Use of 8-hydroxyquinoline derivatives

Abstract

The present invention relates to the use of an 8-hydroxyquinoline derivative 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 particular, the use thereof in the preparation of an anti-human papillomavirus drug. The definitions of each group in general formula (I) are the same as in the specification. JPEG2025537866000239.jpg24170

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to the use of an 8-hydroxyquinoline derivative. In particular, the present invention relates to the use of an 8-hydroxyquinoline derivative of 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 particular an anti-human papillomavirus drug. [Background technology]

[0002] Background of the Invention Human papillomaviruses (HPVs) are DNA viruses belonging to the Papillomaviridae family. They are extremely common worldwide, and their members have a tropism for mucosal and cutaneous epithelia. They can cause various genital tract diseases, such as genital warts, as well as various malignant tumors, including cervical cancer, penile cancer, anal cancer, oral cancer, pharyngeal and laryngeal cancer, tonsillar cancer, and esophageal cancer. There are over 100 types of HPVs, at least 12 of which can cause cancer, making them the most important type of human tumor virus. These viruses have a high infection rate and strong pathogenicity, and are extremely harmful to the population, especially women. They have attracted significant attention from the domestic and international medical communities. Currently, there are clinically available prophylactic multivalent vaccines (e.g., HPV6, HPV11, HPV16, and HPV18) that can prevent infection with multiple types of viruses. However, the use of prophylactic vaccines in infected patients has not shown significant therapeutic benefits. The development of effective drugs that target multiple types of HPV may provide new approaches for the clinical treatment and prevention of human papillomavirus-associated diseases, including malignancies. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2022028321 [Non-patent literature]

[0004] [Non-Patent Document 1] Beadle, J. et al. Synthesis and Antiviral Evaluation of Octadecyloxyethyl Benzyl 9-[(2-Phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG), a Potent Inhibitor of Transient HPV DNA Amplification. J Med Chem. 2016; 59 (23): 10470-8. [Non-patent document 2] Kachaeva, M. et al. In vitro activity of novel 1,3-oxazole derivatives against HPV. Ibnosina J Med Biomed Sci. 2017; 9 (4): 111-8. [Non-patent document 3] Fiedler, H. (1960).Synthese von Methyl-8-hydroxy-chinolin-aldehyden.Archiv Der Pharmazie, 293(6), 609-621.Doi:10.1002 / ardp.19602930606 Summary of the Invention

[0005] SUMMARY OF THE INVENTION The present invention relates to the use of a compound of 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 medicament, in particular an anti-human papillomavirus (HPV) medicament.

[0006] The present invention solves the above technical problems through the following technical solutions: Use of a compound of 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 medicament is provided.

[0007] [ka]

[0008] (In the formula, R x are each independently optional, and h is each independently 1, 2, or 3; R y is selected from the group consisting of nitro and cyano, and k is 1 or 2; However, all R x but not H atoms at the same time).

[0009] In one embodiment, there is provided the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, wherein the compound is of formula (IA), 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 medicament.

[0010] [ka]

[0011] (In the formula, R 11 is H atom, halogen, D atom and C 1~6 selected from the group consisting of alkyl; R 12 is a H atom, 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 selected from the group consisting of: R 13 is H atom, D atom, C 1~6 Alkyl, halogen, C 1~6 Alkoxy, hydroxy, haloC 1~6Alkyl, HaloC 1~6 Alkoxy, Cyano, C 3~8 Cycloalkyl, -(CH2) n -3 to 8-membered heterocyclyl, 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 and the 3- to 8-membered heterocyclyl is optionally selected from the group consisting of C 1~6 Alkyl, C 1~6 Alkoxy, halogen, haloC 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 is further substituted by one or more substituents selected from the group consisting of aryl; R 14 is an H atom, halogen, cyano, C 1~6 Alkyl, C 3~8 Cycloalkyl, HaloC 1~6 Alkyl, Hydroxy C 1~6 Alkyl, -CH2-NR 17 R 18 and -CH2-NR 19 R 110 selected from the group consisting of: R 15 is H atom, D atom, halogen, C 1~6 Alkyl and -NR 17 R 18 selected from the group consisting of: R 16 is C1~6 is alkyl; R 17 and R 18 is a H atom, C 1~6 are independently selected from the group consisting of alkyl and 3- to 8-membered heterocyclyl; R 19 and R 110 together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclyl, which optionally contains, in addition to N, one or more heteroatoms selected from the group consisting of N, O and S, and which 3- to 8-membered nitrogen-containing heterocyclyl is optionally further substituted by one or more oxo groups; R 111 is a halogen, C 3~8 Cycloalkyl, C6 ~14 Aryl, HaloC 1~6 Alkyl, C 1~6 Alkyl and C 1~6 selected from the group consisting of alkoxy; m is 1; n is 0, 1, 2 or 3; x is 2).

[0012] In one embodiment, in a compound of formula (IA), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof: R 11 is selected from the group consisting of H atoms, F atoms, —CH3 and D atoms; and / or R 12 But H atom, -CH3,

[0013] [ka]

[0014] selected from the group consisting of: and / or R 13 But H atom, -CH3,

[0015] [ka]

[0016] Cl atoms

[0017]

change

[0018] Br atom

[0019]

change

[0020] OCH3

[0021]

change

[0022] ,F atom,

[0023]

change

[0024] -OH

[0025]

change

[0026] -OCH2CH3, -CF3,

[0027]

change

[0028] -CHF2

[0029]

change

[0030] and D atoms; and / or R 14 are H atoms, I atoms, -CH3, Cl atoms, -CN, F atoms,

[0031] [ka]

[0032] , —CHF2, —CH2OH and Br atoms; and / or R 15 is selected from the group consisting of an H atom, —CH3, an F atom, a Br atom, a Cl atom, a D atom, and —NHCH3.

[0033] In one embodiment, in the compound of formula (IA), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, the compound of formula (IA) is:

[0034] [ka]

[0035] [ka]

[0036] [ka]

[0037] [ka]

[0038] [ka]

[0039] [ka]

[0040] is selected from the group consisting of:

[0041] In one embodiment, in a compound of formula (IA), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof: R 11 is selected from the group consisting of H atoms, halogens, D atoms, and C1-C6 alkyl; R 12 is a H atom, a C1-C6 alkyl, or C 3~8 is cycloalkyl; R 13 H atom, D atom, C1-C6 alkyl, halogen, C 1~6 Alkoxy, hydroxy, cyano, haloC 1~6 Alkyl and C 3~8 cycloalkyl; R 14 H atoms, halogens, cyano, haloC 1~6 selected from the group consisting of alkyl and C1-C6 alkyl; R 15 is H atom, D atom, halogen, C1-C6 alkyl and -NR 17 R 18 selected from the group consisting of: R 17 and R 18 are each independently a H atom or C 1~6 It is alkyl.

[0042] In one embodiment, in the compound of formula (IA), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, the compound of formula (IA) is:

[0043] [ka]

[0044] [ka]

[0045] is selected from the group consisting of:

[0046] In one embodiment, in a compound of formula (IA), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof: R 11 is an H atom; R 12 is H atom or C 3~8 is cycloalkyl; R 13 But H atom, halo C 1~6 Alkyl and C 3~8 cycloalkyl; R 14 is a H atom or a halogen; R 15 H atoms, halogens and -NR 17 R 18 selected from the group consisting of: R 17 and R 18 are each independently a H atom or C 1~6 It is alkyl.

[0047] In one embodiment, in the compound of formula (IA), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, the compound of formula (IA) is:

[0048] [ka]

[0049] Preferably, the compound is selected from the group consisting of:

[0050] [ka]

[0051] is selected from the group consisting of:

[0052] In another embodiment, there is provided the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, wherein the compound is of formula (IB), 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 medicament.

[0053] [ka]

[0054] (In the formula, R 21 represents a hydrogen atom, halogen, cyano, alkyl, alkenyl, cycloalkyl, heterocyclyl, 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 are each optionally further substituted with one or more groups selected from Q; R 22 is selected from the group consisting of a hydrogen atom, halogen, alkyl, and cycloalkyl; R 23 is selected from the group consisting of a hydrogen atom, halogen, and alkyl; R 24 represents a hydrogen atom, halogen, alkyl, -C(O)OR a and -C(O)NR a R b and R a and R b are each independently selected from the group consisting of a hydrogen atom, a C1-C6 alkyl, a C3-C6 cycloalkyl, and a C3-C6 cycloalkyl-C1-C6 alkyl; R 25 is selected from the group consisting of a hydrogen atom, halogen, and alkyl; Ra and R b are each independently selected from the group consisting of a hydrogen atom, alkyl, and cycloalkyl; 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 and; R c and R d are each independently selected from the group consisting of a hydrogen atom, alkyl, aryl, and heteroaryl, each of which is optionally further substituted with alkoxy; Or R c and R d together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl, which optionally contains, in addition to N, one or more heteroatoms selected from the group consisting of N and O; p is 1 or 2; q is an integer from 0 to 6; However, R 21 , R 22 , R 23 , R 24 and R 25 is not a hydrogen atom at the same time).

[0055] In another embodiment, in a compound of formula (IB), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof: R 21 is as defined above, and halogen is chlorine or fluorine; and / or R 21 is as defined above, wherein alkyl is C1-C6 alkyl; C1-C6 alkyl is preferably C1-C6 alkyl substituted by halogen, more preferably -CF3, -CHF2 or -CH2F, even more preferably -CF3; and / or R21 is as defined above, and alkenyl is C2-C6 alkenyl; preferably, C2-C6 alkenyl is alkenyl 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 or -C(O)N(R c )(CH2) q R d and R c and R d is as defined above; more preferably, C2-C6 alkenyl is -CH=CH-COOH,

[0056] [ka]

[0057] and; and / or R 21 is as defined above, and cycloalkyl is C3 to C 10 cycloalkyl, preferably C3-C6 cycloalkyl, more preferably unsubstituted C3-C6 cycloalkyl, even more preferably unsubstituted cyclopropyl, unsubstituted cyclopentyl or unsubstituted cyclohexyl; and / or R 21 is as defined above, and heterocyclyl is C4-C7 heterocyclyl; preferably, C4-C7 heterocyclyl is nitrogen-containing C4-C7 heterocyclyl; more preferably, C4-C7 heterocyclyl is -NR e R f and R e and R ftogether with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl, which optionally contains, in addition to N, one or more heteroatoms selected from the group consisting of N and O, and which nitrogen-containing heterocyclyl is optionally further substituted by one or more groups selected from Q, where Q is C1-C6 alkyl, oxo or C1-C6 alkoxycarbonyl, wherein C1-C6 alkyl is preferably methyl and C1-C6 alkoxycarbonyl is preferably —C(O)OCH2CH3; even more preferably, C4-C7 heterocyclyl is

[0058] [ka]

[0059] and; and / or R 21 is as defined above, and aryl is C6-C 10 aryl, preferably unsubstituted phenyl; and / or R 21 is as defined above, and heteroaryl is a 5-10 membered heteroaryl, preferably pyridyl, pyrazolyl or imidazolyl unsubstituted or substituted by C1-C6 alkyl, more preferably

[0060] [ka]

[0061] and; and / or R 21 is as defined above, -C(O)OR c Medium, R g is C1-C6 alkyl; preferably —C(O)OR c is -C(O)OCH2CH3; and / or R 21 is as defined above, and -NR a R b is -NH2 or -N(CH3)2; and / or R 21 is as defined above, -OR a is -OCH3; and / or R 21 is as defined above, -S(O) p R a is -S(O)2CH3; and / or R 22 is as defined above, and halogen is fluorine or chlorine; and / or R 22 is as defined above, and alkyl is C1-C6 alkyl, preferably methyl; and / or R 22 is as defined above, and cycloalkyl is C1-C6 cycloalkyl, preferably cyclopropyl; and / or R 23 is as defined above, and halogen is fluorine or chlorine; and / or R 23 is as defined above, and alkyl is C1-C6 alkyl, preferably methyl; and / or R 24 is as defined above, and halogen is fluorine or chlorine; and / or R 24 is as defined above, and alkyl is C1-C6 alkyl, preferably methyl; and / or R 24 is as defined above, -C(O)OR a R a is alkyl or cycloalkyl, where alkyl is C1-C6 alkyl, preferably ethyl; cycloalkyl is C1-C6 cycloalkyl, preferably methylcyclopropyl or cyclohexyl; and / or R 24 is as defined above, and —C(O)NR a R b R a and R bare each independently alkyl, and the alkyl is C1 to C6 alkyl, preferably ethyl, methyl, or isopropyl; and / or R 25 is as defined above, and halogen is fluorine or chlorine; and / or R 25 is as defined above, and alkyl is C1-C6 alkyl, preferably methyl; However, R 21 , R 22 , R 23 , R 24 and R 25 But at the same time, it is not a hydrogen atom.

[0062] In another embodiment, in the compound of formula (IB), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, the compound of formula (IB) is:

[0063] [ka]

[0064] [ka]

[0065] is selected from the group consisting of:

[0066] In another embodiment, in a compound of formula (IB), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof: R 21 is a hydrogen atom, halogen, cyano, C1-C6 alkyl, 4-8 membered heterocyclyl, haloC1-C6 alkyl, -C(O)OR a and C3-C6 cycloalkyl; R 22 is selected from the group consisting of a hydrogen atom, halogen, and C1-C6 alkyl; R 23is selected from the group consisting of a hydrogen atom, halogen, and C1-C6 alkyl; R 24 is a hydrogen atom, halogen, C1-C6 alkyl, and -C(O)OR a and R a is selected from the group consisting of a hydrogen atom, C1-C6 alkyl, and C3-C6 cycloalkyl; R 25 is selected from the group consisting of a hydrogen atom, halogen, and C1-C6 alkyl; However, R 21 , R 22 , R 23 , R 24 and R 25 But at the same time, it is not a hydrogen atom.

[0067] In another embodiment, in the compound of formula (IB), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, the compound of formula (IB) is:

[0068] [ka]

[0069] is selected from the group consisting of:

[0070] In another embodiment, in a compound of formula (IB), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof: R 21 is a hydrogen atom, 4-8 membered heterocyclyl, haloC1-C6 alkyl, -C(O)OR a and C3-C6 cycloalkyl; R 22 is a hydrogen atom; R 23 is a hydrogen atom; R 24 is a hydrogen atom or -C(O)OR a and; R 25 is a hydrogen atom; Ra is a hydrogen atom or a C1-C6 alkyl.

[0071] In another embodiment, in the compound of formula (IB), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, the compound of formula (IB) is:

[0072] [ka]

[0073] is selected from the group consisting of:

[0074] In another embodiment, the compound of formula (I), a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof is a compound of formula (IC), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0075] [ka]

[0076] (In the formula, R 31 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 32 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 33is selected from the group consisting of a hydrogen atom, alkyl, halogen, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 34 is selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, carboxy, hydroxy, 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, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; However, R 31 , R 32 , R 33 , R 34 and R 35 is not a hydrogen atom at the same time).

[0077] In another embodiment, in the compound of formula (IC), its stereoisomer, or its pharmaceutically acceptable salt, R 34 is a hydrogen atom, halogen, C1-6 alkyl, haloC 1~6 is selected from the group consisting of alkyl, carboxy and hydroxy, and is preferably a hydrogen atom, a halogen, C 1~6 Alkyl, HaloC 1~6 It is selected from the group consisting of alkyl and carboxy, and more preferably selected from the group consisting of hydrogen atom, bromine atom, chlorine atom, methyl, trifluoromethyl and carboxy.

[0078] In another embodiment, in the compound of formula (IC), its stereoisomer, or its pharmaceutically acceptable salt, R 33 is a hydrogen atom, C 1~6 Alkyl, halogen and hydroxy, preferably a hydrogen atom or C 1~6It is more preferably selected from the group consisting of alkyl, hydrogen or methyl.

[0079] In another embodiment, in the compound of formula (IC), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (IC) is

[0080] [ka]

[0081] and preferably selected from the group consisting of:

[0082] [ka]

[0083] is selected from the group consisting of:

[0084] In another embodiment, there is provided the use of a compound of 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 medicament, wherein the antiviral medicament is for use in a mammal, preferably a human.

[0085] In another embodiment, there is provided use of a compound of 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 medicament, wherein the virus is a 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.

[0086] In another embodiment, there is provided use of a compound of 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 medicament, 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.

[0087] In another embodiment, there is provided use of a compound of 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 medicament, wherein the medicament further comprises another antiviral agent, preferably the antiviral agent is selected from the group consisting of acyclovir, valacyclovir, zidovudine, ganciclovir, penciclovir, famciclovir, foscarnet, ribavirin, lamivudine, amantadine, IFNα, cidofovir, and rimantadine.

[0088] In another embodiment, there is provided the use of a compound of 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 medicament, wherein the medicament is in the following dosage form: oral liquid, suspension, powder, granules, tablet, capsule, pill, emulsion, syrup, aerosol, or injection.

[0089] In another embodiment, there is provided the use of a compound of 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 medicament, wherein the medicament is administered via oral, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, sublingual, intranasal, intracerebral, intraventricular, intrathecal, intravaginal, rectal, inhalable or topical route.

[0090] In another embodiment, the present invention further provides a method of preventing or treating a viral infection, comprising the step of administering to a subject a therapeutically effective amount of an 8-hydroxyquinoline derivative, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof as defined in the preceding use.

[0091] In another embodiment, there is provided a method for preventing or treating a viral infection in a mammal, comprising the step of administering to a subject a therapeutically effective amount of an 8-hydroxyquinoline derivative, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof as defined in the preceding use, wherein the mammal is preferably a human.

[0092] In another embodiment, the present invention provides a method for in vitro disinfection, comprising: contacting the environment or object to be treated with an effective amount of an 8-hydroxyquinoline derivative, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, or an isotopic derivative thereof, as defined in the preceding use; Further provided is a method comprising:

[0093] In another embodiment, in the method for preventing or treating a viral infection in a mammal, or in a method for in vitro disinfection, the virus is a 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).

[0094] In another embodiment, the present invention further provides a pharmaceutical composition for treating a viral infection, comprising an 8-hydroxyquinoline derivative as defined in the preceding use, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.

[0095] In another embodiment, there is provided a pharmaceutical composition for treating a viral infection in a mammal, comprising an 8-hydroxyquinoline derivative as defined in the preceding use, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.

[0096] In another embodiment, in the pharmaceutical composition for treating a viral infection in a mammal, the virus is a 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).

[0097] The pharmaceutical compositions of the present invention can be in various conventional dosage forms, such as tablets, aqueous suspensions, oily 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.

[0098] It is well known to those skilled in the art that the dosage of a drug depends on various factors, including, but not limited to, the activity of the specific compound, the patient's age, the patient's weight, the patient's overall health, the patient's behavior, the patient's diet, the administration time, the administration route, the excretion rate, drug combinations, etc. Furthermore, the optimal treatment, e.g., the treatment mode, the daily dose of the compound or the type of its pharmaceutically acceptable salt, can be verified according to traditional treatment regimens.

[0099] Definition of Terms For terms not defined herein, these terms have the meanings commonly understood by one of ordinary skill in the art. For terms defined herein, these terms have the meanings defined in the specification.

[0100] The term "substituted" or "substituent" refers to the replacement of one or more hydrogen atoms with the indicated group. If the substitution position is not indicated, the substitution may occur at any position that allows for the formation of a stable or chemically feasible chemical compound.

[0101] The term "optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur; such description includes cases where the event or circumstance occurs or cases where the event or circumstance does not occur.

[0102] When any variable (e.g., R) occurs more than one time in the structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted with 0 to 2 R, the group may optionally be substituted with up to 2 R, and R has an independent option at each occurrence.

[0103] 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. 1~10 Alkyl, more preferably C 1~6Examples of alkyl 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-dimethyl Examples of alkyl ethers include ethylpentyl, 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.

[0104] 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, which can be located anywhere within the alkenyl. Alkenyl is preferably C 2~5 Examples of alkenyl 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.

[0105] 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, which can be located anywhere within the alkynyl. Alkynyl is preferably C 2~5Examples of alkynyl include, but are not limited to, -C≡CH, -C≡C-CH, -CH-C≡CH, -C≡C-CH-CH, -CH-CH-C≡CH, -CH(CH)C≡CH, and -CH-C≡C-CH.

[0106] The term "cycloalkyl" encompasses two categories, one is conventional cycloalkyl and the other is heterostructured cycloalkyl.

[0107] 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. Conventional cycloalkyl is 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. Conventional cycloalkyl optionally contains one or more double or triple bonds.

