Nitroxoline derivatives, process for their preparation and use thereof

Abstract

The present application discloses nitroxoline derivatives, and a preparation method and use thereof. Specifically, the present application discloses a compound shown in general formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and use thereof in treating infectious diseases or cancer. The compound of the present application has excellent anti-tumor activity and bacteriostatic activity, and can be developed into a drug for treating tumors and infectious diseases. Definitions of each group in general formula (I) are the same as those in the specification.

Description

TECHNICAL FIELD

[0001] The present application relates to nitroxoline derivatives, and the preparation method and use thereof. BACKGROUND

[0002] Nitroxoline, also known as 5-nitro-8-hydroxyquinoline, was developed as an oral antibiotic in the 1960s, mainly for urinary system infections, and has a relatively safe use history. It was later replaced by new antibiotics. However, with the increasingly prominent problem of bacterial drug resistance in the field of antibiotics, the scope of application of existing antibacterial drugs in the clinic is facing different degrees of challenges. The development of antibacterial drugs against multi-drug resistant bacteria is in urgent need in the clinic, and no obvious bacterial drug resistance has been found for nitroxoline.

[0003] In addition, in recent years, new research has found that nitroxoline can simultaneously inhibit methionine aminopeptidase MetAP2 in vascular endothelial cells and SIRT1, a silent information regulator 2-related enzyme, and has a synergistic inhibitory effect on tumor angiogenesis, and also has an inhibitory effect on the proliferation of tumor cells. Therefore, nitroxoline has been redeveloped for the treatment of tumors including bladder cancer. It would be even more desirable for researchers to develop a compound with better anticancer activity than nitroxoline. SUMMARY

[0004] The present inventors have designed and synthesized a series of nitroxoline derivatives through intensive research, which show excellent antitumor activity and antibacterial activity, and can be developed as drugs for treating tumors and infectious diseases.

[0005] Therefore, the present application provides a compound represented by general formula (I) or meso body, or a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or a solvate of any of the foregoing, or a prodrug or a metabolite of any of the foregoing, or a racemate containing the same, or a mixture containing the same, wherein "the same" refers to the compound,

[0006]

[0007] wherein:

[0008] R 1 is selected from hydrogen, halogen, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b , -OR a , -SR a , -C(O)R a, -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -N(R b )C(O)R a , -S(O) p R a , -S(O) p NR a R b and -N(R b )S(O) p R a , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from Q;

[0009] R 2 is selected from hydrogen, halogen, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b , -OR a , -SR a , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -N(R b )C(O)R a , -S(O) p R a , -S(O) p NR a R b and -N(R b )S(O) p R a , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0010] R 3 is selected from hydrogen, halogen, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b , -OR a , -SR a , -C(O)R a , -O(O)CR a, -C(O)OR a , -C(O)NR a R b , -N(R b )C(O)R a , -S(O) p R a , -S(O) p NR a R b , and -N(R b )S(O) p R a , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0011] R 4 is selected from hydrogen, halo, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b , -OR a , -SR a , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -N(R b )C(O)R a , -S(O) p R a , -S(O) p NR a R b , and -N(R b )S(O) p R a , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0012] R 5 is selected from hydrogen, halo, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b , -OR a , -SR a-C(O)R a -O(O)CR a -C(O)OR a -C(O)NR a R b -N(R) b )C(O)R a -S(O) p R a -S(O) p NR a R b and -N(R) b S(O) p R a The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0013] R a and R b Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted by one or more groups selected from Q;

[0014] Or, R a and R b Together with the nitrogen atom attached thereto, a nitrogen-containing heterocyclic group is formed, wherein the nitrogen-containing heterocyclic group optionally contains one or more heteroatoms selected from N, O and S in addition to N, and the nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from Q;

[0015] Q represents halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR c R d -OR c -SR c -C(O)R c -O(O)CR c -C(O)OR c -C(O)NR c R d -C(O)N(R) c (CH2) q R d -NR c C(O)R d-S(O) p R c -S(O) p NR c R d or -NR c S(O) p R d wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0016] R c and R d are each independently selected from hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0017] or, R c and R d together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl, which optionally contains one or more heteroatoms selected from N, O and S in addition to N, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0018] p is 1 or 2;

[0019] q is an integer from 0 to 6;

[0020] with the proviso that R 1 , R 2 , R 3 , R 4 and R 5 are not simultaneously hydrogen.

[0021] In some preferred embodiments, R 1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b , -OR a , -SR a , -C(O)R a , -C(O)ORa -C(O)NR a R b -N(R b )C(O)R a -S(O) p R a -S(O) p NR a R b -N(R b )S(O) p R a wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from Q;

[0022] R a and R b are each independently selected from hydrogen, alkyl and cycloalkyl;

[0023] or, R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group, said nitrogen-containing heterocyclyl group optionally containing one or more heteroatoms in addition to N selected from N, O and S, said nitrogen-containing heterocyclyl group being optionally further substituted with one or more groups selected from Q;

[0024] Q is halogen, oxo, alkyl, -NR c R d , -OR c , -SR c , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(O)N(R c )(CH2) q R d , -S(O) p R c or -S(O) p NR c R d , said alkyl being optionally further substituted with one or more groups selected from halogen;

[0025] R c and R d are each independently selected from hydrogen, alkyl, aryl and heteroaryl, wherein said alkyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0026] or R c and R d together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group, which optionally contains one or more heteroatoms in addition to N, selected from N, O and S, which nitrogen-containing heterocyclyl group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0027] p is 1 or 2;

[0028] q is an integer from 0 to 6.

[0029] In other preferred embodiments, R 1 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl; wherein said C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl are optionally further substituted by one or more groups selected from halogen.

[0030] In other preferred embodiments, R 1 is selected from -NR a R b ;

[0031] R a and R b are each independently selected from hydrogen and C1-C6 alkyl;

[0032] or R a and R b together with the nitrogen atom to which they are attached form a 5- to 7- membered nitrogen-containing heterocyclyl group, which optionally contains one or more heteroatoms in addition to N, selected from N, O and S, preferably said nitrogen-containing heterocyclyl group is selected from said 5- to 7- membered nitrogen-containing heterocyclyl group is optionally further substituted by one or more groups selected from Q;

[0033] Q is halogen, oxo, C1-C6 alkyl, -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(O)N(R c )(CH2) q R d or -S(O) p R c ;

[0034] R c and R deach independently selected from the group consisting of hydrogen or Ci-C6alkyl, wherein said Ci-C6alkyl is optionally further substituted with one or more radicals selected from halogen;

[0035] R c and R d together with the nitrogen atom to which they are attached form a 5- to 7- membered nitrogen containing heterocyclyl, said 5- to 7- membered nitrogen containing heterocyclyl optionally containing one or more heteroatoms selected from N, O and S in addition to N, said 5- to 7- membered nitrogen containing heterocyclyl being optionally further substituted with one or more radicals selected from halogen and Ci-C6alkyl;

[0036] p is 1 or 2;

[0037] q is an integer from 0 to 6.

[0038] R 1 is selected from the group consisting of C3-C6cycloalkyl, preferably C3-C6cycloalkyl, more preferably cyclopropyl, cyclopentyl and cyclohexyl, said cycloalkyl being optionally further substituted with one or more radicals selected from halogen and Ci-C6alkyl. 10 C3-C6cycloalkyl, preferably C3-C6cycloalkyl, more preferably cyclopropyl, cyclopentyl and cyclohexyl, said cycloalkyl being optionally further substituted with one or more radicals selected from halogen and Ci-C6alkyl.

[0039] R 1 is selected from the group consisting of C6-Ci0aryl, preferably phenyl, or 5- to 10- membered heteroaryl, preferably pyridinyl, said C6-Ci0aryl or 5- to 10- membered heteroaryl being optionally further substituted with one or more radicals selected from halogen and Ci-C6alkyl. 10 C6-Ci0aryl, preferably phenyl, or 5- to 10- membered heteroaryl, preferably pyridinyl, said C6-Ci0aryl or 5- to 10- membered heteroaryl being optionally further substituted with one or more radicals selected from halogen and Ci-C6alkyl. 10 C6-Ci0aryl, preferably phenyl, or 5- to 10- membered heteroaryl, preferably pyridinyl, said C6-Ci0aryl or 5- to 10- membered heteroaryl being optionally further substituted with one or more radicals selected from halogen and Ci-C6alkyl.

[0040] R 1 is selected from the group consisting of C2-C6alkenyl, said C2-C6alkenyl being optionally further substituted with one or more radicals selected from -C(O)OR c , -C(O)NR c R d , -C(O)N(R c )(CH2) q R d , -S(O) p R c and -S(O) p NR c R d ; preferably with one or more radicals selected from -C(O)OR c and -C(O)NR c R d ;

[0041] R c and R dEach is independently selected from hydrogen, C1-C6 alkyl, C6-C 10 The aryl group is preferably phenyl, wherein the C1-C6 alkyl group and the C6-C6 alkyl group are... 10 The aryl group may be further substituted with one or more groups selected from halogens, C1-C6 alkyl groups and C1-C6 alkoxy groups;

[0042] Or, R c and R d Together with the nitrogen atom attached thereto, a 5- to 7-membered nitrogen-containing heterocyclic group is formed, wherein the 5- to 7-membered nitrogen-containing heterocyclic group optionally contains one or more heteroatoms selected from N, O and S in addition to N, preferably morpholino, and the 5- to 7-membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from halogens and C1-C6 alkyl groups;

[0043] p is 1 or 2;

[0044] q is an integer from 0 to 6, preferably an integer from 1 to 4.

[0045] In other preferred embodiments, R 1 Selected from -C(O)R a -C(O)OR a -C(O)NR a R b -S(O) p R a and -S(O) p NR a R b ;

[0046] R a and R b Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0047] Or, R a and R b Together with the nitrogen atom attached thereto, a 5- to 7-membered nitrogen-containing heterocyclic group is formed, wherein the 5- to 7-membered nitrogen-containing heterocyclic group optionally contains one or more heteroatoms selected from N, O and S in addition to N, and the 5- to 7-membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from halogens and C1-C6 alkyl groups;

[0048] p is 1 or 2.

[0049] In other preferred embodiments, R 2 Selected from hydrogen, halogens, C1-C6 cycloalkyl groups, and C1-C6 alkyl groups; R 3 It is selected from hydrogen, halogens and C1-C6 alkyl groups.

[0050] In other preferred embodiments, R 4selected from the group consisting of hydrogen, halogen, C1-C6alkyl, -C(O)OR a and -C(O)NR a R b wherein R a and R b are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C6alkyl; 5 is selected from the group consisting of hydrogen, halogen and C1-C6alkyl.

[0051] The present application also provides a compound represented by general formula (I) or a meso body, or a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or a solvate of any of the foregoing, or a prodrug or a metabolite of any of the foregoing, or a racemate containing the same, or a mixture containing the same, wherein "the same" refers to the compound,

[0052]

[0053] wherein:

[0054] R 2 is selected from the group consisting of hydrogen, halogen, alkyl and cycloalkyl;

[0055] R 3 is selected from the group consisting of hydrogen, halogen and alkyl;

[0056] R 4 is selected from the group consisting of hydrogen, halogen, alkyl, -C(O)OR a and -C(O)NR a R b wherein R a and R b are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl-C1-C6alkyl;

[0057] R 5 is selected from the group consisting of hydrogen, halogen and alkyl;

[0058] R a and R b are each independently selected from the group consisting of hydrogen, alkyl and cycloalkyl;

[0059] Q is halogen, alkyl, oxo, -C(O)R c , -C(O)OR c , -C(O)NR c R d or -C(O)N(R c )(CH2) q R d ;

[0060] R c and R d are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl, wherein said alkyl, aryl and heteroaryl are optionally further substituted with alkoxy;

[0061] or, R c and R d together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group, said nitrogen-containing heterocyclyl group optionally containing one or more heteroatoms selected from the group consisting of N and O in addition to N;

[0062] p is 1 or 2;

[0063] q is an integer from 0 to 6;

[0064] with the proviso that R 1 , R 2 , R 3 , R 4 and R 5 are not simultaneously hydrogen.

[0065] In some embodiments of the present application, R 1 is as previously defined, and said halogen is preferably chlorine or fluorine.

[0066] In other embodiments of the present application, R 1 is as previously defined, and said alkyl is preferably a C1-C6 alkyl, more preferably a C1-C6 alkyl substituted with a halogen, further more preferably -CF3, -CHF2 or -CH2F, still further more preferably -CF3.

[0067] In other embodiments of the present application, R 1 is as previously defined, preferably said alkenyl is a C2-C6 alkenyl; more preferably said C2-C6 alkenyl is an alkenyl substituted with one or more groups selected from Q, Q being -C(O)R c , -C(O)OR c , -C(O)NR c R d and -C(O)N(R c )(CH2) q R d , R c and R d are as previously defined; still more preferably said C2-C6 alkenyl is -CH=CH-COOH,

[0068] In other embodiments of the present application, R 1 is as previously defined, and said cycloalkyl is preferably a C3-C10 Cycloalkyl, more preferably C3-C6 cycloalkyl, further more preferably unsubstituted C3-C6 cycloalkyl, for example unsubstituted cyclopropyl, unsubstituted cyclopentyl or unsubstituted cyclohexyl.

[0069] In some embodiments of the application, R 1 is as defined above, preferably said heterocyclyl is C4-C7 heterocyclyl. More preferably, said C4-C7 heterocyclyl is C4-C7 nitrogen containing heterocyclyl. Further more preferably, said C4-C7 heterocyclyl is -NR e R f , R e and R f together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl, said nitrogen containing heterocyclyl optionally containing one or more heteroatoms in addition to N selected from the group consisting of N and O, said nitrogen containing heterocyclyl being optionally further substituted by one or more groups selected from Q, Q being C1-C6 alkyl, oxo and C1-C6 ester; wherein said C1-C6 alkyl is preferably methyl and said C1-C6 ester is preferably -C(O)OCH2CH3. Still further more preferably, said C4-C7 heterocyclyl is

[0070] In some embodiments of the application, R 1 is as defined above, and said aryl is preferably C6-C 10 aryl, more preferably unsubstituted phenyl.

[0071] In some embodiments of the application, R 1 is as defined above, and said heteroaryl is preferably 5-10 membered heteroaryl, more preferably pyridyl, pyrazolyl, imidazolyl, substituted or unsubstituted by C1-C6 alkyl, more preferably

[0072] In some embodiments of the application, R 1 is as defined above, and said -C(O)OR c , R g is C1-C6 alkyl; more preferably -C(O)OR c is -C(O)OCH2CH3.

[0073] In some embodiments of the application, R 1 is as defined above, and said -NR a R b is preferably -NH2 or -N(CH3)2.

[0074] In some embodiments of the application, R 1R is as defined above, and said -OR a is preferably -OCH3.

[0075] In some preferred embodiments of the application, R 1 R is as defined above, and said -OR p R a is preferably -S(O)2CH3.

[0076] In some preferred embodiments of the application, R 1 is selected from the group consisting of halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl and -OR a , each group being as defined above; preferably, R 1 is selected from the group consisting of chloro, and -OCH3; more preferably, R 2 , R 3 , R 4 , R 5 are all hydrogen. The compounds of the above technical solution have an IC50lower than that of nitroxoline at least for one selected from the group consisting of an endothelial cell line, a bladder cancer cell line, a prostate cancer cell line and a mouse prostate cancer cell line.

[0077] In some preferred embodiments of the application, R 1 is selected from the group consisting of halogen, cycloalkyl, heterocyclyl and aryl, each group being as defined above; preferably, R 1 is selected from the group consisting of chloro, More preferably, R 2 , R 3 , R 4 , R 5 are all hydrogen. The compounds of the above technical solution have an IC50lower than that of nitroxoline for an endothelial cell line, a bladder cancer cell line, a prostate cancer cell line and a mouse prostate cancer cell line.

[0078] In some preferred embodiments of the application, R 2 R is as defined above, and said halogen is preferably fluorine or chlorine.

[0079] In some preferred embodiments of the application, R 2 R is as defined above, and said alkyl is preferably a C1-C6alkyl, more preferably a methyl group.

[0080] In some preferred embodiments of the application, R 2 R is as defined above, and said cycloalkyl is a C1-C6cycloalkyl, preferably a cyclopropyl group.

[0081] In some preferred embodiments of the application, R 3 R is as defined above, and said halogen is preferably fluorine or chlorine.

