 mmol) and sodium iodide (45 mg, 0.32 mmol) at 0°C. The reaction solution was stirred at 60°C for 4 hours. The reaction solution was cooled to room temperature, quenched with water, and extracted with dichloromethane (100 mL x 3). 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 obtain a yellow solid product (5-nitroquinolin-8-yloxy)methyl 4-methylpiperazine-1-carboxylate (150 mg, yield 14%).

¹ H NMR (400MHz, CDCl ₃ ) δ: 9.20 (dd, J =8.8, 1.6Hz, 1H), 9.06 (dd, J =4.0, 1.2Hz, 1H), 8.51 (d, J =8.8Hz, 1H), 7.72 (dd, J =8.8, 4.4Hz, 1H), 7.41 (d, J =8.4Hz,1H),6.21(s,2H),3.52(dd, J =10.0,4.8Hz,4H),2.39(t, J =4.8Hz,2H),2.32(t, J =4.8Hz,2H),2.28(s,3H).

MS calculated: 346.13; MS measured: 347.1 [M+H] ⁺ .

Example 7: Synthesis of (5-nitroquinolin-8-yloxy)methylmorpholine-4-carboxylate ( 7 )

The preparation method is the same as that of Example 6, except that morpholine is used instead of 1-methylpiperazine in step 1 to obtain (5-nitroquinoline-8-yloxy)methylmorpholine-4-carboxylate.

¹ H NMR (400MHz, CDCl ₃ ) δ: 9.20-9.18 (s, 1H), 9.07-9.06 (s, 1H), 8.50 (d, J =8.8Hz, 1H), 7.73-7.70 (m, 1H), 7.40 (d, J =8.8Hz,1H),6.22(s,2H),3.68(s,2H),3.61(s,2H),3.50(s,4H).

MS calculated: 333; MS found: 334 [M+H] ⁺ .

Example 8: Synthesis of 4-((5-nitroquinolin-8-yloxy)methoxy)-4-oxobutanoic acid ( 8 )

Step 1: Preparation of tert-butyl (((5-nitroquinolin-8-yl)oxy)methyl)succinate ( 8a )

8-(Chloromethoxy)-5-nitroquinoline (400mg, 1.68mmol) and 4-(tert-butoxy)-4-oxobutanoic 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 (20mL x 2), and the organic phases were combined and 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 tert-butyl (((5-nitroquinolin-8-yl)oxy)methyl) succinate.

Step 2: Preparation of 4-((5-nitroquinolin-8-yloxy)methoxy)-4-oxobutanoic acid ( 8 )

Tert-butyl (((5-nitroquinolin-8-yl)oxy)methyl)succinate (230 mg, 0.718 mmol) was placed in 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-oxobutanoic acid (128 mg, yield 65%), a yellow solid.

¹ H-NMR (400MHz, DMSO-d6) δ: 12.3(br,1H).9.05(d, J =2.8Hz,1H),9.00(d, J =8.8Hz,1H),8.55(d, J =8.8Hz,1H),7.87(dd, J =8.8,4.0Hz,1H),7.54(d, J =8.8Hz,1H),6.14(s,2H),2.60~2.65(m,2Hz,4H),2.50~2.55(m,2H).

MS calculated: 320.26; MS measured: 321.1 [M+H] ⁺ .

Example 9: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-(pyridin-3-yl)acetate ( 9 )

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 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 ~ 0: 1) to obtain the product ((5-nitroquinolin-8-yl)oxy)methyl 2-(pyridin-3-yl)acetate (90 mg, yield 26%), a green solid with a purity of 97%.

¹ H NMR (400MHz, 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 =8.4Hz,1H),6.18(s,2H),3.89(s,2H),4.72~4.75(m,2H).

MS calculated: 339.31; MS measured: 340.1 [M+H] ⁺ .

Example 10: Synthesis of (5-nitroquinolin-8-yloxy)methyl 8-hydroxyoctanoate

At room temperature, add 8-hydroxyoctanoic acid (201 mg, 1.25 mmol), potassium carbonate (209 mg, 1.51 mmol), sodium iodide (19 mg, 0.13 mmol) to N,N-dimethylformamide (6 mL) and stir to mix. Heat the reaction system to 60°C and stir for 10 minutes, then add 5-nitro-8-chloromethyloxyquinoline (1a) (300 mg, 1.26 mmol) and stir for 1 hour. Add water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated saline solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography (eluted with dichloromethane) to obtain (5-nitroquinolin-8-yloxy)methyl 8-hydroxyoctanoate (200 mg, yield 44%).

¹ H NMR (400MHz, DMSO-d6)δ 9.04(dd, J =4.1,1.6Hz,1H),9.00(dd, J =8.9,1.6Hz,1H),8.56(d, J =8.8Hz,1H),7.87(dd, J =8.9,4.1Hz,1H),7.55(d, J =8.9Hz,1H),6.14(s,2H),3.30(t, J =6.6Hz,2H),2.39(t, J =7.3Hz,2H),1.56-1.45(m,2H),1.35-1.24(m,2H),1.15(s,6H).

MS calculated: 362.4; MS measured: 363.3 [M+H] ⁺ .

Example 11: Synthesis of methyl (5-nitroquinolin-8-yloxy) methyl adipate ( 11 )

The same preparation method as in Example 10 was used, except that monomethyl adipate was used instead of 8-hydroxyoctanoic acid to obtain methyl (5-nitroquinolin-8-yloxy)methyl adipate ( 11 ).

¹ H NMR (400MHz, DMSO-d6)δ 10.03(dd, J =4.1,1.6Hz,1H),9.99(dd, J =8.9,1.5Hz,1H),9.55(d, J =8.8Hz,1H),8.86(dd, J =8.9,4.1Hz,1H),8.54(d, J =8.9Hz,1H),7.13(s,2H),4.53(s,3H),4.32(s,4H),3.42(t, J =7.0Hz,2H),3.25(t, J =7.1Hz,2H).

MS calculated: 362.3; MS measured: 363.3 [M+H] ⁺ .

Example 12: Synthesis of (5-nitroquinolin-8-yloxy)methyl 7-(tert-butoxycarbonylamino)heptanoate ( 12 )

The preparation method is the same as that of Example 10, except that 7-(tert-butyloxycarbonyl-amino)-heptanoic acid (purchased from Darry Chemical) is used instead of 8-hydroxyoctanoic acid to obtain (5-nitroquinolin-8-yloxy)methyl 7-(tert-butyloxycarbonylamino)heptanoate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.6Hz,1H),9.07(dd, J =4.1,1.6Hz,1H),8.50(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.36(d, J =8.8Hz,1H),6.18(s,2H),4.47(s,1H),3.07(d, J =6.4Hz,2H),2.40(t, J =7.5Hz,2H),1.69-1.60(m,2H),1.42(d, J =10.2Hz,11H),1.35-1.25(m,4H).

MS calculated: 447.5; MS found: 448.4 [M+H] ⁺ .

Example 13: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 2-(tert-butoxycarbonylamino)-3-phenylpropanoate ( 13 )

The same preparation method as in Example 10 was used, except that tert-butyloxycarbonyl-L-phenylalanine was used instead of 8-hydroxyoctanoic acid to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 2-(tert-butyloxycarbonylamino)-3-phenylpropanoate ( 13 ).

¹ H NMR (400MHz, CDCl ₃ ) δ 9.19 (dd, J =8.9, 1.5Hz, 1H), 9.08 (dd, J = 4.1, 1.5Hz, 1H), 8.41 (d, J = 8.8Hz, 1H), 7.72 (dd, J =8.9,4.1Hz,1H),7.20-7.03(m,6H),6.17(dd, J =63.5,6.5Hz,2H),4.95(d, J =7.7Hz,1H),4.62(dd, J =13.8,6.8Hz,1H),3.06(d, J =6.3Hz,2H),1.40(s,9H).

MS calculated: 467.5; MS found: 468.3 [M+H] ⁺ .

Example 14: Synthesis of (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-acetamidosuccinate ( 14 )

Step 1: Preparation of (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-(tert-butoxycarbonylamino)succinate (14a)

Add N-(tert-butyloxycarbonyl L)-S-methyl-L-cysteine (590 mg, 2.5 mmol), potassium carbonate (580 mg, 4.2 mmol), and potassium iodide (83 mg, 0.5 mmol) to N,N-dimethylformamide (5 mL) and stir to mix. Heat the reaction system to 60°C, stir for 10 minutes, add 5-nitro-8-chloromethoxyquinoline (1a) (500 mg, 2.1 mmol), and stir for 1 hour. Add water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated salt solution, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by silica gel chromatography (developer: 5% methanol/95% dichloromethane) to obtain (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-(tert-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 dichloromethane (5 mL) solution of (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-(tert-butoxycarbonylamino)succinate (200 mg, 0.46 mmol) 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-acetamidosuccinate ( 14 )

Dissolve (S)-4-methyl 1-(5-nitroquinolin-8-yloxy)methyl 2-aminosuccinate (200mg, 0.68mmol) and acetyl chloride (80mg, 1.0mmol) in dichloromethane (10mL), slowly add triethylamine (140mg, 2.0mmol) in an ice-water bath, heat to room temperature and stir for 1 hour. Add dichloromethane (100mL) to the reaction solution, wash once with water, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (178mg, yield 57%).

¹ H-NMR (400Hz, CDCl3) δ: 9.20(dd,J=8.8,1.6Hz,1H),9.10(dd,J=4,1.6Hz,1H),8.50(d,J=8.8Hz,1H),7.77(dd,J=8.8Hz,4.4Hz,1H),7.35( d,J=8.8Hz,1H),6.49(d,J=8Hz,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).

Example 15: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-acetamido-4-methylpentanamido)acetate ( 15 )

Step 1: Preparation of (5-nitroquinolin-8-yloxy)methyl 2-(tert-butoxycarbonylamino)acetate (15a)

Potassium carbonate (0.65 g, 4.2 mmol) was added to a solution of Boc-glycine (700 mg, 4.1 mmol) and 5-nitro-8-(chloromethoxy)quinoline ( 1a ) (500 mg, 2.1 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was reacted at room temperature for 2 hours, and then 30 mL of water and dichloromethane (20 mL x 2) were added for extraction. 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 600 mg 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, add (5-nitroquinolin-8-yloxy)methyl 2-(tert-butoxycarbonylamino)acetate (600 mg, 1.59 mmol) to 10 mL of HCl/dioxane solution and stir at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain 600 mg of the product as a white solid with a purity of 97%.

Step 3: Preparation of ((S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-(tert-butoxycarbonylamino)-4-methylpentanamido)acetate ( 15c )

At room temperature, (5-nitroquinolin-8-yloxy)methyl 2-aminoacetic acid ester hydrochloride (500 mg, 1.6 mmol) and Boc-L-leucine (553 mg, 2.4 mmol) were placed in 10 mL of DMF, cooled 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 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-methylpentanamido)acetate hydrochloride ( 15d )

Place ((S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-(tert-butoxycarbonylamino)-4-methylpentanamido)acetate (80 mg, 0.16 mmol) in 10 mL of HCl/dioxane (4 M) and stir 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-acetamido-4-methylpentanamido)acetate (15)

(S)-(5-nitroquinolin-8-yloxy)methyl 2-(2-amino-4-methylpentanamido)acetate hydrochloride (70 mg, 0.16 mmol) was placed in 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-acetamido-4-methylpentanamido)acetate (40 mg, 57% yield). Light yellow solid, purity 97%.

¹ H-NMR (400MHz, DMSO-d6) δ: 9.05 (dd, J =4.4Hz, 1.4Hz, 1H), 9.00 (dd, J =8.8Hz, 1.6Hz, 1H), 8.55 (d, J =8.8Hz,1H),8.41(t,J=6Hz,1H),8.00(d,J=8.8Hz,1H),7.88(dd, J =8.8Hz,4.0Hz,1H), 7.54(d, J =8.8Hz,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 calculated: 432.16; MS measured: 433.2[M+H]+.

Example 16: Synthesis of (R)-(5-nitroquinolin-8-yloxy)methyl 2-acetamido-3-(methylthio)propionate (16)

Step 1: Preparation of (R)-(5-nitroquinolin-8-yloxy)methyl 2-(tert-butoxycarbonylamino)-3-(methylthio)propionate ( 16a ) At room temperature, N-(tert-butoxycarbonyl)-S-methyl-L-cysteine (590 mg, 2.5 mmol), potassium carbonate (580 mg, 4.2 mmol), and potassium iodide (83 mg, 0.5 mmol) were added to N,N-dimethylformamide (5 mL) and stirred to mix. The reaction system was heated to 60°C and stirred for 10 minutes, then 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 aqueous solution of common salt, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing agent: 5% methanol/95% dichloromethane) to obtain (R)-(5-nitroquinolin-8-yloxy)methyl 2-(tert-butoxycarbonylamino)-3-(methylthio)propanoate (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-(tert-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-acetamido-3-(methylthio)propanoate ( 16 )

At 0°C, (R)-(5-nitroquinolin-8-yloxy)methyl 2-amino-3-(methylthio)propionate (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 in an ice-water bath, and the mixture was heated to room temperature and stirred for 1 hour. Dichloromethane (100 mL) was added to the reaction solution, and the mixture was washed once with water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (chromatographic column: Eclipse XDB-C18 (21.2mm×250mm, 7μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0mL/min) to obtain the product (R)-(5-nitroquinolin-8-yloxy)methyl 2-acetamido-3-(methylthio)propionate (178mg, yield 57%).

¹ H-NMR (400Hz, CDCl3) δ: 9.37-9.41(m,1H),9.17-9.19(m,1H),8.60(d, J =8.8Hz,1H),7.89(dd, J =8.8,4.4Hz,1H),7.48(d, J =8.8Hz,1H),6.56(d, J =6.8Hz,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 calculated: 379.39; MS measured: 380.1 [M+H] ⁺ .

Example 17: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-(N-methylacetamido)acetate (17)

The preparation method is the same as that of Example 16, except that tert-butyloxycarbonylsarcosine is used to replace N-(tert-butyloxycarbonyl)-S-methyl-L-cysteine in step 1 to obtain (5-nitroquinolin-8-yloxy)methyl 2-(N-methylacetamido)acetate.

