Nitroquinoline derivates, preparation method and use thereof

Abstract

This invention discloses nitrohydroxyquinoline derivatives, their preparation methods, and uses. Specifically, this invention discloses compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing them, and their uses in treating infectious diseases or cancer. The compounds of this invention possess excellent antitumor and antibacterial activities and can be developed into drugs for treating tumors and infectious diseases. The definitions of each group in general formula (I) are the same as in the specification.

Description

Technical Field

[0001] This invention relates to nitrohydroxyquinoline derivatives, their preparation methods, and uses. Prior Technology

[0002] Nitroxoline, chemically known as 5-nitro-8-hydroxyquinoline, was developed as an oral antibiotic in the 1960s, primarily for urinary tract infections, and had a relatively safe history of use. However, it was superseded by the discovery and use of newer antibiotics. Nevertheless, with the increasing prominence of bacterial resistance in the antibiotic field, the applicability of existing antibacterial drugs in clinical practice faces varying degrees of challenges. The development of antibacterial drugs targeting multidrug-resistant bacteria is urgently needed in clinical practice, and nitroxoline has not yet shown significant bacterial resistance.

[0003] Furthermore, recent studies have found that nitroquinoline can simultaneously inhibit methionine aminopeptidase MetAP2 and the silencing information regulator 2-related enzyme SIRT1 in vascular endothelial cells, exerting a synergistic inhibitory effect on tumor angiogenesis and also inhibiting tumor cell proliferation. Therefore, nitroquinoline has been redeveloped for the treatment of tumors, including bladder cancer. Developing a compound with anticancer activity superior to nitroquinoline would be even more exciting for researchers. Summary of the Invention

[0004] Through dedicated research, the inventors have designed and synthesized a series of nitrohydroxyquinoline derivatives, which exhibit excellent antitumor and antibacterial activities and can be developed into drugs for the treatment of tumors and infectious diseases.

[0005] Therefore, the present invention provides a compound or meso compound of general formula (I), or a tautomer, stereoisomer, enantiomer, diastereomer, or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystal form or solvate thereof, or a prodrug or metabolite thereof, or a racemic mixture thereof, or a mixture thereof, wherein "therefore" refers to the compound.

[0006] in,

[0007] R1 is selected from hydrogen, halogen, nitro, cyano, syloxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NRaRb, -ORa, -SRa, -C(O)Ra, -O(O)CRa, -C(O)ORa, -C(O)NRaRb, -N(Rb)C(O)Ra, -S(O)pRa, -S(O)pNRaRb and -N(Rb)S(O)pRa, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted by one or more groups selected from Q;

[0008] R2 is selected from hydrogen, halogen, nitro, cyano, septyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NRaRb, -ORa, -SRa, -C(O)Ra, -O(O)CRa, -C(O)ORa, -C(O)NRaRb, -N(Rb)C(O)Ra, -S(O)pRa, -S(O)pNRaRb and -N(Rb)S(O)pRa, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, septyl, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0009] R3 is selected from hydrogen, halogen, nitro, cyano, septyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NRaRb, -ORa, -SRa, -C(O)Ra, -O(O)CRa, -C(O)ORa, -C(O)NRaRb, -N(Rb)C(O)Ra, -S(O)pRa, -S(O)pNRaRb and -N(Rb)S(O)pRa, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, septyl, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0010] R4 is selected from hydrogen, halogen, nitro, cyano, septyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NRaRb, -ORa, -SRa, -C(O)Ra, -O(O)CRa, -C(O)ORa, -C(O)NRaRb, -N(Rb)C(O)Ra, -S(O)pRa, -S(O)pNRaRb and -N(Rb)S(O)pRa, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, septyl, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0011] R5 is selected from hydrogen, halogen, nitro, cyano, septyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NRaRb, -ORa, -SRa, -C(O)Ra, -O(O)CRa, -C(O)ORa, -C(O)NRaRb, -N(Rb)C(O)Ra, -S(O)pRa, -S(O)pNRaRb and -N(Rb)S(O)pRa, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, septyl, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0012] Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, syloxy, 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;

[0013] Alternatively, Ra and Rb together with the nitrogen atom they are attached to form a nitrogen-containing heterocyclic group, which 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;

[0014] Q is a halogen, amino, nitro, cyano, oxy-side group, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NRcRd, -ORc, -SRc, -C(O)Rc, -O(O)CRc, -C(O)ORc, -C(O)NRcRd, -C(O)N(Rc)(CH2)qRd, -NRcC(O)Rd, -S(O)pRc, -S(O)pNRcRd or -NRcS(O)pRd, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl may optionally be further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxy-side group, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0015] Rc and Rd are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, septyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, septyl, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0016] Alternatively, Rc and Rd together with the nitrogen atom they are attached to form a nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N, O, and S in addition to N, and which optionally is further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxy, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0017] p is 1 or 2;

[0018] q is an integer from 0 to 6;

[0019] The condition is that R1, R2, R3, R4, and R5 are not all hydrogen at the same time.

[0020] In some preferred embodiments, R1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NRaRb, -ORa, -SRa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -N(Rb)C(O)Ra, -S(O)pRa, -S(O)pNRaRb and -N(Rb)S(O)pRa, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted by one or more groups selected from Q;

[0021] Ra and Rb are each independently selected from hydrogen, alkyl, and cycloalkyl groups;

[0022] Alternatively, Ra and Rb together with the nitrogen atom they are attached to form a nitrogen-containing heterocyclic group, which 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;

[0023] Q is a halogen, a side oxygen group, an alkyl group, -NRcRd, -ORc, -SRc, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(O)N(Rc)(CH2)qRd, -S(O)pRc, or -S(O)pNRcRd, wherein the alkyl group may optionally be further substituted with one or more groups selected from halogens;

[0024] Rc and Rd are each independently selected from hydrogen, alkyl, aryl, and heteroaryl, wherein the alkyl, aryl, and heteroaryl groups are optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, sero-oxygen, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0025] Alternatively, Rc and Rd together with the nitrogen atom they are attached to form a nitrogen-containing heterocyclic group, which 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 halogen, amino, nitro, cyano, oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0026] p is 1 or 2;

[0027] q is an integer from 0 to 6.

[0028] In some other preferred embodiments, R1 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl may optionally be further substituted with one or more groups selected from halogens.

[0029] In some other preferred embodiments, R1 is selected from -NRaRb;

[0030] Ra and Rb are each independently selected from hydrogen and C1-C6 alkyl groups;

[0031] Alternatively, Ra and Rb together with their attached nitrogen atom form a 5- to 7-membered nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N, O, and S in addition to N. Preferably, the nitrogen-containing heterocyclic group is selected from... , , , , , and The 5 to 7 nitrogen-containing heterocyclic groups may optionally be further substituted by one or more groups selected from Q;

[0032] Q can be a halogen, a side oxygen group, a C1-C6 alkyl group, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(O)N(Rc)(CH2)qRd, or -S(O)pRc;

[0033] Rc and Rd are each independently selected from hydrogen or C1-C6 alkyl groups, wherein the C1-C6 alkyl group may optionally be further substituted with one or more groups selected from halogens;

[0034] Alternatively, Rc and Rd together with the nitrogen atom they are attached to form a 5- to 7-membered nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N, O, and S in addition to N, and which optionally is further substituted by one or more groups selected from halogens and C1-C6 alkyl groups;

[0035] p is 1 or 2;

[0036] q is an integer from 0 to 6.

[0037] In some other preferred embodiments, R1 is selected from C3-C10 cycloalkyl, preferably C3-C6 cycloalkyl, more preferably cyclopropyl, cyclopentyl and cyclohexyl, the cycloalkyl group optionally further substituted with one or more groups selected from halogens and C1-C6 alkyl.

[0038] In some other preferred embodiments, R1 is selected from C6-C10 aryl, preferably phenyl, or 5 to 10 heteroaryl, preferably pyridyl, wherein the C6-C10 aryl or 5 to 10 heteroaryl may optionally be further substituted with one or more groups selected from halogens and C1-C6 alkyl groups.

[0039] In other preferred embodiments, R1 is selected from C2-C6 alkenyl groups, which may optionally be further substituted with one or more groups selected from -C(O)ORc, -C(O)NRcRd, -C(O)N(Rc)(CH2)qRd, -S(O)pRc, and -S(O)pNRcRd; preferably, it is substituted with one or more groups selected from -C(O)ORc and -C(O)NRcRd.

[0040] Rc and Rd are each independently selected from hydrogen, C1-C6 alkyl, C6-C10 aryl (preferably phenyl), wherein the C1-C6 alkyl and C6-C10 aryl groups are optionally further substituted with one or more groups selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0041] Alternatively, Rc and Rd together with the nitrogen atom they are attached to form a 5- to 7-membered nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N, O and S in addition to N, preferably a morpholino group, 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;

[0042] p is 1 or 2;

[0043] q is an integer from 0 to 6, preferably an integer from 1 to 4.

[0044] In some other preferred embodiments, R1 is selected from -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -S(O)pRa, and -S(O)pNRaRb;

[0045] Ra and Rb are each independently selected from hydrogen and C1-C6 alkyl groups;

[0046] Alternatively, Ra and Rb together with the nitrogen atom they are attached to form a 5- to 7-membered nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N, O, and S in addition to N, and which optionally is further substituted by one or more groups selected from halogens and C1-C6 alkyl groups;

[0047] p is 1 or 2.

[0048] In some other preferred embodiments, R2 is selected from hydrogen, halogen, C1-C6 cycloalkyl, and C1-C6 alkyl; R3 is selected from hydrogen, halogen, and C1-C6 alkyl.

[0049] In some other preferred embodiments, R4 is selected from hydrogen, halogen, C1-C6 alkyl, -C(O)ORa and -C(O)NRaRb, wherein Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl; and R5 is selected from hydrogen, halogen and C1-C6 alkyl.

[0050] The present invention also provides a compound or meso compound of general formula (I), or a tautomer, stereoisomer, enantiomer, diastereomer, or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystal form or solvate thereof, or a prodrug or metabolite thereof, or a racemic mixture thereof, or a mixture thereof, wherein "therefore" refers to the compound.

[0051] in,

[0052] R2 is selected from hydrogen, halogens, alkyl groups, and cycloalkyl groups;

[0053] R3 is selected from hydrogen, halogens, and alkyl groups;

[0054] R4 is selected from hydrogen, halogen, alkyl, -C(O)ORa and -C(O)NRaRb, wherein Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl;

[0055] R5 is selected from hydrogen, halogens, and alkyl groups;

[0056] Ra and Rb are each independently selected from hydrogen, alkyl, and cycloalkyl groups;

[0057] Q can be a halogen, alkyl group, lateral oxy group, -C(O)Rc, -C(O)ORc, -C(O)NRcRd or -C(O)N(Rc)(CH2)qRd;

[0058] Rc and Rd are each independently selected from hydrogen, alkyl, aryl, and heteroaryl, wherein the alkyl, aryl, and heteroaryl groups may optionally be further substituted with alkoxy groups;

[0059] Alternatively, Rc and Rd together with the nitrogen atom they are attached to form a nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N and O in addition to N;

[0060] p is 1 or 2;

[0061] q is an integer from 0 to 6;

[0062] The condition is that R1, R2, R3, R4, and R5 are not all hydrogen at the same time.

[0063] In some embodiments of the present invention, R1 is defined as described above, and the halogen is preferably chlorine or fluorine.

[0064] In other embodiments of the invention, R1 is defined as described above, and the alkyl group is preferably a C1-C6 alkyl group, more preferably a C1-C6 alkyl group substituted with a halogen, further preferably -CF3, -CHF2 or -CH2F, and even more preferably -CF3.

[0065] In other embodiments of the present invention, R1 is defined as described above. Preferably, the alkenyl group is a C2-C6 alkenyl group; more preferably, the C2-C6 alkenyl group is an alkenyl group substituted with one or more groups selected from Q, where Q is -C(O)Rc, -C(O)ORc, -C(O)NRcRd, and -C(O)N(Rc)(CH2)qRd, and Rc and Rd are defined as described above; even more preferably, the C2-C6 alkenyl group is -CH=CH-COOH, or

[0066] In other embodiments of the invention, R1 is defined as described above, and the cycloalkyl group is preferably a C3-C10 cycloalkyl group, more preferably a C3-C6 cycloalkyl group, and even more preferably an unsubstituted C3-C6 cycloalkyl group, such as an unsubstituted cyclopropyl group, an unsubstituted cyclopentyl group, or an unsubstituted cyclohexyl group.

[0067] In other embodiments of the invention, R1 is defined as described above. Preferably, the heterocyclic group is a C4-C7 heterocyclic group. More preferably, the C4-C7 heterocyclic group is a C4-C7 nitrogen-containing heterocyclic group. Even more preferably, the C4-C7 heterocyclic group is -NReRf, where Re and Rf together with the nitrogen atom attached to them form a nitrogen-containing heterocyclic group. This nitrogen-containing heterocyclic group optionally contains one or more heteroatoms selected from N and O in addition to N. The nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from Q, where Q is a C1-C6 alkyl, a side-oxygen group, and a C1-C6 ester group; wherein the C1-C6 alkyl group is preferably methyl, and the C1-C6 ester group is preferably -C(O)OCH2CH3. Even more preferably, the C4-C7 heterocyclic group is... , , ,

[0068] In other embodiments of the invention, R1 is defined as described above, and the aryl group is preferably a C6-C10 aryl group, more preferably an unsubstituted phenyl group.

[0069] In other embodiments of the invention, R1 is defined as described above, and the heteroaryl group is preferably a 5-10 member heteroaryl group, more preferably a pyridyl, pyrazolyl, or imidazolyl group substituted or unsubstituted with a C1-C6 alkyl group, and even more preferably a C1-C6 alkyl group substituted or unsubstituted with a C1-C6 alkyl group. , or .

[0070] In other embodiments of the present invention, R1 is defined as described above, and in the -C(O)ORc, Rg is a C1-C6 alkyl group; more preferably, -C(O)ORc is -C(O)OCH2CH3.

[0071] In other embodiments of the invention, R1 is defined as described above, and the -NRaRb is preferably -NH2 or -N(CH3)2.

[0072] In other embodiments of the invention, R1 is defined as described above, and the -ORa is preferably -OCH3.

[0073] In other embodiments of the invention, R1 is defined as described above, and the -S(O)pRa is preferably -S(O)2CH3.

[0074] In some preferred embodiments of the present invention, R1 is selected from halogens, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, and -ORa groups, and the definitions of each group are as described above; preferably, R1 is selected from chlorine, , , , , , , , , , , And -OCH3; more preferably, R2, R3, R4, and R5 are all hydrogen. The compound in the above technical solution has an IC50 lower than that of nitrohydroxyquinoline for at least one of the endothelial cell lines, bladder cancer cell lines, prostate cancer cell lines, and mouse prostate cancer cell lines.