[0082] In other embodiments of the invention, R 3 The definition is as described above, and the alkyl group is preferably a C1-C6 alkyl group, more preferably a methyl group.

[0083] In other preferred embodiments of the invention, R 2 and R 3 Both are hydrogen.

[0084] In other embodiments of the invention, R 4 The definition is as described above, and the halogen is preferably fluorine or chlorine.

[0085] In other embodiments of the invention, R 4 The definition is as described above, and the alkyl group is preferably a C1-C6 alkyl group, more preferably a methyl group.

[0086] In other embodiments of the invention, R 4 The definition is as described above, and the -C(O)OR a Chinese R a It is an alkyl or cycloalkyl group, wherein the alkyl group is C1-C6 alkyl, preferably ethyl; and the cycloalkyl group is C1-C6 cycloalkyl, preferably methylcyclopropyl or cyclohexyl.

[0087] In other embodiments of the invention, R 4 The definition is as described above, and the -C(O)NR a R b Chinese R a R b Each of the components is an alkyl group, wherein the alkyl group is a C1-C6 alkyl group, preferably ethyl, methyl, or isopropyl.

[0088] In other embodiments of the invention, R 5 The definition is as described above, and the halogen is preferably fluorine or chlorine.

[0089] In other embodiments of the invention, R 5 The definition is as described above, and the alkyl group is preferably a C1-C6 alkyl group, more preferably a methyl group.

[0090] In other preferred embodiments of the invention, R 4 and R 5 Both are hydrogen.

[0091] Typical compounds of this invention include, but are not limited to, the following compounds:

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100] or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0101] The present application further provides a method for preparing a compound according to general formula (I) or a mesomer thereof, or a tautomer, stereoisomer, enantiomer, diastereomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing, or a prodrug or metabolite of any of the foregoing, or a racemate containing the same, or a mixture containing the same, comprising the following steps:

[0102] when R 1 is -NR a R b ,

[0103]

[0104] under heating conditions, in a solvent, a compound of formula (IA) is reacted with an amine compound NHR a R b to obtain a compound of general formula (I); wherein the solvent is preferably DMF, and the heating conditions are preferably 100°C to the reflux temperature of the solvent,

[0105] wherein,

[0106] X is selected from halogen, preferably chlorine and bromine;

[0107] R a and R b are each independently selected from hydrogen and C1-C6 alkyl;

[0108] alternatively, R a and R b together with the nitrogen atom to which they are attached form a 5- to 7- membered nitrogen-containing heterocyclyl group, which optionally contains one or more heteroatoms selected from N, O and S in addition to N, preferably the heterocyclyl group is selected from said 5- to 7-membered nitrogen-containing heterocyclyl is optionally further substituted by one or more radicals selected from Q;

[0109] Q is halogen, oxo, C1-C6alkyl, -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(O)N(R c )(CH2) q R d and -S(O) p R c ;

[0110] R c and R d are each independently selected from hydrogen or C1-C6alkyl, wherein said C1-C6alkyl is optionally further substituted by one or more radicals selected from halogen;

[0111] or, R c and R d together with the nitrogen atom to which they are attached form a 5- to 7-membered nitrogen-containing heterocyclyl, said 5- to 7-membered nitrogen-containing heterocyclyl optionally containing one or more heteroatoms selected from N, O and S in addition to N, said 5- to 7-membered nitrogen-containing heterocyclyl being optionally further substituted by one or more radicals selected from halogen and C1-C6alkyl;

[0112] p is 1 or 2;

[0113] q is an integer from 0 to 6;

[0114] R 2 , R 3 , R 4 and R 5 are as previously described.

[0115] The present application further provides a method for preparing a compound according to the present application, or a racemate, or a tautomer thereof, or a stereoisomer thereof, or an enantiomer thereof, or a diastereomer thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or a solvate of any of the foregoing, or a prodrug or a metabolite of any of the foregoing, or a racemate containing thereof, or a mixture containing thereof, comprising the step of:

[0116] when R 1 is C3-C 10 cycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl,

[0117]

[0118] In the presence of a catalyst and a base, compound Ib is reacted with boronic acid compound R 1 -B(OH)2to give compound of formula (IB); wherein the catalyst is preferably tetrakis triphenylphosphine palladium and the base is preferably potassium carbonate; then,

[0119] Compound of formula (IB) is subjected to demethylation reaction in the presence of a demethylating agent in a solvent under heating; wherein the solvent is preferably DMF, the demethylating agent is preferably LiCl and the heating is preferably at the reflux temperature of the solvent to give compound of general formula (I);

[0120] wherein X is selected from halogen, preferably chlorine and bromine;

[0121] R 2 , R 3 , R 4 and R 5 are as defined earlier.

[0122] The present application further provides a process for the preparation of a compound of general formula (I) or meso, or a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or a solvate of any of the foregoing, or a prodrug or a metabolite of any of the foregoing, or a racemate comprising the same, or a mixture comprising the same, according to the present application, comprising the step of:

[0123] when R 1 is -C(O)OR a or -S(O) p R a ,

[0124]

[0125] Compound of formula (IA) is reacted with compound MO-R 1 in a solvent under heating to give compound of general formula (I); wherein M is an alkali metal, such as Na, K or Mg; the solvent is preferably DMF; and the heating is preferably at 100 °C to the reflux temperature of the solvent;

[0126] wherein,

[0127] X is selected from halogen, preferably chlorine and bromine;

[0128] R a is selected from hydrogen and C1-C6 alkyl;

[0129] p is 1 or 2;

[0130] R 2 , R 3 , R 4 and R5 The definitions are as previously described.

[0131] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the present application represented by the general formula (I) or meso, or a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or a solvate of any of the foregoing, or a prodrug or a metabolite of any of the foregoing, or a racemate comprising the same, or a mixture comprising the same, and a pharmaceutically acceptable carrier; wherein "the same" refers to the compound.

[0132] The present application also provides a use of a compound according to the present application represented by the general formula (I) or meso, or a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or a solvate of any of the foregoing, or a prodrug or a metabolite of any of the foregoing, or a racemate comprising the same, or a mixture comprising the same, or a pharmaceutical composition of the foregoing, in the manufacture of a medicament for treating an infectious disease or a cancer, wherein the infectious disease is a systemic infection, a reproductive system infection or a urinary system infection, preferably the infectious disease is a urinary system infection, more preferably the infectious disease is an infection caused by a gram-negative bacterium and / or a gram-positive bacterium, the gram-negative bacterium includes Escherichia coli, Acinetobacter baumannii, the gram-positive bacterium includes Staphylococcus aureus, and the cancer is preferably bladder cancer.

[0133] The present application also provides a compound according to the present application represented by the general formula (I) or meso, or a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or a solvate of any of the foregoing, or a prodrug or a metabolite of any of the foregoing, or a racemate comprising the same, or a mixture comprising the same, or a pharmaceutical composition of the foregoing, for use in treating an infectious disease or a cancer, wherein the infectious disease is a systemic infection, a reproductive system infection or a urinary system infection, preferably the infectious disease is a urinary system infection, more preferably the infectious disease is an infection caused by a gram-negative bacterium and / or a gram-positive bacterium, the gram-negative bacterium includes Escherichia coli, Acinetobacter baumannii, the gram-positive bacterium includes Staphylococcus aureus, and the cancer is preferably bladder cancer.

[0134] The present application also provides a method for treating an infectious disease or cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) or meso form according to the present application, or a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or a solvate of any of the foregoing, or a prodrug or a metabolite of any of the foregoing, or a racemate containing the same, or a mixture containing the same, or a pharmaceutical composition of any of the foregoing; wherein the infectious disease is a systemic infection, a reproductive system infection, or a urinary system infection, preferably the infectious disease is a urinary system infection, more preferably the infectious disease is an infection caused by gram-negative bacteria including Escherichia coli, Acinetobacter baumannii, and / or gram-positive bacteria including Staphylococcus aureus, and the cancer is preferably bladder cancer.

[0135] According to the conventional methods in the field of the present application, the compound represented by general formula (I) of the present application can form a pharmaceutically acceptable basic addition salt or an acid addition salt with a base or an acid. The base includes inorganic bases and organic bases, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide, etc. The acid includes inorganic acids and organic acids, and acceptable inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, etc., and acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid, etc.

[0136] The pharmaceutical composition containing the active ingredient can be in a form suitable for oral use, for example, as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir. The oral composition can be prepared according to any known method for preparing pharmaceutical compositions in the art, and such compositions can contain one or more ingredients selected from the following: a sweetening agent, a flavoring agent, a coloring agent, and a preserving agent, to provide a palatable and pleasant-tasting pharmaceutical preparation. The tablet contains the active ingredient and a suitable excipient, which is non-toxic and pharmaceutically acceptable. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; a granulating agent and a disintegrating agent, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; a binder, such as starch, gelatin, polyvinylpyrrolidone or acacia; and a lubricant, such as magnesium stearate, stearic acid or talc. These tablets can be uncoated or they can be coated by known techniques to mask the taste of the drug or delay the disintegration and absorption in the gastrointestinal tract and thus provide a sustained release of the drug in the body. For example, a water-soluble taste masking material such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or a time-extended material such as ethylcellulose, cellulose acetate butyrate can be used.

[0137] Oral preparations can also be provided in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water soluble carrier, such as polyethylene glycol or an oil, such as peanut oil, liquid paraffin or olive oil.

[0138] Aqueous suspensions contain the active material in admixture with a suitable excipient which is a liquid, for example, water, a solvent such as ethanol or a glycol, or a mixture thereof. The suspensions can also contain one or more of the following: a thickening agent, such as a naturally occurring or modified gum, for example, acacia, agar, cornstarch, or gum tragacanth; a dispersing agent, such as a naturally occurring or modified gum, for example, acacia, agar, cornstarch, or gum tragacanth; a wetting agent, for example, a naturally occurring or modified gum, for example, acacia, agar, cornstarch, or gum tragacanth; a sweetening agent, such as sucrose or saccharin; a flavoring agent, such as peppermint, methyl salicylate or orange flavoring; and a coloring agent, such as a tar dye or a natural color such as chlorophyll. Aqueous suspensions can also contain one or more of the following: a wetting agent, a dispersing agent, or a preservative.

[0139] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

[0140] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition thereto of water can provide the active ingredient together with a dispersing or wetting agent, suspending agent, or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those set forth above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0141] The pharmaceutical compositions of this application can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin or its mixtures. Suitable emulsifying agents can be naturally occurring phosphatides, such as soybean phoshatide, and esters or partial esters made from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening, flavoring, and preservative agents.

[0142] The pharmaceutical compositions of this application can be in the form of a sterile injectable aqueous or oleagenous suspension. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol alone or in combination with a wetting agent or emulsifier. Other acceptable diluents and solvents are propylene glycol, polyethylene glycol, vegetable oils, including olive oil, and injectable organic esters such as ethyl oleate. The aqueous and oleagenous suspensions can contain suitable excipients such as wetting agents, dispersing agents, sweetening, flavoring, or preservative agents.

[0143] The pharmaceutical compositions of this application can be in the form of a sterile injectable aqueous or oleagenous suspension. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol alone or in combination with a wetting agent or emulsifier. Other acceptable diluents and solvents are propylene glycol, polyethylene glycol, vegetable oils, including olive oil, and injectable organic esters such as ethyl oleate. The aqueous and oleagenous suspensions can contain suitable excipients such as wetting agents, dispersing agents, sweetening, flavoring, or preservative agents.

[0144] The compounds of this application can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and other glycerides.

[0145] It is well within the skill of the art to determine the appropriate dosage of a drug depending on a variety of factors, including but not limited to the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the like. Also, the optimum therapeutic regimen can be determined in accordance with conventional therapeutic practice, e.g., the mode of treatment, the daily amount of the compound of general formula or the kind of the pharmaceutically acceptable salt.

[0146] The present application can contain a compound represented by general formula (I), and pharmaceutically acceptable salts, hydrates or solvates thereof 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 application can be used in combination with other active ingredients, provided that they do not produce other adverse effects, such as allergic reactions, etc. The compound of the present application can be used as the only active ingredient, or in combination with other drugs for treating diseases associated with tyrosine kinase activity. Combination therapy is achieved by administering each therapeutic component simultaneously, separately or sequentially.

[0147] Detailed description of the invention

[0148] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0149] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 12 carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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 can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylate.

[0150] 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, for example ethenyl, 1- propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent groups are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0151] 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, for example ethynyl, propynyl, butynyl, and the like. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent groups are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0152] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 10 carbon atoms, further preferably comprising 3 to 8 carbon atoms, most preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0153] The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (termed a spiro atom) between rings, which can contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified as mono-, bi-, or polyspirocycloalkyl groups, preferably mono- and bi- spirocycloalkyl groups, depending on the number of spiro atoms shared between the rings. More preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0154]

[0155] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of 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 fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0156]

[0157] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0158]

[0159] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl 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, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0160] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). mring members are carbon. Preferably, 3 to 12 ring members, of which 1 to 4 are heteroatoms; most preferably, 3 to 8 ring members, of which 1 to 3 are heteroatoms; most preferably, 5 to 7 ring members, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably 1,2,5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclyl groups include spiro, fused, and bridged ring heterocyclyl groups.

[0161] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members sharing one atom (referred to as a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m ring members are carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably, 6 to 14 members, more preferably, 7 to 10 members. Spiroheterocyclyl groups are classified as mono-, bi-, or polycyclic depending on the number of spiro atoms shared between rings, preferably mono- and bi- spiroheterocyclyl groups. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono- spiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups include:

[0162]

[0163] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of atoms with other rings in the system, one or more rings can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m ring members are carbon. Preferably, 6 to 14 members, more preferably, 7 to 10 members. Fused heterocyclyl groups are classified as bi-, tri-, tetra-, or polycyclic depending on the number of rings comprising the group, preferably bi- or tri-cyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bi-cyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups include:

[0164]

[0165] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two non-adjacent atoms, which can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)m heteroatoms, the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Depending on the number of rings comprising the ring, it can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0166]

[0167] The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl ring, non-limiting examples of which include:

[0168] and the like.

[0169] The heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0170] The term "aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0171]

[0172] The aryl group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0173] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 membered or 6 membered, containing 1 to 2 heteroatoms; preferably for example imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0174]

[0175] The heteroaryl group can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0176] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy. The alkoxy group can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0177] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0178] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0179] The term "hydroxyl" refers to the -OH group.

[0180] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0181] The term "amino" refers to -NH2.

[0182] The term "cyano" refers to -CN.

[0183] The term "nitro" refers to -NO2.

[0184] The term "oxo" means =O.

[0185] The term "carboxyl" means -C(O)OH.

[0186] The term "mercapto" means -SH.

[0187] The term "ester" means -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0188] The term "acyl" means a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0189] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, such that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, such that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0190] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of a group are independently replaced with a corresponding number of substituents. It is understood that substituents are only placed at their possible chemical locations, as can be determined (experimentally or theoretically) by one skilled in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0191] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient, thereby facilitating biological activity.

[0192] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in mammals, and which possess the desired biological activity.

[0193] Methods for the synthesis of the compounds of the invention

[0194] To accomplish the objectives of the present application, the compounds of the present application of general formula (I) are prepared using the following synthetic schemes.

[0195] Scheme 1:

[0196] when R 1 is -NR e R f when R

[0197]

[0198] Scheme 1

[0199] 1) nitration of compound la in the presence of a nitration reagent, preferably nitric acid, and a dehydrating agent, preferably concentrated sulfuric acid and acetic anhydride, to give compound lb;

[0200] 2) demethylation of compound lb in the presence of a demethylating agent, preferably LiCl, in a solvent, preferably DMF, under heating, preferably at the reflux temperature of the solvent, to give a compound of formula (IA);

[0201] 3) reaction of compound of formula (IA) with an amine compound NHR e R f in a solvent, preferably DMF, under heating, preferably at 100 °C to the reflux temperature of the solvent, to give a compound of general formula (I);

[0202] wherein,

[0203] R e and R f together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group, optionally containing one or more heteroatoms selected from N and O in addition to N, which is optionally further substituted by one or more groups selected from Q;

[0204] Q is C1-C6 alkyl and ester; wherein the C1-C6 alkyl is preferably methyl and the ester is preferably -C(O)OCH2CH3;

[0205] Preferably, the heterocyclyl group is

[0206] Scheme 2:

[0207] when R 1 is C3-C 10 cycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl,

[0208]

[0209] Scheme 2

[0210] 1) reaction of compound lb with a boronic acid compound R 1 -B(OH)2in the presence of a catalyst, preferably tetrakis triphenylphosphine palladium, and a base, preferably potassium carbonate, to give a compound of formula (IB);

[0211] 2) the compound of formula (IB) is subjected to a demethylation reaction in the presence of a demethylating agent in a solvent under heating conditions; the solvent is preferably DMF, the demethylating agent is preferably LiCl, and the heating conditions are preferably the reflux temperature of the solvent.