[0108] A conventional cycloalkyl can be a monocyclic cycloalkyl. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. A conventional cycloalkyl can also be a polycyclic cycloalkyl (e.g., bicycloalkyl and tricycloalkyl). Polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0109] The term "spirocycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) spirocycloalkyl. The spirocycloalkyl is preferably a 6- to 14-membered spirocycloalkyl, more preferably a 7- to 10-membered spirocycloalkyl. The spirocycloalkyl can be a monospirocycloalkyl, a dispirocycloalkyl, or a polyspirocycloalkyl, and the spirocycloalkyl is 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 spirocycloalkyls include, but are not limited to,

[0110] [ka]

[0111] Examples include:

[0112] The term "fused cycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) fused cycloalkyl. The fused cycloalkyl is preferably a 6- to 14-membered fused cycloalkyl, more preferably a 7- to 10-membered fused cycloalkyl. The fused cycloalkyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic, or higher fused cycloalkyl, and the fused cycloalkyl is preferably a bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered fused cycloalkyl. Examples of fused cycloalkyl include, but are not limited to,

[0113] [ka]

[0114] Examples include:

[0115] The term "bridged cycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) bridged cycloalkyl. The bridged cycloalkyl is preferably a 6- to 14-membered bridged cycloalkyl, more preferably a 7- to 10-membered bridged cycloalkyl. The bridged cycloalkyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic or higher bridged cycloalkyl, and the bridged cycloalkyl is preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Examples of bridged cycloalkyls include, but are not limited to:

[0116] [ka]

[0117] Examples include:

[0118] The term "heterostructured cycloalkyl" includes monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls fused to any one selected from the group consisting of conventional aryls, conventional heteroaryls, and conventional heterocyclyls, where the point of attachment is on the corresponding conventional cycloalkyl (referring to monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkyls, or bridged cycloalkyls). Examples of heterostructured cycloalkyls include, but are not limited to:

[0119] [ka]

[0120] Examples include:

[0121] The term "heterocyclyl" encompasses two categories, one being conventional heterocyclyl and the other being heterostructured heterocyclyl.

[0122] Conventional heterocyclyl 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) ring atoms in which one or more ring atoms are replaced by one or more members selected from the group consisting of N, O, S, S(O), and S(O)2, and in which the replacement does not form -OO-, -OS-, or -SS-. Conventional heterocyclyl is preferably a C1-C1 ring in which one to four (e.g., one, two, three, and four) atoms are heteroatoms. 3~12 Conventional heterocyclyl; more preferably C in which 1 to 3 (e.g., 1, 2, and 3) atoms are heteroatoms 3~8 Conventional heterocyclyl; most preferably C in which 1-2 or 1-3 atoms are heteroatoms 5~7 It is a conventional heterocyclyl.

[0123] A conventional heterocyclyl may be a monocyclic heterocyclyl. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, preferably 1,2,5-oxadiazolyl, pyranyl, or morpholinyl. A conventional heterocyclyl may also be a polycyclic heterocyclyl. Polycyclic heterocyclyls include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl.

[0124] The term "spiroheterocyclyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) spiroheterocyclyl. The spiroheterocyclyl is preferably a 6- to 14-membered spiroheterocyclyl, more preferably a 7- to 10-membered spiroheterocyclyl. The spiroheterocyclyl can be a monospiroheterocyclyl, a dispiroheterocyclyl, or a polyspiroheterocyclyl, and the spiroheterocyclyl is preferably a monospiroheterocyclyl or a dispiroheterocyclyl, 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 spiroheterocyclyl include, but are not limited to,

[0125] [ka]

[0126] Examples include:

[0127] The term "fused heterocyclyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) fused heterocyclyl. The fused heterocyclyl is preferably a 6- to 14-membered fused heterocyclyl, more preferably a 7- to 10-membered fused heterocyclyl. The fused heterocyclyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic or higher fused heterocyclyl, and the fused heterocyclyl is preferably a bicyclic or tricyclic fused heterocyclyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Examples of fused heterocyclyls include, but are not limited to,

[0128] [ka]

[0129] Examples include:

[0130] The term "bridged heterocyclyl" refers to a 5- to 14-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) bridged heterocyclyl. The bridged heterocyclyl is preferably a 6- to 14-membered bridged heterocyclyl, more preferably a 7- to 10-membered bridged heterocyclyl. The bridged heterocyclyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic or higher bridged heterocyclyl, and the bridged heterocyclyl is preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Examples of bridged heterocyclyls include, but are not limited to:

[0131] [ka]

[0132] Examples include:

[0133] The term "heterostructured heterocyclyl" includes monocyclic heterocyclyl, spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl fused to any one selected from the group consisting of conventional aryl, conventional heteroaryl, and conventional cycloalkyl, where the point of attachment is on the corresponding conventional heterocyclyl (referring to monocyclic heterocyclyl, spiroheterocyclyl, fused heterocyclyl, or bridged heterocyclyl). Examples of heterostructured heterocyclyl include, but are not limited to:

[0134] [ka]

[0135] Examples include:

[0136] The term "aryl" encompasses two categories, one is conventional aryl and the other is heterostructured aryl.

[0137] Conventional aryl refers to a 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) aromatic hydrocarbon group. Conventional aryl is preferably C 6~10 Conventional aryl is more preferably phenyl, naphthyl, phenanthryl or anthracenyl.

[0138] The term "heterostructured aryl" includes a conventional aryl fused to any one selected from the group consisting of a conventional heteroaryl, a conventional heterocyclyl, and a conventional cycloalkyl, where the point of attachment is on the conventional aryl. Examples of heterostructured aryls include, but are not limited to:

[0139] [ka]

[0140] Examples include:

[0141] The term "heteroaryl" encompasses two categories: conventional heteroaryl and heterostructured heteroaryl.

[0142] Conventional heteroaryl refers to a 5- to 14-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) aromatic hydrocarbon group in which 1 to 4 (e.g., 1, 2, 3, and 4) carbon atoms are replaced by heteroatoms, the heteroatoms being selected from the group consisting of O, S, and N. Preferably, the number of ring atoms is 5 to 10, including 1 to 3 (e.g., 1, 2, and 3) heteroatoms. More preferably, the number of ring atoms is 5 or 6, including 1 to 2 heteroatoms. Examples of conventional heteroaryl include, but are not limited to, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, and pyrazinyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl or thiazolyl.

[0143] The term "heterostructured heteroaryl" includes a conventional heteroaryl fused to any one selected from the group consisting of a conventional aryl, a conventional cycloalkyl, and a conventional heterocyclyl, where the point of attachment is on the conventional heteroaryl. Examples of heterostructured heteroaryls include, but are not limited to:

[0144] [ka]

[0145] Examples include:

[0146] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, where "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.

[0147] The term "haloalkyl" refers to an alkyl substituted with one or more halogens, where alkyl is as defined above.

[0148] The term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, where alkoxy is as defined above.

[0149] The term "hydroxy" refers to the group --OH.

[0150] The term "halogen" refers to a -F, -Cl, -Br or -I group.

[0151] The term "amino" refers to the group --NH.sub.2.

[0152] The term "cyano" refers to the group --CN.

[0153] The term "nitro" refers to the group --NO.sub.2.

[0154] The term "oxo" refers to the group =O.

[0155] The term "carboxy" refers to the group -C(=O)OH.

[0156] The term "thiol" refers to a -SH group.

[0157] The term "alkoxycarbonyl" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0158] The term "acyl" refers to the group -C(=O)R, where R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0159] symbol

[0160] [ka]

[0161] indicates the attachment point.

[0162] The term "pharmaceutically acceptable" refers to substances that are generally safe, non-toxic, biologically satisfactory, and usable in the preparation of pharmaceutical compositions that can be pharmaceutically accepted by mammals, e.g., humans.

[0163] The term "pharmaceutically acceptable salts" should be understood to refer to the following salts that are pharmaceutically acceptable and that possess the expected pharmacological activity of the parent compound (referring to compounds of the formula). Such salts include: (1) acid addition salts formed with inorganic acids or acid addition salts formed with organic acids; wherein the inorganic acid can be one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; and wherein the organic acid can 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 protons present in the parent compound are metal ions, e.g., alkali metal ions (e.g., Na + , K. + Or Li + ), alkaline earth metal ions (e.g., Ca 2+ or Mg 2+ ) or aluminum ion; or salts formed when coordinated with an organic or inorganic base; wherein the organic base can be one or more of pyridine, imidazole, pyrazine, indole, purine, tertiary amine, and aniline, preferably one or more of pyridine, methylpyridine, 4-dimethylaminopyridine, 2-methyl-5-ethylpyridine, triethylamine, N,N-diisopropylethanamine, N,N-dimethylaniline, diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, and tromethamine; and the inorganic base can be one or more of aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Includes:

[0164] The term "isotopic derivative" refers to a compound that differs from a parent compound described herein only in the presence of one or more isotopically enriched atoms. For example, an isotopic derivative can be one in which hydrogen has been replaced by "deuterium" or "tritium" and / or fluorine has been replaced by18 and / or carbon is replaced by F 11 C. 13 C or 14 The isotopic derivative has a structure shown by the formula: wherein R is replaced by C, while the remainder remains unchanged. Isotopic derivatives can be used as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds often retain activity comparable to that of non-deuterated compounds, and when deuterated at certain sites, can achieve greater metabolic stability, resulting in certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements). Therefore, isotopic derivatives are preferably deuterated compounds.

[0165] The term "solvate" refers to a substance formed from a parent compound described herein and a suitable solvent, preferably water or an organic solvent.

[0166] The term "prodrug" refers to a derivative of a parent compound described herein that contains a biologically reactive functional group, such that the biologically reactive functional group can be cleaved from the derivative or otherwise reacted under biological conditions (in vitro or in vivo) to provide the parent compound described herein. Typically, prodrugs are inactive, or at least less active than the parent compound itself, such that the parent compound described herein cannot exert its activity until separated from the biologically reactive functional group. The biologically reactive functional group can be hydrolyzed or oxidized under biological conditions to provide the parent compound described herein. For example, a prodrug can contain a biologically hydrolyzable functional group; examples of biologically hydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureidos.

[0167] The term "pharmaceutical composition" refers to a mixture of a pharmaceutical compound (which refers to one or more of the compounds of the formulae, including those described herein, pharmaceutically acceptable salts thereof, tautomers thereof, stereoisomers thereof, enantiomers thereof, diastereoisomers thereof, isotopic derivatives thereof, crystalline forms thereof, solvates thereof, prodrugs thereof, metabolites thereof, and racemates thereof) and a pharmaceutically acceptable excipient.

[0168] The term "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable excipient used to deliver the pharmaceutical compounds described herein to a subject. Depending on the method of administration, the pharmaceutical composition may contain 0.1% to 99% by weight of the pharmaceutical compound.

[0169] The term "subject" refers to a mammal, including, for example, a camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, rabbit, guinea pig, mouse, or primate. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human susceptible to, suspected of having, or suffering from cancer or a bacterial infection.

[0170] The term "treatment" refers to eliminating the disease, preventing 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 prolonging the survival of a subject with the disease.

[0171] The term "effective amount" refers to the amount of the active ingredient (referring to a pharmaceutical compound) of a drug that induces a desired effect in a subject. In certain embodiments, the selection of an effective amount can be determined by one of ordinary skill in the art (e.g., through clinical trials) based on consideration of various factors, including the disease being 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 of ordinary skill in the art. The effective amount can be obtained from dose-response curves derived from animal model test systems and can be determined according to the physician's opinion and each patient's circumstances. The correlation between animal dosage and human dosage 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.

[0172] As used 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 multiple smaller doses administered at certain time intervals. It should be understood that the exact dose, 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. Administration can include a single administration, or two or more administrations at appropriate time intervals. Here, the time interval between two adjacent administrations can 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, 1.5 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.

[0173] Each active pharmaceutical ingredient (each pharmaceutical compound) referred to 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) so long as these compounds do not cause other adverse effects, such as allergic reactions. Co-administration includes simultaneous or sequential administration of each active compound.

[0174] The term "co-administration" refers to a method of providing two or more active compounds to a subject for therapeutic purposes, either simultaneously or sequentially. When "co-administration" is involved, the time interval between each administration is sufficient to achieve a synergistic effect between each active compound administered.

[0175] When the term "about" is applied to a parameter, such as mass, volume, pH, concentration, temperature, etc., it is intended that the parameter may vary by ±10%, sometimes more preferably within ±5%. Those of skill in the art will recognize that when the parameter is not critical, the number is generally given for illustrative purposes only and not for purposes of limitation. DETAILED DESCRIPTION OF THE INVENTION

[0176] Detailed Description of the Invention The present invention will be further described through the following examples, but is not intended to limit the scope of the present invention. In the following examples, experimental methods without specific conditions are selected according to conventional methods and conditions or according to product instructions.

[0177] The compounds of the present invention are prepared by using conventional starting materials and general preparation procedures. The present invention provides typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can be adopted. Although optimal conditions may vary depending on the use of specific reactants or solvents, the optimized steps and conditions for the reaction can be determined under normal circumstances.

[0178] Additionally, certain protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Suitable protecting groups for various functional groups and the conditions for their protection or deprotection are well known to those skilled in the art. For example, "Protective Groups in Organic Synthesis" by TW Greene and GM Wuts (3rd ed., Wiley, New York, 1999) and citations therein provide detailed descriptions of the protection or deprotection of numerous protecting groups.

[0179] The isolation and purification of compounds and intermediates are carried out by suitable methods and procedures according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. The specific methods used can be referred to in the examples described in the present invention. Of course, other similar isolation and purification methods can also be used. They can be characterized using conventional methods (including physical constants and spectral data).

[0180] The purity analysis method is as follows: a Kinetex EVO C18 (50 × 4.6 mm, 5 μm, 100 Å) chromatography column is used, acetonitrile-water is used as the mobile phase for gradient elution, the flow rate is 1.5 mL / min, and the detection wavelength is 220 nm.

[0181] MS was determined by LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (photodiode array detector).

[0182] The structure of the compound is identified by hydrogen nuclear magnetic resonance, and the instrument model is WNMR-I-400MHz.

[0183] Preparative liquid chromatography is performed on an Agilent 1260 Infinity II high performance liquid chromatograph (manufacturer: Agilent). The chromatography column is Daisogel C18 10 μm 100A (30 mm × 250 mm), and the mobile phase is acetonitrile / water.

[0184] Qingdao Haiyang Chemical Company's GF254 silica gel plates were used for thin-layer chromatography (TLC). The specifications for the silica gel plates used were 0.20 mm to 0.25 mm for reaction monitoring and 0.5 mm for separation and purification.

[0185] Silica gel of 100-200 mesh, 200-300 mesh or 300-400 mesh from Qingdao Haiyang Chemical Company is used as a carrier for silica gel column chromatography.

[0186] The known starting materials of the present invention can be prepared by methods known in the art or can be purchased from Wanghua Mall Co., Ltd., Beijing Ouhe Technology Co., Ltd., Sigma Co., Ltd., J&K Scientific Co., Ltd., Yishiming Co., Ltd., Shanghai Shuya Chemical Co., Ltd., Shanghai Innochem Science & Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Bide Pharmatech Co., Ltd., etc.

[0187] Unless otherwise stated, reactions are carried out under a nitrogen atmosphere.

[0188] Nitrogen atmosphere means that the reaction flask is equipped with a nitrogen balloon (approximately 1 L).

[0189] Reaction solvent, organic solvent or inert solvent refers to a solvent used that does not participate in the reaction under the reaction conditions described, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, N-methylpyrrolidone (NMP).

[0190] Unless otherwise specified in the examples, solutions refer to aqueous solutions.

[0191] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0192] Unless otherwise specified, the mixing ratios of different solvents are by volume. [Example]

[0193] Example 1 Synthesis of 7-nitroquinolin-8-ol (1)

[0194] [ka]

[0195] 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 adjusted to approximately 5 to 6 with saturated aqueous potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (10.0 mL × 3) and evaporated to dryness in vacuo to give 8-hydroxy-7-nitroquinoline-5-sulfonic acid (1b) (9.0 g, 76% yield).

[0196] 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 adjusted to approximately 6 to 7 with ammonia (25 to 28 wt%, NH content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed successively with water (10.0 mL × 2) and methanol (5.0 mL × 2) and evaporated to dryness in vacuo to give 7-nitroquinolin-8-ol (1) (5.0 g, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (dd, J = 4.0, 1.6 Hz, 1H), 8.52 (dd, J = 8.4, 1.6 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.81 (dd, J = 8.4, 4.4Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H). MS calculated: 190.04, MS found: 191.2 [M+H] + .

[0197] Example 2 Synthesis of 6-methyl-7-nitroquinolin-8-ol (2)

[0198] [ka]

[0199] At room temperature, 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 1.0 M hydrochloric acid (40.0 mL). The reaction mixture was stirred at 110 °C for 24 hours and cooled to room temperature. 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 × 3), and the combined 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: dichloromethane / methanol = 10 / 1) to give 6-methylquinolin-8-ol (2b) (0.81 g, 63% yield).

[0200] 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 aqueous sodium thiosulfate (10 wt%) (30.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 2). The combined organic phase was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 5-iodo-6-methylquinolin-8-ol (2c) (232.0 mg, 92% yield).

[0201] At 0°C, a solution of sodium nitrite (59.4 mg, 0.70 mol) and lanthanum nitrate hexahydrate (30.2 mg, 0.070 mmol) in 6.0 M hydrochloric acid (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). The reaction mixture was warmed to room temperature, stirred for 1 h, and extracted with ethyl acetate (50.0 mL × 3). The combined organic phase was 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).

[0202] 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 solution was stirred at 140 °C in a microwave reactor for 30 minutes, cooled to room temperature, and diluted with 2.0 M ammonia (20.0 mL). The resulting mixture was extracted with ethyl acetate (20.0 mL × 2). The combined organic phase was 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). 1 H NMR (400 MHz, 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). MS calculated: 204.05; MS found: 205.0 [M+H] + .

[0203] Example 3 Synthesis of 5-iodo-7-nitroquinolin-8-ol (3)

[0204] [ka]

[0205] 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 aqueous sodium thiosulfate (10 wt%) (20.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 2). The combined organic phase was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 5-iodo-7-nitroquinolin-8-ol (3) (367.0 mg, 88% yield). 1 H NMR (400 MHz, 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). MS calculated: 315.93; MS found: 316.9 [M+H] + .

[0206] Example 4 Synthesis of 5-methyl-7-nitroquinolin-8-ol (4)

[0207] [ka]

[0208] At room temperature, 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 1.0 M hydrochloric acid (40.0 mL). The reaction mixture was stirred at 110 °C for 24 hours and cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 7 to 8 with solid sodium carbonate. The resulting mixture was extracted with dichloromethane (30.0 mL × 3), and the combined 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 = 1 / 1) to give 5-methylquinolin-8-ol (4b) (0.50 g, 46% yield).

[0209] At 0°C, 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). 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 adjusted to approximately 6 to 7 with saturated aqueous potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (2.5 mL × 3) and evaporated to dryness in vacuo to give 5-methyl-7-nitroquinolin-8-ol (4) (180.0 mg, 70% yield). 1 H NMR (400 MHz, 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). MS calculated: 204.05; MS found: 205.1 [M+H] + .

[0210] Example 5 Synthesis of 2-fluoro-7-nitroquinolin-8-ol (5)

[0211] [ka]

[0212] At 0°C, 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). 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 then purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 8-hydroxy-N,N,N-trimethylquinolin-2-aminium (5b) (1.7 g, 73% yield).

[0213] A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.0 M, 3.0 mL) was added to a solution of 8-hydroxy-N,N,N-trimethylquinolin-2-aminium (5b) (203.0 mg, 1.0 mmol) in N,N-dimethylformamide (5.0 mL) at room temperature. The reaction solution was stirred at 90 °C for 1 hour, cooled to room temperature, diluted with ethyl acetate (20.0 mL), and washed successively 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).

[0214] At room temperature, 0.2 mL of fuming sulfuric acid (18 to 24 wt% SO content) was added to a solution of 2-fluoroquinolin-8-ol (5c) (100.0 mg, 0.61 mmol) in 0.4 mL of sulfuric acid (98 wt%). The reaction solution 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 × 3) and evaporated to dryness in vacuo to give 2-fluoro-8-hydroxyquinoline-5-sulfonic acid (5d) (130.0 mg, 94% yield).

[0215] At 0°C, 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). 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 adjusted to approximately 5 to 6 with saturated aqueous potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL × 3) and evaporated to dryness in vacuo to give 2-fluoro-8-hydroxy-7-nitroquinoline-5-sulfonic acid (5e) (90.0 mg, 76% yield).

[0216] 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 adjusted to approximately 6 to 7 with ammonia (25 to 28 wt%, NH content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL × 2) and evaporated to dryness to give 2-fluoro-7-nitroquinolin-8-ol (5) (52.0 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ: 9.50-9.46 (m, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.22 (s, 1H), 7.42-7.39 (m, 1H), 7.28 (s, 1H). MS calculated: 208.03; MS observed: 207.1 [MH] - .

[0217] Example 6 Synthesis of 2-methyl-7-nitroquinolin-8-ol (6)

[0218] [ka]

[0219] At room temperature, 2.0 mL of fuming sulfuric acid (18 to 24 wt% SO content) was added to a solution of 2-methyl-8-hydroxyquinoline (6a) (1.0 g, 6.28 mmol) in 4.0 mL of sulfuric acid (98 wt%). The reaction solution was stirred at 65 °C for 2 h, 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 min, and filtered under reduced pressure. The filter cake was washed with acetone (15.0 mL × 2) and evaporated to dryness in vacuo to give 8-hydroxy-2-methylquinoline-5-sulfonic acid (6b) (1.4 g, 94% yield).