¹ H-NMR (400Hz, CDCl3) δ: 9.23 (d, J =8.8Hz, 1H), 9.11 (d, J =2.8Hz, 1H), 8.53 (d, J =8.8Hz, 1H), 7.77 (dd, J =8.8, 4.4Hz, 1H), 7.40 (d, J =8.8Hz,1H),6.21(s,2H),4.20(s,2H),3.11(s,3H),2.16(s,3H).

MS calculated: 333.30; MS found: 334.1 [M+H] ⁺ .

Example 18: Synthesis of (S)-2-(5-nitroquinolin-8-yloxy)methyl 1-propylpyrrolidine-1,2-dicarboxylate (18)

Step 1: Preparation of 1-(tert-butyl)2-(((5-nitroquinolin-8-yl)oxy)methyl)(S)-pyrrole-1,2-carbonic acid diester (18a)

At room temperature, 5-nitro-8-(chloromethoxy)quinoline (1a) (1.5 g, 6.3 mmol) and L-Boc proline (2.02 g, 9.4 mmol) were dissolved in 15 mL of DMF, and potassium carbonate (1.73 g, 12.6 mmol) was added. The mixture was reacted at room temperature for 3 hours, 70 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine, 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-(tert-butyl)2-(((5-nitroquinolin-8-yl)oxy)methyl)(S)-pyrrole-1,2-carbonic acid diester (2.8 g, yield 106%).

Step 2: Preparation of ((5-nitroquinolin-8-yl)oxy)methyl L-proline ester hydrochloride (18b)

At 0°C, 1-(tert-butyl) 2-(((5-nitroquinolin-8-yl)oxy)methyl)(S)-pyrrole-1,2-carbonic acid diester (2.8 g, 6.71 mmol) was placed in 30 mL 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, yield 97%).

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 hydrochloride (150mg, 0.424mmol) was placed in 10mL of DCM, cooled to 0~5℃ in an ice bath, and propyl chloroformate (104mg, 0.85mmol) was added, and then TEA (170mg, 1.7mmol) was slowly added. After the addition, 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 (70mg, yield 40%).

¹ H-NMR (400MHz, 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: 403.39MS measured: 426.1[M+Na ⁺ ].

Example 19: Synthesis of (S)-2-(5-nitroquinolin-8-yloxy)methyl 1-acetylpyrrolidine-2-carboxylate (19)

The preparation method is the same as that of Example 18, except that acetyl chloride is used instead of propyl chloroformate in step 3 to obtain (S)-2-(5-nitroquinolin-8-yloxy)methyl 1-acetylpyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, DMSO-d6): δ: 9.05 (dd, J =4.0Hz, 1.2Hz, 1H), 9.00 (dd, J =8.8Hz, 1.2Hz, 1H), 8.55 (d, J =8.8Hz, 1H), 7.88 (dd, J =4.0Hz, 8.8Hz, 1H), 7.55 (d, J =8.8Hz,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 calculated: 359.3; MS measured: 360.2 [M+H] ⁺ .

Example 20: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropanoylpyrrolidine-2-carboxylate (20)

The preparation method is the same as that of Example 18, except that isobutyl chloride is used instead of propyl chloroformate in step 3 to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropanoylpyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, DMSO-d6): δ: 9.05 (d, J =4.0Hz, 1H), 9.00 (d, J =8.8Hz, 1H), 8.56 (d, J =8.8Hz, 1H), 7.89-7.86 (dd, J =4.0Hz, 8.8Hz, 1H), 7.55 (d, J =8.8Hz,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 =6.8Hz.3H),0.89(d, J =6.8Hz.3H).

MS calculated: 387.3; MS measured: 388.2 [M+H] ⁺ .

Example 21: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-tivalylpyrrolidine-2-carboxylate (21)

The preparation method is the same as that of Example 18, except that propyl chloroformate in step 3 is replaced with trivaleryl chloride to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-trivalerylpyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, DMSO-d6): δ: 9.05 (m, 1H), 9.00 (m, 1H), 8.56 (d, J =8.0Hz, 1H), 7.88 (d, J =5.2Hz, 1H), 7.55 (d, J =7.6Hz,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 calculated: 401.4; MS measured: 402.2 [M+H] ⁺ .

Example 22: Synthesis of (R)-2-(5-nitroquinolin-8-yloxy)methyl 1-acetylpyrrolidine-2-carboxylate (22)

The preparation method is the same as that of Example 19, except that D-Boc proline is used instead of L-Boc proline in step 1 to obtain (R)-2-(5-nitroquinolin-8-yloxy)methyl 1-acetylpyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, DMSO-d6): δ: 9.05 (dd, J =4.0Hz, 1.2Hz, 1H), 9.00 (dd, J =8.8Hz, 1.2Hz, 1H), 8.56 (d, J =8.8Hz, 1H), 7.88 (dd, J = 4.0Hz, 8.8Hz, 1H), 7.55 (d, J =8.8Hz, 1H) =8.8Hz,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] ⁺ .

Example 23: Synthesis of (R)-(5-nitroquinolin-8-yloxy)methyl 1-isopropanoylpyrrolidine-2-carboxylate (23)

The preparation method is the same as that of Example 22, except that isobutyl chloride is used instead of propyl chloroformate in step 3 to obtain (R)-(5-nitroquinolin-8-yloxy)methyl 1-isopropanoylpyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, DMSO-d6): δ: 9.05 (d, J =2.8Hz, 1H), 9.00 (d, J =8.4Hz, 1H), 8.56 (d, J =8.8Hz, 1H), 7.88 (dd, J =4.0Hz, 8.8Hz, 1H), 7.55 (d, J =8.8Hz,1H),6.19(d, J =6.4Hz,1H),6.11(d, J =6.4Hz,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 =6.8Hz,3H),0.89(d, J =6.8Hz,3H).

MS calculated: 387.3; MS measured: 388.2 [M+H] ⁺ .

Example 24: Synthesis of (R)-(5-nitroquinolin-8-yloxy)methyl 1-tivalylpyrrolidine-2-carboxylate (24)

The preparation method is the same as that of Example 22, except that propyl chloroformate in step 3 is replaced with trivaleryl chloride to obtain (R)-(5-nitroquinolin-8-yloxy)methyl 1-trivalerylpyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, DMSO-d6): δ: 9.06 (dd, J =4.0Hz, 1.2Hz, 1H), 9.00 (dd, J =8.8Hz, 1.2Hz, 1H), 8.55 (d, J =8.8Hz, 1H), 7.88 (dd, J = 4.0Hz, 8.8Hz, 1H), 7.55 (d, J =8.8Hz, 1H) =8.8Hz,1H),6.19(d, J =6.8Hz,1H),6.11(d, J =6.8Hz,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 calculated: 401.2; MS measured: 402.2 [M+H] ⁺ .

Example 25: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-pyridinylmethylpyrrolidine-2-carboxylate (25):

At room temperature, ((5-nitroquinolin-8-yl)oxy)methyl L-proline 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-benzotriazole (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 0-20°C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=1:1~0:1) to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-pyridylpyrrolidine-2-carboxylate (30 mg, yield 17%).

¹ H-NMR (400MHz, 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 calculated: 422.4; MS found: 423.2 [M+H] ⁺ .

Example 26: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-nicotinylpyrrolidine-2-carboxylate ( 26 )

The preparation method is the same as that of Example 25, except that 3-pyridinecarboxylic acid is used instead of 2-pyridinecarboxylic acid to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-nicotinylpyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, 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 calculated: 422.4; MS found: 423.1 [M+H] ⁺ .

Example 27: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-isocyanatopyrrolidine-2-carboxylate (27)

The preparation method is the same as that of Example 25, except that 4-pyridinecarboxylic acid is used instead of 2-pyridinecarboxylic acid to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-isocyanatopyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, 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 calculated: 422.4; MS found: 423.1 [M+H] ⁺ .

Example 28: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-((S)-2-acetamido-3-(4-hydroxyphenyl)propionyl)pyrrolidine-2-carboxylate (28)

((5-Nitroquinolin-8-yl)oxy)methyl L-proline hydrochloride ( 18b ) (300 mg, 0.85 mmol) was added to anhydrous DMF (10 mL), cooled in an ice bath, and 2-(7-benzotriazole oxide)-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 sequence. 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=1:1~0:1) to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-((S)-2-acetamido-3-(4-hydroxyphenyl)propionyl)pyrrolidine-2-carboxylate (100 mg, yield 22.5%).

¹ H-NMR (400MHz, 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 calculated: 522.51; MS found: 523.2 [M+H] ⁺ .

Example 29: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-((2S,3R)-2-(tert-butyloxycarbonylamino)-3-hydroxybutyl)pyrrolidine-2-carboxylate (29)

The preparation method is the same as that of Example 28, except that N-Boc-L-threonine is used instead of N-acetyl-L-tyrosine to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-((2S,3R)-2-(tert-butyloxycarbonylamino)-3-hydroxybutyl)pyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, 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 calculated: 518.52; MS found: 519.2 [M+H] ⁺ .

Example 30: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 1-((S)-2-acetamido-3-hydroxypropionyl)pyrrolidine-2-carboxylate (30)

The preparation method is the same as that of Example 28, except that N-acetyl-L-serine is used instead of N-acetyl-L-tyrosine to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 1-((S)-2-acetamido-3-hydroxypropionyl)pyrrolidine-2-carboxylate.

¹ H-NMR (400MHz, 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 calculated: 446.42; MS observed: 447.1 [M+H] ⁺ .

Example 31: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-methoxyacetate (31)

The preparation method is the same as that of Example 1, except that methoxyacetic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl 2-methoxyacetate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.6Hz,1H),9.07(dd, J =4.1,1.6Hz,1H),8.49(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.37(d, J =8.8Hz,1H),6.26(s,2H),4.12(s,2H),3.45(s,3H).

MS calculated: 292.2; MS found: 293.1 [M+H] ⁺ .

Example 32: Synthesis of (5-nitroquinolin-8-yloxy)methylcyclobutanecarboxylate ( 32 )

The preparation method is the same as that of Example 1, except that cyclobutylcarboxylic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methylcyclobutanecarboxylate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.5Hz,1H),9.07(dd, J =4.1,1.5Hz,1H),8.50(d, J =8.8Hz,1H),7.71(dd, J =8.9,4.1Hz,1H),7.36(d, J =8.8Hz,1H),6.18(s,2H),3.22(p, J =8.3Hz,1H),2.37-2.16(m,4H),2.06-1.84(m,2H).

MS calculated: 302.3; MS found: 303.1 [M+H] ⁺ .

Example 33: Synthesis of (5-nitroquinolin-8-yloxy)methyltetrahydrofuran-3-carboxylate ( 33 )

The preparation method is the same as that of Example 1, except that 3-tetrahydrofurancarboxylic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl tetrahydrofuran-3-carboxylate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.6Hz,1H),9.07(dd, J =4.1,1.5Hz,1H),8.50(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.36(d, J =8.8Hz,1H),6.21(q, J =6.5Hz,2H),4.01-3.91(m,2H),3.84(qd, J =14.9,8.3Hz,2H),3.18(ddt, J =8.9,7.8,5.9Hz,1H),2.28-2.09(m,2H).

MS calculated: 318.3; MS found: 319.1 [M+H] ⁺ .

Example 34: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-acetyloxybenzoate ( 34 )

The preparation method is the same as that of Example 1, except that o-acetylsalicylic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl 2-acetyloxybenzoate.

¹ H NMR (400MHz, CDCl ₃ )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 =7.3Hz,1H),7.47(s,1H),7.31(s,1H),7.13(d, J =8.0Hz,1H),6.40(s,2H),2.31(s,3H).

MS calculated: 382.3; MS found: 383.1 [M+H] ⁺ .

Example 35: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-(2,4-dichlorophenoxy)acetate (35)

The preparation method is the same as that of Example 1, except that sodium 2,4-dichlorophenoxyacetate (purchased from Darry Chemical) is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl 2-(2,4-dichlorophenoxy)acetate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.18(dd, J =8.9,1.5Hz,1H),9.06(dd, J =4.1,1.5Hz,1H),8.40(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.29(d, J =2.5Hz,1H),7.24(d, J =8.8Hz,1H),6.91(dd, J =8.8,2.5Hz,1H),6.68(d, J =8.8Hz,1H),6.26(s,2H),4.79(s,2H).

MS calculated: 423.2; MS found: 423.0 [M+H] ⁺ .

Example 36: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-quinoline acetate ( 36 )

The preparation method is the same as that of Example 1, except that 4-morpholinoacetic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl 2-morpholinoacetate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.6Hz,1H),9.07(dd, J =4.1,1.6Hz,1H),8.49(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.37(d, J =8.8Hz,1H),6.23(s,2H),3.77-3.68(m,4H),3.31(s,2H),2.63-2.53(m,4H).

MS calculated: 347.3; MS measured: 348.2 [M+H] ⁺ .

Example 37: Synthesis of (R)-(5-nitroquinolin-8-yloxy)methyl 2-hydroxy-2-phenyl acetate (37)

At room temperature, add (S)-mandelic acid (64 mg, 0.42 mmol), triethylamine (51 mg, 0.50 mmol), and pyridine (33 mg, 0.42 mmol) to N,N-dimethylformamide (1 mL) and stir to mix. Heat the reaction system to 35 °C, stir for 10 minutes, add 5-nitro-8-chloromethoxyquinoline ( 1a ) (100 mg, 0.42 mmol), and stir for 1 hour. Add water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated saline solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: 5% methanol/95% dichloromethane) to give (R)-(5-nitroquinolin-8-yloxy)methyl 2-hydroxy-2-phenylacetate (50 mg, yield 34%).