[0075] In other preferred embodiments of the present invention, R1 is selected from halogens, cycloalkyl groups, heterocyclic groups, and aryl groups, with each group defined as described above; preferably, R1 is selected from chlorine, cycloalkyl, heterocyclic, and aryl groups. , , and More preferably, R2, R3, R4, and R5 are all hydrogen. The compounds in the above technical solutions all exhibit IC50 values ​​lower than nitrohydroxyquinoline against endothelial cell lines, bladder cancer cell lines, prostate cancer cell lines, and mouse prostate cancer cell lines.

[0076] In other embodiments of the invention, R2 is defined as described above, and the halogen is preferably fluorine or chlorine.

[0077] In other embodiments of the invention, R2 is defined as described above, and the alkyl group is preferably a C1-C6 alkyl group, and more preferably a methyl group.

[0078] In other embodiments of the invention, R2 is defined as described above, and the cycloalkyl group is a C1-C6 cycloalkyl group, preferably a cyclopropyl group.

[0079] In other embodiments of the invention, R3 is defined as described above, and the halogen is preferably fluorine or chlorine.

[0080] In other embodiments of the invention, R3 is defined as described above, and the alkyl group is preferably a C1-C6 alkyl group, and more preferably a methyl group.

[0081] In some other preferred embodiments of the invention, R2 and R3 are both hydrogen.

[0082] In other embodiments of the invention, R4 is defined as described above, and the halogen is preferably fluorine or chlorine.

[0083] In other embodiments of the invention, R4 is defined as described above, and the alkyl group is preferably a C1-C6 alkyl group, and more preferably a methyl group.

[0084] In other embodiments of the present invention, R4 is defined as described above, and Ra in -C(O)ORa is an alkyl or cycloalkyl group, wherein the alkyl group is a C1-C6 alkyl group, preferably an ethyl group; and the cycloalkyl group is a C1-C6 cycloalkyl group, preferably a methylcyclopropyl or cyclohexyl group.

[0085] In other embodiments of the invention, R4 is defined as described above, and Ra and Rb in -C(O)NRaRb are each independently an alkyl group, which is a C1-C6 alkyl group, preferably ethyl, methyl, or isopropyl.

[0086] In other embodiments of the invention, R5 is defined as described above, and the halogen is preferably fluorine or chlorine.

[0087] In other embodiments of the invention, R5 is defined as described above, and the alkyl group is preferably a C1-C6 alkyl group, and more preferably a methyl group.

[0088] In some other preferred embodiments of the invention, both R4 and R5 are hydrogen.

[0089] Typical compounds of this invention include, but are not limited to, the following compounds:

[0090] Or its tautomers, mesosomes, racemates, enantiomers or diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0091] The present invention further provides a method for preparing a compound or meso compound of general formula (I) according to the present invention, or a tautomer, stereoisomer, enantiomer, diastereomer, or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystal form or solvate thereof, or a prodrug or metabolite thereof, or a racemic mixture thereof, or a mixture thereof, comprising the following steps:

[0092] When R1 is -NRaRb

[0093] Under heating conditions, in a solvent, the compound of formula (IA) reacts with the amine compound NHRaRb to yield 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.

[0094] in,

[0095] X is selected from halogens, preferably chlorine and bromine;

[0096] Ra and Rb are each independently selected from hydrogen and C1-C6 alkyl groups;

[0097] Alternatively, Ra and Rb together with their attached nitrogen atom form a 5- to 7-membered nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N, O, and S in addition to N. Preferably, the heterocyclic group is selected from... , , , , , and The 5 to 7 nitrogen-containing heterocyclic groups may optionally be further substituted by one or more groups selected from Q;

[0098] Q can be a halogen, a side oxygen group, a C1-C6 alkyl group, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(O)N(Rc)(CH2)qRd, or -S(O)pRc;

[0099] Rc and Rd are each independently selected from hydrogen or C1-C6 alkyl groups, wherein the C1-C6 alkyl group may optionally be further substituted with one or more groups selected from halogens;

[0100] Alternatively, Rc and Rd together with the nitrogen atom they are attached to form a 5- to 7-membered nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N, O, and S in addition to N, and which optionally is further substituted by one or more groups selected from halogens and C1-C6 alkyl groups;

[0101] p is 1 or 2;

[0102] q is an integer from 0 to 6;

[0103] The definitions of R2, R3, R4, and R5 are as described above.

[0104] The present invention further provides a method for preparing a compound or meso compound of general formula (I) according to the present invention, or a tautomer, stereoisomer, enantiomer, diastereomer, or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystal form or solvate thereof, or a prodrug or metabolite thereof, or a racemic mixture thereof, or a mixture thereof, comprising the following steps:

[0105] When R1 is a C3-C10 cycloalkyl, C6-C10 aryl, or 5 to 10 heteroaryl

[0106] In the presence of a catalyst and a base, compound Ib reacts with boric acid compound R1-B(OH)2 to give compound (IB); wherein the catalyst is preferably tetratetraphenylphosphine palladium, and the base is preferably potassium carbonate; then,

[0107] Under heating conditions, in a solvent, and in the presence of a demethylating agent, compound (IB) undergoes a demethylation reaction to yield compound (I); wherein, DMF is preferred as the solvent, LiCl is preferred as the demethylating agent, and the reflux temperature of the solvent is preferred as the heating condition.

[0108] Wherein, X is selected from halogens, preferably chlorine and bromine;

[0109] The definitions of R2, R3, R4, and R5 are as described above.

[0110] The present invention further provides a method for preparing a compound or meso compound of general formula (I) according to the present invention, or a tautomer, stereoisomer, enantiomer, diastereomer, or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystal form or solvate thereof, or a prodrug or metabolite thereof, or a racemic mixture thereof, or a mixture thereof, comprising the following steps:

[0111] When R1 is -C(O)ORa or -S(O)pRa

[0112] The compound of formula (IA) reacts with compound MO-R1 in a solvent under heating conditions to give the compound of general formula (I); wherein M is an alkali metal, such as Na, K or Mg; the solvent is preferably DMF; the heating conditions are preferably 100°C to the reflux temperature of the solvent;

[0113] in,

[0114] X is selected from halogens, preferably chlorine and bromine;

[0115] Ra is selected from hydrogen and C1-C6 alkyl groups;

[0116] p is 1 or 2;

[0117] The definitions of R2, R3, R4, and R5 are as described above.

[0118] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or meso compound of general formula (I) according to the present invention, or a tautomer thereof, stereoisomer thereof, enantiomer thereof, diastereomer thereof, or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystal form or solvate thereof, or a prodrug or metabolite thereof, or a racemic mixture thereof, or a mixture thereof, and a pharmaceutically acceptable carrier thereof; wherein “therefore” refers to the compound.

[0119] The present invention also provides the use of a compound or meso compound of general formula (I) according to the present invention, or its 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 racemic mixture thereof, or a mixture thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating infectious diseases or cancer, wherein the infectious disease is a systemic infection, a reproductive system infection or a urinary tract infection, preferably a urinary tract infection, more preferably an infection caused by Gram-negative bacteria and / or Gram-positive bacteria, the Gram-negative bacteria including Escherichia coli and Acinetobacter baumannii, the Gram-positive bacteria including Staphylococcus aureus, and the cancer preferably bladder cancer.

[0120] The present invention also provides a compound or meso compound of general formula (I) according to the present invention, or its tautomer, stereoisomer, enantiomer, diastereomer, or isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or solvate of any of the foregoing, or a prodrug or metabolite of any of the foregoing, or a racemic mixture thereof, or a mixture thereof, or a pharmaceutical composition thereof, for the treatment of infectious diseases or cancer, wherein the infectious disease is a systemic infection, a reproductive system infection, or a urinary tract infection, preferably a urinary tract infection, more preferably an infection caused by Gram-negative bacteria and / or Gram-positive bacteria, the Gram-negative bacteria including Escherichia coli and Acinetobacter baumannii, the Gram-positive bacteria including Staphylococcus aureus, and the cancer preferably bladder cancer.

[0121] The present invention also provides a method for treating an infectious disease or cancer in a patient, comprising administering to a patient in need a therapeutically effective amount of a compound or meso compound of general formula (I) according to the present invention, or a tautomer, stereoisomer, enantiomer, diastereomer, or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form or solvate thereof, or a prodrug or metabolite thereof, or a racemic mixture thereof, or a mixture thereof, or a pharmaceutical composition thereof; wherein the infectious disease is a systemic infection, a reproductive system infection, or a urinary tract infection, preferably a urinary tract infection, more preferably an infection caused by Gram-negative bacteria and / or Gram-positive bacteria, the Gram-negative bacteria including Escherichia coli and Acinetobacter baumannii, the Gram-positive bacteria including Staphylococcus aureus, and the cancer preferably bladder cancer.

[0122] According to conventional methods in the field of this invention, the compound represented by general formula (I) can react with a base or acid to form a pharmaceutically acceptable basic addition salt or acid addition salt. The base includes inorganic and organic bases; acceptable organic bases include diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, and aminobutanetriol, etc., and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide, etc. The acid includes inorganic and organic acids; acceptable inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrobromic acid, etc., and acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, and ascorbic acid, etc.

[0123] Pharmaceutical compositions containing an active ingredient may be in forms suitable for oral administration, such as tablets, sugar tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from: sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginate; binders such as starch, gelatin, polyvinylpyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or coated using known techniques that provide sustained release over a longer period of time by masking the taste of the drug or by delaying disintegration and absorption in the gastrointestinal tract. For example, water-soluble taste-masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose may be used, or time-extending substances such as ethylcellulose or cellulose acetate butyrate may be used.

[0124] Oral formulations can also be provided in hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil solvent such as peanut oil, liquid paraffin or olive oil.

[0125] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of olefinic oxygen and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene dehydrated sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin, or aspartame.

[0126] Oil suspensions can be formulated by suspending the active ingredients in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin. Oil suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents can be added to provide a palatable formulation. These components can be preserved by adding antioxidants such as butylated hydroxyanisole (BHA) or α-tocopherol.

[0127] By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can provide active ingredients and dispersants or wetting agents, suspending agents, or one or more preservatives for mixing. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These components are preserved by adding antioxidants such as ascorbic acid.

[0128] The pharmaceutical composition of this invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, and condensation products of such metaesters and ethylene oxide, such as poly(ethylene oxide) sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose can be used. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0129] The pharmaceutical composition of the present invention can be in the form of a sterile injectable aqueous solution. Acceptable solvents and media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated with a mixture of water and glycerol to form a microemulsion. The injection solution or microemulsion can be injected into the patient's bloodstream by local large-volume injection. Alternatively, it is preferable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device can be used.

[0130] The pharmaceutical composition of the present invention can be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. This suspension can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulation can also be a sterile injectable solution or suspension prepared in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, a sterile fixative oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixative oil, including synthetic mono- or diglycerides of glycerol, can be used. Additionally, fatty acids such as oleic acid can also be used to prepare the injectable formulation.

[0131] The compounds of the present invention can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug. Such substances include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycol of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0132] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, weight, health condition, lifestyle, diet, timing of administration, route of administration, excretion rate, and combination of drugs. Furthermore, optimal treatment methods, such as treatment regimens, daily dosage of general-formula compounds, or types of pharmaceutically acceptable salts, can be validated based on conventional treatment protocols.

[0133] This invention can contain compounds of general formula (I) and their pharmaceutically acceptable salts, hydrates, or solvates as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare compositions, and formulated into clinically acceptable dosage forms. Derivatives of this invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions. The compounds of this invention can be used as the sole active ingredient or in combination with other drugs for treating diseases related to tyrosine kinase activity. Combination therapy is achieved by administering the various therapeutic components simultaneously, separately, or sequentially.

[0134] Detailed description of the invention

[0135] Unless otherwise stated, the terms used in the specification and the scope of the patent application shall have the following meanings.

[0136] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tributyl, dibutyl, 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tributyl, dibutyl, 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, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, syloxy, carboxyl, and carboxylic acid ester group.

[0137] The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0138] The term "alkynyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, etc. Alynyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0139] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, further preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0140] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being more preferred. More preferably, they are 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0141] 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 the 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 members, more preferably 7 to 10 members. 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 groups include:

[0142] The term "bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group with 5 to 20 members, 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 has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0143] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group. 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, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, cycloalkylthio, syloxy, carboxyl, or carboxylic acid ester group.

[0144] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it comprises 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it comprises 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0145] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being more preferred. More preferably, it consists of 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0146] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0147] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0148] The heterocyclic ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include: and wait.

[0149] The heterocyclic group can 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, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, syloxy, carboxyl, or carboxylic acid ester group.

[0150] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0151] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0152] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferred examples include imidazolyl, furanyl, thiophenel, thiazolyl, pyrazolyl, oxazolyl, pyrrolel, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl, or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0153] The heteroaryl group can 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, carboxyl, or carboxylic acid ester group.

[0154] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0155] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0156] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0157] The term "hydroxyl group" refers to the -OH group.

[0158] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0159] The term "amine" refers to -NH2.

[0160] The term "cyano" refers to -CN.

[0161] The term "nitro" refers to -NO2.

[0162] The term "side radical" refers to =O.

[0163] The term "carboxyl group" refers to -C(O)OH.

[0164] The term "thiol" refers to -SH.

[0165] The term "ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0166] The term "acetylated" refers to a compound containing a -C(O)R group, where R is an alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group.

[0167] "Optional" or "optionally" means that the event or environment described below may, but does not have to, occur, and the description includes the possibility that the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic groups" means that alkyl groups may, but do not have to, be present, and the description includes cases where heterocyclic groups are substituted with alkyl groups and cases where heterocyclic groups are not substituted with alkyl groups.

[0168] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, each independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) the possible or impossible substitutions without much effort. For example, an amino group or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (such as an alkene).

[0169] "Pharmaceutical composition" refers to a mixture containing one or more of the compound described herein or its physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate drug delivery to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0170] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0171] Method for synthesizing the compounds of the present invention

[0172] In order to achieve the objectives of this invention, the following synthetic scheme is used to prepare the compound of general formula (I) of this invention.

[0173] Option 1:

[0174] When R1 is -NReRf

[0175] Option 1

[0176] 1) In the presence of a nitrating agent and a dehydrating agent, compound Ia undergoes a nitration reaction to yield compound Ib; wherein, nitric acid is preferred as the nitrating agent, and concentrated sulfuric acid and acetic anhydride are preferred as the dehydrating agent;

[0177] 2) Under heating conditions, in a solvent, and in the presence of a demethylating agent, compound Ib undergoes a demethylation reaction to give compound (IA); wherein, DMF is preferred as the solvent, LiCl is preferred as the demethylating agent, and the reflux temperature of the solvent is preferred as the heating condition;

[0178] 3) Under heating conditions, in a solvent, the compound of formula (IA) reacts with the amine compound NHReRf 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;

[0179] in,

[0180] Re and Rf together with the nitrogen atom they are attached to form a nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N and O in addition to N, and the nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from Q;

[0181] Q is a C1-C6 alkyl group and an ester group; wherein, the C1-C6 alkyl group is preferably methyl, and the ester group is preferably -C(O)OCH2CH3;

[0182] Preferably, the heterocyclic group is

[0183] Option 2:

[0184] When R1 is a C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 heteroaryl

[0185] Option 2

[0186] 1) In the presence of a catalyst and a base, compound Ib reacts with boric acid compound R1-B(OH)2 to give compound (IB); wherein, tetratetraphenylphosphine palladium is preferred as the catalyst, and potassium carbonate is preferred as the base;

[0187] 2) 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; preferably DMF is the solvent, preferably LiCl is the demethylating agent, and preferably the reflux temperature of the solvent is the heating condition.

