Application of 8-hydroxyquinoline derivative

Abstract

The invention relates to application of an 8-hydroxyquinoline derivative, in particular to application of the 8-hydroxyquinoline derivative shown in a general formula (I), pharmaceutically acceptable salt, crystal form, solvate, isotope derivative or prodrug of the 8-hydroxyquinoline derivative in preparation of antiviral drugs, in particular to application of the 8-hydroxyquinoline derivative in preparation of anti-human papilloma virus drugs. The definition of each group in the general formula (I) is the same as that in the specification. # imgabs0 #

Description

Uses of 8-hydroxyquinoline derivatives Technical Field

[0001] The present invention relates to the use of 8-hydroxyquinoline derivatives. In particular, the present invention relates to the use of 8-hydroxyquinoline derivatives represented by general formula (I), pharmaceutically acceptable salts, crystalline forms, solvates, isotopic derivatives, or prodrugs thereof in the preparation of antiviral drugs, in particular, in the preparation of anti-human papillomavirus drugs. Background Art

[0002] Human papillomavirus (HPV) is a DNA virus belonging to the family Papillomaviridae. It is extremely common worldwide. Its members have tropism for mucosal and cutaneous epithelia. In addition to causing various reproductive tract diseases such as genital warts, HPV can also cause a variety of malignancies, including cervical cancer, penile cancer, anal cancer, oral cancer, pharyngeal cancer, tonsil cancer, and esophageal cancer. There are over 100 types of HPV, at least a dozen of which can cause cancer, making it the most important class of human tumor viruses. These viruses have a high infection rate and are highly pathogenic, causing significant harm to the general population, especially women, and have attracted widespread attention from the medical community both domestically and internationally. Currently, there are preventive multivalent vaccines (HPV6, HPV11, HPV16, HPV18, etc.) that can prevent infection with multiple types of HPV, but these vaccines have no significant therapeutic effect on patients already infected. The development of effective drugs that target multiple HPV types could provide new approaches for the treatment and prevention of HPV-related diseases, including malignancies.

[0003] Summary of the Invention

[0004] The present invention relates to the use of a compound of general formula (I), a pharmaceutically acceptable salt, a crystal form, a solvate, an isotopic derivative or a prodrug thereof in the preparation of antiviral drugs, especially in the preparation of anti-human papillomavirus (HPV) drugs.

[0005] The present invention solves the above technical problems through the following technical solutions:

[0006] A use of a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof or a prodrug thereof in the preparation of an antiviral drug,

[0007] in:

[0008] R x Each independently selected, h is each independently 1, 2 or 3;

[0009] R y is selected from nitro or cyano, k is 1 or 2;

[0010] The condition is that each R x Not all H atoms.

[0011] In one embodiment, the compound represented by general formula (I), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, which is the compound represented by general formula (IA), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug in the preparation of antiviral drugs,

[0012] in:

[0013] R 11 Selected from H atoms, halogens, D atoms and C 1-6 alkyl;

[0014] R 12 Selected from H atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 Aryl, -C(O)-OR 16 、-CH2-NR 17 R 18 and -CH2-NR 19 R 110 ;

[0015] R 13 Selected from H atoms, D atoms, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl, -(CH2) n -3-8 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -NR 17 R 18 、-O-(CH2) n -NR 17 R 18 、-O-(CH2) n -R 111 、-(CH=CH) m C(O)-NR 17 R 18 and -(CH=CH) m C(O)-NR 19 R 110 wherein the 3-8 membered heterocyclic group is optionally further selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, halogenated C1-6 Alkyl, oxo, -C(O)-NR 17 R 18 、-C(O)-OR 16 、-C(O)-R 16 、-S(O) x R 16 、-O-(CH2) n -R 111 and C 6-14 substituted by one or more substituents in the aryl group;

[0016] R 14 Selected from H atoms, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, -CH2-NR 17 R 18 and -CH2-NR 19 R 110 ;

[0017] R 15 Selected from H atoms, D atoms, halogens, C 1-6 Alkyl and -NR 17 R 18 ;

[0018] R 16 C 1-6 alkyl;

[0019] R 17 and R 18 Each independently selected from H atoms, C 1-6 Alkyl and 3-8 membered heterocyclic group;

[0020] R 19 and R 110 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered nitrogen-containing heterocyclic group, wherein the 3-8 membered nitrogen-containing heterocyclic group optionally contains one or more heteroatoms selected from N, O and S in addition to N, and the 3-8 membered nitrogen-containing heterocyclic group is optionally further substituted with one or more oxo groups;

[0021] R 111 Selected from halogen, C 3-8 Cycloalkyl, C 6-14 Aryl, halogenated C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 alkoxy;

[0022] m is 1;

[0023] n is 0, 1, 2 or 3; and

[0024] x is 2.

[0025] In one embodiment, the compound represented by general formula (IA), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein:

[0026] R 11 is selected from the group consisting of H atoms, F atoms, -CH3 and D atoms;

[0027] and / or, R 12 Selected from H atoms, -CH3,

[0028] and / or, R 13 Selected from H atoms, -CH3, Cl atoms, Br atoms, -OCH3, F atom, -OH, -OCH2CH3, -CF3, -CN, -CHF2, and D atoms;

[0029] and / or, R 14 Selected from H atom, I atom, -CH3, Cl atom, -CN, F atom, -CHF2, -CH2OH and Br atoms;

[0030] and / or, R 15 is selected from the group consisting of H atom, -CH3, F atom, Br atom, Cl atom, D atom and -NHCH3.

[0031] In one embodiment, the compound represented by the general formula (IA), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein the compound of the general formula (IA) is selected from:

[0032] In one embodiment, the compound represented by general formula (IA), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein:

[0033] R 11 is selected from H atoms, halogens, D atoms and C1-C6 alkyl groups;

[0034] R 12 H atoms, C1-C6 alkyl and C 3-8 Cycloalkyl;

[0035] R 13 Selected from H atoms, D atoms, C1-C6 alkyl, halogen, C 1-6 Alkoxy, hydroxy, cyano, halogenated C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0036] R 14 Selected from H atoms, halogen, cyano, halogenated C 1-6 Alkyl and C1-C6 alkyl;

[0037] R 15 Selected from H atoms, D atoms, halogen, C1-C6 alkyl and -NR 17 R 18 ;

[0038] R 17 and R 18 Each independently is a H atom or a C 1-6 alkyl.

[0039] In one embodiment, the compound represented by the general formula (IA), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein the compound of the general formula (IA) is selected from:

[0040] In one embodiment, the compound represented by general formula (IA), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein:

[0041] R 11 is a H atom;

[0042] R 12 is a H atom or a C 3-8 Cycloalkyl;

[0043] R 13 Selected from H atoms, halogenated C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0044] R14 is a H atom or a halogen;

[0045] R 15 Selected from H atoms, halogens and -NR 17 R 18 ;

[0046] R 17 and R 18 Each independently is a H atom or a C 1-6 alkyl.

[0047] In one embodiment, the compound represented by the general formula (IA), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein the compound of the general formula (IA) is selected from: Preferably selected from

[0048] In another embodiment, the compound represented by general formula (I), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, which is the use of the compound represented by general formula (IB), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug in the preparation of antiviral drugs,

[0049] in:

[0050] R 21 Selected from hydrogen, halogen, cyano, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR a 、-NR a R b 、-OR a and -S(O) p R a ; wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more groups selected from Q;

[0051] R 22 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a cycloalkyl group;

[0052] R 23 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group;

[0053] R 24 Selected from hydrogen atom, halogen, alkyl, -C(O)OR a and -C(O)NR a R b , where Ra and R b Each is independently selected from a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-C1-C6 alkyl group;

[0054] R 25 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group;

[0055] R a and R b are each independently selected from a hydrogen atom, an alkyl group, and a cycloalkyl group;

[0056] Q is halogen, alkyl, oxo, -C(O)R c 、-C(O)OR c 、-C(O)NR c R d or -C(O)N(R c )(CH2) q R d ;

[0057] R c and R d are each independently selected from a hydrogen atom, an alkyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the aryl group, and the heteroaryl group are optionally further substituted with an alkoxy group;

[0058] Or, R c and R d Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N and O in addition to N;

[0059] p is 1 or 2;

[0060] q is an integer from 0 to 6;

[0061] The condition is that R 21 、R 22 、R 23 、R 24 and R 25 Not all hydrogen atoms.

[0062] In another embodiment, the compound represented by general formula (IB), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein:

[0063] R 21 is as defined above, and the halogen is chlorine or fluorine;

[0064] and / or, R 21The definition is as described above, and the alkyl group is a C1-C6 alkyl group; the C1-C6 alkyl group is preferably a C1-C6 alkyl group substituted by halogen, more preferably -CF3, -CHF2 or -CH2F, and even more preferably -CF3;

[0065] and / or, R 21 The definition is as described above, and the alkenyl group is a C2-C6 alkenyl group; preferably, the C2-C6 alkenyl group is an alkenyl group substituted by one or more groups selected from Q, and Q is -C(O)R c 、-C(O)OR c 、-C(O)NR c R d and -C(O)N(R c )(CH2) q R d , R c and R d The definition is as described above; more preferably, the C2-C6 alkenyl is -CH=CH-COOH,

[0066] and / or, R 21 The definition is as described above, and the cycloalkyl group is C3-C 10 Cycloalkyl, preferably C3-C6 cycloalkyl, more preferably unsubstituted C3-C6 cycloalkyl, further more preferably unsubstituted cyclopropyl, unsubstituted cyclopentyl or unsubstituted cyclohexyl;

[0067] and / or, R 21 The definition is as described above, and the heterocyclic group is a C4-C7 heterocyclic group; preferably, the C4-C7 heterocyclic group is a C4-C7 nitrogen-containing heterocyclic group; more preferably, the C4-C7 heterocyclic group is -NR e R f , and R e and R f Together with the nitrogen atom to which it is connected, a nitrogen-containing heterocyclic group is formed, wherein the nitrogen-containing heterocyclic group 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, wherein Q is a C1-C6 alkyl, an oxo group or a C1-C6 ester group, wherein the C1-C6 alkyl is preferably methyl, and the C1-C6 ester group is preferably -C(O)OCH2CH3; further more preferably, the C4-C7 heterocyclic group is

[0068] and / or, R 21 The definition of is as described above, and the aryl group is C6-C 10 Aryl, preferably unsubstituted phenyl;

[0069] and / or, R21 The definition of is as described above, and the heteroaryl is a 5-10 membered heteroaryl, preferably a pyridyl, pyrazolyl, imidazolyl substituted or unsubstituted by a C1-C6 alkyl, more preferably

[0070] and / or, R 21 The definition is as described above, and the -C(O)OR c In, R g is C1-C6 alkyl; preferably -C(O)OR c is -C(O)OCH2CH3;

[0071] and / or, R 21 is as defined above, and the -NR a R b is -NH2 or -N(CH3)2;

[0072] and / or, R 21 is as defined above, and the -OR a is -OCH3;

[0073] and / or, R 21 is as defined above, and the -S(O) p R a is -S(O)2CH3;

[0074] and / or, R 22 is as defined above, and the halogen is fluorine or chlorine;

[0075] and / or, R 22 The definition is as described above, and the alkyl group is a C1-C6 alkyl group, preferably a methyl group;

[0076] and / or, R 22 The definition is as described above, and the cycloalkyl group is a C1-C6 cycloalkyl group, preferably a cyclopropyl group;

[0077] and / or, R 23 is as defined above, and the halogen is fluorine or chlorine;

[0078] and / or, R 23 The definition is as described in the above 9, and the alkyl group is a C1-C6 alkyl group, preferably a methyl group;

[0079] and / or, R 24 is as defined above, and the halogen is fluorine or chlorine;

[0080] and / or, R 24 The definition is as described above, and the alkyl group is a C1-C6 alkyl group, preferably a methyl group;

[0081] and / or, R 24 The definition is as described above, and the -C(O)OR a Medium R a is an alkyl group or a cycloalkyl group, wherein the alkyl group is a C1-C6 alkyl group, preferably an ethyl group; the cycloalkyl group is a C1-C6 cycloalkyl group, preferably a methylcyclopropyl group or a cyclohexyl group;

[0082] and / or, R 24 The definition of is as described above, and the -C(O)NR a R b Medium R a 、R b Each is independently an alkyl group, wherein the alkyl group is a C1-C6 alkyl group, preferably an ethyl group, a methyl group, or an isopropyl group;

[0083] and / or, R 25 is as defined above, and the halogen is fluorine or chlorine;

[0084] and / or, R 25 The definition is as described above, and the alkyl group is a C1-C6 alkyl group, preferably a methyl group;

[0085] The condition is that R 21 、R 22 、R 23 、R 24 and R 25 Not all hydrogen atoms.

[0086] In another embodiment, the compound represented by general formula (IB), its pharmaceutically acceptable salt, its crystalline form, its solvate, its isotopic derivative or its prodrug, wherein the compound of general formula (IB) is selected from:

[0087] In another embodiment, the compound represented by general formula (IB), its pharmaceutically acceptable salt, its crystalline form, its solvate, its isotopic derivative or its prodrug, wherein:

[0088] R 21 Selected from hydrogen atom, halogen, cyano, C1-C6 alkyl, 4-8 membered heterocyclic group, halogenated C1-C6 alkyl, -C(O)OR a and C3-C6 cycloalkyl;

[0089] R 22 is selected from the group consisting of a hydrogen atom, a halogen and a C1-C6 alkyl group;

[0090] R 23 is selected from the group consisting of a hydrogen atom, a halogen and a C1-C6 alkyl group;

[0091] R 24Selected from hydrogen atom, halogen, C1-C6 alkyl and -C(O)OR a , where R a is selected from a hydrogen atom, a C1-C6 alkyl group and a C3-C6 cycloalkyl group; and

[0092] R 25 is selected from the group consisting of a hydrogen atom, a halogen and a C1-C6 alkyl group;

[0093] The condition is that R 21 、R 22 、R 23 、R 24 and R 25 Not all hydrogen atoms.

[0094] In another embodiment, the compound represented by general formula (IB), its pharmaceutically acceptable salt, its crystalline form, its solvate, its isotopic derivative or its prodrug, wherein the compound of general formula (IB) is selected from:

[0095] In another embodiment, the compound represented by general formula (IB), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein:

[0096] R 21 Selected from hydrogen atom, 4-8 membered heterocyclic group, halogenated C1-C6 alkyl, -C(O)OR a and C3-C6 cycloalkyl;

[0097] R 22 is a hydrogen atom;

[0098] R 23 is a hydrogen atom;

[0099] R 24 A hydrogen atom or -C(O)OR a ;

[0100] R 25 is a hydrogen atom;

[0101] where R a is a hydrogen atom or a C1-C6 alkyl group.

[0102] In another embodiment, the compound represented by general formula (IB), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug, wherein the compound of general formula (IB) is selected from

[0103] In another embodiment, the compound represented by general formula (I), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug is a compound represented by general formula (IC), its stereoisomer or its pharmaceutically acceptable salt:

[0104] in:

[0105] R 31 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0106] R 32 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0107] R 33 is selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0108] R 34 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, thiol, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0109] R 35 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0110] The condition is that R 31 、R 32 、R 33 、R 34 and R 35 Not all hydrogen atoms.

[0111] In another embodiment, the compound represented by the general formula (IC), its stereoisomers or pharmaceutically acceptable salts thereof, wherein R 34 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl, carboxyl and hydroxyl groups, preferably selected from hydrogen atoms, halogen, C 1-6 Alkyl, halogenated C 1-6The alkyl group and the carboxyl group are more preferably selected from a hydrogen atom, a bromine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a carboxyl group.

[0112] In another embodiment, the compound represented by the general formula (IC), its stereoisomers or pharmaceutically acceptable salts thereof, wherein R 33 Selected from hydrogen atoms, C 1-6 Alkyl, halogen and hydroxyl, preferably hydrogen atom or C 1-6 The alkyl group is more preferably a hydrogen atom or a methyl group.

[0113] In another embodiment, the compound represented by the general formula (IC), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of the general formula (IC) is selected from:

[0114] Preferably selected from

[0115] In another embodiment, the compound represented by general formula (I), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug is used in the preparation of an antiviral drug, wherein the antiviral drug is used for mammals, preferably for humans.

[0116] In another embodiment, the compound of general formula (I), its pharmaceutically acceptable salt, its crystalline form, its solvate, its isotopic derivative or its prodrug is used in the preparation of an antiviral drug, wherein the virus is human papillomavirus; preferably one or more of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) and human papillomavirus 18 (HPV18); more preferably human papillomavirus 6, human papillomavirus 11, human papillomavirus 16 or human papillomavirus 18.

[0117] In another embodiment, the use of the compound represented by general formula (I), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug in the preparation of antiviral drugs, wherein the daily dose of the compound of general formula (I) is 0.01 mg to 1000 mg per kilogram of body weight, preferably 0.1 mg to 500 mg per kilogram of body weight.

[0118] In another embodiment, the use of the compound represented by general formula (I), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug in the preparation of an antiviral drug, wherein the drug further comprises another antiviral agent, preferably, the antiviral agent is selected from acyclovir, valacyclovir, zidovudine, ganciclovir, penciclovir, famciclovir, foscarnet, ribavirin, lamivudine, amantadine, IFNα, cidofovir and rimantadine.

[0119] In another embodiment, the compound represented by general formula (I), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug is used in the preparation of antiviral drugs, wherein the drug is in the following dosage forms: oral solution, suspension, powder, granules, tablets, capsules, pills, emulsion, syrup or aerosol injection.

[0120] In another embodiment, the compound of general formula (I), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug is used in the preparation of antiviral drugs, wherein the drug is administered orally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intranasally, intracerebrally, intraventricularly, intrathecally, intravaginally, rectally, by inhalation and topically.

[0121] In another embodiment, the present invention also provides a method for preventing or treating viral infection, comprising the steps of administering to a subject a therapeutically effective amount of the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystalline form, its solvate, its isotopic derivative or its prodrug as described in the aforementioned use.

[0122] In another embodiment, the method for preventing or treating viral infection in a mammal comprises the following steps: administering to a subject a therapeutically effective amount of the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug as described in the above-mentioned use; wherein the mammal is preferably a human.

[0123] In another embodiment, the present invention also provides a method for in vitro disinfection, comprising the steps of:

[0124] The environment or object to be treated is contacted with an effective amount of the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystal form, its solvate, or its isotopic derivative as described in the above-mentioned use.

[0125] In another embodiment, in the method for preventing or treating a viral infection in a mammal or the method for in vitro disinfection, the virus is human papillomavirus; preferably one or more of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) and human papillomavirus 18 (HPV18); more preferably human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) or human papillomavirus 18 (HPV18).

[0126] In another embodiment, the present invention also provides a pharmaceutical composition for treating viral infection, comprising the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug as described in the above-mentioned use, and a pharmaceutically acceptable excipient.

[0127] In another embodiment, the pharmaceutical composition for treating viral infection in mammals comprises the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug as described in the above-mentioned use, and a pharmaceutically acceptable excipient.

[0128] In another embodiment, in the pharmaceutical composition for treating viral infection in a mammal, the virus is human papillomavirus; preferably one or more of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) and human papillomavirus 18 (HPV18); more preferably human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) or human papillomavirus 18 (HPV18).

[0129] The pharmaceutical composition of the present invention can be in various conventional dosage forms, such as tablets, aqueous suspensions, oil suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, sterile aqueous solutions for injection, sterile oil-in-water microemulsions for injection, sterile powders for injection, creams, ointments, gels, films, patches, plasters, sprays, lotions, or suppositories. Each of the above dosage forms can be prepared by conventional preparation methods.

[0130] 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 following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0131] Definition of terms

[0132] For terms not defined herein, they have the meanings commonly understood by those skilled in the art. For terms defined herein, they have the meanings set in the specification.

[0133] The term "substituted" or "substituent" means that one or more hydrogen atoms are replaced by a specified group. When the position of the substitution is not specified, the substitution can be at any position, but only if a stable or chemically feasible compound is formed.

[0134] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0135] When any variable (e.g., R) occurs more than once in a compound's structure, its definition at each occurrence is independent. For example, if a group is substituted with 0-2 R, then the group may be optionally substituted with up to 2 R, and each occurrence of R is independently selectable.

[0136] The term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C 1-10 Alkyl, more preferably C 1-6 Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-3-ethylhexyl, n-decyl, and 3,3-diethylhexyl.

[0137] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond may be located at any position within the alkenyl group, preferably C 2-5 Alkenyl. Examples of alkenyl groups include, but are not limited to, -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -CH=C(CH3)-CH3, and -CH2-C(CH3)=CH2.

[0138] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond may be located at any position within the alkynyl group, preferably C 2-5Alkynyl. Examples of alkynyl groups include, but are not limited to, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C≡C-CH2-CH3, -CH2-CH2-C≡CH, -CH(CH3)C≡CH, and -CH2-C≡C-CH3.

[0139] The term "cycloalkyl" includes two types, one is a conventional cycloalkyl group and the other is a heterostructure cycloalkyl group.

[0140] Conventional cycloalkyl refers to an aliphatic, saturated or partially unsaturated monovalent cyclic hydrocarbon group having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C 3-12 Conventional cycloalkyl, more preferably C 3-10 Conventional cycloalkyl, more preferably C 3-8 Conventional cycloalkyl, most preferably C 3-6 Conventional cycloalkyl groups. Conventional cycloalkyl groups optionally contain one or more double or triple bonds.

[0141] Conventional cycloalkyl can be a monocyclic alkyl, and examples of monocyclic alkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl. Conventional cycloalkyl can also be polycyclic alkyl (such as bicyclic alkyl and tricyclic alkyl), and polycyclic alkyl includes spirocyclic alkyl, fused cyclic alkyl and bridged cyclic alkyl.

[0142] The term "spirocycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) spirocycloalkyl, preferably a 6-14 membered spirocycloalkyl, more preferably a 7-10 membered spirocycloalkyl. The spirocycloalkyl may be a monospirocycloalkyl, a dispirocycloalkyl, or a polyspirocycloalkyl, preferably a monospirocycloalkyl, more preferably a 4 membered / 4 membered, 4 membered / 5 membered, 4 membered / 6 membered, 5 membered / 5 membered, or 5 membered / 6 membered monospirocycloalkyl. Examples of spirocycloalkyl include, but are not limited to:

[0143] The term "fused cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) fused cycloalkyl, preferably a 6-14 membered fused cycloalkyl, more preferably a 7-10 membered fused cycloalkyl. The fused cycloalkyl may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher ring fused cycloalkyl, preferably a bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered fused cycloalkyl. Examples of fused cycloalkyls include, but are not limited to:

[0144] The term "bridged cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) bridged cycloalkyl group, preferably a 6-14 membered bridged cycloalkyl group, more preferably a 7-10 membered bridged cycloalkyl group. The bridged cycloalkyl group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl group, more preferably a bicyclic or tricyclic bridged cycloalkyl group. Examples of bridged cycloalkyl groups include, but are not limited to:

[0145] The term "heterocyclic alkyl" includes monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl and bridged cyclic alkyl fused to any one of conventional aryl, conventional heteroaryl and conventional heterocyclic groups, and the connection point is located on the corresponding conventional cycloalkyl (referring to monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl or bridged cycloalkyl). Examples of heterocyclic alkyl groups include, but are not limited to:

[0146] The term "heterocyclic group" includes two types, one is a conventional heterocyclic group and the other is a heterostructure heterocyclic group.

[0147] Conventional heterocyclic groups refer to aliphatic, saturated or partially unsaturated, monovalent cyclic hydrocarbon groups having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) ring atoms, wherein one or more ring atoms are substituted by one or more elements selected from nitrogen, oxygen, S, S(O), and S(O)2, and the substitution does not form -OO-, -OS-, or -SS-; preferably C 3-12 Conventional heterocyclic groups, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, C 3-8 Conventional heterocyclic groups, wherein 1 to 3 (e.g. 1, 2 and 3) are heteroatoms; most preferably C 5-7 Conventional heterocyclic groups, wherein 1-2 or 1-3 are heteroatoms.

[0148] Conventional heterocyclic groups can be monocyclic heterocyclic groups. Examples of monocyclic heterocyclic groups include, but are not limited to, oxetanyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, preferably 1,2,5-oxadiazolyl, pyranyl, or morpholinyl. Conventional heterocyclic groups can also be polycyclic heterocyclic groups, including spirocyclic heterocyclic groups, fused-ring heterocyclic groups, and bridged-ring heterocyclic groups.

[0149] The term "spiroheterocyclyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) spiroheterocyclyl, preferably a 6-14 membered spiroheterocyclyl, more preferably a 7-10 membered spiroheterocyclyl. The spiroheterocyclyl may be a monospiroheterocyclyl, a bispiroheterocyclyl, or a polyspiroheterocyclyl, preferably a monospiroheterocyclyl or a bispiroheterocyclyl, more preferably a 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Examples of spiroheterocyclyls include, but are not limited to:

[0150] The term "fused heterocyclic group" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) fused heterocyclic group, preferably a 6-14 membered fused heterocyclic group, more preferably a 7-10 membered fused heterocyclic group. The fused heterocyclic group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Examples of fused heterocyclic groups include, but are not limited to:

[0151] The term "bridged heterocyclic group" refers to a 5-14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) bridged heterocyclic group, preferably a 6-14 membered bridged heterocyclic group, more preferably a 7-10 membered bridged heterocyclic group. The bridged heterocyclic group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. Examples of bridged heterocyclic groups include, but are not limited to:

[0152] The term "heterocyclic group" includes monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups fused to any one of conventional aryl groups, conventional heteroaryl groups and conventional cycloalkyl groups, and the connection point is located on the corresponding conventional heterocyclic group (referring to monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups or bridged heterocyclic groups). Examples of heterocyclic groups include, but are not limited to:

[0153] The term "aryl" includes two types, one is a conventional aryl group and the other is a heterostructure aryl group.

[0154] Conventional aryl refers to 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) aromatic hydrocarbon groups, preferably C 6-10 Conventional aryl groups are more preferably phenyl, naphthyl, phenanthrenyl or anthracenyl.

[0155] The term "heteroaryl" includes a conventional aryl fused to any one of conventional heteroaryl, conventional heterocyclyl and conventional cycloalkyl, with the attachment point being located on the conventional aryl. Examples of heteroaryl groups include, but are not limited to:

[0156] The term "heteroaryl" includes two types, one is a conventional heteroaryl and the other is a heterostructural heteroaryl.

[0157] Conventional heteroaryl refers to 1-4 (e.g., 1, 2, 3, and 4) carbon atoms in a 5-14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) aromatic hydrocarbon group replaced with heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5-10, wherein 1-3 (e.g., 1, 2, and 3) heteroatoms are contained. More preferably, the number of ring atoms is 5 or 6, wherein 1-2 heteroatoms are contained. Examples of conventional heteroaryl include, but are not limited to, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazinyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl or thiazolyl.

[0158] The term "heteroaryl" includes a conventional heteroaryl fused to any one of a conventional aryl, a conventional cycloalkyl, and a conventional heterocyclic group, with the point of attachment being located on the conventional heteroaryl. Examples of heteroaryl groups include, but are not limited to:

[0159] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, wherein "alkyl" and "cycloalkyl" are as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0160] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0161] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0162] The term "hydroxy" refers to -OH.

[0163] The term "halogen" refers to -F, -Cl, -Br or -I.

[0164] The term "amino" refers to -NH2.

[0165] The term "cyano" refers to -CN.

[0166] The term "nitro" refers to -NO2.

[0167] The term "oxo" refers to =0.

[0168] The term "carboxyl" refers to -C(=O)OH.

[0169] The term "mercapto" refers to -SH.

[0170] The term "ester group" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0171] The term "acyl" refers to -C(=O)R, where R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0172] symbol Refers to the attachment site.

[0173] The term "pharmaceutically acceptable" means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, biologically satisfactory and that can be accepted and used as a drug in mammals (such as humans).

[0174] The term "pharmaceutically acceptable salt" should be understood to refer to salts that are pharmaceutically acceptable salts and that possess the intended pharmacological activity of the parent compound (referring to the compound represented by the general formula). Such salts include:

[0175] (1) an acid addition salt formed with an inorganic acid or an acid addition salt formed with an organic acid; wherein the inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; wherein the organic acid may be one or more of formic acid, oxalic acid, succinic acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid and trifluoroacetic acid; and (2) the acid proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion (e.g., Na + , K + or Li + ), alkaline earth metal ions (such as Ca 2+ or Mg 2+) or aluminum ion; or, a salt formed when coordinated with an organic base or an inorganic base; wherein the organic base may be one or more of pyridine, imidazole, pyrazine, indole, purine, tertiary amine and aniline organic bases, preferably one or more of pyridine, picoline, 4-dimethylaminopyridine, 2-methyl-5-ethylpyridine, triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, diethanolamine, ethanolamine, N-methylglucamine, triethanolamine and tromethamine; the inorganic base may be one or more of aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

[0176] The term "isotopic derivative" refers to a compound that differs from the parent compound described herein only in the presence of one or more isotopically enriched atoms. For example, a compound having the structure shown in the general formula with the substitution of "deuterium" or "tritium" for hydrogen and / or "isotopic derivative" for hydrogen. 18 F replaces fluorine, and / or, with 11 C. 13 C or 14 C replaces carbon, while the rest of the moiety remains unchanged. The above-mentioned isotopic derivatives can be used as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements). Therefore, the isotopic derivatives are preferably deuterated compounds.

[0177] The term "solvate" refers to a compound described herein formed with a suitable solvent, preferably water or an organic solvent.

[0178] The term "prodrug" refers to a derivative of a parent compound described herein that contains a bioreactive functional group, such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the derivative or otherwise reacted to provide the parent compound described herein. Typically, the prodrug is inactive, or at least less active than the parent compound itself, such that the parent compound described herein cannot exert its activity until it is separated from the bioreactive functional group. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the parent compound described herein. For example, the prodrug can contain a biohydrolyzable group; examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureides.

[0179] The term "pharmaceutical composition" refers to a mixture containing a pharmaceutical compound (referring to one or more of the compounds represented by the general formula described herein, their pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, diastereomers, isotopic derivatives, crystal forms, solvates, prodrugs, metabolites and racemates thereof) and pharmaceutically acceptable excipients.

[0180] The term "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable excipient used to deliver the pharmaceutical compound herein to a subject. Depending on the method of administration, the pharmaceutical composition may contain 0.1 wt% to 99 wt% of the pharmaceutical compound.

[0181] The term "subject" refers to a mammal, including, for example, camels, donkeys, zebras, cows, pigs, horses, goats, sheep, cats, dogs, rats, rabbits, guinea pigs, mice, and primates. In some specific embodiments, the subject is a human. In some specific embodiments, the subject is a human susceptible to, suspected of having, or already suffering from cancer or bacterial infection.

[0182] The term "treat" refers to eliminating the disease, arresting the progression of the disease, slowing the progression of the disease, reducing the duration of one or more symptoms associated with the disease, improving or reversing at least one measurable parameter associated with the disease, or increasing the survival of a subject suffering from the disease.

[0183] The term "effective amount" refers to the amount of a pharmaceutically active ingredient (referring to a pharmaceutical compound) that elicits the desired effect in a subject. In specific embodiments, those skilled in the art can determine the selection of an effective amount based on consideration of a variety of factors (e.g., through clinical trials), including the disease to be treated, the symptoms involved, the route of administration, the severity of the disease, the patient's weight, the patient's immune status, and other factors known to those skilled in the art. The effective amount can be derived from dose-response curves derived from animal model test systems and can be determined based on the physician's judgment and the circumstances of each patient. The relationship between animal and human dosages is described in Freireich et al. 1966, Cancer Chemother Rep 50:219, and the human body surface area can be approximately determined by the patient's height and weight. The effective amount of the pharmaceutical compound of the present invention can be 0.5 mg / kg to 500 mg / kg, preferably 1 mg / kg to 200 mg / kg, and more preferably 10 mg / kg to 100 mg / kg.

[0184] Herein, the same active pharmaceutical ingredient (referring to a single pharmaceutical compound) or different active pharmaceutical ingredients (referring to two or more pharmaceutical compounds) can be administered at once, or can be divided into many smaller doses and administered at certain time intervals. It should be understood that the exact dosage, duration, and interval of treatment are a function of the disease being treated and can be determined by inference using animal or clinical trial data. The administration may include a single administration, or two or more administrations separated by appropriate time intervals. The interval between two adjacent administrations may be 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, one and a half days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months.

[0185] Each active pharmaceutical ingredient (each pharmaceutical compound) mentioned herein can be used as the sole active compound, or can be administered in combination with other active compounds (referring to compounds other than the pharmaceutical compounds described herein), as long as they do not produce other adverse effects, such as allergic reactions, etc. Combined administration includes the simultaneous or sequential use of the active compounds.

[0186] The term "combined administration" refers to a method in which two or more active compounds are administered to a subject simultaneously or sequentially for therapeutic purposes. When "combined administration" is used, the time interval between each administration is sufficient to achieve a synergistic effect between the active compounds administered.