¹ H NMR (400MHz, CDCl ₃ )δ 9.14(dd, J =8.9,1.6Hz,1H),9.03(dd, J =4.1,1.6Hz,1H),8.24(d, J =8.8Hz,1H),7.70(dd, J =8.9,4.1Hz,1H),7.35(dd, J =7.1,2.4Hz,2H),7.25(dd, J =5.2,1.9Hz,2H),6.91(d, J =8.8Hz,1H),6.18(dd, J =31.0,6.4Hz,2H),5.24(s,1H),3.39(s,1H).

MS calculated: 354.3; MS found: 355.1 [M+H] ⁺ .

Example 38: Synthesis of (S)-(5-nitroquinolin-8-yloxy)methyl 2-hydroxy-2-phenyl acetate ( 38 )

The preparation method is the same as that of Example 37, except that (R)-mandelic acid is used instead of (S)-mandelic acid to obtain (S)-(5-nitroquinolin-8-yloxy)methyl 2-hydroxy-2-phenyl acetate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.14(dd, J =8.9,1.6Hz,1H),9.03(dd, J =4.1,1.6Hz,1H),8.24(d, J =8.8Hz,1H),7.70(dd, J =8.9,4.1Hz,1H),7.35(dd, J =7.1,2.4Hz,2H),7.25(dd, J =5.2,1.9Hz,2H),6.91(d, J =8.8Hz,1H),6.18(dd, J =31.1,6.4Hz,2H),5.24(s,1H),3.40(s,1H).

MS calculated: 354.3; MS found: 355.1 [M+H] ⁺ .

Example 39: Synthesis of (5-nitroquinolin-8-yloxy)methylbutyrate ( 39 )

The preparation method is the same as that of Example 1, except that n-butyric acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methylbutyrate.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.19 (dd, J =8.9, 1.6Hz, 1H), 9.07 (dd, J =4.1, 1.6Hz, 1H), 8.50 (d, J =8.8Hz, 1H), 7.72 (dd, J =8.9, 4.1 Hz, 1H), 7.37 (d, J =8.8Hz,1H),6.18(s,2H),2.39(t, J =7.4Hz,2H),1.69(dt, J =14.8,7.4Hz,2H),0.94(t, J =7.4Hz,3H).

MS calculated: 290.3; MS found: 291.1 [M+H] ⁺ .

Example 40: Synthesis of (5-nitroquinolin-8-yloxy)methyl n-hexanoate ( 40 )

The preparation method is the same as that of Example 1, except that n-hexanoic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl n-hexanoate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.6Hz,1H),9.07(dd, J =4.1,1.6Hz,1H),8.50(d, J =8.8Hz,1H),7.71(dd, J =8.9,4.1Hz,1H),7.36(d, J =8.8Hz,1H),6.18(s,2H),2.40(t, J =7.5Hz,2H),1.68-1.60(m,2H),1.33-1.22(m,4H),0.91-0.79(m,3H).

MS calculated: 318.3; MS found: 319.2 [M+H] ⁺ .

Example 41: Synthesis of (5-nitroquinolin-8-yloxy)methyl n-octanoate ( 41 )

The preparation method is the same as that of Example 1, except that octanoic acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl octanoate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.6Hz,1H),9.07 (dd, J =4.1,1.6Hz,1H),8.50(d, J =8.8Hz,1H),7.72(dd, J =8.9,4.1Hz,1H),7.37(d, J =8.8Hz,1H),6.18(s,2H),2.40(t, J =7.5Hz,2H),1.64(dd, J =14.6,7.4Hz,2H),1.32-1.16(m,8H),0.84(t, J =7.0Hz,3H).

MS calculated: 346.4; MS measured: 347.2 [M+H] ⁺ .

Example 42: Synthesis of (5-nitroquinolin-8-yloxy)methyl n-decanoate ( 42 )

The preparation method is the same as that of Example 1, except that acetic acid in step 2 is replaced by decanoic acid to obtain (5-nitroquinolin-8-yloxy)methyl decanoate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.20(dd, J =8.9,1.6Hz,1H),9.07(dd, J =4.1,1.6Hz,1H),8.50(d, J =8.8Hz,1H),7.71(dd, J =8.9,4.1Hz,1H),7.36(d, J =8.8Hz,1H),6.18(s,2H),2.40(t, J =7.5Hz,2H),1.63(dt, J =15.2,7.5Hz,2H),1.32-1.17(m,12H),0.86(t, J =6.9Hz,3H).

MS calculated: 374.4; MS found: 375.2 [M+H] ⁺ .

Example 43: Synthesis of (5-nitroquinolin-8-yloxy)methyl dodecanoate ( 43 )

The preparation method is the same as that of Example 1, except that lauric acid is used instead of acetic acid in step 2 to obtain (5-nitroquinolin-8-yloxy)methyl dodecanoate.

¹ H-NMR (400Hz, CDCl3) δ: 9.22 (dd, J =8.8, 1.2Hz, 1H), 9.10 (dd, J =4.0, 1.6Hz, 1H), 8.52 (d, J =8.8Hz, 1H), 7.77 (dd, J =8.8Hz, 4.0Hz, 1H), 7.35 (d, J =9.2Hz,1H),6.20(s,2H),2.41(t, J =3.6Hz,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 calculated: 402.49; MS measured: 403.3 [M+H] ⁺ .

Example 44: Synthesis of 6-(5-nitroquinolin-8-yloxy)-tetrahydropyran-2-one ( 44 )

Step 1: Preparation of 2-((5-nitroquinolin-8-yl)oxy)cyclopentane-1-one (44a)

At room temperature, sodium methoxide (170 mg, 3.15 mmol) and potassium iodide (87 mg, 0.52 mmol) were added to a solution of nitrohydroxyquinoline (500 mg, 2.63 mmol) in N-methylpyrrolidone (12.5 mL). The reaction system was heated to 60°C and stirred for 15 minutes. 2-Chlorocyclopentanone (623 mg, 5.25 mmol) was added and stirred for 7 hours. Add water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated saline solution, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, purify by silica gel chromatography 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 )

At room temperature, 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). The reaction system was cooled to 0°C, and m-chloroperbenzoic acid (m-CPBA) (purity: 85%, 136 mg, 0.67 mmol) was added. The temperature was naturally raised to room temperature and stirred for 16 hours. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: 5% methanol/95% dichloromethane) to give 6-(5-nitroquinolin-8-yloxy)-tetrahydropyran-2-one (94 mg, yield 63%).

¹ H NMR (400MHz, CDCl ₃ )δ 9.17(dd, J =8.9,1.5Hz,1H),9.04(dd, J =4.1,1.5Hz,1H),8.48(d, J =8.8Hz,1H),7.70(dd, J =8.9,4.1Hz,1H),7.51(d, J =8.8Hz,1H),6.39(t, J =3.3Hz,1H),2.89-2.63(m,2H),2.56-2.44(m,2H),2.37-1.97(m,2H).

MS calculated: 288.3; MS found: 289.1 [M+H] ⁺ .

Example 45: Synthesis of ((5-nitroquinolin-8-yl)oxy)methyl 2-(2-(2-methoxyethoxy)ethoxy)acetate ( 45 )

The preparation method is the same as that of Example 1, except that 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (purchased from Darry Chemical) is used instead of acetic acid in step 2 to obtain ((5-nitroquinolin-8-yl)oxy)methyl 2-(2-(2-methoxyethoxy)ethoxy)acetate.

¹ H-NMR (400Hz, CDCl3) δ: 9.20 (dd, J =6.0Hz, 1H), 9.08 (d, J =2.8Hz, 1H), 8.51 (d, J =8.8Hz, 1H), 7.77 (dd, J =8.8Hz, 4.0Hz, 1H), 7.40 (d, J =8.8Hz,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 calculated: 380.35; MS found: 381.1 [M+H] ⁺ .

Example 46: Synthesis of bis(5-nitroquinolin-8-yloxy)-methyl adipate ( 46 )

At room temperature, add adipic acid (300 mg, 2.05 mmol), potassium carbonate (680 mg, 4.92 mmol), and sodium iodide (62 mg, 0.41 mmol) to N,N-dimethylformamide (20 mL) and stir to mix. Heat the reaction system to 60°C, stir for 10 minutes, add 5-nitro-8-chloromethoxyquinoline ( 1a ) (980 mg, 4.11 mmol), and stir for 2 hours. Add water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated saline solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: 5% methanol/95% dichloromethane) to give bis(5-nitroquinolin-8-yloxy)-methyl adipate (78 mg, 7% yield).

¹ H NMR (400MHz, CDCl ₃ )δ 9.18(dd, J =8.9,1.6Hz,2H),9.06(dd, J =4.1,1.6Hz,2H),8.49(d, J =8.8Hz,2H),7.71(dd, J =8.9,4.1Hz,2H),7.34(d, J =8.8Hz,2H),6.16(s,4H),2.41(s,4H),1.68(t, J = 3.2Hz,4H).

MS calculated: 550.5; MS found: 551.3 [M+H] ⁺ .

Example 47: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl acetate ( 47 )

Step 1: Preparation of 1-chloroethyl acetate ( 47a )

At 0°C, acetyl chloride (1.00 g, 12.74 mmol) was slowly added to a dichloromethane (20 mL) solution of acetaldehyde (0.56 g, 12.71 mmol) and zinc chloride (0.17 g, 1.25 mmol). 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 brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 1-chloroethyl acetate (1.39 g).

Step 2: Preparation of 1-(5-nitroquinolin-8-yloxy)ethyl acetate ( 47 )

At room temperature, sodium methoxide (68 mg, 1.26 mmol) and potassium iodide (17 mg, 0.10 mmol) were added to a solution of nitrohydroxyquinoline (200 mg, 1.05 mmol) in N-methylpyrrolidone (5 mL). The reaction system was heated to 60°C and stirred for 15 minutes. 1-Chloroethyl acetate (193 mg, 1.57 mmol) was added and stirred for 16 hours. The reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: 5% methanol/95% dichloromethane) to obtain 1-(5-nitroquinolin- 8-yloxy)ethyl acetate (124 mg, yield 43%).

1H NMR(400MHz,CDCl3)δ 9.18(dd,J=8.9,1.6Hz,1H),9.08(dd,J=4.1,1.6Hz,1H),8.47(d,J=8.8Hz,1H),7.70(dd,J=8. 9,4.1Hz,1H),7.21(d,J=8.8Hz,1H),6.97(q,J=5.3Hz,1H),2.10(s,3H),1.87(d,J=5.3Hz,3H).

MS calculated: 276.2; MS found: 277.1 [M+H] ⁺ .

Example 48: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl propionate ( 48 )

The preparation method is the same as that of Example 47, except that propionyl chloride is used instead of acetyl chloride in step 1 to obtain 1-(5-nitroquinolin-8-yloxy)ethyl propionate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.18(dd, J =8.9,1.5Hz,1H),9.08(dd, J =4.1,1.5Hz,1H),8.46(d, J =8.8Hz,1H),7.70(dd, J =8.9,4.1Hz,1H),7.20(d, J =8.8Hz,1H),6.99(q, J =5.2Hz,1H),2.38(q, J =7.5Hz,2H),1.87(d, J =5.3Hz,3H),1.12(t, J =7.5Hz,3H).

MS calc.: 290.3; MS found: 291.1 [M+H] ⁺ .

Example 49: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl isobutyrate (49)

The preparation method is the same as that of Example 47, except that isobutylyl chloride is used instead of acetyl chloride in step 1 to obtain 1-(5-nitroquinolin-8-yloxy)ethyl isobutyrate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.18(dd, J =8.9,1.2Hz,1H),9.08(dd, J =3.9,1.1Hz,1H),8.46(d, J =8.8Hz,1H),7.70(dd, J =8.9,4.1Hz,1H),7.18(d, J =8.8Hz,1H),6.98(q, J =5.2Hz,1H),2.64-2.51(m,1H),1.87(d, J =5.2Hz,3H),1.14(dd, J =14.4,7.0Hz,6H).

MS calculated: 304.3; MS measured: 305.2 [M+H] ⁺ .

Example 50: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl pivalate ( 50 )

The preparation method is the same as that of Example 47, except that acetyl chloride in step 1 is replaced by pivaloyl chloride to obtain 1-(5-nitroquinolin-8-yloxy)ethyl pivalate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.19(dd, J =8.9,1.5Hz,1H),9.08(dd, J =4.1,1.5Hz,1H),8.45(d, J =8.8Hz,1H),7.70(dd, J =8.9,4.1Hz,1H),7.15(d, J =8.8Hz,1H),6.96(q, J =5.2Hz,1H),1.88(d, J =5.2Hz,3H),1.17(s,9H).

MS calc.: 318.3; MS found: 319.2 [M+H] ⁺ .

Example 51: Synthesis of 1-(5-nitroquinolin-8-yloxy)ethyl 2-ethylbutyrate ( 51 )

The preparation method is the same as that of Example 47, except that 2-ethylbutyryl chloride is used instead of acetyl chloride in step 1 to obtain 1-(5-nitroquinolin-8-yloxy)ethyl 2-ethylbutyrate.

¹ H NMR (400MHz, CDCl ₃ ) δ: 9.20-9.17(m,1H),9.08-9.07(m,1H),8.45(d, J =8.4Hz,1H),7.72-7.68(m,1H),7.21(d, J =8.8Hz,1H),7.03-7.01(m,1H),2.25-2.11(m,1H),1.88(d, J =5.2Hz,3H),1.60-1.49(m,4H),0.88-0.81(m,6H).

MS calculated: 332; MS found: 333 [M+H] ⁺ .

Example 52: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2,3-dihydroxypropyl(methyl)carbamate (52)

Step 1: Preparation of chloromethyl 2,3-dihydroxypropyl (methyl) carbamate (52a)

Dissolve N-methyl-2,3-dihydroxypropylamine (1g, 10mmol) in a mixed solvent of acetonitrile (40mL) and methanol (8mL), slowly add triethylamine (1.15g, 11.4mmol) and chloromethyl chloroformate (1.35g, 10.48mmol) in an ice-water bath, stir the reaction solution at 0℃ for 30 minutes, then raise the temperature to 25℃ and stir for 16 hours. Quench the reaction solution with water (50mL), extract with dichloromethane (100mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product chloromethyl 2,3-dihydroxypropyl (methyl) carbamate (1.7g, yield 89%).