[0188] Option 3:

[0189] When R1 is -C(O)ORa or -S(O)pRa

[0190] Option 3

[0191] The compound of formula (IA) reacts with compound MO-R1 (M is an alkali metal, such as Na, K, Mg, etc.) in a solvent under heating conditions to obtain 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;

[0192] in,

[0193] Ra is selected from hydrogen and C1-C6 alkyl groups;

[0194] p is 1 or 2.

[0195] In the above scheme, X is a halogen, preferably chlorine or bromine; R2, R3, R4 and R5 are as defined in general formula (I).

[0196] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0197] The reagents and raw materials used in this invention are all commercially available.

[0198] The positive and progressive effects of this invention are that the compounds of this invention exhibit excellent anti-tumor activity and can be developed into drugs for treating tumors. Implementation

[0199] The following examples further illustrate the compounds of the present invention and their preparation, explaining methods for preparing or using the compounds. However, it should be understood that these examples do not limit the invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.

[0200] The compounds of this invention are prepared using convenient starting materials and common preparation steps. Typical or preferred reaction conditions are provided, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions may be adopted. Optimal conditions may vary depending on the specific reactants or solvents used, but in general, the optimal reaction steps and conditions can be determined.

[0201] In addition, this invention may employ protecting groups to protect certain functional groups from unwanted reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, TW Greene and GMWuts's "Protecting Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and cited references therein) provides a detailed description of the protection or deprotection of numerous protecting groups.

[0202] The separation and purification of compounds and intermediates are carried out using appropriate methods and procedures depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. Specific usage methods can be found in the examples described in this invention. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectroscopic data) can be used for characterization.

[0203] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Brukerdps 400 NMR spectrometer with deuterated dimethyl monoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0204] MS measurements were performed using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector).

[0205] Preparative liquid chromatography was performed using an Agilent 1260 Infinity II high-performance liquid chromatograph (manufacturer: Agilent). The chromatographic column was a Daisogel C18 10μm 100A (30mm × 250mm), and the mobile phase was acetonitrile / water.

[0206] Thin-layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silicone plates. The silicone plates used for reaction monitoring in TLC have a diameter of 0.20 mm to 0.25 mm, while the silicone plates used for separation and purification in TLC have a diameter of 0.5 mm.

[0207] Silicone column chromatography uses Qingdao marine silicone 100-200 mesh, 200-300 mesh and 300-400 mesh silicone as carriers.

[0208] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as NetEase, Beijing Ouhe, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, and Shanghai Bide.

[0209] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0210] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0211] The reaction solvent, organic solvent, or inert solvent, is defined as the solvent used under the described reaction conditions and does not participate in the reaction. These solvents include, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, N-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0212] The chemical reactions described in this invention are generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, at one atmosphere, between -78°C and 200°C, approximately 1 to 24 hours. If the reaction is carried out overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, between 20°C and 30°C.

[0213] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the methods of this invention.

[0214] Unless otherwise specified, the temperatures indicated in the examples are the temperatures of the heating medium (dimethyl silicone oil), and the mixing ratios of different solvents are volume ratios.

[0215] In the following text, the mass fraction of palladium in palladium / carbon is 10%.

[0216] Example 1: Synthesis of 7-fluoro-5-nitroquinoline-8-phenol (1)

[0217] Step 1) Preparation of 7-fluoroquinoline-8-ol (1b)

[0218] At room temperature, 2-amino-6-fluorophenol (1a) (5.0 g, 39.3 mmol), glycerol (18 g, 196.6 mmol), nitrobenzene (50.0 mL), and concentrated sulfuric acid (5.0 mL, 93.8 mmol) were added sequentially to a sealed tube. The tube was sealed, and the reaction mixture 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 resulting mixture was filtered, and the organic phase was removed by separation. The aqueous phase was adjusted to pH 6-7 with ammonia and then extracted with ethyl acetate (50.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction agent: petroleum ether / ethyl acetate = 5 / 1) to give 7-fluoroquinoline-8-phenol (1b) (4.7 g, yield 73%).

[0219] Step 2) Preparation of 7-fluoro-5-nitroquinoline-8-phenol (1)

[0220] Nitric acid (65 wt.%) (5.0 mL) was slowly added dropwise to a 15.0 mL solution of 7-fluoroquinoline-8-phenol (1b) (4.7 g, 28.8 mmol) in acetic acid 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 pH of the aqueous phase was adjusted to approximately 6-7 with ammonia. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (50.0 mL) and dried under reduced pressure. The resulting 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 obtain 7-fluoro-5-nitroquinoline-8-phenol (2.5 g, yield 42%).

[0221] 1H NMR(400MHz, DMSO-d 6)δ 9.24(dd,J=8.8,1.4Hz,1H),9.02(dd,J=4.2,1.2Hz,1H),8.63(d,J=11.6Hz,1H),7.90(dd,J=8.8,4.2Hz,1H).

[0222] MS calculation: 208.03; MS measured: 209.1 [M+H]+.

[0223] Example 2: Synthesis of 4-chloro-5-nitroquinoline-8-phenol (2)

[0224] Step 1) Preparation of 4-chloro-5-nitro-8-methoxyquinoline (2b)

[0225] At 0 °C, nitric acid (65 wt.%) (3.0 mL, 43.6 mmol) was slowly added to a solution of 4-chloro-8-methoxyquinoline (2a) (5.0 g, 25.1 mmol) in acetic anhydride (40.0 mL). After stirring for 10 minutes, concentrated sulfuric acid (98 wt.%) (3.0 mL, 55.2 mmol) was slowly added dropwise. The reaction mixture was brought to room temperature and stirred for 1 hour. Ice water (50.0 mL) was added, and the pH of the aqueous phase was slowly adjusted to approximately 8-9 with ammonia. The aqueous phase was extracted with dichloromethane (10.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (extraction agent: petroleum ether / ethyl acetate = 2 / 1) to give 4-chloro-5-nitro-8-methoxyquinoline (2b) (3.8 g, yield 63%).

[0226] Step 2) Preparation of 4-chloro-5-nitroquinoline-8-phenol (2)

[0227] At room temperature, 4-chloro-5-nitro-8-methoxyquinoline (2b) (2.3 g, 9.6 mmol) and lithium chloride (4.0 g, 96.0 mmol) were added to N,N-dimethylformamide (10.0 mL). The reaction mixture was stirred at 160 °C for 1 hour and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. Water (30.0 mL) was added to the residue, and the mixture was stirred for 3 minutes and filtered under reduced pressure. The filter cake was washed with water (3.0 mL x 3) and then dried under vacuum to give 4-chloro-5-nitroquinoline-8-phenol (2) (2.1 g, 97% yield).

[0228] 1H NMR(400MHz, DMSO-d 6)δ 11.34(s,1H),8.93(d,J=4.8Hz,1H),8.13(d,J=8.4Hz,1H),8.00(d,J=4.8Hz,1H),7.21(d,J=8.4Hz,1H).

[0229] MS calculated value: 224.00; MS measured value: 225.1 [M+H]+.

[0230] Example 3: Synthesis of 6-chloro-5-nitroquinoline-8-phenol (3)

[0231] Step 1) Preparation of 6-chloroquinoline-8-phenol (3b)

[0232] At room temperature, 2-amino-5-chlorophenol (3a) (1.0 g, 6.9 mmol), glycerol (2.6 mL, 34.8 mmol), nitrobenzene (5.0 mL), and concentrated sulfuric acid (1.0 mL, 18.8 mmol) were added sequentially to a sealed tube. The tube was sealed, and the reaction mixture was stirred at 140 °C for 6 h. After cooling to room temperature, ice water (20.0 mL) was added, and the pH of the aqueous phase was slowly adjusted to approximately 8-9 with ammonia. The aqueous phase was extracted with dichloromethane (10.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction solvent: dichloromethane / methanol = 10 / 1) to give 6-chloroquinoline-8-phenol (3b) (300 mg, yield 24%).

[0233] Step 2) Preparation of 6-chloro-5-nitroquinoline-8-phenol (3)

[0234] At 0°C, nitric acid (65 wt.%) (1.0 mL) was slowly added dropwise to an acetic acid solution (5.0 mL) of 6-chloroquinoline-8-phenol (3b) (100 mg, 0.63 mmol). The reaction mixture was stirred at 0°C for 0.5 hours, then allowed to rise to room temperature for 1 hour. Ice water (10.0 mL) was added to the reaction mixture, and the pH of the aqueous phase was slowly adjusted to approximately 8-9 with ammonia. The mixture was then extracted with dichloromethane (100.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reversed-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase water / acetonitrile = 100%-70% / 30%, gradient elution (0.1 v% formic acid was added to the aforementioned mobile phase during gradient elution), flow rate 20.0 mL / min) to obtain 6-chloro-5-nitroquinoline-8-phenol (3) (62.5 mg, yield 50%).

[0235] 1H NMR (400MHz, CDCl3) 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).

[0236] MS calculated value: 224.00; MS measured value: 225.1 [M+H]+.

[0237] Example 4: Synthesis of 6-methyl-5-nitroquinoline-8-phenol (4)

[0238] Step 1) Preparation of 6-methylquinoline-8-phenol (4b)

[0239] At room temperature, 2-amino-5-methylphenol (300.0 mg, 2.43 mmol), glycerol (0.48 mL, 6.5 mmol), nitrobenzene (1.0 mL), and concentrated sulfuric acid (98 wt.%) (0.2 mL, 3.75 mmol) were added sequentially to a sealed tube. The tube was sealed, and the reaction mixture was stirred at 140 °C for 6 h. After cooling to room temperature, ice water (10.0 mL) was added, and the pH of the aqueous phase was slowly adjusted to approximately 8-9 with ammonia. The aqueous phase was extracted with dichloromethane (10.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction agent: petroleum ether / ethyl acetate = 1 / 1) to give 6-methylquinoline-8-phenol (4b) (194 mg, 50% yield).

[0240] Step 2) Preparation of 6-methyl-5-nitroquinoline-8-phenol (4)

[0241] Nitric acid (65 wt.%) (0.1 mL) was slowly added dropwise to a 2.0 mL acetic acid solution of 6-methylquinoline-8-phenol (100.0 mg, 0.63 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hours, then heated to room temperature and stirred for 2 hours. Ice water (10.0 mL) was added to the reaction mixture, and the pH of the aqueous phase was slowly adjusted to approximately 8-9 with ammonia. The aqueous phase was extracted with dichloromethane (100.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reversed-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase water / acetonitrile = 100%-70% / 30%, gradient elution (0.1 v% formic acid was added to the aforementioned mobile phase during gradient elution), flow rate 20.0 mL / min) to obtain 6-methyl-5-nitroquinoline-8-phenol (60 mg, yield 47%).

[0242] 1H NMR (400MHz, CDCl3) 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=4.0Hz,1H),3.78(s,3H).

[0243] MS calculation: 204.05; MS measurement: 205.1 [M+H]+.

[0244] Example 5: Synthesis of 4-morpholine-5-nitroquinoline-8-phenol (5)

[0245] At room temperature, 4-chloro-5-nitroquinoline-8-phenol (2) (55.0 mg, 0.24 mmol) and morpholine (87.0 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at 110 °C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (1.0 mL) was added to the residue, and the mixture was stirred for 3 minutes and then filtered under reduced pressure. The filter cake was washed with water (2 x 0.5 mL) and dried under vacuum to give 4-morpholine-5-nitroquinoline-8-phenol (5) (56.0 mg, yield 85%).

[0246] 1H NMR(400MHz,DMSO-d 6)δ 8.61(d,J=8.0Hz,1H),7.99(d,J=8.0Hz,1H),7.33(d,J=4.0Hz,1H),6.84(d,J=8.0Hz,1H),3.76(t,J=4.0,4H),3.07(t,J=4.0,4H).

[0247] MS calculation: 275.09; MS measurement: 276.1 [M+H]+.

[0248] Example 6: Synthesis of 5-nitro-4-(piperidin-1-yl)quinoline-8-phenol (6)

[0249] The same synthesis method as in Example 5 was used to obtain 5-nitro-4-(piperidin-1-yl)quinoline-8-phenol (6) (30.6 mg, 47% yield) from 4-chloro-5-nitroquinoline-8-phenol (2) (55.0 mg, 0.24 mmol) and hexahydropyridine (110.0 mg, 1.2 mmol).

[0250] 1H NMR(400MHz,DMSO-d 6)δ 8.40(d,J=8.0Hz,1H),8.00(d,J=8.0Hz,1H),7.21(d,J=4.0Hz,1H),6.56(d ,J=8.0Hz,1H),2.96(t,J=5.6Hz,4H),1.70-1.60(m,4H),1.59-1.50(m,2H).

[0251] MS calculation: 273.11; MS measurement: 274.1 [M+H]+.

[0252] Example 7: Synthesis of 5-nitro-4-(pyrrolidone-1-yl)quinoline-8-phenol (7)

[0253] The same synthesis method as in Example 5 was used to obtain 5-nitro-4-(pyrrolidine-1-yl)quinoline-8-phenol (7) (53.0 mg, 85% yield) from 4-chloro-5-nitroquinoline-8-phenol (2) (55.0 mg, 0.24 mmol) and tetrahydropyrrole (80.0 mg, 1.2 mmol).

[0254] 1H NMR(400MHz,DMSO-d 6)δ 8.25-8.16(m,2H),7.00(d,J=8.8Hz,1H),6.92(d,J=7.2Hz,1H),3.43(t,J=6.0Hz,1H ),3.58-3.50(m,1H),3.21(t,J=6.0Hz,1H),3.10(p,J=6.5Hz,1H),1.86-1.74(m,4H).

[0255] MS calculation: 245.08; MS measured: 246.1 [M+H]+.

[0256] Example 8: Synthesis of 4-fluoro-5-nitroquinoline-8-phenol (8)

[0257] At room temperature, 4-chloro-5-nitroquinoline-8-phenol (2) (113.0 mg, 0.50 mmol) and cesium fluoride (760.0 mg, 5.0 mmol) were dissolved in anhydrous dimethyl sulfoxide (2.0 mL). The reaction mixture was stirred at 150 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with dichloromethane (50.0 mL), washed once with water (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reversed-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase water / acetonitrile = 100%-70% / 30%, gradient elution (0.1 v% formic acid was added to the aforementioned mobile phase during gradient elution), flow rate 20.0 mL / min) to obtain the product 4-fluoro-5-nitroquinoline-8-phenol (8) (50.0 mg, yield 44%).