[0187] When the term "about" is applied to a parameter such as weight, volume, pH, concentration, temperature, etc., it indicates that the parameter can vary within ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting. DETAILED DESCRIPTION

[0188] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0189] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0190] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts's "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0191] The separation and purification of compounds and intermediates can be performed using appropriate methods and steps depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize the compounds and intermediates.

[0192] Purity analysis was performed using Kinetex EVO C18 (50 × 4.6 mm, 5 μm, ) column, acetonitrile-water was used as the mobile phase for gradient elution, the flow rate was 1.5 mL / min, and the detection wavelength was 220 nm.

[0193] MS was measured using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector).

[0194] The structure of the compound was confirmed by hydrogen spectrum using WNMR-I-400MHz.

[0195] Preparative liquid chromatography was performed using an Agilent 1260 Infinity II high performance liquid chromatograph (manufacturer: Agilent), with a Daisogel C18 10 μm 100A column (30 mm × 250 mm) and acetonitrile / water as the mobile phase.

[0196] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring were of a size of 0.20 mm to 0.25 mm, and the silica gel plates used for separation and purification were of a size of 0.5 mm.

[0197] Silica gel column chromatography method uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0198] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Bid, etc.

[0199] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0200] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0201] The reaction solvent, organic solvent or inert solvent is each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, N-methylpyrrolidone (NMP).

[0202] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0203] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0204] Unless otherwise specified, the mixing ratios of different solvents are by volume.

[0205] Example 1

[0206] Synthesis of 7-nitroquinolin-8-ol (1)

[0207] Nitric acid (65 wt%) (8.0 mL, 116.4 mmol) was slowly added dropwise to a suspension of 8-hydroxyquinoline-5-sulfonic acid (1a) (10.0 g, 44.4 mmol) in sulfuric acid (98 wt%) (40.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, poured into ice water (50.0 mL), and stirred for 15 minutes. The pH of the aqueous phase was then adjusted to approximately 5-6 with a saturated aqueous solution of potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (10.0 mL x 3) and dried under vacuum to afford 8-hydroxy-7-nitroquinoline-5-sulfonic acid (1b) (9.0 g, 76% yield).

[0208] At room temperature, sulfuric acid (98 wt%) (2.8 mL) was slowly added to a suspension of 8-hydroxy-7-nitroquinoline-5-sulfonic acid (1b) (9.0 g, 33.3 mmol) in acetic acid (28.0 mL). The resulting mixture was stirred at 120°C for 6 hours, cooled to room temperature, poured into ice water (100.0 mL) and stirred for 15 minutes. The pH of the aqueous phase was then adjusted to approximately 6-7 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (10.0 mL x 2) and methanol (5.0 mL x 2) in that order. After vacuum drying, 7-nitroquinolin-8-ol (1) (5.0 g, 78% yield) was obtained.

[0209] 1 H NMR (400MHz, DMSO-d6) δ: 9.02 (dd, J=4.0, 1.6Hz, 1H), 8.52 (dd, J=8.4, 1.6Hz, 1H), 8.04 (d, J = 9.2Hz, 1H), 7.81 (dd, J = 8.4, 4.4Hz, 1H), 7.48 (d, J = 9.2Hz, 1H).

[0210] MS calculated: 190.04; MS found: 191.2 [M+H] + .

[0211] Example 2

[0212] Synthesis of 6-methyl-7-nitroquinolin-8-ol (2)

[0213] Acrolein diethyl acetal (1.5 mL, 20.25 mmol) was added to a solution of 2-amino-5-methylphenol (2a) (1.0 g, 8.1 mmol) in hydrochloric acid (1.0 M) (40.0 mL) at room temperature. The reaction mixture was stirred at 110°C for 24 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7 with solid sodium carbonate. The resulting mixture was extracted with dichloromethane (30.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to provide 6-methylquinolin-8-ol (2b) (0.81 g, 63% yield).

[0214] 6-Methylquinolin-8-ol (2b) (500.0 mg, 3.12 mmol) and N-iodosuccinimide (858.0 mg, 3.0 mmol) were added to chloroform (40.0 mL) at room temperature. The resulting mixture was stirred at 40°C for 15 minutes, cooled to room temperature, and diluted with 10 wt% sodium thiosulfate aqueous solution (30.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to provide 5-iodo-6-methylquinolin-8-ol (2c) (232.0 mg, 92% yield).

[0215] A solution of sodium nitrate (59.4 mg, 0.70 mol) and lanthanum nitrate hexahydrate (30.2 mg, 0.070 mmol) in hydrochloric acid (6.0 M) (14.4 mL) was added dropwise to a solution of 5-iodo-6-methylquinolin-8-ol (2c) (200.0 mg, 0.70 mmol) in diethyl ether (20.0 mL) at 0°C. The reaction mixture was warmed to room temperature, stirred for 1 hour, and extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 5-iodo-6-methyl-7-nitroquinolin-8-ol (2d) (50.0 mg, 22% yield).

[0216] 5-Iodo-6-methyl-7-nitroquinolin-8-ol (2d) (50.0 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium (7.27 mg, 0.015 mmol) were added to N,N-dimethylformamide (3.0 mL) at room temperature. The reaction mixture was stirred at 140°C for 30 minutes in a microwave reactor, cooled to room temperature, and diluted with aqueous ammonia (2.0 M) (20.0 mL). The resulting mixture was extracted with ethyl acetate (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 6-methyl-7-nitroquinolin-8-ol (2) (16.0 mg, 52% yield).

[0217] 1 H NMR(400MHz, DMSO-d6)δ:8.95-8.93(m,1H),8.29-8.27(m,1H),7.93-7.90(m,1H),7.10(s,1H),2.51(s,3H).

[0218] MS calculated: 204.05; MS found: 205.0 [M+H] + .

[0219] Example 3

[0220] Synthesis of 5-iodo-7-nitroquinolin-8-ol (3)

[0221] 7-Nitroquinolin-8-ol (250.0 mg, 1.31 mmol) and N-iodosuccinimide (429.0 mg, 1.5 mmol) were added to chloroform (15.0 mL) at room temperature. The resulting mixture was stirred at 40°C for 15 minutes, cooled to room temperature, and diluted with a 10 wt% sodium thiosulfate aqueous solution (20.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 5-iodo-7-nitroquinolin-8-ol (3) (367.0 mg, 88% yield).

[0222] 1 H NMR (400MHz, DMSO-d6) δ: 9.02 (d, J = 2.8 Hz, 1H), 8.55 (d, J = 3.6 Hz, 1H), 8.45–8.42 (m, 1H), 7.95–7.92 (m, 1H).

[0223] MS calculated: 315.93; MS found: 316.9 [M+H] + .

[0224] Example 4

[0225] Synthesis of 5-methyl-7-nitroquinolin-8-ol (4)

[0226] Acrolein diethyl acetal (1.5 mL, 20.25 mmol) was added to a solution of 2-amino-4-methylphenol (4a) (1.0 g, 8.1 mmol) in hydrochloric acid (1.0 M) (40.0 mL) at room temperature. The reaction mixture was stirred at 110°C for 24 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with solid sodium carbonate. The resulting mixture was extracted with dichloromethane (30.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide 5-methylquinolin-8-ol (4b) (0.50 g, 46% yield).

[0227] Nitric acid (65 wt%) (0.8 mL, 11.6 mmol) was slowly added dropwise to a suspension of 5-methylquinolin-8-ol (200.0 mg, 1.26 mmol) in sulfuric acid (98 wt%) (4.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, poured into ice water (15.0 mL) and stirred for 15 minutes. The pH of the aqueous phase was then adjusted to approximately 6-7 with a saturated aqueous sodium carbonate solution. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (2.5 mL x 3) and dried in vacuo to afford 5-methyl-7-nitroquinolin-8-ol (4) (180.0 mg, 70% yield).

[0228] 1 H NMR(400MHz, DMSO-d6)δ:9.04–9.03(m,1H),8.55–8.52(m,1H),7.89(s,1H),7.85–7.82(m,1H),2.59(s,3H).

[0229] MS calculated: 204.05; MS found: 205.1 [M+H] + .

[0230] Example 5

[0231] Synthesis of 2-Fluoro-7-nitroquinolin-8-ol (5)

[0232] Trifluoroacetic anhydride (2.5 mL, 37.0 mmol) was added to a solution of 8-hydroxyquinoline-N-oxide (5a) (2.0 g, 12.5 mmol) and trimethylamine (6.0 mL, 125.0 mmol) in dichloromethane (15.0 mL) at 0°C. The resulting mixture was warmed to room temperature, stirred for 2 hours, and concentrated under reduced pressure to remove the organic solvent. Diethyl ether (10.0 mL) was added to the resulting residue, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was washed with diethyl ether (10.0 mL) and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 8-hydroxy-N,N,N-trimethylquinolin-2-ammonium (5b) (1.7 g, 73% yield).

[0233] At room temperature, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M) (3.0 mL) was added to a solution of 8-hydroxy-N,N,N-trimethylquinolin-2-ammonium (5b) (203.0 mg, 1.0 mmol) in N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at 90°C for 1 hour, cooled to room temperature, diluted with ethyl acetate (20.0 mL), and washed sequentially with water (20.0 mL) and saturated brine (20.0 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 2-fluoroquinolin-8-ol (5c) (106.0 mg, 65% yield).

[0234] Fuming sulfuric acid (18-24 wt% SO3 content) (0.2 mL) was added to a solution of 2-fluoroquinolin-8-ol (5c) (100.0 mg, 0.61 mmol) in sulfuric acid (98 wt%) (0.4 mL) at room temperature. The reaction mixture was stirred at 65°C for 2 hours, cooled to room temperature, poured into ice water (5.0 mL), and filtered under reduced pressure. The filter cake was washed with acetone (2.0 mL x 3) and dried under vacuum to afford 2-fluoro-8-hydroxyquinoline-5-sulfonic acid (5d) (130.0 mg, 94% yield).

[0235] Nitric acid (65 wt%) (0.8 mL, 11.6 mmol) was added dropwise to a solution of 2-fluoro-8-hydroxyquinoline-5-sulfonic acid (5d) (100.0 mg, 0.41 mmol) in sulfuric acid (98 wt%) (4.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, poured into ice water (15.0 mL), and stirred for another 15 minutes. The pH of the aqueous phase was then adjusted to approximately 5-6 with a saturated aqueous solution of potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL x 3) and dried under vacuum to afford 2-fluoro-8-hydroxy-7-nitroquinoline-5-sulfonic acid (5e) (90.0 mg, 76% yield).

[0236] At room temperature, sulfuric acid (98 wt%) (0.8 mL) was slowly added to a suspension of 2-fluoro-8-hydroxy-7-nitroquinoline-5-sulfonic acid (5e) (90.0 mg, 0.32 mmol) in acetic acid (2.8 mL). The resulting mixture was stirred at 120°C for 6 hours, cooled to room temperature, poured into ice water (15.0 mL), and stirred for 15 minutes. The pH of the aqueous phase was then adjusted to approximately 6-7 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL x 2) and dried in vacuo to afford 2-fluoro-7-nitroquinolin-8-ol (5) (52.0 mg, 78% yield).

[0237] 1 H NMR (400MHz, CDCl3) δ: 9.50-9.46 (m, 1H), 8.56 (d, J = 8.8Hz, 1H), 8.22 (s, 1H), 7.42-7.39 (m, 1H), 7.28 (s, 1H).

[0238] MS calculated: 208.03; MS measured: 207.1 [MH] - .

[0239] Example 6

[0240] Synthesis of 2-methyl-7-nitroquinolin-8-ol (6)

[0241] Fuming sulfuric acid (18-24 wt% SO3 content) (2.0 mL) was added to a solution of 2-methyl-8-hydroxyquinoline (6a) (1.0 g, 6.28 mmol) in sulfuric acid (98 wt%) (4.0 mL) at room temperature. The reaction mixture was stirred at 65°C for 2 hours, cooled to room temperature, and poured into ice water (20.0 mL). The resulting suspension was diluted with acetone (60.0 mL), stirred for 10 minutes, and filtered under reduced pressure. The filter cake was washed with acetone (15.0 mL x 2) and dried under vacuum to give 8-hydroxy-2-methylquinoline-5-sulfonic acid (6b) (1.4 g, 94% yield).

[0242] Nitric acid (65 wt%) (0.8 mL, 11.6 mmol) was added dropwise to a solution of 8-hydroxy-2-methylquinoline-5-sulfonic acid (6b) (100.0 mg, 0.42 mmol) in sulfuric acid (98 wt%) (4.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, poured into ice water (15.0 mL), and stirred for another 15 minutes. The pH of the aqueous phase was then adjusted to approximately 5-6 with a saturated aqueous solution of potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL x 3) and dried in vacuo to afford 8-hydroxy-2-methyl-7-nitroquinoline-5-sulfonic acid (6c) (94.3 mg, 79% yield).

[0243] At room temperature, sulfuric acid (98 wt%) (0.8 mL) was slowly added to a suspension of 8-hydroxy-2-methyl-7-nitroquinoline-5-sulfonic acid (6c) (90.0 mg, 0.32 mmol) in acetic acid (2.8 mL). The resulting mixture was stirred at 120°C for 6 hours, cooled to room temperature, poured into ice water (15.0 mL), and stirred for 15 minutes. The pH of the aqueous phase was then adjusted to approximately 6-7 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL x 2) and dried in vacuo to afford 2-methyl-7-nitroquinolin-8-ol (6) (51.0 mg, 78% yield).

[0244] 1 H NMR (400MHz, DMSO-d6) δ: 8.38 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 2.77 (s, 3H).

[0245] MS calculated: 204.05; MS found: 205.1 [M+H] + .

[0246] Example 7

[0247] Synthesis of 5-chloro-6-(methylamino)-7-nitroquinolin-8-ol (7)

[0248] At room temperature, 4-bromo-5-chloro-2-methoxyaniline (7a) (3.80 g, 16.1 mmol), sodium 3-nitrobenzenesulfonate (4.34 g, 19.3 mmol), and glycerol (2.96 mL, 40.2 mmol) were sequentially added with sulfuric acid (70 wt.%) (40.4 mL). The resulting mixture was stirred at 140°C for 4 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with dichloromethane (50.0 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product of 6-bromo-5-chloro-8-methoxyquinoline (7b) (3.80 g, crude yield 87%).

[0249] At 0°C, nitric acid (65 wt.%) (8.4 mL, 198.0 mmol) was slowly added dropwise to a solution of the crude product of 6-bromo-5-chloro-8-methoxyquinoline (7b) (1.80 g, 6.6 mmol) in acetic anhydride (30.0 mL). The mixture was stirred for 30 minutes, and then sulfuric acid (98 wt.%) (1.20 mL, 22.6 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 48 hours. The mixture was then cooled to 0°C and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 9 / 1-2 / 1) to give 6-bromo-5-chloro-8-methoxy-7-nitroquinoline (7c) (0.551 g, yield 24%).

[0250] At room temperature, 6-bromo-5-chloro-8-methoxy-7-nitroquinoline (7c) (300.0 mg, 0.94 mmol), tert-butyl carbamate (165.0 mg, 1.41 mmol), palladium acetate (21.0 mg, 0.094 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (108.0 mg, 0.187 mmol), and cesium carbonate (606.0 mg, 1.86 mmol) were added sequentially to 1,4-dioxane (6.0 mL). The resulting mixture was stirred at 95°C for 4 hours, cooled to room temperature, and filtered through celite. The filter cake was washed with ethyl acetate (10.0 mL x 3). The filtrates were combined and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 9 / 1-2 / 1) to give tert-butyl (5-chloro-8-methoxy-7-nitroquinolin-6-yl)carbamate (7d) (130.0 mg, yield 56%).

[0251] At room temperature, tert-butyl (5-chloro-8-methoxy-7-nitroquinolin-6-yl)carbamate (7d) (120.0 mg, 0.34 mmol), cesium carbonate (332.0 mg, 1.02 mmol), and iodomethane (62.8 mg, 0.44 mmol) were added sequentially to N,N-dimethylformamide (3.0 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1.5 / 1) to give tert-butyl (5-chloro-8-methoxy-7-nitroquinolin-6-yl)(methyl)carbamate (7e) (122.0 mg, 96% yield).

[0252] At room temperature, tert-butyl (5-chloro-8-methoxy-7-nitroquinolin-6-yl)(methyl)carbamate (7e) (122.0 mg, 0.33 mmol) and lithium chloride (278.6 mg, 6.6 mmol) were added to N,N-dimethylformamide (4.0 mL). The resulting mixture was stirred at 120°C for 1.5 hours, cooled to room temperature, and concentrated to dryness under reduced pressure. A 4.0 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL) was added to the resulting residue, stirred at room temperature for 2 hours, and concentrated to dryness under reduced pressure. Aqueous ammonia (25-28 wt.%, NH3 content) was added to the resulting residue to adjust the pH of the aqueous phase to approximately 9-10. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (0.5 mL x 2) and dried under vacuum to obtain 5-chloro-6-(methylamino)-7-nitroquinolin-8-ol (7) (31.0 mg, 37% yield).

[0253] 1 H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.50 (dd, J = 8.4, 4.0Hz, 1H), 5.62 (br s, 1H), 2.80 (s, 3H).

[0254] MS calculated: 253.03; MS observed: 254.1, 256.1 [M+H] + .

[0255] Example 8

[0256] Synthesis of 3-methyl-7-nitroquinolin-8-ol (8)

[0257] At 110°C, 2-methylacrolein (1.0 mL, 4.0 mmol) was slowly added dropwise to a solution of 2-aminophenol (8a) (200.0 mg, 1.83 mmol) in hydrochloric acid (6.0 M) (10.0 mL). The reaction mixture was stirred at 110°C for 2 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with aqueous sodium hydroxide solution (6.0 M). The resulting mixture was extracted with ethyl acetate (15.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give 3-methylquinolin-8-ol (8b) (172.0 mg, 52% yield).

[0258] Fuming sulfuric acid (18-24 wt% SO3 content) (2.0 mL) was added to a solution of 3-methylquinolin-8-ol (8b) (100.0 mg, 0.63 mmol) in sulfuric acid (98 wt%) (4.0 mL) at room temperature. The reaction mixture was stirred at 65°C for 2 hours, cooled to room temperature, and poured into ice water (20.0 mL). The resulting suspension was diluted with acetone (60.0 mL), stirred for 10 minutes, and filtered under reduced pressure. The filter cake was washed with acetone (15.0 mL x 2) and dried under vacuum to afford 8-hydroxy-3-methylquinoline-5-sulfonic acid (8c) (139.0 mg, 77% yield).

[0259] Nitric acid (65 wt%) (0.8 mL, 11.6 mmol) was added dropwise to a solution of 8-hydroxy-3-methylquinoline-5-sulfonic acid (8c) (139.0 mg, 0.58 mmol) in sulfuric acid (98 wt%) (4.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, poured into ice water (15.0 mL), and stirred for another 15 minutes. The pH of the aqueous phase was then adjusted to approximately 5-6 with a saturated aqueous solution of potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL x 3) and dried under vacuum to afford 8-hydroxy-3-methyl-7-nitroquinoline-5-sulfonic acid (8d) (128.6 mg, 78% yield).

[0260] At room temperature, sulfuric acid (98 wt%) (0.8 mL) was slowly added to a suspension of 8-hydroxy-3-methyl-7-nitroquinoline-5-sulfonic acid (8d) (100.0 mg, 0.35 mmol) in acetic acid (2.8 mL). The resulting mixture was stirred at 120°C for 6 hours, cooled to room temperature, poured into ice water (15.0 mL), and stirred for 15 minutes. The pH of the aqueous phase was then adjusted to approximately 6-7 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL x 2) and dried in vacuo to afford 3-methyl-7-nitroquinolin-8-ol (8) (49.3 mg, 69% yield).

[0261] 1 H NMR (400MHz, DMSO-d6) δ: 8.87 (s, 1H), 8.25 (s, 1H), 8.01 (d, J = 9.2Hz, 1H), 7.32 (d, J = 8.0Hz, 1H), 2.54 (s, 3H).

[0262] MS calculated: 204.05; MS found: 205.0 [M+H] + .

[0263] Example 9

[0264] Synthesis of 8-Hydroxy-7-nitroquinoline-5-carbonitrile (9)

[0265] 5-Iodo-7-nitroquinolin-8-ol (200.0 mg, 0.63 mmol), zinc cyanide (147.0 mg, 1.26 mmol) and tetrakis(triphenylphosphine)palladium (72.7 mg, 0.063 mmol) were added to N,N-dimethylformamide (3.0 mL) in sequence at room temperature. The reaction mixture was stirred at 140°C for 30 minutes in a microwave reactor, cooled to room temperature, and diluted with aqueous ammonia (2.0 M) (20.0 mL). The resulting mixture was extracted with ethyl acetate (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 8-hydroxy-7-nitroquinoline-5-carbonitrile (9) (36.0 mg, 27% yield).

[0266] 1 H NMR (400MHz, DMSO-d6) δ: 8.64 (s, 1H), 8.58 (s, 1H), 8.46 (s, J = 8.0Hz, 1H), 7.93–7.90 (m, 1H), 7.06 (s, 1H).

[0267] MS calculated: 215.03; MS found: 216.0 [M+H] + .

[0268] Example 10

[0269] Synthesis of 4-methyl-7-nitroquinolin-8-ol (10)

[0270] 4-Hydroxy-2-butanone (10a) (12.3 g, 139.6 mmol) was added to a mixture of methanol (10.0 mL) and water (2.0 mL) at room temperature, followed by the addition of phosphoric acid (85 wt%) (0.4 mL). The resulting mixture was stirred at room temperature for 30 minutes, then distilled under reduced pressure (pressure range: 150.0-200.0 mmHg), and the fraction with a boiling point of 80°C was collected. Saturated brine (10.0 mL) was added to the collected fraction, and the mixture was stirred at 4°C for 1 hour. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered to obtain 3-buten-2-one (10b) (0.86 g, 9% yield).

[0271] 3-Buten-2-one (10b) (0.86 g, 12.3 mmol) was slowly added dropwise to a solution of 2-aminophenol (200.0 mg, 1.83 mmol) in hydrochloric acid (6.0 M) (10.0 mL) at 110°C. The reaction mixture was stirred at 110°C for 2 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with ethyl acetate (20.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to provide 4-methylquinolin-8-ol (10c) (171.9 mg, 63% yield).

[0272] Fuming sulfuric acid (18-24 wt% SO3 content) (2.0 mL) was added to a solution of 4-methylquinolin-8-ol (10c) (171.9 mg, 1.08 mmol) in sulfuric acid (98 wt%) (4.0 mL) at room temperature. The reaction mixture was stirred at 65°C for 2 hours, cooled to room temperature, and poured into ice water (20.0 mL). The resulting suspension was diluted with acetone (60.0 mL), stirred for 10 minutes, and filtered under reduced pressure. The filter cake was washed with acetone (15.0 mL x 2) and dried under vacuum to afford 8-hydroxy-4-methylquinoline-5-sulfonic acid (10d) (193.8 mg, 75% yield).

[0273] Nitric acid (65 wt%) (0.8 mL, 11.6 mmol) was added dropwise to a solution of 8-hydroxy-4-methylquinoline-5-sulfonic acid (10d) (193.8 mg, 0.81 mmol) in sulfuric acid (98 wt%) (4.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, poured into ice water (15.0 mL), and stirred for another 15 minutes. The pH of the aqueous phase was then adjusted to approximately 5-6 with a saturated aqueous solution of potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL x 3) and dried under vacuum to afford 8-hydroxy-4-methyl-7-nitroquinoline-5-sulfonic acid (10e) (179.6 mg, 78% yield).

[0274] At room temperature, sulfuric acid (98 wt%) (0.8 mL) was slowly added to a suspension of 8-hydroxy-4-methyl-7-nitroquinoline-5-sulfonic acid (10e) (90.0 mg, 0.32 mmol) in acetic acid (2.8 mL). The resulting mixture was stirred at 120°C for 6 hours, cooled to room temperature, poured into ice water (15.0 mL), and stirred for 15 minutes. The pH of the aqueous phase was then adjusted to approximately 6-7 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL x 2) and dried in vacuo to afford 4-methyl-7-nitroquinolin-8-ol (10) (51.0 mg, 78% yield).

[0275] 1 H NMR (400MHz, DMSO-d6) δ: 8.87 (s, 1H), 8.25 (s, 1H), 8.01 (d, J = 9.2Hz, 1H), 7.32 (d, J = 8.0Hz, 1H), 2.54 (s, 3H).

[0276] MS calculated: 204.05; MS found: 205.0 [M+H] + .

[0277] Example 11

[0278] Synthesis of 4-cyclopropyl-7-nitroquinolin-8-ol (11)

[0279] 4-Hydroxy-8-methoxyquinoline (11a) (3.0 g, 17.1 mmol) and phosphorus tribromide (9.3 g, 34.2 mmol) were added sequentially to N,N-dimethylformamide (25.0 mL) at room temperature. The reaction mixture was stirred at 65°C for 6 h, cooled to 0°C, diluted with water (50.0 mL), and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous ammonia (25-28% by weight, NH3 content). The resulting mixture was extracted with ethyl acetate (100.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3) to provide 4-bromo-8-methoxyquinoline (11b) (3.7 g, 91% yield).

[0280] At 0°C, 4-bromo-8-methoxyquinoline (11b) (3.0 g, 12.7 mmol), concentrated nitric acid (65 wt%) (10.0 mL), and concentrated sulfuric acid (98 wt%) (7.0 mL) were added sequentially with acetic anhydride (25.0 mL). The reaction mixture was warmed to room temperature and stirred for 2 hours. Ice water (100.0 mL) was added to dilute the mixture, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture was extracted with dichloromethane (100.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 4-bromo-7-nitro-8-methoxyquinoline (11c) (0.30 g, 8% yield).

[0281] 4-Bromo-7-nitro-8-methoxyquinoline (11c) (100.0 mg, 0.35 mmol), cyclopropylboronic acid (61.6 mg, 0.72 mmol), tetrakistriphenylphosphine palladium (82.0 mg, 0.07 mmol), and potassium carbonate (147.0 mg, 1.07 mmol) were added sequentially to a mixture of toluene (5.0 mL) and water (0.5 mL) at room temperature. The reaction mixture was stirred at 100°C for 2 hours, cooled to room temperature, and diluted with water (20.0 mL). The resulting mixture was extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 4-cyclopropyl-7-nitro-8-methoxyquinoline (11d) (60.0 mg, 70% yield).

[0282] 4-Cyclopropyl-7-nitro-8-methoxyquinoline (11d) (60.0 mg, 0.25 mmol) and lithium chloride (105.0 mg, 2.5 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 180°C for 1 hour and cooled to room temperature. The organic solvent was removed by concentration under reduced pressure. Water (3.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in that order and dried under vacuum to give 4-cyclopropyl-7-nitroquinoline-8-ol (11) (16.0 mg, 28% yield).

[0283] 1 H-NMR(400Hz,DMSO-d6)δ:8.50–8.40(m,1H),8.00–7.88(m,1H),7.15–7.06(m,1 H),6.95–6.86(m,1H),2.30–2.45(m,1H),1.20–1.05(m,2H),0.90–0.70(m,2H).

[0284] MS calculated: 230.07; MS found: 231.1 [M+H] + .

[0285] Example 12

[0286] Synthesis of 4-chloro-7-nitroquinolin-8-ol (12)

[0287] At 0°C, a 1.0 M solution of boron tribromide in dichloromethane (50.0 mL, 50.0 mmol) was slowly added dropwise to a solution of 4-chloro-8-methoxyquinoline (12a) (2.0 g, 10.0 mmol) in dichloromethane (20.0 mL). The reaction mixture was warmed to room temperature and stirred for 30 minutes. The pH of the aqueous phase was adjusted to approximately 8-9 with a saturated aqueous sodium bicarbonate solution. The organic phase was separated and extracted with dichloromethane (20.0 mL x 2). The combined organic phases were dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The resulting residue was dried under vacuum to yield the crude product 4-chloro-8-hydroxyquinoline (12b) (1.6 g, crude yield 89%).

[0288] Sodium nitrite (2.0 g, 30.0 mmol) was added portionwise to a suspension of 4-chloro-8-hydroxyquinoline (1.08 g, 6.0 mmol) (12b) in hydrochloric acid (2.0 M) (36.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 4 hours, and filtered under reduced pressure. The filter cake was added to methanol (30.0 mL), stirred for 15 minutes, and filtered under reduced pressure. The newly collected filter cake was washed with methanol (5.0 mL x 2) and dried under vacuum to give 4-chloro-7-nitroquinolin-8-ol (12) (0.80 g, 59% yield).

[0289] 1 H-NMR (400MHz, DMSO-d6): δ7.68 (d, J = 9.6 Hz, 1H), 8.04 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 9.6 Hz, 1H), 8.95 (d, J = 4.8 Hz, 1H).

[0290] MS calculated: 224.60; MS found: 225.0 [M+H] + .

[0291] Example 13

[0292] Synthesis of 7-nitro-4-(pyrrolidin-1-yl)quinolin-8-ol

[0293] Tetrahydropyrrole (142.0 mg, 4.45 mmol) was added to a solution of 4-chloro-7-nitroquinolin-8-ol (12) (100.0 mg, 0.45 mmol) in N,N-dimethylformamide (5.0 mL) at room temperature. The reaction mixture was stirred at 120°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (10.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (1.0 mL x 3) and dried under vacuum to give 7-nitro-4-(pyrrolidin-1-yl)quinolin-8-ol (13) (92.0 mg, 79% yield).

[0294] 1 H-NMR (400MHz, DMSO-d6) δ: 13.10 (br s, 1H), 8.08 (d, J = 5.6Hz, 1H), 7.80 (d, J = 9.6Hz, 1H), 6.92 (d, J = 10.0Hz, 1H), 6.73 (d, J = 4.4Hz, 1H), 3.84 (br s,4H),2.01(br s,4H).

[0295] MS calculated: 259.10; MS found: 260.1 [M+H] + .

[0296] Example 14

[0297] Synthesis of 4-morpholino-7-nitroquinolin-8-ol (14)

[0298] The same synthesis method as in Example 13 was used to obtain 4-morpholino-7-nitroquinoline-8-ol (14) (110.0 mg, yield 91%) from 4-chloro-7-nitroquinoline-8-ol (12) (100.0 mg, 0.44 mmol) and morpholine (192.0 mg, 2.2 mmol).

[0299] 1 H NMR (400MHz, DMSO-d6) δ: 8.44 (d, J = 5.6 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 6.66 (d, J = 9.6 Hz, 1H), 3.85 (br s, 4H), 3.54 (br s, 4H).

[0300] MS calculated: 275.09; MS found: 276.1 [M+H] + .

[0301] Example 15

[0302] Synthesis of 4-(1H-imidazol-1-yl)-7-nitroquinolin-8-ol (15)

[0303] The same synthesis method as in Example 13 was used to obtain 4-(1H-imidazol-1-yl)-7-nitroquinolin-8-ol (15) (50.0 mg, yield 85%) from 4-chloro-7-nitroquinolin-8-ol (12) (50.0 mg, 0.23 mmol) and imidazole (61.5 mg, 0.9 mmol).

[0304] 1 H-NMR(400MHz,DMSO-d6)δ:8.15(s,1H),8.05–8.08(m,2H),7.78(s,1H),7.71(m,1H),7.26(s,1H),7.21(s,1H).

[0305] MS calculated: 256.06; MS found: 257.1 [M+H] + .

[0306] Example 16

[0307] Synthesis of 4-bromo-7-nitroquinolin-8-ol (16)

[0308] At 0°C, a dichloromethane solution (1.0 M) of boron tribromide (36.4 mL, 36.4 mmol) was slowly added dropwise to a dichloromethane solution (25.0 mL) of 4-bromo-8-methoxyquinoline (11b) (1.9 g, 8.1 mmol). The reaction mixture was warmed to room temperature and stirred for 24 hours. The pH of the aqueous phase was adjusted to approximately 8-9 with a saturated aqueous sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19 / 1) to give 4-bromoquinolin-8-ol (16a) (1.0 g, 55% yield).

[0309] Sodium nitrite (1.4 g, 20.3 mmol) was added portionwise to a suspension of 4-bromoquinolin-8-ol (16a) (460 mg, 2.05 mmol) in hydrochloric acid (2.0 M) (30.0 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 24 hours. Aqueous ammonia (25-28 wt%, NH3 content) was added to adjust the pH of the aqueous phase to approximately 8-9. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with ethanol (4.0 mL x 3) and dried in vacuo to afford 4-bromo-7-nitroquinolin-8-ol (16) (500.0 mg, 91% yield).

[0310] 1 H-NMR(400Hz, DMSO-d6)δ:8.84–7.77(m,1H),8.20–8.12(m,2H),7.60–7.55(m,1H).

[0311] MS calculated: 267.95; MS found: 269.0 [M+H] + .

[0312] Example 17

[0313] Synthesis of 4-(dimethylamino)-7-nitroquinolin-8-ol (17)

[0314] 4-Chloro-7-nitroquinolin-8-ol (12) (100.0 mg, 0.44 mmol) was added to a dimethylamine aqueous solution (40 wt%) (10.0 mL) at room temperature. The reaction mixture was stirred at 110°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the solvent. Ethanol (5.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with ethanol (1.0 mL x 2) and dried under vacuum to give 4-(dimethylamino)-7-nitroquinolin-8-ol (17) (36.0 mg, 35% yield).