Step 2: Preparation of (5-nitroquinolin-8-yloxy)methyl 2,3-dihydroxypropyl(methyl)carbamate (52)

Nitrohydroxyquinoline (600 mg, 3.16 mmol) and chloromethyl 2,3-dihydroxypropyl (methyl) carbamate (940 mg, 4.7 mmol) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of potassium carbonate (871 mg, 6.31 mmol) and sodium iodide (47 mg, 0.32 mmol) at 0°C, and the reaction solution was stirred at 60°C for 4 hours. The reaction was returned to room temperature, quenched with water, extracted with dichloromethane (100 mL x 3), 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 obtain the product (5-nitroquinolin-8-yloxy)methyl 2,3-dihydroxypropyl(methyl)carbamate (300 mg, yield 27%).

¹ H NMR (400MHz, CDCl ₃ ) δ: 9.20-9.18(m,1H),9.06(dd, J =4.0,1.2Hz,1H),8.51(d, J =8.8Hz,1H),7.73-7.70(m,1H),7.40(d, J =8.8Hz,1H),6.21-6.13(m,2H),3.88(s,1H),3.67-3.40(m,4H),3.04-2.95(m,5H).

MS calculated: 351.11; MS found: 352.1 [M+H] ⁺ .

Example 53: Synthesis of methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)formamido)acetate (53)

Step 1: Preparation of methyl 2-(2,4-dimethoxybenzylamino)acetate (53a)

At 0°C, 2,4-dimethoxybenzaldehyde (720 mg, 4.34 mmol) and sodium acetate borohydride (1.38 g, 6.51 mmol) were slowly added to a solution of triethylamine (658 mg, 6.51 mmol) and 2-amino-acetic acid methyl ester hydrochloride (1.00 g, 6.51 mmol) in dichloromethane (40 mL). 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 (100 mL x 3). The organic phase was washed with 1M hydrochloric acid, 1M sodium bicarbonate aqueous solution and saturated brine, 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 obtain methyl 2-(2,4-dimethoxybenzylamino)acetate (1.1 g, yield 95%).

MS [M+H] ⁺ : 240.0.

Step 2: Preparation of methyl 2-(((chloromethoxy)formyl)(2,4-dimethoxybenzyl)amino)acetate (53b)

Chloromethyl chloroformate (595 mg, 4.60 mmol) was slowly added dropwise to a solution of methyl 2-(2,4-dimethoxybenzylamino)acetate (1.0 g, 4.39 mmol) and triethylamine (485 mg, 4.80 mmol) in dichloromethane (20 mL) at 0°C. 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 then the reaction solution was extracted with dichloromethane (100 mL x 3). The organic phase was washed with 1 M hydrochloric acid, 1 M sodium bicarbonate aqueous solution and saturated brine, 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 obtain methyl 2-(((chloromethoxy)formyl)(2,4-dimethoxybenzyl)amino)acetate (1.00 g, 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, methyl 2-(((chloromethoxy)formyl)(2,4-dimethoxybenzyl)amino)acetate (1.05 g, 2.79 mmol) was added to a solution of nitrohydroxyquinoline (360 mg, 1.9 mmol), potassium carbonate (385 mg, 2.79 mmol), and sodium iodide (30 mg, 0.19 mmol) in N,N-dimethylformamide (15 mL). The reaction solution was stirred at 50 °C for 2 hours and then cooled to room temperature. The reaction was quenched by adding water, and then the reaction solution was extracted with dichloromethane (100 mL x 3). The organic phase was washed with 1 M hydrochloric acid, 1 M sodium bicarbonate aqueous solution and saturated brine, 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 obtain 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)formamido)acetate (53)

Trifluoroacetic acid (8 mL) was added dropwise to a solution of methyl 2-((2,4-dimethoxybenzyl)(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)acetate (440 mg, 0.91 mmol) in dichloromethane (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then quenched with water. The reaction mixture 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 brine, 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 obtain methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)formamido)acetate (200 mg, yield 67%).

¹ H NMR (400MHz, CDCl ₃ ) δ: 9.18 (dd, J =8.8, 1.6Hz, 1H), 9.06 (dd, J =4.0, 1.6Hz, 1H), 8.49 (d, J =8.8Hz, 1H), 7.70 (dd, J =8.4, 4.4Hz, 1H), 7.40 (d, J =9.2Hz,1H),6.18(s,2H),5.41(s,1H),4.01(d, J =5.6Hz,2H),3.77(s,3H).

MS calculated: 335.08; MS found: 336.1 [M+H] ⁺ .

Example 54: Synthesis of methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)formamido)butyrate ( 54 )

The preparation method is the same as that of Example 53, except that 2-amino-butyric acid methyl ester is used instead of 2-amino-acetic acid methyl ester hydrochloride in step 1 to obtain 2-(((5-nitroquinolin-8-yloxy)methoxy)formamido)butyric acid methyl ester.

¹ H NMR (400MHz, CDCl ₃ ): δ 9.19 (dd, J =8.8, 1.6Hz, 1H), 9.06 (s, 1H), 8.49 (d, J =8.8Hz, 1H), 7.70 (d, J =8.8Hz, 1H), 7.40 (d, J =8.8Hz, 1H), 6.17 (d, J =8.8Hz, 1H ) =7.6Hz,2H),5.43(d, J =8.0Hz,1H),4.36(d, J =5.6Hz,1H),3.75(s,3H),1.90(s,1H),1.72(d, J =7.2Hz,1H),0.90(d, J =7.4Hz,3H).

MS calculated: 363; MS measured: 364.

Example 55: Synthesis of methyl 3-methyl-2-(((5-nitroquinolin-8-yloxy)methoxy)formamido)pentanoate ( 55 )

The preparation method is the same as that of Example 53, except that 2-amino-3-methylpentanoic acid methyl ester hydrochloride is used instead of 2-amino-acetic acid methyl ester hydrochloride in step 1 to obtain 3-methyl-2-(((5-nitroquinolin-8-yloxy)methoxy)formamido)pentanoic acid methyl ester.

¹ H NMR (400MHz, CDCl ₃ ) δ: 9.19 (dd, J =9.2, 1.2Hz, 1H), 9.06 (dd, J =4.0, 1.6Hz, 1H), 8.49 (d, J =8.8Hz, 1H), 7.70 (dd, J =9.2, 4.4Hz, 1H), 7.40 (dd, J =8.8,1.2Hz,1H),6.18-6.16(m,2H),5.38(m,1H),4.45(dd, J =9.2,4.0Hz,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 =8.8Hz,2H).

MS calculated: 391.14; MS found: 392.1 [M+H] ⁺ .

Example 56: Synthesis of methyl 3-methyl-2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)pentanoate ( 56 )

Step 1: Preparation of N-benzyl-2-amino-3-methylpentanoic acid methyl ester (56a)

At 0°C, 2-amino-3-methylpentanoic acid methyl ester hydrochloride (4.0 g, 21.9 mmol) and sodium acetate borohydride (9.2 g, 43.4 mmol) were slowly added 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 solution was stirred at 0°C for 30 minutes, then warmed to room temperature and continued to stir for 16 hours. The reaction was quenched with saturated sodium bicarbonate aqueous solution (20 mL), and the reaction solution was extracted with dichloromethane (150 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure to obtain crude N-benzyl-2-amino-3-methylpentanoic acid methyl ester. (4.2g, yield 100%).

MS [M+H] ⁺ : 236.0.

Step 2: Preparation of N-methyl-N-benzyl-2-amino-3-methylpentanoic acid methyl ester (56b)

At 0°C, 37% formaldehyde (5.4 g, 179 mmol) aqueous solution, sodium cyanoborohydride (2.5 g, 39.4 mmol) and acetic acid (2 mL) were added sequentially to a solution of N-benzyl-2-amino-3-methylpentanoic acid methyl ester (4.2 g, 17.9 mmol) in acetonitrile (100 mL). The reaction solution was stirred at room temperature for 16 hours and then quenched with saturated sodium bicarbonate (100 mL) aqueous solution. The reaction solution was extracted with dichloromethane (150 mL x 3), 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 obtain N-methyl-N-benzyl-2-amino-3-methylpentanoic acid methyl ester (4.2 g, yield 93%).

MS [M+H] ⁺ : 250.0.

Step 3: Preparation of N-methyl-N-Boc-2-amino-3-methylpentanoic acid methyl ester (56c)

Add N-methyl-N-benzyl-2-amino-3-methylpentanoic acid methyl ester (4.2 g, 16.8 mmol), Pd/C (900 mg) and Boc ₂ O (10 mL) to methanol (30 mL). Stir the reaction solution at 50°C for 16 hours under a hydrogen atmosphere. After filtering off the solid, concentrate under reduced pressure to obtain crude N-methyl-N-Boc-2-amino-3-methylpentanoic acid methyl ester (5.2 g, yield 100%).

MS [M+H] ⁺ : 260.0.

Step 4: Preparation of N-methyl-2-amino-3-methylpentanoic acid methyl ester (56d)

At 0°C, add 5M hydrochloric acid in 1,4-dioxane (10 mL) to a tetrahydrofuran (50 mL) solution of N-methyl-N-Boc-2-amino-3-methylpentanoic acid methyl ester (5.2 g, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to obtain N-methyl-2-amino-3-methylpentanoic acid methyl ester (3.2 g, yield 82%).

MS [M+H] ⁺ : 160.0.

Step 5: Preparation of N-methyl-N-chloromethoxymethyl-2-amino-3-methylpentanoic acid methyl ester (56e)

At 0°C, chloromethyl chloroformate (0.48mL, 5.37mmol) was slowly added dropwise to a solution of N-methyl-2-amino-3-methylpentanoic acid methyl ester (1g, 5.12mmol) and triethylamine (1.8mL, 12.8mmol) in dichloromethane (30mL). The reaction solution was stirred at 0°C for 30 minutes and then heated to room temperature and stirred for 16 hours. After quenching the reaction with water (25mL), the reaction solution was extracted with dichloromethane (100mL x 3), the organic phase was dried with magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude N-methyl-N-chloromethoxyformyl-2-amino-3-methylpentanoic acid methyl ester (638mg, yield 49%).

MS [M+H] ⁺ : 252.0.

Step 6: Preparation of methyl 3-methyl-2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)pentanoate (56)

At room temperature, N-methyl-N-chloromethoxyformyl-2-amino-3-methylpentanoic acid methyl ester (638 mg, 2.53 mmol) was slowly added dropwise to a solution of nitrohydroxyquinoline (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 x 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 obtain methyl 3-methyl-2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)pentanoate (70 mg, yield 10%).

^1H NMR (400MHz, CDCl ₃ )δ 9.20(d,J=8.8Hz,1H),9.07-9.06(m,1H),8.50(dd,J=8.8,3.2Hz,1H),7.72(dd,J=8.8,4.0Hz,1H),7.42(d,J=8.8Hz,1H),6.2 5-6.21(m,2H),4.61-4.30(m,1H),3.71-3.58(m,3H),2.94-2.89(m,3H),1.98(brs,1H),1.39-1.34(m,1H),0.95-0.75(m,7H).

MS calculated: 405.15; MS observed: 406.1 [M+H] ⁺ .

Example 57: Synthesis of methyl 2-(methyl((5-nitroquinolin-8-yloxy)formyl)amino)acetate (57)

Triphosgene (296.8 mg, 1 mmol) and pyridine (790 mg, 10 mmol) were added to dichloromethane (6 mL) in batches at 0°C. After the reaction solution was stirred at room temperature for 20 minutes, a solution of methyl N-methyl-2-aminoacetate (124 mg, 1.2 mmol) in acetonitrile (2 mL) was slowly added dropwise to the reaction solution and stirred at room temperature for 1 hour. After the solvent was removed by reducing pressure, pyridine (2 mL) was added, and nitrohydroxyquinoline (190 mg, 1 mmol) was added in batches. The reaction solution was heated in a microwave at 110°C for 2 hours. The reaction was quenched by adding water, and the reaction solution was extracted with dichloromethane (100 mL x 3). The organic phase was washed with 1M hydrochloric acid, 1M sodium bicarbonate aqueous solution and saturated brine, 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 obtain methyl 2-(methyl((5-nitroquinolin-8-yloxy)formyl)amino)acetate (100 mg, yield 31%).

¹ H NMR (400MHz, CDCl ₃ ) δ: 9.10-9.04 (m, 2H), 8.47-8.43 (m, 1H), 7.68-7.60 (m, 2H), 4.30 (d, J =84.8Hz, 2H), 3.82 (d, J =13.6Hz, 3H), 3.27 (d, J =88.0Hz,3H).

MS calculated: 319.08; MS found: 320.0 [M+H] ⁺ .

Example 58: Synthesis of (S )-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)formamido)-3-phenylpropanoate (58)

The preparation method is the same as that of Example 53, except that L-phenylalanine methyl ester is used instead of 2-amino-acetic acid methyl ester hydrochloride in step 1 to obtain ( S )-2-(((5-nitroquinolin-8-yloxy)methoxy)formamido)-3-phenylpropionic acid methyl ester.

¹ H-NMR (400Hz, CDCl3) δ: 9.35 (dd, J =8.8, 1.6Hz, 1H), 9.15 (dd, J =4.4, 1.6Hz, 1H), 8.53 (d, J =8.8Hz, 1H), 7.83 (dd, J =8.8Hz,4.4Hz,1H),7.56(br,1H),7.40(d, J =8.8Hz,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 calculated: 425.40; MS found: 426.3 [M+H] ⁺ .

Example 59: Synthesis of (2S,6R)-(5-nitroquinolin-8-yloxy)methyl 2,6-dimethylmorpholine-4-carboxylate (59)

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 sequence, stirred for 30 minutes, and then heated to room temperature and stirred for 4 hours. After quenching with water (50mL), it was extracted with dichloromethane (100mL x 3), and the organic phases were combined and dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product N-chloromethoxyformyl-(2S,6R)-2,6-dimethylmorpholine (0.5g, yield 60%).