[0258] 1H NMR(400MHz, DMSO-d 6)δ 8.79-8.57(m,1H),8.11(d,J=8.0Hz,1H),7.56-7.36(m,1H),6.39(d,J=8.0Hz,1H).

[0259] MS calculation: 208.03; MS measurement: 209.0 [M+H]+.

[0260] Example 9: Synthesis of 5-nitro-4-phenylquinoline-8-phenol (9)

[0261] Step 1) Preparation of 4-bromo-8-methoxyquinoline (9b)

[0262] At room temperature, 4-hydroxy-8-methoxyquinoline (9a) (3.0 g, 17.14 mmol) and phosphorus tribromide (9.3 g, 34.2 mmol) were added sequentially to N,N-dimethylformamide (25.0 mL), and the reaction mixture was heated to 65 °C and stirred for 5 h. After cooling to room temperature, ice water (50.0 mL) was added, and the pH of the aqueous phase was adjusted to approximately 9 with ammonia. The resulting mixture was extracted with ethyl acetate (100.0 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction solvent: petroleum ether / ethyl acetate = 7 / 3) to give 4-bromo-8-methoxyquinoline (9b) (3.7 g, 91% yield).

[0263] Step 2) Preparation of 4-bromo-5-nitro-8-methoxyquinoline (9c)

[0264] At 0 °C, nitric acid (65 wt.%) (5.0 mL) was slowly added to a solution of 4-bromo-8-methoxyquinoline (9b) (3.0 g, 12.66 mmol) in acetic anhydride (25.0 mL). After stirring for 10 minutes, concentrated sulfuric acid (98 wt.%) (2.0 mL) was slowly added dropwise. The reaction mixture was brought to room temperature and stirred for 12 hours. Then, ice water (100.0 mL) was added, and the pH of the aqueous phase was adjusted to approximately 9 with ammonia. The mixture was extracted with dichloromethane (100.0 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 (extraction solvent: petroleum ether / ethyl acetate = 4 / 1) to give 4-bromo-5-nitro-8-methoxyquinoline (9c) (1.5 g, 40% yield).

[0265] Step 3) Preparation of 8-methoxy-5-nitro-4-phenylquinoline (9d)

[0266] 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 (extraction solvent: petroleum ether / ethyl acetate = 1 / 4) to give 8-methoxy-5-nitro-4-phenylquinoline (9d) (60.0 mg, yield 61%).

[0267] Step 4) Preparation of 5-nitro-4-phenylquinoline-8-phenol (9)

[0268] 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).

[0269] 1H NMR (400MHz, DMSO-d 6)δ 8.79-8.52(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).

[0270] MS calculation: 266.07; MS measured: 267.1 [M+H]+.

[0271] Example 10: Synthesis of 5-nitro-4-(piperazin-1-yl)quinoline-8-phenol (10)

[0272] The same synthesis method as in Example 5 was used to obtain 5-nitro-4-(piperazin-1-yl)quinoline-8-phenol (10) (64.0 mg, yield 58%) from 4-chloro-5-nitroquinoline-8-phenol (2) (100.0 mg, 0.44 mmol) and piperazine (192.0 mg, 2.0 mmol).

[0273] 1H NMR (400MHz, CDCl3) δ 8.79-8.71 (m, 1H), 7.92-7.85 (m, 1H), 7.73-7.67 (m, 1H), 7.22-7.15 (m, 1H).

[0274] MS calculated value: 224.00; MS measured value: 225.0 [M+H]+.

[0275] Example 11: Synthesis of 4-(dimethylamino)-5-nitroquinoline-8-phenol (11)

[0276] The same synthesis method as in Example 5 was used to obtain 4-(dimethylamino)-5-nitroquinoline-8-phenol (11) (64.0 mg, yield 68%) from an aqueous solution of 4-chloro-5-nitroquinoline-8-phenol (2) (100.0 mg, 0.44 mmol) and dimethylamine (40 wt.%) (90.0 mg, 2.0 mmol).

[0277] 1H NMR(400MHz, DMSO-d 6)δ 8.33-7.97(m,2H),7.03(d,J=8.0Hz,1H),6.35(d,J=8.0Hz,1H),3.06(s,6H).

[0278] MS calculation: 233.08; MS measured: 234.1 [M+H]+.

[0279] Example 12: Synthesis of 4-(methanesulfonyl)-5-nitroquinoline-8-phenol (12)

[0280] At room temperature, 4-chloro-5-nitroquinoline-8-phenol (2) (120.0 mg, 0.53 mmol), 4-dimethylaminopyridine (13.0 mg, 0.1 mmol), and sodium methanesulfinate (102.0 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (5.0 mL). The reaction mixture was heated to 100 °C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Water (10.0 mL) was added to the residue, and the mixture was stirred for 3 minutes. The residue was filtered, and the filter cake was dried to obtain 4-(methanesulfonyl)-5-nitroquinoline-8-phenol (12) (22.0 mg, 50% yield).

[0281] 1H NMR(400MHz, DMSO-d 6)δ 9.08(d,J=4.0Hz,1H),8.40-8.21(m,2H),8.18(d,J=8.0Hz,1H),6.95-6.84(m,1H),6.74(d,J=8.0Hz,1H),3.12(s,3H).

[0282] MS calculation: 268.02; MS measured: 269.0 [M+H]+.

[0283] Example 13: Synthesis of 4-(2-methylpiperidin-1-yl)-5-nitroquinoline-8-phenol (13)

[0284] The same synthesis method as in Example 5 was used to obtain 4-(2-methylpiperidin-1-yl)-5-nitroquinoline-8-phenol (13) (86.0 mg, 75% yield) from 4-chloro-5-nitroquinoline-8-phenol (2) (100.0 mg, 0.44 mmol) and 2-methylpiperidine (180.0 mg, 2.0 mmol).

[0285] 1H NMR(400MHz,DMSO-d 6)δ 8.38(d,J=8.0Hz,1H),7.99(d,J=8.0Hz,1H),7.08(d,J=4.0Hz,1H),6.47(d,J=8.0Hz,1H),3.00-2.73(m,3H),1.72-1.29(m,9H).

[0286] MS calculation: 287.13; MS measured: 288.1 [M+H]+.

[0287] Example 14: Synthesis of 5-nitro-4-(pyridin-4-yl)quinoline-8-phenol (14)

[0288] Step 1) Preparation of 8-methoxy-4-(pyridin-4-yl)quinoline (14a)

[0289] At room temperature, 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), and potassium carbonate (695.0 mg, 5.04 mmol) were added sequentially to a mixture of toluene (10.0 mL) and water (1.0 mL). 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction solvent: dichloromethane / methanol = 5 / 1) to give 8-methoxy-4-(pyridin-4-yl)quinoline (14a) (330.0 mg, yield 87%).

[0290] Step 2) Preparation of 5-nitro-4-(pyridin-4-yl)-8-methoxyquinoline (14b)

[0291] Nitric acid (65 wt.%) (2.0 mL) was slowly added dropwise to a 3.0 mL solution of acetic anhydride containing 180.0 mg (0.76 mmol) of 8-methoxy-4-(pyridin-4-yl)quinoline (14a) at 0 °C. After stirring at 0 °C for 1 hour, the solution was diluted with 15.0 mL of water, and the pH of the aqueous phase was slowly adjusted to approximately 9-10 with ammonia. The solution was then extracted with dichloromethane (30.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (extraction solvent: dichloromethane / methanol = 19 / 1) to give 5-nitro-4-(pyridin-4-yl)-8-methoxyquinoline (14b) (30.0 mg, yield 14%).

[0292] Step 3) Preparation of 5-nitro-4-(pyridin-4-yl)quinoline-8-phenol (14)

[0293] At room temperature, 5-nitro-4-(pyridin-4-yl)-8-methoxyquinoline (14b) (30.0 mg, 0.11 mmol) and lithium chloride (22.0 mg, 0.55 mmol) were dissolved in N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at 160 °C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the residue, and the mixture was 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 5-nitro-4-(pyridin-4-yl)quinoline-8-phenol (14) (18 mg, yield 61%).

[0294] 1H-NMR (400Hz, DMSO-d 6) δ: 8.85-8.75 (m, 1 H), 7.68-7.53 (m, 2 H), 7.40-7.19 (m, 6 H), 6.81-6.64 (m, 1 H).

[0295] MS calculation: 222.08; MS measured: 223.1 [M+H]+.

[0296] Example 15: Synthesis of 4-(cycloheximine-1-yl)-5-nitroquinoline-8-phenol (15)

[0297] The same synthesis method as in Example 5 was used to obtain 4-(cycloheximine-1-yl)-5-nitroquinoline-8-phenol (15) (68.0 mg, 45% yield) from 4-chloro-5-nitroquinoline-8-phenol (2) (120.0 mg, 0.53 mmol) and cycloheximine (250.0 mg, 2.5 mmol).

[0298] 1H NMR(400MHz,DMSO-d 6)δ 8.16(d,J=8.0Hz,1H),8.10-7.96(m,1H),7.11(d,J=8.0Hz,1H),6.27(d,J=8.0Hz,1H),3.92-3.68(m,2H),3.65- 3.52(m,2H),1.99-1.43(m,8H).

[0299] MS calculation: 287.13; MS measured: 288.1 [M+H]+.

[0300] Example 16: Synthesis of 4-methoxy-5-nitroquinoline-8-phenol (16)

[0301] 4-Chloro-5-nitroquinoline-8-phenol (2) (100.0 mg 0.44 mmol) and sodium methoxide (50.0 mg 0.88 mmol) were dissolved in anhydrous dimethyl sulfoxide (2.0 mL) at room temperature. The reaction mixture was heated to 100 °C and stirred for 2 hours, then cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Water (10.0 mL) was added to the residue, and the mixture was 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-methoxy-5-nitroquinoline-8-phenol (16) (22.0 mg, yield 50%).

[0302] 1H NMR (400MHz, DMSO-d 6)δ 8.84(d,J=4.0Hz,1H),7.82(d,J=8.0Hz,1H),7.31(d,J=4.0Hz,1H),7.10(d,J=8.0Hz,1H),3.98(s,3H).

[0303] MS calculation: 220.05; MS measured: 221.1 [M+H]+.

[0304] Example 17: Synthesis of 5-nitro-4-(pyridin-3-yl)quinoline-8-phenol (17)

[0305] Step 1) Preparation of 4-(pyridin-3-yl)-5-nitro-8-methoxyquinoline (17a)

[0306] At room temperature, 4-bromo-5-nitro-8-methoxyquinoline (9c) (100.0 mg, 0.35 mmol), potassium 3-pyridyltrifluoroborate (150.0 mg, 0.83 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (30.0 mg, 0.04 mmol), and potassium carbonate (120.0 mg, 0.83 mmol) were added sequentially to a mixture of toluene (2.0 mL) and water (0.5 mL). The reaction mixture was stirred at 100 °C for 5 h, cooled to room temperature, diluted with ethyl acetate (50.0 mL), and washed sequentially with water (10.0 mL) and saturated brine (10.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction agent: petroleum ether / ethyl acetate = 1 / 1) to give 4-(pyridin-3-yl)-5-nitro-8-methoxyquinoline (17a) (50.0 mg, yield 51%).

[0307] Step 2) Preparation of 5-nitro-4-(pyridin-3-yl)quinoline-8-phenol (17)

[0308] At room temperature, 4-(pyridin-3-yl)-5-nitro-8-methoxyquinoline (17a) (50.0 mg, 0.18 mmol) and lithium chloride (76.3 mg, 1.8 mmol) were added to N,N-dimethylformamide (2.0 mL). The reaction mixture was heated to 160 °C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Dichloromethane (5.0 mL) was added to the residue, and the mixture was stirred for 3 minutes and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and the residue was separated by reversed-phase high-performance liquid chromatography (HPLC) using an Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), a mobile phase of water / acetonitrile = 100%-70% / 30%, gradient elution (with 0.1 v% formic acid added to the aforementioned mobile phase during gradient elution), at a flow rate of 20.0 mL / min, yielding 5-nitro-4-(pyridin-3-yl)quinoline-8-phenol (17) (35.0 mg, yield 73%).

[0309] 1H NMR(400MHz,DMSO-d 6)δ 9.07(d,J=4.0Hz,1H),8.71-8.57 (m,2H),8.17(d,J=8.0Hz,1H),7.85-7.72(m,2H),7.51-7.45(m,2H),7.21(d,J=8.0Hz,1H).

[0310] MS calculation: 267.06; MS measured: 268.1 [M+H]+.

[0311] Example 18: Synthesis of 4-(8-hydroxy-5-nitroquinoline-4-yl)-1-methylpiperazin-2-one (18)

[0312] The same synthesis method as in Example 5 was used to obtain 4-(8-hydroxy-5-nitroquinoline-4-yl)-1-methylpiperazin-2-one (18) (35.0 mg, yield 26%) from 4-chloro-5-nitroquinoline-8-phenol (2) (100.0 mg, 0.44 mmol) and 1-methylpiperazin-2-one (150.0 mg, 1.3 mmol).

[0313] 1H NMR(400MHz,DMSO-d 6)δ 8.55(d,J=4.0Hz,1H),8.08(d,J=8.0Hz,1H),7.35(d,J=4.0Hz,1H),6.78(d,J =8.8Hz,1H),3.85(s,2H),3.57-3.45(m,2H),3.34-3.27(m,2H),2.87(s,3H).

[0314] MS calculation: 302.10; MS measurement: 303.1 [M+H]+.

[0315] Example 19: Synthesis of 4-cyclopropyl-5-nitroquinoline-8-phenol (19)

[0316] Step 1) Preparation of 4-cyclopropyl-5-nitro-8-methoxyquinoline (19a)

[0317] At room temperature, 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), and potassium carbonate (147 mg, 1.07 mmol) were added sequentially to a mixture of toluene (5 mL) and water (0.5 mL). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was 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 (extraction solvent: petroleum ether / ethyl acetate = 4 / 1) to give 4-cyclopropyl-5-nitro-8-methoxyquinoline (19a) (60.0 mg, 70% yield).

[0318] Step 2) Preparation of 4-cyclopropyl-5-nitroquinoline-8-phenol (19)

[0319] At room temperature, 4-cyclopropyl-5-nitro-8-methoxyquinoline (19a) (60.0 mg, 0.25 mmol) and lithium chloride (105.0 mg, 2.5 mmol) were added sequentially to N,N-dimethylformamide (2.0 mL). The reaction mixture was reacted 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. The mixture was stirred for 3 minutes and filtered. The filter cake was washed sequentially with water (0.5 mL x 2) and ethanol (0.5 mL x 2), and dried under vacuum to obtain 4-cyclopropyl-5-nitroquinoline-8-phenol (19) (11.0 mg, yield 19%).