[0315] 1 H NMR (400MHz, DMSO-d6) δ: 8.18 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 9.8 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.70 (d, J = 9.8 Hz, 1H), 3.32 (s, 6H).

[0316] MS calculated: 233.08; MS found: 234.1 [M+H] + .

[0317] Example 18

[0318] Synthesis of 4-(4-methylpiperazinyl)-7-nitroquinolin-8-ol (18)

[0319] The same synthesis method as in Example 13 was used to obtain 4-(4-methylpiperazinyl)-7-nitroquinolin-8-ol (18) (40.0 mg, yield 63%) from 4-chloro-7-nitroquinolin-8-ol (12) (50.0 mg, 0.22 mmol) and 1-methylpiperazine (116.0 mg, 1.1 mmol).

[0320] 1 H NMR(400MHz, DMSO-d6)δ:8.57(d,J=6.0Hz,1H),7.98(d,J=9.6Hz,1H),7.34(d,J=6.0Hz,1H),6.80(d,J=9.6Hz,1H),3.55–3.21(br s,8H),2.86(s,3H).

[0321] MS calculated: 288.12; MS found: 289.1 [M+H] + .

[0322] Example 19

[0323] Synthesis of 7-nitro-4-(3-oxetanylamino)quinolin-8-ol (19)

[0324] 3-Oxetanamine (78.9 mg, 1.08 mmol) was added to a solution of 4-chloro-7-nitroquinolin-8-ol (12) (80.0 mg, 0.36 mmol) in dimethyl sulfoxide (5.0 mL) at room temperature. The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (5.0 mL) was added to the resulting residue, stirred for three minutes, and filtered under reduced pressure. The resulting filter cake was mixed with methanol (10.0 mL), stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with methanol (1.0 mL x 2) and dried under vacuum to give 7-nitro-4-(3-oxetanylamino)quinolin-8-ol (19) (65.0 mg, 69% yield).

[0325] 1 H NMR(400MHz, DMSO-d6)δ:8.89(d,J=4.4Hz,1H),8.16(d,J=6.8Hz,1H),7.96(d,J=9.6Hz,1H),6.93(d, J=9.6Hz,1H),6.57(d,J=6.8Hz,1H),5.01–4.96(m,1H),4.93(t,J=6.0Hz,2H),4.74(t,J=6.0Hz,2H).

[0326] MS calculated: 261.07; MS found: 262.1 [M+H] + .

[0327] Example 20

[0328] Synthesis of 4-(2-methylpiperidinyl)-7-nitroquinolin-8-ol (20)

[0329] The same synthesis method as in Example 13 was used to obtain 4-(2-methylpiperidinyl)-7-nitroquinolin-8-ol (20) (19.0 mg, 15% yield) from 4-chloro-7-nitroquinolin-8-ol (12) (100.0 mg, 0.44 mmol) and 2-methylpiperidine (220.0 mg, 2.2 mmol).

[0330] 1 H NMR(400MHz, DMSO-d6)δ:8.02–7.86(m,2H),7.20–7.10(m,1H),6.76–6.62(m,1H),3.14–2.83(m,3H),1.85–1.55(m,6H),1.10–0.95(m,3H).

[0331] MS calculated: 287.13; MS found: 288.1 [M+H] + .

[0332] Example 21

[0333] Synthesis of 4-methoxy-7-nitroquinolin-8-ol (21)

[0334] The same synthesis method as in Example 13 was used to obtain 4-methoxy-7-nitroquinolin-8-ol (21) (26.0 mg, yield 54%) from 4-chloro-7-nitroquinolin-8-ol (12) (50.0 mg, 0.22 mmol) and sodium methoxide (120.0 mg, 2.2 mmol).

[0335] 1 H NMR(400MHz, DMSO-d6)δ:8.56–8.42(m,1H),7.91–7.84(m,1H),7.10–7.03(m,1H),6.65–6.56(m,1H),4.01(s,3H).

[0336] MS calculated: 220.05; MS found: 221.0 [M+H] + .

[0337] Example 22

[0338] Synthesis of 4-phenyl-7-nitroquinolin-8-ol (22)

[0339] 4-Bromo-7-nitro-8-methoxyquinoline (11c) (60.0 mg, 0.25 mmol), phenylboronic acid (62.0 mg, 0.50 mmol), tetrakis(triphenylphosphine)palladium (58.0 mg, 0.05 mmol), and potassium carbonate (100.0 mg, 0.75 mmol) were added sequentially to a mixed solvent of toluene (2.0 mL) and water (0.2 mL) at room temperature. The reaction mixture was stirred at 110°C for 2 hours, cooled to room temperature, and diluted with water (10.0 mL). The resulting mixture was extracted with ethyl acetate (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 (eluent: petroleum ether / ethyl acetate = 7 / 3) to give 4-phenyl-7-nitro-8-methoxyquinoline (22a) (60.0 mg, 86% yield).

[0340] 4-Phenyl-7-nitro-8-methoxyquinoline (22a) (60.0 mg, 0.21 mmol) and lithium chloride (90.0 mg, 2.1 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. 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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in that order and dried under vacuum to give 4-phenyl-7-nitroquinolin-8-ol (22) (25.0 mg, 45% yield).

[0341] 1 H-NMR(400MHz, DMSO-d6)δ:8.70–8.60(m,1H),7.93–7.84(m,1H),7.61–7.48(m,5H),7.46–7.41(m,1H),6.42–6.33(m,1H).

[0342] MS calculated: 266.07; MS found: 267.1 [M+H] + .

[0343] Example 23

[0344] Synthesis of 4-(2,5-dihydro-1H-pyrrole)-7-nitroquinolin-8-ol (23)

[0345] The same synthesis method as in Example 19 was used to react 4-chloro-7-nitroquinolin-8-ol (12) (60.0 mg, 0.27 mmol) with 3-pyrroline (91.0 mg, 1.32 mmol) at 100°C to obtain 4-(2,5-dihydro-1H-pyrrole)-7-nitroquinolin-8-ol (23) (34.6 mg, yield 50%).

[0346] 1 H-NMR(400MHz, DMSO-d6)δ:8.20–8.12(m,1H),7.87–7.80(m,1H),7.14–7.07(m,1H),6.75–6.70(m,1H),6.11(s,2H),4.75(s,4H).

[0347] MS calculated: 257.08; MS found: 258.1 [M+H] + .

[0348] Example 24

[0349] Synthesis of 4-(2-(dimethylamino)ethoxy)-7-nitroquinolin-8-ol (24)

[0350] Sodium hydride (60 wt%, mineral oil mixture) (130.0 mg, 3.24 mmol) was added to a solution of N,N-dimethylethanolamine (238.0 mg, 2.7 mmol) in dimethyl sulfoxide (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, and 4-chloro-7-nitroquinolin-8-ol (12) (60.0 mg, 0.27 mmol) was added. The resulting mixture was heated to 95°C, stirred for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (3.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in that order, and dried under vacuum to give 4-(2-(dimethylamino)ethoxy)-7-nitroquinolin-8-ol (24) (25.7 mg, 34% yield).

[0351] 1 H NMR(400MHz, DMSO-d6)δ:8.90–8.70(m,1H),8.20–8.10(m,1H),7.60–7.35(m,2H),4.71–4.50(m,2H),3.80–3.60(m,2H),3.10–2.80(m,4H).

[0352] MS calculated: 277.11; MS found: 278.1 [M+H] + .

[0353] Example 25

[0354] Synthesis of 4-(8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxamide (25)

[0355] The same synthesis method as in Example 19 was used to react 4-chloro-7-nitroquinolin-8-ol (12) (60.0 mg, 0.27 mmol) with N,N-dimethylpiperazine-1-carboxamide (126.0 mg, 0.81 mmol) at 100°C to obtain 4-(8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxamide (25) (20.0 mg, yield 21%).

[0356] 1 H NMR(400MHz, DMSO-d6)δ:8.46–8.42(m,1H),7.97–7.91(m,1H),7.23–7.18(m,1H),6.73–6.67(m,1H),3.69–3.63(m,7H),3.60–3.53(m,4H).

[0357] MS calculated: 345.14; MS found: 346.1 [M+H] + .

[0358] Example 26

[0359] Synthesis of 4-(8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxylic acid methyl ester (26)

[0360] The same synthesis method as in Example 19 was used to react 4-chloro-7-nitroquinolin-8-ol (12) (60.0 mg, 0.27 mmol) with methyl piperazine-1-carboxylate (130.0 mg, 0.90 mmol) at 100°C to obtain methyl 4-(8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxylate (26) (21.7 mg, 24% yield).

[0361] 1 H NMR(400MHz, DMSO-d6)δ:8.46–8.42(m,1H),7.97–7.91(m,1H),7.23–7.18(m,1H),6.73–6.67(m,1H),3.69–3.63(m,7H),3.60–3.53(m,4H).

[0362] MS calculated: 332.11; MS found: 333.1 [M+H] + .

[0363] Example 27

[0364] Synthesis of 4-Fluoro-7-nitroquinolin-8-ol (27)

[0365] At 0°C, nitric acid (65 wt%) (3.0 mL, 43.6 mmol) was slowly added to a solution of 4-chloro-8-methoxyquinoline (12a) (5.0 g, 25.1 mmol) in acetic anhydride (40.0 mL). After stirring for 10 minutes, sulfuric acid (98 wt%) (3.0 mL, 55.2 mmol) was slowly added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. Ice water (50.0 mL) was added to dilute the mixture, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture 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 resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to provide 4-chloro-7-nitro-8-methoxyquinoline (27a) (1.19 g, 20% yield).

[0366] 4-Chloro-7-nitro-8-methoxyquinoline (27a) (150.0 mg, 0.63 mmol) and cesium fluoride (480.0 mg, 3.1 mmol) were added to dimethyl sulfoxide (2.0 mL) at room temperature. The reaction mixture was stirred at 160°C for 30 min, cooled to room temperature, diluted with dichloromethane (10.0 mL), and washed with water (10.0 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 4-fluoro-7-nitro-8-methoxyquinoline (27b) (50.0 mg, 36% yield).

[0367] 4-Fluoro-7-nitro-8-methoxyquinoline (27b) (50.0 mg, 0.22 mmol) and lithium chloride (100.0 mg, 2.2 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 120°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in that order, and dried under vacuum to give 4-fluoro-7-nitroquinolin-8-ol (27) (46.0 mg, 98% yield).

[0368] 1 H NMR (400MHz, DMSO-d6) δ8.84–8.37(m,1H),7.95(d,J=8.0Hz,1H),7.50–7.22(m,1H),6.44(d,J=8.0Hz,1H).

[0369] MS calculated: 208.03; MS found: 209.0 [M+H] + .

[0370] Example 28

[0371] Synthesis of (8-Hydroxy-7-nitroquinolin-4-yl)-L-proline methyl ester (28)

[0372] L-Proline methyl ester hydrochloride (178.0 mg, 1.07 mmol) and N,N-diisopropylethylamine (139.0 mg, 1.08 mmol) were added to dimethyl sulfoxide (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and 4-chloro-7-nitroquinolin-8-ol (12) (80.0 mg, 0.36 mmol) was added. The resulting mixture was stirred at 100°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The residue was separated by reverse-phase high performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-70% / 30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to obtain the product (8-hydroxy-7-nitroquinolin-4-yl)-L-proline methyl ester (28) (115.0 mg, yield 99%).

[0373] 1 H NMR(400MHz,DMSO-d6)δ:8.22–8.11(m,1H),7.89–7.72(m,1H),6.85–6.77(m,1H),6.7 4–6.66(m,1H),5.16–5.06(m,1H),4.10–3.95(m,2H),3.67(s,3H),2.16–1.89(m,4H).

[0374] MS calculated: 317.10; MS found: 318.1 [M+H] + .

[0375] Example 29

[0376] Synthesis of 4,5-dichloro-7-nitroquinolin-8-ol (29)

[0377] At 0°C, N-chlorosuccinimide (588 mg, 4.4 mmol) was added in three portions to a solution of 4-chloroquinolin-8-ol (12b) (790.0 mg, 4.4 mmol) in sulfuric acid (98 wt%) (5.0 mL). The reaction mixture was stirred at 0°C for 0.5 hours, then warmed to room temperature and stirred for 2 hours. Aqueous ammonia (25-28 wt%, NH3 content) was added to adjust the pH of the aqueous phase to approximately 8-9. The resulting mixture was extracted with dichloromethane (20.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide 4,5-dichloroquinolin-8-ol (29a) (703.0 mg, 75% yield).

[0378] Sodium nitrite (2.28 g, 33.0 mmol) was added portionwise to a suspension of 4,5-dichloroquinolin-8-ol (29a) (0.703 g, 3.3 mmol) in hydrochloric acid (3.0 M) (20.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h, then warmed to room temperature and stirred for 12 h. Aqueous ammonia (25-28 wt%, NH3 content) was added to adjust the pH of the aqueous phase to approximately 8-9. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (3.0 mL x 2) and dried under vacuum to afford 4,5-dichloro-7-nitroquinolin-8-ol (29) (0.641 g, 75% yield).

[0379] 1 H NMR (400MHz, DMSO-d6) δ 8.93 (d, J = 4.8 Hz, 1H), 8.22 (s, 1H), 8.05 (d, J = 4.8 Hz, 1H).

[0380] MS calculated: 257.96; MS found: 259.0 [M+H] + .

[0381] Example 30

[0382] Synthesis of 7-nitroquinoline-4,8-diphenol (30)

[0383] At 0°C, nitric acid (65 wt%) (10.0 mL, 145.5 mmol) was slowly added to a solution of 4-hydroxy-8-methoxyquinoline (11a) (3.0 g, 17.14 mmol) in acetic anhydride (25.0 mL). After stirring for 10 minutes, sulfuric acid (98 wt%) (7.0 mL, 128.7 mmol) was slowly added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 hours. Ice water (100.0 mL) was added to dilute the mixture, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous ammonia (25-28 wt%, NH3 content). The resulting 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 resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 4) to give 8-methoxy-7-nitroquinolin-4-ol (30a) (0.30 g, 8% yield).

[0384] 4-Cyclopropyl-7-nitro-8-methoxyquinoline (70.0 mg, 0.32 mmol) and lithium chloride (200.0 mg, 4.78 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. 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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in that order, and dried under vacuum to give 7-nitroquinoline-4,8-diol (30) (37.0 mg, 56% yield).

[0385] 1 H NMR(400MHz, DMSO-d6)δ:11.31(br s,1H),7.71–6.65(m,1H),7.62–7.56(m,1H),6.65–6.55(m,1H),6.10–6.00(m,1H).

[0386] MS calculated: 206.03; MS found: 207.1 [M+H] + .

[0387] Example 31

[0388] Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-piperazine-1-carboxylic acid methyl ester (31)

[0389] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) and piperazine-1-carboxylic acid methyl ester (82.2 mg, 0.57 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 100°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in sequence and dried under vacuum to give 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-piperazine-1-carboxylic acid methyl ester (30.0 mg, 43% yield).

[0390] 1 H NMR (400MHz, DMSO-d6) δ8.49–8.29(m,1H),8.00–7.85(m,1H),7.46–7.28(m,1H),3.63(s,3H),3.37(br s,8H).

[0391] MS calculated: 366.07; MS found: 367.1 [M+H] + .

[0392] Example 32

[0393] Synthesis of 4-cyclohexyl-7-nitroquinolin-8-ol (32)

[0394] 4-Chloro-8-methoxyquinoline (12a) (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 added sequentially to a mixed solvent of toluene (10.0 mL), ethanol (1.0 mL), and water (2.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 12 hours, cooled to room temperature, and diluted with water (20.0 mL). The resulting mixture was 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-cyclohexenyl-8-methoxyquinoline (32a) (1.1 g, 89% yield).

[0395] 4-Cyclohexenyl-8-methoxyquinoline (32a) (850.0 mg, 3.5 mmol) and palladium / carbon (10 wt% palladium loading) (85.0 mg, 0.080 mmol) were added to methanol (20.0 mL) in sequence at room temperature. The reaction mixture was stirred under a hydrogen atmosphere for 3 hours and filtered under reduced pressure. The filter cake was washed with ethyl acetate (10.0 mL x 3), and the resulting filtrate was concentrated to dryness under reduced pressure to give 4-cyclohexyl-8-methoxyquinoline (32b) (850.0 mg, 99% yield).

[0396] At 0°C, nitric acid (65 wt%) (1.0 mL, 14.5 mmol) was slowly added to a solution of 4-cyclohexyl-8-methoxyquinoline (32b) (800.0 mg, 3.3 mmol) in acetic anhydride (5.0 mL). The mixture was stirred for 10 minutes, and then concentrated sulfuric acid (0.5 mL, 9.2 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 1 hour, diluted with water (20.0 mL), and the pH of the aqueous phase was adjusted to approximately 9-10 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture was extracted with ethyl acetate (30.0 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-cyclohexyl-7-nitro-8-methoxyquinoline (32c) (220.0 mg, 23% yield).

[0397] 4-Cyclohexyl-7-nitro-8-methoxyquinoline (32c) (150.0 mg, 0.53 mmol) and lithium chloride (230.0 mg, 5.3 mmol) were added to N,N-dimethylformamide (5.0 mL) at room temperature. 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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (1.0 mL x 2) and dried under vacuum to give 4-cyclohexyl-7-nitroquinoline-8-ol (32) (124.9 mg, 87% yield).

[0398] 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=4.0Hz,1H),7.93(d,J=8.0Hz,1H),7.40(d,J=4.0Hz,1H),6.7 1(d,J=8.0Hz,1H),3.25–3.09(m,1H),1.94–1.78(m,4H),1.58–1.38(m,4H),1.38–1.20(m,2H).

[0399] MS calculated: 272.12; MS found: 273.1 [M+H] + .

[0400] Example 33

[0401] Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-acetylpiperazine (33)

[0402] The same synthesis method as in Example 31 was used to obtain 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-acetylpiperazine (33) (38.0 mg, yield 35%) from 4,5-dichloro-7-nitroquinolin-8-ol (29) (80.0 mg, 0.31 mmol) and 1-acetylpiperazine (119.0 mg, 0.93 mmol).

[0403] 1 H NMR(400MHz, DMSO-d6)δ:8.40–8.33(m,1H),7.93(s,1H),7.43–7.35(m,1H),3.80–3.40(m,8H),2.04(s,3H).

[0404] MS calculated: 350.08; MS found: 351.1 [M+H] + .

[0405] Example 34

[0406] Synthesis of 5-chloro-4-methoxy-7-nitroquinolin-8-ol (34)

[0407] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and sodium methoxide (62.1 mg, 1.15 mmol) were added to dimethyl sulfoxide (2.0 mL) at room temperature. The reaction mixture was stirred at 120°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in sequence and dried under vacuum to give 5-chloro-4-methoxy-7-nitroquinolin-8-ol (34) (51.0 mg, 87% yield).

[0408] 1 H NMR(400MHz, DMSO-d6)δ:8.50–8.44(m,1H),7.83(s,1H),7.15–7.09(m,1H),3.93(s,3H).

[0409] MS calculated: 254.01; MS observed: 255.0, 257.0 [M+H] + .

[0410] Example 35

[0411] Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxamide (35)

[0412] The same synthesis method as in Example 31 was used to obtain 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxamide (35) (30.0 mg, yield 42%) from 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) and N,N-dimethylpiperazine-1-carboxamide (300.0 mg, 1.9 mmol).

[0413] 1 H NMR (400MHz, DMSO-d6) δ8.36(d,J=8.0Hz,1H),7.92(s,1H),7.39(d,J=8.0Hz,1H),3.78–3.48(m,8H),2.78(s,6H).

[0414] MS calculated: 379.10; MS found: 380.1 [M+H] + .

[0415] Example 36

[0416] Synthesis of 5-chloro-7-nitro-4-piperidinylquinolin-8-ol (36)

[0417] The same synthesis method as in Example 31 was used to obtain 5-chloro-7-nitro-4-piperidinylquinoline-8-ol (36) (50.0 mg, yield 71%) from 4,5-dichloro-7-nitroquinoline-8-ol (29) (60.0 mg, 0.23 mmol) and piperidine (170.0 mg, 2.3 mmol).

[0418] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=8.0Hz,1H),7.82(s,1H),7.19(d,J=4.0Hz,1H),3.12–3.01(m,4H),1.79–1.61(m,6H).

[0419] MS calculated: 307.07; MS found: 308.1 [M+H] + .

[0420] Example 37

[0421] Synthesis of 5-chloro-7-nitro-4-(piperazin-1-yl)quinolin-8-ol (37)

[0422] The same synthesis method as in Example 31 was used to obtain 5-chloro-7-nitro-4-(piperazin-1-yl)quinoline-8-ol (37) (200.0 mg, yield 65%) from 4,5-dichloro-7-nitroquinoline-8-ol (29) (259.0 mg, 1.0 mmol) and piperazine (258.6 mg, 3.0 mmol).

[0423] 1 H NMR (400MHz, CDCl3) δ8.89–8.70(m,1H),8.25–8.06(m,1H),7.88–7.73(m,1H),3.05–2.97(m,4H),2.29–1.98(m,4H).

[0424] MS calculated: 308.07; MS found: 309.1 [M+H] + .

[0425] Example 38

[0426] Synthesis of 5-chloro-4-(4-methoxypiperidin-1-yl)-7-nitroquinolin-8-ol (38)

[0427] The same synthesis method as in Example 31 was used to obtain 5-chloro-4-(4-methoxypiperidin-1-yl)-7-nitroquinoline-8-ol (38) (40.0 mg, yield 51%) from 4,5-dichloro-7-nitroquinoline-8-ol (29) (60.0 mg, 0.23 mmol) and 4-methoxypiperidine (177.0 mg, 1.54 mmol).

[0428] 1 H NMR (400MHz, DMSO-d6) δ8.33–8.28(m,1H),7.92(s,1H),7.43–7.39(m,1H),3.82–3.73(m,2H),3.62–3.52(m,2H ),3.43–3.34(m,1H),3.24(s,3H),2.06–1.96(m,1H),1.94–1.83(m,1H),1.83–1.73(m,1H),1.53–1.42(m,1H).

[0429] MS calculated: 337.08; MS found: 338.1 [M+H] + .

[0430] Example 39

[0431] Synthesis of 5-chloro-7-nitro-4-(4-(trifluoromethyl)piperidin-1-yl)quinolin-8-ol (39)

[0432] The same synthesis method as in Example 34 was used to obtain 5-chloro-7-nitro-4-(4-(trifluoromethyl)piperidin-1-yl)quinoline-8-ol (39) (80.0 mg, yield 93%) from 4,5-dichloro-7-nitroquinoline-8-ol (29) (60.0 mg, 0.23 mmol) and 4-(trifluoromethyl)piperidine (142.0 mg, 0.93 mmol).

[0433] 1 H NMR(400MHz, DMSO-d6)δ:8.50–8.40(m,1H),7.87(s,1H),7.25–7.14(m,1H),3.70–3.50(m,1H),3.00–2.60(m,4H),2.00–1.55(m,4H).

[0434] MS calculated: 375.06; MS found: 376.0 [M+H] + .

[0435] Example 40

[0436] Synthesis of 5-chloro-4-(4-methylpiperazin-1-yl)-7-nitroquinolin-8-ol (40)

[0437] The same synthesis method as in Example 34 was used to obtain 5-chloro-4-(4-methylpiperazin-1-yl)-7-nitroquinolin-8-ol (40) (23.0 mg, 31% yield) from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and 1-methylpiperazine (116.0 mg, 1.16 mmol).

[0438] 1 H NMR(400MHz, DMSO-d6)δ:8.50–8.35(m,1H),8.14(s,1H),7.94(s,1H),7.46–7.38(m,1H),3.85–3.50(m,4H),3.15–2.90(m,4H),2.65–2.55(m,3H).

[0439] MS calculated: 322.08; MS found: 323.1 [M+H] + .

[0440] Example 41

[0441] Synthesis of 5-chloro-4-(4,4-dimethylpiperidin-1-yl)-7-nitroquinolin-8-ol (41)

[0442] At room temperature, 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol), 4,4-dimethylpiperidine hydrochloride (87.0 mg, 0.58 mmol), and triethylamine (39.0 mg, 0.38 mmol) were added to acetonitrile (1.0 mL) in sequence. The reaction mixture was stirred at 80°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in sequence and dried in vacuo to give 5-chloro-4-(4,4-dimethylpiperidin-1-yl)-7-nitroquinolin-8-ol (41) (52.0 mg, 80% yield).

[0443] 1H NMR(400MHz, DMSO-d6)δ8.23(d,J=6.6Hz,1H),7.86(s,1H),7.35(d,J=6.8Hz,1H), 3.76–3.54(m,4H),1.59–1.50(m,2H),1.48–1.40(m,2H)1.06(s,3H),0.91(s,3H).

[0444] MS calculated: 335.1; MS found: 336.1 [M+H] + .

[0445] Example 42

[0446] Synthesis of 5-chloro-7-nitro-4-(pyrrolidin-1-yl)quinolin-8-ol (42)

[0447] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and tetrahydropyrrole (66.0 mg, 0.93 mmol) were added to acetonitrile (6.0 mL) at room temperature. The reaction mixture was stirred at 100°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in that order and dried under vacuum to give 5-chloro-7-nitro-4-(pyrrolidin-1-yl)quinolin-8-ol (42) (58.0 mg, 86% yield).

[0448] 1 H NMR(400MHz, DMSO-d6)δ:8.30–8.10(m,1H),7.74(s,1H),7.00–6.85(m,1H),7.46–7.38(m,1H),2.00–1.75(m,8H).

[0449] MS calculated: 293.06; MS found: 294.0 [M+H] + .

[0450] Example 43

[0451] Preparation of 5-chloro-4-(2-fluoroethoxy)-7-nitroquinolin-8-ol (43)

[0452] Sodium hydride (60 wt%, mineral oil mixture) (46.0 mg, 1.16 mmol) was added to a solution of 2-fluoroethanol (147.0 mg, 2.3 mmol) in dimethyl sulfoxide (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) was added. The resulting mixture was stirred at 100°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (3.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in that order, and dried under vacuum to give 5-chloro-4-(2-fluoroethoxy)-7-nitroquinolin-8-ol (43) (40.0 mg, 61% yield).

[0453] 1 H NMR(400MHz,DMSO-d6)δ:8.46(d,J=4.4Hz,1H),7.85(s,1H),7.13(d,J=5.2Hz,1 H),4.91–4.88(m,1H),4.79–4.76(m,1H),4.46–4.43(m,1H),4.39–4.36(m,1H).

[0454] MS calculated: 286.02; MS found: 287.0 [M+H] + .

[0455] Example 44

[0456] Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-N-methylpiperazine-1-carboxamide (44)

[0457] To a solution of 5-chloro-7-nitro-4-(piperazin-1-yl)quinolin-8-ol (37) (60.0 mg, 0.19 mmol) in dichloromethane (5.0 mL) were added triethylamine (60.0 mg, 0.58 mmol), methylaminocarbonyl chloride (55.0 mg, 0.58 mmol), and N,N-dimethylformamide (0.1 mL) in sequence at 0°C. The reaction mixture was warmed to room temperature, stirred for 1 hour, and diluted with water (10.0 mL). The resulting mixture 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 resulting residue was separated by reverse-phase high performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-70% / 30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to give 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-N-methylpiperazine-1-carboxamide (44) (46.0 mg, yield 66%).

[0458] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=8.0Hz,1H),7.91(s,1H),7.39(d,J=8.0Hz,1H) ,6.63–6.55(m,1H),3.68–3.60(m,4H),3.56–3.51(m,4H),2.58(d,J=4.0Hz,3H).

[0459] MS calculated: 365.09; MS found: 366.1 [M+H] + .

[0460] Example 45

[0461] Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-(2,2,2-trimethylacetyl)piperazine (45)

[0462] The same synthesis method as in Example 44 was used to obtain 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-(2,2,2-trimethylacetyl)piperazine (45) (56.0 mg, yield 75%) from 5-chloro-7-nitro-4-(piperazin-1-yl)quinolin-8-ol (37) (60.0 mg, 0.19 mmol), trimethylacetyl chloride (73.0 mg, 0.60 mmol) and triethylamine (70.0 mg, 0.60 mmol).

[0463] 1H NMR (400MHz, DMSO-d6) δ8.38(d,J=8.0Hz,1H),7.93(s,1H),7.37(d,J=8.0Hz,1H),4.02–3.84(m,4H),3.72–3.62(m,4H),1.21(s,9H).

[0464] MS calculated: 392.13; MS found: 393.1 [M+H] + .

[0465] Example 46

[0466] Synthesis of ethyl 1-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperidine-4-carboxylate (46)

[0467] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) and ethyl 4-piperidinol (91.0 mg, 0.58 mmol) were added to acetonitrile (1.0 mL) at room temperature. The reaction mixture was stirred at 80°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 resulting residue, stirred for 30 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give ethyl 1-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperidinol-4-carboxylate (46) (47.0 mg, 64% yield).

[0468] 1 H NMR(400MHz, DMSO-d6)δ:8.37(d,J=6.0Hz,1H),8.20(d,J=6.8Hz,1H),7.92(s,1H),4.12(q,J=6.8Hz,2H),3.92(d,J=13.6Hz,1 H),3.73(d,J=11.4Hz,1H),3.62-3.57(m,1H),3.06-2.98(m,1H),2.81(m,1H),1.95(m,3H),1.57(m,1H),1.15(t,J=6.8Hz,3H).

[0469] MS calculated: 379.1; MS observed: 380.1 [M+H] + .

[0470] Example 47

[0471] Synthesis of 5-chloro-7-nitro-4-phenoxyquinolin-8-ol (47)

[0472] The same synthesis method as in Example 31 was used to obtain 5-chloro-7-nitro-4-phenoxyquinoline-8-phenol (47) (71.9 mg, yield 99%) from 4,5-dichloro-7-nitroquinoline-8-phenol (29) (60.0 mg, 0.23 mmol) and sodium phenolate (107.5 mg, 0.93 mmol).

[0473] 1 H NMR(400MHz, DMSO-d6)δ:8.53–8.48(m,2H),7.94(s,1H),7.52–7.45(m,2H),7.30–7.22(m,1H),7.16–7.10(m,2H), 6.92–6.88(m,1H).

[0474] MS calculated: 316.03; MS found: 317.1 [M+H] + .

[0475] Example 48

[0476] Synthesis of 5-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)-7-nitroquinolin-8-ol (48)

[0477] The same synthesis method as in Example 31 was used to obtain 5-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)-7-nitroquinoline-8-ol (48) (62.0 mg, yield 70%) from 4,5-dichloro-7-nitroquinoline-8-ol (29) (60.0 mg, 0.23 mmol) and 1-(methylsulfonyl)piperazine (113.0 mg, 0.69 mmol).

[0478] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=5.6Hz,1H),7.88(s,1H),7.25(d,J=5.8Hz,1H),3.20–3.17(m,4H),3.02–2.99(m,4H),2.91(s,3H).

[0479] MS calculated: 386.05; MS found: 387.1 [M+H] + .

[0480] Example 49

[0481] Synthesis of 5-chloro-4-cyclopropyl-7-nitroquinolin-8-ol (49)

[0482] 2,2-Dimethyl-1,3-dioxane-4,6-dione (12.0 g, 83.3 mmol) and triethyl orthoformate (13.7 g, 95.1 mmol) were added to ethanol (83.0 mL) at room temperature. The reaction mixture was stirred at 90°C for 4 hours, followed by the addition of 5-chloro-2-methoxyaniline (49a) (12.0 g, 76.4 mmol). Stirring was continued for 1 hour, and the mixture was cooled to room temperature. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with ethanol (15.0 mL x 2) and dried under vacuum to afford 5-(((5-chloro-2-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (49b) (23.0 g, 97% yield).

[0483] 5-(((5-Chloro-2-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (49b) (23.0 g, 74.0 mmol) was added to diphenyl ether (125.0 mL) at room temperature. The reaction mixture was heated to 240°C and stirred for 3.5 hours. The mixture was then cooled to room temperature, diluted with petroleum ether (60-90°C boiling range) (600.0 mL), and stirred for an additional 2 hours. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with petroleum ether (60-90°C boiling range) (50.0 mL x 3) and dried under vacuum to afford 5-chloro-8-methoxyquinolin-4-ol (49c) (12.5 g, 81% yield).

[0484] 5-Chloro-8-methoxyquinolin-4-ol (49c) (2.0 g, 7.35 mmol) was added to a mixed solvent of chloroform (20.0 mL) and N,N-dimethylformamide (2.0 mL) at room temperature, followed by the slow dropwise addition of phosphorus oxybromide (4.2 g, 14.7 mmol). The reaction mixture was heated to 60°C and stirred for 2 hours. The mixture was cooled to room temperature, ice water (30.0 mL) was added, and the pH of the aqueous phase was adjusted to approximately 9-10 with aqueous ammonia (25-28 wt%, NH3 content). The resulting mixture was extracted with dichloromethane (100.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to afford 4-bromo-5-chloro-8-methoxyquinoline (49d) (1.4 g, 70% yield).