[0212] Scheme 3:

[0213] when R 1 is -C(O)OR a or -S(O) p R a ,

[0214]

[0215] Scheme 3

[0216] the compound of formula (IA) is reacted with a compound MO-R 1 (M is an alkali metal, such as Na, K, Mg, etc.) in a solvent under heating conditions to give the compound of general formula (I); wherein the solvent is preferably DMF, and the heating conditions are preferably 100 °C to the reflux temperature of the solvent;

[0217] wherein,

[0218] R a is selected from hydrogen and C1-C6 alkyl;

[0219] p is 1 or 2.

[0220] In the above scheme, X is halogen, preferably chlorine or bromine; R 2 , R 3 , R 4 and R 5 are as defined in general formula (I).

[0221] Without deviating from the common general knowledge in the art, the above-mentioned preferred conditions can be combined in any manner, i.e. to obtain preferred embodiments of the present application.

[0222] The reagents and starting materials used in the present application are commercially available.

[0223] The positive progress effect of the present application is that the compounds of the present application show excellent anti-tumor activity and can be developed as drugs for treating tumors. DETAILED DESCRIPTION

[0224] The compounds of the present application and their preparation are further understood by the following examples, which illustrate some methods of preparing or using the compounds. It is to be understood, however, that these examples do not limit the present application. Presently known or further developed variations of the present application are considered to fall within the scope of the present application as described and claimed herein.

[0225] The compounds of the present application are prepared using convenient starting materials and general synthetic procedures. The present application provides exemplary or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratios of reactants. However, other reaction conditions can be used unless otherwise specified. Optimum reaction conditions can vary depending on the particular reactants or solvents used, but they are determined by the skilled person in the art and are typically determined by reaction optimization procedures and conditions.

[0226] In addition, some protecting groups can be used in the present application to protect certain functional groups from unwanted reactions. Suitable protecting groups for various functional groups and their protecting or deprotecting conditions are well known to those skilled in the art. For example, T. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis (3rded., Wiley, New York, 1999 and references therein) describe a large number of protecting groups and their protection or deprotection in detail.

[0227] The isolation and purification of compounds and intermediates are carried out by appropriate methods and procedures depending on the specific requirements, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a combination of the above. The specific use thereof can be found in the examples described in the present application. Of course, other similar isolation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.

[0228] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts are given in δ (ppm) units. NMR measurements are carried out using a Bruker dpxs 400 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCI3), deuterated methanol (CD3OD) as the measuring solvent and tetramethylsilane (TMS) as the internal standard. -6 (ppm) units. NMR measurements are carried out using a Bruker dpxs 400 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCI3), deuterated methanol (CD3OD) as the measuring solvent and tetramethylsilane (TMS) as the internal standard.

[0229] MS measurements are carried out using LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector).

[0230] Preparative liquid chromatography is carried out using an Agilent 1260 Infinity II high performance liquid chromatograph (manufacturer: Agilent). The chromatographic column is a Daisogel C18 10 μm 100 A (30 mm x 250 mm) and the mobile phase is acetonitrile / water.

[0231] Thin layer chromatography (TLC) uses Qingdao Haoyang Chemical GF254 silica gel plate, the specification of silica gel plate used in reaction monitoring thin layer chromatography is 0.20mm-0.25mm, and the specification of silica gel plate used in separation and purification thin layer chromatography is 0.5mm.

[0232] Silica gel column chromatography uses Qingdao Haoyang silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as carrier.

[0233] Known starting materials of the present application can be synthesized or purchased from commercial sources according to methods known in the art.

[0234] Unless otherwise specified, the reactions in the examples can be carried out under nitrogen atmosphere.

[0235] Argon atmosphere or nitrogen atmosphere refers to that a reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1L.

[0236] Reaction solvent, organic solvent or inert solvent are respectively described as the solvent used in the described reaction conditions does not participate in the reaction, including, such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, nitrogen-methyl pyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0237] The chemical reactions described in the present application are generally carried out under normal pressure. The reaction temperature is between-78℃ and 200℃. The reaction time and conditions are, for example, completed in about 1 to 24 hours at one atmosphere, between-78℃ and 200℃. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃-30℃.

[0238] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as familiar to those skilled in the art. In addition, any method and material similar or equivalent to those described can be applied to the method of the present application.

[0239] Unless otherwise specified, the temperature indicated in the examples is the temperature of the heating medium (dimethyl silicone oil), and the mixing ratio of different solvents is the volume ratio.

[0240] In the following, the mass fraction of palladium in palladium / carbon is 10%.

[0241] Example 1: Synthesis of 7-fluoro-5-nitroquinolin-8-ol (1)

[0242]

[0243] Step 1) Preparation of 7-fluoroquinolin-8-ol (1b)

[0244] To a solution of 2-amino-6-fluorophenol (1a) (5.0 g, 39.3 mmol) in glycerol (18 g, 196.6 mmol) was added nitrobenzene (50.0 mL) and concentrated sulfuric acid (5.0 mL, 93.8 mmol) successively at room temperature in a sealed tube. The tube was sealed and the reaction was stirred at 140 °C for 2 h, then cooled to room temperature. Ice water (100.0 mL) and tert-butyl methyl ether (50.0 mL) were added. The mixture was filtered and the organic phase was separated. The aqueous phase was adjusted to pH 6-7 with ammonia water and extracted with ethyl acetate (50.0 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 7-fluoroquinolin-8-ol (1b) (4.7 g, yield 73%).

[0245] Step 2) Preparation of 7-fluoro-5-nitroquinolin-8-ol (1)

[0246] To a solution of 7-fluoroquinolin-8-ol (1b) (4.7 g, 28.8 mmol) in acetic acid (15.0 mL) was added nitric acid (65 wt.%) (5.0 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 60 min and then at room temperature for 30 min. Water (80.0 mL) was added to dilute the reaction mixture and the aqueous phase was adjusted to pH 6-7 with ammonia water. The mixture was filtered under reduced pressure, the filter cake was washed with water (50.0 mL) and dried under reduced pressure. The solid was mixed with methanol (50.0 mL), stirred for 5 min, filtered under reduced pressure and the filter cake was dried under vacuum to give 7-fluoro-5-nitroquinolin-8-ol (2.5 g, yield 42%).

[0247] 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (dd, J = 8.8, 1.4 Hz, 1H), 9.02 (dd, J = 4.2, 1.2 Hz, 1H), 8.63 (d, J = 11.6 Hz, 1H), 7.90 (dd, J = 8.8, 4.2 Hz, 1H).

[0248] MS calculated: 208.03; MS found: 209.1 [M+H] + .

[0249] Example 2: Synthesis of 4-chloro-5-nitroquinolin-8-ol (2)

[0250]

[0251] Step 1) Preparation of 4-chloro-5-nitro-8-methoxyquinoline (2b)

[0252] To a solution of 4-chloro-8-methoxyquinoline (2a) (5.0 g, 25.1 mmol) in acetic anhydride (40.0 mL) was added nitric acid (65 wt.%) (3.0 mL, 43.6 mmol) slowly at 0 °C, after stirring for 10 min, concentrated sulfuric acid (98 wt.%) (3.0 mL, 55.2 mmol) was added dropwise slowly. The reaction mixture was warmed to room temperature and stirred for 1 h, ice water (50.0 mL) was added, and the aqueous phase was adjusted to pH 8-9 with ammonia water slowly. The aqueous phase was extracted with dichloromethane (10.0 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 4-chloro-5-nitro-8-methoxyquinoline (2b) (3.8 g, yield 63%).

[0253] Step 2) Preparation of 4-chloro-5-nitroquinolin-8-ol (2)

[0254] To a solution of 4-chloro-5-nitro-8-methoxyquinoline (2b) (2.3 g, 9.6 mmol) and lithium chloride (4.0 g, 96.0 mmol) in N,N-dimethylformamide (10.0 mL) was added at room temperature. The reaction mixture was stirred at 160 °C for 1 h, and cooled to room temperature. The reaction was concentrated under reduced pressure to remove the organic solvent. To the residue was added water (30.0 mL), stirred for 3 min, and filtered under reduced pressure. The filter cake was washed with water (3.0 mL x 3), and dried under vacuum to give 4-chloro-5-nitroquinolin-8-ol (2) (2.1 g, yield 97%).

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.93 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 4.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H).

[0256] MS calculated: 224.00; MS found: 225.1 [M+H] + .

[0257] Example 3: Synthesis of 6-chloro-5-nitroquinolin-8-ol (3)

[0258]

[0259]

[0260] Step 1) Preparation of 6-chloroquinolin-8-ol (3b)

[0261] To a solution of 2-amino-5-chlorophenol (3a) (1.0 g, 6.9 mmol) in glycerol (2.6 mL, 34.8 mmol) was added nitrobenzene (5.0 mL) and concentrated sulfuric acid (1.0 mL, 18.8 mmol) successively at room temperature in a sealed tube. The reaction was stirred at 140 °C for 6 h, cooled to room temperature, and then ice water (20.0 mL) was added. The aqueous phase was slowly adjusted to pH 8-9 with aqueous ammonia, and then extracted with dichloromethane (10.0 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 6-chloroquinolin-8-ol (3b) (300 mg, yield 24%).

[0262] Step 2) Preparation of 6-chloro-5-nitroquinolin-8-ol (3)

[0263] To a solution of 6-chloroquinolin-8-ol (3b) (100 mg, 0.63 mmol) in acetic acid (5.0 mL) was added nitric acid (65 wt.%) (1.0 mL) dropwise at 0 °C. The reaction was stirred at 0 °C for 0.5 h and then at room temperature for 1 h. Ice water (10.0 mL) was added to the reaction, and the aqueous phase was slowly adjusted to pH 8-9 with aqueous ammonia. The aqueous phase was extracted with dichloromethane (100.0 mL x 3), and the combined organic phase was 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 (column: Eclipse XDB-C18 (21.2 mm x 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 70% (0.1 v% formic acid was added to the mobile phase during the gradient elution), flow rate: 20.0 mL / min) to give 6-chloro-5-nitroquinolin-8-ol (3) (62.5 mg, yield 50%).

[0264] 1 H NMR (400 MHz, CDC13) δ 8.91 (dd, J = 4.2, 1.4 Hz, 1H), 8.26 (dd, J = 8.8, 1.4 Hz, 1H), 7.69 (dd, J = 8.8, 4.2 Hz, 1H), 7.29 (s, 1H).

[0265] MS calculated: 224.00; MS found: 225.1 [M+H] + .

[0266] Example 4: Synthesis of 6-methyl-5-nitroquinolin-8-ol (4)

[0267]

[0268] Step 1) Preparation of 6-methylquinolin-8-ol (4b)

[0269] To a solution of 6-methylquinolin-8-ol (100.0 mg, 0.63 mmol) in acetic acid (2.0 mL) was added nitric acid (65 wt.%) (0.1 mL) dropwise at 0 °C. The reaction was stirred at 0 °C for 0.5 h and then was allowed to warm to room temperature and stirred for 2 h. To the reaction was added ice water (10.0 mL), and the aqueous phase was adjusted to pH 8-9 with ammonia water. The aqueous phase was extracted with dichloromethane (100.0 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by reverse-phase high performance liquid chromatography (column: Eclipse XDB-C18 (21.2 mm x 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 30% with gradient elution (0.1 v% formic acid was added based on the mobile phase), flow rate: 20.0 mL / min) to give 6-methyl-5-nitroquinolin-8-ol (60 mg, 47% yield).

[0270] Step 2) Preparation of 6-methyl-5-nitroquinolin-8-ol (4)

[0271] To a solution of 6-methylquinolin-8-ol (100.0 mg, 0.63 mmol) in acetic acid (2.0 mL) was added nitric acid (65 wt.%) (0.1 mL) dropwise at 0 °C. The reaction was stirred at 0 °C for 0.5 h and then was allowed to warm to room temperature and stirred for 2 h. To the reaction was added ice water (10.0 mL), and the aqueous phase was adjusted to pH 8-9 with ammonia water. The aqueous phase was extracted with dichloromethane (100.0 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by reverse-phase high performance liquid chromatography (column: Eclipse XDB-C18 (21.2 mm x 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 30% with gradient elution (0.1 v% formic acid was added based on the mobile phase), flow rate: 20.0 mL / min) to give 6-methyl-5-nitroquinolin-8-ol (60 mg, 47% yield).

[0272] 1 H NMR (400 MHz, CDC13) δ 8.88 - 8.77 (m, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.39 (d, J = 4.0 Hz, 1H), 3.78 (s, 3H).

[0273] MS calculated: 204.05; MS found: 205.1 [M+H] + .

[0274] Example 5: Synthesis of 4-morpholin-5-nitroquinolin-8-ol (5)

[0275]

[0276] To 4-chloro-5-nitroquinolin-8-ol (2) (55.0 mg, 0.24 mmol) and morpholine (87.0 mg, 1.0 mmol) in N,N-dimethylformamide (1.0 mL) was added water (1.0 mL) at room temperature. The reaction mixture was stirred at 110 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. To the resulting residue was added water (1.0 mL), and after stirring for 3 min, it was filtered under reduced pressure. The filter cake was washed with water (2 x 0.5 mL) and dried under vacuum to give 4-morpholin-5-nitroquinolin-8-ol (5) (56.0 mg, 85% yield).

[0277] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.76 (t, J = 4.0, 4H), 3.07 (t, J = 4.0, 4H).

[0278] MS calculated: 275.09; MS found: 276.1 [M+H] + .

[0279] Example 6: Synthesis of 5-nitro-4-(piperidin-l-yl)quinolin-8-ol (6)

[0280]

[0281] From 4-chloro-5-nitroquinolin-8-ol (2) (55.0 mg, 0.24 mmol) and hexahydropyridine (110.0 mg, 1.2 mmol) was obtained 5-nitro-4-(piperidin-l-yl)quinolin-8-ol (6) (30.6 mg, 47% yield) in the same manner as the synthesis of Example 5.

[0282] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 4.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 2.96 (t, J = 5.6 Hz, 4H), 1.70 - 1.60 (m, 4H), 1.59 - 1.50 (m, 2H).

[0283] MS calculated: 273.11; MS found: 274.1 [M+H]+ .

[0284] Example 7: Synthesis of 5-nitro-4-(pyrrolidin-l-yl)quinolin-8-ol (7)

[0285]

[0286] From 4-chloro-5-nitroquinolin-8-ol (2) (55.0 mg, 0.24 mmol) and tetrahydro- pyrrole (80.0 mg, 1.2 mmol) was obtained 5-nitro-4-(pyrrolidin-l-yl)quinolin-8-ol (7) (53.0 mg, yield 85%) using the same synthetic procedure as Example 5.

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 8.25 - 8.16 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 3.43 (t, J = 6.0 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.21 (t, J = 6.0 Hz, 1H), 3.10 (p, J = 6.5 Hz, 1H), 1.86 - 1.74 (m, 4H).

[0288] MS calculated: 245.08; MS found: 246.1 [M+H] + .

[0289] Example 8: Synthesis of 4-fluoro-5-nitroquinolin-8-ol (8)

[0290]

[0291] To 4-chloro-5-nitroquinolin-8-ol (2) (113.0 mg, 0.50 mmol) and cesium fluoride (760.0 mg, 5.0 mmol) in anhydrous dimethyl sulfoxide (2.0 mL) was added at room temperature. The reaction was stirred at 150 °C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction was diluted with dichloromethane (50.0 mL) and washed once with water (20.0 mL). The organic phase was 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 (Eclipse XDB-C18 (21.2 mm x 250 mm, 7 μm) column, mobile phase: water / acetonitrile = 100% - 70% / 30% gradient elution (0.1 v% formic acid was added based on the mobile phase during the gradient elution), flow rate: 20.0 mL / min) to give the product 4-fluoro-5-nitroquinolin-8-ol (8) (50.0 mg, yield 44%).