[0220] 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 15 minutes. The pH of the aqueous phase was adjusted to approximately 5 to 6 with saturated aqueous potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL × 3) and evaporated to dryness in vacuo to give 8-hydroxy-2-methyl-7-nitroquinoline-5-sulfonic acid (6c) (94.3 mg, 79% yield).

[0221] 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 h, cooled to room temperature, poured into ice water (15.0 mL), and stirred for 15 min. The pH of the aqueous phase was adjusted to approximately 6 to 7 with ammonia (25 to 28 wt%, NH content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL × 2) and evaporated to dryness in vacuo to give 2-methyl-7-nitroquinolin-8-ol (6) (51.0 mg, 78% yield). 1 H NMR (400 MHz, 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). MS calculated: 204.05; MS found: 205.1 [M+H] + .

[0222] Example 7 Synthesis of 5-chloro-6-(methylamino)-7-nitroquinolin-8-ol (7)

[0223] [ka]

[0224] 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 added sequentially to sulfuric acid (70 wt%) (40.4 mL). The resulting mixture was stirred at 140 °C for 4 hours and cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 8 to 9 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (50.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude 6-bromo-5-chloro-8-methoxyquinoline (7b) (3.80 g, crude yield 87%).

[0225] Nitric acid (65 wt%) (8.4 mL, 198.0 mmol) was slowly added dropwise to a solution of crude 6-bromo-5-chloro-8-methoxyquinoline (7b) (1.80 g, 6.6 mmol) in acetic anhydride (30.0 mL) at 0°C and stirred for 30 minutes. 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, stirred for 48 hours, and then cooled to 0°C. The pH of the aqueous phase was adjusted to approximately 8 to 9 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with ethyl acetate (50.0 mL × 3). The organic phases were combined, 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 (gradient elution, eluent: petroleum ether / ethyl acetate=9 / 1 to 2 / 1) to give 6-bromo-5-chloro-8-methoxy-7-nitroquinoline (7c) (0.551 g, yield 24%).

[0226] 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) at room temperature. The resulting mixture was stirred at 95 °C for 4 hours, cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (10.0 mL × 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 to 2 / 1) to give tert-butyl (5-chloro-8-methoxy-7-nitroquinolin-6-yl)carbamate (7d) (130.0 mg, yield 56%).

[0227] 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 methyl iodide (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 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).

[0228] 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 solution of hydrogen chloride in 1,4-dioxane (4.0 M) (1.0 mL) was added to the resulting residue, stirred at room temperature for 2 hours, and concentrated to dryness under reduced pressure. The pH of the aqueous phase was adjusted to approximately 9 to 10 by the addition of ammonia (25 to 28 wt %, NH content) to obtain a residue. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (0.5 mL x 2) and dried in vacuo to give 5-chloro-6-(methylamino)-7-nitroquinolin-8-ol (7) (31.0 mg, yield 37%). 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.4, 4.0 Hz, 1H), 5.62 (br s, 1H), 2.80 (s, 3H). MS calculated: 253.03; MS found: 254.1, 256.1 [M+H] + .

[0229] Example 8 Synthesis of 3-methyl-7-nitroquinolin-8-ol (8)

[0230] [ka]

[0231] 2-Methacrolein (1.0 mL, 4.0 mmol) was slowly added dropwise to a solution of 2-aminophenol (8a) (200.0 mg, 1.83 mmol) in 6.0 M hydrochloric acid (10.0 mL) at 110 °C. The reaction mixture was stirred at 110 °C for 2 h and cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 7 to 8 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with ethyl acetate (15.0 mL × 3). The combined organic phase was 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).

[0232] At room temperature, fuming sulfuric acid (18 to 24 wt% SO 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). The reaction solution was stirred at 65 °C for 2 h, 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 min, and filtered under reduced pressure. The filter cake was washed with acetone (15.0 mL × 2) and evaporated to dryness in vacuo to give 8-hydroxy-3-methylquinoline-5-sulfonic acid (8c) (139.0 mg, 77% yield).

[0233] At 0°C, 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). 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 adjusted to approximately 5 to 6 with saturated aqueous potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL × 3) and evaporated to dryness in vacuo to give 8-hydroxy-3-methyl-7-nitroquinoline-5-sulfonic acid (8d) (128.6 mg, 78% yield).

[0234] 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 adjusted to approximately 6 to 7 with ammonia (25 to 28 wt%, NH content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL × 2) and evaporated to dryness to give 3-methyl-7-nitroquinolin-8-ol (8) (49.3 mg, 69% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 8.25 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 2.54(s, 3H). MS calculated: 204.05; MS found: 205.0 [M+H] + .

[0235] Example 9 Synthesis of 8-hydroxy-7-nitroquinoline-5-carbonitrile (9)

[0236] [ka]

[0237] 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 sequentially to N,N-dimethylformamide (3.0 mL) at room temperature. The reaction mixture was stirred at 140 °C in a microwave reactor for 30 minutes, cooled to room temperature, and diluted with ammonia (2.0 M) (20.0 mL). The resulting mixture was extracted with ethyl acetate (20.0 mL × 2). The combined organic phase was washed with saturated brine (20.0 mL × 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 obtain 8-hydroxy-7-nitroquinoline-5-carbonitrile (9) (36.0 mg, yield 27%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.64 (s, 1H), 8.58 (s, 1H), 8.46 (s, J = 8.0 Hz, 1H), 7.93 - 7.90 (m, 1H), 7.06 (s, 1H). MS calculated: 215.03; MS found: 216.0 [M+H] + .

[0238] Example 10 Synthesis of 4-methyl-7-nitroquinolin-8-ol (10)

[0239] [ka]

[0240] At room temperature, 4-hydroxy-2-butanone (10a) (12.3 g, 139.6 mmol) was added to a mixture of methanol (10 mL) and water (2 mL), followed by the addition of phosphoric acid (85 wt%) (0.4 mL). The resulting mixture was stirred at room temperature for 30 minutes and then distilled under reduced pressure (pressure range: 150.0 to 200.0 mmHg) to collect the fraction with a boiling point of 80 °C. Saturated brine (10 mL) was added to the collected fraction and stirred at 4 °C for 1 hour. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered to give but-3-en-2-one (10b) (0.86 g, 9% yield).

[0241] But-3-en-2-one (10b) (0.86 g, 12.3 mmol) was slowly added dropwise to a solution of 2-aminophenol (200 mg, 1.83 mmol) in 6.0 M hydrochloric acid (10 mL) at 110 °C. The reaction mixture was stirred at 110 °C for 2 h and cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 7 to 8 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 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 4-methylquinolin-8-ol (10c) (171.9 mg, 63% yield).

[0242] At room temperature, 2.0 mL of fuming sulfuric acid (18 to 24 wt.% SO₃ content) was added to a solution of 171.9 mg of 4-methylquinolin-8-ol (10c) (1.08 mmol) in 4.0 mL of sulfuric acid (98 wt.%). The reaction solution was stirred at 65°C for 2 hours, cooled to room temperature, and poured into 20.0 mL of ice water. The resulting suspension was diluted with 60.0 mL of acetone, stirred for 10 minutes, and filtered under reduced pressure. The filter cake was washed with 2 x 15.0 mL of acetone and evaporated to dryness to give 193.8 mg of 8-hydroxy-4-methylquinoline-5-sulfonic acid (10d) (75% yield).

[0243] At 0°C, 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). 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 adjusted to approximately 5 to 6 with saturated aqueous potassium carbonate. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL × 3) and evaporated to dryness in vacuo to give 8-hydroxy-4-methyl-7-nitroquinoline-5-sulfonic acid (10e) (179.6 mg, 78% yield).

[0244] 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 adjusted to approximately 6 to 7 with ammonia (25 to 28 wt%, NH content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (1.0 mL × 2) and evaporated to dryness in vacuo to give 4-methyl-7-nitroquinolin-8-ol (10) (51.0 mg, 78% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 8.25 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 2.54(s, 3H). MS calculated: 204.05; MS found: 205.0 [M+H] + .

[0245] Example 11 Synthesis of 4-cyclopropyl-7-nitroquinolin-8-ol (11)

[0246] [ka]

[0247] 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, and diluted with water (50.0 mL). The pH of the aqueous phase was adjusted to approximately 8 to 9 with ammonia (25 to 28 wt%, NH content). The resulting mixture was extracted with ethyl acetate (100.0 mL × 3), and the combined 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 = 7 / 3) to give 4-bromo-8-methoxyquinoline (11b) (3.7 g, 91% yield).

[0248] 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 to acetic anhydride (25.0 mL). The reaction mixture was warmed to room temperature, stirred for 2 h, and diluted with ice water (100.0 mL). The pH of the aqueous phase was adjusted to approximately 8 to 9 with ammonia (25 to 28 wt%, NH3 content). The resulting mixture was extracted with dichloromethane (100.0 mL × 3), and the combined 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-bromo-7-nitro-8-methoxyquinoline (11c) (0.30 g, 8% yield).

[0249] 4-Bromo-7-nitro-8-methoxyquinoline (11c) (100.0 mg, 0.35 mmol), cyclopropylboronic acid (61.6 mg, 0.72 mmol), tetrakis(triphenylphosphine)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 solution 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 × 3), and the combined 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=3 / 1) to obtain 4-cyclopropyl-7-nitro-8-methoxyquinoline (11d) (60.0 mg, yield 70%).

[0250] At room temperature, 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). The reaction solution was stirred at 180 °C for 1 hour and cooled to room temperature. The reaction solution was 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 4-cyclopropyl-7-nitroquinolin-8-ol (11) (16.0 mg, 28% yield). 1 H-NMR (400 Hz, DMSO-d6) δ: 8.50 - 8.40 (m, 1H), 8.00 - 7.88 (m, 1H), 7.15 - 7.06 (m, 1H), 6.95 - 6.86 (m, 1H), 2.30 - 2.45 (m, 1H), 1.20 - 1.05 (m, 2H), 0.90 - 0.70 (m, 2H). MS calculated: 230.07; MS found: 231.1 [M+H] + .

[0251] Example 12 Synthesis of 4-chloro-7-nitroquinolin-8-ol (12)

[0252] [ka]

[0253] At 0°C, a solution of boron tribromide in dichloromethane (1.0 M) (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 saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was evaporated to dryness in vacuo to give crude 4-chloro-8-hydroxyquinoline (12b) (1.6 g, crude yield 89%).

[0254] Sodium nitrite (2.0 g, 30.0 mmol) was added in portions to a suspension of 4-chloro-8-hydroxyquinoline (1.08 g, 6.0 mmol) (12b) in 2.0 M hydrochloric acid (36.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and then at room temperature 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 resulting filter cake was washed with methanol (5.0 mL × 2) and evaporated to dryness in vacuo to give 4-chloro-7-nitroquinolin-8-ol (12) (0.80 g, 59% yield). 1 H-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 9.6Hz,1H), 8.04 (d, J = 4.8Hz,1H), 8.18 (d, J = 9.6Hz,1H), 8.95 (d, J = 4.8Hz,1H). MS calculated: 224.60; MS found: 225.0 [M+H] + .

[0255] Example 13 Synthesis of 7-nitro-4-(pyrrolidin-1-yl)quinolin-8-ol

[0256] [ka]

[0257] 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 resulting 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 × 3) and evaporated to dryness in vacuo to give 7-nitro-4-(pyrrolidin-1-yl)quinolin-8-ol (13) (92.0 mg, 79% yield). 1 H-NMR (400 MHz, DMSO-d6) δ: 13.10 (br s, 1H), 8.08 (d, J = 5.6 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 6.92 (d, J = 10.0 Hz, 1H), 6.73 (d, J = 4.4 Hz, 1H), 3.84 (br s, 4H), 2.01 (br s, 4H). MS calculated: 259.10; MS found: 260.1 [M+H] + .

[0258] Example 14 Synthesis of 4-morpholino-7-nitroquinolin-8-ol (14)

[0259] [ka]

[0260] Following the same synthetic method as in Example 13, 4-morpholino-7-nitroquinolin-8-ol (14) (110.0 mg, 91% yield) was obtained from 4-chloro-7-nitroquinolin-8-ol (12) (100.0 mg, 0.44 mmol) and morpholine (192.0 mg, 2.2 mmol). 1 H NMR (400 MHz, 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). MS calculated: 275.09; MS found: 276.1 [M+H] + .

[0261] Example 15 Synthesis of 4-(1H-imidazol-1-yl)-7-nitroquinolin-8-ol (15)

[0262] [ka]

[0263] Following the same synthetic method as in Example 13, 4-(1H-imidazol-1-yl)-7-nitroquinolin-8-ol (15) (50.0 mg, 85% yield) was obtained from 4-chloro-7-nitroquinolin-8-ol (12) (50.0 mg, 0.23 mmol) and imidazole (61.5 mg, 0.9 mmol). 1 H-NMR (400 MHz, 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). MS calculated: 256.06; MS found: 257.1 [M+H] + .

[0264] Example 16 Synthesis of 4-bromo-7-nitroquinolin-8-ol (16)

[0265] [ka]

[0266] At 0°C, a 1.0 M solution of boron tribromide in dichloromethane (36.4 mL, 36.4 mmol) was slowly added dropwise to a solution of 4-bromo-8-methoxyquinoline (11b) (1.9 g, 8.1 mmol) in dichloromethane (25.0 mL). The reaction mixture was warmed to room temperature and stirred for 24 hours. The pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50.0 mL × 3). The combined 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: dichloromethane / methanol = 19 / 1) to give 4-bromoquinolin-8-ol (16a) (1.0 g, 55% yield).

[0267] Sodium nitrite (1.4 g, 20.3 mmol) was added in portions to a suspension of 4-bromoquinolin-8-ol (16a) (460 mg, 2.05 mmol) in 2.0 M hydrochloric acid (30.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 24 h. The pH of the aqueous phase was adjusted to approximately 8 to 9 with ammonia (25 to 28 wt %, NH content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with ethanol (4.0 mL × 3) and evaporated to dryness to give 4-bromo-7-nitroquinolin-8-ol (16) (500.0 mg, 91% yield). 1 H-NMR (400 Hz, DMSO-d6) δ: 8.84 - 7.77 (m, 1 H), 8.20 - 8.12 (m, 2 H), 7.60 - 7.55 (m, 1 H). MS calculated: 267.95; MS found: 269.0 [M+H] + .

[0268] Example 17 Synthesis of 4-(dimethylamino)-7-nitroquinolin-8-ol (17)

[0269] [ka]

[0270] At room temperature, 4-chloro-7-nitroquinolin-8-ol (12) (100.0 mg, 0.44 mmol) was added to 10.0 mL of aqueous dimethylamine (40 wt%). 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 × 2) and evaporated to dryness in vacuo to give 4-(dimethylamino)-7-nitroquinolin-8-ol (17) (36.0 mg, 35% yield). 1 H NMR (400 MHz, 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). MS calculated: 233.08; MS found: 234.1 [M+H] + .

[0271] Example 18 Synthesis of 4-(4-methylpiperazinyl)-7-nitroquinolin-8-ol (18)

[0272] [ka]

[0273] Following the same synthetic method as in Example 13, 4-(4-methylpiperazinyl)-7-nitroquinolin-8-ol (18) (40.0 mg, 63% yield) was obtained from 4-chloro-7-nitroquinolin-8-ol (12) (50.0 mg, 0.22 mmol) and 1-methylpiperazine (116.0 mg, 1.1 mmol). 1 H NMR (400 MHz, DMSO-d6) δ: 8.57 (d, J = 6.0 Hz, 1H), 7.98 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 6.0 Hz, 1H), 6.80 (d, J = 9.6 Hz, 1H), 3.55 - 3.21 (br s, 8H), 2.86 (s, 3H). MS calculated: 288.12; MS found: 289.1 [M+H] + .

[0274] Example 19 Synthesis of 7-nitro-4-(3-oxetanylamino)quinolin-8-ol (19)

[0275] [ka]

[0276] At room temperature, 3-oxetamine (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). The resulting 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 3 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 × 2) and evaporated to dryness to give 7-nitro-4-(3-oxetanylamino)quinolin-8-ol (19) (65.0 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.89 (d, J = 4.4 Hz, 1H), 8.16 (d, J = 6.8 Hz, 1H), 7.96 (d, J = 9.6 Hz, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.57 (d, J = 6.8 Hz, 1H), 5.01 - 4.96 (m, 1H), 4.93 (t, J = 6.0 Hz, 2H), 4.74 (t, J = 6.0 Hz, 2H). MS calculated: 261.07; MS found: 262.1 [M+H] + .

[0277] Example 20 Synthesis of 4-(2-methylpiperidinyl)-7-nitroquinolin-8-ol (20)

[0278] [ka]

[0279] Following the same synthetic method as in Example 13, 4-(2-methylpiperidinyl)-7-nitroquinolin-8-ol (20) (19.0 mg, 15% yield) was obtained from 4-chloro-7-nitroquinolin-8-ol (12) (100.0 mg, 0.44 mmol) and 2-methylpiperidine (220.0 mg, 2.2 mmol). 1 H NMR (400 MHz, 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). MS calculated: 287.13; MS found: 288.1 [M+H] + .

[0280] Example 21 Synthesis of 4-methoxy-7-nitroquinolin-8-ol (21)

[0281] [ka]

[0282] Following the same synthetic method as in Example 13, 4-methoxy-7-nitroquinolin-8-ol (21) (26.0 mg, 54% yield) was obtained from 4-chloro-7-nitroquinolin-8-ol (12) (50.0 mg, 0.22 mmol) and sodium methoxide (120.0 mg, 2.2 mmol). 1 H NMR (400 MHz, 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). MS calculated: 220.05; MS found: 221.0 [M+H] + .

[0283] Example 22 Synthesis of 4-phenyl-7-nitroquinolin-8-ol (22)

[0284] [ka]

[0285] At room temperature, 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 mixture of toluene (2.0 mL) and water (0.2 mL). 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 × 3). 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=7 / 3) to give 4-phenyl-7-nitro-8-methoxyquinoline (22a) (60.0 mg, yield 86%).

[0286] At room temperature, 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). 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 4-phenyl-7-nitroquinolin-8-ol (22) (25.0 mg, 45% yield). 1 H-NMR (400 MHz, 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). MS calculated: 266.07; MS found: 267.1 [M+H] + .

[0287] Example 23 Synthesis of 4-(2,5-dihydro-1H-pyrrolyl)-7-nitroquinolin-8-ol (23)

[0288] [ka]

[0289] Following the same synthesis method as in Example 19, 4-chloro-7-nitroquinolin-8-ol (12) (60.0 mg, 0.27 mmol) and 3-pyrroline (91.0 mg, 1.32 mmol) were reacted at 100°C to give 4-(2,5-dihydro-1H-pyrrolyl)-7-nitroquinolin-8-ol (23) (34.6 mg, 50% yield). 1 H-NMR (400 MHz, DMSO-d6) δ: 8.20 - 8.12 (m, 1 H), 7.87 - 7.80 (m, 1 H), 7.14 - 7.07 (m, 1 H), 6.75 - 6.70 (m, 1 H), 6.11 (s, 2 H), 4.75 (s, 4 H). MS calculated: 257.08; MS found: 258.1 [M+H] + .

[0290] Example 24 Synthesis of 4-(2-(dimethylamino)ethoxy)-7-nitroquinolin-8-ol (24)

[0291] [ka]

[0292] Sodium hydride (60% by weight, mixture in mineral oil) (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, followed by the addition of 4-chloro-7-nitroquinolin-8-ol (12) (60.0 mg, 0.27 mmol). The resulting mixture was warmed 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 4-(2-(dimethylamino)ethoxy)-7-nitroquinolin-8-ol (24) (25.7 mg, 34% yield). 1 H NMR (400 MHz, 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). MS calculated: 277.11; MS found: 278.1 [M+H] + .

[0293] Example 25 Synthesis of 4-(8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxamide (25)

[0294] [ka]

[0295] Following the same synthesis method as in Example 19, 4-chloro-7-nitroquinolin-8-ol (12) (60.0 mg, 0.27 mmol) and N,N-dimethylpiperazine-1-carboxamide (126.0 mg, 0.81 mmol) were reacted at 100°C to give 4-(8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxamide (25) (20.0 mg, 21% yield). 1 H NMR (400 MHz, 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). MS calculated: 345.14; MS found: 346.1 [M+H] + .

[0296] Example 26 Synthesis of methyl 4-(8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxylate (26)

[0297] [ka]

[0298] Following the same synthesis method as in Example 19, 4-chloro-7-nitroquinolin-8-ol (12) (60.0 mg, 0.27 mmol) and methyl piperazine-1-carboxylate (130.0 mg, 0.90 mmol) were reacted at 100°C to give methyl 4-(8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxylate (26) (21.7 mg, 24% yield). 1H NMR (400 MHz, 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). MS calculated: 332.11; MS found: 333.1 [M+H] + .

[0299] Example 27 Synthesis of 4-fluoro-7-nitroquinolin-8-ol (27)

[0300] [ka]

[0301] 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) at 0°C and stirred 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, stirred for 1 hour, and diluted with ice water (50.0 mL). The pH of the aqueous phase was adjusted to approximately 8-9 with ammonia (25-28 wt%, NH3 content). The resulting mixture was extracted with dichloromethane (10.0 mL × 3). 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=2 / 1) to give 4-chloro-7-nitro-8-methoxyquinoline (27a) (1.19 g, yield 20%).