[0485] 4-Bromo-5-chloro-8-methoxyquinoline (49d) (225.0 mg, 0.83 mmol), cyclopropylboronic acid (107.4 mg, 1.25 mmol), tetrakis(triphenylphosphine)palladium (129.1 mg, 0.083 mmol), and potassium carbonate (229.1 mg, 1.66 mmol) were added sequentially to a mixed solvent of toluene (10.0 mL), ethanol (1.0 mL), and water (2.0 mL) at room temperature. The reaction mixture was stirred at 90°C for 12 hours, cooled to room temperature, and diluted with water (20.0 mL). The resulting mixture was extracted with ethyl acetate (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 5-chloro-4-cyclopropyl-8-methoxyquinoline (49e) (100.0 mg, yield 52%).

[0486] 5-Chloro-4-cyclopropyl-8-methoxyquinoline (49e) (100.0 mg, 0.42 mmol) was added to a dichloromethane solution (1.0 M) of boron tribromide (1.3 mL, 1.3 mmol) at room temperature. The reaction mixture was stirred at 50°C for 5 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 80 / 1) to provide 5-chloro-4-cyclopropylquinolin-8-ol (49f) (60.0 mg, 65% yield).

[0487] Sodium nitrite (186.3 mg, 2.7 mmol) was added portionwise to a suspension of 5-chloro-4-cyclopropylquinolin-8-ol (49f) (60.0 mg, 0.27 mmol) in hydrochloric acid (2.0 M) (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent. The resulting residue was separated by reverse-phase HPLC (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100%-70% / 30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate 20.0 mL / min) to give the product 5-chloro-4-cyclopropyl-7-nitroquinolin-8-ol (49) (8.5 mg, 12% yield).

[0488] 1H NMR(400MHz, DMSO-d6)δ:9.04–8.79(m,1H),8.22–7.93(m,1H),7.75–7.41(m,1H),3.00–2.92(m,1H),1.24–1.17(m,2H),1.03–0.95(m,2H).

[0489] MS calculated: 264.03; MS found: 265.0 [M+H] + .

[0490] Example 50

[0491] Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-(2,2-dimethylacetyl)piperazine (50)

[0492] The same synthesis method as in Example 44 was used to obtain 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-(2,2-dimethylacetyl)piperazine (50) (15.0 mg, yield 22%) from 5-chloro-7-nitro-4-(piperazin-1-yl)quinolin-8-ol (37) (56.0 mg, 0.18 mmol), isobutyryl chloride (38.4 mg, 0.36 mmol) and triethylamine (36.4 mg, 0.36 mmol).

[0493] 1 H NMR (400 MHz, DMSO-d6) δ: 8.15 (s, 1H), 7.91 (s, 1H), 7.25 (s, 1H), 4.35–4.21 (br s, 2H), 4.01–3.90 (br s, 2H), 2.95–2.88 (br s, 2H), 2.81–2.69 (br s, 2H), 2.05–1.94 (m, 1H), 1.01 (overlapping s, 6H).

[0494] MS calculated: 394.10; MS observed: 395.1, 396.1 [M+H] + .

[0495] Example 51

[0496] Synthesis of 5-chloro-7-nitro-4-phenylquinolin-8-ol hydrochloride (51)

[0497] 4-Bromo-5-chloro-8-methoxyquinoline (49d) (200.0 mg, 0.73 mmol), phenylboronic acid (134.0 mg, 1.10 mmol), tetrakis(triphenylphosphine)palladium (156.0 mg, 0.10 mmol), and potassium carbonate (207.0 mg, 1.50 mmol) were added sequentially to 1,4-dioxane (10.0 mL) at room temperature. The reaction mixture was stirred at 90°C for 12 hours, cooled to room temperature, and diluted with water (20.0 mL). The resulting mixture was extracted with dichloromethane (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3) to provide 5-chloro-8-methoxy-4-phenylquinoline (51a) (150.0 mg, 76% yield).

[0498] At 0°C, a dichloromethane solution (1.0 M) of boron tribromide (1.5 mL, 1.5 mmol) was slowly added to a dichloromethane solution (2.0 mL) of 5-chloro-8-methoxy-4-phenylquinoline (51a) (150.0 mg, 0.56 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour, then stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature and the pH of the aqueous phase was adjusted to approximately 8-9 by adding saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (20.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 5-chloro-4-phenylquinolin-8-ol (51b) (80.0 mg, 56% yield).

[0499] Sodium nitrite (162.0 mg, 2.3 mmol) was added portionwise to a suspension of 5-chloro-4-phenylquinolin-8-ol (60.0 mg, 0.23 mmol) in hydrochloric acid (3.0 M) (5.0 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours, then filtered under reduced pressure. The filter cake was washed with ethanol (0.5 mL x 2) and dried under vacuum to give 5-chloro-7-nitro-4-phenylquinolin-8-ol hydrochloride (51) (8.5 mg, 12% yield).

[0500] 1 H NMR (400MHz, DMSO-d6) δ: 9.05 (d, J = 4.0 Hz, 1H), 8.09 (s, 1H), 7.70 (d, J = 4.0 Hz, 1H), 7.51–7.43 (m, 3H), 7.40–7.35 (m, 2H).

[0501] MS calculated: 300.03; MS found: 301.0 [M+H] + .

[0502] Example 52

[0503] Synthesis of ethyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylate (52)

[0504] The same synthesis method as in Example 31 was used to obtain 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylic acid ethyl ester (52) (73.0 mg, yield 83%) from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and piperazine-1-carboxylic acid ethyl ester (110.0 mg, 0.70 mmol).

[0505] 1 H NMR (400MHz, DMSO-d6) δ8.38(d,J=4.0Hz,1H),7.92(s,1H),7.38(d,J=8.0Hz,1H),4.13–4.05(m,2H),3.74–3.62(m,8H),1.20(t,J=7.0Hz,3H).

[0506] MS calculated: 380.09; MS found: 381.1 [M+H] + .

[0507] Example 53

[0508] Synthesis of 5-chloro-4-(cyclopropylmethoxy)-7-nitroquinolin-8-ol (53)

[0509] The same synthesis method as in Example 43 was used to obtain 5-chloro-4-(cyclopropylmethoxy)-7-nitroquinolin-8-ol (53) (14.0 mg, yield 21%) from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol), cyclopropylmethanol (250.0 mg, 1.16 mmol) and sodium hydride (60 wt%, mineral oil mixture) (46.0 mg, 1.16 mmol).

[0510] 1 H NMR(400MHz,DMSO-d6)δ:8.45–8.35(m,1H),7.83(s,1H),7.10–7.00(m,1H), 4.10–3.95(m,2H),1.40–1.25(m,1H),0.65–0.55(m,2H),0.46–0.35(m,2H).

[0511] MS calculated: 294.04; MS found: 295.0 [M+H] + .

[0512] Example 54

[0513] Synthesis of 5-chloro-4-(4-(3-methoxypropoxy)piperidin-1-yl)-7-nitroquinolin-8-ol dihydrochloride (54)

[0514] At room temperature, tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 5.0 mmol) (54a) and sodium hydride (60 wt%, mineral oil mixture) (0.50 g, 12.5 mmol) were added sequentially to N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at room temperature for 1.5 hours, 1-bromo-3-methoxypropane (2.3 g, 15.0 mmol) was added, and the mixture was heated to 50°C and stirred for 4 hours. The mixture was cooled to room temperature and diluted with water (20.0 mL) and dichloromethane (20.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 30 / 1-20 / 1) to give tert-butyl 4-(3-methoxypropoxy)piperidine-1-carboxylate (54b) (0.34 g, yield 25%).

[0515] A 4.0 M solution of hydrogen chloride in 1,4-dioxane (3.1 mL, 12.4 mmol) was added to tert-butyl 4-(3-methoxypropoxy)piperidine-1-carboxylate (54b) (340.0 mg, 1.24 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure to provide crude 4-(3-methoxypropoxy)piperidine hydrochloride (54c) (310.0 mg, crude yield >100%).

[0516] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (40.0 mg, 0.15 mmol) and 4-(3-methoxypropoxy)piperidine hydrochloride (54c) (310.0 mg, 1.8 mmol) were added to N,N-dimethylformamide (3.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 4 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The residue was separated by reverse-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% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to give 5-chloro-4-(4-(3-methoxypropoxy)piperidin-1-yl)-7-nitroquinolin-8-ol dihydrochloride (54) (14.0 mg, yield 24%).

[0517] 1 H NMR(400MHz, DMSO-d6)δ:8.35–8.20(m,1H),7.90–7.82(m,1H),7.42–7.30(m,1H),3.40–3.28(m,12H),2.10–1.60(m,6H).

[0518] MS calculated: 395.12; MS found: 396.1 [M+H] + .

[0519] Example 55

[0520] Synthesis of 5-chloro-4-(4,4-difluoropiperidin-1-yl)-7-nitroquinolin-8-ol (55)

[0521] The same synthesis method as in Example 31 was used to obtain 5-chloro-4-(4,4-difluoropiperidin-1-yl)-7-nitroquinoline-8-phenol (55) (43.0 mg, yield 54%) from 4,5-dichloro-7-nitroquinoline-8-phenol (29) (60.0 mg, 0.23 mmol) and 4,4-difluoropiperidine (140.0 mg, 1.16 mmol).

[0522] 1 H NMR (400MHz, DMSO-d6) δ: 8.39 (d, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 3.80–3.60 (m, 4H), 2.35–2.05 (m, 4H).

[0523] MS calculated: 343.05; MS found: 344.1 [M+H] +.

[0524] Example 56

[0525] Synthesis of 1-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperidin-4-one (56)

[0526] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (40.0 mg, 0.15 mmol), 4-piperidone hydrochloride (37.0 mg, 0.37 mmol), and triethylamine (45.0 mg, 0.45 mmol) were added sequentially to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 1-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperidin-4-one (56) (20.0 mg, 41% yield).

[0527] 1 H NMR (400MHz, DMSO-d6) δ8.39–8.34(m,1H),7.93–7.86(m,1H),7.42–7.35(m,1H),3.95–3.64(m,8H).

[0528] MS calculated: 321.05; MS found: 322.1 [M+H] + .

[0529] Example 57

[0530] Synthesis of (1-methyl)propyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylate (57)

[0531] The same synthesis method as in Example 44 was used to obtain 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylic acid-(1-methyl)propyl ester (57) (50.0 mg, yield 68%) from 5-chloro-7-nitro-4-(piperazin-1-yl)quinolin-8-ol (37) (56.0 mg, 0.18 mmol), sec-butyl chloroformate (75.0 mg, 0.55 mmol) and triethylamine (54.6 mg, 0.54 mmol).

[0532] 1H NMR (400MHz, DMSO-d6) δ8.38(d,J=4.0Hz,1H),7.92(s,1H),7.39(d,J=8.0Hz,1H),4.68– 4.62(m,1H),3.76–3.53(m,8H),1.56–1.49(m,2H),1.20–1.14(m,3H),0.90–0.81(m,3H).

[0533] MS calculated: 408.12; MS observed: 409.1 [M+H] + .

[0534] Example 58

[0535] Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylic acid isopropyl ester (58)

[0536] The same synthesis method as in Example 44 was used to obtain 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylic acid isopropyl ester (58) (46.0 mg, yield 61%) from 5-chloro-7-nitro-4-(piperazin-1-yl)quinolin-8-ol (37) (60.0 mg, 0.19 mmol), isopropyl chloroformate (73.8 mg, 0.60 mmol) and triethylamine (67.0 mg, 0.60 mmol).

[0537] 1 H NMR (400MHz, DMSO-d6) δ8.38(d,J=4.0Hz,1H),7.92(s,1H),7.38(d,J=8.0Hz,1H),4.86–4.74(m,1H),3.73–3.45(m,8H),1.25–1.16(m,6H).

[0538] MS calculated: 394.10; MS found: 395.1 [M+H] + .

[0539] Example 59

[0540] Synthesis of 5-chloro-4-(cyclopentyloxy)-7-nitroquinolin-8-ol (59)

[0541] Cyclopentanol (166.0 mg, 1.93 mmol) and sodium hydride (60 wt%, mineral oil mixture) (38.8 mg, 0.97 mmol) were added sequentially to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) was added. The resulting mixture was stirred at 100°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The residue was separated by reverse-phase HPLC (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100%-70% / 30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to give 5-chloro-4-(cyclopentyloxy)-7-nitroquinolin-8-ol (59) (11.0 mg, 19% yield).

[0542] 1 H NMR(400MHz, DMSO-d6)δ:8.80-8.60(m,1H),8.05-7.95(m,1H),7.50-7.35(m,1H),5.38-5.22(m,1H),2.10-1.60(m,9H).

[0543] MS calculated: 308.06; MS found: 309.0 [M+H] + .

[0544] Example 60

[0545] Synthesis of 5-chloro-4-(cyclohexyloxy)-7-nitroquinolin-8-ol (60)

[0546] The same synthesis method as in Example 59 was used to obtain 5-chloro-4-(cyclohexyloxy)-7-nitroquinolin-8-ol (60) (30.0 mg, yield 16%) from 4,5-dichloro-7-nitroquinolin-8-ol (29) (150.0 mg, 0.58 mmol), cyclohexanol (117.0 mg, 1.16 mmol) and sodium hydride (60 wt%, mineral oil mixture) (47.0 mg, 1.16 mmol).

[0547] 1 H NMR(400MHz, DMSO-d6)δ:8.65(d,J=8.0Hz,1H),7.98(s,1H),7.54(d,J=8.0Hz,1 H),5.13–4.85(m,1H),2.10–1.86(m,2H),1.84–1.62(m,4H),1.56–1.38(m,4H).

[0548] MS calculated: 322.07; MS found: 323.1 [M+H] + .

[0549] Example 61

[0550] Synthesis of 5-chloro-4-ethoxy-7-nitroquinolin-8-ol (61)

[0551] The same synthesis method as in Example 43 was used to obtain 5-chloro-4-ethoxy-7-nitroquinoline-8-phenol (61) (23.3 mg, yield 38%) from 4,5-dichloro-7-nitroquinoline-8-phenol (29) (60.0 mg, 0.23 mmol), ethanol (6.0 mL, 102.7 mmol) and sodium hydride (60 wt%, mineral oil mixture) (50.6 mg, 1.26 mmol).

[0552] 1 H NMR(400MHz, DMSO-d6)δ:8.75–8.70(m,1H),8.00(s,1H),7.48–7.41(m,1H),4.50–4.40(m,2H),1.57–1.45(m,3H).

[0553] MS calculated: 268.03; MS found: 269.0 [M+H] + .

[0554] Example 62

[0555] Synthesis of 7-nitro-4-trifluoromethylquinolin-8-ol (62)

[0556] At room temperature, o-anisidine (62a) (2.36 g, 19.2 mmol), ethyl 4,4,4-trifluoroacetoacetate (62b) (2.95 g, 16.0 mmol), and triethylamine (3.24 g, 32.0 mmol) were added to toluene (16.0 mL). The reaction mixture was stirred at 125°C 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 sequentially with hydrochloric acid (2.0 M) (15.0 mL x 2), saturated aqueous sodium bicarbonate solution (20.0 mL), and water (15.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 4,4,4-trifluoro-N-(2-methoxyphenyl)-3-oxobutanamide (62c) (3.48 g, crude yield 78%).

[0557] 4,4,4-Trifluoro-N-(2-methoxyphenyl)-3-oxobutanamide (62c) (2.81 g, 10.7 mmol) was completely dissolved in polyphosphoric acid (14.0 g) at 90°C. The reaction mixture was stirred at 90°C for 3 hours, cooled to room temperature, 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), and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1) to give 8-methoxy-4-trifluoromethyl-2(1H)-quinolinone (62d) (2.21 g, 84% yield).

[0558] 8-Methoxy-4-trifluoromethyl-2(1H)-quinolinone (62d) (2.09 g, 8.6 mmol) was added to phosphorus oxychloride (8.6 mL) at room temperature. The reaction mixture was stirred at 100°C 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 aqueous sodium carbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (15.0 mL x 2). The combined organic phases were washed sequentially with saturated aqueous sodium carbonate (25.0 mL), water (25.0 mL), and saturated brine (25.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude 2-chloro-8-methoxy-4-trifluoromethylquinoline (62e) (2.26 g, crude yield 100%).

[0559] 2-Chloro-8-methoxy-4-trifluoromethylquinoline (62e) (520.0 mg, 2.0 mmol) was added to a mixture of tetrahydrofuran (10.0 mL) and methanol (10.0 mL) at room temperature, followed by palladium on carbon (10 wt% palladium loading) (210.0 mg, 0.2 mmol). The reaction mixture was stirred under a hydrogen atmosphere for 1 hour, filtered through celite, and the filter cake was washed with a mixture of dichloromethane and methanol (volume ratio, dichloromethane / methanol = 20 / 1) (30.0 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (20.0 mL), washed with saturated aqueous sodium bicarbonate (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 8-methoxy-4-trifluoromethylquinoline (62f) (380.0 mg, yield 84%).

[0560] Nitric acid (65 wt%) (0.69 mL, 10.0 mmol) was slowly added dropwise to a solution of 8-methoxy-4-trifluoromethylquinoline (62f) (380.0 mg, 1.7 mmol) in acetic anhydride (5.0 mL) at 0°C. The mixture was stirred for 10 minutes, and then sulfuric acid (98 wt%) (0.12 mL, 2.2 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, and an aqueous solution of sodium hydroxide (1.0 M) was added to adjust the pH of the aqueous phase to approximately 9-10. The resulting mixture was extracted with dichloromethane (10.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to provide 8-methoxy-7-nitro-4-trifluoromethylquinoline (62 g) (93.5 mg, 20% yield).

[0561] 8-Methoxy-7-nitro-4-trifluoromethylquinoline (62 g) (93.5 mg, 0.34 mmol) and lithium chloride (144.0 mg, 3.4 mmol) were added to N,N-dimethylformamide (0.4 mL) at room temperature. The reaction mixture was stirred at 170°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (1.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.2 mL x 2) and dried under vacuum to give 7-nitro-4-trifluoromethylquinolin-8-ol (62) (70.0 mg, 79% yield).

[0562] 1 H NMR (400MHz, DMSO-d6) δ: 8.79 (d, J = 3.6 Hz, 1H), 8.10 (d, J = 9.6 Hz, 1H), 7.88 (d, J = 4.4 Hz, 1H), 6.52 (dd, J = 9.6, 2.4 Hz, 1H).

[0563] MS calculated: 258.03; MS found: 259.1 [M+H] + .

[0564] Example 63

[0565] Synthesis of 5-chloro-7-nitro-4-(6-azaspiro[2.5]octan-6-yl)quinolin-8-ol (63)

[0566] 6-Azaspiro[2.5]octane hydrochloride (85.4 mg, 0.58 mmol) and N,N-diisopropylethylamine (125.0 mg, 0.96 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, and 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) was added. The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by reverse-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% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to give 5-chloro-7-nitro-4-(6-azaspiro[2.5]octan-6-yl)quinolin-8-ol (63) (3.5 mg, 6% yield).

[0567] 1 H NMR(400MHz,DMSO-d6)δ:8.32–8.20(m,1H),7.90–7.85(m,1H),7.44–7.33(m,1 H),3.75–3.60(m,4H),2.05–1.95(m,1H),1.65–1.35(m,4H),0.50–0.28(m,4H).

[0568] MS calculated: 333.09; MS found: 334.1 [M+H] + .

[0569] Example 64

[0570] Synthesis of 5-chloro-4-cyclohexyl-7-nitroquinolin-8-ol (64)

[0571] 4-Chloro-8-methoxyquinoline (12a) (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 added sequentially to a mixed solvent of toluene (10.0 mL), ethanol (1.0 mL), and water (2.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 12 hours, cooled to room temperature, and diluted with water (20.0 mL). The resulting mixture was extracted with ethyl acetate (30.0 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-cyclohexenyl-8-methoxyquinoline (64a) (1.1 g, 89% yield).

[0572] 4-Cyclohexenyl-8-methoxyquinoline (64a) (850.0 mg, 3.5 mmol) and palladium / carbon (10 wt%, palladium loading) (85.0 mg, 0.080 mmol) were added sequentially to methanol (20.0 mL) at room temperature. The resulting mixture was stirred under a hydrogen atmosphere for 3 hours, filtered through celite, and the filter cake was washed with ethyl acetate (10.0 mL x 3). The filtrate was concentrated to dryness under reduced pressure to provide 4-cyclohexyl-8-methoxyquinoline (64b) (850.0 mg, 99% yield).

[0573] At 0°C, a dichloromethane solution (1.0 M) of boron tribromide (7.0 mL, 7.0 mmol) was slowly added dropwise to a dichloromethane solution (2.0 mL) of 4-cyclohexyl-8-methoxyquinoline (64b) (420.0 mg, 1.7 mmol). The reaction mixture was warmed to room temperature and stirred at 50°C for 5 hours. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution was added to adjust the pH of the aqueous phase to approximately 8-9. The resulting mixture was extracted with ethyl acetate (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 resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 4-cyclohexylquinolin-8-ol (64c) (250.0 mg, 65% yield).

[0574] N-Chlorosuccinimide (147.0 mg, 1.1 mmol) was added to a solution of 4-cyclohexylquinolin-8-ol (64c) (250.0 mg, 1.1 mmol) in sulfuric acid (98 wt%) (7.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and the pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (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 resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to provide 5-chloro-4-cyclohexylquinolin-8-ol (64d) (230.0 mg, 80% yield).

[0575] Sodium nitrite (600.0 mg, 7.6 mmol) was added portionwise to a suspension of 5-chloro-4-cyclohexylquinolin-8-ol (64d) (200.0 mg, 0.76 mmol) in hydrochloric acid (2.0 M) (10.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous ammonia (25-28% by weight, NH3 content). The resulting mixture was filtered under reduced pressure, and the filter cake was separated by reverse-phase high-performance liquid chromatography (HPLC column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100%-70% / 30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to obtain 5-chloro-4-cyclohexyl-7-nitroquinolin-8-ol (64) (60.0 mg, 26% yield).

[0576] 1 H NMR(400MHz, DMSO-d6)δ:8.85(d,J=4.0Hz,1H),7.72(d,J=4.0Hz,1H),7.68–7.63( m,1H),7.17–7.11(m,1H),4.36–4.26(m,1H),1.97–1.73(m,4H),1.61–1.22(m,6H).

[0577] MS calculated: 261.09; MS found: 262.1 [M+H] + .

[0578] Example 65

[0579] Synthesis of 5-chloro-4-fluoro-7-nitroquinolin-8-ol (65)

[0580] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and cesium fluoride (350.0 mg, 2.3 mmol) were added to dimethyl sulfoxide (2.0 mL) at room temperature. The resulting mixture was stirred at 180°C for 2 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by reverse-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% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to give 5-chloro-4-fluoro-7-nitroquinolin-8-ol (65) (12.0 mg, 22% yield).

[0581] 1 H NMR(400MHz, DMSO-d6)δ:9.13–9.01(m,1H),8.18(s,1H),7.88–7.73(m,1H).

[0582] MS calculated: 241.99; MS found: 243.0 [M+H] + .

[0583] Example 66

[0584] Synthesis of 5-chloro-4-(3-methylpiperidin-1-yl)-7-nitroquinolin-8-ol (66)

[0585] The same synthesis method as in Example 46 was used to obtain 5-chloro-4-(3-methylpiperidin-1-yl)-7-nitroquinolin-8-ol (66) (62.0 mg, yield 99.8%) from 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) and 3-methylpiperidine (57.0 mg, 0.57 mmol).

[0586] 1 H NMR(400MHz, DMSO-d6)δ7.82(dd,J=16.2,1.6Hz,1H),7.27-7.04(m,2H),3.28-3.13(m,3H),2.76(td ,J=12.7,3.0Hz,1H),2.26-2.12(m,1H),2.07-1.95(m,1H),1.81-1.71(m,3H),0.91(d,J=6.5Hz,3H).

[0587] MS calculated: 321.1; MS observed: 322.1 [M+H] + .

[0588] Example 67

[0589] Synthesis of 4-(Benzyloxy)-5-chloro-7-nitroquinolin-8-ol hydrochloride (67)

[0590] Sodium hydride (60 wt%, mineral oil mixture) (55.0 mg, 1.38 mmol) was added to a solution of benzyl alcohol (100.0 mg, 0.93 mmol) in dimethyl sulfoxide (6.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, and 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, hydrochloric acid (36 wt%) (1.5 mL) was added, and the mixture was filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in sequence, and dried under vacuum to give 4-(benzyloxy)-5-chloro-7-nitroquinolin-8-ol hydrochloride (67) (29.5 mg, 35% yield).

[0591] 1 H NMR(400MHz, DMSO-d6)δ:8.83–8.76(m,1H),8.05–8.00(m,1H),7.62–7.55(m,3H),7.49–7.35(m,3H),5.58–5.51(m,2H).

[0592] MS calculated: 330.04; MS found: 331.0 [M+H] + .

[0593] Example 68

[0594] Synthesis of 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68)

[0595] 5-Fluoro-2-methoxyaniline (68a) (1.41 g, 10.0 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (1.73 g, 12.0 mmol), and triethyl orthoformate (3.56 g, 24.0 mmol) were added to ethanol (10.0 mL) at room temperature. The resulting mixture was stirred at 95°C for 3 hours, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with ethanol (5.0 mL x 3) and dried under vacuum to give 5-(((5-fluoro-2-methoxyphenyl)amino)methine)-2,2-dimethyl-1,3-dioxane-4,6-dione (68b) (3.21 g, 99% yield).

[0596] 5-(((5-Fluoro-2-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (68b) (2.70 g, 9.2 mmol) was added to diphenyl ether (46.0 mL) at room temperature. The reaction mixture was stirred at 210°C for 4 hours, cooled to room temperature, diluted with petroleum ether (60°C-90°C boiling range) (250.0 mL), and filtered under reduced pressure. The filter cake was washed with petroleum ether (60°C-90°C boiling range) (8.0 mL x 4) and dried under vacuum to afford 5-fluoro-8-methoxyquinolin-4-ol (68c) (1.49 g, 84% yield).

[0597] Phosphorus oxychloride (7.7 mL) was added to 5-fluoro-8-methoxyquinolin-4-ol (68c) (1.49 g, 7.7 mmol) at room temperature. The reaction mixture was stirred at 100°C for 3 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 aqueous sodium hydroxide (1.0 M). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed sequentially with saturated aqueous sodium carbonate (20.0 mL), water (20.0 mL), and saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / petroleum ether = 2 / 1) to provide 4-chloro-5-fluoro-8-methoxyquinoline (68d) (1.33 g, 81% yield).

[0598] At 0°C, a dichloromethane solution of boron tribromide (1.0 M) (31.4 mL, 31.4 mmol) was slowly added dropwise to 4-chloro-5-fluoro-8-methoxyquinoline (68d) (1.33 g, 6.3 mmol). The reaction mixture was warmed to room temperature and stirred for 5 hours. Ice water (150.0 mL) was added, and the pH of the aqueous phase was adjusted to approximately 9-10 with solid sodium carbonate. The organic phase was separated and extracted with dichloromethane (30.0 mL x 4). The combined organic phases were washed with saturated aqueous sodium carbonate (40.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 100 / 1) to give 4-chloro-5-fluoroquinolin-8-ol (68e) (0.65 g, 52% yield).

[0599] A solution of sodium nitrite (2.27 g, 32.9 mmol) in water (2.7 mL) was added dropwise to a suspension of 4-chloro-5-fluoroquinolin-8-ol (68e) (0.65 g, 3.3 mmol) in hydrochloric acid (2.4 M) (13.7 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 10 hours. The pH of the aqueous phase was adjusted to about 9-10 with solid sodium carbonate and filtered under reduced pressure. The filter cake was washed with water (3.0 mL x 3) and dried under vacuum to give 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68) (0.354 g, 44% yield).

[0600] 1 H NMR (400 MHz, DMSO-d6) δ: 8.62 (s, 1H), 7.79 (overlapping s, 2H).

[0601] MS calculated: 241.99; MS observed: 243.1, 245.1 [M+H] + .

[0602] Example 69

[0603] Synthesis of 4-(4,4-difluoropiperidin-1-yl)-5-fluoro-7-nitroquinolin-8-ol (69)

[0604] 4-Chloro-5-fluoro-7-nitroquinolin-8-ol (68) (42.0 mg, 0.17 mmol) and 4,4-difluoropiperidine (63.0 mg, 0.52 mmol) were added to N,N-dimethylformamide (3.0 mL) at room temperature. The reaction mixture was stirred at 90°C for 4 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 4-(4,4-difluoropiperidin-1-yl)-5-fluoro-7-nitroquinolin-8-ol (69) (30.0 mg, 54% yield).

[0605] 1 H NMR(400MHz, DMSO-d6)δ:8.63–8.50(m,1H),7.78–7.70(m,1H),7.35–7.28(m,1H),3.50–3.40(m,4H),2.30–2.15(m,4H).

[0606] MS calculated: 327.08; MS found: 328.1 [M+H] + .

[0607] Example 70

[0608] Synthesis of 5-fluoro-7-nitro-4-(4-(trifluoromethyl)piperidin-1-yl)quinolin-8-ol (70)

[0609] The same synthesis method as in Example 69 was used to obtain 5-fluoro-7-nitro-4-(4-(trifluoromethyl)piperidin-1-yl)quinoline-8-phenol (70) (40.0 mg, yield 56%) from 4-chloro-5-fluoro-7-nitroquinoline-8-phenol (68) (48.0 mg, 0.20 mmol) and 4-(trifluoromethyl)piperidine (153.0 mg, 1.0 mmol).

[0610] 1 H NMR(400MHz,DMSO-d6)δ:8.58–8.40(m,1H),7.68–7.55(m,1H),7.22–7.11(m,1H),3.74– 3.61(m,2H),3.46–3.39(m,2H),3.01–2.92(m,1H),2.00–1.95(m,2H),1.72–1.65(m,2H).

[0611] MS calculated: 359.09; MS found: 360.1 [M+H] + .

[0612] Example 71

[0613] Synthesis of ethyl 1-(5-fluoro-8-hydroxy-7-nitroquinolin-4-yl)piperidine-4-carboxylate (71)

[0614] The same synthesis method as in Example 69 was used to obtain 1-(5-fluoro-8-hydroxy-7-nitroquinolin-4-yl)piperidine-4-carboxylic acid ethyl ester (71) (33.0 mg, yield 48%) from 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68) (45.0 mg, 0.19 mmol) and 4-piperidinecarboxylic acid ethyl ester (210 mg, 1.33 mmol).

[0615] 1 H NMR(400MHz,DMSO-d6)δ:8.45–8.35(m,1H),7.52–7.44(m,1H),7.05–6.98(m,1H),4.14–4.04(m,2 H),3.30–3.15(m,4H),2.85–2.70(m,1H),2.00–1.90(m,2H),1.80–1.60(m,2H),1.25–1.15(m,3H).

[0616] MS calculated: 363.12; MS found: 364.1 [M+H]+ .

[0617] Example 72

[0618] Synthesis of 4-(cyclopropylmethoxy)-5-fluoro-7-nitroquinolin-8-ol (72)

[0619] The same synthesis method as in Example 69 was used to obtain 4-(cyclopropylmethoxy)-5-fluoro-7-nitroquinolin-8-ol (72) (38.0 mg, 65% yield) from 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68) (50.0 mg, 0.21 mmol) and cyclopropylmethanol (149.0 mg, 2.1 mmol).

[0620] 1 H NMR(400MHz,DMSO-d6)δ:8.82–8.78(m,1H),7.80–7.73(m,1H),7.39–7.33(m,1 H),4.23–4.18(m,2H),0.88–0.80(m,1H),0.62–0.60(m,2H),0.46–0.40(m,2H).

[0621] MS calculated: 278.07; MS found: 279.1 [M+H] + .

[0622] Example 73

[0623] Synthesis of 5-chloro-7-nitro-4-(trifluoromethyl)-quinolin-8-ol hydrochloride (73)

[0624] 8-Methoxy-4-(trifluoromethyl)quinoline (73a) (230.0 mg, 1.0 mmol) was added to a dichloromethane solution (1.0 M) of boron tribromide (5.0 mL, 5.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 7 hours, diluted with dichloromethane (20.0 mL), and the pH of the aqueous phase was adjusted to approximately 9-10 with saturated aqueous sodium carbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to provide 4-trifluoromethyl-8-hydroxyquinoline (73b) (190.0 mg, 88% yield).

[0625] N-Chlorosuccinimide (64.0 mg, 0.48 mmol) was added to a solution of 4-trifluoromethyl-8-hydroxyquinoline (73b) (85.0 mg, 0.4 mmol) in sulfuric acid (98 wt%) (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, and a saturated aqueous sodium carbonate solution was added to adjust the pH of the aqueous phase to approximately 9-10. The resulting mixture was extracted with dichloromethane (5.0 mL x 4), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to give 5-chloro-4-(trifluoromethyl)quinolin-8-ol (73c) (87.0 mg, 88% yield).