Step 2: Preparation of (2S,6R)-(5-nitroquinolin-8-yloxy)methyl 2,6-dimethylmorpholine-4-carboxylate (59)

At room temperature, nitrohydroxyquinoline (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), followed by the addition of potassium carbonate (0.7 g, 5.0 mmol) and potassium iodide (83 mg, 0.5 mmol), and the reaction solution was stirred at 60°C for 4 hours. After the reaction was cooled to room temperature, the reaction was quenched with water, extracted with dichloromethane (100 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (chromatographic column: Eclipse XDB-C18 (21.2mm×250mm, 7μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0mL/min) to obtain (2S,6R)-(5-nitroquinolin-8-yloxy)methyl 2,6-dimethylmorpholine-4-carboxylate (90mg, yield 11%).

¹ H-NMR (400Hz, CDCl3) δ: 9.23 (dd, J =8.8, 1.2Hz, 1H), 9.10 (d, J =3.2Hz, 1H), 8.54 (d, J =8.8Hz, 1H), 7.77 (dd, J =8.8Hz, 4.0Hz, 1H), 7.41 (d, J =8.8Hz,1H),6.49(d, J =8Hz,1H),6.20-6.24(m,2H),4.02(d, J =12.8Hz,1H),3.87(d, J =12.8Hz,1H),3.50-3.60(m,2H),2.52-2.64(m,2H),1.20(d, J =6.4Hz,3H),1.16(d, J =6.0Hz,3H).

MS calculated: 361.35; MS found: 362.3 [M+H] ⁺ .

Example 60: Synthesis of (5-nitroquinolin-8-yloxy)methyl 1,4'-biguanidine-1'-carboxylate (60)

The preparation method is the same as that of Example 59, except that 4-piperidinylpiperidin is used instead of (2S,6R)-2,6-dimethylmorpholine in step 1 to obtain (5-nitroquinolin-8-yloxy)methyl 1,4'-piperidin-1'-carboxylate.

¹ H-NMR (400Hz, 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 calculated: 414.46; MS found: 415.3 [M+H] ⁺ .

Example 61: Synthesis of methyl 4-(((5-nitroquinolin-8-yloxy)methoxy)formamido)butyrate (61)

The preparation method is the same as that of Example 53, except that 4-aminobutyric acid methyl ester hydrochloride is used instead of 2-amino-acetic acid methyl ester hydrochloride in step 1 to obtain 4-(((5-nitroquinolin-8-yloxy)methoxy)formamido)butyric acid methyl ester.

¹ H-NMR (400Hz, CDCl3) δ: 9.23 (dd, J =8.8, 0.8Hz, 1H), 9.22 (dd, J =4.4, 3.6Hz, 1H), 8.60 (d, J =9.2Hz, 1H), 7.91 (dd, J =8.8, 4.4Hz, 1H), 7.50 (d, J =8.8Hz,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),.82-1.86(m,2H).

MS calculated: 363.33; MS measured: 364.3 [M+H] ⁺ .

Example 62: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-methylmorpholine-4-carboxylate (62)

The preparation method is the same as that of Example 59, except that 2-methylmorpholine is used instead of (2S,6R)-2,6-dimethylmorpholine in step 1 to obtain (5-nitroquinolin-8-yloxy)methyl 2-methylmorpholine-4-carboxylate.

¹ H-NMR (400Hz, CDCl3) δ: 9.37-9.39(m,1H),9.18-9.19(m,1H),8.59(d,J=8.4Hz,1H),7.75(dd,J=8.8Hz,4.4Hz,1H),7.44(d,J= 8.8Hz,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 calculated: 347.33; MS measured: 338.3 [M+H] ⁺ .

Example 63: Synthesis of (5-nitroquinolin-8-yloxy)methyl 2-hydroxyethyl (methyl)carbamate (63)

Step 1: Preparation of N-[2-(tert-butyldimethylsilyloxy)ethyl]methylamine (63a)

At 0°C, dissolve N-methyl-2-hydroxyethylamine (3.5g, 46.6mmol) and tert-butyldimethylsilyl chloride (7.7g, 51.2mmol) in dichloromethane (100mL), and slowly add triethylamine (13mL, 93mmol). Stir the reaction solution at 0°C for 30 minutes, then warm it to room temperature and stir overnight. Concentrate the reaction solution and dissolve it in methyl tert-butyl ether (200mL), wash it with 1M sodium bicarbonate aqueous solution and saturated brine, dry it with anhydrous sodium sulfate, filter it, and concentrate the filtrate under reduced pressure to obtain the product N-[2-(tert-butyldimethylsilyloxy)ethyl]methylamine (6g, yield 68%).

Step 2: Preparation of N-(chloromethoxymethyl)-N-[2-(tert-butyldimethylsilyloxy)ethyl]methylamine (63b)

At 0°C, N-[2-(tert-butyldimethylsilyloxy)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 and then warmed to room temperature and stirred overnight. After quenching with water (100mL), it was extracted with dichloromethane (200mL x 3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain N-(chloromethoxymethyl)-N-[2-(tert-butyldimethylsilyloxy)ethyl]methylamine (2g, yield 29%).

Step 3: Preparation of (5-nitroquinolin-8-yloxy)methyl 2-(tert-butyldimethylsilyloxy)ethyl (methyl)carbamate (63c)

At room temperature, nitrohydroxyquinoline (1.75 g, 9.2 mmol) and N-(chloromethoxymethyl)-N-[2-(tert-butyldimethylsilyloxy)ethyl]methylamine (2.0 g, 7.1 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of potassium carbonate (2 g, 14.2 mmol) and potassium iodide (230 mg, 1.4 mmol), 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 (200 mL x 3), and 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 obtain (5-nitroquinolin-8-yloxy)methyl 2-(tert-butyldimethylsilyloxy)ethyl (methyl)carbamate (500 mg, yield 16.2%).

Step 4: Preparation of (5-nitroquinolin-8-yloxy)methyl 2-hydroxyethyl (methyl)carbamate (63)

At room temperature, (5-nitroquinolin-8-yloxy)methyl 2-(tert-butyldimethylsilyloxy)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. The residue was separated by reverse phase high performance liquid chromatography (chromatographic column: Eclipse XDB-C18 (21.2mm×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%).

Example 64: Synthesis of 2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)ethyl acetate (64)

At 0°C, (5-nitroquinolin-8-yloxy)methyl 2-hydroxyethyl (methyl)carbamate (320 mg, 1.0 mmol) and acetyl chloride (100 mg, 1.2 mmol) were dissolved in dichloromethane (10 mL), and pyridine (160 mg, 2.0 mmol) was slowly added dropwise. The mixture was heated to room temperature and stirred for 2 hours. After the reaction was cooled to room temperature, the reaction was quenched with water and extracted with dichloromethane (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (chromatographic column: Eclipse XDB-C18 (21.2mm×250mm, 7μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0mL/min.) to obtain the product 2-(methyl(((5-nitroquinolin-8-yloxy)methoxy)formyl)amino)ethyl acetate.

¹ H-NMR (400Hz, CDCl3) δ: 9.21 (d, J =8.0Hz, 1H), 9.08 (d, J =4Hz, 1H), 8.53 (d, J =8.0Hz, 1H), 7.77 (dd, J =8.0Hz, 4.0Hz, 1H), 7.44 (d, J =8.8Hz,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 calculated: 363.33; MS found: 364.1 [M+H] ⁺ .

Example 65: Synthesis of (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methylacetamido)acetate (65)

Step 1: Preparation of (2-(methylamino)pyridin-3-yl)methyl 2-(tert-butoxycarbonyl(methyl)amino)acetate (65a)

At room temperature, 2-methylamino-3-pyridinemethanol (2.8 g, 20.3 mmol), tert-butyloxycarbonylsarcosine (5 g, 26.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (5.1 g, 26.4 mmol) and 4-dimethylaminopyridine (DMAP) (250 mg, 2 mmol) were added to dichloromethane (100 mL) and stirred overnight. The reaction was quenched by adding water, and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: 5% methanol/95% dichloromethane) to obtain (2-(methylamino)pyridin-3-yl)methyl 2-(tert-butoxycarbonyl(methyl)amino)acetate (3 g, yield 49%).

Step 2: Preparation of (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(tert-butyloxycarbonyl(methyl)amino)acetate (65b)

At 0°C, (2-(methylamino)pyridin-3-yl)methyl 2-(tert-butoxycarbonyl(methyl)amino)acetate (3.4 g, 11 mmol) was dissolved in dichloromethane (80 mL), and N,N-diisopropylethylamine (2.8 g, 22 mmol) and chloromethyl chloroformate (2.1 g, 16.5 mmol) were slowly added dropwise. The reaction mixture was stirred at 0°C for 30 minutes and then heated to room temperature and stirred overnight. After quenching with water (100 mL), it was extracted with dichloromethane (200 mL x 3), and the organic phases were combined and 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-(tert-butoxycarbonyl(methyl)amino)acetate (4 g, yield 91%).

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-(tert-butoxycarbonyl(methyl)amino)acetate (1.7g, 5.6mmol) was dissolved in dichloromethane (50mL), dioxane hydrochloride (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-methylacetamido)acetate (65d)

At 0°C, (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(methylamino)acetate (1 g, 3.3 mmol) and acetyl chloride (390 mg, 5.0 mmol) were dissolved in dichloromethane (50 mL), triethylamine (0.7 mL, 6.6 mmol) was slowly added dropwise, and the temperature was raised to room temperature and stirred for 2 hours. After the reaction was cooled to room temperature, the reaction was quenched with water and extracted with dichloromethane (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(N-methylacetamido)acetate (1.0 g, yield 91%).

Step 5: Preparation of (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methylacetamido)acetate (65)

At room temperature, nitrohydroxyquinoline (1.5 g, 7.9 mmol) and (2-(((chloromethoxy)carbonyl)(methyl) amino)pyridin-3-yl)methyl 2-(N-methylacetamido)acetate (2.7 g, 7.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of potassium carbonate (2.2 g, 16.0 mmol) and potassium iodide (270 mg, 1.6 mmol), 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 (200 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (chromatographic column: Eclipse XDB-C18 (21.2mm×250mm, 7μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0mL/min) to obtain the product (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methylacetamido)acetate (500mg, yield 13%).

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),5.00-5.11(m,2H),4.01-4.06(m,2H),3.34(s,3H),3.00(s,3H),2.13(s,3H).

MS calculated: 497.46; MS observed: 498.2 [M+H] ⁺ .

Example 66: Synthesis of (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methyltert-butylamino)acetate (66)

The preparation method is the same as that of Example 65, except that acetyl chloride in step 4 is replaced by trivaleryl chloride to obtain (2-(methyl(((5-nitroquinolin-8-yl)oxy)methoxy)formyl)amino)pyridin-3-yl)methyl 2-(N-methyltert-butylamino)acetate.

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 calculated: 539.55; MS found: 540.2 [M+H] ⁺ .

Example 67: Synthesis of (5-nitroquinolin-8-yloxy)methylpiperidinium 1-carboxylate (67)

The preparation method is the same as that of Example 6, except that 1-methylpiperidin in step 1 is replaced by piperidine hydrochloride to obtain (5-nitroquinolin-8-yloxy)methylpiperidin 1-carboxylate.

¹ H-NMR (400Hz, CDCl3) δ: 9.23 (dd, J =8.8, 1.6Hz, 1H), 9.09 (dd, J =4.0, 1.6Hz, 1H), 8.53 (d, J =8.8Hz, 1H), 7.77 (dd, J =8.8Hz, 4.0Hz, 1H), 7.35 (d, J =8.8Hz,1H),6.22(s,2H),3.42-3.47(m,4H),1.35-1.63(m,6H).

MS calculated: 331.33; MS measured: 332.3 [M+H] ⁺ .

Example 68: Synthesis of 3-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)propyl acetate (68)

Step 1: Preparation of tert-butyl 3-hydroxypropyl-methylcarbamate (68a)

At room temperature, add triethylamine (1.36g, 13.44mmol) to a solution of 3-methylamino-1-propanol (1.00g, 11.22mmol) in methanol (10mL), and stir to dissolve. Add di-tert-butyl dicarbonate (2.94g, 13.47mmol) dropwise and stir for 16 hours. The reaction solution is concentrated under reduced pressure, diluted with dichloromethane, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain crude tert-butyl 3-hydroxypropyl-methylcarbamate (2.20g).

Step 2: Preparation of 3-(methylamino)propyl acetate (68b)

At room temperature, add triethylamine (0.64g, 6.32mmol) to a solution of tert-butyl 3-hydroxypropyl-methylcarbamate (1.00g, 5.28mmol) in dichloromethane (5mL), and stir to dissolve. Cool the reaction system to 0°C, add acetyl chloride (0.50g, 6.37mmol), and stir for 1 hour after naturally warming to room temperature. Filter the reaction solution, rinse with dichloromethane, and concentrate the filtrate to obtain a solid crude product. At 0°C, add a solution of hydrogen chloride in dioxane (3.3mL, 4M) to the crude product and stir for 16 hours. Concentrate the reaction solution 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 dissolved in dichloromethane (8 mL). At 0°C, triethylamine (1.07 g, 10.57 mmol) and chloromethyl chloroformate (0.68 g, 5.27 mmol) were added to the solution in sequence. The temperature was naturally raised to room temperature and stirred for 1 hour. Water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, 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 obtain 3-(((chloromethoxy)carbonyl)(methyl)amino)propyl acetate (400 mg, yield 34%).

Step 4: Preparation of 3-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)propyl acetate (68)

At room temperature, add nitrohydroxyquinoline (340 mg, 1.79 mmol), potassium carbonate (297 mg, 2.15 mmol), and sodium iodide (27 mg, 0.18 mmol) to N,N-dimethylformamide (8 mL) and stir to mix. Heat the reaction system to 60°C, stir for 15 minutes, add 3-(((chloromethoxy)carbonyl)(methyl)amino)propyl acetate (400 mg, 1.79 mmol), and stir for 16 hours. Add water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated saline solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography (developer: 5% methanol/95% dichloromethane) to obtain 3-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)propyl acetate (196 mg, yield 29%).