[0320] 1H-NMR (400Hz, DMSO-d 6)δ:8.46-8.36(m,1 H),8.15-8.07(m,1 H),7.25-7.15(m,1 H),6.20-6.10(m,1 H),2.10-1.95(m,1 H),0.95-0.87(m,2 H),0.59-0.52(m,2 H).

[0321] MS calculation: 230.07; MS measured: 231.1 [M+H]+.

[0322] Example 20: Synthesis of 4-(3-methylpiperazin-1-yl)-5-nitroquinoline-8-phenol (20)

[0323] The same synthesis method as in Example 5 was used to obtain 4-(3-methylpiperazin-1-yl)-5-nitroquinoline-8-phenol (20) (68.0 mg, yield 53%) from 4-chloro-5-nitroquinoline-8-phenol (2) (100.0 mg, 0.44 mmol) and 2-methylpiperazine (130.0 mg, 1.3 mmol).

[0324] 1H NMR(400MHz,DMSO-d 6)δ 8.57(d,J=4.0Hz,1H),8.00-7.90(m,1H),7.25(d,J=8.0Hz,2H),6.78(d,J=8.0Hz,1H),3.30-3.19(m,7H),2.96-2.75(m,3H).

[0325] MS calculation: 288.12; MS measurement: 289.1 [M+H]+.

[0326] Example 21: Synthesis of 4-(azacyclobutane-1-yl)-5-nitroquinoline-8-phenol (21)

[0327] The same synthesis method as in Example 5 was used to obtain 4-(azacyclobutane-1-yl)-5-nitroquinoline-8-phenol (21) (42.0 mg, yield 39%) from 4-chloro-5-nitroquinoline-8-phenol (2) (100.0 mg, 0.44 mmol) and aziridine (68.0 mg, 1.2 mmol).

[0328] 1H NMR(400MHz,DMSO-d 6)δ 8.26(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).

[0329] MS calculation: 245.08; MS measured: 246.1 [M+H]+.

[0330] Example 22: Synthesis of ethyl 4-(8-hydroxy-5-nitroquinoline-4-yl)piperazine-1-carboxylate (22)

[0331] 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).

[0332] 1H NMR(400MHz,DMSO-d 6)δ 8.64(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),4.15-4.03(m,2 H),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).

[0333] MS calculation: 346.13; MS measured: 347.1 [M+H]+.

[0334] Example 23: Synthesis of 4-(2,5-dihydro-1H-pyrrolo-1-yl)-5-nitroquinoline-8-phenol (23)

[0335] The same synthesis method as in Example 5 was used to obtain 4-(2,5-dihydro-1H-pyrrole-1-yl)-5-nitroquinoline-8-phenol (23) (58.0 mg, 64% yield) from 4-chloro-5-nitroquinoline-8-phenol (2) (80.0 mg, 0.35 mmol) and 2,5-dihydro-1H-pyrrole (74.0 mg, 1.06 mmol).

[0336] 1H NMR (400MHz, DMSO-d 6)δ 8.22(d,J=8.0Hz,1H),8.08(d,J=4.0Hz,1H),6.90(d,J=4.0Hz,1H),6.26(d,J=8.0Hz,1H),5.94(s,2H),4.26(s,4H).

[0337] MS calculation: 257.08; MS measured: 258.1 [M+H]+.

[0338] Example 24: Synthesis of 4-cyclopentyl-5-nitroquinoline-8-phenol (24)

[0339] Step 1) Preparation of 4-(cyclopent-1-en-1-yl)-8-methoxyquinoline (24a)

[0340] At room temperature, 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 sequentially to 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, and extracted with ethyl acetate (100.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (extraction solvent: petroleum ether / ethyl acetate = 3 / 1) to give 4-(cyclopent-1-en-1-yl)-8-methoxyquinoline (24a) (330.0 mg, 87% yield).

[0341] Step 2) Preparation of 4-cyclopentyl-8-methoxyquinoline (24b)

[0342] At room temperature, palladium / carbon (200.0 mg) was added to an ethanol solution (16.0 mL) of 4-(cyclopent-1-en-1-yl)-8-methoxyquinoline (24a) (330.0 mg, 1.46 mmol). The reaction mixture was stirred for 3 hours under a hydrogen atmosphere and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to give 4-cyclopentyl-8-methoxyquinoline (24b) (300.0 mg, 90% yield).

[0343] Step 3) Preparation of 4-cyclopentyl-8-methoxy-5-nitroquinoline (24c)

[0344] At 0 °C, nitric acid (65 wt.%) (3.0 mL) was slowly added to a 5.0 mL solution of acetic anhydride containing 300.0 mg (1.32 mmol) of 4-cyclopentyl-8-methoxyquinoline (24b) in 300.0 mg, 1.32 mmol. After stirring for 10 minutes, concentrated sulfuric acid (0.5 mL) was slowly added dropwise. The reaction mixture was brought to room temperature and stirred for 2 hours. Ice water (15.0 mL) was added, and the pH of the aqueous phase was adjusted to approximately 9 with ammonia. The mixture was then extracted with dichloromethane (50.0 mL x 2). 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 (extraction agent: petroleum ether / ethyl acetate = 7 / 3) to give 4-cyclopentyl-8-methoxy-5-nitroquinoline (24c) (70.0 mg, yield 20%).

[0345] Step 4) Preparation of 4-cyclopentyl-5-nitroquinoline-8-phenol (24)

[0346] At room temperature, 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). The reaction mixture 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, and the mixture was stirred for 3 minutes and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and then dried under vacuum to give 4-cyclopentyl-5-nitroquinoline-8-phenol (24) (27.0 mg, yield 41%).

[0347] 1H-NMR(400Hz, DMSO-d 6)δ:8.92-8.83(m,1 H),8.11-8.04(m,1 H),7.81-7.84(m,1 H),3.10-3.04(m,1 H),2.13-2.00(m,2 H),1.87-1.53​​(m,6 H).

[0348] MS calculation: 258.10; MS measurement: 259.1 [M+H]+.

[0349] Example 25: Synthesis of 4-cyclohexyl-5-nitroquinoline-8-phenol (25)

[0350] Step 1) Preparation of 4-cyclohexenyl-8-methoxyquinoline (25a)

[0351] At room temperature, 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) were dissolved in a mixed solvent of toluene (10.0 mL), ethanol (1.0 mL), and water (2.0 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours, then cooled to room temperature and diluted with water (20.0 mL). The resulting mixture was extracted with ethyl acetate (100.0 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction solvent: petroleum ether / ethyl acetate = 1 / 1) to give 4-cyclohexenyl-8-methoxyquinoline (1.1 g, 89% yield).

[0352] Step 2) Preparation of 4-cyclohexyl-8-methoxyquinoline (25b)

[0353] At room temperature, 4-cyclohexenyl-8-methoxyquinoline (25a) (850.0 mg, 3.5 mmol) was dissolved in methanol (20.0 mL), followed by the addition of palladium / carbon (85.0 mg). The resulting suspension was stirred for 3 hours under a hydrogen atmosphere, 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-cyclohexenyl-8-methoxyquinoline (25b) (850.0 mg, 99% yield).

[0354] Step 3) Preparation of 4-cyclohexyl-5-nitro-8-methoxyquinoline (25c)

[0355] At 0°C, nitric acid (65 wt.%) (1.0 mL) was slowly added to a 5.0 mL solution of acetic anhydride containing 800.0 mg (3.3 mmol) of 4-cyclohexyl-8-methoxyquinoline (25b). After stirring for 10 minutes, concentrated sulfuric acid (0.5 mL) was slowly added dropwise. The reaction mixture was stirred at 0°C for 1 hour, then diluted with water (20.0 mL). The pH of the aqueous phase was slowly adjusted to approximately 9-10 with ammonia. Extraction was then performed with ethyl acetate (30.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction agent: petroleum ether / ethyl acetate = 1 / 1) to give 4-cyclohexyl-5-nitro-8-methoxyquinoline (25c) (500.0 mg, yield 53%).

[0356] Step 4) Preparation of 4-cyclohexyl-5-nitroquinoline-8-phenol (25)

[0357] At room temperature, 4-cyclohexyl-5-nitro-8-methoxyquinoline (25c) (500.0 mg, 1.7 mmol) and lithium chloride (740.0 mg, 17.0 mmol) were added to N,N-dimethylformamide (10.0 mL). The reaction mixture was stirred at 160 °C for 1 hour, 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 minutes and filtered under reduced pressure. The filter cake was washed with water (3.0 mL x 2) and then dried under vacuum to give 4-cyclohexyl-5-nitroquinoline-8-phenol (25) (221 mg, yield 48%).

[0358] 1H NMR(400MHz,DMSO-d 6)δ 8.58(d,J=4.0Hz,1H),8.11(d,J=8.0Hz,1H),7.54(d,J=4.0Hz,1H),6.37(d,J=8.0H z,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).

[0359] MS calculation: 272.12; MS measurement: 273.1 [M+H]+.

[0360] Example 26: Synthesis of 5-nitro-4-trifluoromethylquinoline-8-phenol (26)

[0361] Step 1) Preparation of 4,4,4-trifluoro-N-(2-methoxyphenyl)-3-t-oxybutyramine (26b)

[0362] At room temperature, o-methoxyaniline (26a) (2.36 g, 19.2 mmol), ethyl 4,4,4-trifluoroacetyl acetate (2.95 g, 16.0 mmol), and triethylamine (3.24 g, 32.0 mmol) were dissolved in toluene (16.0 mL). The reaction mixture was stirred at 125ºC for 4 hours, 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 sodium bicarbonate aqueous solution (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 crude 4,4,4-trifluoro-N-(2-methoxyphenyl)-3-t-oxybutyramine (26b) (3.48 g, crude yield 78%). This crude product was used directly in the next step without purification.

[0363] Step 2) Preparation of 8-methoxy-4-trifluoromethyl-2(1H)-quinolinone (26c)

[0364] 4,4,4-trifluoro-N-(2-methoxyphenyl)-3-t-oxybutyramine (26b) (2.81 g, 10.7 mmol) was dissolved in polyphosphoric acid (14.0 g) at 90°C. The reaction mixture was stirred at 90°C for 3 hours, and diluted with water (100.0 mL) until the polyphosphoric acid was completely dissolved. The resulting mixture was extracted with dichloromethane (40.0 mL x 3), the organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction solvent: petroleum ether / ethyl acetate = 40 / 1) to give 8-methoxy-4-trifluoromethyl-2(1H)-quinolinone (26c) (2.21 g, 84% yield).

[0365] Step 3) Preparation of 2-chloro-8-methoxy-4-trifluoromethylquinoline (26d)

[0366] At room temperature, 2.09 g (8.6 mmol) of 8-methoxy-4-trifluoromethyl-2(1H)-quinoline (26c) was added to phosphorus oxychloride (8.6 mL). The resulting mixture was stirred at 100ºC for 2 hours, cooled to room temperature, diluted with dichloromethane (40.0 mL), and the pH of the aqueous phase was adjusted to approximately 9-10 with saturated sodium carbonate aqueous solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (15.0 mL x 2). The combined organic phases were washed successively with saturated sodium carbonate aqueous solution (25.0 mL), water (25.0 mL), and saturated brine (25.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 2-chloro-8-methoxy-4-trifluoromethylquinoline (26d) product (2.26 g, 100% crude yield). This product was used directly in the next step without purification.

[0367] Step 4) Preparation of 8-methoxy-4-trifluoromethylquinoline (26e)

[0368] 2-Chloro-8-methoxy-4-trifluoromethylquinoline (26d) (0.52 g, 2.0 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10.0 mL) and methanol (10.0 mL) at room temperature, and then palladium / carbon (0.21 g) was added. The resulting mixture was stirred for 1 hour under a hydrogen atmosphere, filtered through diatomaceous earth, and the filter cake was washed with a mixed solvent of dichloromethane and methanol (dichloromethane / methanol = 20 / 1, 30.0 mL). The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20.0 mL), washed with saturated sodium bicarbonate aqueous solution (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (extraction solvent: petroleum ether / ethyl acetate = 3 / 1) to give 8-methoxy-4-trifluoromethylquinoline (26e) (0.38 g, 84% yield).

[0369] Step 5) Preparation of 8-methoxy-5-nitro-4-trifluoromethylquinoline (26f)

[0370] At 0ºC, nitric acid (65 wt.%) (0.69 mL, 10.0 mmol) was slowly added dropwise to a solution of 8-methoxy-4-trifluoromethylquinoline (26e) (0.38 g, 1.7 mmol) in acetic anhydride (5.0 mL). After stirring for 10 minutes, sulfuric acid (98 wt.%) (0.12 mL, 2.2 mmol) was slowly added dropwise, and stirring continued for 30 minutes. The pH of the aqueous phase was then adjusted to approximately 10 by adding an aqueous solution of sodium hydroxide (1.0 M). The phase was then extracted with dichloromethane (10.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (extraction solvent: petroleum ether / ethyl acetate = 2 / 1) to give 8-methoxy-5-nitro-4-trifluoromethylquinoline (26f) (0.36 g, 78% yield).

[0371] Step 6) Preparation of 5-nitro-4-trifluoromethylquinoline-8-phenol (26)

[0372] At room temperature, 8-methoxy-5-nitro-4-trifluoromethylquinoline (26f) (0.36 g, 1.32 mmol) and lithium chloride (0.56 g, 13.2 mmol) were added to N,N-dimethylformamide (1.7 mL). The resulting mixture was stirred at 170ºC for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The residue was added to water (1.5 mL), 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 5-nitro-4-trifluoromethylquinoline-8-phenol (26) (0.29 g, 85% yield).

[0373] 1H NMR(400MHz, DMSO-d 6)δ 8.92(d,J=3.2Hz,1H),8.29(d,J=9.2Hz,1H),8.01(d,J=4.0Hz,1H),6.59(d,J=9.2Hz,1H).

[0374] MS calculation: 258.03; MS measured: 259.0 [M+H]+.

[0375] Example 27: Synthesis of 4-cyano-5-nitroquinoline-8-phenol (27)

[0376] Step 1) Preparation of 4-cyano-8-methoxyquinoline (27a)

[0377] At room temperature, 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). Under nitrogen protection, the reaction mixture was stirred at 100°C for 2.5 hours, cooled to room temperature, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and the resulting residue was 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, 84% yield).

[0378] Step 2) Preparation of 4-cyano-5-nitro-8-methoxyquinoline (27b)

[0379] At 0ºC, nitric acid (65 wt.%) (0.45 mL, 6.52 mmol) was slowly added to a suspension of 4-cyano-8-methoxyquinoline (27a) (200.0 mg, 1.08 mmol) in acetic anhydride (5.0 mL). The reaction mixture was stirred at 0ºC for 10 minutes, followed by slow dropwise addition of sulfuric acid (98 wt.%) (0.1 mL, 1.87 mmol), and stirring continued for 30 minutes. The pH of the aqueous phase was then adjusted to approximately 10 with a 1.0 M sodium hydroxide solution. Dichloromethane (10.0 mL) was added, and the organic phase was separated. The organic phase was 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 silicone column chromatography (extraction agent: petroleum ether / ethyl acetate = 4 / 1) to give 4-cyano-5-nitro-8-methoxyquinoline (27b) (205.0 mg, 82% yield).