[0626] Sodium nitrite (240.0 mg, 3.5 mmol) was added portionwise to a suspension of 5-chloro-4-(trifluoromethyl)quinolin-8-ol (73c) (87.0 mg, 0.35 mmol) in hydrochloric acid (2.0 M) (1.75 mL) at 0°C. The reaction mixture was warmed to room temperature, stirred for 54 hours, and filtered under reduced pressure. The filter cake was washed with a mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (1.0 mL x 2) and dried in vacuo to give 5-chloro-7-nitro-4-(trifluoromethyl)quinolin-8-ol hydrochloride (73) (69.0 mg, 60% yield).

[0627] 1 H NMR (400 MHz, DMSO-d6) δ: 9.28 (d, J=4.4 Hz, 1H), 8.41 (overlapping s, 2H).

[0628] MS calculated: 291.99; MS observed: 293.0, 295.0 [M+H] + .

[0629] Example 74

[0630] Synthesis of 4-chloro-3-cyclopropyl-7-nitroquinolin-8-ol

[0631] Sodium methoxide (10.7 g, 198.0 mmol) was slowly added to a solution of 2,6-dinitrochlorobenzene 74a) (10.0 g, 49.5 mmol) in methanol (100.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure to remove the organic solvent. The resulting residue was dissolved in water (30.0 mL) and dichloromethane (30.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 2-methoxy-1,3-dinitrobenzene (74b) (9.8 g, 99% yield).

[0632] Reduced iron powder (3.38 g, 60.6 mmol) was added to a solution of 2-methoxy-1,3-dinitrobenzene (74b) (4.0 g, 20.2 mmol) in acetic acid (50.0 mL) at room temperature. The reaction mixture was stirred at 65°C for 1.5 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Dichloromethane (30.0 mL) was added to the resulting residue, and the pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous sodium bicarbonate. The resulting mixture was filtered under reduced pressure, and the organic phase was separated from the filtrate, washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 8 / 1 / 1) to provide 2-methoxy-3-nitroaniline (74c) (2.06 g, 61% yield).

[0633] 2-Methoxy-3-nitroaniline (74c) (2.06 g, 12.3 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.12 g, 14.7 mmol), and triethyl orthoformate (4.36 g, 29.4 mmol) were added to ethanol (15.0 mL) at room temperature. The reaction mixture was stirred at 98°C for 4 hours, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with petroleum ether (60°C-90°C boiling range) (10.0 mL x 3) and dried under vacuum to afford 5-(((2-methoxy-3-nitrophenyl)amino)methine)-2,2-dimethyl-1,3-dioxane-4,6-dione (74d) (3.85 g, 97% yield).

[0634] 5-(((2-Methoxy-3-nitrophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (74d) (3.85 g, 11.9 mmol) was added to diphenyl ether (50.0 mL) at room temperature. The reaction mixture was stirred at 265°C for 2 hours, cooled to room temperature, diluted with petroleum ether (60°C-90°C boiling range) (250.0 mL), and filtered under reduced pressure. The filter cake was washed with petroleum ether (60°C-90°C boiling range) (10.0 mL x 4) and dried under vacuum to afford 8-methoxy-7-nitroquinolin-4-ol (30a) (2.33 g, 89% yield).

[0635] N-Bromosuccinimide (404.0 mg, 2.3 mmol) was added to a suspension of 8-methoxy-7-nitroquinolin-4-ol (30a) (500.0 mg, 2.3 mmol) in acetonitrile (6.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the organic solvent. Water (30.0 mL) was added to the resulting residue, stirred for 15 minutes, and filtered under reduced pressure. The filter cake was washed with water (5.0 mL x 2) and dried under vacuum to give the crude product of 3-bromo-8-methoxy-7-nitroquinolin-4-ol (74e) (628.0 mg, crude yield 93%).

[0636] 3-Bromo-8-methoxy-7-nitroquinolin-4-ol (74e) (628.0 mg, 0.45 mmol) was added to phosphorus oxychloride (8.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the phosphorus oxychloride. The resulting residue was dissolved in dichloromethane (15.0 mL), and the pH of the aqueous phase was adjusted to approximately 9-10 with saturated aqueous sodium carbonate. The organic phase was separated, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of 3-bromo-4-chloro-8-methoxy-7-nitroquinoline (74f) (670.0 mg, crude yield 100%).

[0637] 3-Bromo-4-chloro-8-methoxy-7-nitroquinoline (74f) (350.0 mg, 1.1 mmol), cyclopropylboronic acid (123.0 mg, 1.43 mmol), palladium acetate (25.0 mg, 0.11 mmol), tricyclohexylphosphine (62.0 mg, 0.22 mmol), and potassium phosphate (817.0 mg, 3.85 mmol) were added sequentially to a mixed solvent of toluene (7.0 mL) and water (0.70 mL) at room temperature. The reaction mixture was stirred at 95°C for 3 hours, cooled to room temperature, and diluted with ethyl acetate (10.0 mL) and water (10.0 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 7 / 2 / 1) to give 4-chloro-3-cyclopropyl-8-methoxy-7-nitroquinoline (74 g) (117.0 mg, yield 38%).

[0638] 4-Chloro-3-cyclopropyl-8-methoxy-7-nitroquinoline (74 g) (45.0 mg, 0.16 mmol) and lithium chloride (68.0 mg, 1.6 mmol) were added to 1-methyl-2-pyrrolidone (2.0 mL) at room temperature. The reaction mixture was stirred at 180°C for 30 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with a mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (2.0 mL x 2) and dried in vacuo to give 4-chloro-3-cyclopropyl-7-nitroquinolin-8-ol (74) (50.7 mg, 91% yield).

[0639] 1 H NMR (400MHz, DMSO-d6) δ: 8.22 (s, 1H), 8.01 (d, J = 10.0Hz, 1H), 6.63 (d, J = 9.6Hz, 1H), 2.30-2.24 (m, 1H), 1.17–1.12 (m, 2H), 0.97–0.91 (m, 2H).

[0640] MS calculated: 264.03; MS observed: 265.1, 267.0 [M+H] + .

[0641] Example 75

[0642] Synthesis of 3-cyclopropyl-4-methoxy-7-nitroquinolin-8-ol (75)

[0643] 4-Chloro-3-cyclopropyl-7-nitroquinolin-8-ol (74) (42.0 mg, 0.16 mmol) and sodium methoxide (43.0 mg, 0.80 mmol) were added to a mixed solvent of 1-methyl-2-pyrrolidone (1.0 mL) and dimethyl sulfoxide (1.0 mL) at room temperature. The reaction mixture was stirred at 120°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-10% / 90%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate 20.0 mL / min) to give 3-cyclopropyl-4-methoxy-7-nitroquinolin-8-ol (75) (10.7 mg, 26% yield).

[0644] 1H NMR(400MHz,DMSO-d6)δ:7.97(d,J=9.6Hz,1H),7.86(s,1H),6.80(d,J =10.0Hz,1H),3.98(s,3H),2.29–2.27(m,1H),1.13–1.07(m,2H),1.06–1.01(m,2H).

[0645] MS calculated: 260.08; MS found: 261.1 [M+H] + .

[0646] Example 76

[0647] Synthesis of 8-Hydroxy-7-nitroquinoline-4-carbonitrile (76)

[0648] 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 (11b) (1.0 g, 4.2 mmol) in N,N-dimethylformamide (15.0 mL) at room temperature. 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 to remove the organic solvent, 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 concentrated under reduced pressure. Ethyl acetate (5.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with ethyl acetate (2.5 mL x 2) and dried under vacuum to give 8-methoxyquinoline-4-carbonitrile (76a) (650.0 mg, 84% yield).

[0649] Nitric acid (65 wt%) (0.45 mL, 6.52 mmol) was slowly added to a solution of 8-methoxyquinoline-4-carbonitrile (76a) (200.0 mg, 1.08 mmol) in acetic anhydride (5.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, and sulfuric acid (98 wt%) (0.1 mL, 1.87 mmol) was slowly added dropwise. Stirring was continued for 30 minutes, and the pH of the aqueous phase was adjusted to approximately 9-10 with aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to provide 8-methoxy-7-nitroquinoline-4-carbonitrile (76b) (65.0 mg, 26% yield).

[0650] 8-Methoxy-7-nitroquinoline-4-carbonitrile (76b) (65.0 mg, 0.28 mmol) and lithium chloride (119.0 mg, 2.8 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 160°C for 30 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with ethanol (2.0 mL) and water (2.0 mL) in that order and dried under vacuum to give 8-hydroxy-7-nitroquinoline-4-carbonitrile (76) (44.0 mg, 72% yield).

[0651] 1 H NMR (400MHz, DMSO-d6) δ: 8.75 (d, J = 4.4Hz, 1H), 8.15 (d, J = 9.2Hz, 1H), 8.02 (d, J = 4.4Hz, 1H), 6.54 (d, J = 9.6Hz, 1H).

[0652] MS calculated: 215.03; MS found: 216.1 [M+H] + .

[0653] Example 77

[0654] Synthesis of 4-(difluoromethoxy)-7-nitroquinolin-8-ol (77)

[0655] 8-Methoxy-7-nitroquinolin-4-ol (30a) (66.1 mg, 0.30 mmol) and sodium difluorochloroacetate (137.0 mg, 0.90 mmol) were added sequentially to a suspension of cesium carbonate (293.0 mg, 0.30 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, then heated to 80°C and stirred for 30 minutes. The mixture was cooled to room temperature and diluted with water (10.0 mL) and dichloromethane (10.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / petroleum ether = 3 / 1) to give 4-(difluoromethoxy)-8-methoxy-7-nitroquinoline (77a) (52.6 mg, yield 65%).

[0656] 4-(Difluoromethoxy)-8-methoxy-7-nitroquinoline (77a) (52.6 mg, 0.195 mmol) and lithium chloride (82.5 mg, 1.95 mmol) were added to N,N-dimethylformamide (0.24 mL) at room temperature. The reaction mixture was stirred at 160°C for 30 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (1.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with a mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (0.5 mL x 3) and dried in vacuo to give 4-(difluoromethoxy)-7-nitroquinolin-8-ol (77) (37.2 mg, 74% yield).

[0657] 1 H NMR (400MHz, DMSO-d6) δ: 8.59 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 9.6 Hz, 1H), 7.62 (t, J = 72.8 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 6.59 (d, J = 9.6 Hz, 1H).

[0658] MS calculated: 256.03; MS found: 257.1 [M+H] + .

[0659] Example 78

[0660] Synthesis of 3-(8-hydroxy-7-nitroquinolin-4-yl)-N-acryloylmorpholine (78)

[0661] 8-Methoxy-7-nitroquinolin-4-ol (30a) (5.07 g, 23.0 mmol) and N,N-diisopropylethylamine (12.3 mL, 70.3 mmol) were added to N,N-dimethylformamide (75.0 mL) at room temperature, followed by the slow addition of N-phenylbis(trifluoromethanesulfonyl)imide (11.1 g, 31.1 mmol). The reaction mixture was stirred at room temperature for 12 hours, diluted with ethyl acetate (100.0 mL) and water (100.0 mL), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1) to afford 8-methoxy-7-nitroquinolin-4-trifluoromethanesulfonate (78a) (3.99 g, 50% yield).

[0662] 8-Methoxy-7-nitroquinolin-4-yl trifluoromethanesulfonate (78a) (3.99 g, 11.3 mmol), methyl acrylate (2.2 mL, 24.3 mmol), palladium acetate (254.0 mg, 1.13 mmol), tri(o-methylphenyl)phosphine (516.0 mg, 1.7 mmol), and triethylamine (4.3 mL, 31.5 mmol) were added sequentially to N,N-dimethylformamide (75.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 12 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Ethyl acetate (40.0 mL) and water (40.0 mL) were added to the resulting residue, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 8 / 1 / 1) to give methyl 3-(8-methoxy-7-nitroquinolin-4-yl)acrylate (78b) (618.9 mg, yield 19%).

[0663] Methyl 3-(8-methoxy-7-nitroquinolin-4-yl)acrylate (78b) (618.9 mg, 2.15 mmol) was added to a mixed solvent of tetrahydrofuran (8.0 mL), methanol (8.0 mL), and water (2.7 mL) at room temperature, followed by the addition of lithium hydroxide (77.4 mg, 3.23 mmol). The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure to remove the organic solvent. Ethyl acetate (15.0 mL) and water (15.0 mL) were added to the resulting residue, and the aqueous phase was separated and the pH of the aqueous phase was adjusted to approximately 3-4 with hydrochloric acid (1.0 M). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (2.0 mL x 2) and dried under vacuum to afford 3-(8-methoxy-7-nitroquinolin-4-yl)acrylic acid (78c) (560.1 mg, 95% yield).

[0664] 3-(8-Methoxy-7-nitroquinolin-4-yl)acrylic acid (78c) (143.0 mg, 0.52 mmol), morpholine (68.0 mg, 0.78 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (297.0 mg, 0.78 mmol), and N,N-diisopropylethylamine (0.28 mL, 1.56 mmol) were added sequentially to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure to remove the organic solvent. Ethyl acetate (10.0 mL) and water (10.0 mL) were added to the resulting residue, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 7 / 3) to give 3-(8-methoxy-7-nitroquinolin-4-yl)-N-acryloylmorpholine (78d) (88.0 mg, yield 49%).

[0665] 3-(8-Methoxy-7-nitroquinolin-4-yl)-N-acryloylmorpholine (78d) (44.0 mg, 0.13 mmol) and lithium chloride (53.8 mg, 1.3 mmol) were added to N,N-dimethylformamide (1.0 mL) at room temperature. 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. The resulting residue was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-80% / 20%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate 20.0 mL / min) to give 3-(8-hydroxy-7-nitroquinolin-4-yl)-N-acryloylmorpholine (78) (20.2 mg, 24% yield).

[0666] 1 H NMR(400MHz, DMSO-d6)δ:8.70(d,J=4.6Hz,1H),8.09(d,J=15.6Hz,1H),8.02(d,J=9.6Hz,1H),7.99(d,J=4.6Hz ,1H),7.51(d,J=15.2Hz,1H),6.87(d,J=10.0Hz,1H),3.81–3.74(m,2H),3.68–3.60(m,4H),3.44–3.37(m,2H).

[0667] MS calculated: 329.10; MS found: 330.2 [M+H] + .

[0668] Example 79

[0669] Synthesis of 3-(8-hydroxy-7-nitroquinolin-4-yl)-N-methylacrylamide (79)

[0670] 3-(8-Methoxy-7-nitroquinolin-4-yl)acrylic acid (79a) (150.0 mg, 0.55 mmol), methylamine hydrochloride (55.0 mg, 0.82 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (312.0 mg, 0.82 mmol), and N,N-diisopropylethylamine (0.30 mL, 1.64 mmol) were added sequentially to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure to remove the organic solvent. Ethyl acetate (10.0 mL) and water (10.0 mL) were added to the resulting residue, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 7 / 3) to give 3-(8-methoxy-7-nitroquinolin-4-yl)-N-methylacrylamide (79b) (105.0 mg, yield 67%).

[0671] 3-(8-Methoxy-7-nitroquinolin-4-yl)-N-methylacrylamide (79b) (105.0 mg, 0.37 mmol) and lithium chloride (157.0 mg, 3.7 mmol) were added to N,N-dimethylformamide (3.0 mL) at room temperature. 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. The resulting residue was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-80% / 20%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate 20.0 mL / min) to give 3-(8-hydroxy-7-nitroquinolin-4-yl)-N-methylacrylamide (79) (18.7 mg, 19% yield).

[0672] 1H NMR(400MHz, DMSO-d6)δ:9.03(d,J=4.8Hz,1H),8.44(d,J=4.4Hz,1H),8.12(d,J=9.6Hz,1H),8.08(d,J= 16.0Hz, 1H), 7.97 (d, J = 4.4Hz, 1H), 7.70 (d, J = 9.2Hz, 1H), 6.92 (d, J = 15.6Hz, 1H), 2.79 (d, J = 4.8Hz, 3H).

[0673] MS calculated: 273.07; MS found: 274.1 [M+H] + .

[0674] Example 80

[0675] Synthesis of 4-ethynyl-7-nitroquinolin-8-ol (80)

[0676] 8-Methoxy-7-nitroquinolin-4-ol (30a) (300.0 mg, 1.36 mmol) and pyridine (129.0 mg, 1.63 mmol) were added to dichloromethane (6.0 mL) at 0°C, followed by the slow dropwise addition of trifluoromethanesulfonic anhydride (751.0 mg, 2.66 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3.5 hours. Sodium iodide (1.02 g, 6.8 mmol) was then added, followed by the slow dropwise addition of trifluoromethanesulfonic acid (0.2 mL, 2.26 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours, and the pH of the aqueous phase was adjusted to approximately 9-10 by the addition of saturated aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (10.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 4-iodo-8-methoxy-7-nitroquinoline (80a) (210.0 mg, yield 47%).

[0677] To a solution of 4-iodo-8-methoxy-7-nitroquinoline (80a) (210.0 mg, 0.64 mmol) in N,N-dimethylformamide (5.0 mL) was added (trimethylsilyl)acetylene (188.0 mg, 1.9 mmol), bistriphenylphosphine palladium dichloride (45.0 mg, 0.06 mmol), cuprous iodide (6.0 mg, 0.03 mmol), and triethylamine (0.27 mL, 1.9 mmol) sequentially at room temperature. The reaction mixture was stirred at 60°C for 16 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to afford 8-methoxy-7-nitro-4-(trimethylsilyl)ethynyl)quinoline (80b) (91.0 mg, 48% yield).

[0678] 8-Methoxy-7-nitro-4-((trimethylsilyl)ethynyl)quinoline (80b) (81.0 mg, 0.27 mmol) and lithium chloride (113.0 mg, 2.7 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 150°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Potassium carbonate (372.0 mg, 2.7 mmol) and methanol (5.0 mL) were added to the resulting residue, stirred at room temperature for 2 hours, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The resulting filter cake was added to a mixed solvent of ethanol (2.0 mL) and water (2.0 mL), stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give 4-ethynyl-7-nitroquinolin-8-ol (80) (57.0 mg, 99% yield).

[0679] 1 H NMR (400MHz, DMSO-d6) δ: 8.58 (s, 1H), 8.01 (d, J = 9.5 Hz, 1H), 7.62 (s, 1H), 6.67 (d, J = 9.5 Hz, 1H), 4.96 (s, 1H).

[0680] MS calculated: 214.04; MS found: 215.1 [M+H] + .

[0681] Example 81

[0682] Synthesis of 4-(difluoromethyl)-7-nitroquinolin-8-ol (81)

[0683] 8-Methoxy-7-nitroquinolin-4-ol (30a) (1.5 g, 6.81 mmol) was added to phosphorus oxychloride (15.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure. Dichloromethane (20.0 mL) was added to the resulting residue, and the pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 4-chloro-8-methoxy-7-nitroquinoline (81a) (510.0 mg, 32% yield).

[0684] 4-Chloro-8-methoxy-7-nitroquinoline (81a) (510.0 mg, 2.13 mmol), potassium vinyl trifluoroborate (458.0 mg, 3.42 mmol), bis(diphenylphosphino)ferrocenepalladium dichloride (234.0 mg, 0.32 mmol), and potassium carbonate (885.0 mg, 6.41 mmol) were added sequentially to a mixed solvent of 1,4-dioxane (8.0 mL) and water (2.0 mL) at room temperature. The reaction mixture was stirred at 95°C for 16 hours, cooled to room temperature, and concentrated under reduced pressure. Dichloromethane (10.0 mL) and water (10.0 mL) were added to the resulting residue, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 8-methoxy-7-nitro-4-vinylquinoline (81b) (350.0 mg, yield 71%).

[0685] 8-Methoxy-7-nitro-4-vinylquinoline (81b) (350.0 mg, 1.52 mmol) and potassium osmate dihydrate (56.0 mg, 0.15 mmol) were added sequentially to a mixed solvent of tetrahydrofuran (18.0 mL) and water (4.5 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, and sodium periodate (975.0 mg, 4.56 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 16 hours. Ethyl acetate (10.0 mL) and water (10.0 mL) were then added to dilute the mixture. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product of 8-methoxy-7-nitroquinoline-4-carbaldehyde (81c) (355.0 mg, crude yield 100%).

[0686] Diethylaminosulfur trifluoride (180 mg, 1.11 mmol) was slowly added dropwise to a solution of 8-methoxy-7-nitroquinoline-4-carbaldehyde (81c) (86.0 mg, 0.37 mmol) in dichloromethane (18.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 3 hours. The pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to provide 4-(difluoromethyl)-8-methoxy-7-nitroquinoline (81d) (65.0 mg, 69% yield).

[0687] 4-(Difluoromethyl)-8-methoxy-7-nitroquinoline (81d) (65.0 mg, 0.256 mmol) and lithium chloride (107.0 mg, 2.56 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 160°C for 40 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. A mixed solvent of ethanol (2.0 mL) and water (2.0 mL) was added to the resulting filter cake, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give 4-(difluoromethyl)-7-nitroquinolin-8-ol (81) (47.3 mg, 77% yield).

[0688] 1 H NMR (400MHz, DMSO-d6) δ: 8.74 (d, J = 4.3Hz, 1H), 8.03 (d, J = 9.6Hz, 1H), 7.72 (d, J = 4.3Hz, 1H), 7.55 (t, J = 54.0Hz, 1H), 6.62 (d, J = 9.6Hz, 1H).

[0689] MS calculated: 240.03; MS found: 241.1 [M+H] + .

[0690] Example 82

[0691] Synthesis of 4-chloro-7-nitro-3-phenylquinolin-8-ol (82)

[0692] 3-Bromo-4-chloro-8-methoxy-7-nitroquinoline (74 g) (120.0 mg, 0.38 mmol), phenylboronic acid (48.0 mg, 0.40 mmol), palladium acetate (8.5 mg, 0.038 mmol), tricyclohexylphosphine (21.2 mg, 0.076 mmol), and potassium phosphate (281.0 mg, 1.32 mmol) were added sequentially to a mixed solvent of toluene (3.0 mL) and water (0.5 mL) at room temperature. The reaction mixture was stirred at 92°C for 3 hours, cooled to room temperature, and diluted with ethyl acetate (10.0 mL) and water (10.0 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate ==8 / 1 / 1) to give 4-chloro-8-methoxy-7-nitro-3-phenylquinoline (82a) (61.0 mg, 51% yield).

[0693] 4-Chloro-8-methoxy-7-nitro-3-phenylquinoline (82a) (61.0 mg, 0.194 mmol) and lithium chloride (81.0 mg, 1.93 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 160°C for 50 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was added to a mixed solvent of ethanol (2.0 mL) and water (2.0 mL), stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give 4-chloro-7-nitro-3-phenylquinolin-8-ol (82) (57.0 mg, 98% yield).

[0694] 1 H NMR (400MHz, DMSO-d6) δ: 8.54 (s, 1H), 8.09 (d, J = 9.7Hz, 1H), 7.61–7.50 (m, 5H), 6.73 (d, J = 9.7Hz, 1H).

[0695] MS calculated: 300.03; MS observed: 301.1 / 303.0 [M+H] + .

[0696] Example 83

[0697] Synthesis of 5-chloro-3-methyl-7-nitroquinolin-8-ol (83)

[0698] 5-Chloro-2-methoxyaniline (49a) (3.0 g, 19.0 mmol) was added to a solution of hydrochloric acid (6.0 M) (30.0 mL) at room temperature. The reaction mixture was heated to 100°C, and 2-methylacrolein (3.34 g, 47.7 mmol) was slowly added dropwise. The reaction mixture was stirred at 100°C for 2 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with dichloromethane (50.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 7 / 1 to 3 / 1) to provide 3-methyl-5-chloro-8-methoxyquinoline (83a) (1.35 g, 34% yield).

[0699] Nitric acid (65 wt%) (1.35 mL, 19.6 mmol) was slowly added to a solution of 3-methyl-5-chloro-8-methoxyquinoline (83a) (1.35 g, 6.5 mmol) in acetic anhydride (27.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 5 minutes, and sulfuric acid (98 wt%) (0.35 mL, 6.5 mmol) was slowly added dropwise. Stirring was continued for 30 minutes, and the pH of the aqueous phase was adjusted to approximately 9-10 with aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to provide 3-methyl-5-chloro-7-nitro-8-methoxyquinoline (83b) (0.64 g, 39% yield).

[0700] 3-Methyl-5-chloro-7-nitro-8-methoxyquinoline (83b) (30.0 mg, 0.12 mmol) and lithium chloride (50.0 mg, 1.2 mmol) were added to N,N-dimethylformamide (1.0 mL) at room temperature. The reaction mixture was stirred at 140°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with a mixed solvent of water and ethanol (volume ratio, water / ethanol = 1 / 1) (0.2 mL x 2) and dried in vacuo to give 3-methyl-5-chloro-7-nitro-8-hydroxyquinoline (83) (19.0 mg, 67% yield).

[0701] 1 H NMR (400MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.03 (d, J = 12.3Hz, 2H), 2.50 (s, 3H).

[0702] MS calculated: 238.01; MS found: 239.0 [M+H] + .

[0703] Example 84

[0704] Synthesis of 5-cyclopropyl-3-methyl-7-nitroquinolin-8-ol (84)

[0705] 5-Bromo-2-methoxyaniline (84a) (1.5 g, 7.43 mmol) was added to a 6.0 M hydrochloric acid solution (40.0 mL) at room temperature. The reaction mixture was heated to 110°C, and 2-methylacrolein (1.8 mL, 22.2 mmol) was slowly added dropwise. The mixture was stirred for 3 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with a 6.0 M sodium hydroxide solution. The resulting mixture was extracted with ethyl acetate (50.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3) to provide 5-bromo-8-methoxy-3-methylquinoline (84b) (1.0 g, 53% yield).

[0706] Nitric acid (65 wt%) (0.51 mL, 12.0 mmol) was slowly added dropwise to a solution of 5-bromo-8-methoxy-3-methylquinoline (84b) (251.0 mg, 1.0 mmol) in acetic anhydride (5.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, sulfuric acid (98 wt%) (0.12 mL, 2.4 mmol) was added, and stirring was continued for 2 hours. The mixture was diluted with water (30.0 mL), and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 85% / 15%) to provide 5-bromo-8-methoxy-3-methyl-7-nitroquinoline (84c) (50.0 mg, 17% yield).

[0707] 5-Bromo-8-methoxy-3-methyl-7-nitroquinoline (84c) (50.0 mg, 0.17 mmol), cyclopropylboronic acid (29.0 mg, 0.34 mmol), tetrakistriphenylphosphine palladium (39.0 mg, 0.034 mmol), and potassium carbonate (70.4 mg, 0.51 mmol) were added sequentially to a mixed solvent of toluene (3.0 mL) and water (0.3 mL) at room temperature. The reaction mixture was stirred at 105°C for 3 hours, cooled to room temperature, and extracted with ethyl acetate (10.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to provide 5-cyclopropyl-8-methoxy-3-methyl-7-nitroquinoline (84d) (28.0 mg, 64% yield).

[0708] 5-Cyclopropyl-8-methoxy-3-methyl-7-nitroquinoline (84d) (28.0 mg, 0.11 mmol) and lithium chloride (45.6 mg, 1.1 mmol) were added to N,N-dimethylformamide (1.0 mL) at room temperature. The reaction mixture was stirred at 150°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and ethanol (0.5 mL x 2) in that order, and dried under vacuum to give 5-cyclopropyl-3-methyl-7-nitroquinolin-8-ol (84) (16.0 mg, 60% yield).

[0709] 1 H NMR(400MHz,DMSO-d6)δ:8.55–8.48(m,1H),8.36–8.30(m,1H),7.71 –7.64(m,1H),2.52–2.50(m,3H),2.05–1.97(m,1H),0.98–0.90(m,2H),0.58–0.52(m,2H).

[0710] MS calculated: 244.08; MS found: 245.1 [M+H] + .

[0711] Example 85

[0712] Synthesis of 7-nitro-4-(piperidin-1-yl-methyl)quinolin-8-ol (85)

[0713] 8-Methoxy-7-nitroquinoline-4-carbaldehyde (81c) (110.0 mg, 0.47 mmol) and piperidine (52.0 mg, 0.61 mmol) were added sequentially to a mixed solvent of tetrahydrofuran (3.0 mL) and dichloromethane (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 90 minutes, and sodium triacetoxyborohydride (301.0 mg, 1.42 mmol) was added. Stirring was continued for 3 hours, and saturated aqueous sodium bicarbonate was added to adjust the pH of the aqueous phase to approximately 7-8. The resulting mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: dichloromethane / methanol = 16 / 1) to give 8-methoxy-7-nitro-4-(piperidin-1-ylmethyl)quinoline (85a) (130.0 mg, yield 72%).

[0714] 8-Methoxy-7-nitro-4-(piperidin-1-yl-methyl)quinoline (85a) (130.0 mg, 0.43 mmol) and lithium chloride (180 mg, 4.3 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. 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. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. A mixed solvent of ethanol (2.0 mL) and water (2.0 mL) was added to the resulting filter cake, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give 7-nitro-4-(piperidin-1-yl-methyl)quinolin-8-ol (85) (112.0 mg, 91% yield).

[0715] 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=4.3Hz,1H),7.92(d,J=9.7Hz,1H),7.54(d,J=4.3Hz,1H),6 .76(d,J=9.7Hz,1H),3.76(s,2H),2.43(s,4H),1.53(d,J=4.8Hz,4H),1.43(d,J=3.6Hz,2H).

[0716] MS calculated: 287.13; MS found: 288.1 [M+H] + .

[0717] Example 86

[0718] Synthesis of 5-fluoro-3-methyl-7-nitroquinolin-8-ol (86)

[0719] 2-Amino-4-fluorophenol (86a) (2.00 g, 15.7 mmol) was added to a 6.0 M hydrochloric acid solution (20.0 mL) at room temperature. The reaction mixture was heated to 100°C, and 2-methylacrolein (3.3 mL, 39.4 mmol) was slowly added dropwise. The mixture was stirred for 2 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with a 6.0 M sodium hydroxide solution. The resulting mixture was extracted with dichloromethane (50.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to provide 5-fluoro-3-methylquinolin-8-ol (86b) (400 mg, 14.3% yield).

[0720] Sodium nitrite (350.0 mg, 4.1 mmol) was added to a solution of 5-fluoro-3-methylquinolin-8-ol (86b) (90.0 mg, 0.51 mmol) in acetic acid (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and the pH of the aqueous phase was adjusted to approximately 8-9 by adding saturated aqueous sodium bicarbonate solution. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with a mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (1.0 mL x 2) and dried in vacuo to afford 5-fluoro-3-methyl-7-nitroquinolin-8-ol (86) (65.0 mg, 58% yield).

[0721] 1 H NMR (400MHz, DMSO-d6) δ 8.77 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 12.5Hz, 1H), 2.49 (s, 3H).

[0722] MS calculated: 222.04; MS found: 223.0 [M+H] + .

[0723] Example 87

[0724] Synthesis of 5-(morpholinomethyl)-7-nitroquinolin-8-ol acetate (87)

[0725] 5-(Chloromethyl)quinolin-8-ol hydrochloride (87a) (120.0 mg, 0.62 mmol) and morpholine (270.0 mg, 2.5 mmol) were added sequentially to dichloromethane (3.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 49 / 1, with 0.5% aqueous ammonia (25-28% by weight, NH3 content) added based on the total solvent volume) to give 5-(morpholinomethyl)quinolin-8-ol (87b) (80.0 mg, 53% yield).

[0726] Sodium nitrite (34.0 mg, 0.49 mmol) was added to a solution of 5-(morpholinomethyl)quinolin-8-ol (87a) (80.0 mg, 0.33 mmol) in acetic acid (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to remove the organic solvent. Water (1.0 mL) was added to the resulting residue, stirred for 10 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-(morpholinomethyl)-7-nitroquinolin-8-ol acetate (87) (76.0 mg, 45% yield).

[0727] 1 H NMR(400MHz,DMSO-d6)δ:9.08–9.035(m,1H),9.02–8.97(m,1H),8.42–8.36(s,1 H),8.01–7.95(m,1H),4.80–4.70(m,2H),3.96–3.64(m,4H),3.35–3.22(m,4H).

[0728] MS calculated: 289.11; MS found: 290.1 ​​[M+H] + .

[0729] Example 88

[0730] Synthesis of 8-Hydroxy-7-nitroquinoline-3-carboxylic acid ethyl ester (88)

[0731] Phosphorus oxychloride (2.3 mL, 24.3 mmol) was added to a solution of ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate (88a) (2.0 g, 8.1 mmol) in acetonitrile (20.0 mL) at room temperature. The reaction mixture was stirred at 90°C for 2.5 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (30.0 mL), and triethylamine (4.91 g, 48.5 mmol) was added, stirred for 30 minutes, and filtered under reduced pressure. The filter cake was washed with dichloromethane (5.0 mL x 3), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give ethyl 4-chloro-8-methoxyquinoline-3-carboxylate (88b) (2.1 g, 98% yield).

[0732] Ethyl 4-chloro-8-methoxyquinoline-3-carboxylate (88b) (2.1 g, 7.9 mmol), triethylamine (1.2 g, 11.9 mmol), and palladium / carbon (10 wt%, palladium loading) (0.42 g, 0.39 mmol) were added sequentially to a mixed solvent of tetrahydrofuran (10.0 mL) and methanol (10.0 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours, filtered through celite, and the filter cake was washed with tetrahydrofuran (10.0 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (20.0 mL), washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude ethyl 8-methoxyquinoline-3-carboxylate (88c) (1.8 g, 99% yield).