¹ H NMR (400MHz, CDCl ₃ ) δ 9.20 (dd, J =8.8, 2.4Hz, 1H), 9.07 (d, J =1.4Hz,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 =28.3,3.6Hz,2H),3.38(dd, J =14.3,7.2Hz,2H),3.02-2.89(m,3H),2.03(dd, J =17.5,3.7Hz,3H),1.86(d, J =24.3Hz,2H).

MS calculated: 377.3; MS found: 378.2 [M+H] ⁺ .

Example 69: Synthesis of 4-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)butyl acetate (69)

The preparation method is the same as that of Example 68, except that 4-methylamino-1-butanol is used instead of 3-methylamino-1-propanol in step 1 to obtain 4-(methyl(((5-nitroquinolin-8-yloxy)methoxy)carbonyl)amino)butyl acetate.

¹ H NMR (400MHz, CDCl ₃ )δ 9.18(dd, J =8.9,1.3Hz,1H),9.06(d, J =4.0Hz,1H),8.50(d, J =8.8Hz,1H),7.70(dd, J =8.9,4.1Hz,1H),7.42(dd, J =8.8,3.9Hz,1H),6.20(d, J =4.7Hz,2H),4.04(dd, J =27.3,21.6Hz,2H),3.36-3.22(m,2H),2.96-2.86(m,3H),2.01(d, J =19.7Hz,3H),1.64-1.57(m,2H),1.53(s,2H).

MS calculated: 391.4; MS found: 392.2 [M+H] ⁺ .

Examples 70 and 71: Synthesis of di-tert-butyl (5-nitroquinolin-8-yloxy) methyl phosphate (70) and (5-nitroquinolin-8-yloxy) methyl dihydrogen phosphate (71)

Step 1: Preparation of di-tert-butyl (5-nitroquinolin-8-yloxy) methyl phosphate (70)

Potassium carbonate (1.45 g, 10.52 mmol) was added to a solution of nitrohydroxyquinoline (1.0 g, 5.26 mmol) and di-tert-butyl chloromethyl phosphate (2.04 g, 7.89 mmol) in N,N-dimethylformamide (17 mL) at room temperature. The reaction solution was stirred at 60 °C for 2 hours. The reaction was quenched by adding water, extracted with dichloromethane (100 mL x 3), and the organic phase was washed with 1 M hydrochloric acid, 1 M sodium bicarbonate aqueous solution and saturated brine, 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 obtain di-tert-butyl (5-nitroquinolin-8-yloxy) methyl phosphate (570 mg, yield: 26%).

MS [M+H] ⁺ : 413.3.

Step 2: Preparation of (5-nitroquinolin-8-yloxy)methyl dihydrogen phosphate (71)

At room temperature, trifluoroacetic acid (7 ml) was slowly added dropwise to a solution of di-tert-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, a solid precipitated and the crude product was obtained by filtration. The crude product was purified by preparative liquid phase (Agilent 1260 preparative liquid phase: acetonitrile/water gradient 95/5-50/50) to obtain the product (5-nitroquinolin-8-yloxy) methyl dihydrogen phosphate (100.24 mg, yield: 24%).

¹ H NMR (400MHz, D ₂ O): δ 8.97-8.94(m,1H),8.76-8.75(m,1H),8.42(d, J =8.8Hz,1H),7.69-7.65(m,1H),7.38(d, J =9.2Hz,1H),5.76(d, J =11.2Hz,1H).

MS calculated: 300.0; MS found: 301.0 [M+H] ⁺ .

Example 72: Synthesis of (hydroxy((5-nitroquinolin-8-yloxy)methoxy)phosphatyloxy)methyl isopropyl carboxylate (72)

Step 1: Preparation of (hydroxy((5-nitroquinolin-8-yloxy)methoxy)phosphatyloxy)methyl isopropylcarboxylate (72)

(5-nitroquinolin-8-yloxy)methyl dihydrogen phosphate hydrochloride (672 mg, 2 mmol, see Example 71 for the synthesis steps), chloromethyl carbonate isopropyl ester (1.22 g, 8 mmol) and triethylamine (1.01 g, 10 mmol) were placed in 20 mL 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 phase: acetonitrile/water gradient 95/5-50/50) to obtain (hydroxy((5-nitroquinolin-8-yloxy)methoxy)phosphatyloxy)methyl isopropyl carboxylate (121 mg, yield 14.5%).

¹ H-NMR (400MHz, DMSO-d6) δ: 9.05 (d, J =2.8Hz, 1H), 9.00 (d, J =8.4Hz, 1H), 8.55 (d, J =8.4Hz, 1H), 7.87 (dd, J =8.4, 4.0Hz, 1H), 7.54 (d, J =8.4Hz,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 calculated: 416.28; MS measured: 417.1 [M+H] ⁺ .

Example 73: Synthesis of (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphamido)propionate (73)

Step 1: Preparation of (2S)-methyl 2-(benzyloxy(phenoxy)phosphamidonyl)propionate (73a)

At room temperature, benzyl alcohol (2g, 18.49mmol) and phenyl dichlorophosphate (4.29g, 20.34mmol) were added to 40mL of 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. After stirring for 20 minutes, it was 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)phosphatamido) propionate (4.2g, yield: 65.6%).

Step 2: Preparation of (2S)-methyl 2-(hydroxy(phenoxy)phosphatidyl)propionate (73b)

At room temperature, (2S)-methyl 2-(benzyloxy(phenoxy)phosphoramido) propionate (2.5g, 7.16mmol) was dissolved in 25mL tetrahydrofuran, and 500mg wet Pd/C was added. Under hydrogen atmosphere, the reaction solution was stirred at room temperature for 8 hours. Then the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain (2S)-methyl 2-(hydroxy(phenoxy)phosphoramido) propionate (1.5g, yield: 81%).

Step 3: Preparation of (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphamido)propionate (73)

At room temperature, (2S)-methyl 2-(hydroxy(phenoxy)phosphamido)propionate (1.5 g, 5.79 mmol) and 5-nitro-8-(chloromethoxy)quinoline (1a) (921 mg, 3.86 mmol) were dissolved in 20 mL DMF, and then a catalytic amount of KI (10 mg) and potassium carbonate (1.6 g, 11.58 mmol) were added and stirred 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)phosphamido)propionate (160 mg, yield: 8.9%).

¹ H-NMR (400MHz, 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),5.60(br,1H),3.88~3.97(m,1H),3.54(d,J=10Hz,3H),1.18~1.21(m,3H).

MS calculated: 461.37; MS found: 462.2 [M+H] ⁺ .

Example 74: Synthesis of (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphamido)-3-phenylpropanoate (74)

The preparation method is the same as that of Example 73, except that L-phenylalanine methyl hydrochloride is used instead of L-alanine methyl hydrochloride in step 1 to obtain (2S)-methyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphamido)-3-phenylpropionate.

¹ H-NMR (400MHz, DMSO-d6): δ 9.03(d,J=4Hz,1H),8.99(dd,J=8.8,1.2Hz,1H),8.52(dd,J=8.4,6.4Hz,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,2 H),3.98~4.02(m,1H),3.54(s,3H),2.95~3.01(m,1H),2.75~2.85(m,1H).

MS calculated: 537.46; MS found: 538.3 [M+H] ⁺ .

Example 75: Synthesis of (2S)-isopropyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphamido)propionate (75)

The preparation method is the same as that of Example 73, except that L-alanine isopropyl hydrochloride is used instead of L-alanine methyl hydrochloride in step 1 to obtain (2S)-isopropyl 2-(((5-nitroquinolin-8-yloxy)methoxy)(phenoxy)phosphamido)propionate.

¹ H-NMR (400MHz, 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 calculated: 489.42; MS measured: 490.3 [M+H] ⁺ .

Example 76: Synthesis of (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl(5-nitroquinolin-8-yloxy)methylphosphonic acid monohydrogen ester (76)

Step 1: Preparation of dibenzyl (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy) methyl phosphate (76a)

At 0°C, sodium hydroxide (purity: 60%, 0.42 g, 10.5 mmol) was added to a solution of 6-cyclohexyl-4-methyl-pyridin-1-hydroxy-2-one (purchased from Darry Chemical) (2.00 g, 9.65 mmol) in N,N-dimethylformamide (30 mL). After stirring for 30 minutes, dibenzyl (chloromethyl) phosphate (4.10 g, 12.55 mmol) was added, and the temperature was naturally raised to room temperature and stirred for 5 hours. The reaction was quenched by adding ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed with saturated salt aqueous 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 obtain dibenzyl (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)- yloxy) methyl phosphate (1.58 g, yield 33%).

Step 2: Preparation of (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl dihydrogen phosphate (76b)

At room temperature, add 10% palladium carbon (0.20g) to a tetrahydrofuran (16mL) solution of dibenzyl (6-cyclohexyl-4-methyl-2-oxopyridine-1(2H)-yloxy) methyl phosphate (1.58g, 3.18mmol). Stir for 3 hours under hydrogen atmosphere. Filter the reaction solution, rinse with tetrahydrofuran, and concentrate the filtrate under reduced pressure to obtain (6-cyclohexyl-4-methyl-2-oxopyridine-1(2H)-yloxy) methyl dihydrogen phosphate (0.35g, yield 35%).

Step 3: Preparation of (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl(5-nitroquinolin-8-yloxy)methylphosphonic acid monohydrogen ester (76)

At room temperature, (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl dihydrogen phosphate (350 mg, 1.10 mmol), potassium carbonate (305 mg, 2.21 mmol), sodium iodide (28 mg, 0.19 mmol) were added to N,N-dimethylformamide (7 mL) and stirred to mix. The reaction system was heated to 40°C and stirred for 10 minutes, then 5-nitro-8-chloromethoxyquinoline (1a) (448 mg, 1.88 mmol) was added and stirred for 4 hours. The reaction was quenched by adding water, and the impurities were extracted with ethyl acetate. After the aqueous phase was freeze-dried, it was purified by preparative liquid chromatography (Agilent 1260 preparative liquid phase: acetonitrile/water gradient 95/5-50/50) using a reverse phase system of 95% water/5% acetonitrile to obtain (6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yloxy)methyl(5-nitroquinolin-8-yloxy)methylphosphonic acid monohydrogen ester (66 mg, yield 12%).

¹ H NMR (400MHz, CDCl ₃ ) δ 9.65 (d, J =7.6Hz, 1H), 9.21 (s, 1H), 8.66 (d, J = 8.4Hz, 1H), 8.06 (s, 1H), 7.65 (d, J =8.7Hz,1H),6.36(s,1H),6.07(s,1H),6.00(d, J =15.2Hz,2H),5.73(d, J =12.0Hz,2H),2.15(s,3H),1.94(d, J =10.2Hz,2H),1.79(d, J =11.8Hz, 2H),1.75-1.68(m,1H),1.47-1.13(m,6H).

MS calculated: 519.4; MS found: 520.2 [M+H] ⁺ .

Example 77: Synthesis of 4-methyl-5-((5-nitroquinolin-8-yloxy)methyl)-1,3-dioxazol-2-one (77)

Potassium iodide (83 mg, 0.5 mmol) and 4-chloromethyl-5-methyl-1,3-dioxacyclopentene-2-one (1.8 g, 12 mmol) were added in batches to a solution of nitrohydroxyquinoline (1.9 g, 10 mmol) and potassium carbonate (2.7 g, 20 mmol) in N,N-dimethylformamide (10 mL) at 60°C, and the reaction solution was stirred for 2 hours. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phase was washed with 1 M hydrochloric acid, 1 M sodium bicarbonate aqueous solution and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (chromatographic column: Eclipse XDB-C18 (21.2mm×250mm, 7μm), mobile phase: acetonitrile-0.1% formic acid, flow rate: 20.0mL/min) to obtain 4-methyl-5-((5-nitroquinolin-8-yloxy)methyl)-1,3-dioxazol-2-one (0.6g, yield 20%).

¹ H-NMR (400Hz, CDCl3) δ: 9.23 (dd, J =8.8, 1.6Hz, 1H), 9.09 (dd, J =4.0, 1.6Hz, 1H), 8.53 (d, J =8.8Hz, 1H), 7.77 (dd, J =8.8, 4.0Hz, 1H), 7.22 (d, J =8.8Hz,1H),5.22(s,2H),2.26(s,3H).

MS calculated: 302.24; MS measured: 303.1 [M+H] ⁺ .

Example 78: Synthesis of 5-nitroquinolin-8-yl dimethylcarbamate (78)

At 0°C, pyridine (790 mg, 10 mmol) was slowly added to a solution of triphosgene (296.75 mg, 1 mmol) in dichloromethane (6 mL). After stirring at room temperature for 20 minutes, a solution of dimethylamine in tetrahydrofuran (0.53 mL, 1.07 mmol) was added. After stirring the reaction solution for 1 hour, the solvent was removed by reducing the pressure, and pyridine (1 mL) and nitrohydroxyquinoline (190 mg, 1 mmol) were added in sequence. The reaction solution was stirred at 110°C for 3 hours. The reaction was quenched by adding water, and extracted with dichloromethane (100 mL x 3). The organic phase was washed with 1M hydrochloric acid, 1M sodium bicarbonate aqueous solution and saturated brine, 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 obtain 5-nitroquinolin-8-yl dimethylcarbamate (80 mg, yield 31%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ: 9.09 (dd, J =4.0, 1.2Hz, 1H), 8.93 (dd, J =9.2, 1.6Hz, 1H), 8.52 (d, J =8.4Hz, 1H), 7.86 (dd, J =8.8, 4.0Hz, 1H), 7.75 (d, J =8.4Hz,1H),3.21(s,3H),2.96(s,3H).

MS calculated: 261.07; MS found: 262.0 [M+H] ⁺ .