[0302] 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 minutes, cooled to room temperature, diluted with dichloromethane (10.0 mL), and washed with water (10.0 mL × 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).

[0303] At room temperature, 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). 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 4-fluoro-7-nitroquinolin-8-ol (27) (46.0 mg, 98% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.84 - 8.37 (m, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.50 - 7.22 (m, 1H), 6.44 (d, J = 8.0 Hz, 1H). MS calculated: 208.03; MS found: 209.0 [M+H] + .

[0304] Example 28 Synthesis of methyl(8-hydroxy-7-nitroquinolin-4-yl)-L-prolinate (28)

[0305] [ka]

[0306] Methyl L-prolinate 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 solution was stirred at room temperature for 1 hour, followed by the addition of 4-chloro-7-nitroquinolin-8-ol (12) (80.0 mg, 0.36 mmol). 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 resulting residue was purified by reversed-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0 to 70% / 30%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, flow rate: 20.0 mL / min) to obtain the product methyl (8-hydroxy-7-nitroquinolin-4-yl)-L-prolinate (28) (115.0 mg, yield: 99%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.22 - 8.11 (m, 1H), 7.89 - 7.72 (m, 1H), 6.85 - 6.77 (m, 1H), 6.74 - 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). MS calculated: 317.10; MS found: 318.1 [M+H] + .

[0307] Example 29 Synthesis of 4,5-dichloro-7-nitroquinolin-8-ol (29)

[0308] [ka]

[0309] 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) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h and then at room temperature for 2 h. The pH of the aqueous phase was adjusted to approximately 8 to 9 with ammonia (25 to 28 wt%, NH content). The resulting mixture was extracted with dichloromethane (20.0 mL × 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 give 4,5-dichloroquinolin-8-ol (29a) (703.0 mg, 75% yield).

[0310] Sodium nitrite (2.28 g, 33.0 mmol) was added in portions to a suspension of 4,5-dichloroquinolin-8-ol (29a) (0.703 g, 3.3 mmol) in 20.0 mL of 3.0 M hydrochloric acid at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h and then at room temperature for 12 h. The pH of the aqueous phase was adjusted to approximately 8 to 9 with ammonia (25 to 28 wt %, NH content). The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (3.0 mL × 2) and evaporated to dryness to give 4,5-dichloro-7-nitroquinolin-8-ol (29) (0.641 g, 75% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 4.8 Hz, 1H), 8.22 (s, 1H), 8.05 (d, J = 4.8 Hz, 1H). MS calculated: 257.96; MS found: 259.0 [M+H] + .

[0311] Example 30 Synthesis of 7-nitroquinoline-4,8-diol (30)

[0312] [ka]

[0313] 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) at 0°C and stirred 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, stirred for 2 hours, and diluted with ice water (100.0 mL). The pH of the aqueous phase was adjusted to approximately 8-9 with ammonia (25-28 wt%, NH3 content). The resulting mixture was extracted with dichloromethane (100.0 mL × 3). 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, yield 8%).

[0314] At room temperature, 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). 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 7-nitroquinoline-4,8-diol (30) (37.0 mg, 56% yield). 1 H NMR (400 MHz, 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). MS calculated: 206.03; MS found: 207.1 [M+H] + .

[0315] Example 31 Synthesis of methyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-piperazine-1-carboxylate (31)

[0316] [ka]

[0317] At room temperature, 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) and methyl piperazine-1-carboxylate (82.2 mg, 0.57 mmol) were added to N,N-dimethylformamide (2.0 mL). The reaction solution 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give methyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-piperazine-1-carboxylate (30.0 mg, 43% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.49 - 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). MS calculated: 366.07; MS found: 367.1 [M+H] + .

[0318] Example 32 Synthesis of 4-cyclohexyl-7-nitroquinolin-8-ol (32)

[0319] [ka]

[0320] At room temperature, 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 mixture of toluene (10.0 mL), ethanol (1.0 mL), and water (2.0 mL). 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 × 2). 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-cyclohexenyl-8-methoxyquinoline (32a) (1.1 g, yield 89%).

[0321] 4-Cyclohexenyl-8-methoxyquinoline (32a) (850.0 mg, 3.5 mmol) and palladium on carbon (palladium loading: 10 wt%) (85.0 mg, 0.080 mmol) were added sequentially to methanol (20.0 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere for 3 hours and then filtered under reduced pressure. The filter cake was washed with ethyl acetate (10.0 mL × 3), and the resulting filtrate was concentrated to dryness under reduced pressure to give 4-cyclohexyl-8-methoxyquinoline (32b) (850.0 mg, 99% yield).

[0322] 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) at 0°C and stirred for 10 minutes. Concentrated sulfuric acid (0.5 mL, 9.2 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 1 hour and diluted with water (20.0 mL). The pH of the aqueous phase was adjusted to approximately 9-10 with ammonia (25-28 wt%, NH3 content). The resulting mixture was extracted with ethyl acetate (30.0 mL × 3). 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 obtain 4-cyclohexyl-7-nitro-8-methoxyquinoline (32c) (220.0 mg, yield 23%).

[0323] At room temperature, 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). 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 × 2) and evaporated to dryness in vacuo to give 4-cyclohexyl-7-nitroquinolin-8-ol (32) (124.9 mg, 87% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 4.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 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). MS calculated: 272.12; MS found: 273.1 [M+H] + .

[0324] Example 33 Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-acetylpiperazine (33)

[0325] [ka]

[0326] Following the same synthetic method as in Example 31, 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-acetylpiperazine (33) (38.0 mg, 35% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (80.0 mg, 0.31 mmol) and 1-acetylpiperazine (119.0 mg, 0.93 mmol). 1 H NMR (400 MHz, 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). MS calculated: 350.08; MS found: 351.1 [M+H] + .

[0327] Example 34 Synthesis of 5-chloro-4-methoxy-7-nitroquinolin-8-ol (34)

[0328] [ka]

[0329] At room temperature, 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). 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 5-chloro-4-methoxy-7-nitroquinolin-8-ol (34) (51.0 mg, 87% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.50 - 8.44 (m, 1H), 7.83 (s, 1H), 7.15 - 7.09 (m, 1H), 3.93 (s, 3H). MS calculated: 254.01; MS found: 255.0, 257.0 [M+H] + .

[0330] Example 35 Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxamide (35)

[0331] [ka]

[0332] Following the same synthetic method as in Example 31, 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-N,N-dimethylpiperazine-1-carboxamide (35) (30.0 mg, 42% yield) was obtained 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). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.78 - 3.48 (m, 8H), 2.78 (s, 6H). MS calculated: 379.10; MS found: 380.1 [M+H] + .

[0333] Example 36 Synthesis of 5-chloro-7-nitro-4-piperidinylquinolin-8-ol (36)

[0334] [ka]

[0335] Following the same synthetic method as in Example 31, 5-chloro-7-nitro-4-piperidinylquinolin-8-ol (36) (50.0 mg, 71% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and piperidine (170.0 mg, 2.3 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.19 (d, J = 4.0 Hz, 1H), 3.12 - 3.01 (m, 4H), 1.79 - 1.61 (m, 6H). MS calculated: 307.07; MS found: 308.1 [M+H] + .

[0336] Example 37 Synthesis of 5-chloro-7-nitro-4-(piperazin-1-yl)quinolin-8-ol (37)

[0337] [ka]

[0338] Following the same synthetic method as in Example 31, 5-chloro-7-nitro-4-(piperazin-1-yl)quinolin-8-ol (37) (200.0 mg, 65% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (259.0 mg, 1.0 mmol) and piperazine (258.6 mg, 3.0 mmol). 1 H NMR (400 MHz, CDCl3) δ 8.89 - 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). MS calculated: 308.07; MS found: 309.1 [M+H] + .

[0339] Example 38 Synthesis of 5-chloro-4-(4-methoxypiperidin-1-yl)-7-nitroquinolin-8-ol (38)

[0340] [ka]

[0341] Following the same synthetic method as in Example 31, 5-chloro-4-(4-methoxypiperidin-1-yl)-7-nitroquinolin-8-ol (38) (40.0 mg, 51% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and 4-methoxypiperidine (177.0 mg, 1.54 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.33 - 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). MS calculated: 337.08; MS found: 338.1 [M+H] + .

[0342] Example 39 Synthesis of 5-chloro-7-nitro-4-(4-(trifluoromethyl)piperidin-1-yl)quinolin-8-ol (39)

[0343] [ka]

[0344] Following the same synthetic method as in Example 34, 5-chloro-7-nitro-4-(4-(trifluoromethyl)piperidin-1-yl)quinolin-8-ol (39) (80.0 mg, 93% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and 4-(trifluoromethyl)piperidine (142.0 mg, 0.93 mmol). 1 H NMR (400 MHz, 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). MS calculated: 375.06; MS found: 376.0 [M+H] + .

[0345] Example 40 Synthesis of 5-chloro-4-(4-methylpiperazin-1-yl)-7-nitroquinolin-8-ol (40)

[0346] [ka]

[0347] Following the same synthetic method as in Example 34, 5-chloro-4-(4-methylpiperazin-1-yl)-7-nitroquinolin-8-ol (40) (23.0 mg, 31% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and 1-methylpiperazine (116.0 mg, 1.16 mmol). 1 H NMR (400 MHz, 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). MS calculated: 322.08; MS found: 323.1 [M+H] + .

[0348] Example 41 Synthesis of 5-chloro-4-(4,4-dimethylpiperidin-1-yl)-7-nitroquinolin-8-ol (41)

[0349] [ka]

[0350] 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 sequentially to acetonitrile (1.0 mL). 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 5-chloro-4-(4,4-dimethylpiperidin-1-yl)-7-nitroquinolin-8-ol (41) (52.0 mg, 80% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 6.6 Hz, 1H), 7.86 (s, 1H), 7.35 (d, J = 6.8 Hz, 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). MS calculated: 335.1; MS found: 336.1 [M+H] + .

[0351] Example 42 Synthesis of 5-chloro-7-nitro-4-(pyrrolidin-1-yl)quinolin-8-ol (42)

[0352] [ka]

[0353] At room temperature, 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). 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 5-chloro-7-nitro-4-(pyrrolidin-1-yl)quinolin-8-ol (42) (58.0 mg, 86% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.30 - 8.10 (m, 1H), 7.74 (s, 1H), 7.00 - 6.85 (m, 1H), 7.46 - 7.38 (m, 1 H), 2.00 - 1.75 (m, 8 H). MS calculated: 293.06; MS found: 294.0 [M+H] + .

[0354] Example 43 Preparation of 5-chloro-4-(2-fluoroethoxy)-7-nitroquinolin-8-ol (43)

[0355] [ka]

[0356] Sodium hydride (60% by weight, mixture in mineral oil) (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 resulting mixture was stirred at room temperature for 1 hour, followed by the addition of 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol). 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 5-chloro-4-(2-fluoroethoxy)-7-nitroquinolin-8-ol (43) (40.0 mg, 61% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.46 (d, J = 4.4Hz, 1H), 7.85 (s, 1H), 7.13 (d, J = 5.2Hz, 1H), 4.91 - 4.88 (m, 1H), 4.79 - 4.76 (m, 1H), 4.46 - 4.43 (m, 1H), 4.39 - 4.36 (m, 1H). MS calculated: 286.02; MS found: 287.0 [M+H] + .

[0357] Example 44 Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-N-methylpiperazine-1-carboxamide (44)

[0358] [ka]

[0359] At 0°C, triethylamine (60.0 mg, 0.58 mmol), methylaminoformyl chloride (55.0 mg, 0.58 mmol), and N,N-dimethylformamide (0.1 mL) were added sequentially 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). 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). 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 reversed-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0 to 70% / 30%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, flow rate: 20.0 mL / min) to obtain 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-N-methylpiperazine-1-carboxamide (44) (46.0 mg, yield: 66%). 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.63 - 6.55 (m, 1H), 3.68 - 3.60 (m, 4H), 3.56 - 3.51 (m, 4H), 2.58 (d, J = 4.0 Hz, 3H). MS calculated: 365.09; MS found: 366.1 [M+H] + .

[0360] Example 45 Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-(2,2,2-trimethylacetyl)piperazine (45)

[0361] [ka]

[0362] Following the same synthetic method as in Example 44, 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-(2,2,2-trimethylacetyl)piperazine (45) (56.0 mg, 75% yield) was obtained 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). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.02 - 3.84 (m, 4H), 3.72 - 3.62 (m, 4H), 1.21 (s, 9H). MS calculated: 392.13; MS found: 393.1 [M+H] + .

[0363] Example 46 Synthesis of ethyl 1-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperidine-4-carboxylate (46)

[0364] [ka]

[0365] At room temperature, 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) and ethyl 4-piperidinecarboxylate (91.0 mg, 0.58 mmol) were added to acetonitrile (1.0 mL). 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 × 2) and evaporated to dryness in vacuo to give ethyl 1-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperidine-4-carboxylate (46) (47.0 mg, 64% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.37 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 6.8 Hz, 1H), 7.92 (s, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.92 (d, J = 13.6 Hz, 1H), 3.73 (d, J = 11.4 Hz, 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). MS calculated: 379.1; MS found: 380.1 [M+H] + .

[0366] Example 47 Synthesis of 5-chloro-7-nitro-4-phenoxyquinolin-8-ol (47)

[0367] [ka]

[0368] Following the same synthetic method as in Example 31, 5-chloro-7-nitro-4-phenoxyquinolin-8-ol (47) (71.9 mg, 99% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and sodium phenolate (107.5 mg, 0.93 mmol). 1 H NMR (400 MHz, 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). MS calculated: 316.03; MS found: 317.1 [M+H] + .

[0369] Example 48 Synthesis of 5-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)-7-nitroquinolin-8-ol (48)

[0370] [ka]

[0371] Following the same synthetic method as in Example 31, 5-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)-7-nitroquinolin-8-ol (48) (62.0 mg, 70% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and 1-(methylsulfonyl)piperazine (113.0 mg, 0.69 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 5.6 Hz, 1H), 7.88 (s, 1H), 7.25 (d, J = 5.8 Hz, 1H), 3.20 - 3.17 (m, 4H), 3.02 - 2.99 (m, 4H), 2.91 (s, 3H). MS calculated: 386.05; MS found: 387.1 [M+H] + .

[0372] Example 49 Synthesis of 5-chloro-4-cyclopropyl-7-nitroquinolin-8-ol (49)

[0373] [ka]

[0374] 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 for 1 hour, and cooling to room temperature. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with ethanol (15.0 mL × 2) and evaporated to dryness to give 5-(((5-chloro-2-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (49b) (23.0 g, 97% yield).

[0375] 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 h. The mixture was cooled to room temperature, diluted with petroleum ether (boiling point range: 60 °C to 90 °C) (600.0 mL), and stirred for 2 h. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with petroleum ether (boiling point range: 60 °C to 90 °C) (50.0 mL × 3) and evaporated to dryness in vacuo to give 5-chloro-8-methoxyquinolin-4-ol (49c) (12.5 g, 81% yield).

[0376] 5-Chloro-8-methoxyquinolin-4-ol (49c) (2.0 g, 7.35 mmol) was added to a mixture 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, stirred for 2 h, cooled to room temperature, and then ice water (30.0 mL) was added. The pH of the aqueous phase was adjusted to approximately 9 to 10 with ammonia (25 to 28 wt%, NH content). The resulting mixture was extracted with dichloromethane (100.0 mL × 3). 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-bromo-5-chloro-8-methoxyquinoline (49d) (1.4 g, yield 70%).

[0377] 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 mixture 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 × 3). 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 5-chloro-4-cyclopropyl-8-methoxyquinoline (49e) (100.0 mg, yield 52%).

[0378] At room temperature, 5-chloro-4-cyclopropyl-8-methoxyquinoline (49e) (100.0 mg, 0.42 mmol) was added to a 1.0 M solution of boron tribromide in dichloromethane (1.3 mL, 1.3 mmol). The reaction mixture was stirred at 50 °C for 5 hours and cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (10.0 mL × 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 give 5-chloro-4-cyclopropylquinolin-8-ol (49f) (60.0 mg, 65% yield).

[0379] Sodium nitrite (186.3 mg, 2.7 mmol) was added in portions to a suspension of 5-chloro-4-cyclopropylquinolin-8-ol (49f) (60 mg, 0.27 mmol) in 2.0 M hydrochloric acid (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 purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm); mobile phase: water / acetonitrile = 100% to 70% / 30%, gradient elution with 0.1% formic acid added by volume at a flow rate of 20.0 mL / min) to give the product 5-chloro-4-cyclopropyl-7-nitroquinolin-8-ol (49) (8.5 mg, 12% yield). 1 H NMR (400 MHz, 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). MS calculated: 264.03; MS found: 265.0 [M+H] + .

[0380] Example 50 Synthesis of 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-(2,2-dimethylacetyl)piperazine (50)

[0381] [ka]

[0382] Following the same synthetic method as in Example 44, 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)-1-(2,2-dimethylacetyl)piperazine (50) (15.0 mg, 22% yield) was obtained 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). 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 (duplicate s, 6H). MS calculated: 394.10; MS found: 395.1, 396.1 [M+H] + .

[0383] Example 51 Synthesis of 5-chloro-7-nitro-4-phenylquinolin-8-ol hydrochloride (51)

[0384] [ka]

[0385] 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 × 3). 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=7 / 3) to give 5-chloro-8-methoxy-4-phenylquinoline (51a) (150.0 mg, yield 76%).

[0386] At 0°C, a 1.0 M solution of boron tribromide in dichloromethane (1.5 mL, 1.5 mmol) was slowly added to a solution of 5-chloro-8-methoxy-4-phenylquinoline (51a) (150.0 mg, 0.56 mmol) in dichloromethane (2.0 mL). The reaction solution was warmed to room temperature and stirred for 1 hour, then stirred at 50°C for 3 hours, and cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (20.0 mL × 3). 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 5-chloro-4-phenylquinolin-8-ol (51b) (80.0 mg, 56% yield).

[0387] Sodium nitrite (162.0 mg, 2.3 mmol) was added in portions to a suspension of 5-chloro-4-phenylquinolin-8-ol (60.0 mg, 0.23 mmol) in 5.0 mL of 3.0 M hydrochloric acid at 0°C. The reaction mixture was warmed to room temperature, stirred for 12 hours, and filtered under reduced pressure. The filter cake was washed with ethanol (0.5 mL × 2) and evaporated to dryness to give 5-chloro-7-nitro-4-phenylquinolin-8-ol hydrochloride (51) (8.5 mg, 12% yield). 1 H NMR (400 MHz, 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). MS calculated: 300.03; MS found: 301.0 [M+H] + .

[0388] Example 52 Synthesis of ethyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylate (52)

[0389] [ka]

[0390] Following the same synthetic method as in Example 31, ethyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylate (52) (73.0 mg, 83% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and ethyl piperazine-1-carboxylate (110.0 mg, 0.70 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 4.0 Hz, 1H), 7.92 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 4.13 - 4.05 (m, 2H), 3.74 - 3.62 (m, 8H), 1.20 (t, J = 7.0 Hz, 3H). MS calculated: 380.09; MS found: 381.1 [M+H] + .

[0391] Example 53 Synthesis of 5-chloro-4-(cyclopropylmethoxy)-7-nitroquinolin-8-ol (53)

[0392] [ka]

[0393] Following the same synthetic method as in Example 43, 5-chloro-4-(cyclopropylmethoxy)-7-nitroquinolin-8-ol (53) (14.0 mg, 21% yield) was obtained 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%, mixture in mineral oil) (46.0 mg, 1.16 mmol). 1 H NMR (400 MHz, 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). MS calculated: 294.04; MS found: 295.0 [M+H] + .

[0394] Example 54 Synthesis of 5-chloro-4-(4-(3-methoxypropoxy)piperidin-1-yl)-7-nitroquinolin-8-ol dihydrochloride (54)

[0395] [ka]

[0396] At room temperature, tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 5.0 mmol) (54a) and sodium hydride (60 wt %, mixture in mineral oil) (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, followed by the addition of 1-bromo-3-methoxypropane (2.3 g, 15.0 mmol). The reaction mixture was warmed to 50 °C, stirred for 4 hours, 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 × 3). 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=30 / 1 to 20 / 1) to give tert-butyl 4-(3-methoxypropoxy)piperidine-1-carboxylate (54b) (0.34 g, yield 25%).

[0397] A solution of hydrogen chloride in 1,4-dioxane (4.0 M) (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 concentrated to dryness under reduced pressure to give crude product 4-(3-methoxypropoxy)piperidine hydrochloride (54c) (310.0 mg, crude yield >100%).

[0398] 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 resulting residue was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% to 70% / 30%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, 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%). 1 H NMR (400 MHz, 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, 12 H), 2.10 - 1.60 (m, 6 H). MS calculated: 395.12; MS found: 396.1 [M+H] + .

[0399] Example 55 Synthesis of 5-chloro-4-(4,4-difluoropiperidin-1-yl)-7-nitroquinolin-8-ol (55)

[0400] [ka]

[0401] Following the same synthetic method as in Example 31, 5-chloro-4-(4,4-difluoropiperidin-1-yl)-7-nitroquinolin-8-ol (55) (43.0 mg, 54% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol) and 4,4-difluoroperidin (140.0 mg, 1.16 mmol). 1 H NMR (400 MHz, 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, 4 H), 2.35 - 2.05 (m, 4 H). MS calculated: 343.05; MS found: 344.1 [M+H] + .