[0733] At 0°C, nitric acid (65 wt%) (0.45 mL, 6.5 mmol) was slowly added to a solution of 8-methoxyquinoline-3-carboxylic acid ethyl ester (88c) (500.0 mg, 2.2 mmol) in acetic anhydride (10.0 mL). The mixture was stirred for 10 minutes, and then concentrated sulfuric acid (98 wt%) (0.12 mL, 2.2 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 2 hours, diluted with water (20.0 mL), and the pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with dichloromethane (30.0 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 8-methoxy-7-nitroquinoline-3-carboxylic acid ethyl ester (88d) (88.0 mg, 15% yield).

[0734] Ethyl 8-methoxy-7-nitroquinoline-3-carboxylate (88d) (88.0 mg, 0.32 mmol) and lithium chloride (135.0 mg, 3.2 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 130°C for 45 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 x 2 mL) and dried under vacuum to give ethyl 8-hydroxy-7-nitroquinoline-3-carboxylate (88) (71.0 mg, 85% yield).

[0735] 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.63 (d, J = 1.5Hz, 1H), 7.96 (d, J = 9.3Hz, 1H), 6.60 (d, J = 9.1Hz, 1H), 4.39 (q, J = 7.1Hz, 2H), 1.37 (t, J = 7.1Hz, 3H).

[0736] MS calculated: 262.06; MS found: 263.1 [M+H] + .

[0737] Example 89

[0738] Synthesis of 4-(morpholinomethyl)-7-nitroquinolin-8-ol (89)

[0739] 8-Methoxy-7-nitroquinoline-4-carbaldehyde (81c) (77.0 mg, 0.33 mmol) and morpholine (58.0 mg, 0.61 mmol) were added sequentially to a mixed solvent of tetrahydrofuran (2.0 mL) and dichloromethane (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and sodium triacetoxyborohydride (210.0 mg, 0.99 mmol) was added. Stirring was continued for 4.5 hours, and saturated aqueous sodium bicarbonate was added to adjust the pH of the aqueous phase to approximately 7-8. The resulting mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 80 / 1-70 / 1) to give 4-((8-methoxy-7-nitroquinolin-4-yl)methyl)morpholine (89a) (61.0 mg, yield 61%).

[0740] 4-((8-Methoxy-7-nitroquinolin-4-yl)methyl)morpholine (89a) (61.0 mg, 0.2 mmol) and lithium chloride (85.0 mg, 2.0 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 160°C for 40 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. A mixed solvent of ethanol (2.0 mL) and water (2.0 mL) was added to the resulting filter cake, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give 4-(morpholinomethyl)-7-nitroquinolin-8-ol (89) (38.9 mg, 67% yield).

[0741] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.4Hz,1H),7.94(d,J=9.7Hz,1H),7.56(d, J=4.5Hz,1H),6.78(d,J=9.7Hz,1H),3.82(s,2H),3.66–3.58(m,4H),2.47(br s,4H).

[0742] MS calculated: 289.11; MS found: 290.1 ​​[M+H] + .

[0743] Example 90

[0744] Synthesis of 5-chloro-3-((diethylamino)methyl)-7-nitroquinolin-8-ol ditrifluoroacetate (90)

[0745] 5-Chloro-2-methoxyaniline (49a) (6.0 g, 38.0 mmol) was added to a 6.0 M hydrochloric acid solution (60.0 mL) at room temperature. The reaction mixture was heated to 100°C, and 2-methylacrolein (7.8 mL, 95.4 mmol) was slowly added dropwise. The mixture was stirred for 2 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with a 6.0 M sodium hydroxide solution. The resulting mixture was extracted with dichloromethane (100.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 7 / 1 to 3 / 1) to provide 5-chloro-8-methoxy-3-methylquinoline (90a) (2.7 g, 34% yield).

[0746] Nitric acid (65 wt%) (1.50 mL, 21.9 mmol) was slowly added dropwise to a solution of 5-chloro-8-methoxy-3-methylquinoline (90a) (1.5 g, 7.2 mmol) in acetic anhydride (30.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and sulfuric acid (98 wt%) (0.39 mL, 7.2 mmol) was slowly added dropwise. Stirring was continued for 2 hours, diluted with water (50.0 mL), and the pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous potassium carbonate. The resulting mixture was extracted with dichloromethane (50.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to provide 5-chloro-8-methoxy-3-methyl-7-nitroquinoline (90b) (660.0 mg, 36% yield).

[0747] 5-Chloro-8-methoxy-3-methyl-7-nitroquinoline (90b) (660.0 mg, 2.5 mmol), N-bromosuccinimide (473.0 mg, 2.6 mmol), and 2,2'-azobisisobutyronitrile (250.0 mg, 1.5 mmol) were added sequentially to carbon tetrachloride (20.0 mL) at room temperature. The reaction mixture was heated to 80°C, stirred for 12 hours, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with carbon tetrachloride (10.0 mL x 3), and the filtrate was concentrated under reduced pressure to give the crude product of 3-(bromomethyl)-5-chloro-8-methoxy-7-nitroquinoline (90c) (838.0 mg, crude yield >100%).

[0748] The crude product of 3-(bromomethyl)-5-chloro-8-methoxy-7-nitroquinoline (90c) (102.0 mg, 0.31 mmol) and diethylamine (225.0 mg, 3.1 mmol) were added sequentially to tetrahydrofuran (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate = 3 / 1) to afford 5-chloro-3-(diethylamino)methyl-8-methoxy-7-nitroquinoline (90d) (65.0 mg, 65% yield).

[0749] 5-Chloro-3-(diethylamino)methyl-8-methoxy-7-nitroquinoline (90d) (65.0 mg, 0.2 mmol) and lithium chloride (85.0 mg, 2.0 mmol) were added to N,N-dimethylformamide (1.5 mL) at room temperature. The reaction mixture was stirred at 130°C for 1.5 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The obtained residue was completely dissolved in a mixed solvent of trifluoroacetic acid (0.5 mL) and water (2.0 mL), and then separated by reverse phase high performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-75% / 25%, gradient elution, flow rate: 20.0 mL / min) to give 5-chloro-3-((diethylamino)methyl)-7-nitroquinolin-8-ol ditrifluoroacetate (90) (17.0 mg, yield 16%).

[0750] 1 H NMR (400MHz, DMSO-d6) δ: 8.87 (s, 1H), 8.49 (s, 1H), 8.11 (s, 1H), 4.51 (s, 2H), 3.13 (dd, J = 13.9, 6.8Hz, 4H), 1.25 (t, J = 7.1Hz, 6H).

[0751] MS calculated: 309.09; MS found: 310.1 [M+H] + .

[0752] Example 91

[0753] Synthesis of 7-nitro-5-(piperidin-1-ylmethyl)quinolin-8-ol acetate (91)

[0754] 5-(Chloromethyl)quinolin-8-ol hydrochloride (87a) (120.0 mg, 0.62 mmol) and piperidine (264.0 mg, 3.1 mmol) were added sequentially to dichloromethane (3.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 49 / 1, and 0.5% aqueous ammonia (25-28% by weight, NH3 content) was added based on the total volume of the solvent) to give 5-(piperidin-1-ylmethyl)quinolin-8-ol (91a) (100.0 mg, 67% yield).

[0755] Sodium nitrite (68.0 mg, 0.99 mmol) was added to a solution of 5-(piperidin-1-ylmethyl)quinolin-8-ol (91a) (100.0 mg, 0.41 mmol) in acetic acid (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 7-nitro-5-(piperidin-1-ylmethyl)quinolin-8-ol acetate (91) (129.0 mg, 88% yield).

[0756] 1 H NMR (400 MHz, DMSO-d6) δ: 9.01-8.97 (m, 1H), 8.92-8.87 (m, 1H), 8.38-8.35 (s, 1H), 7.95-7.89 (m, 1H), 4.71–4.65 (m, 2H), 3.35–3.10 (m, 4H), 1.93 (s, 3.57H, methyl signal of acetic acid), 1.80–1.65 (m, 4H), 1.60–1.45 (m, 2H).

[0757] MS calculated: 287.11; MS found: 288.1 [M+H] + .

[0758] Example 92

[0759] Synthesis of 5-chloro-7-nitro-3-(piperidin-1-ylmethyl)quinolin-8-ol (92)

[0760] The crude product of 3-(bromomethyl)-5-chloro-8-methoxy-7-nitroquinoline (90c) (88.0 mg, 0.27 mmol) and piperidine (113.0 mg, 1.33 mmol) were added sequentially to tetrahydrofuran (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (developing solvent: dichloromethane / methanol = 25 / 1) to give 5-chloro-8-methoxy-7-nitro-3-(piperidin-1-ylmethyl)quinoline (92a) (35.0 mg, 39% yield).

[0761] 5-Chloro-8-methoxy-7-nitro-3-(piperidin-1-ylmethyl)quinoline (92a) (35.0 mg, 0.10 mmol) and lithium chloride (44.0 mg, 1.0 mmol) were added to N,N-dimethylformamide (1.0 mL) at room temperature. The reaction mixture was stirred at 130°C for 45 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (1.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 3) and dried under vacuum to give 5-chloro-7-nitro-3-(piperidin-1-ylmethyl)quinolin-8-ol (92) (30.7 mg, 92% yield).

[0762] 1 H NMR (400MHz, DMSO-d6) δ: 8.62 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 3.65 (s, 2H), 2.37 (s, 4H), 1.54–1.47 (m, 4H), 1.39 (d, J = 4.4Hz, 2H).

[0763] MS calculated: 321.09; MS found: 322.1 [M+H] + .

[0764] Example 93

[0765] Synthesis of 7-nitro-5-(pyrrolidin-1-ylmethyl)quinolin-8-ol acetate (93)

[0766] 5-(Chloromethyl)quinolin-8-ol hydrochloride (87a) (100.0 mg, 0.43 mmol) and tetrahydropyrrole (147.0 mg, 2.1 mmol) were added sequentially to dichloromethane (2.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 49 / 1, with 0.5% aqueous ammonia (25-28% by weight, NH3 content) added based on the total volume of the solvent) to afford 5-(pyrrolidin-1-ylmethyl)quinolin-8-ol (93a) (55.0 mg, 47% yield).

[0767] Sodium nitrite (50.0 mg, 0.72 mmol) was added to a solution of 5-(pyrrolidin-1-ylmethyl)quinolin-8-ol (93a) (55.0 mg, 0.24 mmol) in acetic acid (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 7-nitro-5-(pyrrolidin-1-ylmethyl)quinolin-8-ol acetate (93) (22.7 mg, 31% yield).

[0768] 1 H NMR(400MHz,DMSO-d6)δ:9.08-9.04(m,1H),8.96-8.92(m,1H),8.42(s,1H),8.01-7.95 (m,1H),4.82(s,2H),3.75-3.40(m,5H),2.04-1.93(m,3H),1.94(s,1.34H,overlapped with CH3COOH in 1:0.45mol.ratio).

[0769] MS calculated: 273.11; MS found: 274.1 [M+H] + .

[0770] Example 94

[0771] Synthesis of 5-((Diethylamino)methyl)-7-nitroquinolin-8-ol (94)

[0772] 5-(Chloromethyl)quinolin-8-ol hydrochloride (87a) (110.0 mg, 0.48 mmol) and diethylamine (140.0 mg, 1.91 mmol) were added to dichloromethane (2.5 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. Acetic acid (2.0 mL) and sodium nitrite (99.0 mg, 1.43 mmol) were added to the residue. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-70% / 30%, gradient elution, flow rate 20.0 mL / min) to give 5-((diethylamino)methyl)-7-nitroquinolin-8-ol (94) (27.0 mg, 31% yield).

[0773] 1 H NMR(400MHz, DMSO-d6)δ:8.82-8.75(m,1H),8.56-8.49(m,1H),8.07(s,1H),7.67-7.62(m,1H),4.21(s,2H),2.95-2.88(m,4H),1.20-1.15(m,4H).

[0774] MS calculated: 275.13; MS found: 276.1 [M+H] + .

[0775] Example 95

[0776] Synthesis of 7-nitro-3-(piperidin-1-ylmethyl)quinolin-8-ol (95)

[0777] Sodium methoxide (5.35 g, 99.0 mmol) was slowly added to a solution of 2,6-dinitrochlorobenzene (corrected in the reaction equation) (95a) (4.7 g, 23.2 mmol) in methanol (50.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to remove the organic solvent. The resulting residue was dissolved in dichloromethane (20.0 mL) and water (20.0 mL). The organic phase was separated and extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain crude 2-methoxy-1,3-dinitrobenzene (95b) (4.56 g, 99% yield).

[0778] Reduced iron powder (3.86 g, 69.1 mmol) was added to a solution of 2-methoxy-1,3-dinitrobenzene (95b) (4.56 g, 23.0 mmol) in acetic acid (60.0 mL) at room temperature. The reaction mixture was stirred at 65°C for 1.5 hours. The organic solvent was removed by concentration under reduced pressure. Dichloromethane (20.0 mL) was added to the resulting residue, and the pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous sodium bicarbonate. The resulting mixture was filtered under reduced pressure, and the organic phase was separated from the filtrate, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 8 / 1 / 1) to provide 2-methoxy-3-nitroaniline (95c) (3.23 g, 84% yield).

[0779] 2-Methoxy-3-nitroaniline (95c) (3.23 g, 19.2 mmol) was added to a 6.0 M hydrochloric acid solution (60.0 mL) at room temperature. The reaction mixture was heated to 100°C, and 2-methylacrolein (3.96 mL, 48.0 mmol) was slowly added dropwise. The mixture was stirred for 2 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with a 6.0 M sodium hydroxide solution. The resulting mixture was extracted with dichloromethane (50.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 85% / 15%) to provide 8-methoxy-3-methyl-7-nitroquinoline (95d) (1.67 g, 40% yield).

[0780] At room temperature, 8-methoxy-3-methyl-7-nitroquinoline (95d) (106.0 mg, 0.48 mmol), N-bromosuccinimide (95.0 mg, 0.53 mmol), and 2,2'-azobisisobutyronitrile (16.0 mg, 0.1 mmol) were added sequentially to carbon tetrachloride (6.0 mL). The reaction mixture was heated to 90°C, stirred for 16 hours, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with carbon tetrachloride (5.0 mL x 3), and the filtrate was concentrated under reduced pressure to afford crude 3-(bromomethyl)-8-methoxy-7-nitroquinoline (95e) (143.0 mg, crude yield >100%).

[0781] A solution of crude 3-(bromomethyl)-8-methoxy-7-nitroquinoline (95e) (143.0 mg, 0.48 mmol) in dichloromethane (3.0 mL) was slowly added dropwise to a solution of piperidine (123.0 mg, 1.44 mmol) in dichloromethane (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, diluted with dichloromethane (20.0 mL) and water (20.0 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 80 / 1-60 / 1) to give 8-methoxy-7-nitro-3-(piperidin-1-ylmethyl)quinoline (95f) (37.0 mg, yield 25%).

[0782] 8-Methoxy-7-nitro-3-(piperidin-1-ylmethyl)quinoline (95f) (37.0 mg, 0.12 mmol) and lithium chloride (51.6 mg, 1.22 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 150°C for 50 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. Water (2.0 mL) was added to the resulting filter cake, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give 7-nitro-3-(piperidin-1-ylmethyl)quinolin-8-ol (95) (21.3 mg, 60% yield).

[0783] 1 H NMR (400MHz, DMSO-d6) δ: 8.53 (s, 1H), 7.97 (s, 1H), 7.90 (d, J = 9.4Hz, 1H), 6.50 (d, J=9.4Hz,1H),3.60(s,2H),2.38(s,4H),1.59–1.48(m,4H),1.42(d,J=4.4Hz,2H).

[0784] MS calculated: 287.13; MS found: 288.1 [M+H] + .

[0785] Example 96

[0786] Synthesis of 5-chloro-3-(morpholinomethyl)-7-nitroquinolin-8-ol (96)

[0787] The crude product of 3-(bromomethyl)-5-chloro-8-methoxy-7-nitroquinoline (90c) (113.0 mg, 0.34 mmol) and morpholine (148.0 mg, 1.70 mmol) were added sequentially to tetrahydrofuran (2.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: dichloromethane / methanol = 24 / 1) to give 5-chloro-8-methoxy-7-nitro-3-(morpholinomethyl)quinoline (96a) (52.0 mg, 45% yield).

[0788] 5-Chloro-8-methoxy-7-nitro-3-(morpholinomethyl)quinoline (96a) (52.0 mg, 0.15 mmol) and lithium chloride (65.0 mg, 1.5 mmol) were added to N,N-dimethylformamide (1.5 mL) at room temperature. The reaction mixture was stirred at 130°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (1.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with a mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (0.5 mL x 2) and dried in vacuo to give 5-chloro-3-(morpholinomethyl)-7-nitroquinolin-8-ol (96) (38.7 mg, 78% yield).

[0789] 1 H NMR (400MHz, DMSO-d6) δ: 8.76 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 3.69 (s, 2H), 3.58 (br s, 4H), 2.40 (br s, 4H).

[0790] MS calculated: 323.07; MS found: 324.1 [M+H] + .

[0791] Example 97

[0792] Synthesis of 3-(morpholinomethyl)-7-nitroquinolin-8-ol (97)

[0793] A solution of crude 3-(bromomethyl)-8-methoxy-7-nitroquinoline (95e) (238.0 mg, 0.8 mmol) in dichloromethane (3.0 mL) was slowly added dropwise to a solution of morpholine (209.0 mg, 2.4 mmol) in dichloromethane (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, diluted with dichloromethane (20.0 mL) and water (20.0 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 61.5 / 1) to provide 8-methoxy-7-nitro-3-(morpholinomethyl)quinoline (97a) (61.0 mg, 25% yield).

[0794] 8-Methoxy-7-nitro-3-(morpholinomethyl)quinoline (97a) (61.0 mg, 0.2 mmol) and lithium chloride (84.8 mg, 2.0 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 150°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. Water (2.0 mL) was added to the resulting filter cake, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give 3-(morpholinomethyl)-7-nitroquinolin-8-ol (97) (48.5 mg, 83% yield).

[0795] 1 H NMR (400MHz, DMSO-d6) δ: 8.55 (s, 1H), 8.01 (s, 1H), 7.91 (d, J = 9.4Hz, 1H), 6.51 (d, J = 9.4Hz, 1H), 3.64 (s, 2H), 3.62–3.58 (m, 4H), 2.41 (s, 4H).

[0796] MS calculated: 289.11; MS found: 290.2 [M+H] + .

[0797] Example 98

[0798] Synthesis of 3-((Diethylamino)methyl)-7-nitroquinolin-8-ol (98)

[0799] A solution of crude 3-(bromomethyl)-8-methoxy-7-nitroquinoline (95e) (238.0 mg, 0.80 mmol) in dichloromethane (3.0 mL) was slowly added dropwise to a solution of diethylamine (176.8 mg, 2.4 mmol) in dichloromethane (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, diluted with dichloromethane (20.0 mL) and water (20.0 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5.7 / 1) to provide 8-methoxy-7-nitro-3-((diethylamino)methyl)quinoline (98a) (47.0 mg, 20% yield).

[0800] 8-Methoxy-7-nitro-3-((diethylamino)methyl)quinoline (98a) (47.0 mg, 0.16 mmol) and lithium chloride (67.8 mg, 1.6 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 150°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. Water (2.0 mL) was added to the resulting filter cake, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to give 3-((diethylamino)methyl)-7-nitroquinolin-8-ol (98) (25.8 mg, 58% yield).

[0801] 1 H NMR(400MHz,DMSO-d6)δ:8.55(s,1H),7.99(s,1H),7.90(d,J=9.4Hz,1H),6 .50(d,J=9.4Hz,1H),3.69(s,2H),2.52–2.47(m,4H),1.02(t,J=7.1Hz,6H).

[0802] MS calculated: 275.13; MS found: 276.2 [M+H] + .

[0803] Example 99

[0804] Synthesis of 5-((Methylamino)methyl)-7-nitroquinolin-8-ol dihydrochloride (99)

[0805] 5-(Chloromethyl)quinolin-8-ol hydrochloride (87a) (135.0 mg, 0.59 mmol) and tert-butyl N-methylcarbamate (384.0 mg, 2.93 mmol) were added to acetonitrile (4.0 mL) in sequence at 0°C. The reaction mixture was stirred at 85°C for 2 h, cooled to room temperature, and concentrated to dryness under reduced pressure to give crude tert-butyl N-((8-hydroxyquinolin-5-yl)methyl)-N-methylcarbamate (99a) (436.6 mg, crude yield >100%).

[0806] Sodium nitrite (108.0 mg, 1.56 mmol) was added to a solution of crude tert-butyl N-((8-hydroxyquinolin-5-yl)methyl)-N-methylcarbamate (99a) (436.6 mg, 0.59 mmol) in acetic acid (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by reverse-phase HPLC (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-30% / 70%, gradient elution, flow rate 20.0 mL / min) to give tert-butyl N-(8-hydroxy-7-nitroquinolin-5-yl)methyl-N-methylcarbamate (99b) (30.0 mg, 17% yield).

[0807] A solution of hydrogen chloride in 1,4-dioxane (4.0 M) (1.5 mL, 6.0 mmol) was added dropwise to a solution of tert-butyl N-(8-hydroxy-7-nitroquinolin-5-yl)methyl-N-methylcarbamate (99b) (30.0 mg, 0.090 mmol) in dichloromethane (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure to provide 5-((methylamino)methyl)-7-nitroquinolin-8-ol dihydrochloride (99) (27.0 mg, 98% yield).

[0808] 1 H NMR(400MHz,DMSO-d6)δ9.22(br s,2H),9.07(d,J=3.2Hz,1H),8.96(d,J=8.4Hz,1H),8.40(s,1H),7.97(dd,J=8.8,4.4Hz,1H),4.59(t,J=4.8Hz,2H),2.65(t,J=4.8Hz,3H).

[0809] MS calculated: 233.08; MS found: 234.1 [M+H] + .

[0810] Example 100

[0811] Synthesis of 4-((8-hydroxy-7-nitroquinolin-3-yl)methyl)piperazin-2-one (100)

[0812] 2-Piperazinone (275.3 mg, 2.8 mmol) was added to a mixed solvent of dichloromethane (3.0 mL) and N,N-dimethylformamide (2.0 mL) at room temperature, followed by a solution of crude 3-(bromomethyl)-8-methoxy-7-nitroquinoline (95e) (272.0 mg, 0.92 mmol) in dichloromethane (3.0 mL) slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane (20.0 mL) and water (20.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to give 4-((8-methoxy-7-nitroquinolin-3-yl)methyl)piperazin-2-one (100a) (75.0 mg, yield 26%).

[0813] 4-((8-Methoxy-7-nitroquinolin-3-yl)methyl)piperazin-2-one (100a) (75.0 mg, 0.24 mmol) and lithium chloride (99.6 mg, 2.4 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 150°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was dissolved in water (5.0 mL) and separated by reverse-phase high-performance liquid chromatography (HPLC) using an Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm) and a mobile phase of water / acetonitrile (100% / 0-70% / 30%), gradient elution, at a flow rate of 20.0 mL / min, to afford 4-((8-hydroxy-7-nitroquinolin-3-yl)methyl)piperazin-2-one (100) (41.3 mg, 58% yield).

[0814] 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.05(s,1H),7.92(d,J=9.4Hz,1H),7.83(s,1H) ,6.53(d,J=9.4Hz,1H),3.73(s,2H),3.18(s,2H),3.00(s,2H),2.60(t,J=5.2Hz,2H).

[0815] MS calculated: 302.10; MS observed: 303.1 [M+H] + .

[0816] Example 101

[0817] Synthesis of 7-nitro-5-(piperazin-1-ylmethyl)quinolin-8-ol trihydrochloride (101)

[0818] 5-(Chloromethyl)quinolin-8-ol hydrochloride (87a) (69.0 mg, 0.3 mmol) and tert-butyl 1-piperazinecarboxylate (56.0 mg, 0.3 mmol) were added sequentially to acetonitrile (4.0 mL) at 0°C. The reaction mixture was stirred at 85°C for 2 h, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 49 / 1, with 0.5% aqueous ammonia (25-28% by weight, NH3 content) added based on the total solvent volume) to afford tert-butyl 4-((8-hydroxyquinolin-5-yl)methyl)piperazine-1-carboxylate (101a) (100.0 mg, 97% yield).

[0819] Sodium nitrite (56.0 mg, 0.81 mmol) was added to a solution of tert-butyl 4-((8-hydroxyquinolin-5-yl)methyl)piperazine-1-carboxylate (101a) (100.0 mg, 0.27 mmol) in acetic acid (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and filtered under reduced pressure. The filter cake was washed with ethanol (0.5 mL x 2) and dried under vacuum to afford tert-butyl 4-((8-hydroxy-7-nitroquinolin-5-yl)methyl)piperazine-1-carboxylate (101b) (30.0 mg, 29% yield).

[0820] A solution of hydrogen chloride in 1,4-dioxane (4.0 M) (1.5 mL, 6.0 mmol) was added dropwise to a solution of tert-butyl 4-((8-hydroxy-7-nitroquinolin-5-yl)methyl)piperazine-1-carboxylate (101b) (30.0 mg, 0.077 mmol) in dichloromethane (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure to provide 7-nitro-5-(piperazin-1-ylmethyl)quinolin-8-ol trihydrochloride (101) (24.0 mg, 78% yield).

[0821] 1 H NMR(400MHz,DMSO-d6)δ:10.09(br s,1H),9.15(s,1H),9.04(d,J=4.0Hz,1H),8.49(s,1H),7.95(dd,J=8.4,4.2Hz,1H),4.95–4.72(m,2H),3.46–3.38(m,2H).

[0822] MS calculated: 288.12; MS found: 289.1 [M+H] + .

[0823] Example 102

[0824] Synthesis of 7-nitro-3-(piperazin-1-ylmethyl)quinolin-8-ol trihydrochloride (102)

[0825] A solution of crude 3-(bromomethyl)-8-methoxy-7-nitroquinoline (95e) (272.0 mg, 0.92 mmol) in dichloromethane (3.0 mL) was slowly added dropwise to a solution of tert-butyl 1-piperazinecarboxylate (853.0 mg, 4.6 mmol) in dichloromethane (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane (20.0 mL) and water (20.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 70 / 1) to give tert-butyl 4-((8-methoxy-7-nitroquinolin-3-yl)methyl)piperazine-1-carboxylate (102a) (83.0 mg, yield 23%).

[0826] tert-Butyl 4-((8-methoxy-7-nitroquinolin-3-yl)methyl)piperazine-1-carboxylate (102a) (83.0 mg, 0.21 mmol) and lithium chloride (89.0 mg, 2.1 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 150°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. Water (2.0 mL) was added to the resulting filter cake, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was dried under vacuum to yield tert-butyl 4-((8-hydroxy-7-nitroquinolin-3-yl)methyl)piperazine-1-carboxylate (102b) (80.0 mg, 99% yield).

[0827] Tert-butyl 4-((8-hydroxy-7-nitroquinolin-3-yl)methyl)piperazine-1-carboxylate (102b) (80.0 mg, 0.21 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4.0 M) (6.0 mL, 24.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the organic solvent. Ethyl acetate (5.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with ethyl acetate (0.5 mL x 2) and dried under vacuum to give 7-nitro-3-(piperazin-1-ylmethyl)quinolin-8-ol trihydrochloride (102) (62.7 mg, 77% yield).

[0828] 1 H NMR (400MHz, D2O-d6) δ: 10.03 (s, 2H), 9.31 (s, 1H), 8.76 (s, 1H), 8.07 (d, J = 9.2Hz, 1H), 7.49 (d, J = 9.2Hz, 1H), 4.66 (s, 2H), 3.45 (m, 8H).

[0829] MS calculated: 288.12; MS found: 289.1 [M+H] + .

[0830] Example 103

[0831] Synthesis of 5-((Ethylamino)methyl)-7-nitroquinolin-8-ol dihydrochloride (103)

[0832] 5-(Chloromethyl)quinolin-8-ol hydrochloride (87a) (115.0 mg, 0.5 mmol) and tert-butyl N-ethylcarbamate (290.0 mg, 2.0 mmol) were added sequentially to acetonitrile (4.0 mL) at 0°C. The reaction mixture was stirred at 85°C for 2 h, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with acetonitrile (1.0 mL x 2), and the filtrate was concentrated to dryness under reduced pressure to afford tert-butyl N-(8-hydroxyquinolin-5-yl)methyl-N-ethylcarbamate (103a) (94.0 mg, 60% yield).

[0833] Sodium nitrite (37.0 mg, 0.54 mmol) was added to a solution of tert-butyl N-(8-hydroxyquinolin-5-yl)methyl-N-ethylcarbamate (103a) (54.0 mg, 0.18 mmol) in acetic acid (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and filtered under reduced pressure. The filtrate was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-30% / 70%, gradient elution, flow rate 20.0 mL / min) to give tert-butyl N-(8-hydroxy-7-nitroquinolin-5-yl)methyl-N-ethylcarbamate (103b) (28.0 mg, 45% yield).

[0834] A solution of hydrogen chloride in 1,4-dioxane (4.0 M) (1.5 mL, 6.0 mmol) was added dropwise to a solution of tert-butyl N-(8-hydroxy-7-nitroquinolin-5-yl)methyl-N-ethylcarbamate (103b) (28.0 mg, 0.081 mmol) in dichloromethane (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure to provide 5-((ethylamino)methyl)-7-nitroquinolin-8-ol dihydrochloride (103) (26.0 mg, 88% yield).

[0835] 1 H NMR(400MHz,DMSO-d6)δ:9.30(br s,2H),9.08(d,J=4.0Hz,1H),8.97(d,J=8.6Hz,1H),8.43(s,1H),7.97(dd,J=8.4,4. 4Hz, 1H), 4.59 (t, J = 5.6Hz, 2H), 3.11 (dd, J = 12.4, 6.8Hz, 2H), 1.29 (t, J = 7.2Hz, 3H).

[0836] MS calculated: 247.25; MS found: 248.1 [M+H] + .

[0837] Example 104

[0838] Synthesis of 5-((dimethylamino)methyl)-7-nitro-4-(trifluoromethyl)quinolin-8-ol (104)

[0839] 2-Methoxy-5-methylaniline (104a) (27.4 g, 199.73 mmol) was added to ethyl 4,4,4-trifluoroacetoacetate (75.0 g, 399.47 mmol) at room temperature. The reaction mixture was heated to 135°C and stirred for 1 hour. The mixture was then cooled to 0°C, water (4.0 mL) was added, and stirred for 30 minutes. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with petroleum ether (60-90°C boiling range) (25.0 mL x 3) and dried under vacuum to give the crude product 4,4,4-trifluoro-N-(2-methoxy-5-methylphenyl)-3-oxobutanamide (104b) (28.0 g, crude yield 51%).

[0840] The crude product of 4,4,4-trifluoro-N-(2-methoxy-5-methylphenyl)-3-oxobutanamide (104b) (6.0 g, 21.80 mmol) was added to polyphosphoric acid (30.0 mL) at room temperature. The reaction mixture was heated to 150°C and stirred for 1 hour. The mixture was then cooled to approximately 60-70°C, ice water (100.0 mL) was added, and the mixture was vigorously stirred for 30 minutes. The mixture was then filtered under reduced pressure. The filter cake was washed with water (20.0 mL x 4) and dried under vacuum to afford the crude product of 8-methoxy-5-methyl-4-trifluoromethyl-2(1H)-quinolinone (104c) (5.0 g, crude yield 89%).

[0841] Crude 8-methoxy-5-methyl-4-trifluoromethyl-2(1H)-quinolinone (104c) (5.0 g, 19.4 mmol) was added to phosphorus oxychloride (20.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 3 hours, cooled to room temperature, and ice water (100.0 mL) was added. The mixture was stirred vigorously for 30 minutes and filtered under reduced pressure. The filter cake was washed with water (20.0 mL x 3) and dried under vacuum to afford crude 2-chloro-8-methoxy-5-methyl-4-(trifluoromethyl)quinoline (104d) (4.5 g, crude yield 84%).

[0842] At room temperature, the crude product of 2-chloro-8-methoxy-5-methyl-4-(trifluoromethyl)quinoline (104d) (1.7 g, 6.17 mmol) and an aqueous solution of hydrazine hydrate (80 wt%) (2.2 g, 43.17 mmol) were added sequentially to ethanol (20.0 mL), followed by palladium on carbon (10 wt% palladium loading) (0.17 g, 0.16 mmol). The reaction mixture was stirred at 90°C for 5 hours, cooled to room temperature, and filtered through celite. The filter cake was washed with ethyl acetate (10.0 mL x 4), and the filtrate was concentrated under reduced pressure. Ethyl acetate (20.0 mL) and water (20.0 mL) were added to the resulting residue, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 8-methoxy-5-methyl-4-(trifluoromethyl)quinoline (104e) (1.0 g, yield 67%).