[0292] 1H NMR (400 MHz, DMSO-d6) δ 8.79 - 8.57 (m, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.56 - 7.36 (m, 1H), 6.39 (d, J = 8.0 Hz, 1H).

[0293] MS calculated: 208.03; MS found: 209.0 [M+H] + .

[0294] Example 9: Synthesis of 5-nitro-4-phenylquinolin-8-ol (9)

[0295]

[0296]

[0297] Step 1) Preparation of 4-bromo-8-methoxyquinoline (9b)

[0298] To a solution of 4-hydroxy-8-methoxyquinoline (9a) (3.0 g, 17.14 mmol) and phosphorus tribromide (9.3 g, 34.2 mmol) in N,N-dimethylformamide (25.0 mL) was added at room temperature. The reaction solution was heated to 65 °C and stirred for 5 h. After cooling to room temperature, ice water (50.0 mL) was added, and the aqueous phase was adjusted to pH about 9 with ammonia water. The resulting mixture was extracted with ethyl acetate (100.0 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3) to give 4-bromo-8-methoxyquinoline (9b) (3.7 g, yield 91%).

[0299] Step 2) Preparation of 4-bromo-5-nitro-8-methoxyquinoline (9c)

[0300] To a solution of 4-bromo-8-methoxyquinoline (9b) (3.0 g, 12.66 mmol) in acetic anhydride (25.0 mL) was slowly added nitric acid (65 wt.%) (5.0 mL) at 0 °C. After stirring for 10 min, concentrated sulfuric acid (98 wt.%) (2.0 mL) was slowly added dropwise. The reaction solution was warmed to room temperature and stirred for 12 h. After adding ice water (100.0 mL), the aqueous phase was adjusted to pH about 9 with ammonia water, and extracted with dichloromethane (100.0 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 4-bromo-5-nitro-8-methoxyquinoline (9c) (1.5 g, yield 40%).

[0301] Step 3) Preparation of 8-methoxy-5-nitro-4-phenylquinoline (9d)

[0302] At room temperature, 4-bromo-5-nitro-8-methoxyquinoline (9c) (100.0 mg, 0.35 mmol), phenylboronic acid (61.6 mg, 0.72 mmol), tetrakis(triphenylphosphine)palladium (76.0 mg, 0.05 mmol), and potassium carbonate (97.0 mg, 0.70 mmol) were added sequentially to a mixture of toluene (5.0 mL) and water (0.50 mL). The reaction mixture was stirred at 100 °C for 5 h, cooled to room temperature, and water (20.0 mL) was added. The mixture was extracted with ethyl acetate (50.0 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 4) to give 8-methoxy-5-nitro-4-phenylquinoline (9d) (60.0 mg, yield 61%).

[0303] Step 4) Preparation of 5-nitro-4-phenylquinoline-8-phenol (9)

[0304] At room temperature, 8-methoxy-5-nitro-4-phenylquinoline (9d) (60.0 mg, 0.21 mmol) and lithium chloride (91.0 mg, 2.1 mmol) were added to N,N-dimethylformamide (2.0 mL). The reaction mixture was heated to 160 °C and stirred for 1 h, then cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Water (5.0 mL) was added to the residue, and the mixture was stirred for 3 min and filtered under reduced pressure. The filter cake was washed successively with water (0.5 mL x 2) and ethanol (0.5 mL x 2), and the filter cake was dried under vacuum to obtain 5-nitro-4-phenylquinoline-8-phenol (9) (50.0 mg, 90% yield).

[0305] 1 H NMR (400MHz, DMSO-d6) δ8.79–8.52(m,1H),8.35–8.05(m,1H),7.89–7.62(m,1H),7.61–7.18(m,5H),6.98–6.55(m,1H).

[0306] MS calculation: 266.07; MS measured: 267.1 [M+H] + .

[0307] Example 10: Synthesis of 5-nitro-4-(piperazin-1-yl)quinoline-8-phenol (10)

[0308]

[0309] In the same manner as the synthesis of example 5, 4-(dimethylamino)-5-nitroquinolin-8- ol (11) was obtained from 4-chloro-5-nitroquinolin-8-ol (2) (100.0 mg, 0.44 mmol) and aqueous solution of dimethylamine (40 wt.%) (90.0 mg, 2.0 mmol) (64.0 mg, yield 68%).

[0310] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 - 7.97 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 3.06 (s, 6H).

[0311] MS calculated: 224.00; MS found: 225.0 [M+H] + .

[0312] Example 11 : Synthesis of 4-(dimethylamino)-5-nitroquinolin-8-ol (11)

[0313]

[0314] In the same manner as the synthesis of example 5, 4-(dimethylamino)-5-nitroquinolin-8- ol (11) was obtained from 4-chloro-5-nitroquinolin-8-ol (2) (100.0 mg, 0.44 mmol) and aqueous solution of dimethylamine (40 wt.%) (90.0 mg, 2.0 mmol) (64.0 mg, yield 68%).

[0315] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 - 7.97 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 3.06 (s, 6H).

[0316] MS calculated: 224.00; MS found: 225.0 [M+H] + .

[0317] Example 12: Synthesis of 4-(methylsulfonyl)-5-nitroquinolin-8-ol (12)

[0318]

[0319] In the same manner as the synthesis of example 5, 4-(dimethylamino)-5-nitroquinolin-8- ol (11) was obtained from 4-chloro-5-nitroquinolin-8-ol (2) (100.0 mg, 0.44 mmol) and aqueous solution of dimethylamine (40 wt.%) (90.0 mg, 2.0 mmol) (64.0 mg, yield 68%).​To a solution of 4-chloro-5-nitroquinolin-8-ol (2) (120.0 mg, 0.53 mmol), 4- dimethylaminopyridine (13.0 mg, 0.1 mmol) and sodium methanesulfinate (102.0 mg, 1.0 mmol) in N,N-dimethylformamide (5.0 mL) was added at room temperature. The reaction was heated to 100 °C and stirred for 1 h, cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. To the residue was added water (10.0 mL) and stirred for 3 min, filtered and dried the filter cake to give 4-(methylsulfonyl)-5-nitroquinolin-8-ol (12) (22.0 mg, yield 50%).

[0320] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 4.0 Hz, 1H), 8.40 - 8.21 (m, 2H), 8.18 (d, J = 8.0 Hz, 1H), 6.95 - 6.84 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H), 3.12 (s, 3H).

[0321] MS Calculated: 268.02; MS Found: 269.0 [M+H] + .

[0322] Example 13: Synthesis of 4-(2-methylpiperidin-l-yl)-5-nitroquinolin-8-ol (13)

[0323]

[0324]

[0325] From 4-chloro-5-nitroquinolin-8-ol (2) (100.0 mg, 0.44 mmol) and 2- methylpiperidine (180.0 mg, 2.0 mmol) was obtained 4-(2-methylpiperidin-l-yl)-5- nitroquinolin-8-ol (13) (86.0 mg, yield 75%) in the same manner as the synthesis of Example 5.

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 3.00 - 2.73 (m, 3H), 1.72 - 1.29 (m, 9H).

[0327] MS Calculated: 287.13; MS Found: 288.1 [M+H] + .

[0328] Example 14: Synthesis of 5-nitro-4-(pyridin-4-yl)quinolin-8-ol (14)

[0329]

[0330] Step 1) Preparation of 8-methoxy-4-(pyridin-4-yl)quinoline (14a)

[0331] To a mixture of 4-bromo-8-methoxyquinoline (9b) (400.0 mg, 1.68 mmol), pyridine-4-boronic acid (416.0 mg, 3.38 mmol), tetrakis(triphenylphosphine)palladium (393.0 mg, 0.34 mmol), potassium carbonate (695.0 mg, 5.04 mmol) in toluene (10.0 mL) and water (1.0 mL) was added at room temperature. The resulting reaction mixture was stirred at 105 °C for 3 hours, cooled to room temperature, extracted with ethyl acetate (10.0 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1) to give 8-methoxy-4-(pyridin-4-yl)quinoline (14a) (330.0 mg, yield 87%).

[0332] Step 2) Preparation of 5-nitro-4-(pyridin-4-yl)-8-methoxyquinoline (14b)

[0333] To a solution of 8-methoxy-4-(pyridin-4-yl)quinoline (14a) (180.0 mg, 0.76 mmol) in acetic anhydride (3.0 mL) was added nitric acid (65 wt.%) (2.0 mL) dropwise at 0 °C. After the reaction solution was stirred at 0 °C for 1 hour, water (15.0 mL) was added to dilute, and the aqueous phase was slowly adjusted to pH 9-10 with ammonia water, then extracted with dichloromethane (30.0 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19 / 1) to give 5-nitro-4-(pyridin-4-yl)-8-methoxyquinoline (14b) (30.0 mg, yield 14%).

[0334] Step 3) Preparation of 5-nitro-4-(pyridin-4-yl)quinolin-8-ol (14)

[0335] To a solution of 5-nitro-4-(pyridin-4-yl)-8-methoxyquinoline (14b) (30.0 mg, 0.11 mmol) and lithium chloride (22.0 mg, 0.55 mmol) in N,N-dimethylformamide (2.0 mL) was added at room temperature. The reaction mixture was stirred at 160 °C for 1 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. To the residue was added water (2.0 mL), stirred for 3 min, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 5-nitro-4-(pyridin-4-yl)quinolin-8-ol (14) (18 mg, yield 61%).

[0336] 1 H-NMR (400 Hz, DMSO-d6) δ: 8.85-8.75 (m, 1H), 7.68-7.53 (m, 2H), 7.40-7.19 (m, 6H), 6.81-6.64 (m, 1H).

[0337] MS calculated: 222.08; MS found: 223.1 [M+H] + .

[0338] Example 15: Synthesis of 4-(cyclohexanimine-l-yl)-5-nitroquinolin-8-ol (15)

[0339]

[0340] From 4-chloro-5-nitroquinolin-8-ol (2) (120.0 mg, 0.53 mmol) and cyclohexanimine (250.0 mg, 2.5 mmol) was obtained 4-(cyclohexanimine-l-yl)-5-nitroquinolin-8-ol (15) (68.0 mg, yield 45%) in the same manner as the synthesis of Example 5.

[0341] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.0 Hz, 1H), 8.10 - 7.96 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 3.92 - 3.68 (m, 2H), 3.65 - 3.52 (m, 2H), 1.99 - 1.43 (m, 8H).

[0342] MS calculated: 287.13; MS found: 288.1 [M+H] + .

[0343] Example 16: Synthesis of 4-methoxy-5-nitroquinolin-8-ol (16)

[0344]

[0345] To a solution of 4-chloro-5-nitroquinolin-8-ol (2) (100.0 mg, 0.44 mmol) and sodium methoxide (50.0 mg, 0.88 mmol) in anhydrous dimethyl sulfoxide (2.0 mL) was added at room temperature. The reaction was heated to 100 °C and stirred for 2 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (10.0 mL) was added to the residue, stirred for 3 min, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 4-methoxy-5-nitroquinolin-8-ol (16) (22.0 mg, yield 50%).

[0346] 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 4.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H).

[0347] MS calculated: 220.05; MS found: 221.1 [M+H] + .

[0348] Example 17: Synthesis of 5-nitro-4-(pyridin-3-yl)quinolin-8-ol (17)

[0349]

[0350] Step 1) Preparation of 4-(pyridin-3-yl)-5-nitro-8-methoxyquinoline (17a)

[0351] To a solution of 4-bromo-5-nitro-8-methoxyquinoline (9c) (100.0 mg, 0.35 mmol), 3-pyridylpotassium trifluoroborate (150.0 mg, 0.83 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride (30.0 mg, 0.04 mmol), potassium carbonate (120.0 mg, 0.83 mmol) was added to a mixture of toluene (2.0 mL) and water (0.5 mL) at room temperature. The reaction mixture was stirred at 100 °C for 5 h, cooled to room temperature, diluted with ethyl acetate (50.0 mL), and washed with water (10.0 mL) and saturated brine (10.0 mL) in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-(pyridin-3-yl)-5-nitro-8-methoxyquinoline (17a) (50.0 mg, yield 51%).

[0352] Step 2) Preparation of 5-nitro-4-(pyridin-3-yl)quinolin-8-ol (17)

[0353] To a solution of 4-(8-hydroxy-5-nitroquinolin-4-yl)-1 -methylpiperazin-2-one (18) (35.0 mg, 0.12 mmol) in N,N-dimethylformamide (2.0 mL) was added lithium chloride (47.0 mg, 1.1 mmol) at room temperature. The reaction mixture was heated to 160 °C for 1 h, cooled to room temperature, and concentrated under reduced pressure. To the residue was added dichloromethane (5.0 mL), stirred for 3 min, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and the residue was separated by reverse-phase high performance liquid chromatography (Eclipse XDB-C18 (21.2 mm x 250 mm, 7 μm) with water / acetonitrile = 100% - 70% / 30% gradient elution (0.1 v% formic acid was added based on the mobile phase during the gradient elution) at a flow rate of 20.0 mL / min) to give 4-(8-hydroxy-5-nitroquinolin-4-yl)-1 -methylpiperazin-2-one (18) (35.0 mg, yield 73%).

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 4.0 Hz, 1H), 8.71 - 8.57 (m, 2H), 8.17 (d, J = 8.0 Hz, 1H), 7.85 - 7.72 (m, 2H), 7.51 - 7.45 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H).

[0355] MS calculated: 267.06; MS found: 268.1 [M+H] + .

[0356] Example 18: Synthesis of 4-(8-hydroxy-5-nitroquinolin-4-yl)-1 -methylpiperazin-2-one (18)

[0357]

[0358] From 4-chloro-5-nitroquinolin-8-ol (2) (100.0 mg, 0.44 mmol) and 1 -methylpiperazin-2-one (150.0 mg, 1.3 mmol) was obtained 4-(8-hydroxy-5-nitroquinolin-4-yl)-1 -methylpiperazin-2-one (18) (35.0 mg, yield 26%) in the same manner as the synthesis of Example 5.

[0359] 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 4.0 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 3.85 (s, 2H), 3.57 - 3.45 (m, 2H), 3.34 - 3.27 (m, 2H), 2.87 (s, 3H).

[0360] MS calculated: 302.10; MS found: 303.1 [M+H] + .

[0361] Example 19: Synthesis of 4-cyclopropyl-5-nitroquinolin-8-ol (19)

[0362]

[0363] Step 1) Preparation of 4-cyclopropyl-5-nitro-8-methoxyquinoline (19a)

[0364] To a mixture of 4-bromo-5-nitro-8-methoxyquinoline (9c) (100 mg, 0.35 mmol), cyclopropylboronic acid (61.6 mg, 0.72 mmol), tetrakis(triphenylphosphine)palladium (82 mg, 0.07 mmol), potassium carbonate (147 mg, 1.07 mmol) were added successively into a mixture of toluene (5 mL) and water (0.5 mL) at room temperature. The reaction mixture was stirred at 100 °C for 2 h. The reaction was cooled to room temperature, water (20.0 mL) was added, extracted with ethyl acetate (50.0 mL x 3), the organic phase was 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: petroleum ether / ethyl acetate = 4 / 1) to give 4-cyclopropyl-5-nitro-8-methoxyquinoline (19a) (60.0 mg, yield 70%).

[0365] Step 2) Preparation of 4-cyclopropyl-5-nitroquinolin-8-ol (19)

[0366] To a mixture of 4-cyclopropyl-5-nitro-8-methoxyquinoline (19a) (60.0 mg, 0.25 mmol), lithium chloride (105.0 mg, 2.5 mmol) were added successively into N,N-dimethylformamide (2.0 mL) at room temperature. The reaction was stirred at 180 °C for 1 h, cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and then water (3.0 mL) was added, stirred for 3 min, and filtered. The filter cake was washed successively with water (0.5 mL x 2) and ethanol (0.5 mL x 2), and dried under vacuum to give 4-cyclopropyl-5-nitroquinolin-8-ol (19) (11.0 mg, yield 19%).

[0367] 1 H-NMR (400 Hz, DMSO-d6) δ: 8.46-8.36 (m, 1H), 8.15-8.07 (m, 1H), 7.25-7.15 (m, 1H), 6.20-6.10 (m, 1H), 2.10-1.95 (m, 1H), 0.95-0.87 (m, 2H), 0.59-0.52 (m, 2H).