Example 79: Synthesis of bis(5-nitroquinolin-8-yl)sebacate (79)

At 0°C, nitrohydroxyquinoline (332 mg, 1.76 mmol) and pyridine (417 mg, 5.28 mmol) were added in batches to a solution of decanedioyl chloride (200 mg, 0.84 mmol) in dichloromethane (6 mL). The reaction solution was stirred at room temperature for 2 hours, and then water was added to quench the reaction. The reaction solution was extracted with dichloromethane (100 mL x 3), and the organic phase was washed with 1M hydrochloric acid, 1M sodium bicarbonate aqueous solution and saturated brine, 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 obtain bis(5-nitroquinolin-8-yl) sebacate (100 mg, yield 22%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ: 9.05 (dd, J =4.4, 1.6Hz, 2H), 8.92 (dd, J =8.4, 1.6Hz, 2H), 8.52 (d, J =8.8Hz, 2H), 7.85 (dd, J =9.2, 4.4Hz, 2H), 7.77 (d, J =8.8Hz,2H),2.80(t, J =7.2Hz,4H),1.76(d, J =7.2Hz,4H),1.52-1.41(m,8H).

MS calculated: 546.18; MS found: 547.2 [M+H] ⁺ .

Test Example 1: Determination of water solubility of the compound of the present invention

According to the compound of formula (I) of the present invention, after entering the human body, the active ingredient nitroquinoline can be slowly released, which can simultaneously inhibit the methionine aminopeptidase MetAP2 and silent information regulatory factor 2-related enzymes in vascular endothelial cells, exerting a synergistic effect of inhibiting tumor angiogenesis. At the same time, nitroquinoline also has an inhibitory effect on the proliferation of tumor cells. In addition, the released active ingredient nitroquinoline exerts an antibacterial effect by inhibiting the bacterial methionine aminopeptidase MetAP.

The inventor first studied the water solubility of nitrohydroxyquinoline and nitrohydroxyquinoline prodrug.

Experimental instruments: 96-well filter plate (MSHVN4510 or MSHVN4550, Millipore); electronic digital display vortex (MS3 Digital, IKA); circulating water multi-purpose vacuum pump (SHB-Ⅲ, Zhengzhou Great Wall Science and Industry Trade Co., Ltd.); balance (XSLT05, Mettler-Toledo); comfortable mixer (Eppendorf AG 22331 Hamburg, Eppendorf); liquid chromatograph (LC-30AD, Shimadzu); mass spectrometer (API4000, American Applied) injector (Anylytics AG System, CTC). Nitroxyquinoline was commissioned to Haimen Polymerization to synthesize according to the method published in Journal of Heterocyclic Chemistry, 1971, vol.8, p821.

Experimental process: Take 500μL of phosphate buffer (pH=1.2, 4.5, 6.8 or 7.4) and add it to a glass bottle, add 2mg of compound powder, add a stopper, put it on a mixer (VORTEX-GENIE2), and mix it at room temperature for 24 hours. Then vacuum filter, and after the filtrate is treated, use LC/MS/MS to measure the concentration of the compound.

The solubility results of the compounds of the present invention are shown in Table 1 below.

Conclusion:

By optimizing the structure of the prodrug molecule, we can significantly improve the water solubility of the prodrug molecule compared to nitroquinoline. For example, the water solubility of compounds 20, 23, 30, 52, 65, 66, 70, 72, etc. has increased several times. The water solubility of the water-permeable part of the compound does not change with the change of pH value. This feature is particularly important in the development of drug formulations.

Test 2: Determination of the liver microsome and plasma stability of the compounds of the present invention

It is expected that the compound of formula (I) of the present invention will decompose into nitrohydroxyquinoline in the body, thereby exerting an anti-cancer effect. Liver microsomal enzymes and plasma metabolites are important ways for compounds to be metabolized in the body, so in vitro experiments were conducted to determine the stability of the compound of the present invention in liver microsomes and plasma.

1. Determination of liver microsome stability

Experimental instruments: constant temperature oscillator (SHA-B, Guohua Enterprise); centrifuge (5810R, Eppendorf), mass spectrometer (API4000, Applied Sciences), liquid chromatography (LC-30AD, Shimadzu); injector (CTCA not applicable to lytics AG System, CTC).

Experimental procedure: 25 μg/mL of 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, a portion was added with 1 mM reduced nicotinamide adenine dinucleotide phosphate (Aldrich Reagents) and 5 mM uridine diphosphate glucuronic acid (Aldrich Reagents) 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. After mixing, 50 μL of the solution was immediately taken out as the 0-minute sample, and 50 μL of the remaining sample was taken out after incubation at 37°C for 30 minutes. All samples were immediately precipitated for protein, and the supernatant was centrifuged and the compound concentration was determined by LC/MS/MS.

The microsomal stability results of the compounds of the present invention are shown in Table 2 below.

Conclusion:

By optimizing the structure of the prodrug molecule, different types of microsomal stable compounds can be obtained. The microsomal stability of compounds 6, 7, 52, 53, etc. indicates that such compounds may have a longer half-life in the body. Another type of microsomal unstable compounds indicates that the compounds can be quickly converted into nitroquinoline after entering the body, reducing the possibility of unnecessary biological toxicity. Both types of analysis have advantages and characteristics in drug development.

2. Plasma stability test

Experimental instruments: constant temperature oscillator (SHA-B, Guohua Enterprise); centrifuge (5810R, Eppendorf), mass spectrometer (API4000, Applied Sciences), liquid chromatograph (LC-30AD, Shimadzu); sample injector (CTC A is not applicable to CTC AG System, CTC).

Experimental animals: Plasma of humans (Batch No.: BRH1343165), rats (Batch No.: RAT336728), mice (Batch No.: MSE280000), dogs (Batch No.: BGL99137), and monkeys (Batch No.: PH-Monkey-20180821) were obtained from Shanghai Sixin Biotechnology Co., Ltd.

Experimental process: Dissolve the compound of the present invention into a 1mM working solution with an organic solvent, then take 3μL and add it to 597μL pre-incubated human or rat plasma and mix evenly. Then quickly take out 50μL as the 0-minute sample, and incubate the remaining samples at 37°C. Take 50μL each at 15, 30, 60 and 120 minutes. Immediately precipitate the protein after taking out all samples, centrifuge and take the supernatant to measure the compound concentration by LC/MS/MS.

The plasma stability results of the compounds of the present invention are shown in Table 3 below.

Conclusion:

By optimizing the structure of the prodrug molecule, different types of plasma stable compounds can be obtained. The plasma stability of compounds 6, 7, 52, 53, 54, 55, 56, 57, 58, 59, 62, 70, 75, etc. indicates that the compounds may have a longer half-life in the body. Another type of plasma unstable compounds indicates that the compounds can be quickly converted into nitrohydroxyquinoline after entering the body, reducing the possibility of unnecessary biological toxicity. Both types of analysis have advantages and characteristics for drug development.

Test Example 3: Pharmacokinetics of the compounds of the present invention in rats

Nitroquinoline is mainly metabolized in the liver in phase II, with a fast metabolic rate, so it has a short half-life in the body. The present invention has modified its structure and prepared 13 compounds of formula (I) by chemical synthesis. This experiment studied the concentration changes of the compound nitroquinoline in the plasma of rats after a single intravenous or oral administration of nitroquinoline and the compound of formula (I) to rats, so as to evaluate the pharmacokinetic behavior of nitroquinoline and the compound of formula (I) in rats.

1. Experimental instruments

Tandem quadrupole mass spectrometer (API4000, Applied Biosystems, USA), liquid chromatography (1200, Agilent), autosampler (CTCAlytics HTC PAL), Applied Biosystems Alyst v1.6.2, cryogenic centrifuge (1-15PK, Sigma), vortex oscillator (VX-Ⅲ, Beijing Tajin Technology Co., Ltd.).

2. Pharmacokinetics experiments

Male SD rats (Beijing Weitonglihua Experimental Animal Technology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2016-0006, experimental animal qualification certificate number: 11400700325643), 3 rats per group, body weight 180-250g, 6-7 weeks old, fasted the night before drug administration, free access to water, and food 4 hours after drug administration. The compound to be tested was placed in an EP tube, DMSO 1.017mL, solutol 2.035mL and sterile water for injection (the volume ratio of the three was 1:2:17, v:v:v), and ultrasonicated for 20 minutes to fully dissolve it (the preparation concentration of the compound was: 0.005mmol/mL). The intravenous dosage was 0.01mmol/kg, and the oral dosage was 0.1mmol/kg. 0.3 ml of whole blood was collected from the orbital venous cluster before drug administration (0 hour) and at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, 28, 32, and 48 hours after drug administration (the sampling point was adjusted according to the situation), and placed in a centrifuge tube containing EDTA-K2 (Aldrich Reagent Company) anticoagulant, and placed in crushed ice after collection. Within 0.5 hour, centrifuge at 5000 rpm for 5 minutes to separate all clean plasma, place it in another clean centrifuge tube, add stabilizer at a ratio of 100:3 (plasma/stabilizer, v/v), and place it in a -20℃ refrigerator for testing.

Preparation of stabilizing solution: Dissolve 200 mg of vitamin C (Aldrich Reagent Company) in 8 mL of physiological saline, then add 2 mL of formic acid and mix thoroughly.

3. Sample concentration measurement

Standard curve: Prepare a series of working solutions for the standard curve, take 5μL and add it to 50μL blank rat plasma, add 150μL internal standard working solution (acetonitrile solution containing 2ng/mL diphenhydramine (Aldrich Reagent Company)), vortex for 1 minute. Centrifuge at 4℃, 12000 rpm for 10 minutes, take 100μL of the supernatant into the injection tube, and inject 10μL into the LC-MS system for determination.

Samples to be tested: 50μL of plasma sample to be tested, add 5μL of dilution of working solution, then add 150μL of internal standard working solution (acetonitrile solution containing 2ng/mL diphenhydramine), vortex for 1 minute. Centrifuge at 4℃, 12000 rpm for 10 minutes, take 100μL of supernatant into the injection tube, and inject 10μL into the LC-MS system for measurement. WinNonlin V6.2 non-compartmental model was used to calculate pharmacokinetic parameters.

The test results are shown in Tables 4 to 45 below.

Conclusion:

By optimizing the structure of the prodrug molecule, the absorption and half-life of the prodrug molecule in rats are significantly improved compared to nitroquinoline. This improves the compliance of the drug molecule in terms of reducing the dosage or the number of times it is administered.

Test Example 4: Canine pharmacokinetic determination of the compounds of the present invention

Nitroquinoline is mainly metabolized in the liver in phase II, with a fast metabolic rate, so it has a short half-life in the body. The present invention has modified its structure and prepared 13 compounds of formula (I) by chemical synthesis. This experiment studied the concentration changes of the compound nitroquinoline in dog plasma after a single intravenous or oral administration of nitroquinoline and the compound of formula (I) to dogs, so as to evaluate the pharmacokinetic behavior of nitroquinoline and the compound of formula (I) in the body.

1. Experimental instruments

Tandem quadrupole mass spectrometer (API5500, Applied Biosystems, USA), liquid chromatography (1200, Agilent), autosampler (CTCAlytics HTC PAL), Applied Biosystems Alyst v1.6.2.

2. Pharmacokinetics experiments

Male beagle dogs (Beijing Mars Biotechnology Co., Ltd., Laboratory Animal Production License No.: SCXK (Beijing) 2016-0001, Laboratory Animal Quality Certificate No.: 11400600001728), 3 dogs per group, weight 10-13kg, 20-22 months old, fasted the night before drug administration, free access to water, and fed 4 hours after drug administration. The compound to be tested was placed in an EP tube, DMSO, solutol and sterile water for injection (the volume ratio of the three was 1:2:17, v:v:v), and ultrasonicated for 20 minutes to fully dissolve it (the compound was prepared at a concentration of 0.005mmol/mL). The intravenous dosage was 0.01mmol/kg, and the oral dosage was 0.1mmol/kg. 0.3 ml of whole blood was collected from the cervical vein before drug administration (0 hour) and at 0.0833, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, and 12 hours after drug administration (the sampling point was adjusted according to the situation), placed in a centrifuge tube containing EDTA-K2 (Aldrich Reagent Company) anticoagulant, and placed in crushed ice after collection. Within 0.5 hour, centrifuge at 1530g for 10 minutes to separate all clean plasma, place it in another clean centrifuge tube, and place it in a -20℃ refrigerator for testing.

3. Sample concentration measurement

Prepare a series of standard curve solutions. Take 10μL of the standard curve solution and the sample and add 1000μL of the internal standard working solution (containing 5ng/mL of verapamil (Aldrich Reagent Company), 50ng/mL of glibenclamide (Aldrich Reagent Company) and 50ng/mL of diclofenac (Aldrich Reagent Company) in acetonitrile), and vortex for 5 minutes. Centrifuge at 4℃ and 3700 rpm for 10 minutes, take 60μL of the supernatant into the injection tube and mix with 120μL of water, and inject 10μL into the LC-MS system for determination. WinNonlin V6.2 non-compartmental model was used to calculate the pharmacokinetic parameters.

The test results are shown in Tables 46 to 52 below.

Table 46 Plasma concentration of nitroquinoline after intravenous administration of nitroquinoline in beagle dogs

Conclusion:

From the data, we can see that compared with nitrohydroxyquinoline, prodrug compounds 5, 20, and 51 have good absorption in beagle dogs, indicating that the dosage of drug molecules can be effectively reduced through prodrug molecules.