[0380] Step 3) Preparation of 4-cyano-5-nitroquinoline-8-phenol (27)

[0381] At room temperature, 4-cyano-5-nitro-8-methoxyquinoline (27b) (100.0 mg, 0.44 mmol) and lithium chloride (184.0 mg, 4.4 mmol) were added to N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at 160ºC 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, and the mixture was stirred for 3 minutes and filtered under reduced pressure. The filter cake was washed successively with ethanol (2.0 mL) and water (2.0 mL), and then dried under vacuum to give 4-cyano-5-nitroquinoline-8-phenol (27) (91.0 mg, 97% yield).

[0382] 1H NMR(400MHz, DMSO-d 6)δ 8.69(d,J=4.4Hz,1H),8.32(d,J=9.8Hz,1H),8.02(d,J=4.4Hz,1H),6.30(d,J=9.8Hz,1H).

[0383] MS calculation: 215.03; MS measured: 216.1 [M+H]+.

[0384] Example 28: Synthesis of 3-(8-hydroxy-5-nitroquinoline-4-yl)-acrylic acid (28)

[0385] Step 1) Preparation of methyl 3-(8-methoxy-5-nitroquinoline-4-yl)-acrylate (28a)

[0386] At room temperature, 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), tris(o-methylphenyl)phosphine (144.0 mg, 0.47 mmol), and triethylamine (1.35 mL, 9.7 mmol) were added to N,N-dimethylformamide (18.0 mL). The reaction mixture was stirred at 100ºC for 12 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by silicone column chromatography (extraction solvent: petroleum ether / ethyl acetate = 1 / 1.5) to give 3-(8-methoxy-5-nitroquinoline-4-yl)-methyl acrylate (28a) (486.0 mg, yield 53%).

[0387] Step 2) Preparation of 3-(8-methoxy-5-nitroquinoline-4-yl)-acrylic acid (28b)

[0388] At room temperature, methyl 3-(8-methoxy-5-nitroquinoline-4-yl)-acrylate (28a) (486.0 mg, 1.7 mmol) and lithium hydroxide (60.6 mg, 2.53 mmol) were dissolved in a mixture of methanol (14.0 mL) and water (3.5 mL). The reaction mixture was stirred at room temperature for 12 hours, and the organic solvent was removed by vacuum concentration. The residue was adjusted to pH 4 with aqueous hydrochloric acid (1.0 M), and dichloromethane (5.0 mL) was added. The mixture was stirred for 15 minutes, filtered under reduced pressure, and the filter cake was dried under vacuum to give 3-(8-methoxy-5-nitroquinoline-4-yl)-acrylate (28b) (303.0 mg, yield 75%).

[0389] Step 3) Preparation of 3-(8-hydroxy-5-nitroquinoline-4-yl)-acrylic acid (28)

[0390] At room temperature, 3-(8-methoxy-5-nitroquinoline-4-yl)acrylic acid (28b) (70.0 mg, 0.26 mmol) and lithium chloride (107.0 mg, 2.55 mmol) were added to N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at 160ºC for 40 minutes, 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 filtrate was concentrated under reduced pressure, and the residue was purified by C18 reversed-phase column chromatography (the column was Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), the mobile phase was water / methanol = 100%-75% / 25%, gradient elution, and the flow rate was 20.0 mL / min). The residue was then dried under vacuum to obtain 3-(8-hydroxy-5-nitroquinoline-4-yl)-acrylic acid (28) (26.1 mg, yield 39%).

[0391] 1H NMR (400MHz, DMSO-d 6)δ 8.95-8.84(m,1H),8.26(d,J=9.0Hz,1H),7.88(d,J=4.4Hz,1H),7.52(d,J=15.7Hz,1H),6.44(d,J=15.7Hz,1H).

[0392] MS calculation: 260.04; MS measured: 261.1 [M+H]+.

[0393] Example 29: Synthesis of 3-(8-hydroxy-5-nitroquinoline-4-yl)-N-acrylomorpholine (29)

[0394] Step 1) Preparation of 3-(8-methoxy-5-nitroquinoline-4-yl)-N-acrylomorpholine (29a)

[0395] At room temperature, 3-(8-methoxy-5-nitroquinoline-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) were added to DMF (1.5 mL). The reaction mixture 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 sodium bicarbonate aqueous solution (10.0 mL) were added to the residue to separate the organic phase. The organic phase was 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 silicone column chromatography (dichloromethane / ethyl acetate = 100% dichloromethane-100% ethyl acetate, gradient elution) to give 3-(8-methoxy-5-nitroquinoline-4-yl)-N-acrylomorpholine (29a) (115.0 mg, yield 92%).

[0396] Step 2) Preparation of 3-(8-hydroxy-5-nitroquinoline-4-yl)-N-acrylomorpholine (29)

[0397] At room temperature, 3-(8-methoxy-5-nitroquinoline-4-yl)-N-acrylmorpholine (29a) (87.0 mg, 0.25 mmol) and lithium chloride (106.0 mg, 2.5 mmol) were added to N,N-dimethylformamide (3.0 mL). The reaction mixture was stirred at 160 °C for 45 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The residue was dissolved in water (3.0 mL) and purified by C18 reversed-phase column chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100%-75% / 25%, gradient elution) to obtain 3-(8-hydroxy-5-nitroquinoline-4-yl)-N-acrylmorpholine (29) (50.0 mg, yield 45%).

[0398] 1H NMR(400MHz,DMSO-d6)δ 8.59(d,J=4.5Hz,1H),8.23(d,J=9.5Hz,1H),7.79(d,J=4.6Hz,1H),7.32(d,J=15 .2Hz,1H),7.13(d,J=15.2Hz,1H),6.22(d,J=9.6Hz,1H),3.61(t,J=21.9Hz,8H).

[0399] MS calculation: 329.31, MS measured: 330.1 [M+H]+.

[0400] Example 30: Synthesis of 3-(8-hydroxy-5-nitroquinoline-4-yl)-N-(4-methoxybenzyl)-acrylamide (30)

[0401] The same synthesis method as in Example 29 was used to obtain 3-(8-methoxy-5-nitroquinoline-4-yl)-acrylic acid (28) (100.0 mg, 0.36 mmol) and (4-methoxyphenyl)methylamine (75.5 mg, 0.55 mmol) as starting materials to obtain 3-(8-methoxy-5-nitroquinoline-4-yl)-N-(4-methoxybenzyl)-acrylamide (30) (34.3 mg, yield 26%).

[0402] 1H NMR(400MHz,DMSO-d 6)δ 8.64-8.55(m,2H),8.25(d,J=9.5Hz,1H),7.58(d,J=4.6Hz,1H),7.31(d,J=15.6Hz,1H),7.25(d,J=8.6Hz,2 H),6.93(d,J=8.6Hz,2H),6.53(d,J=15.6Hz,1H),6.23(d,J=9.6Hz,1H),4.34(d,J=5.7Hz,2H),3.76(s,3H).

[0403] MS calculation: 379.12, MS measured: 380.2 [M+H]+.

[0404] Example 31: Synthesis of ethyl 8-hydroxy-5-nitroquinoline-4-carboxylate (31)

[0405] Step 1) Preparation of ethyl 8-methoxyquinoline-4-carboxylate (31a)

[0406] At room temperature, sulfuric acid (98 wt.%) (0.6 mL) was slowly added to an ethanol (6.0 mL) solution of 8-methoxyquinoline-4-carboxylic acid (31a) (385.0 mg, 1.89 mmol). The reaction mixture was heated to 90 °C and stirred for 16 hours, then cooled to room temperature and concentrated under reduced pressure to remove the organic solvent. Ethyl acetate (10.0 mL) and saturated sodium carbonate aqueous solution (10.0 mL) were added to the residue to adjust the pH of the aqueous phase to approximately 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 subjected to silica gel column chromatography (extraction solvent: petroleum ether / ethyl acetate = 100%-65% / 35%, gradient elution) to obtain ethyl 8-methoxyquinoline-4-carboxylate (31a) (247.0 mg, yield 56%).

[0407] Step 2) Preparation of ethyl 8-methoxy-5-nitro-4-carboxylate (31b)

[0408] At 0°C, nitric acid (65 wt.%) (0.45 mL, 6.41 mmol) was slowly added to a suspension of ethyl 8-methoxyquinoline-4-carboxylate (31a) (247.0 mg, 1.07 mmol) in acetic anhydride (6.0 mL). After stirring the reaction solution at 0°C for 10 minutes, concentrated sulfuric acid (0.1 mL, 1.87 mmol) was slowly added, and stirring continued for 50 minutes. Sodium hydroxide aqueous solution (1.0 M) was added to the reaction solution to adjust the pH of the aqueous phase to approximately 8, followed by the addition of dichloromethane (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. The residue was purified by silicone column chromatography (extraction agent: petroleum ether / ethyl acetate = 100%-60% / 40%, gradient elution) to give ethyl 8-methoxy-5-nitro-4-carboxylate (31b) (228.0 mg, yield 77%).

[0409] Step 3) Preparation of ethyl 8-hydroxy-5-nitroquinoline-4-carboxylate (31)

[0410] Ethyl 8-methoxy-5-nitro-4-carboxylate (31b) (228.0 mg, 0.82 mmol) and lithium chloride (347.0 mg, 8.2 mmol) were added to N,N-dimethylformamide (3.0 mL) at room temperature. The reaction mixture was stirred at 160 °C for 35 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 the mixture was stirred for 3 min and filtered under reduced pressure. The filter cake was washed with water (1.0 x 2 mL) and then dried under vacuum to give ethyl 8-hydroxy-5-nitroquinoline-4-carboxylate (31) (153.9 mg, 71% yield).

[0411] 1H NMR (400MHz, DMSO-d 6)δ 8.82(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).

[0412] MS calculation: 262.06; MS measured: 263.1 [M+H]+.

[0413] Example 32: Synthesis of ethyl 8-hydroxy-5-nitroquinoline-3-carboxylate (32)

[0414] Step 1) Preparation of ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (32b)

[0415] 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, then cooled to room temperature. 50 mL of dichloromethane was added for dilution, and triethylamine was added to the system. A solid precipitated out. 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 (extraction agent: petroleum ether / ethyl acetate = 3:1) to give ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (32b) (2.19 g, yield 97.7%).

[0416] Step 2) Preparation of ethyl 8-methoxy-quinoline-3-carboxylate (32c)

[0417] 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%).

[0418] Step 3) Preparation of ethyl 8-methoxy-5-nitroquinoline-3-carboxylate (32d)

[0419] At room temperature, ethyl 8-methoxy-quinoline-3-carboxylate (32c) (500.0 mg, 2.16 mmol) and Ac₂O (10 mL) were added to a reaction flask and stirred until clear. Concentrated HNO₃ was added dropwise at 0 °C, and the mixture was stirred for 5 minutes. Concentrated sulfuric acid was then added dropwise to the system, and the mixture was stirred for 2 hours. The reaction system was quenched at 0 °C in a saturated Na₂CO₃ solution, the pH was adjusted to 8-9, and the mixture was extracted with DCM, dried, and concentrated to obtain 550 mg of crude product. The crude product was then purified by column chromatography to obtain ethyl 8-methoxy-5-nitroquinoline-3-carboxylate (32d) (430 mg, 72%).

[0420] Step 4) Preparation of ethyl 8-hydroxy-5-nitroquinoline-3-carboxylate (32)

[0421] N,N-dimethylformamide (2.5 mL) was added to ethyl 8-methoxy-5-nitroquinoline-3-carboxylate (32d) (100 mg, 0.36 mmol) and lithium chloride (153.0 mg, 3.6 mmol). The reaction mixture 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 the mixture was stirred for 3 min and filtered under reduced pressure. The filter cake was washed with water (1.0 x 2 mL) and then dried under vacuum to give ethyl 8-hydroxy-5-nitroquinoline-3-carboxylate (32) (55 mg, yield 57.9%).

[0422] 1H NMR (400MHz, DMSO-d 6)δ 10.04(s,1H),8.46(d,J=9.8Hz,1H),9.03(s,1H),6.33(d,J=9.8Hz,1H),4.42(q,J=7Hz,2H),1.38(t,J=7.1Hz,3H).

[0423] MS calculation: 262.06; MS measured: 263.1 [M+H]+.

[0424] Example 33: Synthesis of 8-hydroxy-6-isopropyl-5-nitroquinoline (33)

[0425] Step 1) Preparation of 8-methoxy-6-isopropyl-quinoline (33b)

[0426] At room temperature, 2.37 g (10 mmol) of 8-methoxy-6-bromo-quinoline (33a) was added to a 100 mL reaction flask, followed by isopropylboric acid (880 mg, 10 mmol), Na₂CO₃ (2.12 g, 20 mmol), and EtOH / H₂O (40 mL / 10 mL). The mixture was stirred and heated to 100 °C for 6 h. The reaction solution was concentrated under reduced pressure, and 50 mL of water and 50 mL of EA were added to extract the product. The organic phase was concentrated, and the residue was purified by silicone column chromatography (ethyl acetate / petroleum ether-90 / 10) to obtain product 33b (1.4 g, 70%).

[0427] Step 2) Preparation of 8-methoxy-6-isopropyl-5-nitro-quinoline (33c)

[0428] At 0-15℃, 8-methoxy-6-isopropyl-quinoline (33b) (610 mg, 3 mmol) was added to 6 mL of concentrated sulfuric acid and stirred until dissolved. Then, concentrated nitric acid (900 mg, 64% wt, 9 mmol) was slowly added, and the mixture was stirred at room temperature for 2 h after the addition was complete. The reaction solution was slowly poured into 50 mL of ice water, and the pH was adjusted to 7-8 with 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%).

[0429] Step 3) Preparation of 8-hydroxy-6-isopropyl-5-nitroquinoline (33)

[0430] 8-Methoxy-6-isopropyl-5-nitro-quinoline (33c) (250 mg, 1 mmol) and LiCl (420 mg, 10 mmol) were added to 3 mL of DMF. The reaction mixture was stirred at 120 °C for 1 hour, concentrated under reduced pressure, slurried with 5 mL of water, filtered, and dried to obtain a yellow solid product, 8-hydroxy-6-isopropyl-5-nitro-quinoline (33) (160 mg), with a yield of 70%.

[0431] MS calculation: 232.08; MS measured: 233.1 [M+H]+.

[0432] Example 34: Synthesis of 8-hydroxy-6-cyclopropyl-5-nitroquinoline (34)

[0433] Step 1) Preparation of 8-methoxy-6-cyclopropyl-quinoline (34b)

[0434] At room temperature, 8-methoxy-6-bromo-quinoline (33a) (2.37 g, 10 mmol) was added to a 100 mL reaction flask, followed by cyclopropylboronic acid (860 mg, 10 mmol), Na₂CO₃ (2.12 g, 20 mmol), and EtOH / H₂O (40 mL / 10 mL). The mixture was stirred and heated to 100 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the product was extracted with 50 mL of water and 50 mL of EA. The organic phase was concentrated under reduced pressure, and the residue was purified by silicone column chromatography (ethyl acetate / petroleum ether = 90 / 10) to obtain product 33b (1.27 g, 63.5%).