[0843] Nitric acid (65 wt%) (2.6 mL, 37.3 mmol) was slowly added dropwise to a solution of 8-methoxy-5-methyl-4-(trifluoromethyl)quinoline (104e) (1.5 g, 6.22 mmol) in acetic anhydride (15.0 mL) at 0°C. The mixture was stirred for 10 minutes, and then sulfuric acid (98 wt%) (0.41 mL, 7.50 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 10 minutes, and an aqueous solution of sodium hydroxide (1.0 M) was added to adjust the pH of the aqueous phase to approximately 9-10. The resulting mixture was extracted with ethyl acetate (50.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to provide 8-methoxy-5-methyl-7-nitro-4-(trifluoromethyl)quinoline (104f) (0.15 g, 8% yield).

[0844] N-Bromosuccinimide (87.3 mg, 0.44 mmol) and 2,2'-azobisisobutyronitrile (120.4 mg, 0.74 mmol) were added sequentially to a solution of 8-methoxy-5-methyl-7-nitro-4-(trifluoromethyl)quinoline (104f) (105.0 mg, 0.37 mmol) in 1,2-dichloroethane (4.0 mL) at room temperature. The reaction mixture was heated to 90°C, stirred for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to provide 5-(bromomethyl)-8-methoxy-7-nitro-4-(trifluoromethyl)quinoline (104g) (100.0 mg, 74% yield).

[0845] To a solution of 5-(bromomethyl)-8-methoxy-7-nitro-4-(trifluoromethyl)quinoline (104g) (100.0 mg, 0.27 mmol) in dichloromethane (2.0 mL) was added dimethylamine hydrochloride (44.6 mg, 0.55 mmol) and triethylamine (110.9 mg, 1.10 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 5-((dimethylamino)methyl)-8-methoxy-7-nitro-4-(trifluoromethyl)quinoline (104h) (70.0 mg, 79% yield).

[0846] 5-((Dimethylamino)methyl)-8-methoxy-7-nitro-4-(trifluoromethyl)quinoline (104h) (70.0 mg, 0.21 mmol) and lithium chloride (26.5 mg, 0.63 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 150°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-70% / 30%, gradient elution, flow rate 20.0 mL / min) to give 5-((dimethylamino)methyl)-7-nitro-4-(trifluoromethyl)quinolin-8-ol (108) (15.1 mg, 23% yield).

[0847] 1 H NMR (400MHz, MeOH-d4) δ9.18(s,1H),8.55(s,1H),8.26(s,1H),4.77(s,2H),2.82(s,6H).

[0848] MS calculated: 315.08; MS found: 316.1 [M+H] + .

[0849] Example 105

[0850] Synthesis of 7-nitro-4-(piperidin-4-yl)quinolin-8-ol (105)

[0851] 4-Bromo-8-methoxyquinoline (11b) (3.0 g, 12.68 mmol) and N-tert-butyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (4.7 g, 15.22 mmol) were added to a mixture of 1,4-dioxane (60.0 mL) and water (15.0 mL) at room temperature. Sodium carbonate (4.03 g, 38.04 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.03 g, 1.27 mmol) were then added sequentially. The resulting reaction mixture was stirred at 80°C for 16 hours, cooled to room temperature, and ethyl acetate (100.0 mL) and water (100.0 ml) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50.0 mL). The combined organic phases were washed with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 4-(8-methoxyquinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (105a) (4.0 g, yield 93%).

[0852] Tert-butyl 4-(8-methoxyquinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (105a) (4.0 g, 11.76 mmol) and palladium / carbon (10 wt% palladium loading) (0.40 g, 0.376 mmol) were added sequentially to anhydrous methanol (40.0 mL) at room temperature. The resulting reaction mixture was stirred under a hydrogen atmosphere for 16 hours, filtered through celite, and the filter cake was washed with ethyl acetate (10.0 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give tert-butyl 4-(8-methoxyquinolin-4-yl)piperidine-1-carboxylate (105b) (3.2 g, 80% yield).

[0853] Tert-butyl 4-(8-methoxyquinolin-4-yl)piperidine-1-carboxylate (105b) (1.5 g, 4.37 mmol) was added to a 3.0 M solution of hydrogen chloride in ethyl acetate (20.0 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour and then concentrated to dryness under reduced pressure to afford crude 8-methoxy-4-(piperidin-4-yl)quinoline (105c) (1.1 g, 90% crude yield).

[0854] Triethylamine (0.94 g, 9.26 mmol) and trifluoroacetic anhydride (0.778 g, 3.71 mmol) were added sequentially to a solution of 8-methoxy-4-(piperidin-4-yl)quinoline (105c) (0.86 g, 3.09 mmol) in dichloromethane (15.0 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (30.0 mL) and water (30.0 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20.0 mL). The combined organic phases were washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide N-trifluoroacetyl-8-methoxy-4-(piperidin-4-yl)quinoline (105d) (0.67 g, 64% yield).

[0855] Nitric acid (65 wt%) (0.79 mL, 11.89 mmol) was slowly added dropwise to a solution of N-trifluoroacetyl-8-methoxy-4-(piperidin-4-yl)quinoline (105d) (0.67 g, 1.98 mmol) in acetic anhydride (6.0 mL) at 0°C. The mixture was stirred for 10 minutes, and then sulfuric acid (98 wt%) (0.13 mL, 2.38 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 10 minutes, and an aqueous solution of sodium hydroxide (1.0 M) was added to adjust the pH of the aqueous phase to approximately 9-10. The resulting mixture was extracted with ethyl acetate (50.0 mL x 2). The combined organic phases were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give N-trifluoroacetyl-7-nitro-8-methoxy-4-(piperidin-4-yl)quinoline (105e) (0.15 g, yield 20%).

[0856] N-Trifluoroacetyl-7-nitro-8-methoxy-4-(piperidin-4-yl)quinoline (105e) (0.15 g, 0.39 mmol) and lithium chloride (0.050 g, 2.38 mmol) were added to N,N-dimethylformamide (10.0 mL) at room temperature. The reaction mixture was stirred at 150°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent to provide crude N-trifluoroacetyl-7-nitro-4-(piperidin-4-yl)quinolin-8-ol (105f) (0.20 g, crude yield >100%).

[0857] Crude N-trifluoroacetyl-7-nitro-4-(piperidin-4-yl)quinolin-8-ol (105f) (0.20 g, 0.39 mmol (theoretical amount)) was added to a mixture of methanol (8.0 mL) and water (2.0 mL) at room temperature, followed by the addition of potassium hydroxide (0.11 g, 1.95 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness under reduced pressure. The resulting residue was separated by reverse-phase HPLC (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-30% / 70%, gradient elution, flow rate 20.0 mL / min) to give 7-nitro-4-(piperidin-4-yl)-quinolin-8-ol (105) (0.042 g, 29% yield).

[0858] 1 H NMR (400MHz, MeOH-d4) δ8.91(d,J=4.6Hz,1H),8.18(d,J=9.6Hz,1H),7.73(d,J=9.6Hz,1H),7.65(d,J=4.6Hz ,1H),3.80(s,1H),3.57(d,J=13.1Hz,2H),3.33(d,J=13.2Hz,2H),2.22(d,J=13.3Hz,2H),2.07–1.96(m,3H).

[0859] MS calculated: 273.11, MS found: 274.35 [M+H] + .

[0860] Example 106

[0861] Synthesis of 5-Fluoro-7-nitroquinolin-8-ol (106)

[0862] 5-Fluoro-2-methoxyaniline (68a) (1.0 g, 7.08 mmol) was added to hydrochloric acid (6.0 M) (10.0 mL) at room temperature. The reaction mixture was heated to 110°C, and acrolein diethyl acetal (2.31 g, 17.7 mmol) was slowly added dropwise. The mixture was stirred for 2 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with saturated aqueous potassium carbonate. The resulting mixture was extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 7 / 1 to 4 / 1) to provide 5-fluoro-8-methoxyquinoline (106a) (0.20 g, 16% yield).

[0863] Nitric acid (65 wt%) (0.23 mL, 3.56 mmol) was slowly added dropwise to a solution of 5-fluoro-8-methoxyquinoline (106a) (0.20 g, 1.13 mmol) in acetic anhydride (4.0 mL) at 0°C. The mixture was stirred for 10 minutes, and then sulfuric acid (98 wt%) (0.061 mL, 1.13 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 2 hours, and an aqueous solution of sodium hydroxide (1.0 M) was added to adjust the pH of the aqueous phase to approximately 9-10. The resulting mixture was extracted with ethyl acetate (10.0 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1) to provide 5-fluoro-8-methoxy-7-nitroquinoline (106b) (0.165 g, 66% yield).

[0864] 5-Fluoro-8-methoxy-7-nitroquinoline (106b) (65.0 mg, 0.29 mmol) and lithium chloride (124.0 mg, 2.90 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 130°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The resulting filter cake was washed with a mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (1.0 mL x 2) and dried in vacuo to give 5-fluoro-7-nitroquinolin-8-ol (106) (56.0 mg, 92% yield).

[0865] 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 1H), 8.21 (dd, J = 8.1, 0.9Hz, 1H), 7.68 (d, J = 12.8Hz, 1H), 7.65 (dd, J = 8.4, 4.5Hz, 1H).

[0866] MS calculated: 208.03, MS found: 209.15 [M+H] + .

[0867] Example 107

[0868] Synthesis of 5-chloro-6-methyl-7-nitroquinolin-8-ol (107)

[0869] 4-Chloro-5-methyl-2-nitrophenol (107a) (1.0 g, 5.35 mmol), iron powder (1.5 g, 26.74 mmol), and ammonium chloride (2.8 g, 53.78 mmol) were added sequentially to a mixture of ethanol (15.0 mL) and water (8.0 mL) at room temperature. The resulting reaction mixture was stirred at 95°C for 2 hours, cooled to room temperature, and filtered through celite. The filter cake was washed with ethyl acetate (10.0 mL x 4). The filtrates were combined, the organic phase separated, and the aqueous phase was extracted with ethyl acetate (5.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2-amino-4-chloro-5-methylphenol (107b) (0.57 g, crude yield 68%).

[0870] At room temperature, the crude product of 2-amino-4-chloro-5-methylphenol (107b) (0.435 g, 2.77 mmol) was added to hydrochloric acid (6.0 M) (10.0 mL). The reaction mixture was heated to 110°C, and acrolein diethyl acetal (1.2 mL, 8.31 mmol) was slowly added dropwise. The mixture was stirred for 5 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with saturated aqueous potassium carbonate. The resulting mixture was extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to provide 5-chloro-6-methylquinolin-8-ol (107c) (0.41 g, 77% yield).

[0871] Sodium nitrite (128.6 mg, 1.86 mmol) was added to a solution of 5-chloro-6-methylquinolin-8-ol (107c) (60.0 mg, 0.31 mmol) in acetic acid (3.0 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 3 hours and filtered under reduced pressure. The filter cake was washed with a mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (1.0 mL x 2) and dried in vacuo to afford 5-chloro-6-methyl-7-nitroquinolin-8-ol (107) (73.0 mg, 99% yield).

[0872] 1 H-NMR(400MHz, DMSO-d6)δ:10.22-10.00(bs,1H),8.93-8.86(m,1H),8.56-8.49(m,1H),7.75-7.67(m,1H),7.13(s,1H),2.56-2.51(m,3H).

[0873] MS calculated: 238.63; MS found: 239.1 [M+H] + .

[0874] Example 108

[0875] Synthesis of 5-(Difluoromethyl)-7-nitroquinolin-8-ol trifluoroacetate (108)

[0876] Bromomethyl methyl ether (1.0 mL, 12.25 mmol) was slowly added dropwise to a solution of 5-bromo-8-hydroxyquinoline (108a) (2.04 g, 9.10 mmol) and diisopropylethylamine (4.4 mL, 24.90 mmol) in dichloromethane (40.0 mL) at 0°C. The resulting mixture was warmed to room temperature and stirred for 5 hours. Water (20.0 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-2 / 1) to provide 5-bromo-8-(methoxymethoxy)quinoline (108b) (2.33 g, 96% yield).

[0877] 5-Bromo-8-(methoxymethoxy)quinoline (108b) (616.0 mg, 2.30 mmol), potassium vinyl trifluoroborate (493.0 mg, 3.70 mmol), bis(diphenylphosphino)ferrocenepalladium dichloride (168.0 mg, 0.23 mmol), and potassium carbonate (952.0 mg, 6.90 mmol) were added sequentially to a mixture of 1,4-dioxane (10.0 mL) and water (2.5 mL) at room temperature. The resulting mixture was stirred at 90°C for 18 hours, cooled to room temperature, and concentrated to dryness under reduced pressure. Dichloromethane (10.0 mL) and water (10.0 mL) were added to the resulting residue, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-4 / 1) to give 5-vinyl-8-(methoxymethoxy)quinoline (108c) (441.0 mg, yield 89%).

[0878] Potassium osmate dihydrate (75.0 mg, 0.20 mmol) was added to a solution of 5-vinyl-8-(methoxymethoxy)quinoline (108c) (441.0 mg, 2.05 mmol) in tetrahydrofuran (36 mL) at 0°C, followed by the addition of water (9.0 mL). The reaction mixture was stirred at 0°C for 10 minutes, sodium periodate (1.32 g, 6.15 mmol) was added, and the mixture was warmed to room temperature and stirred for 16 hours. Ethyl acetate (15.0 mL) and water (10.0 mL) were then added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (10.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to afford crude 8-(methoxymethoxy)quinoline-5-carboxaldehyde (108d) (475.0 mg, crude yield 100%).

[0879] Diethylaminosulfur trifluoride (610.0 mg, 3.77 mmol) was slowly added dropwise to a solution of 8-(methoxymethoxy)quinoline-5-aldehyde (108d) (230.0 mg, 1.06 mmol) in dichloromethane (10.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 16 hours. The mixture was then cooled to 0°C and the pH of the aqueous phase was adjusted to approximately 7-8 by slowly adding saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-1 / 1) to afford 5-(difluoromethyl)-8-(methoxymethoxy)quinoline (108e) (132.0 mg, 52% yield).

[0880] 5-(Difluoromethyl)-8-(methoxymethoxy)quinoline (108e) (55.0 mg, 0.23 mmol) was added to trifluoroacetic acid (3.0 mL) at room temperature. The resulting reaction solution was stirred at room temperature for 3 hours and then concentrated to dryness under reduced pressure to provide crude 5-(difluoromethyl)-8-hydroxyquinoline trifluoroacetate (108f) (45.0 mg, crude yield >100%).

[0881] Sodium nitrite (49.0 mg, 0.71 mmol) was added to a solution of 5-(difluoromethyl)-8-hydroxyquinoline trifluoroacetate (108f) (45.0 mg, 0.23 mmol) in acetic acid (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and filtered under reduced pressure. The filter cake was washed with a mixture of ethanol and water (volume ratio, ethanol / water = 1 / 1) (1.0 mL x 2) and dried under vacuum to give 5-(difluoromethyl)-7-nitroquinolin-8-ol trifluoroacetate (108) (75.6 mg, 93% total yield for the above two steps).

[0882] 1 H NMR (400MHz, DMSO-d6) δ9.07 (d, J = 4.6 Hz, 1H), 8.82 (t, J = 8.6 Hz, 1H), 8.45 (s, 1H), 8.03 (dd, J = 8.6, 4.6 Hz, 1H), 7.48 (t, J = 54.2 Hz, 1H).

[0883] MS calculated: 240.03; MS found: 241.1 [M+H] + .

[0884] Example 109

[0885] Synthesis of 5-(Hydroxymethyl)-7-nitroquinolin-8-ol (109)

[0886] 8-(Methoxymethoxy)quinoline-5-carboxylate (108d) (760.0 mg, 3.5 mmol) was added to trifluoroacetic acid (20.0 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 3 hours and then concentrated to dryness under reduced pressure to afford crude 8-hydroxyquinoline-5-carboxylate (109a) (606.0 mg, crude yield 100%).

[0887] Crude 8-hydroxyquinoline-5-aldehyde (109a) (606.0 mg, 3.5 mmol) was added to nitric acid (9 wt%) (10.0 mL) at room temperature. The reaction mixture was stirred at 90°C for 1 hour, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with water (3.0 mL x 3) and dried under vacuum to afford 8-hydroxy-7-nitroquinoline-5-aldehyde (109b) (459.0 mg, 60% total yield for the two steps).

[0888] 8-Hydroxy-7-nitroquinoline-5-aldehyde (109b) (178.0 mg, 0.80 mmol) was added to a mixture of tetrahydrofuran (3.0 mL) and methanol (1.0 mL) at room temperature. The resulting reaction solution was cooled to 0°C, and sodium borohydride (34.0 mg, 0.90 mmol) was added. The reaction mixture was stirred at 0°C for 1.5 hours and then concentrated to dryness under reduced pressure. The resulting residue was separated by reverse-phase HPLC (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-99% / 1%, gradient elution, flow rate 20.0 mL / min) to give 5-(hydroxymethyl)-7-nitroquinolin-8-ol (109) (30.6 mg, 17% yield).

[0889] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=4.2Hz,1H),8.27(d,J=8.1Hz,1H),7.92(s,1H),7.54(dd,J=8.1,4.2Hz,1H),5.00(s,1H),4.64(s,2H).

[0890] MS calculated: 220.05; MS found: 221.1 [M+H] + .

[0891] Example 110

[0892] Synthesis of 5-chloro-6-fluoro-7-nitroquinolin-8-ol (110)

[0893] At room temperature, 3-fluoro-4-chlorophenol (110a) (1.5 g, 10.20 mmol) and tetrabutylammonium bromide (0.33 g, 0.102 mmol) were added sequentially to 1,2-dichloroethane (15.0 mL), followed by the slow addition of nitric acid (7 wt%) (18.0 mL). The reaction mixture was stirred at room temperature for 4 hours and diluted with water (20.0 mL). The resulting mixture was extracted with dichloromethane (20.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-10 / 1) to give 4-chloro-5-fluoro-2-nitrophenol (110b) (1.45 g, 74% yield).

[0894] 4-Chloro-5-fluoro-2-nitrophenol (110b) (1.45 g, 7.57 mmol) was added to a mixture of acetic acid (14.5 mL) and water (4.5 mL) at room temperature, followed by the addition of reduced iron powder (2.11 g, 37.85 mmol). The resulting mixture was stirred at 100°C for 0.5 h, cooled to room temperature, and filtered through celite. The filter cake was washed with dichloromethane (10.0 mL x 4). The combined filtrates were washed sequentially with saturated aqueous sodium bicarbonate (30.0 mL x 4) and saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 7 / 1 to 5 / 1) to provide 2-amino-4-chloro-5-fluorophenol (110c) (0.247 g, 20% yield).

[0895] At room temperature, 2-amino-4-chloro-5-fluorophenol (110c) (0.247 g, 1.53 mmol), sodium 3-nitrobenzenesulfonate (0.413 g, 1.84 mmol), and glycerol (0.352 g, 3.83 mmol) were sequentially added to sulfuric acid (70 wt%) (2.0 mL). The resulting mixture was stirred at 140°C for 3 hours, cooled to room temperature, and saturated aqueous sodium carbonate solution was slowly added dropwise to adjust the pH of the aqueous phase to approximately 8-9. The resulting mixture was extracted with dichloromethane (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to provide 5-chloro-6-fluoroquinolin-8-ol (110d) (0.12 g, 40% yield).

[0896] Sodium nitrite (175.0 mg, 2.5 mmol) was added portionwise to a suspension of 5-chloro-6-fluoroquinolin-8-ol (110d) (50.0 mg, 0.25 mmol) in hydrochloric acid (3.0 M) (1.67 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours, and then saturated aqueous sodium carbonate solution was slowly added to adjust the pH of the aqueous phase to approximately 8-9. The resulting mixture was filtered under reduced pressure, and the filter cake was washed sequentially with water (1.0 mL x 2) and a mixture of ethanol and water (volume ratio, ethanol / water = 1 / 1) (0.5 mL x 2). After vacuum drying, 5-chloro-6-fluoro-7-nitroquinolin-8-ol (110) (31.0 mg, 50% yield) was obtained.

[0897] 1 H NMR (400MHz, DMSO-d6) δ9.06 (d, J = 3.7 Hz, 1H), 8.66 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 8.5, 4.2 Hz, 1H).

[0898] MS calculated: 241.99; MS observed: 243.0, 245.0 [M+H] + .

[0899] Example 111

[0900] Synthesis of 5-chloro-7-nitro-4-(3-phenylpiperidin-1-yl)quinolin-8-ol (111)

[0901] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (200.0 mg, 0.77 mmol) and 3-phenylpiperidine hydrochloride (161.0 mg, 1.0 mmol) were added to N,N-dimethylformamide (4.0 mL) at room temperature. The resulting mixture was stirred at 130°C for 5 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-33% / 67%, gradient elution, flow rate 20.0 mL / min) to give 5-chloro-7-nitro-4-(3-phenylpiperidin-1-yl)quinolin-8-ol (111) (26.4 mg, 9% yield).

[0902] 1 H NMR(400MHz,DMSO-d6)δ:8.10-8.04(m,1H),7.96-7.92(m,1H),7.82-7.78(m,1 H),7.40-7.25(m,5H),3.68-3.30(m,2H),3.08-2.92(m,1H),2.06-1.56(m,6H).

[0903] MS calculated: 383.10; MS observed: 384.1, 386.1 [M+H] + .

[0904] Example 112

[0905] Synthesis of 3-cyclopropyl-7-nitroquinolin-8-ol (112)

[0906] At 100°C, N-bromosuccinimide (5.34 g, 30.0 mmol) was added in three portions to a solution of 8-nitroquinoline (112a) (5.23 g, 30.0 mmol) in acetic acid (30.0 mL). The reaction mixture was stirred for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Dichloromethane (50.0 mL) was added to the resulting residue, and the pH of the aqueous phase was adjusted to approximately 7-8 by adding saturated aqueous sodium carbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 3 / 1 to 1.5 / 1) to give 3-bromo-8-nitroquinoline (112b) (4.61 g, 61% yield).

[0907] 3-Bromo-8-nitroquinoline (112b) (4.23 g, 16.7 mmol), reduced iron powder (6.99 g, 125.3 mmol), and ammonium chloride (1.79 g, 33.4 mmol) were added sequentially to a mixture of ethanol (33.4 mL) and water (16.7 mL) at room temperature. The resulting reaction mixture was stirred at 100°C for 4 hours, cooled to room temperature, and filtered through celite. The filter cake was washed with ethyl acetate (10.0 mL x 4). The filtrates were combined, the organic phase separated, and the aqueous phase was extracted with ethyl acetate (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 1.5 / 1 to 1 / 1) to give 3-bromoquinolin-8-amine (112c) (3.16 g, 85% yield).

[0908] At 0°C, a solution of sodium nitrite (75.9 mg, 1.1 mmol) in water (1.0 mL) was added to a suspension of 3-bromoquinolin-8-amine (112c) (223.0 mg, 1.0 mmol) in sulfuric acid (26 wt%) (19.2 mL). The resulting mixture was stirred at 0°C for 20 minutes and then transferred portionwise to a room temperature aqueous copper sulfate solution (11 wt%) (145.0 mL), followed by the addition of cuprous oxide (143.0 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 30 minutes and extracted with dichloromethane (30.0 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 200 / 1) to give 3-bromoquinolin-8-ol (112d) (143.0 mg, 64% yield).

[0909] At room temperature, 3-bromoquinolin-8-ol (112d) (143.0 mg, 0.64 mmol), triethylamine (0.13 mL, 0.96 mmol), and di-tert-butyl dicarbonate (168.0 mg, 0.768 mmol) were added sequentially to dichloromethane (3.2 mL), followed by 4-(dimethylamino)pyridine (7.8 mg, 0.064 mmol). The reaction mixture was stirred for 2 hours and then concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 30 / 1) to give 3-bromoquinolin-8-yl tert-butyl carbonate (112e) (188.0 mg, 91% yield).

[0910] 3-Bromoquinolin-8-yl tert-butyl carbonate (112e) (188.0 mg, 0.58 mmol), cyclopropylboronic acid (124.5 mg, 1.45 mmol), palladium acetate (26.0 mg, 0.116 mmol), tricyclohexylphosphine (65.0 mg, 0.232 mmol), and potassium phosphate (369.0 mg, 1.74 mmol) were added sequentially to a mixture of toluene (2.9 mL) and water (0.72 mL) at room temperature. The reaction mixture was stirred at 90°C for 26 hours, cooled to room temperature, and diluted with dichloromethane (10.0 mL) and water (10.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / dichloromethane = 1.5 / 1-1 / 1) to give tert-butyl (3-cyclopropylquinolin-8-yl) carbonate (112f) (134.0 mg, yield 81%).

[0911] A solution of tert-butyl (3-cyclopropylquinolin-8-yl) carbonate (112f) (134.0 mg, 0.47 mmol) in 1,4-dioxane (0.59 mL) was added to a 4.0 M solution of hydrogen chloride in 1,4-dioxane (1.76 mL) at room temperature. The resulting mixture was stirred for 24 hours and then concentrated to dryness under reduced pressure. Dichloromethane (10.0 mL) and saturated aqueous sodium bicarbonate (10.0 mL) were added to the resulting residue, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to provide the crude product of 3-cyclopropylquinolin-8-ol (112 g) (95.4 mg, crude yield >100%).

[0912] Sodium nitrite (50.0 mg, 0.725 mmol) was added to a solution of crude 3-cyclopropylquinolin-8-ol (112 g) (54.6 mg, 0.29 mmol (theoretical amount)) in acetic acid (1.16 mL) at room temperature. The reaction mixture was stirred for 3 hours and concentrated to dryness under reduced pressure. A mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (1.0 mL) was added to the resulting residue, stirred for 5 minutes, and filtered under reduced pressure. The filter cake was washed with a mixed solvent of ethanol and water (volume ratio, ethanol / water = 2 / 1) (0.5 mL x 3) and dried in vacuo to give 3-cyclopropyl-7-nitroquinolin-8-ol (112) (42.1 mg, 63% yield).

[0913] 1H NMR(400MHz, DMSO-d6)δ:9.24(s,1H),8.82(d,J=1.2Hz,1H),8.74(d,J=1.6Hz,1H),8.51(d,J=8.8 Hz,1H),7.11(d,J=8.8Hz,1H),2.34–2.26(m,1H),1.21(dd,J=8.1,1.8Hz,2H),0.99–0.97(m,2H).

[0914] MS calculated: 230.07; MS found: 231.1 [M+H] + .

[0915] Example 113

[0916] Synthesis of 5-chloro-7-nitroquinolin-2-deuterated-8-phenol (113)

[0917] At 0°C, iodomethane (0.68 mL, 10.8 mmol) was slowly added dropwise to a solution of 5-chloro-8-hydroxyquinoline (113a) (1.5 g, 8.35 mmol) and potassium carbonate (2.3 g, 16.7 mmol) in N,N-dimethylformamide (15.0 mL). The resulting mixture was warmed to room temperature and stirred for 16 hours. Water (50.0 mL) was added to dilute the mixture, and the mixture was extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 8 / 1 to 2 / 1) to give 5-chloro-8-methoxyquinoline (113b) (1.48 g, 92% yield).

[0918] 3-Chloroperoxybenzoic acid (85 wt%) (2.02 g, 9.95 mmol) was added portionwise to a solution of 5-chloro-8-methoxyquinoline (113b) (1.288 g, 6.65 mmol) in dichloromethane (20.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours, cooled to 0°C, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide (1.0 M). The organic phase was separated and extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 100% / 0-91% / 9%) to provide 5-chloro-8-methoxyquinoline-1-oxide (113c) (1.0 g, 72% yield).

[0919] 5-Chloro-8-methoxyquinoline-1-oxide (113c) (1.0 g, 4.77 mmol) was added portionwise to a solution of sodium hydroxide (0.458 g, 11.45 mmol) in deuterated water (5.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 6 hours, cooled to room temperature, and diluted with water (15.0 mL). The resulting mixture was extracted with dichloromethane (20.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to provide 5-chloro-8-methoxyquinoline-1-oxide-2-deuterium (113d) (0.969 g, 96% yield).

[0920] Phosphorus tribromide (0.43 mL, 4.6 mmol) was slowly added dropwise to a solution of 5-chloro-8-methoxyquinoline-1-oxide-2-deuterium (113d) (0.486 g, 2.3 mmol) in N,N-dimethylformamide (6.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, cooled to 0°C, and the pH of the aqueous phase was adjusted to approximately 8-9 with saturated aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (10.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to provide 5-chloro-8-methoxyquinoline-2-deuterium (113e) (0.268 g, 60% yield).

[0921] Nitric acid (65 wt%) (0.57 mL, 8.3 mmol) was slowly added dropwise to a solution of 5-chloro-8-methoxyquinoline-2-deuterium (113e) (0.268 g, 1.37 mmol) in acetic anhydride (6.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, and sulfuric acid (98 wt%) (0.1 mL, 1.84 mmol) was slowly added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 hours, then cooled to 0°C and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 20 / 1-10 / 1) to give 5-chloro-7-nitro-8-methoxyquinoline-2-deuterium (113f) (0.094 g, yield 29%).

[0922] 5-Chloro-7-nitro-8-methoxyquinolin-2-deuterium (113f) (94.0 mg, 0.39 mmol) and lithium chloride (165.0 mg, 3.9 mmol) were added to N,N-dimethylformamide (3.0 mL) at room temperature. The reaction mixture was stirred at 140°C for 45 minutes, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The resulting filter cake was washed with water (1.0 mL x 2) and dried under vacuum to give 5-chloro-7-nitroquinolin-2-deuterium-8-ol (113) (84.0 mg, 95% yield).

[0923] 1 H NMR (400MHz, DMSO-d6) δ: 8.30 (d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H).

[0924] MS calculated: 225.01; MS found: 226.0 [M+H] + .

[0925] Example 114

[0926] Synthesis of 6-bromo-5-chloro-7-nitroquinolin-8-ol (114)

[0927] 6-Bromo-5-chloro-7-nitro-8-methoxyquinoline (7c) (1.65 g, 5.21 mmol) and lithium chloride (2.2 g, 52.4 mmol) were added to N,N-dimethylformamide (15.0 mL) at room temperature. The reaction mixture was stirred at 120°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (25.0 mL) was added to the resulting residue, stirred for 5 minutes, and filtered under reduced pressure. The filter cake was washed with water (5.0 mL x 2) and dried under vacuum to give 6-bromo-5-chloro-7-nitroquinolin-8-ol (114) (1.41 g, 89% yield).

[0928] 1 H NMR (400MHz, DMSO-d6) δ: 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.41 (dd, J = 8.6, 1.4 Hz, 1H), 7.68 (dd, J = 8.4, 4.0 Hz, 1H).

[0929] MS calculated: 301.91, 303.91; MS measured: 303.0, 305.0 [M+H] + .

[0930] Example 115

[0931] Synthesis of 5,6-dichloro-7-nitroquinolin-8-ol (115)

[0932] 2-Amino-4,5-dichlorophenol (115a) (5.0 g, 28.1 mmol) was added to hydrochloric acid (6.0 M) (140.0 mL) at room temperature. The reaction mixture was heated to 110°C, and acrolein diethyl acetal (12.0 mL, 73.8 mmol) was slowly added dropwise. The mixture was stirred for 1.5 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 9-10 by slowly adding saturated aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate (200.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to provide 5,6-dichloro-8-hydroxyquinoline (115b) (3.9 g, 65% yield).

[0933] At room temperature, iodomethane (1.35 mL, 21.7 mmol) was slowly added dropwise to a suspension of 5,6-dichloro-8-hydroxyquinoline (115b) (3.9 g, 18.2 mmol) and potassium carbonate (5.03 g, 36.4 mmol) in N,N-dimethylformamide (25.0 mL). The resulting mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to remove the organic solvent. Water (30.0 mL) was added to the resulting residue, which was then extracted with ethyl acetate (30.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to afford 5,6-dichloro-8-methoxyquinoline (115c) (3.5 g, 71% yield).

[0934] At 0°C, nitric acid (65 wt%) (13.0 mL, 197.8 mmol) was slowly added dropwise to a solution of 5,6-dichloro-8-methoxyquinoline (115c) (3.5 g, 15.4 mmol) in acetic anhydride (75.0 mL). The mixture was stirred for 10 minutes, and then sulfuric acid (98 wt%) (2.5 mL, 47.0 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 72 hours. The mixture was then cooled to 0°C, and an aqueous solution of sodium hydroxide (1.0 M) was added to adjust the pH of the aqueous phase to approximately 9-10. The resulting mixture was extracted with dichloromethane (50.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to provide 5,6-dichloro-8-methoxy-7-nitroquinoline (115d) (0.718 g, 17% yield).

[0935] 5,6-Dichloro-8-methoxy-7-nitroquinoline (115d) (0.718 g, 2.64 mmol) and lithium chloride (1.38 g, 32.9 mmol) were added to N,N-dimethylformamide (15.0 mL) at room temperature. The reaction mixture was stirred at 120°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (25.0 mL) was added to the resulting residue, stirred for 5 minutes, and filtered under reduced pressure. The filter cake was washed with water (5.0 mL x 2) and dried under vacuum to give 5,6-dichloro-7-nitroquinolin-8-ol (115) (0.555 g, 81% yield).