[0402] Example 56 Synthesis of 1-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperidin-4-one (56)

[0403] [ka]

[0404] At room temperature, 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). 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 × 2) and evaporated to dryness in vacuo to give 1-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperidin-4-one (56) (20.0 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.39 - 8.34 (m, 1H), 7.93 - 7.86 (m, 1H), 7.42 - 7.35 (m, 1H), 3.95 - 3.64 (m, 8H). MS calculated: 321.05; MS found: 322.1 [M+H] + .

[0405] Example 57 Synthesis of (1-methyl)propyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylate (57)

[0406] [ka]

[0407] Following the same synthetic method as in Example 44, (1-methyl)propyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylate (57) (50.0 mg, 68% yield) was obtained 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). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 4.0 Hz, 1H), 7.92 (s, 1H), 7.39 (d, J = 8.0 Hz, 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). MS calculated: 408.12; MS found: 409.1 [M+H] + .

[0408] Example 58 Synthesis of isopropyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylate (58)

[0409] [ka]

[0410] Following the same synthetic method as in Example 44, isopropyl 4-(5-chloro-8-hydroxy-7-nitroquinolin-4-yl)piperazine-1-carboxylate (58) (46.0 mg, 61% yield) was obtained 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). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 4.0 Hz, 1H), 7.92 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 4.86 - 4.74 (m, 1H), 3.73 - 3.45 (m, 8H), 1.25 - 1.16 (m, 6H). MS calculated: 394.10; MS found: 395.1 [M+H] + .

[0411] Example 59 Synthesis of 5-chloro-4-(cyclopentyloxy)-7-nitroquinolin-8-ol (59)

[0412] [ka]

[0413] Cyclopentanol (166.0 mg, 1.93 mmol) and sodium hydride (60 wt %, mixture in mineral oil) (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, followed by the addition of 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol). 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 resulting residue was purified by reversed-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% to 70% / 30%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, flow rate: 20.0 mL / min) to obtain 5-chloro-4-(cyclopentyloxy)-7-nitroquinolin-8-ol (59) (11.0 mg, yield: 19%). 1 H NMR (400 MHz, 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, 1 H), 2.10-1.60(m, 9 H). MS calculated: 308.06; MS found: 309.0 [M+H] + .

[0414] Example 60 Synthesis of 5-chloro-4-(cyclohexyloxy)-7-nitroquinolin-8-ol (60)

[0415] [ka]

[0416] Following the same synthetic method as in Example 59, 5-chloro-4-(cyclohexyloxy)-7-nitroquinolin-8-ol (60) (30.0 mg, 16% yield) was obtained 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 %, mixture in mineral oil) (47.0 mg, 1.16 mmol). 1 H NMR (400 MHz, DMSO-d6) δ: 8.65 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 5.13 - 4.85 (m, 1H), 2.10 - 1.86 (m, 2H), 1.84 - 1.62 (m, 4H), 1.56 - 1.38 (m, 4H). MS calculated: 322.07; MS found: 323.1 [M+H] + .

[0417] Example 61 Synthesis of 5-chloro-4-ethoxy-7-nitroquinolin-8-ol (61)

[0418] [ka]

[0419] Following the same synthetic method as in Example 43, 5-chloro-4-ethoxy-7-nitroquinolin-8-ol (61) (23.3 mg, 38% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol), ethanol (6.0 mL, 102.7 mmol), and sodium hydride (60 wt%, mixture in mineral oil) (50.6 mg, 1.26 mmol). 1H NMR (400 MHz, 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). MS calculated: 268.03; MS found: 269.0 [M+H] + .

[0420] Example 62 Synthesis of 7-nitro-4-trifluoromethylquinolin-8-ol (62)

[0421] [ka]

[0422] o-Methoxyaniline (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) at room temperature. 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 successively with 2.0 M hydrochloric acid (15.0 mL × 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, 78% crude yield).

[0423] 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 × 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate solution (30.0 mL × 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).

[0424] At room temperature, 8-methoxy-4-trifluoromethyl-2(1H)-quinolinone (62d) (2.09 g, 8.6 mmol) was added to phosphorus oxychloride (8.6 mL). The reaction mixture was stirred at 100 °C for 2 hours, cooled to room temperature, and diluted with dichloromethane (40.0 mL). The pH of the aqueous phase was adjusted to approximately 9 to 10 with saturated aqueous sodium carbonate solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (15.0 mL × 2). The combined organic phase was washed successively with saturated aqueous sodium carbonate solution (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 give crude product 2-chloro-8-methoxy-4-trifluoromethylquinoline (62e) (2.26 g, crude yield 100%).

[0425] At room temperature, 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), followed by the addition of 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 and then filtered through diatomaceous earth. 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. The resulting residue was dissolved in dichloromethane (20.0 mL), washed with saturated aqueous sodium bicarbonate (10.0 mL × 2), 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 give 8-methoxy-4-trifluoromethylquinoline (62f) (380.0 mg, yield 84%).

[0426] 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 and stirred for 10 minutes. 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 the pH of the aqueous phase was adjusted to approximately 9 to 10 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 8-methoxy-7-nitro-4-trifluoromethylquinoline (62g) (93.5 mg, 20% yield).

[0427] At room temperature, 8-methoxy-7-nitro-4-trifluoromethylquinoline (62g) (93.5 mg, 0.34 mmol) and lithium chloride (144.0 mg, 3.4 mmol) were added to N,N-dimethylformamide (0.4 mL). 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 × 2) and evaporated to dryness in vacuo to give 7-nitro-4-trifluoromethylquinolin-8-ol (62) (70.0 mg, 79% yield). 1 H NMR (400 MHz, 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). MS calculated: 258.03; MS found: 259.1 [M+H] + .

[0428] Example 63 Synthesis of 5-chloro-7-nitro-4-(6-azaspiro[2.5]octan-6-yl)quinolin-8-ol (63)

[0429] [ka]

[0430] 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, followed by the addition of 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol). 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 purified by reversed-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% to 70% / 30%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, flow rate: 20.0 mL / min) to obtain 5-chloro-7-nitro-4-(6-azaspiro[2.5]octan-6-yl)quinolin-8-ol (63) (3.5 mg, yield: 6%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.32 - 8.20 (m, 1H), 7.90 - 7.85 (m, 1H), 7.44 - 7.33 (m, 1H), 3.75 - 3.60 (m, 4H), 2.05 - 1.95 (m, 1H), 1.65 - 1.35 (m, 4H), 0.50 - 0.28 (m, 4H). MS calculated: 333.09; MS found: 334.1 [M+H] + .

[0431] Example 64 Synthesis of 5-chloro-4-cyclohexyl-7-nitroquinolin-8-ol (64)

[0432] [ka]

[0433] At room temperature, 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 mixture of toluene (10.0 mL), ethanol (1.0 mL), and water (2.0 mL). 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 × 2). 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-cyclohexenyl-8-methoxyquinoline (64a) (1.1 g, yield 89%).

[0434] 4-Cyclohexenyl-8-methoxyquinoline (64a) (850.0 mg, 3.5 mmol) and palladium on carbon (palladium loading: 10 wt%) (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 diatomaceous earth, and the filter cake was washed with ethyl acetate (10.0 mL × 3). The filtrate was concentrated to dryness under reduced pressure to give 4-cyclohexyl-8-methoxyquinoline (64b) (850.0 mg, 99% yield).

[0435] At 0°C, a 1.0 M solution of boron tribromide in dichloromethane (7.0 mL, 7.0 mmol) was slowly added dropwise to a solution of 4-cyclohexyl-8-methoxyquinoline (64b) (420.0 mg, 1.7 mmol) in dichloromethane (2.0 mL). The reaction mixture was warmed to room temperature, stirred at 50°C for 5 hours, and cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (10.0 mL × 3). 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 = 2 / 1) to give 4-cyclohexylquinolin-8-ol (64c) (250.0 mg, 65% yield).

[0436] 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 h, and the pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (10.0 mL × 3). 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 = 3 / 1) to give 5-chloro-4-cyclohexylquinolin-8-ol (64d) (230.0 mg, 80% yield).

[0437] Sodium nitrite (600.0 mg, 7.6 mmol) was added in several portions to a suspension of 5-chloro-4-cyclohexylquinolin-8-ol (64d) (200.0 mg, 0.76 mmol) in 10.0 mL of 2.0 M hydrochloric acid at room temperature. The reaction mixture was stirred at room temperature for 5 h, and the pH of the aqueous phase was adjusted to approximately 8 to 9 with ammonia (25 to 28 wt %, NH3 content). The resulting mixture was filtered under reduced pressure, and the filter cake was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% to 70% / 30%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, flow rate: 20.0 mL / min) to obtain 5-chloro-4-cyclohexyl-7-nitroquinolin-8-ol (64) (60.0 mg, yield: 26%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.85 (d, J = 4.0 Hz, 1H), 7.72 (d, J = 4.0 Hz, 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). MS calculated: 261.09; MS found: 262.1 [M+H] + .

[0438] Example 65 Synthesis of 5-chloro-4-fluoro-7-nitroquinolin-8-ol (65)

[0439] [ka]

[0440] 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 purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm); mobile phase: water / acetonitrile = 100% to 70% / 30%, gradient elution with 0.1% formic acid added by volume; flow rate: 20.0 mL / min) to give 5-chloro-4-fluoro-7-nitroquinolin-8-ol (65) (12.0 mg, 22% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 9.13 - 9.01 (m, 1H), 8.18 (s, 1H), 7.88 - 7.73 (m, 1H). MS calculated: 241.99; MS found: 243.0 [M+H] + .

[0441] Example 66 Synthesis of 5-chloro-4-(3-methylpiperidin-1-yl)-7-nitroquinolin-8-ol (66)

[0442] [ka]

[0443] Following the same synthetic method as in Example 46, 5-chloro-4-(3-methylpiperidin-1-yl)-7-nitroquinolin-8-ol (66) (62.0 mg, 99.8% yield) was obtained from 4,5-dichloro-7-nitroquinolin-8-ol (29) (50.0 mg, 0.19 mmol) and 3-methylpiperidine (57.0 mg, 0.57 mmol). 1H NMR (400 MHz, DMSO-d6) δ 7.82 (dd, J = 16.2, 1.6 Hz, 1H), 7.27 - 7.04 (m, 2H), 3.28 - 3.13 (m, 3H), 2.76 (td, J = 12.7, 3.0 Hz, 1H), 2.26 - 2.12 (m, 1H), 2.07 - 1.95 (m, 1H), 1.81 - 1.71 (m, 3H), 0.91 (d, J = 6.5 Hz, 3H). MS calculated: 321.1; MS found: 322.1 [M+H] + .

[0444] Example 67 Synthesis of 4-(benzyloxy)-5-chloro-7-nitroquinolin-8-ol hydrochloride (67)

[0445] [ka]

[0446] Sodium hydride (60 wt %, mixture in mineral oil) (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, followed by the addition of 4,5-dichloro-7-nitroquinolin-8-ol (29) (60.0 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 3 hours, followed by the addition of hydrochloric acid (36 wt %) (1.5 mL) and filtration under reduced pressure. The filter cake was washed successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 4-(benzyloxy)-5-chloro-7-nitroquinolin-8-ol hydrochloride (67) (29.5 mg, 35% yield). 1 H NMR (400 MHz, 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, 3 H), 5.58 - 5.51 (m, 2 H). MS calculated: 330.04; MS found: 331.0 [M+H] + .

[0447] Example 68 Synthesis of 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68)

[0448] [ka]

[0449] 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 × 3) and evaporated to dryness to give 5-(((5-fluoro-2-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (68b) (3.21 g, 99% yield).

[0450] 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 (boiling range: 60 °C to 90 °C) (250.0 mL), and filtered under reduced pressure. The filter cake was washed with petroleum ether (boiling range: 60 °C to 90 °C) (8.0 mL × 4) and evaporated to dryness in vacuo to give 5-fluoro-8-methoxyquinolin-4-ol (68c) (1.49 g, 84% yield).

[0451] At room temperature, phosphorus oxychloride (7.7 mL) was added to 5-fluoro-8-methoxyquinolin-4-ol (68c) (1.49 g, 7.7 mmol). The reaction mixture was stirred at 100° C. for 3 hours, cooled to room temperature, and diluted with dichloromethane (40.0 mL). The pH of the aqueous phase was adjusted to approximately 9 to 10 with aqueous sodium hydroxide (1.0 M). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 2). The combined organic phase was washed successively 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 give 4-chloro-5-fluoro-8-methoxyquinoline (68d) (1.33 g, yield 81%).

[0452] At 0°C, a solution of boron tribromide in dichloromethane (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, followed by the addition of ice water (150 mL). The pH of the aqueous phase was adjusted to approximately 9 to 10 with solid sodium carbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL x 4). The combined organic phase was washed with saturated aqueous sodium carbonate (40 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, yield 52%).

[0453] At 0°C, 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 2.4 M hydrochloric acid (13.7 mL). The reaction mixture was warmed to room temperature and stirred for 10 hours. The pH of the aqueous phase was adjusted to approximately 9 to 10 with solid sodium carbonate, and the mixture was filtered under reduced pressure. The filter cake was washed with water (3.0 mL × 3) and evaporated to dryness in vacuo to give 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68) (0.354 g, 44% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.62 (s, 1H), 7.79 (overlap s, 2H). MS calculated: 241.99; MS found: 243.1, 245.1 [M+H] + .

[0454] Example 69 Synthesis of 4-(4,4-difluoropiperidin-1-yl)-5-fluoro-7-nitroquinolin-8-ol (69)

[0455] [ka]

[0456] At room temperature, 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68) (42.0 mg, 0.17 mmol) and 4,4-difluoroperidin (63.0 mg, 0.52 mmol) were added to N,N-dimethylformamide (3.0 mL). 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 × 2) and evaporated to dryness in vacuo to give 4-(4,4-difluoropiperidin-1-yl)-5-fluoro-7-nitroquinolin-8-ol (69) (30.0 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.63 - 8.50 (m, 1 H), 7.78 - 7.70 (m, 1 H), 7.35 - 7.28 (m, 1 H), 3.50 - 3.40 (m, 4 H), 2.30 - 2.15 (m, 4 H). MS calculated: 327.08; MS found: 328.1 [M+H] + .

[0457] Example 70 Synthesis of 5-fluoro-7-nitro-4-(4-(trifluoromethyl)piperidin-1-yl)quinolin-8-ol (70)

[0458] [ka]

[0459] Following the same synthetic method as in Example 69, 5-fluoro-7-nitro-4-(4-(trifluoromethyl)piperidin-1-yl)quinolin-8-ol (70) (40.0 mg, 56% yield) was obtained from 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68) (48.0 mg, 0.20 mmol) and 4-(trifluoromethyl)piperidine (153.0 mg, 1.0 mmol). 1 H NMR (400 MHz, DMSO-d6) δ: 8.58 - 8.40 (m, 1 H), 7.68 - 7.55 (m, 1 H), 7.22 - 7.11 (m, 1 H), 3.74 - 3.61 (m, 2 H), 3.46 - 3.39 (m, 2 H), 3.01 - 2.92 (m, 1 H), 2.00 - 1.95 (m, 2 H), 1.72 - 1.65 (m, 2 H). MS calculated: 359.09; MS found: 360.1 [M+H] + .

[0460] Example 71 Synthesis of ethyl 1-(5-fluoro-8-hydroxy-7-nitroquinolin-4-yl)piperidine-4-carboxylate (71)

[0461] [ka]

[0462] Following the same synthetic method as in Example 69, ethyl 1-(5-fluoro-8-hydroxy-7-nitroquinolin-4-yl)piperidine-4-carboxylate (71) (33.0 mg, 48% yield) was obtained from 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68) (45.0 mg, 0.19 mmol) and ethyl 4-piperidinecarboxylate (210 mg, 1.33 mmol). 1 H NMR (400 MHz, 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, 2H), 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). MS calculated: 363.12; MS found: 364.1 [M+H] + .

[0463] Example 72 Synthesis of 4-(cyclopropylmethoxy)-5-fluoro-7-nitroquinolin-8-ol (72)

[0464] [ka]

[0465] Following the same synthetic method as in Example 69, 4-(cyclopropylmethoxy)-5-fluoro-7-nitroquinolin-8-ol (72) (38.0 mg, 65% yield) was obtained from 4-chloro-5-fluoro-7-nitroquinolin-8-ol (68) (50.0 mg, 0.21 mmol) and cyclopropylmethanol (149.0 mg, 2.1 mmol). 1 H NMR (400 MHz, DMSO-d6) δ: 8.82 - 8.78 (m, 1H), 7.80 - 7.73 (m, 1H), 7.39 - 7.33 (m, 1H), 4.23 - 4.18 (m, 2H), 0.88 - 0.80 (m, 1H), 0.62 - 0.60 (m, 2H), 0.46 - 0.40 (m, 2H). MS calculated: 278.07; MS found: 279.1 [M+H] + .

[0466] Example 73 Synthesis of 5-chloro-7-nitro-4-(trifluoromethyl)-quinolin-8-ol hydrochloride (73)

[0467] [ka]

[0468] At room temperature, 8-methoxy-4-(trifluoromethyl)quinoline (73a) (230.0 mg, 1.0 mmol) was added to a solution of boron tribromide in dichloromethane (1.0 M) (5.0 mL, 5.0 mmol). The reaction mixture was stirred at room temperature for 7 hours and diluted with dichloromethane (20.0 mL). The pH of the aqueous phase was adjusted to approximately 9 to 10 with saturated aqueous sodium carbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 4). The combined organic phase was 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 4-trifluoromethyl-8-hydroxyquinoline (73b) (190.0 mg, 88% yield).

[0469] 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 the pH of the aqueous phase was adjusted to approximately 9 to 10 with saturated aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (5.0 mL × 4), and the combined organic phase was 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).

[0470] Sodium nitrite (240.0 mg, 3.5 mmol) was added in portions to a suspension of 5-chloro-4-(trifluoromethyl)quinolin-8-ol (73c) (87.0 mg, 0.35 mmol) in 2.0 M hydrochloric acid (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 mixture of ethanol and water (volume ratio, ethanol / water = 1 / 1) (1.0 mL × 2) and evaporated to dryness in vacuo to give 5-chloro-7-nitro-4-(trifluoromethyl)quinolin-8-ol hydrochloride (73) (69.0 mg, 60% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 9.28 (d, J = 4.4 Hz, 1H), 8.41 (overlaps, 2H). MS calculated: 291.99; MS found: 293.0, 295.0 [M+H] + .

[0471] Example 74 Synthesis of 4-chloro-3-cyclopropyl-7-nitroquinolin-8-ol

[0472] [ka]

[0473] 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 × 2). The combined organic phase was 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).

[0474] At room temperature, 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). 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 to 9 with saturated aqueous sodium bicarbonate. The resulting mixture was filtered under reduced pressure. 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 give 2-methoxy-3-nitroaniline (74c) (2.06 g, 61% yield).

[0475] 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 (boiling point range: 60 °C to 90 °C) (10.0 mL × 3) and evaporated to dryness in vacuo to give 5-(((2-methoxy-3-nitrophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (74d) (3.85 g, 97% yield).

[0476] 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 (boiling range: 60 °C to 90 °C) (250.0 mL), and filtered under reduced pressure. The filter cake was washed with petroleum ether (boiling range: 60 °C to 90 °C) (10.0 mL × 4) and evaporated to dryness in vacuo to give 8-methoxy-7-nitroquinolin-4-ol (30a) (2.33 g, 89% yield).

[0477] 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 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 × 2) and evaporated to dryness in vacuo to give crude product 3-bromo-8-methoxy-7-nitroquinolin-4-ol (74e) (628.0 mg, crude yield 93%).

[0478] At room temperature, 3-bromo-8-methoxy-7-nitroquinolin-4-ol (74e) (628.0 mg, 0.45 mmol) was added to phosphorus oxychloride (8.0 mL). The reaction mixture was stirred at 100 °C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to remove phosphorus oxychloride. The resulting residue was dissolved in dichloromethane (15.0 mL), and the pH of the aqueous phase was adjusted to approximately 9 to 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 give crude product 3-bromo-4-chloro-8-methoxy-7-nitroquinoline (74f) (670.0 mg, crude yield 100%).

[0479] 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 mixture of toluene (7.0 mL) and water (0.70 mL) at room temperature. The reaction solution 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 × 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: petroleum ether / dichloromethane / ethyl acetate=7 / 2 / 1) to give 4-chloro-3-cyclopropyl-8-methoxy-7-nitroquinoline (74g) (117.0 mg, yield 38%).

[0480] At room temperature, 4-chloro-3-cyclopropyl-8-methoxy-7-nitroquinoline (74g) (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). 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 × 2) and evaporated to dryness in vacuo to give 4-chloro-3-cyclopropyl-7-nitroquinolin-8-ol (74) (50.7 mg, 91% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.22 (s, 1H), 8.01 (d, J = 10.0 Hz, 1H), 6.63 (d, J = 9.6 Hz, 1H), 2.30-2.24 (m, 1H), 1.17 - 1.12 (m, 2H), 0.97 - 0.91(m, 2H). MS calculated: 264.03; MS found: 265.1, 267.0 [M+H] + .