[0368] MS calc: 230.07; MS found: 231.1 [M+H] + .

[0369] Example 20: Synthesis of 4-(3-methylpiperazin-1-yl)-5-nitroquinolin-8-ol (20)

[0370]

[0371]

[0372] Using the same synthetic procedure as Example 5, 4-(3-methylpiperazin-1-yl)-5- nitroquinolin-8-ol (20) was obtained (68.0 mg, 53% yield) from 4-chloro-5-nitroquinolin- 8-ol (2) (100.0 mg, 0.44 mmol) and 2-methylpiperazine (130.0 mg, 1.3 mmol).

[0373] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 4.0 Hz, 1H), 8.00 - 7.90 (m, 1H), 7.25 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 3.30 - 3.19 (m, 7H), 2.96 - 2.75 (m, 3H).

[0374] MS calc: 288.12; MS found: 289.1 [M+H] + .

[0375] Example 21: Synthesis of 4-(azetidin-1-yl)-5-nitroquinolin-8-ol (21)

[0376]

[0377] Using the same synthetic procedure as Example 5, 4-(azetidin-1-yl)-5-nitroquinolin-8-ol (21) was obtained (42.0 mg, 39% yield) from 4-chloro-5-nitroquinolin-8-ol (2) (100.0 mg, 0.44 mmol) and azetidine (68.0 mg, 1.2 mmol).

[0378] 1 H NMR (400MHz, DMSO-d6) δ8.26(d,J=8.0Hz,1H),8.20(d,J=8.0Hz,1H),7.35(d,J= 8.0Hz, 1H), 6.66 (d, J = 8.0Hz, 1H), 4.31 (t, J = 7.6Hz, 4H), 2.36 (p, J = 7.6Hz, 2H).

[0379] MS calculated value: 245.08; MS measured value: 246.1 [M+H] + .

[0380] Example 22: Synthesis of ethyl 4-(8-hydroxy-5-nitroquinoline-4-yl)piperazine-1-carboxylate (22)

[0381]

[0382] The same synthesis method as in Example 5 was used to obtain 4-(8-hydroxy-5-nitroquinoline-4-yl)piperazine-1-carboxylic acid ethyl ester (22) (12.0 mg, yield 10%) from 4-chloro-5-nitroquinoline-8-phenol (2) (80.0 mg, 0.35 mmol) and 1-piperazine carboxylic acid ethyl ester (110.0 mg, 0.70 mmol).

[0383] 1 H NMR (400MHz, DMSO-d6) δ8.64(d,J=4.0Hz,1H),7.99(d,J=8.0Hz,1H),7.67–7.20(m,1H),6.88(d,J=8.0Hz,1H),4.1 5–4.03(m,2H),3.90–3.72(m,2H),3.25–3.22(m,2H),3.14–3.02(m,2H),3.00–2.89(m,2H),1.19(t,J=7.2Hz,3H).

[0384] MS calculation: 346.13; MS measured: 347.1 [M+H] + .

[0385] Example 23: Synthesis of 4-(2,5-dihydro-1H-pyrrolo-1-yl)-5-nitroquinoline-8-phenol (23)

[0386]

[0387] Example 5 was obtained from 4-chloro-5-nitroquinolin-8-ol (2) (80.0 mg, 0.35 mmol) and 2,5-dihydro-lH-pyrrole (74.0 mg, 1.06 mmol) in the same manner as the synthetic method of Example 5 to give 4-(2,5-dihydro-lH-pyrrol-l-yl)-5-nitroquinolin-8-ol (23) (58.0 mg, yield 64%).

[0388] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 4.0 Hz, 1H), 6.90 (d, J = 4.0 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 5.94 (s, 2H), 4.26 (s, 4H).

[0389] MS calculated: 257.08; MS found: 258.1 [M+H] + .

[0390] Example 24: Synthesis of 4-cyclopentyl-5-nitroquinolin-8-ol (24)

[0391]

[0392] Step 1) Preparation of 4-(cyclopent-l-en-l-yl)-8-methoxyquinoline (24a)

[0393] To a mixture of 4-bromo-8-methoxyquinoline (9b) (400.0 mg, 1.68 mmol), 1-cyclopentenylboronic acid (376.0 mg, 3.36 mmol), tetrakis triphenylphosphine palladium (388.0 mg, 0.336 mmol) and potassium carbonate (695.0 mg, 5.04 mmol) were added 4-bromo-8-methoxyquinoline (9b) (400.0 mg, 1.68 mmol), 1-cyclopentenylboronic acid (376.0 mg, 3.36 mmol), tetrakis triphenylphosphine palladium (388.0 mg, 0.336 mmol) and potassium carbonate (695.0 mg, 5.04 mmol) successively at room temperature into a mixture of toluene (5.0 mL) and water (0.5 mL). The reaction mixture was stirred at 107 °C for 3 hours, cooled to room temperature, extracted with ethyl acetate (100.0 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 4-(cyclopent-l-en-l-yl)-8-methoxyquinoline (24a) (330.0 mg, yield 87%).

[0394] Step 2) Preparation of 4-cyclopentyl-8-methoxyquinoline (24b)

[0395] Palladium on carbon (200.0 mg) was added to a solution of 4-(cyclopent-1-en-1- yl)-8-methoxyquinoline (24a) (330.0 mg, 1.46 mmol) in ethanol (16.0 mL) at room temperature. The reaction mixture was stirred under hydrogen atmosphere for 3 hours and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to give 4-cyclopentyl-8-methoxyquinoline (24b) (300.0 mg, yield 90%).

[0396] Step 3) Preparation of 4-cyclopentyl-8-methoxy-5-nitroquinoline (24c)

[0397] To a solution of 4-cyclopentyl-8-methoxyquinoline (24b) (300.0 mg, 1.32 mmol) in acetic anhydride (5.0 mL) was slowly added nitric acid (65 wt.%) (3.0 mL) at 0 °C, and after stirring for 10 minutes, concentrated sulfuric acid (0.5 mL) was slowly added dropwise. The reaction solution was raised to room temperature and stirred for 2 hours. Ice water (15.0 mL) was added, and the aqueous phase was adjusted to pH about 9 with ammonia water, and then extracted with dichloromethane (50.0 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3) to give 4-cyclopentyl-8-methoxy-5-nitroquinoline (24c) (70.0 mg, yield 20%).

[0398] Step 4) Preparation of 4-cyclopentyl-5-nitroquinolin-8-ol (24)

[0399] 4-cyclopentyl-8-methoxy-5-nitroquinoline (24c) (70.0 mg, 0.26 mmol) and lithium chloride (105.0 mg, 2.5 mmol) were added to N,N-dimethylformamide (3.0 mL) at room temperature. The reaction solution was stirred at 180 °C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (3.0 mL) was added to the residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 4-cyclopentyl-5-nitroquinolin-8-ol (24) (27.0 mg, yield 41%).

[0400] 1 H-NMR (400 Hz, DMSO-d6) δ: 8.92-8.83 (m, 1H), 8.11-8.04 (m, 1H), 7.81-7.84 (m, 1H), 3.10-3.04 (m, 1H), 2.13-2.00 (m, 2H), 1.87-1.53 (m, 6H).

[0401] MS calculated: 258.10; MS found: 259.1 [M+H] + .

[0402] Example 25: Synthesis of 4-cyclohexyl-5-nitroquinolin-8-ol (25)

[0403]

[0404] Step 1) Preparation of 4-cyclohexenyl-8-methoxyquinoline (25a)

[0405] To a solution of 4-chloro-8-methoxyquinoline (2a) (1.0 g, 5.2 mmol), cyclohexenylboronic acid (0.975 g, 7.7 mmol), tetrakis(triphenylphosphine)palladium (0.600 g, 0.50 mmol) and potassium carbonate (1.5 g, 11.0 mmol) in a mixture solvent of toluene (10.0 mL), ethanol (1.0 mL) and water (2.0 mL) was added at room temperature. The reaction was heated to 100 °C and stirred for 12 h, then cooled to room temperature. Water (20.0 mL) was added to dilute the reaction. The resulting mixture was extracted with ethyl acetate (100.0 mL x 2), the organic phase was 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: petroleum ether / ethyl acetate = 1 / 1) to give 4-cyclohexenyl-8-methoxyquinoline (1.1 g, yield 89%).

[0406] Step 2) Preparation of 4-cyclohexyl-8-methoxyquinoline (25b)

[0407] To a solution of 4-cyclohexenyl-8-methoxyquinoline (25a) (850.0 mg, 3.5 mmol) in methanol (20.0 mL) was added palladium on carbon (85.0 mg) at room temperature. The resulting suspension was stirred under hydrogen atmosphere for 3 h, then filtered under reduced pressure and the filter cake was washed with ethyl acetate (10.0 mL x 3). The filtrate was concentrated to dryness under reduced pressure to give 4-cyclohexyl-8-methoxyquinoline (25b) (850.0 mg, yield 99%).

[0408] Step 3) Preparation of 4-cyclohexyl-5-nitro-8-methoxyquinoline (25c)

[0409] To a solution of 4-cyclohexyl-8-methoxyquinoline (25b) (800.0 mg, 3.3 mmol) in acetic anhydride (5.0 mL) was added nitric acid (65 wt.%) (1.0 mL) slowly at 0 °C, and concentrated sulfuric acid (0.5 mL) was added dropwise after stirring for 10 min. The reaction solution was stirred at 0 °C for 1 h, diluted with water (20.0 mL), and the aqueous phase was adjusted to pH 9-10 with ammonia water, and then extracted with ethyl acetate (30.0 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-cyclohexyl-5-nitro-8-methoxyquinoline (25c) (500.0 mg, 53% yield).

[0410] Step 4) Preparation of 4-cyclohexyl-5-nitroquinolin-8-ol (25)

[0411] To a solution of 4-cyclohexyl-5-nitro-8-methoxyquinoline (25c) (500.0 mg, 1.7 mmol) and lithium chloride (740.0 mg, 17.0 mmol) in N,N-dimethylformamide (10.0 mL) was added at room temperature. The reaction solution was stirred at 160 °C for 1 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. To the residue was added water (5.0 mL), stirred for 3 min, and filtered under reduced pressure. The filter cake was washed with water (3.0 mL x 2) and dried under vacuum to give 4-cyclohexyl-5-nitroquinolin-8-ol (25) (221 mg, 48% yield).

[0412] 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 4.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 4.0 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 2.62 - 2.54 (m, 1H), 1.83 - 1.74 (m, 4H), 1.48 - 1.37 (m, 2H), 1.30 - 1.21 (m, 4H).

[0413] MS calculated: 272.12; MS found: 273.1 [M+H] + .

[0414] Example 26: Synthesis of 5-nitro-4-trifluoromethylquinolin-8-ol (26)

[0415]

[0416]

[0417] Step 1) Preparation of 4,4,4-trifluoro-N-(2-methoxyphenyl)-3-oxobutanamide (26b)

[0418] To a solution of 2-methoxyaniline (26a) (2.36 g, 19.2 mmol), 4,4,4-trifluoroacetoacetate ethyl ester (2.95 g, 16.0 mmol) and triethylamine (3.24 g, 32.0 mmol) in toluene (16.0 mL) was added at room temperature. The reaction was stirred at 125 °C for 4 h, cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The resulting residue was dissolved in dichloromethane (50.0 mL) and washed successively with hydrochloric acid (2.0 M) (15.0 mL x 2), saturated aqueous sodium bicarbonate (20.0 mL) and water (15.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 4,4,4-trifluoro-N-(2-methoxyphenyl)-3-oxobutanamide (26b) as a crude product (3.48 g, crude yield 78%). It was used directly in the next step without purification.

[0419] Step 2) Preparation of 8-methoxy-4-trifluoromethyl-2(lH)-quinolinone (26c)

[0420] To a solution of 4,4,4-trifluoro-N-(2-methoxyphenyl)-3-oxobutanamide (26b) (2.81 g, 10.7 mmol) in polyphosphoric acid (14.0 g) was added at 90 °C. The reaction was stirred at 90 °C for 3 h and diluted with water (100.0 mL) to dissolve the polyphosphoric acid completely. The resulting mixture was extracted with dichloromethane (40.0 mL x 3) and the combined organic phase was washed with saturated aqueous sodium bicarbonate (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1) to give 8-methoxy-4-trifluoromethyl-2(lH)-quinolinone (26c) (2.21 g, yield 84%).

[0421] Step 3) Preparation of 2-chloro-8-methoxy-4-trifluoromethylquinoline (26d)

[0422] To a solution of 8-methoxy-4-trifluoromethyl-2(lH)-quinolinone (26c) (2.09 g, 8.6 mmol) in phosphorus oxychloride (8.6 mL) was added at room temperature. The resulting mixture was stirred at 100 °C for 2 hours, then cooled to room temperature, diluted with dichloromethane (40.0 mL), and the aqueous phase was adjusted to pH 9-10 with saturated aqueous sodium carbonate solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (15.0 mL x 2). The combined organic phase was washed with saturated aqueous sodium carbonate solution (25.0 mL), water (25.0 mL), and saturated brine (25.0 mL), respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-chloro-8-methoxy-4-trifluoromethylquinoline (26d) as a crude product (2.26 g, crude yield 100%). It was used in the next step without purification.

[0423] Step 4) Preparation of 8-methoxy-4-trifluoromethylquinoline (26e)

[0424] To a solution of 2-chloro-8-methoxy-4-trifluoromethylquinoline (26d) (0.52 g, 2.0 mmol) in a mixture of tetrahydrofuran (10.0 mL) and methanol (10.0 mL) was added palladium on carbon (0.21 g) at room temperature. The resulting mixture was stirred under hydrogen atmosphere for 1 hour, filtered through celite, and the filter cake was washed with a mixture of dichloromethane and methanol (dichloromethane / methanol = 20 / 1, 30.0 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (20.0 mL), washed with saturated aqueous sodium bicarbonate solution (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 8-methoxy-4-trifluoromethylquinoline (26e) (0.38 g, yield 84%).

[0425] Step 5) Preparation of 8-methoxy-5-nitro-4-trifluoromethylquinoline (26f)

[0426] To a solution of 8-methoxy-4-trifluoromethylquinoline (26e) (0.38 g, 1.7 mmol) in acetic anhydride (5.0 mL) was added nitric acid (65 wt.%) (0.69 mL, 10.0 mmol) slowly at 0 °C. After stirring for 10 min, sulfuric acid (98 wt.%) (0.12 mL, 2.2 mmol) was added slowly. The stirring was continued for 30 min. The pH of the aqueous phase was adjusted to about 10 by adding aqueous sodium hydroxide solution (1.0 M). The mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 8-methoxy-5-nitro-4-trifluoromethylquinoline (26f) (0.36 g, 78% yield).

[0427] Step 6) Preparation of 5-nitro-4-trifluoromethylquinolin-8-ol (26)

[0428] To a solution of 8-methoxy-5-nitro-4-trifluoromethylquinoline (26f) (0.36 g, 1.32 mmol) and lithium chloride (0.56 g, 13.2 mmol) in N,N-dimethylformamide (1.7 mL) was added at room temperature. The mixture was stirred at 170 °C for 1 h, cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The residue was added to water (1.5 mL) and stirred for 3 min. The mixture was filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 5-nitro-4-trifluoromethylquinolin-8-ol (26) (0.29 g, 85% yield).

[0429] 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 3.2 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 4.0 Hz, 1H), 6.59 (d, J = 9.2 Hz, 1H).

[0430] MS calculated: 258.03; MS found: 259.0 [M+H] + .

[0431] Example 27: Synthesis of 4-cyano-5-nitroquinolin-8-ol (27)

[0432]

[0433] Step 1) Preparation of 4-cyano-8-methoxyquinoline (27a)

[0434] Zinc cyanide (788.0 mg, 6.71 mmol) and tetrakis triphenylphosphine palladium (728.0 mg, 0.63 mmol) were added to a solution of 4-bromo-8-methoxyquinoline (9b) (1.0 g, 4.2 mmol) in N,N-dimethylformamide (15.0 mL) at room temperature. The reaction was stirred at 100 °C for 2.5 hours under nitrogen atmosphere, cooled to room temperature and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane (15.0 mL) and water (15.0 mL), the organic phase was separated, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate (5.0 mL) was added to the residue, stirred for 3 minutes, filtered under reduced pressure and the filter cake was dried under vacuum to give 4-cyano-8-methoxyquinoline (27a) (650.0 mg, yield 84%).