[0435] Step 2) Preparation of 8-methoxy-6-cyclopropyl-5-nitro-quinoline (34c)

[0436] At 0-15℃, 8-methoxy-6-cyclopropyl-quinoline (33b) (600 mg, 3 mmol) was added to 6 mL of concentrated sulfuric acid and stirred until dissolved. Then, concentrated nitric acid (900 mg, 64% wt, 9 mmol) was slowly added, and the mixture was stirred at room temperature for 2 h after the addition was complete. The reaction solution was slowly poured into 50 mL of ice water, and the pH was adjusted to 7-8 with 20% Na2CO3 aqueous 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%).

[0437] Step 3) Preparation of 8-hydroxy-6-cyclopropyl-5-nitroquinoline (34)

[0438] 8-Methoxy-6-cyclopropyl-5-nitro-quinoline (33c) (245 mg, 1 mmol) and LiCl (420 mg, 10 mmol) were added to 3 mL of DMF. The reaction mixture was stirred at 120 °C for 1 hour, concentrated under reduced pressure, and then slurried with 5 mL of water. After filtration and drying, a yellow solid product, 8-hydroxy-6-cyclopropyl-5-nitro-quinoline (34) (161 mg), was obtained, with a yield of 70%.

[0439] MS calculation: 230.07; MS measured: 231.1 [M+H]+.

[0440] Example 35: Synthesis of 8-hydroxy-4-(1-methyl-1H-pyrazol-5-yl)-5-nitroquinoline (35)

[0441] At room temperature, 8-hydroxy-4-bromo-5-nitroquinoline (35a) (20 mg, 0.07 mmol), N-methyl-pyrazole-5-boric acid (14 mg, 0.1 mmol), tetrakis(triphenylphosphine)palladium (10 mg, 10%), and sodium carbonate (15 mg, 0.14 mmol) were added to 1 mL of toluene, followed by 0.2 mL of ethanol and 0.4 mL of water. The reaction mixture was stirred at 100ºC for 12 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by silicone column chromatography (extraction solvent: petroleum ether / ethyl acetate = 1 / 1.5) to give 8-hydroxy-4-(1-methyl-1H-pyrazole-5-yl)-5-nitroquinoline (35a) (5 mg, yield 26%).

[0442] MS calculation: 270.08; MS measurement: 271.1 [M+H]+.

[0443] Example 36: Synthesis of 8-hydroxy-4-(4-methylpiperazinyl)-5-nitroquinoline (36)

[0444] At room temperature, 4-chloro-5-nitroquinoline-8-phenol (2) (100 mg, 0.45 mmol) and N-methyl-piperazine (223 mg, 2.2 mmol) were added to 2 mL of DMF. The reaction mixture was stirred at 160ºC for 1 hour, cooled to room temperature, concentrated, and then slurried with 5 mL of water to obtain 8-hydroxy-4-(4-methylpiperazinyl)-5-nitroquinoline (36) (60 mg, yield 46%).

[0445] MS calculation: 288.12; MS measurement: 289.2 [M+H]+.

[0446] Example 37: Synthesis of 3-(8-hydroxy-5-nitroquinoline-4-yl)-N-methyl-acrylamide (37)

[0447] The same synthesis method as in Example 29 was used to obtain 3-(8-hydroxy-5-nitroquinoline-4-yl)-acrylic acid (28) (133.0 mg, 0.485 mmol) and methylamine hydrochloride (49 mg, 0.727 mmol) as starting materials to obtain 3-(8-hydroxy-5-nitroquinoline-4-yl)-N-methyl-acrylamide (37) (7.6 mg, yield 6.18%).

[0448] 1H NMR(400MHz,DMSO-d 6)δ 8.59(d,J=4.5Hz,1H),8.23(d,J=9.5Hz,1H),7.79(d,J=4.6Hz,1H),7.32(d,J=15 .2Hz,1H),7.13(d,J=15.2Hz,1H),6.22(d,J=9.6Hz,1H),3.61(t,J=21.9Hz,8H).

[0449] MS calculation: 273.07, MS measured: 274.10 [M+H]+.

[0450] Example 38: Synthesis of 8-hydroxy-5-nitroquinoline-3-carboxylic acid (38)

[0451] Step 1): Preparation of 8-methoxy-5-nitroquinoline-3-carboxylic acid (38a)

[0452] Ethyl 8-methoxy-5-nitroquinoline-3-carboxylic acid (32d) (330 mg, 1.19 mmol) and LiOH (57 mg, 2.4 mmol) were added to a THF / H2O mixture of 3 mL and 0.3 mL. The reaction mixture was stirred at room temperature for 2 hours, the pH was adjusted to 3-4 with 1N HCl, and the mixture was concentrated under reduced pressure. The residue was then slurried with ethyl acetate, filtered, and dried to give a yellow solid product, 8-methoxy-5-nitroquinoline-3-carboxylic acid (38a) (292 mg), with a yield of 98.5%.

[0453] Step 2): Preparation of 8-hydroxy-5-nitroquinoline-3-carboxylic acid (38)

[0454] 8-Methoxy-5-nitroquinoline-3-carboxylic acid (38a) (40 mg, 0.16 mmol) and LiCl (68 mg, 1.6 mmol) were added to 1 mL of DMF. The reaction mixture was stirred at 130 °C for 1 hour, concentrated under reduced pressure, and the residue was mixed with MeOH / EA at a ratio of 1:1 and slurried. The mixture was filtered and dried to obtain a yellow solid product, 8-hydroxy-5-nitroquinoline-3-carboxylic acid (38a) (30 mg), with a yield of 79.5%.

[0455] 1H NMR (400MHz, DMSO-d 6)δ 9.91(s,1H),9.11(s,1H),8.49(d,J=9.5Hz,1H),6.53(d,J=9.5Hz,1H).

[0456] MS calculation: 234.03; MS measured: 235.1 [M+H]+.

[0457] Example 39: Synthesis of 8-hydroxy-5-nitroquinoline-3-carboxylic acid-cyclopropylmethyl ester (39)

[0458] Step 1): Preparation of cyclopropylmethyl 8-methoxy-5-nitroquinoline-3-carboxylic acid ester (39a)

[0459] 8-Hydroxy-5-nitroquinoline-3-carboxylic acid (38a) (60 mg, 0.24 mmol), cyclopropylmethanol (35 mg, 2.0 eq), triphenylphosphine (152 mg, 2.4 eq), and tetrahydrofuran (1 mL) were mixed. Diisopropyl azodicarbonate (118 mg, 2.4 eq) was added dropwise at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain an oily crude product. The crude product was purified by silica gel thin-layer chromatography (DCM:MeOH = 36:1) to give a pale yellow solid product 39a (68 mg), with a yield of 93.1%.

[0460] Step 2): Preparation of 8-hydroxy-5-nitroquinoline-3-carboxylic acid-cyclopropylmethyl ester (39)

[0461] Cyclopropylmethyl 8-methoxy-5-nitroquinoline-3-carboxylic acid ester (39a) (68 mg, 0.22 mmol), lithium chloride (95 mg, 10.0 eq), and N,N-dimethylformamide (2 mL) were mixed and stirred until homogeneous. Under a nitrogen atmosphere, the reaction system was heated to 130 °C and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and water was added to precipitate the solid. The solid was filtered, and the filter cake was washed with water and an ethanol / water solution (1:1, 0.5 mL), respectively. After drying, a yellow solid product, 8-hydroxy-5-nitroquinoline-3-carboxylic acid-cyclopropylmethyl ester (39) (67 mg), was obtained, with a yield of 100%.

[0462] 1H NMR(400MHz,DMSO)δ 10.06(d,J=1.9Hz,1H),8.99(s,1H),8.45(d,J=9.8Hz,1H),6.31(d,J=9.8Hz,1H), 4.22(d,J=7.3Hz,2H),1.34-1.25(m,1H),0.64-0.57(m,2H),0.41(q,J=4.8Hz,2H).

[0463] MS calculation: 288.01; MS measured: 289.26 [M+H]+.

[0464] Example 40: Synthesis of N,N-diethyl-8-hydroxy-5-nitroquinoline-3-methylamine (40)

[0465] Step 1): Preparation of N,N-diethyl-8-methoxy-5-nitroquinoline-3-methamide (40a)

[0466] 3-Carboxy-5-nitro-8-methoxyquinoline (38a) (60 mg, 0.24 mmol), diethylamine (35 mg, 2.0 eq), diisopropylethylamine (94 mg, 3.0 eq), and N,N-dimethylformamide (1 mL) were mixed and stirred until homogeneous. HATU (138 mg, 1.5 eq) was added to the system at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain an oily crude product. The crude product was purified by silica gel thin-layer chromatography (DCM:MeOH = 20:1) to obtain a yellow solid product, N,N-diethyl-8-methoxy-5-nitroquinoline-3-formamide (40a) (40 mg, yield 54.5%).

[0467] Step 2): Preparation of N,N-diethyl-8-hydroxy-5-nitroquinoline-3-methylamine (40)

[0468] N,N-Diethyl-8-methoxy-5-nitroquinoline-3-methylamine (40a) (40 mg, 0.13 mmol), lithium chloride (56 mg, 10.0 eq), and N,N-dimethylmethylamine (1 mL) were mixed and stirred until homogeneous. Under a nitrogen atmosphere, the system was heated to 130 °C and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to precipitate the solid, and the mixture was filtered. The filter cake was washed with water 2-3 times and dried to obtain the yellow solid product N,N-diethyl-8-hydroxy-5-nitroquinoline-3-methylamine (40) (21 mg, yield 55%).

[0469] 1H NMR(400MHz,DMSO)δ 9.39(s,1H),8.68(s,1H),8.48(d,J=9.6Hz,1H),6.40(d,J=9.5Hz,1H),3.49(d,J=6.1Hz,2H),3.18(s,2H),1.19(s,3H),1.07(s,3H).

[0470] MS calculation: 289.11; MS measured: 290.29 [M+H]+.

[0471] Example 41: Synthesis of N,N-dimethyl-8-hydroxy-5-nitroquinoline-3-methamide (41)

[0472] The preparation method is the same as in Example 40, except that dimethylamine solution is used instead of diethylamine to obtain N,N-dimethyl-8-hydroxy-5-nitroquinoline-3-methylamine (41).

[0473] 1H NMR(400MHz,DMSO)δ 9.46(d,J=1.8Hz,1H),8.71(s,1H),8.49(d,J=9.6Hz,1H),6.38(d,J=9.6Hz,1H),3.07(s,3H),2.99(s,3H).

[0474] MS calculation: 261.07; MS measured: 262.24 [M+H]+.

[0475] Example 42: Synthesis of 8-hydroxy-6-fluoro-5-nitroquinoline (42)

[0476] Step 1): Preparation of 8-methoxy-6-fluoroquinoline (42b)

[0477] 4-Fluoro-2-methoxyaniline (42a) (2.00 g, 14.2 mmol.) and hydrochloric acid (6 M, 20 mL) were mixed and stirred until homogeneous. The system was heated to 110 °C, and acrolein diethanol condensate (4.61 g, 2.5 eq) was added. The mixture 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. The solution was 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 oily crude product. The crude product was purified by silica gel column chromatography (PE:EA = 7:1~3:1) to give a yellow solid product 8-methoxy-6-fluoroquinoline (42b) (443 mg, yield 17.6%).

[0478] Step 2): Preparation of 8-methoxy-6-fluoro-5-nitroquinoline (42c)

[0479] Mix 8-methoxy-6-fluoroquinoline (42b) (220 mg, 1.24 mmol) and acetic anhydride (4.4 mL), and stir until dissolved. At 0 °C, add concentrated nitric acid (65%, 0.258 mL, 3.0 eq) dropwise to the system, and stir for 5 minutes. Then add concentrated sulfuric acid (98%, 0.068 mL, 1.0 eq) dropwise to the system, and stir overnight. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to quench the reaction. The pH of the aqueous phase was adjusted to 8-9, and the solution was extracted with dichloromethane. The organic phase was washed with saturated brine, 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 = 3:1-2:1) to obtain a yellow solid. Further purification was carried out by silica gel thin-layer chromatography (dichloromethane as the developing solvent) to obtain a pale yellow solid product 8-methoxy-6-fluoro-5-nitroquinoline (42c) (103 mg, yield 37.3%).

[0480] Step 3): Preparation of 8-hydroxy-6-fluoro-5-nitroquinoline (42)

[0481] 8-Methoxy-6-fluoro-5-nitroquinoline (42c) (103 mg, 0.47 mmol), lithium chloride (197 mg, 10.0 eq), and N,N-dimethylformamide (2.5 mL) were mixed and stirred until homogeneous. Under a nitrogen atmosphere, the system was heated to 130 °C and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to precipitate the solid, which was filtered. The filter cake was washed twice with water and dried to obtain the yellow solid product 8-hydroxy-6-fluoro-5-nitroquinoline (42c) (49 mg, yield 50.8%).

[0482] 1H NMR(400MHz,DMSO)δ 9.10(d,J=8.7Hz,1H),8.56(d,J=3.2Hz,1H),7.61(dd,J=8.7,4.1Hz,1H),6.14(d,J=17.9Hz,1H).

[0483] MS calculation: 208.15; MS measurement: 209.0 [M+H]+.

[0484] Example 43: Synthesis of cyclohexyl 8-hydroxy-5-nitroquinoline-3-carboxylic acid ester (43)

[0485] Step 1): Preparation of cyclohexyl 5-nitro-8-methoxyquinoline-3-carboxylic acid ester (43a)

[0486] At room temperature, carbonyl diimidazole (CDI) (85 mg, 0.52 mmol) was added in portions to a solution of 5-nitro-8-methoxyquinoline-3-carboxylic acid (38a) (100 mg, 0.4 mmol) in N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour, and cyclohexanol (120 mg, 1.2 mmol) was slowly added. The reaction mixture was stirred at 45ºC for 6 hours. Cool to room temperature, dilute with water (10.0 mL), extract with dichloromethane (10.0 mL x 2), combine the organic phases, wash with saturated brine (10.0 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silicone column chromatography (extraction agent: ethyl acetate / petroleum ether = 0~40%) to give cyclohexyl 5-nitro-8-methoxyquinoline-3-carboxylic acid (43a) (101 mg, yield 75.9%).