[0481] Example 75 Synthesis of 3-cyclopropyl-4-methoxy-7-nitroquinolin-8-ol (75)

[0482] [ka]

[0483] 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 mixture of 1-methyl-2-pyrrolidone (1.0 mL) and dimethyl sulfoxide (1.0 mL) at room temperature. The resulting mixture was stirred at 120 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by reversed-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-10% / 90%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, flow rate: 20.0 mL / min) to give 3-cyclopropyl-4-methoxy-7-nitroquinolin-8-ol (75) (10.7 mg, yield: 26%). 1 H NMR (400 MHz, DMSO-d6) δ: 7.97 (d, J = 9.6 Hz, 1H), 7.86 (s, 1H), 6.80 (d, J = 10.0 Hz, 1H), 3.98 (s, 3H), 2.29 - 2.27 (m, 1H), 1.13 - 1.07 (m, 2H), 1.06 - 1.01 (m, 2H). MS calculated: 260.08; MS found: 261.1 [M+H] + .

[0484] Example 76 Synthesis of 8-hydroxy-7-nitroquinoline-4-carbonitrile (76)

[0485] [ka]

[0486] 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×2) and dried in vacuo to give 8-methoxyquinoline-4-carbonitrile (76a) (650.0 mg, 84% yield).

[0487] At 0°C, 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). The reaction mixture was stirred at 0°C for 10 minutes, followed by the slow dropwise addition of sulfuric acid (98 wt%) (0.1 mL, 1.87 mmol), and stirring was continued for 30 minutes. The pH of the aqueous phase was adjusted to approximately 9 to 10 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, 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 give 8-methoxy-7-nitroquinoline-4-carbonitrile (76b) (65.0 mg, yield 26%).

[0488] At room temperature, 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). 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 successively with ethanol (2.0 mL) and water (2.0 mL) and evaporated to dryness in vacuo to give 8-hydroxy-7-nitroquinoline-4-carbonitrile (76) (44.0 mg, 72% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.75 (d, J = 4.4 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 4.4 Hz, 1H), 6.54 (d, J = 9.6 Hz, 1H). MS calculated: 215.03; MS found: 216.1 [M+H] + .

[0489] Example 77 Synthesis of 4-(difluoromethoxy)-7-nitroquinolin-8-ol (77)

[0490] [ka]

[0491] 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 and then at 80 °C for 30 minutes, 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 × 3). The combined organic phase was 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%).

[0492] 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 × 3) and evaporated to dryness in vacuo to give 4-(difluoromethoxy)-7-nitroquinolin-8-ol (77) (37.2 mg, 74% yield). 1 H NMR (400 MHz, 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). MS calculated: 256.03; MS found: 257.1 [M+H] + .

[0493] Example 78 Synthesis of 3-(8-hydroxy-7-nitroquinolin-4-yl)-N-acryloylmorpholine (78)

[0494] [ka]

[0495] At room temperature, 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), 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 and then diluted with ethyl acetate (100.0 mL) and water (100.0 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50.0 mL x 3). The combined organic phase was 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 give 8-methoxy-7-nitroquinolin-4-yl trifluoromethanesulfonate (78a) (3.99 g, yield 50%).

[0496] At room temperature, 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), tris(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). 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. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20.0 mL × 2). The combined organic phase was 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 methyl 3-(8-methoxy-7-nitroquinolin-4-yl)acrylate (78b) (618.9 mg, yield 19%).

[0497] Methyl 3-(8-methoxy-7-nitroquinolin-4-yl)acrylate (78b) (618.9 mg, 2.15 mmol) was added to a mixture 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 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. The pH of the aqueous phase was adjusted to approximately 3 to 4 with a 1.0 M hydrochloric acid solution. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (2.0 mL × 2) and evaporated to dryness in vacuo to give 3-(8-methoxy-7-nitroquinolin-4-yl)acrylic acid (78c) (560.1 mg, 95% yield).

[0498] 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 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. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10.0 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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%).

[0499] 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 purified by reversed-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0-80% / 20%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, flow rate: 20.0 mL / min) to obtain 3-(8-hydroxy-7-nitroquinolin-4-yl)-N-acryloylmorpholine (78) (20.2 mg, yield 24%). 1H NMR (400 MHz, DMSO-d6) δ: 8.70 (d, J = 4.6 Hz, 1H), 8.09 (d, J = 15.6 Hz, 1H), 8.02 (d, J = 9.6 Hz, 1H), 7.99 (d, J = 4.6 Hz, 1H), 7.51 (d, J = 15.2 Hz, 1H), 6.87 (d, J = 10.0 Hz, 1H), 3.81 - 3.74 (m, 2H), 3.68 - 3.60 (m, 4H), 3.44 - 3.37 (m, 2H). MS calculated: 329.10; MS found: 330.2 [M+H] + .

[0500] Example 79 Synthesis of 3-(8-hydroxy-7-nitroquinolin-4-yl)-N-methacrylamide (79)

[0501] [ka]

[0502] 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 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. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10.0 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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%).

[0503] 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 purified by reversed-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / methanol = 100% / 0 to 80% / 20%, gradient elution, 0.1% formic acid added to the mobile phase by volume percentage, flow rate: 20.0 mL / min) to obtain 3-(8-hydroxy-7-nitroquinolin-4-yl)-N-methacrylamide (79) (18.7 mg, yield: 19%). 1H NMR (400 MHz, DMSO-d6) δ: 9.03 (d, J = 4.8 Hz, 1H), 8.44 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 9.6 Hz, 1H), 8.08 (d, J = 16.0 Hz, 1H), 7.97 (d, J = 4.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 6.92 (d, J = 15.6 Hz, 1H), 2.79 (d, J = 4.8 Hz, 3H). MS calculated: 273.07; MS found: 274.1 [M+H] + .

[0504] Example 80 Synthesis of 4-ethynyl-7-nitroquinolin-8-ol (80)

[0505] [ka]

[0506] At 0°C, 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), followed by the slow, dropwise addition of trifluoromethanesulfonic anhydride (751.0 mg, 2.66 mmol). The reaction mixture was warmed to room temperature and stirred for 3.5 hours, followed by the slow, dropwise addition of sodium iodide (1.02 g, 6.8 mmol). Trifluoromethanesulfonic acid (0.2 mL, 2.26 mmol) was added dropwise 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 with saturated aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (10.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate=5 / 1) to give 4-iodo-8-methoxy-7-nitroquinoline (80a) (210.0 mg, yield 47%).

[0507] At room temperature, (trimethylsilyl)acetylene (188.0 mg, 1.9 mmol), bis(triphenylphosphine)palladium(II) chloride (45.0 mg, 0.06 mmol), copper iodide (6.0 mg, 0.03 mmol), and triethylamine (0.27 mL, 1.9 mmol) were added sequentially to a solution of 4-iodo-8-methoxy-7-nitroquinoline (80a) (210.0 mg, 0.64 mmol) in N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at 60 °C for 16 h, 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 give 8-methoxy-7-nitro-4-((trimethylsilyl)ethynyl)quinoline (80b) (91.0 mg, 48% yield).

[0508] 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. Water (2.0 mL) was added to the resulting residue, stirred for 3 minutes, and filtered under reduced pressure. A mixture 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 evaporated to dryness in vacuo to give 4-ethynyl-7-nitroquinolin-8-ol (80) (57.0 mg, 99% yield). 1 H NMR (400 MHz, 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). MS calculated: 214.04; MS found: 215.1 [M+H]+ .

[0509] Example 81 Synthesis of 4-(difluoromethyl)-7-nitroquinolin-8-ol (81)

[0510] [ka]

[0511] At room temperature, 8-methoxy-7-nitroquinolin-4-ol (30a) (1.5 g, 6.81 mmol) was added to phosphorus oxychloride (15.0 mL). 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 to 9 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 2). The combined organic phase was 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).

[0512] 4-Chloro-8-methoxy-7-nitroquinoline (81a) (510.0 mg, 2.13 mmol), potassium vinyltrifluoroborate (458.0 mg, 3.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (234.0 mg, 0.32 mmol), and potassium carbonate (885.0 mg, 6.41 mmol) were added sequentially to a mixture 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. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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%).

[0513] At 0°C, 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 mixture of tetrahydrofuran (18.0 mL) and water (4.5 mL). The reaction mixture was stirred at 0°C for 10 minutes, followed by the addition of sodium periodate (975.0 mg, 4.56 mmol). The resulting mixture was warmed to room temperature, stirred for 16 hours, 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 phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 8-methoxy-7-nitroquinoline-4-carbaldehyde (81c) (355.0 mg, crude yield 100%).

[0514] At 0 °C, 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). The reaction mixture was stirred at 0 °C for 10 minutes and at room temperature for 3 hours. The pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 2). The combined organic phase was 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-(difluoromethyl)-8-methoxy-7-nitroquinoline (81d) (65.0 mg, 69% yield).

[0515] At room temperature, 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). 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 mixture 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 evaporated to dryness to give 4-(difluoromethyl)-7-nitroquinolin-8-ol (81) (47.3 mg, 77% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.74 (d, J = 4.3 Hz, 1H), 8.03 (d, J = 9.6 Hz, 1H), 7.72 (d, J = 4.3 Hz, 1H), 7.55 (t, J = 54.0 Hz, 1H), 6.62 (d, J = 9.6 Hz, 1H). MS calculated: 240.03; MS found: 241.1 [M+H] + .

[0516] Example 82 Synthesis of 4-chloro-7-nitro-3-phenylquinolin-8-ol (82)

[0517] [ka]

[0518] At room temperature, 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 mixture of toluene (3.0 mL) and water (0.5 mL). 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 × 2). The combined organic phase was 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, yield 51%).

[0519] At room temperature, 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). 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. A mixture 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 evaporated to dryness to give 4-chloro-7-nitro-3-phenylquinolin-8-ol (82) (57.0 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.54 (s, 1H), 8.09 (d, J = 9.7 Hz, 1H), 7.61 - 7.50 (m, 5H), 6.73 (d, J = 9.7 Hz, 1H). MS calculated: 300.03; MS found: 301.1 / 303.0 [M+H] + .

[0520] Example 83 Synthesis of 5-chloro-3-methyl-7-nitroquinolin-8-ol (83)

[0521] [ka]

[0522] 5-Chloro-2-methoxyaniline (49a) (3.0 g, 19.0 mmol) was added to a 6.0 M hydrochloric acid solution (30.0 mL) at room temperature. The reaction mixture was heated to 100 °C, followed by the slow dropwise addition of 2-methacrolein (3.34 g, 47.7 mmol). The reaction mixture was stirred at 100 °C for 2 hours and then cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 7 to 8 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (50.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 7 / 1 to 3 / 1) to give 3-methyl-5-chloro-8-methoxyquinoline (83a) (1.35 g, 34% yield).

[0523] At 0°C, 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). The reaction mixture was stirred at 0°C for 5 minutes, followed by the slow dropwise addition of sulfuric acid (98 wt%) (0.35 mL, 6.5 mmol), and stirring was continued for 30 minutes. The pH of the aqueous phase was adjusted to approximately 9 to 10 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, 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 give 3-methyl-5-chloro-7-nitro-8-methoxyquinoline (83b) (0.64 g, yield 39%).

[0524] 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 × 2) and evaporated to dryness in vacuo to give 3-methyl-5-chloro-7-nitro-8-hydroxyquinoline (83) (19.0 mg, 67% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.03 (d, J = 12.3 Hz, 2H), 2.50 (s, 3H). MS calculated: 238.01; MS found: 239.0 [M+H] + .

[0525] Example 84 Synthesis of 5-cyclopropyl-3-methyl-7-nitroquinolin-8-ol (84)

[0526] [ka]

[0527] 5-Bromo-2-methoxyaniline (84a) (1.5 g, 7.43 mmol) was added to 40.0 mL of 6.0 M hydrochloric acid solution at room temperature. The reaction mixture was heated to 110 °C, followed by the slow dropwise addition of 2-methacrolein (1.8 mL, 22.2 mmol) and stirring for 3 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7 to 8 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with ethyl acetate (50.0 mL × 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 = 7 / 3) to give 5-bromo-8-methoxy-3-methylquinoline (84b) (1.0 g, 53% yield).

[0528] 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, followed by the addition of sulfuric acid (98 wt%) (0.12 mL, 2.4 mmol), and stirring was continued for 2 hours. The reaction mixture was diluted with water (30.0 mL), and the pH of the aqueous phase was adjusted to approximately 8 to 9 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate=85% / 15%) to give 5-bromo-8-methoxy-3-methyl-7-nitroquinoline (84c) (50.0 mg, yield 17%).

[0529] 5-Bromo-8-methoxy-3-methyl-7-nitroquinoline (84c) (50.0 mg, 0.17 mmol), cyclopropylboronic acid (29.0 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (39.0 mg, 0.034 mmol), and potassium carbonate (70.4 mg, 0.51 mmol) were added sequentially to a mixture of toluene (3.0 mL) and water (0.3 mL) at room temperature. The reaction mixture was stirred at 105 °C for 3 h, cooled to room temperature, and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 5-cyclopropyl-8-methoxy-3-methyl-7-nitroquinoline (84d) (28.0 mg, 64% yield).

[0530] 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 successively with water (0.5 mL × 2) and ethanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 5-cyclopropyl-3-methyl-7-nitroquinolin-8-ol (84) (16.0 mg, 60% yield). 1 H NMR (400 MHz, 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). MS calculated: 244.08; MS found: 245.1 [M+H] + .

[0531] Example 85 Synthesis of 7-nitro-4-(piperidin-1-yl-methyl)quinolin-8-ol (85)

[0532] [ka]

[0533] 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 mixture of tetrahydrofuran (3.0 mL) and dichloromethane (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 90 minutes, followed by the addition of sodium triacetoxyborohydride (301.0 mg, 1.42 mmol), and stirring was continued for 3 hours. The pH of the aqueous phase was adjusted to approximately 7 to 8 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, 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 obtain 8-methoxy-7-nitro-4-(piperidin-1-ylmethyl)quinoline (85a) (130.0 mg, yield 72%).

[0534] At room temperature, 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). 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 mixture 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 evaporated to dryness to give 7-nitro-4-(piperidin-1-yl-methyl)quinolin-8-ol (85) (112.0 mg, 91% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 4.3 Hz, 1H), 7.92 (d, J = 9.7 Hz, 1H), 7.54 (d, J = 4.3 Hz, 1H), 6.76 (d, J = 9.7 Hz, 1H), 3.76 (s, 2H), 2.43 (s, 4H), 1.53 (d, J = 4.8 Hz, 4H), 1.43 (d, J = 3.6 Hz, 2H). MS calculated: 287.13; MS found: 288.1 [M+H] + .

[0535] Example 86 Synthesis of 5-fluoro-3-methyl-7-nitroquinolin-8-ol (86)

[0536] [ka]

[0537] 2-Amino-4-fluorophenol (86a) (2.00 g, 15.7 mmol) was added to 20.0 mL of 6.0 M hydrochloric acid solution at room temperature. The reaction mixture was heated to 100 °C, and then 2-methacrolein (3.3 mL, 39.4 mmol) was added dropwise slowly and stirred for 2 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7 to 8 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with dichloromethane (50.0 mL × 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 give 5-fluoro-3-methylquinolin-8-ol (86b) (400 mg, 14.3% yield).

[0538] 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 to 9 with saturated aqueous sodium bicarbonate. 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 × 2) and evaporated to dryness in vacuo to give 5-fluoro-3-methyl-7-nitroquinolin-8-ol (86) (65.0 mg, 58% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 12.5 Hz, 1H), 2.49 (s, 3H). MS calculated: 222.04; MS found: 223.0 [M+H] + .

[0539] Example 87 Synthesis of 5-(morpholinomethyl)-7-nitroquinolin-8-ol acetate (87)

[0540] [ka]

[0541] At 0 °C, 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). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 49 / 1, with 0.5% ammonia (25 to 28 wt%, NH content) added depending on the total volume of the eluent) to give 5-(morpholinomethyl)quinolin-8-ol (87b) (80.0 mg, 53% yield).

[0542] 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 × 2) and evaporated to dryness in vacuo to give 5-(morpholinomethyl)-7-nitroquinolin-8-ol acetate (87) (76.0 mg, 45% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 9.08 - 9.035 (m, 1H), 9.02 - 8.97 (m, 1H), 8.42 - 8.36 (s, 1H), 8.01 - 7.95 (m, 1H), 4.80 - 4.70 (m, 2H), 3.96 - 3.64 (m, 4H), 3.35 - 3.22 (m, 4H). MS calculated: 289.11; MS found: 290.1 ​​[M+H] + .

[0543] Example 88 Synthesis of ethyl 8-hydroxy-7-nitroquinoline-3-carboxylate (88)

[0544] [ka]

[0545] At room temperature, 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). 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), followed by the addition of triethylamine (4.91 g, 48.5 mmol). The mixture was stirred for 30 minutes and filtered under reduced pressure. The filter cake was washed with dichloromethane (5.0 mL × 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).

[0546] Ethyl 4-chloro-8-methoxyquinoline-3-carboxylate (88b) (2.1 g, 7.9 mmol), triethylamine (1.2 g, 11.9 mmol), and palladium on carbon (palladium loading: 10 wt%) (0.42 g, 0.39 mmol) were added sequentially to a mixture of tetrahydrofuran (10 mL) and methanol (10 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours and then filtered through diatomaceous earth. The filter cake was washed with tetrahydrofuran (10 mL × 3), and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product ethyl 8-methoxyquinoline-3-carboxylate (88c) (1.8 g, 99% yield).

[0547] Nitric acid (65 wt%) (0.45 mL, 6.5 mmol) was slowly added to a solution of ethyl 8-methoxyquinoline-3-carboxylate (88c) (500 mg, 2.2 mmol) in acetic anhydride (10 mL) at 0°C and stirred for 10 minutes. 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 and diluted with water (20 mL). The pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with dichloromethane (30 mL × 3). 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 ethyl 8-methoxy-7-nitroquinoline-3-carboxylate (88d) (88.0 mg, yield 15%).

[0548] 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 mL × 2) and evaporated to dryness in vacuo to give ethyl 8-hydroxy-7-nitroquinoline-3-carboxylate (88) (71.0 mg, 85% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.63 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 9.3 Hz, 1H), 6.60 (d, J = 9.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). MS calculated: 262.06; MS found: 263.1 [M+H] + .

[0549] Example 89 Synthesis of 4-(morpholinomethyl)-7-nitroquinolin-8-ol (89)

[0550] [ka]

[0551] 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 mixture of tetrahydrofuran (2.0 mL) and dichloromethane (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of sodium triacetoxyborohydride (210.0 mg, 0.99 mmol), and stirring was continued for 4.5 hours. The pH of the aqueous phase was adjusted to approximately 7 to 8 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, 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 = 80 / 1 to 70 / 1) to give 4-((8-methoxy-7-nitroquinolin-4-yl)methyl)morpholine (89a) (61.0 mg, yield 61%).

[0552] At room temperature, 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). 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 mixture 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 evaporated to dryness to give 4-(morpholinomethyl)-7-nitroquinolin-8-ol (89) (38.9 mg, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 9.7 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 6.78 (d, J = 9.7 Hz, 1H), 3.82 (s, 2H), 3.66 - 3.58 (m, 4H), 2.47 (br s, 4H). MS calculated: 289.11; MS found: 290.1 ​​[M+H] + .

[0553] Example 90 Synthesis of 5-chloro-3-((diethylamino)methyl)-7-nitroquinolin-8-ol ditrifluoroacetate (90)

[0554] [ka]

[0555] 5-Chloro-2-methoxyaniline (49a) (6.0 g, 38.0 mmol) was added to 60.0 mL of 6.0 M hydrochloric acid solution at room temperature. The reaction mixture was heated to 100 °C, and then 2-methacrolein (7.8 mL, 95.4 mmol) was added dropwise slowly and stirred for 2 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7 to 8 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with dichloromethane (100.0 mL × 3). 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: petroleum ether / ethyl acetate = 7 / 1 to 3 / 1) to give 5-chloro-8-methoxy-3-methylquinoline (90a) (2.7 g, 34% yield).

[0556] 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, followed by the slow dropwise addition of sulfuric acid (98 wt%) (0.39 mL, 7.2 mmol), and stirring was continued for 2 hours. The reaction mixture was diluted with water (50.0 mL), and the pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous potassium carbonate. The resulting mixture was extracted with dichloromethane (50.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate=10 / 1) to give 5-chloro-8-methoxy-3-methyl-7-nitroquinoline (90b) (660.0 mg, yield 36%).

[0557] At room temperature, 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). The reaction mixture was warmed to 80 °C and stirred for 12 h, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with carbon tetrachloride (10.0 mL × 3), and the filtrate was concentrated under reduced pressure to give crude product 3-(bromomethyl)-5-chloro-8-methoxy-7-nitroquinoline (90c) (838.0 mg, crude yield >100%).