[0435] Step 2) Preparation of 4-cyano-5-nitro-8-methoxyquinoline (27b)

[0436] To a suspension of 4-cyano-8-methoxyquinoline (27a) (200.0 mg, 1.08 mmol) in acetic anhydride (5.0 mL) at 0 °C, nitric acid (65 wt.%) (0.45 mL, 6.52 mmol) was added slowly. The reaction mixture was stirred at 0 °C for 10 minutes, sulfuric acid (98 wt.%) (0.1 mL, 1.87 mmol) was added slowly and stirring was continued for 30 minutes. The aqueous phase was then adjusted to pH 10 with aqueous sodium hydroxide solution (1.0 M). Dichloromethane (10.0 mL) was added, the organic phase was separated, washed with saturated brine (5.0 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 4-cyano-5-nitro-8-methoxyquinoline (27b) (205.0 mg, yield 82%).

[0437] Step 3) Preparation of 4-cyano-5-nitroquinolin-8-ol (27)

[0438] To a suspension of 4-cyano-5-nitro-8-methoxyquinoline (27b) (100.0 mg, 0.44 mmol) and lithium chloride (184.0 mg, 4.4 mmol) in N,N-dimethylformamide (2.0 mL) at room temperature. The reaction was stirred at 160 °C for 30 minutes, cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the residue, stirred for 3 minutes and filtered under reduced pressure. The filter cake was washed with ethanol (2.0 mL) and water (2.0 mL) sequentially and dried under vacuum to give 4-cyano-5-nitroquinolin-8-ol (27) (91.0 mg, yield 97%).

[0439] 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.4 Hz, 1H), 8.32 (d, J = 9.8 Hz, 1H), 8.02 (d, J = 4.4 Hz, 1H), 6.30 (d, J = 9.8 Hz, 1H).

[0440] MS calculated: 215.03; MS found: 216.1 [M+H] + .

[0441] Example 28: Synthesis of 3-(8-hydroxy-5-nitroquinolin-4-yl)-acrylic acid (28)

[0442]

[0443] Step 1) Preparation of 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid methyl ester (28a)

[0444] To a mixture of 4-bromo-5-nitro-8-methoxyquinoline (9c) (900.0 mg, 3.2 mmol), methyl acrylate (0.80 mL, 8.9 mmol), palladium acetate (72.0 mg, 0.32 mmol), tri(o- tolyl)phosphine (144.0 mg, 0.47 mmol) and triethylamine (1.35 mL, 9.7 mmol) in N,N-dimethylformamide (18.0 mL) was added at room temperature. The reaction was stirred at 100 °C for 12 h, cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 1 / 1.5) to give 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid methyl ester (28a) (486.0 mg, yield 53%).

[0445] Step 2) Preparation of 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid (28b)

[0446] To a mixture of 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid methyl ester (28a) (486.0 mg, 1.7 mmol) and lithium hydroxide (60.6 mg, 2.53 mmol) in a mixture of methanol (14.0 mL) and water (3.5 mL) was added at room temperature. The reaction was stirred at room temperature for 12 h, concentrated under reduced pressure to remove the organic solvent. The residue was adjusted to pH about 4 with aqueous hydrochloric acid (1.0 M), then dichloromethane (5.0 mL) was added, stirred for 15 min, filtered under reduced pressure, and the filter cake was dried under vacuum to give 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid (28b) (303.0 mg, yield 75%).

[0447] Step 3) Preparation of 3-(8-hydroxy-5-nitroquinolin-4-yl)-acrylic acid (28)

[0448] To a solution of 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid (28b) (70.0 mg, 0.26 mmol) in N,N-dimethylformamide (2.0 mL) was added lithium chloride (107.0 mg, 2.55 mmol) at room temperature. The reaction was stirred at 160 °C for 40 min, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (3.0 mL) was added to the residue, stirred for 3 min, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and the residue was purified by C18 reverse phase column chromatography (Eclipse XDB-C18 (21.2 mm x 250 mm, 7 μm) with water / methanol = 100% - 75% / 25% as mobile phase, gradient elution, at a flow rate of 20.0 mL / min), and dried in vacuum to give 3-(8-hydroxy-5-nitroquinolin-4-yl)-acrylic acid (28) (26.1 mg, 39% yield).

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 - 8.84 (m, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 4.4 Hz, 1H), 7.52 (d, J = 15.7 Hz, 1H), 6.44 (d, J = 15.7 Hz, 1H).

[0450] MS calculated: 260.04; MS found: 261.1 [M+H] + .

[0451] Example 29: Synthesis of 3-(8-hydroxy-5-nitroquinolin-4-yl)-N-acrylmorpholine (29)

[0452]

[0453] Step 1) Preparation of 3-(8-methoxy-5-nitroquinolin-4-yl)-N-acrylmorpholine (29a)

[0454] To a solution of 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid (28) (100.0 mg, 0.36 mmol), morpholine (48.0 mg, 0.55 mmol), HATU (209.0 mg, 0.55 mmol) and DIPEA (0.20 mL, 1.08 mmol) in DMF (1.5 mL) was added at room temperature. The reaction was stirred at room temperature for 16 hours, and the organic solvent was removed by concentration under reduced pressure. Ethyl acetate (10.0 mL) and saturated aqueous sodium bicarbonate solution (10.0 mL) were added to the residue, and the organic phase was separated, washed with saturated brine (5.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 100% dichloromethane - 100% ethyl acetate, gradient elution) to give 3-(8-methoxy-5-nitroquinolin-4-yl)-N-acrylmorpholine (29a) (115.0 mg, yield 92%).

[0455] Step 2) Preparation of 3-(8-hydroxy-5-nitroquinolin-4-yl)-N-acrylmorpholine (29)

[0456] To a solution of 3-(8-methoxy-5-nitroquinolin-4-yl)-N-acrylmorpholine (29a) (87.0 mg, 0.25 mmol) and lithium chloride (106.0 mg, 2.5 mmol) in N,N-dimethylformamide (3.0 mL) was added at room temperature. The reaction was stirred at 160°C for 45 minutes, cooled to room temperature, and the organic solvent was removed by concentration under reduced pressure. The residue was dissolved in water (3.0 mL) and purified by C18 reverse phase column liquid chromatography (Eclipse XDB-C18 (21.2 mm x 250 mm, 7 μm) column, mobile phase: water / methanol = 100% - 75% / 25%, gradient elution) to give 3-(8-hydroxy-5-nitroquinolin-4-yl)-N-acrylmorpholine (29) (50.0 mg, yield 45%).

[0457] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 4.5 Hz, 1H), 8.23 (d, J = 9.5 Hz, 1H), 7.79 (d, J = 4.6 Hz, 1H), 7.32 (d, J = 15.2 Hz, 1H), 7.13 (d, J = 15.2 Hz, 1H), 6.22 (d, J = 9.6 Hz, 1H), 3.61 (t, J = 21.9 Hz, 8H).

[0458] MS calculated: 329.31, MS found: 330.1 [M+H] + .

[0459] Example 30: Synthesis of 3-(8-hydroxy-5-nitroquinolin-4-yl)-N-(4- methoxybenzyl)-acrylamide (30)

[0460]

[0461] Using the same synthetic procedure as in Example 29, 3-(8-hydroxy-5-nitroquinolin- 4-yl)-N-(4-methoxybenzyl)-acrylamide (30) (34.3 mg, 26% yield) was obtained from 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid (28) (100.0 mg, 0.36 mmol) and (4-methoxyphenyl)methanamine (75.5 mg, 0.55 mmol) as starting materials.

[0462] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 - 8.55 (m, 2H), 8.25 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 4.6 Hz, 1H), 7.31 (d, J = 15.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.53 (d, J = 15.6 Hz, 1H), 6.23 (d, J = 9.6 Hz, 1H), 4.34 (d, J = 5.7 Hz, 2H), 3.76 (s, 3H).

[0463] MS calculated: 379.12, MS found: 380.2 [M+H] + .

[0464] Example 31: Synthesis of 8-hydroxy-5-nitroquinoline-4-carboxylic acid ethyl ester (31)

[0465]

[0466] Step 1) Preparation of 8-methoxyquinoline-4-carboxylic acid ethyl ester (31a)

[0467] To a solution of 8-methoxyquinoline-4-carboxylic acid (31a) (385.0 mg, 1.89 mmol) in ethanol (6.0 mL) was added slowly sulfuric acid (98 wt.%) (0.6 mL) at room temperature. The reaction was warmed to 90 °C and stirred for 16 h, then cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. To the residue was added ethyl acetate (10.0 mL) and saturated aqueous sodium carbonate solution (10.0 mL), and the aqueous phase was adjusted to pH about 10. The organic phase was separated, washed with saturated brine (5.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100% to 65% / 35% in gradient elution) to give ethyl 8-methoxyquinoline-4-carboxylate (31a) (247.0 mg, 56% yield).

[0468] Step 2) Preparation of ethyl 8-methoxy-5-nitro-4-carboxylate (31b)

[0469] To a suspension of ethyl 8-methoxyquinoline-4-carboxylate (31a) (247.0 mg, 1.07 mmol) in acetic anhydride (6.0 mL) was added slowly nitric acid (65 wt.%)(0.45 mL, 6.41 mmol) at 0 °C. After the reaction was stirred at 0 °C for 10 min, concentrated sulfuric acid (0.1 mL, 1.87 mmol) was added slowly and stirring was continued for 50 min. To the reaction was added aqueous sodium hydroxide solution (1.0 M) and the aqueous phase was adjusted to pH about 8, and then dichloromethane (15.0 mL) was added. The organic phase was separated, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100% to 60% / 40% in gradient elution) to give ethyl 8-methoxy-5-nitro-4-carboxylate (31b) (228.0 mg, 77% yield).

[0470] Step 3) Preparation of ethyl 8-hydroxy-5-nitroquinoline-4-carboxylate (31)

[0471] To a suspension of ethyl 8-methoxy-5-nitro-4-carboxylate (31b) (228.0 mg, 0.82 mmol) and lithium chloride (347.0 mg, 8.2 mmol) in N,N-dimethylformamide (3.0 mL) was added at room temperature. The reaction was stirred at 160 °C for 35 min, then cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. To the residue was added water (3.0 mL) and stirred for 3 min, and then filtered under reduced pressure. The filter cake was washed with water (1.0 x 2 mL) and dried in vacuum to give ethyl 8-hydroxy-5-nitroquinoline-4-carboxylate (31) (153.9 mg, 71% yield).

[0472] 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.31(d,J=8.6Hz,1H),7.76(s,1H),6.50(d,J=8.6Hz,1H),4.24(q,J=8Hz,2H),1.26(t,J=8Hz,3H).

[0473] MS calculation: 262.06; MS measured: 263.1 [M+H] + .

[0474] Example 32: Synthesis of ethyl 8-hydroxy-5-nitroquinoline-3-carboxylate (32)

[0475]

[0476] Step 1) Preparation of ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (32b)

[0477] At room temperature, POCl3 (3.72 g) was slowly added to a solution of ethyl 8-methoxy-4-hydroxyquinoline-3-carboxylate (32a) (2.0 g, 8.08 mmol) in acetonitrile (20.0 mL). The reaction mixture was heated to 90 °C and stirred for 2.5 h. After cooling to room temperature, 50 mL of dichloromethane was added for dilution. Triethylamine was then added to the system, resulting in the precipitation of a solid. The mixture was stirred for 30 min, filtered, and the filter cake was washed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to give ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (32b) (2.19 g, yield 97.7%).

[0478] Step 2) Preparation of ethyl 8-methoxy-quinoline-3-carboxylate (32c)

[0479] Ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (32b) (2.1 g, 7.9 mmol), Pd / C (0.42 g, 10%), THF / MeOH = 1:1 (20 mL), and TEA 1.2 g were added to a reaction flask. The mixture was stirred thoroughly at room temperature and hydrogenated at room temperature for 2 h under a hydrogen atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a yellow oily product, ethyl 8-methoxy-quinoline-3-carboxylate (32c) (1.89 g, 98.5%).

[0480] Step 3) Preparation of ethyl 8-methoxy-5-nitroquinoline-3-carboxylate (32d)

[0481] To a reaction flask was added 8-methoxy-quinoline-3-carboxylic acid ethyl ester (32c) (500.0 mg, 2.16 mmol) and Ac20 (10 mL) at room temperature and stirred until clear. Concentrated HN03 was added dropwise at 0 °C and stirred for 5 min. Concentrated sulfuric acid was added dropwise to the system and stirred for 2 h. The reaction was quenched into saturated Na2C03 solution at 0 °C and the pH was adjusted to 8-9. DCM was added to extract, dried and concentrated to get 550 mg of crude which was purified by column chromatography to get 8-methoxy-5-nitroquinoline-3-carboxylic acid ethyl ester (32d) (430 mg 72%)

[0482] Step 4) Preparation of 8-hydroxy-5-nitroquinoline-3-carboxylic acid ethyl ester (32)

[0483] To 8-methoxy-5-nitroquinoline-3-carboxylic acid ethyl ester (32d) (100 mg, 0.36 mmol), lithium chloride (153.0 mg, 3.6 mmol) was added in N,N-dimethylformamide (2.5 mL). The reaction was stirred at 160 °C for 45 min, cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Water (3.0 mL) was added to the residue and stirred for 3 min. The filtrate was filtered under reduced pressure. The filter cake was washed with water (1.0 x 2 mL) and dried under vacuum to get 8-hydroxy-5-nitroquinoline-3-carboxylic acid ethyl ester (32) (55 mg, 57.9% yield).

[0484] 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.46 (d, J = 9.8 Hz, 1H), 9.03 (s, 1H), 6.33 (d, J = 9.8 Hz, 1H), 4.42 (q, J = 7 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).

[0485] MS calculated: 262.06; MS found: 263.1 [M+H] + .

[0486] Example 33: Synthesis of 8-hydroxy-6-isopropyl-5-nitroquinoline (33)

[0487]

[0488] Step 1) Preparation of 8-methoxy-6-isopropyl-quinoline (33b)

[0489] Into a 100 mL flask, 8-methoxy-6-bromo-quinoline (33a) (2.37 g, 10 mmol) was added, isopropylboronic acid (880 mg, 10 mmol) was added, Na2CO3(2.12 g, 20 mmol) was added, EtOH / H2O = 40 mL / 10 mL was added, the reaction was stirred, and the temperature was raised to 100 °C, and the reaction was allowed to proceed for 6 h. The reaction solution was concentrated under reduced pressure, 50 mL of water was added, and the product was extracted with 50 mL of EA. The organic phase was concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 90 / 10) to obtain the product 33b (1.4 g, 70%).

[0490] Step 2) Preparation of 8-methoxy-6-isopropyl-5-nitro-quinoline (33c)

[0491] Into a 6 mL flask, 8-methoxy-6-isopropyl-quinoline (33b) (610 mg, 3 mmol) was added to concentrated sulfuric acid, and the solution was stirred and dissolved. Concentrated nitric acid (900 mg, 64% wt, 9 mmol) was slowly added, and the reaction was stirred at room temperature for 2 h. The reaction solution was slowly poured into 50 mL of ice water, and the pH was adjusted to 7-8 with a 20% Na2CO3 aqueous solution. The product was extracted with DCM, dried, and concentrated to obtain the target product 8-methoxy-6-isopropyl-5-nitro-quinoline (33c) (500 mg, yield 50%).

[0492] Step 3) Preparation of 8-hydroxy-6-isopropyl-5-nitroquinoline (33)

[0493] Into a 3 mL flask, 8-methoxy-6-isopropyl-5-nitro-quinoline (33c) (250 mg, 1 mmol), LiCl (420 mg, 10 mmol) were added to DMF. The reaction solution was stirred at 120 °C for 1 h, concentrated under reduced pressure, and the residue was washed with 5 mL of water, filtered, and dried to obtain the yellow solid product 8-hydroxy-6-isopropyl-5-nitroquinoline (33) (160 mg, yield 70%).

[0494] MS calculated: 232.08; MS found: 233.1 [M+H] + .