[0936] 1 H NMR (400MHz, DMSO-d6) δ: 8.69 (dd, J = 4.2, 1.2 Hz, 1H), 8.40 (dd, J = 8.4, 1.6 Hz, 1H), 7.70 (dd, J = 8.4, 4.4 Hz, 1H).

[0937] MS calculated: 257.96; MS observed: 259.0, 261.0 [M+H] + .

[0938] Example 116

[0939] Synthesis of 7-nitroquinolin-2-deuterium-8-phenol (116)

[0940] 3-Chloroperoxybenzoic acid (85 wt%) (3.6 g, 17.9 mmol) was added portionwise to a solution of 8-methoxyquinoline (116a) (1.9 g, 11.9 mmol) in dichloromethane (40.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours, cooled to 0°C, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide (1.0 M). The organic phase was separated and extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100% / 0-8 / 1) to provide 8-methoxyquinoline-1-oxide (116b) (0.836 g, 40% yield).

[0941] 8-Methoxyquinoline-1-oxide (116b) (0.836 g, 4.77 mmol) was added portionwise to a solution of sodium hydroxide (0.458 mg, 11.45 mmol) in deuterated water (5.0 mL) at room temperature. The resulting mixture was stirred at 100°C for 6 hours, cooled to room temperature, diluted with water (15.0 mL), and extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to provide 8-methoxyquinoline-1-oxide-2-deuterium (116c) (0.80 g, 95% yield).

[0942] Phosphorus tribromide (0.85 mL, 9 mmol) was slowly added dropwise to a solution of 8-methoxyquinoline-1-oxide-2-deuterium (116c) (0.797 g, 4.52 mmol) in N,N-dimethylformamide (10.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, cooled to 0°C, and the pH of the aqueous phase was adjusted to approximately 8-9 by the slow addition of saturated aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (20.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-1 / 1.5) to afford 8-methoxyquinoline-2-deuterium (116d) (0.418 g, 58% yield).

[0943] At 0°C, a 1.0 M solution of boron tribromide in dichloromethane (13.0 mL, 13.0 mmol) was slowly added dropwise to a solution of 8-methoxyquinoline-2-deuterium (116d) (0.418 g, 2.6 mmol) in dichloromethane (3.0 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. A saturated aqueous sodium carbonate solution was then slowly added to adjust the pH of the aqueous phase to approximately 8-9. The resulting mixture was extracted with dichloromethane (10.0 mL x 3), and the combined organic phases were dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to afford 8-hydroxyquinoline-2-deuterium (116e) (0.203 g, 53% yield).

[0944] At room temperature, sodium nitrite (141.0 mg, 2.0 mmol) was added to a solution of 8-hydroxyquinoline-2-deuterium (116e) (100.0 mg, 0.68 mmol) in acetic acid (3.0 mL). The reaction mixture was stirred for 2 hours and filtered under reduced pressure. The filtrate was adjusted to a pH of approximately 9-10 with aqueous ammonia (25-28% by weight, NH3 content) and filtered under reduced pressure. The resulting filter cake was dissolved in methanol (2.0 mL) and separated by reverse-phase high-performance liquid chromatography (HPLC column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0-92% / 8%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to give 7-nitroquinoline-2-deuterium-8-ol (116) (30.0 mg, 23% yield).

[0945] 1 H NMR (400MHz, DMSO-d6) δ: 9.20 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H).

[0946] MS calculated: 191.04; MS found: 192.2 [M+H] + .

[0947] Example 117

[0948] Synthesis of 7-nitroquinolin-6-deuterium-8-phenol (117)

[0949] 4-Bromo-2-methoxyaniline (117a) (1.0 g, 5.0 mmol) was added to hydrochloric acid (6.0 M) (30.0 mL) at room temperature. The reaction mixture was heated to 110°C, and acrolein diethyl acetal (2.44 mL, 15.0 mmol) was slowly added dropwise. The mixture was stirred for 10 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 9-10 by slowly adding saturated aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate (30.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide 6-bromo-8-methoxyquinoline (117b) (0.5 g, 42% yield).

[0950] 6-Bromo-8-methoxyquinoline (117b) (119.0 mg, 0.5 mmol), potassium methoxide (70.0 mg, 1.0 mmol), and hexamethyldisilane (146.0 mg, 1.0 mmol) were added sequentially to deuterated acetonitrile (10.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 hours, concentrated to dryness under reduced pressure, and water (30.0 mL) was added. The resulting mixture was extracted with ethyl acetate (30.0 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide 8-methoxyquinoline-6-deuterium (117c) (60.0 mg, 75% yield).

[0951] At 0°C, a 1.0 M solution of boron tribromide in dichloromethane (3.0 mL, 3.0 mmol) was slowly added dropwise to a solution of 8-methoxyquinoline-6-deuterium (117c) (60.0 mg, 0.38 mmol) in dichloromethane (1.0 mL). The reaction mixture was warmed to room temperature and stirred for 30 minutes. The pH of the aqueous phase was adjusted to approximately 8-9 with saturated sodium bicarbonate aqueous solution. The organic phase was separated and extracted with dichloromethane (10.0 mL x 2). The combined organic phases were dried over anhydrous sulfuric acid, filtered, and concentrated to dryness under reduced pressure to afford crude quinoline-6-deuterium-8-phenol (117d) (51.0 mg, crude yield 93%).

[0952] Sodium nitrite (75.0 mg, 1.1 mmol) was added to a suspension of the crude product of quinolin-6-deuterium-8-ol (117d) (51.0 mg, 0.35 mmol) in acetic acid (1.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 18 hours, and filtered under reduced pressure. The resulting filter cake was added to methanol (1.0 mL), stirred for 10 minutes, and filtered under reduced pressure. The newly collected filter cake was washed with methanol (0.5 mL x 2) and dried under vacuum to give 7-nitroquinolin-6-deuterium-8-ol (117) (34.0 mg, 51% yield).

[0953] 1 H NMR (400MHz, DMSO-d6) δ: 9.44 (dd, J = 8.8, 1.6 Hz, 1H), 8.62 (dd, J = 4.0, 1.6 Hz, 1H), 7.59 (dd, J = 8.6, 4.0 Hz, 1H), 6.29 (s, 1H).

[0954] MS calculated: 191.04; MS found: 192.0 [M+H] + .

[0955] Example 118

[0956] Synthesis of 5-chloro-4-(3,3-difluoropiperidin-1-yl)-7-nitroquinolin-8-ol (118)

[0957] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (150.0 mg, 0.51 mmol) and 3,3-difluoropiperidine hydrochloride (150.0 mg, 0.95 mmol) were added to N,N-dimethylformamide (4.0 mL) at room temperature. The resulting mixture was stirred at 130°C for 5 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-40% / 60%, gradient elution, flow rate 20.0 mL / min) to give 5-chloro-4-(3,3-difluoropiperidin-1-yl)-7-nitroquinolin-8-ol (118) (30.0 mg, 17% yield).

[0958] 1 H NMR(400MHz, DMSO-d6)δ:8.44(d,J=8Hz,1H),7.99(s,1H),7.50(d,J=8Hz,1H),4.13-4.00(m,1H) ,3.94-3.83(m,1H),3.70-3.63(m,2H),2.30-2.10(m,2H),2.06-1.96(m,1H),1.88-1.78(m,1H).

[0959] MS calculated: 343.05; MS observed: 344.0, 346.0 [M+H] + .

[0960] Example 119

[0961] Synthesis of 5-chloro-4-(3-fluoropiperidin-1-yl)-7-nitroquinolin-8-ol (119)

[0962] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (104.0 mg, 0.4 mmol) and 3-fluoropiperidine hydrochloride (112.0 mg, 0.8 mmol) were added to N,N-dimethylformamide (4.0 mL) at room temperature. The resulting mixture was stirred at 130°C for 5 hours, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by reverse-phase high-performance liquid chromatography (Eclipse XDB-C18 column (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-40% / 60%, gradient elution, flow rate 20.0 mL / min) to give 5-chloro-4-(3-fluoropiperidin-1-yl)-7-nitroquinolin-8-ol (119) (26.4 mg, 20% yield).

[0963] 1 H NMR(400MHz, DMSO-d6)δ:8.44(d,J=8.0Hz,1H),7.99(s,1H),7.50(d,J=8.0Hz,1H),4.13-4.00(m,1 H),3.94-3.83(m,1H),3.70-3.63(m,3H),2.30-2.10(m,2H),2.06-1.96(m,1H),1.88-1.78(m,1H).

[0964] MS calculated: 325.06; MS observed: 326.0, 328.0 [M+H] + .

[0965] Example 120

[0966] Synthesis of 5-chloro-7-nitroquinolin-4-deuterated-8-phenol (120)

[0967] Potassium methoxide (177.0 mg, 2.52 mmol) and hexamethyldisilane (369.0 mg, 2.52 mmol) were added sequentially to a solution of 4-bromo-8-methoxyquinoline (11b) (300.0 mg, 1.26 mmol) in deuterated acetonitrile (2.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours, diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-4 / 1) to afford 8-methoxyquinoline-4-deuterium (120a) (125.0 mg, 62% yield).

[0968] At 0°C, a 1.0 M solution of boron tribromide in dichloromethane (4.0 mL, 4.0 mmol) was slowly added dropwise to a solution of 8-methoxyquinolin-4-deuterium (120a) (125.0 mg, 0.78 mmol) in dichloromethane (2.0 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. A saturated aqueous sodium carbonate solution was then slowly added to adjust the pH of the aqueous phase to approximately 8-9. The organic phase was separated and extracted with dichloromethane (10.0 mL x 2). The combined organic phases were dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 100% / 0-30 / 1) to afford quinolin-4-deuterium-8-ol (120b) (100.0 mg, 88% yield).

[0969] At 0°C, N-chlorosuccinimide (86.8 mg, 0.65 mmol) was added portionwise to a solution of quinolin-4-deuterio-8-ol (120b) (100.0 mg, 0.68 mmol) in sulfuric acid (98 wt%) (2.0 mL). The reaction mixture was stirred at 0°C for 0.5 hours, then warmed to room temperature and stirred for 5 hours. It was then cooled to 0°C and the pH of the aqueous phase was adjusted to approximately 8-9 by the slow addition of saturated aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 100% / 0-30 / 1) to give 5-chloroquinolin-4-deuterio-8-ol (120c) (86.0 mg, 70% yield).

[0970] Sodium nitrite (99.0 mg, 1.43 mmol) was added to a solution of 5-chloroquinolin-4-deuterio-8-ol (120c) (86.0 mg, 0.48 mmol) in acetic acid (2.0 mL) at room temperature. The reaction mixture was stirred for 3 hours, filtered under reduced pressure, and the filter cake was washed with ethyl acetate (1.0 mL x 2). The filtrate was allowed to stand at room temperature for 16 hours, during which time a solid precipitated. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (0.5 mL x 2) and dried under vacuum to afford 5-chloro-7-nitroquinolin-4-deuterio-8-ol (120) (24.0 mg, 22% yield).

[0971] 1 H NMR (400MHz, DMSO-d6) δ: 9.13 (d, J = 4.2 Hz, 1H), 8.25 (s, 1H), 7.98 (d, J = 4.2 Hz, 1H).

[0972] MS calculated: 225.01; MS found: 226.0 [M+H] + .

[0973] Example 121

[0974] Synthesis of 5-bromo-7-nitroquinolin-8-ol (121)

[0975] 5-Bromo-2-methoxyaniline (84a) (2.0 g, 9.9 mmol) was added to hydrochloric acid (6.0 M) (40.0 mL) at room temperature. The reaction mixture was heated to 110°C, and acrolein diethyl acetal (4.88 mL, 30 mmol) was slowly added dropwise. The mixture was stirred for 6 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 9-10 by slowly adding saturated aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate (30.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to provide 5-bromo-8-methoxyquinoline (121a) (0.84 g, 36% yield).

[0976] Nitric acid (65 wt%) (1.0 mL, 23.6 mmol) was slowly added dropwise to a solution of 5-bromo-8-methoxyquinoline (121a) (200.0 mg, 0.84 mmol) in acetic anhydride (2.0 mL) at 0°C. The mixture was stirred for 10 minutes, and then sulfuric acid (98 wt%) (0.2 mL, 3.7 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 18 hours. The mixture was then cooled to 0°C, and an aqueous solution of sodium hydroxide (1.0 M) was added to adjust the pH of the aqueous phase to approximately 9-10. The resulting mixture was extracted with dichloromethane (10.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to provide 5-bromo-8-methoxy-7-nitroquinoline (121b) (60.0 mg, 25% yield).

[0977] 5-Bromo-8-methoxy-7-nitroquinoline (121b) (60.0 mg, 0.21 mmol) and lithium chloride (89.0 mg, 2.1 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 120°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 5-bromo-7-nitroquinolin-8-ol (121) (40.0 mg, 71% yield).

[0978] 1H NMR (400MHz, DMSO-d6) δ: 8.69 (d, J = 4.4Hz, 1H), 8.23 ​​(s, 1H), 8.21-8.19 (m, 1H), 7.68 (dd, J = 8.4, 4.4Hz, 1H).

[0979] MS calculated: 267.95; MS observed: 269.0, 271.0 [M+H] + .

[0980] Example 122

[0981] Synthesis of 6-Fluoro-7-nitroquinolin-8-ol (122)

[0982] 2-Methoxy-3-nitro-4-fluoroaniline (122a) (100.0 mg, 0.537 mmol) was added to hydrochloric acid (6.0 M) (10.0 mL) at room temperature. The reaction mixture was heated to 110°C, and acrolein diethyl acetal (0.25 mL, 1.61 mmol) was slowly added dropwise. The mixture was stirred for 2 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7-8 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with dichloromethane (15.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0 to 7 / 1) to provide 6-fluoro-7-nitro-8-methoxyquinoline (122b) (53.0 mg, 45% yield).

[0983] 6-Fluoro-7-nitro-8-methoxyquinoline (122b) (53.0 mg, 0.24 mmol) and lithium chloride (100.0 mg, 2.4 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 130°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 6-fluoro-7-nitroquinolin-8-ol (122) (46.0 mg, 93% yield).

[0984] 1 H NMR (400MHz, DMSO-d6) δ: 9.13 (d, J = 8.7Hz, 1H), 8.58 (d, J = 3.6Hz, 1H), 7.63 (dt, J = 17.0, 8.5Hz, 1H), 6.14 (d, J = 18.0Hz, 1H).

[0985] MS calculated: 208.03; MS found: 209.1 [M+H]+ .

[0986] Example 123

[0987] Synthesis of 6-chloro-5-fluoro-7-nitroquinolin-8-ol (123)

[0988] 2-Nitro-4-fluoro-5-chlorophenol (123a) (1.92 g, 10.0 mmol) was added to a mixture of tetrahydrofuran (60.0 mL) and water (60.0 mL) at room temperature, followed by the addition of sodium dithionite (85 wt%) (12.3 g, 60.0 mmol) in portions. The reaction mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (30.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-3 / 1) to afford 2-amino-4-fluoro-5-chlorophenol (123b) (0.892 g, 55% yield).

[0989] 2-Amino-4-fluoro-5-chlorophenol (123b) (0.892 g, 5.5 mmol), sodium 3-nitrobenzenesulfonate (1.48 g, 6.57 mmol), and glycerol (1.27 g, 13.8 mmol) were added sequentially to sulfuric acid (70 wt%) (8.0 mL) at room temperature. The resulting mixture was stirred at 140°C for 4 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide solution (6.0 M). The resulting mixture was extracted with dichloromethane (20.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-7 / 1) to give 5-fluoro-6-chloroquinolin-8-ol (123c) (0.411 g, 38% yield).

[0990] At room temperature, iodomethane (0.17 mL, 2.73 mmol) was slowly added dropwise to a suspension of 5-fluoro-6-chloroquinolin-8-ol (123c) (0.411 g, 2.1 mmol) and potassium carbonate (0.58 g, 4.2 mmol) in N,N-dimethylformamide (6.0 mL). The resulting mixture was stirred for 16 hours and then concentrated under reduced pressure to remove the organic solvent. Water (30.0 mL) was added to the resulting residue, which was then extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-3 / 1) to afford 5-fluoro-6-chloro-8-methoxyquinoline (123d) (0.412 g, 94% yield).

[0991] Nitric acid (65 wt%) (0.8 mL, 11.7 mmol) was slowly added dropwise to a solution of 5-fluoro-6-chloro-8-methoxyquinoline (123d) (0.412 g, 1.95 mmol) in acetic anhydride (10.0 mL) at 0°C. The mixture was stirred for 10 minutes, and then sulfuric acid (98 wt%) (0.12 mL, 2.25 mmol) was slowly added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was then cooled to 0°C and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with dichloromethane (20.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0-5 / 1) to give 5-fluoro-6-chloro-7-nitro-8-methoxyquinoline (123e) (84.0 mg, yield 17%).

[0992] 5-Fluoro-6-chloro-7-nitro-8-methoxyquinoline (123e) (84.0 mg, 0.39 mmol) and lithium chloride (162.0 mg, 3.9 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 130°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 resulting residue, stirred for 3 minutes, and filtered under reduced pressure. The resulting filter cake was washed with water (0.5 mL x 2) and dried under vacuum to give 5-fluoro-6-chloro-7-nitroquinolin-8-ol (123) (77.0 mg, 82% yield).

[0993] 1H NMR (400MHz, DMSO-d6) δ: 8.69 (d, J = 3.2 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.63 (dt, J = 12.8, 6.4 Hz, 1H).

[0994] MS calculated: 241.99; MS found: 243.1 [M+H] + .

[0995] Example 124

[0996] Synthesis of 6-bromo-5-fluoro-7-nitroquinolin-8-ol (124)

[0997] At room temperature, 4-bromo-5-fluoro-2-methoxyaniline (68a) (0.396 g, 1.8 mmol), sodium 3-nitrobenzenesulfonate (0.486 g, 2.16 mmol), and glycerol (0.33 mL, 4.5 mmol) were added sequentially to sulfuric acid (70 wt%) (2.7 mL). The resulting mixture was stirred at 140°C for 3 hours, cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 8-9 with aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 4 / 1 to 2 / 1) to provide 6-bromo-5-fluoro-8-methoxyquinoline (124a) (0.418 g, 91% yield).

[0998] Nitric acid (65 wt%) (0.58 mL, 9.6 mmol) was slowly added dropwise to a solution of 6-bromo-5-fluoro-8-methoxyquinoline (124a) (0.246 g, 0.96 mmol) in acetic...

Claims

1. Use of a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof in the preparation of an antiviral drug, in: R x Each independently selected, h is each independently 1, 2 or 3; R y is selected from nitro or cyano, k is 1 or 2; The condition is that each R x Not all H atoms.

2. The use according to claim 1, which is the use of the compound represented by general formula (IA), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug in the preparation of an antiviral drug, in: R 11 Selected from H atoms, halogens, D atoms and C 1-6 alkyl; R 12 Selected from H atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 Aryl, -C(O)-OR 16 、-CH2-NR 17 R 18 and -CH2-NR 19 R 110 ; R 13 Selected from H atoms, D atoms, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl, -(CH2) n -3-8 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -NR 17 R 18 、-O-(CH2) n -NR 17 R 18 、-O-(CH2) n -R 111 、-(CH=CH) m C(O)-NR 17 R 18 and -(CH=CH) m C(O)-NR 19 R 110 wherein the 3-8 membered heterocyclic group is optionally further selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, halogenated C 1-6 Alkyl, oxo, -C(O)-NR 17 R 18 、-C(O)-OR 16 、-C(O)-R 16 、-S(O) x R 16 、-O-(CH2) n -R 111 and C 6-14 substituted by one or more substituents in the aryl group; R 14 Selected from H atoms, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, -CH2-NR 17 R 18 and -CH2-NR 19 R 110 ; R 15 Selected from H atoms, D atoms, halogens, C 1-6 Alkyl and -NR 17 R 18 ; R 16 C 1-6 alkyl; R 17 and R 18 Each independently selected from H atoms, C 1-6 Alkyl and 3-8 membered heterocyclic group; R 19 and R 110 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered nitrogen-containing heterocyclic group, wherein the 3-8 membered nitrogen-containing heterocyclic group optionally contains one or more heteroatoms selected from N, O and S in addition to N, and the 3-8 membered nitrogen-containing heterocyclic group is optionally further substituted with one or more oxo groups; R 111 Selected from halogen, C 3-8 Cycloalkyl, C 6-14 Aryl, halogenated C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 alkoxy; m is 1; n is 0, 1, 2 or 3; and x is 2.

3. The use according to claim 2, wherein: R 11 is selected from the group consisting of H atoms, F atoms, -CH3 and D atoms; and / or, R 12 Selected from H atoms, -CH3, and / or, R 13 Selected from H atoms, -CH3, Cl atoms, Br atoms, -OCH3、 F atoms, -OH、 <h2 style=";text-align:left;direction:ltr">-OCH2CH3,-CF3,<h2 style=";text-align:left;direction:ltr"> -CN、 -CHF2、 and D atoms; and / or, R 14 Selected from H atom, I atom, -CH3, Cl atom, -CN, F atom, -CHF2, -CH2OH and Br atoms; and / or, R 15 is selected from the group consisting of H atom, -CH3, F atom, Br atom, Cl atom, D atom and -NHCH3.

4. The use according to claim 2 or 3, wherein the compound of general formula (IA) is selected from:

5. The use according to claim 1, wherein: R 11 is selected from H atoms, halogens, D atoms and C1-C6 alkyl groups; R 12 H atoms, C1-C6 alkyl and C 3-8 Cycloalkyl; R 13 Selected from H atoms, D atoms, C1-C6 alkyl, halogen, C 1-6 Alkoxy, hydroxy, cyano, halogenated C 1-6 Alkyl and C 3-8 Cycloalkyl; R 14 Selected from H atoms, halogen, cyano, halogenated C 1-6 Alkyl and C1-C6 alkyl; R 15 Selected from H atoms, D atoms, halogen, C1-C6 alkyl and -NR 17 R 18 ; R 17 and R 18 Each independently is a H atom or a C 1-6 alkyl.

6. The use according to claim 5, wherein the compound of formula (IA) is selected from:

7. The use according to claim 1 or 5, wherein: R 11 is a H atom; R 12 is a H atom or a C 3-8 Cycloalkyl; R 13 Selected from H atoms, halogenated C 1-6 Alkyl and C 3-8 Cycloalkyl; R 14 is a H atom or a halogen; R 15 Selected from H atoms, halogens and -NR 17 R 18 ; R 17 and R 18 Each independently is a H atom or a C 1-6 alkyl.

8. The use according to any one of claims 2 to 7, wherein the compound of general formula (IA) is selected from: Preferably selected from 9. The use according to claim 1, which is the use of the compound represented by general formula (IB), its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug in the preparation of an antiviral drug. in: R 21 Selected from hydrogen, halogen, cyano, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR a 、-NR a R b 、-OR a and -S(O) p R a ; wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more groups selected from Q; R 22 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a cycloalkyl group; R 23 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group; R 24 Selected from hydrogen atom, halogen, alkyl, -C(O)OR a and -C(O)NR a R b , where R a and R b Each is independently selected from a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-C1-C6 alkyl group; R 25 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group; R a and R b are each independently selected from a hydrogen atom, an alkyl group, and a cycloalkyl group; Q is halogen, alkyl, oxo, -C(O)R c 、-C(O)OR c 、-C(O)NR c R d or -C(O)N(R c )(CH2) q R d ; R c and R d are each independently selected from a hydrogen atom, an alkyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the aryl group, and the heteroaryl group are optionally further substituted with an alkoxy group; Or, R c and R d Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which optionally contains one or more heteroatoms selected from N and O in addition to N; p is 1 or 2; q is an integer from 0 to 6; The condition is that R 21 、R 22 、R 23 、R 24 and R 25 Not all hydrogen atoms.

10. The use according to claim 9, wherein: R 21 The definition of claim 9, wherein the halogen is chlorine or fluorine; and / or, R 21 The definition as described in claim 9, and the alkyl group is a C1-C6 alkyl group; the C1-C6 alkyl group is preferably a C1-C6 alkyl group substituted by halogen, more preferably -CF3, -CHF2 or -CH2F, and even more preferably -CF3; and / or, R 21 The definition of is as described in claim 9, and the alkenyl group is a C2-C6 alkenyl group; preferably, the C2-C6 alkenyl group is an alkenyl group substituted by one or more groups selected from Q, and Q is -C(O)R c 、-C(O)OR c 、-C(O)NR c R d and -C(O)N(R c )(CH2) q R d , R c and R d The definition as claimed in claim 9; More preferably, the C2-C6 alkenyl group is -CH=CH-COOH, and / or, R 21 The definition of claim 9, wherein the cycloalkyl group is C3-C 10 Cycloalkyl, preferably C3-C6 cycloalkyl, more preferably unsubstituted C3-C6 cycloalkyl, further more preferably unsubstituted cyclopropyl, unsubstituted cyclopentyl or unsubstituted cyclohexyl; and / or, R 21 The definition of is as described in claim 9, and the heterocyclic group is a C4-C7 heterocyclic group; preferably, the C4-C7 heterocyclic group is a C4-C7 nitrogen-containing heterocyclic group; more preferably, the C4-C7 heterocyclic group is -NR e R f , and R e and R f Together with the nitrogen atom to which it is connected, a nitrogen-containing heterocyclic group is formed, wherein the nitrogen-containing heterocyclic group 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, wherein Q is a C1-C6 alkyl, an oxo group or a C1-C6 ester group, wherein the C1-C6 alkyl is preferably methyl, and the C1-C6 ester group is preferably -C(O)OCH2CH3; further more preferably, the C4-C7 heterocyclic group is and / or, R 21 The definition of claim 9 is as described, and the aryl group is C6-C 10 Aryl, preferably substituted phenyl; and / or, R 21 The definition of is as described in claim 9, and the heteroaryl is a 5-10 membered heteroaryl, preferably a pyridyl, pyrazolyl, imidazolyl substituted or unsubstituted by a C1-C6 alkyl, more preferably and / or, R 21 The definition of -C(O)OR c In, R g is C1-C6 alkyl; preferably -C(O)OR c is -C(O)OCH2CH3; and / or, R 21 The definition as described in claim 9, and said -NR a R b is -NH2 or -N(CH3)2; and / or, R 21 The definition of -OR is as described in claim 9, and the -OR a is -OCH3; and / or, R 21 The definition of is as described in claim 9, and said -S(O) p R a is -S(O)2CH3; and / or, R 22 The definition of claim 9, wherein the halogen is fluorine or chlorine; and / or, R 22 The definition as claimed in claim 9, wherein the alkyl group is a C1-C6 alkyl group, preferably a methyl group; and / or, R 22 The definition as claimed in claim 9, wherein the cycloalkyl group is a C1-C6 cycloalkyl group, preferably a cyclopropyl group; and / or, R 23 The definition of claim 9, wherein the halogen is fluorine or chlorine; and / or, R 23 The definition as claimed in claim 9, wherein the alkyl group is a C1-C6 alkyl group, preferably a methyl group; and / or, R 24 The definition of claim 9, wherein the halogen is fluorine or chlorine; and / or, R 24 The definition as claimed in claim 9, wherein the alkyl group is a C1-C6 alkyl group, preferably a methyl group; and / or, R 24 The definition of claim 9, wherein -C(O)OR a Medium R a is an alkyl group or a cycloalkyl group, wherein the alkyl group is a C1-C6 alkyl group, preferably an ethyl group; the cycloalkyl group is a C1-C6 cycloalkyl group, preferably a methylcyclopropyl group or a cyclohexyl group; and / or, R 24 The definition of claim 9 is as follows, and the -C(O)NR a R b Medium R a 、R b Each is independently an alkyl group, wherein the alkyl group is a C1-C6 alkyl group, preferably an ethyl group, a methyl group, or an isopropyl group; and / or, R 25 The definition of claim 9, wherein the halogen is fluorine or chlorine; and / or, R 25 The definition as claimed in claim 9, wherein the alkyl group is a C1-C6 alkyl group, preferably a methyl group; The condition is that R 21 、R 22 、R 23 、R 24 and R 25 Not all hydrogen atoms.

11. The use according to claim 9 or 10, wherein the compound of general formula (IB) is selected from:

12. The method according to claim 9, wherein: R 21 Selected from hydrogen atom, halogen, cyano, C1-C6 alkyl, 4-8 membered heterocyclic group, halogenated C1-C6 alkyl, -C(O)OR a and C3-C6 cycloalkyl; R 22 is selected from the group consisting of a hydrogen atom, a halogen and a C1-C6 alkyl group; R 23 is selected from the group consisting of a hydrogen atom, a halogen and a C1-C6 alkyl group; R 24 Selected from hydrogen atom, halogen, C1-C6 alkyl and -C(O)OR a , where R a is selected from a hydrogen atom, a C1-C6 alkyl group and a C3-C6 cycloalkyl group; and R 25 is selected from the group consisting of a hydrogen atom, a halogen and a C1-C6 alkyl group; The condition is that R 21 、R 22 、R 23 、R 24 and R 25 Not all hydrogen atoms.

13. The use according to claim 12, wherein the compound of formula (IB) is selected from:

14. The use according to claim 9 or 12, wherein: R 21 Selected from hydrogen atom, 4-8 membered heterocyclic group, halogenated C1-C6 alkyl, -C(O)OR a and C3-C6 cycloalkyl; R 22 is a hydrogen atom; R 23 is a hydrogen atom; R 24 A hydrogen atom or -C(O)OR a ; R 25 is a hydrogen atom; where R a is a hydrogen atom or a C1-C6 alkyl group.

15. The use according to any one of claims 9 to 14, wherein the compound of formula (IB) is selected from 16. The use according to claim 1, which is a compound represented by general formula (IC), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in: R 31 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 32 Selected from hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy alkyl, cyano, amino, thiol, nitro, carboxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 33 is selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 34 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, amino, thiol, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 35 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; The condition is that R 31 、R 32 、R 33 、R 34 and R 35 Not all hydrogen atoms.

17. The use according to claim 16, wherein R 34 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, halogenated C 1-6 Alkyl, carboxyl and hydroxyl groups, preferably selected from hydrogen atoms, halogen, C 1-6 Alkyl, halogenated C 1-6 The alkyl group and the carboxyl group are more preferably selected from a hydrogen atom, a bromine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a carboxyl group.

18. The use according to claim 16 or 17, wherein R 33 Selected from hydrogen atoms, C 1-6 Alkyl, halogen and hydroxyl, preferably hydrogen atom or C 1-6 The alkyl group is more preferably a hydrogen atom or a methyl group.

19. The use according to any one of claims 16 to 18, wherein the compound of general formula (IC) is selected from: Preferably selected from 20. The use according to any one of claims 1 to 19, wherein the antiviral drug is for use in mammals, preferably humans.

21. The use according to any one of claims 1 to 20, wherein the virus is human papillomavirus; preferably one or more of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) and human papillomavirus 18 (HPV18); more preferably human papillomavirus 6, human papillomavirus 11, human papillomavirus 16 or human papillomavirus 18.

22. The use according to any one of claims 1 to 21, wherein the daily dose of the compound of formula (I) is 0.01 mg to 1000 mg per kilogram of body weight, preferably 0.1 mg to 500 mg per kilogram of body weight.

23. The use according to any one of claims 1 to 22, wherein the medicament further comprises another antiviral agent, preferably, the antiviral agent is selected from acyclovir, valacyclovir, zidovudine, ganciclovir, penciclovir, famciclovir, foscarnet, ribavirin, lamivudine, amantadine, IFNα, cidofovir and rimantadine.

24. The use according to any one of claims 1 to 23, wherein the drug is in the following dosage forms: oral solution, suspension, powder, granule, tablet, capsule, pill, emulsion, syrup or aerosol injection.

25. The method of claim 1, wherein the drug is administered orally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intranasally, intracerebrally, intraventricularly, intrathecally, intravaginally, rectally, by inhalation, or topically.

26. A method for preventing or treating viral infection, comprising the step of administering to a subject a therapeutically effective amount of the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug according to any one of claims 1 to 19.

27. A method for preventing or treating viral infection in mammals, comprising the steps of administering to a subject a therapeutically effective amount of the 8-hydroxyquinoline derivative, a pharmaceutically acceptable salt, a crystalline form, a solvate, an isotopic derivative, or a prodrug thereof according to any one of claims 1 to 19; wherein, The mammal is preferably a human.

28. A method for in vitro disinfection, comprising the following steps: The environment or object to be treated is contacted with an effective amount of the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystal form, its solvate, or its isotopic derivative according to any one of claims 1 to 19.

29. The method according to any one of claims 26 to 28, wherein the virus is human papillomavirus; preferably one or more of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) and human papillomavirus 18 (HPV18); more preferably human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) or human papillomavirus 18 (HPV18).

30. A pharmaceutical composition for treating viral infection, comprising the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug according to any one of claims 1 to 19, and a pharmaceutically acceptable excipient.

31. A pharmaceutical composition for treating viral infection in mammals, comprising the 8-hydroxyquinoline derivative, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivative or its prodrug according to any one of claims 1 to 19, and a pharmaceutically acceptable excipient.

32. The pharmaceutical composition according to claim 30 or 31, wherein the virus is human papillomavirus; preferably one or more of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) and human papillomavirus 18 (HPV18); more preferably human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16) or human papillomavirus 18 (HPV18).

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