[0558] Crude 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 concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 5-chloro-3-(diethylamino)methyl-8-methoxy-7-nitroquinoline (90d) (65.0 mg, 65% yield).

[0559] 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 resulting residue was completely dissolved in a mixed solvent of trifluoroacetic acid (0.5 mL) and water (2.0 mL) and purified by reversed-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), mobile phase: water / acetonitrile = 100% / 0 to 75% / 25%, gradient elution, flow rate: 20.0 mL / min) to obtain 5-chloro-3-((diethylamino)methyl)-7-nitroquinolin-8-ol ditrifluoroacetate (90) (17.0 mg, yield: 16%). 1 H NMR (400 MHz, 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, 6.8 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H). MS calculated: 309.09; MS found: 310.1 [M+H] + .

[0560] Example 91 Synthesis of 7-nitro-5-(piperidin-1-ylmethyl)quinolin-8-ol acetate (91)

[0561] [ka]

[0562] At 0°C, 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). 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% ammonia (25 to 28 wt%, NH content) added depending on the total volume of the eluent) to give 5-(piperidin-1-ylmethyl)quinolin-8-ol (91a) (100.0 mg, 67% yield).

[0563] 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 × 2) and evaporated to dryness to give 7-nitro-5-(piperidin-1-ylmethyl)quinolin-8-ol acetate (91) (129.0 mg, 88% yield). 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, 3.57 H, methyl signal of acetate), 1.80–1.65 (m, 4H), 1.60–1.45 (m, 2H). MS calculated: 287.11; MS found: 288.1 [M+H]+ .

[0564] Example 92 Synthesis of 5-chloro-7-nitro-3-(piperidin-1-ylmethyl)quinolin-8-ol (92)

[0565] [ka]

[0566] Crude 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 concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: dichloromethane / methanol = 25 / 1) to give 5-chloro-8-methoxy-7-nitro-3-(piperidin-1-ylmethyl)quinoline (92a) (35.0 mg, 39% yield).

[0567] At room temperature, 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). 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 × 3) and evaporated to dryness in vacuo to give 5-chloro-7-nitro-3-(piperidin-1-ylmethyl)quinolin-8-ol (92) (30.7 mg, 92% yield). 1H NMR (400 MHz, 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). MS calculated: 321.09; MS found: 322.1 [M+H] + .

[0568] Example 93 Synthesis of 7-nitro-5-(pyrrolidin-1-ylmethyl)quinolin-8-ol acetate (93)

[0569] [ka]

[0570] At 0°C, 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). 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% ammonia (25 to 28 wt%, NH content) added depending on the total volume of the eluent) to give 5-(pyrrolidin-1-ylmethyl)quinolin-8-ol (93a) (55.0 mg, 47% yield).

[0571] 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 × 2) and evaporated to dryness to give 7-nitro-5-(pyrrolidin-1-ylmethyl)quinolin-8-ol acetate (93) (22.7 mg, 31% yield). 1H NMR (400 MHz, 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, 1.34 H, overlapped with CH3COOH in a 1:0.45 molar ratio). MS calculated: 273.11; MS found: 274.1 [M+H] + .

[0572] Example 94 Synthesis of 5-((diethylamino)methyl)-7-nitroquinolin-8-ol (94)

[0573] [ka]

[0574] At 0°C, 5-(chloromethyl)quinolin-8-ol hydrochloride (87a) (110.0 mg, 0.48 mmol) and diethylamine (140.0 mg, 1.91 mmol) were added sequentially to dichloromethane (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. Acetic acid (2.0 mL) was added to the resulting residue, followed by sodium nitrite (99.0 mg, 1.43 mmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The resulting residue was purified by reversed-phase high-performance liquid chromatography (the chromatography column was an Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), the mobile phase was water / methanol = 100% / 0 to 70% / 30%, gradient elution, and the flow rate was 20.0 mL / min) to obtain 5-((diethylamino)methyl)-7-nitroquinolin-8-ol (94) (27.0 mg, yield 31%). 1H NMR (400 MHz, DMSO-d6) δ: 8.82-8.75 (m, 1H), 8.56-8.49 (m, 1H), 8.07 (s, 1H), 7.67-7.62 (m, 1 H), 4.21 (s, 2 H), 2.95-2.88 (m, 4 H), 1.20-1.15 (m, 4 H). MS calculated: 275.13; MS found: 276.1 [M+H] + .

[0575] Example 95 Synthesis of 7-nitro-3-(piperidin-1-ylmethyl)quinolin-8-ol (95)

[0576] [ka]

[0577] Sodium methoxide (5.35 g, 99.0 mmol) was slowly added to a solution of 2,6-dinitrochlorobenzene (modified in the scheme) (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 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 the aqueous phase was extracted with dichloromethane (20.0 mL × 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 give the crude product 2-methoxy-1,3-dinitrobenzene (95b) (4.56 g, 99% yield).

[0578] At room temperature, 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). The reaction mixture was stirred at 65 °C for 1.5 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. Dichloromethane (20.0 mL) was added to the resulting residue, and the pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous sodium bicarbonate solution. The resulting mixture was filtered under reduced pressure. 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 give 2-methoxy-3-nitroaniline (95c) (3.23 g, 84% yield).

[0579] 2-Methoxy-3-nitroaniline (95c) (3.23 g, 19.2 mmol) was added to 60.0 mL of 6.0 M hydrochloric acid solution at room temperature. The reaction mixture was heated to 100 °C, and then 2-methacrolein (3.96 mL, 48.0 mmol) was added dropwise slowly and stirred for 2 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7 to 8 with aqueous sodium hydroxide (6.0 M). The resulting mixture was extracted with dichloromethane (50.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate = 85% / 15%) to give 8-methoxy-3-methyl-7-nitroquinoline (95d) (1.67 g, 40% yield).

[0580] 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 warmed to 90 °C and stirred for 16 h, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with carbon tetrachloride (5.0 mL × 3), and the filtrate was concentrated under reduced pressure to give crude product 3-(bromomethyl)-8-methoxy-7-nitroquinoline (95e) (143.0 mg, crude yield >100%).

[0581] At room temperature, 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). The reaction mixture was stirred at room temperature for 2 hours and 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 × 2). The combined organic phase was 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=80 / 1 to 60 / 1) to give 8-methoxy-7-nitro-3-(piperidin-1-ylmethyl)quinoline (95f) (37.0 mg, yield 25%).

[0582] At room temperature, 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). 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 evaporated to dryness to give 7-nitro-3-(piperidin-1-ylmethyl)quinolin-8-ol (95) (21.3 mg, 60% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.53 (s, 1H), 7.97 (s, 1H), 7.90 (d, J = 9.4 Hz, 1H), 6.50 (d, J = 9.4 Hz, 1H), 3.60 (s, 2H), 2.38 (s, 4H), 1.59 - 1.48 (m, 4H), 1.42 (d, J = 4.4 Hz, 2H). MS calculated: 287.13; MS found: 288.1 [M+H] + .

[0583] Example 96 Synthesis of 5-chloro-3-(morpholinomethyl)-7-nitroquinolin-8-ol (96)

[0584] [ka]

[0585] Crude 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 concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: dichloromethane / methanol = 24 / 1) to give 5-chloro-8-methoxy-7-nitro-3-(morpholinemethyl)quinoline (96a) (52.0 mg, 45% yield).

[0586] 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 mixture of ethanol and water (volume ratio, ethanol / water = 1 / 1) (0.5 mL × 2) and evaporated to dryness in vacuo to give 5-chloro-3-(morpholinomethyl)-7-nitroquinolin-8-ol (96) (38.7 mg, 78% yield). 1 H NMR (400 MHz, 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). MS calculated: 323.07; MS found: 324.1 [M+H] + .

[0587] Example 97 Synthesis of 3-(morpholinomethyl)-7-nitroquinolin-8-ol (97)

[0588] [ka]

[0589] At room temperature, 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). The reaction mixture was stirred at room temperature for 2 hours and 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 × 2). The combined organic phase was 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 give 8-methoxy-7-nitro-3-(morpholinemethyl)quinoline (97a) (61.0 mg, yield 25%).

[0590] At room temperature, 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). 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 evaporated to dryness in vacuo to give 3-(morpholinomethyl)-7-nitroquinolin-8-ol (97) (48.5 mg, 83% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.55 (s, 1H), 8.01 (s, 1H), 7.91 (d, J = 9.4 Hz, 1H), 6.51 (d, J = 9.4 Hz, 1H), 3.64 (s, 2H), 3.62 - 3.58 (m, 4H), 2.41 (s, 4H). MS calculated: 289.11; MS found: 290.2 [M+H] + .

[0591] Example 98 Synthesis of 3-((diethylamino)methyl)-7-nitroquinolin-8-ol (98)

[0592] [ka]

[0593] At room temperature, 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). The reaction mixture was stirred at room temperature for 2 hours and 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 × 2). The combined organic phase was 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 give 8-methoxy-7-nitro-3-((diethylamino)methyl)quinoline (98a) (47.0 mg, yield 20%).

[0594] At room temperature, 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). 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 evaporated to dryness in vacuo to give 3-((diethylamino)methyl)-7-nitroquinolin-8-ol (98) (25.8 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.55 (s, 1H), 7.99 (s, 1H), 7.90 (d, J = 9.4 Hz, 1H), 6.50 (d, J = 9.4 Hz, 1H), 3.69 (s, 2H), 2.52 - 2.47 (m, 4H), 1.02 (t, J = 7.1 Hz, 6H). MS calculated: 275.13; MS found: 276.2 [M+H] + .

[0595] Example 99 Synthesis of 5-((methylamino)methyl)-7-nitroquinolin-8-ol dihydrochloride (99)

[0596] [ka]

[0597] 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 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 to dryness under reduced pressure to give crude product tert-butyl N-((8-hydroxyquinolin-5-yl)methyl)-N-methylcarbamate (99a) (436.6 mg, crude yield >100%).

[0598] 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 concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (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).

[0599] 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 concentrated to dryness under reduced pressure to give 5-((methylamino)methyl)-7-nitroquinolin-8-ol dihydrochloride (99) (27.0 mg, 98% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (br s, 2H), 9.07 (d, J = 3.2 Hz, 1H), 8.96 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 7.97 (dd, J = 8.8, 4.4 Hz, 1H), 4.59 (t, J = 4.8 Hz, 2H), 2.65 (t, J = 4.8 Hz, 3H). MS calculated: 233.08; MS found: 234.1 [M+H] + .

[0600] Example 100 Synthesis of 4-((8-hydroxy-7-nitroquinolin-3-yl)methyl)piperazin-2-one (100)

[0601] [ka]

[0602] At room temperature, 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). 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. The reaction mixture was stirred at room temperature for 2 hours and 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 × 2). The combined organic phase was 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=15 / 1) to give 4-((8-methoxy-7-nitroquinolin-3-yl)methyl)piperazin-2-one (100a) (75.0 mg, yield 26%).

[0603] 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 purified by reverse-phase high-performance liquid chromatography (the chromatography column was an Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm), the mobile phase was water / acetonitrile = 100% / 0 to 70% / 30%, gradient elution, and the flow rate was 20.0 mL / min) to obtain 4-((8-hydroxy-7-nitroquinolin-3-yl)methyl)piperazin-2-one (100) (41.3 mg, yield 58%). 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.05 (s, 1H), 7.92 (d, J = 9.4 Hz, 1H), 7.83 (s, 1H), 6.53 (d, J = 9.4 Hz, 1H), 3.73 (s, 2H), 3.18 (s, 2H), 3.00 (s, 2H), 2.60 (t, J = 5.2 Hz, 2H). MS calculated: 302.10; MS found: 303.1 [M+H] + .

[0604] Example 101 Synthesis of 7-nitro-5-(piperazin-1-ylmethyl)quinolin-8-ol trihydrochloride (101)

[0605] [ka]

[0606] At 0 °C, 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). 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% ammonia (25 to 28 wt%, NH content) added depending on the total volume of the eluent) to give tert-butyl 4-((8-hydroxyquinolin-5-yl)methyl)piperazine-1-carboxylate (101a) (100.0 mg, 97% yield).

[0607] 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 × 2) and evaporated to dryness in vacuo to give tert-butyl 4-((8-hydroxy-7-nitroquinolin-5-yl)methyl)piperazine-1-carboxylate (101b) (30.0 mg, 29% yield).

[0608] 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 concentrated to dryness under reduced pressure to give 7-nitro-5-(piperazin-1-ylmethyl)quinolin-8-ol trihydrochloride (101) (24.0 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.09 (br s, 1H), 9.15 (s, 1H), 9.04 (d, J = 4.0 Hz, 1H), 8.49 (s, 1H), 7.95 (dd, J = 8.4, 4.2 Hz, 1H), 4.95 - 4.72 (m, 2H), 3.46 - 3.38 (m, 2H). MS calculated: 288.12; MS found: 289.1 [M+H] + .

[0609] Example 102 Synthesis of 7-nitro-3-(piperazin-1-ylmethyl)quinolin-8-ol trihydrochloride (102)

[0610] [ka]

[0611] At room temperature, 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). The reaction mixture was stirred at room temperature for 2 hours and 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 × 2). The combined organic phase was 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=70 / 1) to give tert-butyl 4-((8-methoxy-7-nitroquinolin-3-yl)methyl)piperazine-1-carboxylate (102a) (83.0 mg, yield 23%).

[0612] At room temperature, 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). 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 evaporated to dryness to give tert-butyl 4-((8-hydroxy-7-nitroquinolin-3-yl)methyl)piperazine-1-carboxylate (102b) (80.0 mg, 99% yield).

[0613] At room temperature, 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). The reaction mixture was stirred at room temperature for 2 hours and 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 × 2) and evaporated to dryness in vacuo to give 7-nitro-3-(piperazin-1-ylmethyl)quinolin-8-ol trihydrochloride (102) (62.7 mg, 77% yield). 1 H NMR (400 MHz, D2O-d6) δ: 10.03 (s, 2H), 9.31 (s, 1H), 8.76 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 4.66 (s, 2H), 3.45 (m, 8H). MS calculated: 288.12; MS found: 289.1 [M+H] + .

[0614] (Example 103) Synthesis of 5-((ethylamino)methyl)-7-nitroquinolin-8-ol dihydrochloride (103)

[0615] [ka]

[0616] At 0°C, 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). The reaction mixture was stirred at 85°C for 2 hours, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with acetonitrile (1.0 mL × 2), and the filtrate was concentrated to dryness under reduced pressure to give tert-butyl N-(8-hydroxyquinolin-5-yl)methyl-N-ethylcarbamate (103a) (94.0 mg, 60% yield).

[0617] 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 then filtered under reduced pressure. The resulting filtrate was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (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).

[0618] 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 concentrated to dryness under reduced pressure to give 5-((ethylamino)methyl)-7-nitroquinolin-8-ol dihydrochloride (103) (26.0 mg, 88% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 9.30 (br s, 2H), 9.08 (d, J = 4.0 Hz, 1H), 8.97 (d, J = 8.6 Hz, 1H), 8.43 (s, 1H), 7.97 (dd, J = 8.4, 4.4 Hz, 1H), 4.59 (t, J = 5.6 Hz, 2H), 3.11 (dd, J = 12.4, 6.8 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS calculated: 247.25; MS found: 248.1 [M+H] + .

[0619] Example 104 Synthesis of 5-((dimethylamino)methyl)-7-nitro-4-(trifluoromethyl)quinolin-8-ol (104)

[0620] [ka]

[0621] 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, stirred for 1 h, cooled to 0 °C, and then water (4.0 mL) was added and stirred for 30 min. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with petroleum ether (boiling point range: 60 °C to 90 °C) (25.0 mL × 3) and evaporated to dryness in vacuo to give crude product 4,4,4-trifluoro-N-(2-methoxy-5-methylphenyl)-3-oxobutanamide (104b) (28.0 g, crude yield 51%).

[0622] Crude 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, stirred for 1 h, cooled to approximately 60 to 70 °C, and then ice water (100.0 mL) was added. The mixture was stirred vigorously for 30 min and filtered under reduced pressure. The filter cake was washed with water (20.0 mL × 4) and evaporated to dryness in vacuo to give crude 8-methoxy-5-methyl-4-trifluoromethyl-2(1H)-quinolinone (104c) (5.0 g, 89% crude yield).

[0623] The 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 then ice water (100.0 mL) was added. The mixture was vigorously stirred for 30 minutes and filtered under reduced pressure. The filter cake was washed with water (20.0 mL × 3) and evaporated to dryness in vacuo to give the crude product 2-chloro-8-methoxy-5-methyl-4-(trifluoromethyl)quinoline (104d) (4.5 g, crude yield 84%).

[0624] Crude 2-chloro-8-methoxy-5-methyl-4-(trifluoromethyl)quinoline (104d) (1.7 g, 6.17 mmol) and aqueous hydrazine hydrate (80 wt %) (2.2 g, 43.17 mmol) were added sequentially to ethanol (20 mL) at room temperature, followed by the addition of palladium on carbon (palladium loading: 10 wt %) (0.17 g, 0.16 mmol). The reaction mixture was stirred at 90 °C for 5 hours, cooled to room temperature, and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (10 mL × 4), and the filtrate was concentrated under reduced pressure. Ethyl acetate (20 mL) and water (20 mL) were added to the resulting residue. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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%).

[0625] 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 and stirred for 10 minutes. 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 the pH of the aqueous phase was adjusted to approximately 9-10 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with ethyl acetate (50.0 mL × 2). 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 (eluent: petroleum ether / ethyl acetate=20 / 1) to give 8-methoxy-5-methyl-7-nitro-4-(trifluoromethyl)quinoline (104f) (0.15 g, yield 8%).

[0626] 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 and 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 give 5-(bromomethyl)-8-methoxy-7-nitro-4-(trifluoromethyl)quinoline (104g) (100.0 mg, 74% yield).

[0627] Dimethylamine hydrochloride (44.6 mg, 0.55 mmol) and triethylamine (110.9 mg, 1.10 mmol) were added sequentially 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) at room temperature. 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: petroleum ether / ethyl acetate = 3 / 1) to give 5-((dimethylamino)methyl)-8-methoxy-7-nitro-4-(trifluoromethyl)quinoline (104h) (70.0 mg, 79% yield).

[0628] At room temperature, 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). The reaction mixture was stirred at 150 °C for 1 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm); mobile phase: water / acetonitrile = 100% / 0 to 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). 1 H NMR (400 MHz, MeOH-d4) δ 9.18 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 4.77 (s, 2H), 2.82 (s, 6H). MS calculated: 315.08; MS found: 316.1 [M+H] + .

[0629] Example 105 Synthesis of 7-nitro-4-(piperidin-4-yl)quinolin-8-ol (105)

[0630] [ka]

[0631] At room temperature, 4-bromo-8-methoxyquinoline (11b) (3.0 g, 12.68 mmol) and N-tert-butoxycarbonyl-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 mL) and water (15 mL). Sodium carbonate (4.03 g, 38.04 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.03 g, 1.27 mmol) were added sequentially. The resulting reaction mixture was stirred at 80 °C for 16 hours, cooled to room temperature, and then ethyl acetate (100 mL) and water (100 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phase was washed with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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, 93% yield).

[0632] At room temperature, tert-butyl 4-(8-methoxyquinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (105a) (4.0 g, 11.76 mmol) and palladium on carbon (palladium loading: 10 wt%) (0.40 g, 0.376 mmol) were added sequentially to anhydrous methanol (40.0 mL). The resulting reaction mixture was stirred under a hydrogen atmosphere for 16 hours and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (10.0 mL × 3), 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 tert-butyl 4-(8-methoxyquinolin-4-yl)piperidine-1-carboxylate (105b) (3.2 g, 80% yield).

[0633] At room temperature, tert-butyl 4-(8-methoxyquinolin-4-yl)piperidine-1-carboxylate (105b) (1.5 g, 4.37 mmol) was added to a solution of hydrogen chloride in ethyl acetate (3.0 M) (20.0 mL). The resulting reaction mixture was stirred at room temperature for 1 hour and concentrated to dryness under reduced pressure to give crude product 8-methoxy-4-(piperidin-4-yl)quinoline (105c) (1.1 g, crude yield 90%).

[0634] At room temperature, triethylamine (0.94 g, 9.26 mmol) and trifluoroacetic anhydride (0.778 g, 3.71 mmol) were added successively to a solution of 8-methoxy-4-(piperidin-4-yl)quinoline (105c) (0.86 g, 3.09 mmol) in dichloromethane (15.0 mL). The resulting reaction mixture was stirred at room temperature for 2 hours, followed by the addition of ethyl acetate (30.0 mL) and water (30.0 mL). The organic phase was separated, and 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 give N-trifluoroacetyl-8-methoxy-4-(piperidin-4-yl)quinoline (105d) (0.67 g, yield 64%).

[0635] 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 and stirred for 10 minutes. 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 the pH of the aqueous phase was adjusted to approximately 9 to 10 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, washed with 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 (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%).

[0636] 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 give crude N-trifluoroacetyl-7-nitro-4-(piperidin-4-yl)quinolin-8-ol (105f) (0.20 g, crude yield >100%).