[0495] Example 34: Synthesis of 8-hydroxy-6-cyclopropyl-5-nitroquinoline (34)

[0496]

[0497] Step 1) Preparation of 8-methoxy-6-cyclopropyl-quinoline (34b)

[0498] To a 100 mL flask, 8-methoxy-6-bromo-quinoline (33a) (2.37 g, 10 mmol) was added, followed by cyclopropylboronic acid (860 mg, 10 mmol), Na2CO3(2.12 g, 20 mmol), EtOH / H2O = 40 mL / 10 mL, and the reaction was stirred and heated to 100 °C for 3 h. The reaction solution was concentrated under reduced pressure, 50 mL of water and 50 mL of EA were added to extract the product, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 90 / 10) to obtain the product 33b (1.27 g, 63.5%).

[0499] Step 2) Preparation of 8-methoxy-6-cyclopropyl-5-nitro-quinoline (34c)

[0500] At 0-15 °C, 8-methoxy-6-cyclopropyl-quinoline (33b) (600 mg, 3 mmol) was added to 6 mL of concentrated sulfuric acid, stirred and dissolved, and then concentrated nitric acid (900 mg, 64% wt, 9 mmol) was slowly added. After the addition was completed, the reaction was stirred at room temperature for 2 h. The reaction solution was slowly poured into 50 mL of ice water, and the pH was adjusted to 7-8 with 20% Na2CO3aqueous solution. The product was extracted with DCM, dried and concentrated to obtain the target product 8-methoxy-6-cyclopropyl-5-nitro-quinoline (34c) (446 mg, yield 61%).

[0501] Step 3) Preparation of 8-hydroxy-6-cyclopropyl-5-nitroquinoline (34)

[0502] 8-methoxy-6-cyclopropyl-5-nitro-quinoline (33c) (245 mg, 1 mmol), LiCl (420 mg, 10 mmol) were added to DMF 3 mL. The reaction solution was stirred at 120 °C for 1 h, concentrated under reduced pressure, and then 5 mL of water was added to make a slurry, filtered and dried to obtain the yellow solid product 8-hydroxy-6-cyclopropyl-5-nitroquinoline (34) (161 mg) with a yield of 70%.

[0503] MS calculated: 230.07; MS found: 231.1 [M+H] + .

[0504] Example 35: Synthesis of 8-hydroxy-4-(1-methyl-1H-pyrazol-5-yl)-5-nitroquinoline (35)

[0505]

[0506] To a solution of 8-hydroxy-4-(4-methylpiperazin-l-yl)-5-nitroquinolin (36) (60 mg, 0.21 mmol) in DMF 2 mL was added 4-bromobutyryl chloride (0.05 mL, 0.42 mmol) at room temperature. The reaction mixture was stirred at 160 °C for 1 h, cooled to room temperature, concentrated, and diluted with 5 mL of water to give a slurry. The slurry was filtered to give 8-hydroxy-4-(4-methylpiperazin-l-yl)-5-nitroquinolin-4-yl butanoate (38) (60 mg, yield 73%).

[0507] MS calculated: 270.08; MS found: 271.1 [M+H] + .

[0508] Example 36: Synthesis of 8-hydroxy-4-(4-methylpiperazin-l-yl)-5-nitroquinoline (36)

[0509]

[0510]

[0511] To a solution of 8-hydroxy-4-(4-methylpiperazin-l-yl)-5-nitroquinolin (36) (60 mg, 0.21 mmol) in DMF 2 mL was added 4-bromobutyryl chloride (0.05 mL, 0.42 mmol) at room temperature. The reaction mixture was stirred at 160 °C for 1 h, cooled to room temperature, concentrated, and diluted with 5 mL of water to give a slurry. The slurry was filtered to give 8-hydroxy-4-(4-methylpiperazin-l-yl)-5-nitroquinolin-4-yl butanoate (38) (60 mg, yield 73%).

[0512] MS calculated: 270.08; MS found: 271.1 [M+H] + .

[0513] Example 37: Synthesis of 3-(8-hydroxy-5-nitroquinolin-4-yl)-N-methyl-acrylamide (37)

[0514]

[0515] The same as the synthesis method of Example 29, 3-(8-hydroxy-5-nitroquinolin-4-yl)-N-methyl-acrylamide (37) (7.6 mg, yield 6.18%) was obtained from 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid (28) (133.0 mg, 0.485 mmol) and methylamine hydrochloride (49 mg, 0.727 mmol) as starting materials.

[0516] The same as the synthesis method of Example 29, 3-(8-hydroxy-5-nitroquinolin-4-yl)-N-methyl-acrylamide (37) (7.6 mg, yield 6.18%) was obtained from 3-(8-methoxy-5-nitroquinolin-4-yl)-acrylic acid (28) (133.0 mg, 0.485 mmol) and methylamine hydrochloride (49 mg, 0.727 mmol) as starting materials.1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 4.5 Hz, 1H), 8.23 (d, J = 9.5 Hz, 1H), 7.79 (d, J = 4.6 Hz, 1H), 7.32 (d, J = 15.2 Hz, 1H), 7.13 (d, J = 15.2 Hz, 1H), 6.22 (d, J = 9.6 Hz, 1H), 3.61 (t, J = 21.9 Hz, 8H).

[0517] MS calculated: 273.07, MS found: 274.10 [M+H] + .

[0518] Example 38: Synthesis of 8-hydroxy-5-nitroquinoline-3-carboxylic acid (38)

[0519]

[0520] Step 1): Preparation of 8-methoxy-5-nitroquinoline-3-carboxylic acid (38a)

[0521] Ethyl 8-methoxy-5-nitroquinoline-3-carboxylate (32d) (330 mg, 1.19 mmol), LiOH (57 mg, 2.4 mmol) were added into THF / H2O = 3 mL / 0.3 mL. The reaction was stirred at room temperature for 2 hours, 1N HCl was added to adjust pH to 3-4, concentrated under reduced pressure, the residue was added into ethyl acetate to make slurry, filtered and dried to give 8-methoxy-5-nitroquinoline-3-carboxylic acid (38a) (292 mg) as a yellow solid in 98.5% yield.

[0522] Step 2): Preparation of 8-hydroxy-5-nitroquinoline-3-carboxylic acid (38)

[0523] 8-methoxy-5-nitroquinoline-3-carboxylic acid (38a) (40 mg, 0.16 mmol), LiCl (68 mg, 1.6 mmol) were added into DMF 1 mL. The reaction was stirred at 130 °C for 1 hour, concentrated under reduced pressure, the residue was added into MeOH / EA = 1:1 to make slurry, filtered and dried to give 8-hydroxy-5-nitroquinoline-3-carboxylic acid (38) (30 mg) as a yellow solid in 79.5% yield.

[0524] 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.11 (s, 1H), 8.49 (d, J = 9.5 Hz, 1H), 6.53 (d, J = 9.5 Hz, 1H).

[0525] MS calculated: 234.03; MS found: 235.1 [M+H]+ .

[0526] Example 39: Synthesis of 8-hydroxy-5-nitroquinoline-3-carboxylic acid- cyclopropylmethyl ester (39)

[0527]

[0528] Step 1): Preparation of cyclopropylmethyl 8-methoxy-5-nitroquinoline-3- carboxylate (39a)

[0529] To a mixture of 8-hydroxy-5-nitroquinoline-3-carboxylic acid (38a) (60 mg, 0.24 mmol), cyclopropylmethanol (35 mg, 2.0 e.q.), triphenylphosphine (152 mg, 2.4 e.q.), tetrahydrofuran (1 mL) was added dropwise diisopropyl azodicarboxylate (118 mg, 2.4 e.q.) at room temperature. The reaction was stirred for 1 h. The reaction was concentrated under reduced pressure to give a crude oil. The crude was purified by silica gel thin layer chromatography (DCM:MeOH = 36:1) to give the product 39a (68 mg) as a yellow solid in 93.1% yield.

[0530] Step 2): Preparation of 8-hydroxy-5-nitroquinoline-3-carboxylic acid- cyclopropylmethyl ester (39)

[0531] To a mixture of cyclopropylmethyl 8-methoxy-5-nitroquinoline-3-carboxylate (39a) (68 mg, 0.22 mmol), lithium chloride (95 mg, 10.0 e.q.), N,N- dimethylformamide (2 mL) was stirred well. The reaction was heated to 130 °C under nitrogen atmosphere and stirred for 1 h. The reaction was concentrated under reduced pressure. The solid was precipitated by adding water, filtered, and the filter cake was rinsed with water and ethanol / water solution (1:1, 0.5 mL) separately, and dried to give the product 8-hydroxy-5-nitroquinoline-3-carboxylic acid-cyclopropylmethyl ester (39) (67 mg) as a yellow solid in 100% yield.

[0532] 1 H NMR (400 MHz, DMSO) δ 10.06 (d, J = 1.9 Hz, 1H), 8.99 (s, 1H), 8.45 (d, J = 9.8 Hz, 1H), 6.31 (d, J = 9.8 Hz, 1H), 4.22 (d, J = 7.3 Hz, 2H), 1.34 - 1.25 (m, 1H), 0.64 - 0.57 (m, 2H), 0.41 (q, J = 4.8 Hz, 2H).

[0533] MS Calculated: 288.01; MS Found: 289.26 [M+H] + .

[0534] Example 40: Synthesis of N,N-diethyl-8-hydroxy-5-nitroquinoline-3-carboxamide (40)

[0535]

[0536] Step 1): Preparation of N,N-diethyl-8-methoxy-5-nitroquinoline-3-carboxamide (40a)

[0537] A mixture of 3-carboxy-5-nitro-8-methoxyquinoline (38a) (60 mg, 0.24 mmol), diethylamine (35 mg, 2.0 e.q.), diisopropylethylamine (94 mg, 3.0 e.q.), N,N- dimethylformamide (1 mL) was stirred well. To the system was added HATU (138 mg, 1.5 e.q.) at room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude oil. The crude product was purified by silica gel thin layer chromatography (DCM:MeOH = 20:1) to obtain the yellow solid product N,N-diethyl-8-methoxy-5-nitroquinoline-3-carboxamide (40a) (40 mg, yield 54.5%).

[0538] Step 2): Preparation of N,N-diethyl-8-hydroxy-5-nitroquinoline-3-carboxamide (40)

[0539] A mixture of N,N-diethyl-8-methoxy-5-nitroquinoline-3-carboxamide (40a) (40 mg, 0.13 mmol), lithium chloride (56 mg, 10.0 e.q.), N,N-dimethylformamide (1 mL) was stirred well. The system was warmed to 130°C under nitrogen atmosphere and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the solid was precipitated by adding water, filtered, and the filter cake was washed with water for 2-3 times and dried to obtain the yellow solid product N,N-diethyl-8-hydroxy-5-nitroquinoline-3-carboxamide (40) (21 mg, yield 55%).

[0540] 1 H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 8.68 (s, 1H), 8.48 (d, J = 9.6 Hz, 1H), 6.40 (d, J = 9.5 Hz, 1H), 3.49 (d, J = 6.1 Hz, 2H), 3.18 (s, 2H), 1.19 (s, 3H), 1.07 (s, 3H).

[0541] MS calculated: 289.11; MS found: 290.29 [M+H] + .

[0542] Example 41: Synthesis of N,N-dimethyl-8-hydroxy-5-nitroquinoline-3-carboxamide (41)

[0543]

[0544] The same as the preparation method of Example 40, except using dimethylamine solution instead of diethylamine to obtain N,N-dimethyl-8-hydroxy-5-nitroquinoline-3- carboxamide (41).

[0545] 1 H NMR (400 MHz, DMSO) δ 9.46 (d, J = 1.8 Hz, 1H), 8.71 (s, 1H), 8.49 (d, J = 9.6 Hz, 1H), 6.38 (d, J = 9.6 Hz, 1H), 3.07 (s, 3H), 2.99 (s, 3H).

[0546] MS calculated: 261.07; MS found: 262.24 [M+H] + .

[0547] Example 42: Synthesis of 8-hydroxy-6-fluoro-5-nitroquinoline (42)

[0548]

[0549] Step 1): Preparation of 8-methoxy-6-fluoroquinoline (42b)

[0550] 4-fluoro-2-methoxyaniline (42a) (2.00 g, 14.2 mmol.) was mixed with hydrochloric acid (6 M, 20 mL) and stirred well. The system was warmed to 110 °C, and acrolein diethyl acetal (4.61 g, 2.5 e.q.) was added, and the reaction was stirred for 3 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to neutral with saturated potassium carbonate aqueous solution, and then extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oil of crude product. The crude product was purified by silica gel column chromatography (PE:EA = 7:1 ~ 3:1) to obtain yellow solid product 8-methoxy-6-fluoroquinoline (42b) (443 mg, yield 17.6%).

[0551] Step 2): Preparation of 8-methoxy-6-fluoro-5-nitroquinoline (42c)

[0552] A mixture of 8-methoxy-6-fluoroquinoline (42b) (220 mg, 1.24 mmol), acetic anhydride (4.4 mL) was stirred until dissolved. At 0 °C, concentrated nitric acid (65%, 0.258 mL, 3.0 e.q.) was added dropwise to the mixture, and the reaction was stirred for 5 min. Concentrated sulfuric acid (98%, 0.068 mL, 1.0 e.q.) was added dropwise to the mixture, and the reaction was stirred overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution, and the aqueous phase was adjusted to pH 8-9. The organic phase was extracted with dichloromethane, 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 = 3:1 to 2:1) to give a yellow solid, which was further purified by silica gel thin layer chromatography (dichloromethane as the developing solvent) to give the product 8-methoxy-6-fluoro-5-nitroquinoline (42c) (103 mg, 37.3% yield) as a light yellow solid.

[0553] Step 3) Preparation of 8-hydroxy-6-fluoro-5-nitroquinoline (42)

[0554] A mixture of 8-methoxy-6-fluoro-5-nitroquinoline (42c) (103 mg, 0.47 mmol), lithium chloride (197 mg, 10.0 e.q.), and N,N-dimethylformamide (2.5 mL) was stirred until homogeneous. The mixture was heated to 130 °C under a nitrogen atmosphere and stirred for 1 h. The reaction was concentrated under reduced pressure, and the solid was precipitated by the addition of water. The solid was filtered, washed with water twice, and dried to give the product 8-hydroxy-6-fluoro-5-nitroquinoline (42) (49 mg, 50.8% yield) as a yellow solid.

[0555] 1 H NMR (400 MHz, DMSO) δ 9.10 (d, J = 8.7 Hz, 1H), 8.56 (d, J = 3.2 Hz, 1H), 7.61 (dd, J = 8.7, 4.1 Hz, 1H), 6.14 (d, J = 17.9 Hz, 1H).

[0556] MS calculated: 208.15; MS found: 209.0 [M+H] + .

[0557] Example 43: Synthesis of 8-hydroxy-5-nitroquinoline-3-carboxylic acid cyclohexyl ester (43)

[0558]

[0559] Step 1) Preparation of 5-nitro-8-methoxyquinoline-3-carboxylic acid cyclohexyl ester (43a)

[0560] To a solution of 5-nitro-8-methoxyquinoline-3-carboxylic acid (38a) (100 mg, 0.4 mmol) in N,N-dimethylformamide (2.0 mL) was added carbonyldiimidazole (CDI) (85 mg, 0.52 mmol) portion wise at room temperature. The reaction mixture was stirred at room temperature for 1 h, cyclohexanol (120 mg, 1.2 mmol) was added slowly and the reaction was stirred at 45 °C for 6 h. Cooled to room temperature, diluted with water (10.0 mL), extracted with dichloromethane (10.0 mL x 2), combined organic phase, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 0-40%) to give cyclohexyl 5-nitro-8-methoxyquinoline-3-carboxylate (43a) (101 mg, yield 75.9%).

[0561] Step 2) Preparation of cyclohexyl 8-hydroxy-5-nitroquinoline-3-carboxylate (43)

[0562] To a solution of cyclohexyl 5-nitro-8-methoxyquinoline-3-carboxylate (43a) (50.0 mg, 0.15 mmol) and lithium chloride (63.0 mg, 1.5 mmol) in N,N-dimethylformamide (2.0 mL) was added at room temperature. The reaction mixture was stirred at 130 °C for 1 h. Cooled to room temperature, concentrated under reduced pressure to remove the organic solvent. To the residue was added water (2.0 mL), stirred for 3 min, filtered under reduced pressure. To the filter cake was added water (1.0 mL) and ethanol (1.0 mL), stirred for 10 min, filtered under reduced pressure, the filter cake was dried under vacuum to give cyclohexyl 8-hydroxy-5-nitroquinoline-3-carboxylate (43) (36.5 mg, yield 76.3%).