[0487] Step 2): Preparation of cyclohexyl 8-hydroxy-5-nitroquinoline-3-carboxylic acid ester (43)

[0488] At room temperature, 5-nitro-8-methoxyquinoline-3-carboxylic acid cyclohexyl ester (43a) (50.0 mg, 0.15 mmol) and lithium chloride (63.0 mg, 1.5 mmol) were added to N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at 130 °C for 1 hour. After cooling to room temperature, the organic solvent was removed by concentration under reduced pressure. Water (2.0 mL) was added to the residue, and the mixture was stirred for 3 minutes and filtered under reduced pressure. The resulting filter cake was added to water (1.0 mL) and ethanol (1.0 mL), stirred for 10 minutes, filtered under reduced pressure, and the filter cake was dried under vacuum to give 8-hydroxy-5-nitroquinoline-3-carboxylic acid cyclohexyl ester (43) (36.5 mg, yield 76.3%).

[0489] 1H NMR(400MHz,DMSO-d6)δ:10.08(s,1H),9.00(s,1H),8.48(d,J=9.8Hz,1H),6.34(d,J=9 .8Hz,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).

[0490] MS calculation: 316.11; MS measured: 317.2 [M+H]+.

[0491] Example 44: Synthesis of N-isopropyl-8-hydroxy-5-nitroquinoline-3-methamide (44)

[0492] Step 1): Preparation of N-isopropyl-5-nitro-8-methoxyquinoline-3-methamide (44a)

[0493] At room temperature, carbonyl diimidazole (85 mg, 0.52 mmol) was added in portions to a solution of 5-nitro-8-methoxyquinoline-3-carboxylic acid (38a) (100 mg, 0.4 mmol) in N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour, and isopropylamine (141.9 mg, 2.4 mmol) was slowly added. The reaction mixture was stirred at room temperature for 16 hours. Dilute with water (10.0 mL), extract with dichloromethane (10.0 mL x 2), combine the organic phases, wash with saturated brine (10.0 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silicone column chromatography (extraction solvent: (dichloromethane:methanol = 4:1) / dichloromethane = 0~28%) to obtain N-isopropyl-5-nitro-8-methoxyquinoline-3-methamide (44a) (52.0 mg, yield 44.8%).

[0494] Step 2): Preparation of N-isopropyl-8-hydroxy-5-nitroquinoline-3-methamide (44)

[0495] At room temperature, N-isopropyl-5-nitro-8-methoxyquinoline-3-methamide (44a) (52.0 mg, 0.18 mmol) and lithium chloride (75.5 mg, 1.8 mmol) were added to N,N-dimethylmethamide (2.0 mL). The reaction mixture was stirred at 130 °C for 1.5 h. After cooling to room temperature, the organic solvent was removed by concentration under reduced pressure. Water (2.0 mL) was added to the residue, and the mixture was stirred for 3 min and filtered under reduced pressure. The resulting filter cake was added to water (1.0 mL) and ethanol (1.0 mL), stirred for 10 min, filtered under reduced pressure, and the filter cake was dried under vacuum to give N-isopropyl-8-hydroxy-5-nitroquinoline-3-methamide (44) (35.5 mg, yield 71.7%).

[0496] 1H NMR(400MHz,DMSO-d6)δ:9.84(d,J=1.9Hz,1H),8.93(d,J=1.7Hz,1H),8.70(d,J=7.6Hz,1 H),8.49(d,J=9.7Hz,1H),6.36(d,J=9.7Hz,1H),4.26-4.10(m,1H),1.24(d,J=6.6Hz,6H).

[0497] MS calculation: 275.09; MS measurement: 276.1 [M+H]+.

[0498] Biological tests

[0499] Test Example 1: Determination of the inhibitory activity of the compounds of the present invention against cancer cells.

[0500] Experimental materials, reagents, and testing methods

[0501] 1. Cell lines

[0502] HUVEC (purchased from Auscells Biotechnology (Shanghai) Co., Ltd.); UM-UC-3 (ATCC); LNCaP Clone FGC (ATCC); RM-1 (purchased from Nanjing Kebai Biotechnology Co., Ltd.)

[0503] 2. Reagents

[0504] Allcells (H-004) complete endothelial cell culture medium

[0505] Culture medium RPMI 1640 (ATCC, 30-2001)

[0506] Culture medium EMEM (ATCC, 30-2003),

[0507] Culture medium: DMEM (Gibco, 12430-054)

[0508] Fetal bovine serum (Gibco, 10091148)

[0509] Penicillin-streptomycin bispecific antibody (Gibco, S110JV)

[0510] DPBS (Gibco, 14190-144)

[0511] CellTiter-Glo® Assay Kit (Promega, G7573)

[0512] Trypsin (0.25%), phenol red (Gibco, 25200-056)

[0513] DMSO (Sigma, D2650)

[0514] 3. Instruments

[0515] Biosafety cabinet (Sujing Antai, BSC-1300A II)

[0516] Inverted microscope (Nikon, CKX53)

[0517] Automated cell counter (Life Technologies, Countess II)

[0518] Multifunctional microplate reader (Biotek, H1FM)

[0519] Shaker (Hangzhou Aosheng Instrument Co., Ltd., OS-100)

[0520] GraphPad Prism 5.0 software

[0521] XLFIT 5.3 (Shanghai Jiuzhan Information Technology Co., Ltd.)

[0522] 4. Testing Methods

[0523] The testing method involves conducting the following experiments in a biosafety cabinet, with the specific steps as follows:

[0524] (1) On the first day, cells were seeded into 96-well plates. The previous culture medium was discarded, and 5 mL of DPBS was added to wash the cells. The DPBS was then removed and discarded using a pipette. Next, 1 mL of trypsin (0.25%) was added, and the cells were placed in a cell culture incubator at 37°C with 5% CO2 for digestion. After about 2-5 minutes, the cells were removed. Fresh culture medium was added, and the cells were resuspended evenly by pipetting. The cells were then counted using an automated cell counter.

[0525] Among them, an inverted microscope was used to observe the digestion process.

[0526] Among them, HUVEC used complete endothelial cell culture medium; UM-UC-3 used 89v% EMEM + 10v% fetal bovine serum + 1v% penicillin and streptomycin antibiotics; LNcaP Clone FGC used 89v% RPMI1640 + 10v% fetal bovine serum + 1v% penicillin and streptomycin antibiotics; and RM-1 used 89v% DMEM + 10v% fetal bovine serum + 1v% penicillin and streptomycin antibiotics.

[0527] (2) HUVEC cells were seeded in columns 1 to 11 of a 96-well plate (Corning, catalog number 3610) at a density of 2000 cells per well in 100 μL of medium. Cell-free medium was added to the wells in column 12. The same three cell types were seeded: UM-UC-3 and RM-1 at a density of 3000 cells / well; and LNCap Clone FGC at a density of 5000 cells / well. The plates were then incubated at 37°C in a 5% CO2 incubator for 24 h.

[0528] (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).

[0529] (4) After treatment with the compound of the present invention for 72 hours, the cell viability assay reagent from the CellTiter-Glo® assay kit was added to each well of a 96-well plate at a rate of 50 μL, and the plate was shaken on a shaker in the dark for 5-10 minutes. Then, cell viability was measured using a multi-functional microplate reader. Finally, the growth inhibition of the compound of the present invention on cells was plotted using Graphpad Prism 5.0 software or XLFIT software, and the IC50 value of the compound of the present invention was statistically analyzed.

[0530] The IC50 values ​​of the compounds of this invention against various cancer cells are shown in Table 1 below.

[0531] Table 1. IC50 values ​​of the compounds of this invention in inhibiting cancer cells.

[0532] As can be seen from the data in the table above, the compounds of the present invention have better anti-cancer activity than nitroquinoline.

[0533] Test Example 2: Determination of the inhibitory activity of the compounds of the present invention against bacteria.

[0534] 1. Purpose

[0535] 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). Antibacterial activity was determined using the minimum inhibitory concentration (MIC), MIC50, and MIC90. This test was commissioned to Shanghai Junji Medical Laboratory Co., Ltd., and all test materials except the test drug were provided by Shanghai Junji Medical Laboratory Co., Ltd.

[0536] 2. Test drug

[0537] Compounds of the present invention

[0538] 3. Test bacteria

[0539] The test bacteria included several clinically isolated carbapenem-resistant Escherichia coli strains, several carbapenem-resistant Acinetobacter baumannii strains, several methicillin-resistant Staphylococcus aureus strains, and several susceptible Staphylococcus aureus strains, excluding duplicate strains isolated from the same patient; three quality control strains were also included: Escherichia coli ATCC 25922, Acinetobacter baumannii ATCC 19606, and Staphylococcus aureus ATCC 29213. One or more strains of each of the above test bacteria were selected for activity testing for each compound. The number of some tested strains is shown in the table below.

[0540] Table 2 Number of tested bacterial strains (strains)

[0541] 4. Drug susceptibility testing methods

[0542] As recommended by the Clinical and Laboratory Standards Institute (CLSI) in the United States, the MIC of the compound of this invention against clinical isolates was determined using the microbroth dilution method. A positive control was used without the drug, a negative control was used without bacterial culture, and a blank control was used containing only culture medium without either the drug or bacterial culture.

[0543] 4.1 Antibacterial Drug Preparation: All compounds of this invention were dissolved in DMSO. The drug concentration range was 128 mg / L to 0.06 mg / L. Specific method: The compounds of this invention were serially diluted 1:1 using DMSO to form intermediate series with a concentration range of 25600 mg / L to 12.5 mg / L. 30 μL of each intermediate series of each compound was added to a series of 3 mL / tube single-volume broth tubes and mixed thoroughly to form an intermediate series with a concentration range of 256 mg / L to 0.125 mg / L. The diluted series solutions were then distributed row by row to a susceptibility plate, with 50 μL added to each well. All concentration ranges, after being mixed with an equal volume of bacterial suspension, became the ranges to be investigated: 128–0.06 mg / L.

[0544] 4.2 Culture medium: Cation-adjusted Mueller-Hinton broth (CAMHB) was used for drug sensitivity testing.

[0545] 4.3 Inoculation amount: The test bacteria cultured overnight were prepared into a 0.5 McFarland turbidity tube using the direct colony suspension method, and then diluted 100 times to obtain a final inoculation amount of 10⁵ CFU / mL.

[0546] 4.4 Culture conditions: Cultured at 35±2℃ for 20 hours under air conditions.

[0547] 5. Results Reading and Judgment

[0548] The interpretation of drug susceptibility test results shall be in accordance with the CLSI 2019 edition M100, version 29 standard.

[0549] 6. Data Statistics

[0550] The results of the drug susceptibility test were statistically analyzed using WHONET version 5.6 software.

[0551] 7. Experimental Results

[0552] The inhibitory MIC values ​​(unit: mg / L) of the compounds of this invention against various bacteria are shown in Table 3 below. Among them, the MIC values ​​of the compounds against Gram-negative bacteria are... 128 mg / L indicates the compound exhibits antibacterial activity; optimally, under Gram-positive bacterial conditions, the compound's MIC value is [value missing]. 4 mg / L indicates antibacterial activity. The control group without the drug showed normal bacterial growth; the control group without the drug and the blank control group containing only culture medium (without the drug or bacterial solution) both showed no bacterial growth.

[0553] Table 3. MIC values ​​(mg / L) of the compounds of this invention for inhibiting bacteria.

[0554] As shown in the table above, the compounds of the present invention exhibit excellent antibacterial activity against a wide range of strains of Gram-negative bacteria such as Escherichia coli, Acinetobacter baumannii, and Staphylococcus aureus, with MIC values ​​ranging from 8 mg / L to 128 mg / L, 8 mg / L to 128 mg / L, and 1 mg / L to 64 mg / L, respectively. Specifically, compounds 1, 2, 16, 19, 24-27, and 32-34 of the present invention show antibacterial activity against all three bacteria. Compounds 39, 40, and 42 of the present invention show antibacterial activity against both Escherichia coli and Staphylococcus aureus. Compounds 9 and 43 of the present invention show antibacterial activity against Staphylococcus aureus. Therefore, the compounds of this invention exhibit excellent antibacterial activity against one or more of Escherichia coli, Acinetobacter baumannii, and Staphylococcus aureus, and are capable of treating infectious diseases caused by Gram-negative and / or Gram-positive bacteria. Although specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention 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 invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, 1. Among them, R1 is selected from -NRaRb; Ra and Rb are each independently selected from hydrogen and C1-C6 alkyl; or, Ra and Rb together with the nitrogen atom to which they are attached form a 5- to 7-membered nitrogen-containing heterocyclic group, which 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 a side oxygen, C1-C6 alkyl or -C(O)ORc; Rc is selected from C1-C6 alkyl; or, R1 is selected from C3-C10 cycloalkyl, which optionally is further substituted by one or more groups selected from halogen and C1-C6 alkyl; or, R1 is selected from phenyl or pyridyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is hydrogen.

2. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from -NRaRb; Ra and Rb together with the nitrogen atom they are attached to form a 5 to 7 nitrogen-containing heterocyclic group, which is selected from , , , , , and; the 5 to 7 nitrogen-containing heterocyclic group may optionally be further substituted by one or more groups selected from Q; Q is a side oxygen, C1-C6 alkyl or -C(O)ORc; Rc is selected from C1-C6 alkyl.

3. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from C3-C6 cycloalkyl groups, which may optionally be further substituted with one or more groups selected from halogens and C1-C6 alkyl groups.

4. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from cyclopropyl, cyclopentyl, and cyclohexyl, which may be further substituted by one or more groups selected from halogens and C1-C6 alkyl groups.

5. The general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is an unsubstituted C3-C6 cycloalkyl group.

6. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is an unsubstituted cyclopropyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl.

7. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 can be , , , , , , or.

8. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is an unsubstituted phenyl group.

9. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is OR.

10. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is -N(CH3)2.

11. A compound or a pharmaceutically acceptable salt thereof, wherein, This compound was selected from:

12. A compound or a pharmaceutically acceptable salt thereof, wherein, This compound was selected from:

13. A method for preparing a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, comprising the step of: when R1 is -NRaRb, 13. Under heating conditions in a solvent, a compound of formula (IA) reacts with an amine compound NHRaRb to give a compound of general formula (I); when R1 is a C3-C10 cycloalkyl, phenyl, or pyridyl group, 13. In the presence of a catalyst and a base, compound Ib reacts with boric acid compound R1-B(OH)2 to give compound (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 of general formula (I); wherein, X is selected from halogens; R2, R3, R4, R5, Ra, and Rb are as defined in request item 1.

14. The method as described in claim 13, wherein, When R1 is -NRaRb, the solvent is DMF, and the heating condition is 100°C to the solvent's reflux temperature.

15. The method as described in claim 13, wherein, When R1 is a C3-C10 cycloalkyl, phenyl, or pyridyl group, 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 as described in claim 13, wherein, X represents chlorine and bromine.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as described in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

19. Use of a compound of general formula (I) as described in any one of claims 3 to 6, 8 to 9 and 12, or a pharmaceutically acceptable salt thereof, 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, caused by Gram-negative and / or Gram-positive bacteria.

20. The use as described in claim 19, wherein, The Gram-negative bacteria include Escherichia coli and Acinetobacter baumannii, while the Gram-positive bacteria include Staphylococcus aureus.