Claims (18)

A compound represented by formula (I) or its meso form, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

in

represents a single bond; R ₁ is selected from the group consisting of hydrogen and C _1-6 alkyl; X is selected from the group consisting of O and S; wherein: R ₂ is absent; and R ₀ is selected from

and

The group composed of; Among them, when R ₀ is selected from

when E is selected from the group consisting of O and NR ₁₄ ; R ₁₀ , R ₁₃ , R ₁₄ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, and C _6-10 aryl, wherein the C _1-6 alkyl is optionally further substituted with one or more groups selected from the group consisting of halogen, C _6-10 aryl, C _6-10 arylalkyl, 5-10 membered heteroaryl, 5-10 membered heteroarylalkyl, -OR ₁₂ , -C(O)R ₁₁ , -C(O)OR ₁₂ , -OC(O)R ₁₁ and -OC(O)OR ₁₂ ; when R ₀ is selected from the group consisting of

When Y is selected from the group consisting of O and S, R ₃ is selected from the group consisting of

, and a C _6-10 aryl group, wherein the C _6-10 aryl group is optionally further substituted by -OC(O)R ₁₁ ; and Z is selected from the group consisting of C and N; wherein, when Z is selected from C, R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, C _1-12 alkyl, 5 to 7 membered heterocyclic group, C _6-10 aryl group, 5 to 10 membered heteroaryl group, -OR ₁₂ , -SR ₁₂ , -C(O)R ₁₁ , -C(O)OR ₁₂ , -C(O)-(CH ₂ ) _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) _pRd , ^-S (O) _pN ( ^Ra )(Rb), -O( ^CH2 )mO(CH2) _qR12 , -N( _Rc ) _C (O)-( _CH2 ) _m -N( ^Rc )C(O) ^Rd , wherein the _C1-12 alkyl, _C6-10 aryl and 5-10 membered heteroaryl are optionally further selected from halogen, C1-6 alkyl, OR12, _{SR12 , -C} (O)R11, -C(O) _OR12 , -OC( ^O ) _R11 , -N(Rc)C(O)Rd, -O(CH2)mO(CH2)qR12, and C1-12 alkyl, C6-10 aryl and 5-10 membered heteroaryl are optionally further selected from halogen, _C1-6 alkyl, _OR12 , _SR12 , -C(O)R11, -C( ^O ) _OR12 , -OC(O)R11, -N(Rc)C(O) ^Rd , -O( _CH2 ) _{mO ( CH2} ) _qR12 , and C or one of R ₄ , R ₅ and R ₆ is hydrogen, and the other two together with Z form a C _3-6 cycloalkyl or a 5-7 membered heterocyclic group, wherein the C _3-6 cycloalkyl or the 5-7 membered _heterocyclic group is optionally further substituted by one or more groups selected from the group consisting of -C(O)R ₁₁ and -C(O)OR ₁₂ ; when Z is selected from N, R ₆ is absent, and R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _6-10 aryl, and a 5-10 membered heteroaryl, wherein the C _1-12 alkyl, C _6-10 aryl, and the 5-10 membered heteroaryl are optionally further selected from halogen, C _1- C R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C _{6 alkoxy} , C ₆ -C ₆ aryl, or R ₄ , R _{5 and} Z together form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally further substituted by one or more groups selected from the group consisting of C _1- C ₆ alkyl and a 5-7 membered heterocyclic group; R ₁₁ and R ₁₂ are each independently selected from hydrogen, halogen, hydroxyl, C _1- C ₆ alkyl, C _1- C ₆ alkoxy, C _6- C The C1 _- C6 alkyl, C1- _C6 alkoxy, C6 _{- C10} aryl and 5-10 membered heteroaryl are optionally further substituted by _one or more groups selected from the group consisting of halogen, nitro, hydroxyl, hydroxyl, C1 _{- C6} alkyl, C1 _{- C6} alkoxy, -ORd, -N( _Rc )C( ^O ₎ ^Rd , -C( ^O )N( ^Ra )(Rb), -N( ^Rc )S( ^O ) _pRd , -S(O) _pN ( ^{Ra )} ( ^Rb ), C6 _{- C10} aryl, hydroxyaryl and 5-10 membered heteroaryl; R ^a and R ^b are each independently selected from the group consisting of hydrogen and C1 _- C R ^a and R ^b together with the atoms to which they are attached form a _5- to _7- membered heterocyclic group, and the _5- to 7-membered heterocyclic group is optionally further substituted by one or more groups selected from the group consisting of halogen, oxo, and C _1- C ₆ alkyl; R ^c and R ^d are each independently selected from the group consisting of hydrogen, C 1- C _{6 alkyl, C 1- C 6 alkoxy} , C _6- C ₁₀ aryl, and _5- to 10-membered heteroaryl, wherein the C _1- C ₆ alkyl, C _1- C ₆ alkoxy, C _6- C ₁₀ aryl, and _5- to 10-membered heteroaryl are optionally further selected from the group consisting of halogen, and C _1- C 6 alkyl. ₆ alkyl; m is selected from an integer from 0 to 6; p is selected from a group consisting of 0, 1 and 2; q is selected from an integer from 0 to 6; provided that the compound is not

The compound according to claim 1 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula (II):

wherein _R1 is selected from the group consisting of hydrogen and _C1-6 alkyl; _R4 , _R5 and _R6 are each independently selected from the group consisting of hydrogen, C1 _{- C12} alkyl, 5-7 membered heterocyclic group, _C6 - _C10 aryl group, 5-10 membered heteroaryl group, _-OR12 , _-SR12 , -N( ^Rc )C(O) ^Rd and -O( _CH2 ) _mO ( _CH2 ) _qR12 , wherein the C1 _{- C12} alkyl, _C6 - _C10 aryl group and _5-10 membered heteroaryl group are optionally further selected from _OR12 , _SR12 , -C(O) _R11 , -C(O) _OR12 , -OC(O) _R11 , -N( ^Rc )C(O) ^Rd , and C ₆ -C ₁₀ aryl groups; or one of R ₄ , R ₅ and R ₆ is hydrogen, and the other two together with the carbon atoms to which they are attached form a C ₃ -C ₆ cycloalkyl group or a 5-7 membered heterocyclic group, wherein the C ₃ -C ₆ cycloalkyl group or the 5-7 membered heterocyclic group is optionally further substituted by one or more groups selected from the group consisting of -C(O)R ₁₁ and -C(O)OR ₁₂ ; R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, and a 5-10 membered heteroaryl group, wherein the C ₁ -C ₆ alkyl, C ₁ -C _R a and R b are each independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl is optionally further substituted with one or more groups selected from the group consisting of halogen, nitro, hydroxyl, C ₁ -C ₆ alkyl, C 1 -C 6 ^alkoxy , -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 ), C ₆ -C ₁₀ aryl, and 5 to 10 membered heteroaryl; R ^a and R ^b are each independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl is optionally further substituted with one or more groups selected from the group consisting of halogen; or R ^{R a} and R ^b together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group, wherein the 5- to 7-membered heterocyclic group is optionally further substituted by one or more groups selected from the group consisting of halogen, oxo, and C ₁ -C ₆ alkyl; R ^c and R ^d are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, and 5- to 10-membered heteroaryl are optionally further substituted by one or more groups selected from the group consisting of halogen, and C ₁ -C ₆ alkyl; m is selected from an integer selected from 0 to 6; p is selected from the group consisting of 0, 1 and 2; q is selected from an integer selected from 0 to 6. The compound according to claim 2 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ₄ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ₁₂ , -SR ₁₂ , and N(R c )C(O)R ^d , wherein the C ₁ -C ₁₂ alkyl is optionally further substituted with one or more groups selected from the group consisting of OR _{12 , SR 12 , -C(O)OR 12 , -N(R c )C(O)R d , and C 6 -C 10 aryl; R 11 and R 12 are each independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, -OR 12 ,} ^{-SR 12} _{, and N ( R c )C(O} )R ^d ; R _{a and R b are each independently selected from the group consisting of hydrogen, and C 1 -C 6 alkyl , wherein} the C ₁ -C ₆ alkyl is optionally further substituted with one or more groups selected from the group consisting of halogen, C ₁ -C 6 alkyl, -OR ^d , -N(R ^c )C(O)R ^d , C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl; R ^a and R ^b are each independently selected from the group consisting of hydrogen, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl is optionally further substituted with one or more groups selected from the group consisting of halogen; or R ^a and R ^b together with the atoms to which they are attached form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally further selected from halogen, oxo, and C ₁ -C R ^c and R ^d are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, C _{6 -C 10} aryl, and ₅ to 10 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl and 5 to 10 membered heteroaryl are optionally further substituted by one or more groups selected from the group consisting of halogen and C ₁ -C ₆ alkyl; m is selected from an integer from 0 to 6; q is selected from an integer from 0 to 6. The compound according to claim 2 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein one of R ₄ , R ₅ and R ₆ is hydrogen, and the other two together with the carbon atoms to which they are attached form a C ₃ -C ₆ cycloalkyl group or a 5-7 membered heterocyclic group, wherein the C ₃ -C ₆ cycloalkyl group or the 5-7 membered heterocyclic group is optionally further substituted by one or more groups selected from the group consisting of -C(O)R ₁₁ and -C(O)OR ₁₂ ; R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl group, and a 5-10 membered heteroaryl group, wherein the C ₁ -C ₆ alkyl group is optionally further substituted by one or more groups selected from the group consisting of -OR 12 ^. , -N(R ^c )C(O)R ^d , C ₆ -C ₁₀ aryl, hydroxyaryl, 5- to 10-membered heteroaryl; R ^c and R ^d are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy. The compound according to claim 1 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula (III):

wherein _R1 is selected from the group consisting of hydrogen and _C1-6 alkyl; _R4 and _R5 are each independently selected from the group consisting of hydrogen and _C1 - _C12 alkyl, wherein the _C1 - _C12 alkyl is optionally further substituted by one or more groups selected from the group consisting of _OR12 , _SR12 , -C(O) _R11 , -C(O) _OR12 , -O(O) _CR11 , and _C6 - _C10 aryl; or _R4 , _R5 and the N atom together form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally further substituted by one or more groups selected from the group consisting of _{C1-C6 alkyl} and 5-7 membered heteroaryl; _R11 and _R12 are each independently selected from the group consisting of hydrogen, C1- _{C12 alkyl} ... The present invention relates to a group consisting of a C 1 -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group is optionally further substituted by one or more groups selected from the group consisting of -N(R ^c )C(O)R ^d ; R ^c and R ^d are each independently selected from the group consisting of hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₆ -C ₁₀ aryl group, and a 5-10 membered heteroaryl group, wherein the C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkoxy group, the C ₆ -C ₁₀ aryl group, and the 5-10 membered heteroaryl group are optionally further substituted by one or more groups selected from the group consisting of halogen and C ₁ -C ₆ alkyl group. The compound according to claim 5 or its meso form, racemate, enantiomer, diastereoisomer, or mixture form, or a pharmaceutically acceptable salt thereof, wherein _R4 and _R5 are each independently selected from the group consisting of hydrogen and _C1 - _C12 alkyl, wherein the _C1 - _C12 alkyl is optionally further substituted with one or more groups selected from the group consisting of hydroxyl, hydroxyl, -C(O) _R11 , -C(O) _OR12 , -O(O) _CR11 , and C6- _C10 aryl; _R11 and R12 are each independently selected from the group consisting of hydrogen and C1- _C6 alkyl, wherein the _C1 - _C6 alkyl is optionally further substituted with one or more groups selected from the group consisting of -N(Rc)C(O)R11, -C( _{O )} OR12, -O( ^O )CR11, and C6 _-C10 aryl. R ^c and R ^d are each independently substituted by one or more groups selected from the group consisting of hydrogen and C ₁ ^-C ₆ alkyl. The compound according to claim 5 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula (IV):

wherein _R1 is selected from the group consisting of hydrogen and _C1-6 alkyl; A is selected from the group consisting of C, O and N; _R7 and _R8 are each independently selected from the group consisting of hydrogen and _C1 - _C6 alkyl; _{and R9} is selected from the group consisting of hydrogen, _C1 - _C6 alkyl and 5-7 membered heterocyclic group. The compound according to claim 1 or its meso form, racemate, enantiomer, diastereoisomer, or mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula (V):

wherein R ₁ is selected from hydrogen or C _1-6 alkyl; E is selected from the group consisting of O and NR ₁₄ ; R ₁₀ , R ₁₃ , and R ₁₄ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, or C ₆ -C ₁₀ aryl, wherein the C _1-6 alkyl is optionally further substituted with one or more substituents selected from the group consisting of C ₆ -C ₁₀ aryl, -OR ₁₂ , -C(O)OR ₁₂ , and -OC(O)OR ₁₂ ; R ₁₁ and R ₁₂ are each independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₆ -C _{The 10-} membered aryl group and the 5-10-membered heteroaryl group are optionally further substituted by one or more groups selected from the group consisting of halogen, nitro, hydroxyl, alkyl, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy. A compound or its meso form, racemate, enantiomer, diastereoisomer, or mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

,and

The group formed. A method for preparing a compound represented by formula (II) or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

It includes the following steps:

Compound IIc is reacted with nitrohydroxyquinoline in a solvent in the presence of a base to undergo a nucleophilic reaction to obtain a compound represented by the general formula (II); R ₁ , R ₄ , R ₅ and R ₆ are as defined in claim 2. A method for preparing a compound represented by the following formula or its meso form, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

It includes the following steps:

Compound IIIc is reacted with nitrohydroxyquinoline in a solvent in the presence of a base to undergo a nucleophilic reaction to obtain the compound product represented by the above formula; R ₄ and R ₅ are as defined in claim 5. A method for preparing a compound represented by formula (II') or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

It includes the following steps:

Compound II'b is reacted with compound II'c in the presence of a base in a solvent to undergo a nucleophilic reaction to obtain a compound of formula (II'); R ₄ , R ₅ and R ₆ are as defined in claim 2. A method for preparing a compound represented by formula (V') or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

It includes the following steps:

Compound V'd and compound II'b undergo a nucleophilic reaction in the presence of a base in a solvent to obtain a compound represented by formula (V'); R ₁₀ and R ₁₃ are as defined in claim 8. A method for preparing a compound represented by formula (V") or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

It includes the following steps:

Compound V"a reacts with nitrohydroxyquinoline in the presence of a base in a solvent to undergo a nucleophilic reaction to obtain a compound represented by formula (V"); R ₁₀ and R ₁₃ are as defined in claim 8. The method according to any one of claims 10 to 14, wherein the base 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, tert-butyl alcohol methyl ether. A pharmaceutical composition comprising a compound represented by formula (I) according to any one of claims 1 to 9 or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. Use of a compound represented by formula (I) according to any one of claims 1 to 9 or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16 in the preparation of an anti-infective or anti-tumor drug. The use according to claim 17, wherein the tumor is selected from the group consisting of bladder cancer, prostate cancer and kidney cancer.