[0563] 1 H NMR (400 MHz, DMSO-d6) δ: 10.08 (s, 1H), 9.00 (s, 1H), 8.48 (d, J = 9.8 Hz, 1H), 6.34 (d, J = 9.8 Hz, 1H), 5.16-5.00 (m, 1H), 1.99-1.94 (m, 2H), 1.82-1.78 (m, 2H), 1.70-1.39 (m, 6H).

[0564] MS calculated: 316.11; MS found: 317.2 [M+H] + .

[0565] Example 44: Synthesis of N-isopropyl-8-hydroxy-5-nitroquinoline-3-carboxamide (44)

[0566]

[0567] Step 1) Preparation of N-isopropyl-5-nitro-8-methoxyquinoline-3-carboxamide (44a)

[0568] To a solution of 5-nitro-8-methoxyquinoline-3-carboxylic acid (38a) (100 mg, 0.4 mmol) in N,N-dimethylformamide (2.0 mL) was added carbonyldiimidazole (85 mg, 0.52 mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and isopropylamine (141.9 mg, 2.4 mmol) was added slowly. The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10.0 mL) and extracted with dichloromethane (10.0 mL x 2). The combined organic phase was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0 ~ 28%) to give N-isopropyl-5-nitro-8-methoxyquinoline-3-carboxamide (44a) (52.0 mg, yield 44.8%).

[0569] Step 2) Preparation of N-isopropyl-8-hydroxy-5-nitroquinoline-3-carboxamide (44)

[0570] To a solution of N-isopropyl-5-nitro-8-methoxyquinoline-3-carboxamide (44a) (52.0 mg, 0.18 mmol) and lithium chloride (75.5 mg, 1.8 mmol) in N,N-dimethylformamide (2.0 mL) was added at room temperature. The reaction mixture was stirred at 130°C for 1.5 hours. After cooling to room temperature, the organic solvent was removed by concentration under reduced pressure. To the resulting residue was added water (2.0 mL), stirred for 3 minutes, and filtered under reduced pressure. To the resulting filter cake was added water (1.0 mL) and ethanol (1.0 mL), stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give N-isopropyl-8-hydroxy-5-nitroquinoline-3-carboxamide (44) (35.5 mg, yield 71.7%).

[0571] 1 H NMR (400 MHz, DMSO-d6) δ: 9.84 (d, J = 1.9 Hz, 1H), 8.93 (d, J = 1.7 Hz, 1H), 8.70 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 9.7 Hz, 1H), 6.36 (d, J = 9.7 Hz, 1H), 4.26 - 4.10 (m, 1H), 1.24 (d, J = 6.6 Hz, 6H).

[0572] MS calculated: 275.09; MS found: 276.1 [M+H] + .

[0573] Biological tests

[0574] Test Example 1 Determination of inhibitory activity of the compound of the present application on cancer cells

[0575] Experimental materials and reagents and test methods

[0576] 1. Cell lines

[0577] HUVEC (purchased from Auslaber Biotech (Shanghai) Co., Ltd.); UM-UC-3 (ATCC); LNCaP Clone FGC (ATCC); RM-1 (purchased from Nanjing Kebai Biotechnology Co., Ltd.)

[0578] 2. Reagents

[0579] Endothelial cell complete culture medium (Allcells, H-004)

[0580] Culture medium RPMI1640 (ATCC, 30-2001)

[0581] Culture medium EMEM (ATCC, 30-2003),

[0582] Culture medium DMEM (Gibco, 12430-054),

[0583] Fetal bovine serum (Gibco, 10091148)

[0584] Penicillin-streptomycin double antibody (Gibco, S110JV)

[0585] DPBS (Gibco, 14190-144)

[0586] Detection kit (Promega, G7573)

[0587] Trypsin (0.25%), phenol red (Gibco, 25200-056)

[0588] DMSO (Sigma, D2650)

[0589] 3. Instruments

[0590] Biological safety cabinet (Sunan Antai, BSC-1300A II)

[0591] Inverted microscope (Nikon, CKX53)

[0592] Automatic cell counter (Life Technologies, countess II)

[0593] Multifunctional microplate reader (Biotek, H1FM)

[0594] Shaking table (Hangzhou Aosheng Instrument Co., Ltd., OS-100)

[0595] GraphPad Prism 5.0 software

[0596] XLFIT 5.3 (Shanghai Jiuzhan Information Technology Co., Ltd.)

[0597] 4. Test method

[0598] The test method, in a biological safety cabinet, carried out the following experiment, the specific steps are as follows:

[0599] (1) On the first day, the cells were inoculated in a 96-well plate, the previous culture medium was poured out, 5 mL DPBS was added to wash the cells, and then the DPBS was sucked out with a pipette and discarded. Then, 1 mL of trypsin (0.25%) was added, and the cells were digested in a 37°C, 5% CO2 cell incubator for about 2-5 minutes. New corresponding culture medium was added, and the cells were resuspended by blowing up and down, and then an automatic cell counter was used to count the cells.

[0600] Among them, the inverted microscope was used to observe the digestion situation.

[0601] Among them, HUVEC used endothelial cell complete culture medium; UM-UC-3 used culture medium was 89v% EMEM + 10v% fetal bovine serum + 1v% amphotericin B; LNcaP Clone FGC used culture medium was 89v% RPMI1640 + 10v% fetal bovine serum + 1v% amphotericin B; RM-1 used culture medium was 89v% DMEM + 10v% fetal bovine serum + 1v% amphotericin B.

[0602] (2) HUVEC cells were inoculated in the first column to the eleventh column of a 96-well plate (Corning, item number 3610) at a density of 2000 cells per well in 100 μL of culture medium, and culture medium without cells was added to the twelfth column. Similarly, the other three cells were inoculated, among which UM-UC-3 and RM-1 were inoculated at a density of 3000 / well; LNCap Clone FGC was inoculated at a density of 5000 / well. Then, it was placed in a 37°C, 5% CO2 incubator for 24h.

[0603] (3) On the second day, the compound of the present invention and the control drug nitrohydroxyquinoline (prepared according to the preparation method disclosed in the prior art) were serially diluted 2.5 times starting at 100 μmol to 8 dose points (there are a total of 8 rows of wells; the concentration of the first row of wells is the highest, decreasing sequentially, and the concentration of the last row of wells is the lowest). 10 μL of the serially diluted compound was taken with an 8-channel pipette and added to 100 μL of cells in columns 1 to 10. 10 μL of the corresponding culture medium containing 0.33 v% DMSO was added to columns 11 and 12. The cells were incubated at 37°C in a 5% CO2 incubator for 72 h (Note: column 11 is the MAX well, which contains cells but no compound; column 12 is the MIN well, which contains no cells and no compound).

[0604] (4) After treating with the compound of the present invention for 72 hours, the above-mentioned compound was applied according to the instructions. The cell viability assay reagent in the assay kit was added to each well of a 96-well plate at a dose of 50 μL. The plate was then shaken on a shaker in the dark for 5-10 minutes, followed by cell viability measurement using a multi-functional microplate reader. Finally, the cell growth inhibition effect of the compounds of this invention was plotted using GraphpadPrism 5.0 software or XLFIT software, and the IC50 values ​​of the compounds were statistically analyzed. 50 value.

[0605] The inhibitory effect of the compounds of this invention on various cancer cells (IC50) 50 The values ​​are shown in Table 1 below.

[0606] Table 1. IC50 of the compounds of this invention in inhibiting cancer cells. 50 value

[0607]

[0608]

[0609] As can be seen from the data in the table above, the compounds of the present invention have better anti-cancer activity than nitroquinoline.

[0610] Test Example 2: Determination of the inhibitory activity of the compounds of the present invention against bacteria.

[0611] 1. Purpose

[0612] The purpose of this test was to determine the antibacterial activity of the compounds of the present invention against representative strains (Gram-negative bacteria: Escherichia coli ATCC 25922, Acinetobacter baumannii ATCC 19606; Gram-positive bacteria: Staphylococcus aureus ATCC 29213). The activity was determined by minimum inhibitory concentration (MIC) and MIC... 50 MIC 90Antibacterial activity was determined. The test was commissioned by Shanghai Junji Medical Inspection Co., Ltd. All test materials except the test drug were provided by Shanghai Junji Medical Inspection Co., Ltd.

[0613] 2. Test drug

[0614] Compound of the present application

[0615] 3. Test bacteria

[0616] The test bacteria were several strains of carbapenem-resistant Escherichia coli, several strains of carbapenem-resistant Acinetobacter baumannii, several strains of methicillin-resistant Staphylococcus aureus, and several strains of sensitive Staphylococcus aureus, isolated from clinical. Duplicate strains isolated from the same patient were excluded. In addition, there were three quality control strains of Escherichia coli ATCC 25922, Acinetobacter baumannii ATCC 19606, and Staphylococcus aureus ATCC 29213. Each compound selected one or more strains of the above test bacteria for activity testing. The number of some test strains is shown in the table below.

[0617] Table 2 Number of test strains (strains)

[0618]

[0619] 4. Drug sensitivity test method

[0620] According to the recommendations of the relevant documents of the American Clinical and Laboratory Standardization Institute (Clinical and Laboratory Standards Institute, CLSI), the MIC of the compounds of the present application on clinical isolates was determined by micro-broth dilution method. The test bacteria without drug were used as positive control, the bacteria without drug were used as negative control, and the culture solution without drug and bacteria were used as blank control.

[0621] 4.1 Preparation of antibacterial drugs: The compounds of the present application were dissolved with DMSO. The drug concentration range was 128 mg / L to 0.06 mg / L. The specific method was as follows: the compounds of the present application were sequentially diluted by 1:1 times with DMSO to form an intermediate series with a dilution range of 25600 mg / L to 12.5 mg / L. From each tube of the intermediate series of the compounds, 30 μL was added to 3 mL / tube of the series of single broth tubes and mixed well to form an intermediate series with a range of 256 mg / L to 0.125 mg / L. The diluted series was distributed row by row to the drug sensitivity plate, and 50 μL was added to each well. After mixing with an equal volume of bacteria solution, all the dilution ranges changed to the investigation dilution range: 128-0.06 mg / L.

[0622] 4.2 Culture medium: cation adjusted Mueller-Hinton broth (CAMHB) was used for drug sensitivity.

[0623] 4.3 Inoculum: The overnight pure subculture of the test bacteria was adjusted to 0.5 McFarland turbidity tube turbidity by direct colony suspension method, 100-fold dilution was performed, and the final inoculum was 10 5 CFU / mL.

[0624] 4.4 Culture conditions: 35±2℃ for 20 hours under air state.

[0625] 5. Results reading and judgment

[0626] The drug sensitivity test results were interpreted according to the CLSI 2019 edition M100 29th edition standard.

[0627] 6. Data statistics

[0628] WHONET 5.6 software was used for statistical analysis of the drug sensitivity test results.

[0629] 7. Experimental results

[0630] The MIC values (unit: mg / L) of the compounds of the present application for inhibiting various bacteria are shown in Table 3. Among them, in the case of gram-negative bacteria, the MIC value of the compound ≤128 mg / L has antibacterial activity, which is more optimal, and in the case of gram-positive bacteria, the MIC value of the compound ≤4 mg / L has antibacterial activity. No drug is the positive control of the test bacteria, and the bacteria grow normally; no bacteria liquid is the negative control of the drug and the blank control containing only the culture solution without the drug and the bacteria liquid, and there is no bacterial growth.

[0631] Table 3 MIC values (mg / L) of the compounds of the present application for inhibiting bacteria

[0632]

[0633] From the data in the above table, the MIC value of the compound of the present application to Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus is in the range of 8 mg / L-128 mg / L, 8 mg / L-128 mg / L, 1 mg / L-64 mg / L respectively, and the compound of the present application shows excellent bacteriostatic activity to gram-negative bacteria such as Escherichia coli, Acinetobacter baumannii, gram-positive bacteria such as Staphylococcus aureus and widely used strains. Among them, the compound 1, 2, 16, 19, 24-27, 32-34 of the present application has bacteriostatic activity to all of Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus, the compound 39, 40, 42 of the present application has bacteriostatic activity to Escherichia coli and Staphylococcus aureus, and the compound 9, 43 of the present application has bacteriostatic activity to Staphylococcus aureus. Therefore, the compound of the present application has excellent bacteriostatic activity to one or more of Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus, and can treat infectious diseases caused by gram-negative bacteria and / or gram-positive bacteria. Although the specific embodiments of the present application are described above, those skilled in the art should understand that this is only an example, and the protection scope of the present application is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present application, and these changes and modifications all fall within the protection scope of the present application.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: R 1 Selected from -NR a R b ; R a and R b Each is independently selected from hydrogen and C1-C6 alkyl groups; or, R a and R b Together with the nitrogen atom attached thereto, a 5- to 7-membered nitrogen-containing heterocyclic group is formed, wherein the 5- to 7-membered nitrogen-containing heterocyclic group optionally contains one or more heteroatoms selected from N, O and S in addition to N; the 5- to 7-membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from Q; Q is an oxo group, a C1-C6 alkyl group, or -C(O)OR. c ; R c Selected from C1-C6 alkyl groups; or, R 1 Selected from C3-C 10 The cycloalkyl group may optionally be further substituted with one or more groups selected from halogens and C1-C6 alkyl groups; or, R 1 Selected from phenyl or pyridyl; R 2 It is hydrogen; R 3 It is hydrogen; R 4 It is hydrogen; R 5 It is hydrogen.

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in: R 1 Selected from -NR a R b ; R a and R b Together with the nitrogen atom attached thereto, a 5- to 7-membered nitrogen-containing heterocyclic group is formed, wherein the nitrogen-containing heterocyclic group is selected from... The 5- to 7-membered nitrogen-containing heterocyclic group may be further substituted by one or more groups selected from Q; Q is an oxo group, a C1-C6 alkyl group, or -C(O)OR. c ; R c Selected from C1-C6 alkyl groups.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, Where R 1 The group is selected from C3-C6 cycloalkyl groups, wherein the C3-C6 cycloalkyl groups are optionally further substituted with one or more groups selected from halogens and C1-C6 alkyl groups.

4. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, R 1 It is selected from cyclopropyl, cyclopentyl and cyclohexyl, which may optionally be further substituted with one or more groups selected from halogens and C1-C6 alkyl groups.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in, R 1 It is an unsubstituted C3-C6 cycloalkyl group.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in, R 1 It is an unsubstituted cyclopropyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl group.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in, R 1 for 8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in, R 1 It is an unsubstituted phenyl group.

9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in, R 1 for 10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in, R 1 It is -N(CH3)2.

11. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

12. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

13. A method for preparing a compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, comprising the following steps: When R 1 For -NR a R b hour, Under heating conditions, in a solvent, the compound of formula (IA) reacts with the amine compound NHR. a R b The reaction yields a compound of general formula (I); When R 1 For C3-C 10 When cycloalkyl, phenyl, or pyridyl, In the presence of a catalyst and a base, compound Ib reacts with boric acid compound R. 1 The -B(OH)₂ reaction yields a compound of formula (IB); then, Under heating conditions, in a solvent, and in the presence of a demethylating agent, compound (IB) undergoes a demethylation reaction to give compound (I) of general formula. Wherein, X is selected from halogens; R 2 R 3 R 4 R 5 R a R b As defined in claim 1.

14. The method according to claim 13, wherein, When R 1 For -NR a R b When the solvent is DMF, the heating condition is from 100°C to the reflux temperature of the solvent.

15. The method according to claim 13, wherein, When R 1 For C3-C 10 When the solvent is cycloalkyl, phenyl, or pyridyl, the catalyst is tetrakis(triphenylphosphine)palladium, the base is potassium carbonate, the solvent is DMF, the demethylating agent is LiCl, and the heating condition is the reflux temperature of the solvent.

16. The method according to claim 13, wherein, X is chlorine or bromine.

17. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, and a pharmaceutically acceptable carrier.

18. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 17, in the preparation of a medicament for treating cancer, wherein the cancer is bladder cancer.

19. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 6, 8 to 9 and 12 in the preparation of a medicament for treating infectious diseases, wherein, The infectious disease is a systemic infection, a reproductive system infection, or a urinary system infection, and the infectious disease is caused by Gram-negative bacteria and / or Gram-positive bacteria.

20. The use according to claim 19, wherein, The Gram-negative bacteria include Escherichia coli and Acinetobacter baumannii, and the Gram-positive bacteria include Staphylococcus aureus.

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