[0637] 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 purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (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). 1 H NMR (400 MHz, MeOH-d4) δ 8.91 (d, J = 4.6 Hz, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 4.6 Hz, 1H), 3.80 (s, 1H), 3.57 (d, J = 13.1 Hz, 2H), 3.33 (d, J = 13.2 Hz, 2H), 2.22 (d, J = 13.3 Hz, 2H), 2.07 - 1.96 (m, 3H). MS calculated: 273.11; MS found: 274.35 [M+H] + .

[0638] Example 106 Synthesis of 5-fluoro-7-nitroquinolin-8-ol (106)

[0639] [ka]

[0640] 5-Fluoro-2-methoxyaniline (68a) (1.0 g, 7.08 mmol) was added to 10.0 mL of 6.0 M hydrochloric acid at room temperature. The reaction mixture was heated to 110 °C, and then acrolein diethyl acetal (2.31 g, 17.7 mmol) was slowly added dropwise and stirred for 2 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7 to 8 with saturated aqueous potassium carbonate. The resulting mixture was extracted with ethyl acetate (50.0 mL × 3). 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: petroleum ether / ethyl acetate = 7 / 1 to 4 / 1) to give 5-fluoro-8-methoxyquinoline (106a) (0.20 g, 16% yield).

[0641] 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 and stirred for 10 min. Sulfuric acid (98 wt%) (0.061 mL, 1.13 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 2 h, and the pH of the aqueous phase was adjusted to approximately 9 to 10 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with ethyl acetate (10.0 mL × 2). 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 (eluent: petroleum ether / ethyl acetate = 8 / 1) to give 5-fluoro-8-methoxy-7-nitroquinoline (106b) (0.165 g, 66% yield).

[0642] 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 × 2) and evaporated to dryness in vacuo to give 5-fluoro-7-nitroquinolin-8-ol (106) (56.0 mg, 92% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.21 (dd, J = 8.1, 0.9 Hz, 1H), 7.68 (d, J = 12.8 Hz, 1H), 7.65 (dd, J = 8.4, 4.5 Hz, 1H). MS calculated: 208.03; MS found: 209.15 [M+H] + .

[0643] (Example 107) Synthesis of 5-chloro-6-methyl-7-nitroquinolin-8-ol (107)

[0644] [ka]

[0645] At room temperature, 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). The reaction mixture was stirred at 95 °C for 2 hours, cooled to room temperature, and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (10.0 mL × 4), and the filtrates were combined. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, 2-amino-4-chloro-5-methylphenol (107b) (0.57 g, crude yield 68%).

[0646] Crude 2-amino-4-chloro-5-methylphenol (107b) (0.435 g, 2.77 mmol) was added to 10.0 mL of 6.0 M hydrochloric acid at room temperature. The reaction mixture was heated to 110 °C, and then acrolein diethyl acetal (1.2 mL, 8.31 mmol) was added dropwise slowly and stirred for 5 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 7 to 8 with saturated aqueous potassium carbonate. The resulting mixture was extracted with ethyl acetate (50.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 5-chloro-6-methylquinolin-8-ol (107c) (0.41 g, 77% yield).

[0647] 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 × 2) and evaporated to dryness in vacuo to give 5-chloro-6-methyl-7-nitroquinolin-8-ol (107) (73.0 mg, 99% yield). 1H-NMR (400 MHz, DMSO-d6) δ: 10.22-10.00 (bs, 1 H), 8.93-8.86 (m, 1 H), 8.56-8.49 (m, 1 H), 7.75-7.67 (m, 1 H), 7.13 (s, 1 H), 2.56-2.51 (m, 3 H). MS calculated: 238.63; MS found: 239.1 [M+H] + .

[0648] Example 108 Synthesis of 5-(difluoromethyl)-7-nitroquinolin-8-ol trifluoroacetate (108)

[0649] [ka]

[0650] At 0 °C, 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 mL). The resulting mixture was warmed to room temperature and stirred for 5 h, followed by the addition of water (20 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20 mL × 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 to 2 / 1) to give 5-bromo-8-(methoxymethoxy)quinoline (108b) (2.33 g, 96% yield).

[0651] 5-Bromo-8-(methoxymethoxy)quinoline (108b) (616.0 mg, 2.30 mmol), potassium vinyltrifluoroborate (493.0 mg, 3.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (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. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0 to 4 / 1) to give 5-vinyl-8-(methoxymethoxy)quinoline (108c) (441.0 mg, yield 89%).

[0652] 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 min, followed by the addition of sodium periodate (1.32 g, 6.15 mmol), followed by stirring at room temperature for 16 h. Ethyl acetate (15.0 mL) and water (10.0 mL) were added, the organic phase was separated, and 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 give crude 8-(methoxymethoxy)quinoline-5-carbaldehyde (108d) (475.0 mg, 100% crude yield).

[0653] At 0°C, diethylaminosulfur trifluoride (610.0 mg, 3.77 mmol) was slowly added dropwise to a solution of 8-(methoxymethoxy)quinoline-5-carbaldehyde (108d) (230.0 mg, 1.06 mmol) in dichloromethane (10.0 mL). The reaction mixture was stirred at 0°C for 10 minutes and at room temperature for 16 hours, and then cooled to 0°C. The pH of the aqueous phase was adjusted to approximately 7 to 8 by the slow dropwise addition of saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane (10.0 mL x 3). 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: petroleum ether / ethyl acetate=100% / 0 to 1 / 1) to give 5-(difluoromethyl)-8-(methoxymethoxy)quinoline (108e) (132.0 mg, yield 52%).

[0654] 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 give crude product 5-(difluoromethyl)-8-hydroxyquinoline trifluoroacetate (108f) (45.0 mg, crude yield >100%).

[0655] 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 then 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 × 2) and evaporated to dryness to give 5-(difluoromethyl)-7-nitroquinolin-8-ol trifluoroacetate (108) (75.6 mg, 93% yield overall for the two steps). 1H NMR (400 MHz, DMSO-d6) δ 9.07 (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). MS calculated: 240.03; MS found: 241.1 [M+H] + .

[0656] Example 109 Synthesis of 5-(hydroxymethyl)-7-nitroquinolin-8-ol (109)

[0657] [ka]

[0658] 8-(Methoxymethoxy)quinoline-5-carbaldehyde (108d) (760.0 mg, 3.5 mmol) was added to trifluoroacetic acid (20.0 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 give crude product 8-hydroxyquinoline-5-carbaldehyde (109a) (606.0 mg, crude yield 100%).

[0659] Crude 8-hydroxyquinoline-5-carbaldehyde (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 h, cooled to room temperature, and filtered under reduced pressure. The filter cake was washed with water (3.0 mL × 3) and evaporated to dryness to give 8-hydroxy-7-nitroquinoline-5-carbaldehyde (109b) (459.0 mg, 60% yield overall for the two steps).

[0660] 8-Hydroxy-7-nitroquinoline-5-carbaldehyde (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 then sodium borohydride (34.0 mg, 0.90 mmol) was added. The reaction mixture was stirred at 0 °C for 1.5 h and concentrated to dryness under reduced pressure. The resulting residue was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (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). 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 4.2 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.54 (dd, J = 8.1, 4.2 Hz, 1H), 5.00 (s, 1H), 4.64 (s, 2H). MS calculated: 220.05; MS found: 221.1 [M+H] + .

[0661] Example 110 Synthesis of 5-chloro-6-fluoro-7-nitroquinolin-8-ol (110)

[0662] [ka]

[0663] 3-Fluoro-4-chlorophenol (110a) (1.5 g, 10.20 mmol) and tetrabutylammonium bromide (0.33 g, 0.102 mmol) were added successively to 1,2-dichloroethane (15.0 mL) at room temperature, 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 × 3). 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: petroleum ether / ethyl acetate = 100% / 0 to 10 / 1) to give 4-chloro-5-fluoro-2-nitrophenol (110b) (1.45 g, 74% yield).

[0664] 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, filtered through diatomaceous earth, and the filter cake was washed with dichloromethane (10 mL × 4). The combined filtrate was washed successively with saturated aqueous sodium bicarbonate (30 mL × 4) and saturated brine (30 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 give 2-amino-4-chloro-5-fluorophenol (110c) (0.247 g, 20% yield).

[0665] 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 added sequentially to sulfuric acid (70 wt%) (2.0 mL). The resulting mixture was stirred at 140 °C for 3 hours and cooled to room temperature. The pH of the aqueous phase was adjusted to approximately 8 to 9 by the slow dropwise addition of saturated aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (20.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 5-chloro-6-fluoroquinolin-8-ol (110d) (0.12 g, 40% yield).

[0666] Sodium nitrite (175.0 mg, 2.5 mmol) was added in portions to a suspension of 5-chloro-6-fluoroquinolin-8-ol (110d) (50.0 mg, 0.25 mmol) in 1.67 mL of 3.0 M hydrochloric acid at room temperature. The reaction mixture was stirred at room temperature for 16 hours, and the pH of the aqueous phase was adjusted to approximately 8 to 9 by slowly adding saturated aqueous sodium carbonate solution dropwise. The resulting mixture was filtered under reduced pressure. The filter cake was washed successively with water (1.0 mL × 2) and a mixed solvent of ethanol and water (volume ratio, ethanol / water = 1 / 1) (0.5 mL × 2) and then evaporated to dryness in vacuo to give 5-chloro-6-fluoro-7-nitroquinolin-8-ol (110) (31.0 mg, 50% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 3.7 Hz, 1H), 8.66 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 8.5, 4.2 Hz, 1H). MS calculated: 241.99; MS found: 243.0, 245.0 [M+H] + .

[0667] Example 111 Synthesis of 5-chloro-7-nitro-4-(3-phenylpiperidin-1-yl)quinolin-8-ol (111)

[0668] [ka]

[0669] 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 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (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). 1 H NMR (400 MHz, DMSO-d6) δ: 8.10-8.04 (m, 1H), 7.96-7.92 (m, 1H), 7.82-7.78 (m, 1H), 7.40-7.25 (m, 5H), 3.68-3.30 (m, 2H), 3.08-2.92 (m, 1 H), 2.06-1.56 (m, 6 H). MS calculated: 383.10; MS found: 384.1, 386.1 [M+H] + .

[0670] Example 112 Synthesis of 3-cyclopropyl-7-nitroquinolin-8-ol (112)

[0671] [ka]

[0672] 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) at 100 °C. 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 to 8 with saturated aqueous sodium carbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30.0 mL × 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).

[0673] At room temperature, 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). The resulting reaction mixture was stirred at 100 °C for 4 hours, cooled to room temperature, and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (10.0 mL × 4), and the filtrates were combined. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20.0 mL × 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, yield 85%).

[0674] 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 added in portions to an aqueous solution of copper sulfate (11 wt%) (145.0 mL) at room temperature, 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, yield 64%).

[0675] 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) at room temperature. 4-(Dimethylamino)pyridine (7.8 mg, 0.064 mmol) was added. The reaction mixture was stirred for 2 hours and 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).

[0676] 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 × 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 / dichloromethane=1.5 / 1 to 1 / 1) to give tert-butyl (3-cyclopropylquinolin-8-yl)carbonate (112f) (134.0 mg, yield 81%).

[0677] At room temperature, 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 solution of hydrogen chloride (4.0 M) in 1,4-dioxane (1.76 mL). The resulting mixture was stirred for 24 hours and 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 × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product 3-cyclopropylquinolin-8-ol (112g) (95.4 mg, crude yield >100%).

[0678] 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 mixture 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 mixture of ethanol and water (volume ratio, ethanol / water = 2 / 1) (0.5 mL × 3) and evaporated to dryness in vacuo to give 3-cyclopropyl-7-nitroquinolin-8-ol (112) (42.1 mg, 63% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 9.24 (s, 1H), 8.82 (d, J = 1.2 Hz, 1H), 8.74 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 2.34 - 2.26 (m, 1H), 1.21 (dd, J = 8.1, 1.8 Hz, 2H), 0.99 - 0.97 (m, 2H). MS calculated: 230.07; MS found: 231.1 [M+H] + .

[0679] Example 113 Synthesis of 5-chloro-7-nitroquinolin-2-d-8-ol (113)

[0680] [ka]

[0681] Methyl iodide (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) at 0 °C. The resulting mixture was warmed to room temperature, stirred for 16 h, diluted with water (50.0 mL), and extracted with dichloromethane (20.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The 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).

[0682] At room temperature, 3-chloroperbenzoic acid (85 wt%) (2.02 g, 9.95 mmol) was added in several portions to a solution of 5-chloro-8-methoxyquinoline (113b) (1.288 g, 6.65 mmol) in dichloromethane (20.0 mL). The resulting mixture was stirred at room temperature for 16 hours and cooled to 0 °C. The pH of the aqueous phase was adjusted to approximately 8 to 9 with aqueous sodium hydroxide (1.0 M). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 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 to 91% / 9%) to give 5-chloro-8-methoxyquinoline-1-oxide (113c) (1.0 g, yield 72%).

[0683] At room temperature, 5-chloro-8-methoxyquinoline-1-oxide (113c) (1.0 g, 4.77 mmol) was added in portions to a solution of sodium hydroxide (0.458 g, 11.45 mmol) in deuterium oxide (5.0 mL). The reaction solution 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 × 3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 5-chloro-8-methoxyquinoline-1-oxide-2-d (113d) (0.969 g, 96% yield).

[0684] At 0°C, phosphorus tribromide (0.43 mL, 4.6 mmol) was slowly added dropwise to a solution of 5-chloro-8-methoxyquinoline-1-oxide-2-d (113d) (0.486 g, 2.3 mmol) in N,N-dimethylformamide (6.0 mL). The reaction solution was stirred at room temperature for 2 hours and cooled to 0°C. The pH of the aqueous phase was adjusted to approximately 8 to 9 with saturated aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane (10.0 mL × 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 give 5-chloro-8-methoxyquinoline-2-d (113e) (0.268 g, 60% yield).

[0685] At 0°C, nitric acid (65 wt%) (0.57 mL, 8.3 mmol) was slowly added dropwise to a solution of 5-chloro-8-methoxyquinoline-2-d(113e) (0.268 g, 1.37 mmol) in acetic anhydride (6.0 mL). The reaction mixture was stirred at 0°C for 10 minutes, followed by the slow dropwise addition of sulfuric acid (98 wt%) (0.1 mL, 1.84 mmol). The reaction solution was warmed to room temperature, stirred for 16 hours, and cooled to 0°C. The pH of the aqueous phase was adjusted to approximately 8 to 9 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, 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=20 / 1 to 10 / 1) to give 5-chloro-7-nitro-8-methoxyquinoline-2-d(113f) (0.094 g, yield 29%).

[0686] 5-Chloro-7-nitro-8-methoxyquinoline-2-d (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 × 2) and evaporated to dryness in vacuo to give 5-chloro-7-nitroquinolin-2-d-8-ol (113) (84.0 mg, 95% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.30 (d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H). MS calculated: 225.01; MS found: 226.0 [M+H] + .

[0687] Example 114 Synthesis of 6-bromo-5-chloro-7-nitroquinolin-8-ol (114)

[0688] [ka]

[0689] At room temperature, 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). 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 × 2) and evaporated to dryness in vacuo to give 6-bromo-5-chloro-7-nitroquinolin-8-ol (114) (1.41 g, 89% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.70 (dd, J = 4.4, 1.6 Hz, 1 H), 8.41 (dd, J = 8.6, 1.4 Hz, 1 H), 7.68 (dd, J = 8.4, 4.0 Hz, 1 H). MS calculated: 301.91, 303.91; MS found: 303.0, 305.0 [M+H] + .

[0690] Example 115 Synthesis of 5,6-dichloro-7-nitroquinolin-8-ol (115)

[0691] [ka]

[0692] 2-Amino-4,5-dichlorophenol (115a) (5.0 g, 28.1 mmol) was added to 140.0 mL of 6.0 M hydrochloric acid at room temperature. The reaction mixture was heated to 110 °C, and then acrolein diethyl acetal (12.0 mL, 73.8 mmol) was added dropwise and stirred for 1.5 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 9 to 10 by slowly adding saturated aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate (200.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 5,6-dichloro-8-hydroxyquinoline (115b) (3.9 g, 65% yield).

[0693] Methyl iodide (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) at room temperature. The resulting mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to remove the organic solvent. Water (30.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30.0 mL × 2). 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 = 5 / 1) to give 5,6-dichloro-8-methoxyquinoline (115c) (3.5 g, 71% yield).

[0694] 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) at 0°C and stirred for 10 minutes. 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, stirred for 72 hours, and then cooled to 0°C. The pH of the aqueous phase was adjusted to approximately 9-10 with aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (50.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate=2 / 1) to obtain 5,6-dichloro-8-methoxy-7-nitroquinoline (115d) (0.718 g, yield 17%).

[0695] 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 × 2) and evaporated to dryness in vacuo to give 5,6-dichloro-7-nitroquinolin-8-ol (115) (0.555 g, 81% yield). 1 H NMR (400 MHz, 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). MS calculated: 257.96; MS found: 259.0, 261.0 [M+H] + .

[0696] Example 116 Synthesis of 7-nitroquinolin-2-d-8-ol (116)

[0697] [ka]

[0698] 3-Chloroperbenzoic acid (85 wt%) (3.6 g, 17.9 mmol) was added in portions 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 and cooled to 0 °C. The pH of the aqueous phase was adjusted to approximately 8 to 9 with aqueous sodium hydroxide (1.0 M). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 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 to 8 / 1) to give 8-methoxyquinoline-1-oxide (116b) (0.836 g, 40% yield).

[0699] 8-Methoxyquinoline-1-oxide (116b) (0.836 g, 4.77 mmol) was added in portions to a solution of sodium hydroxide (0.458 mg, 11.45 mmol) in deuterium oxide (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 × 2). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 8-methoxyquinoline-1-oxide-2-d (116c) (0.80 g, 95% yield).

[0700] At 0°C, phosphorus tribromide (0.85 mL, 9 mmol) was slowly added dropwise to a solution of 8-methoxyquinoline-1-oxide-2-d (116c) (0.797 g, 4.52 mmol) in N,N-dimethylformamide (10.0 mL). The reaction solution was stirred at room temperature for 2 hours and cooled to 0°C. The pH of the aqueous phase was adjusted to approximately 8 to 9 by slowly adding saturated aqueous sodium carbonate solution. The resulting mixture was extracted with dichloromethane (20.0 mL × 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 to 1 / 1.5) to give 8-methoxyquinoline-2-d (116d) (0.418 g, 58% yield).

[0701] At 0°C, a solution of boron tribromide in dichloromethane (1.0 M) (13.0 mL, 13.0 mmol) was slowly added dropwise to a solution of 8-methoxyquinoline-2-d (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. The pH of the aqueous phase was adjusted to approximately 8 to 9 by slowly adding saturated aqueous sodium carbonate solution. The resulting mixture was extracted with dichloromethane (10.0 mL × 3). 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 (eluent: dichloromethane / methanol = 30 / 1) to give 8-hydroxyquinoline-2-d (116e) (0.203 g, 53% yield).

[0702] Sodium nitrite (141.0 mg, 2.0 mmol) was added to a solution of 8-hydroxyquinoline-2-d(116e) (100.0 mg, 0.68 mmol) in acetic acid (3.0 mL) at room temperature. The reaction mixture was stirred for 2 hours and filtered under reduced pressure. The pH of the aqueous phase of the filtrate was adjusted to approximately 9 to 10 with ammonia (25 to 28 wt. %, NH3 content), and the mixture was filtered under reduced pressure. The resulting filter cake was dissolved in methanol (2.0 mL) and purified by reversed-phase high-performance liquid chromatography (chromatographic column: Eclipse XDB-C18 (21.2 mm × 250 mm, 7 μm); mobile phase: water / acetonitrile = 100% / 0 to 92% / 8%, gradient elution; 0.1% formic acid was added to the mobile phase by volume percentage; flow rate: 20.0 mL / min) to obtain 7-nitroquinolin-2-d-8-ol (116) (30.0 mg, yield: 23%). 1 H NMR (400 MHz, 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). MS calculated: 191.04; MS found: 192.2 [M+H] + .

[0703] Example 117 Synthesis of 7-nitroquinolin-6-d-8-ol (117)

[0704] [ka]

[0705] 4-Bromo-2-methoxyaniline (117a) (1.0 g, 5.0 mmol) was added to 30.0 mL of 6.0 M hydrochloric acid at room temperature. The reaction mixture was heated to 110 °C, and then acrolein diethyl acetal (2.44 mL, 15.0 mmol) was slowly added dropwise and stirred for 10 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 9 to 10 by slowly adding saturated aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate (30.0 mL × 2). 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 (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 6-bromo-8-methoxyquinoline (117b) (0.5 g, 42% yield).

[0706] 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 then water (30.0 mL) was added. The resulting mixture was extracted with ethyl acetate (30.0 mL × 2). 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 (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 8-methoxyquinoline-6-d (117c) (60.0 mg, 75% yield).

[0707] At 0°C, a solution of boron tribromide in dichloromethane (1.0 M) (3.0 mL, 3.0 mmol) was slowly added dropwise to a solution of 8-methoxyquinoline-6-d (117c) (60.0 mg, 0.38 mmol) in dichloromethane (1.0 mL). The reaction solution was warmed to room temperature and stirred for 30 minutes. 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 × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude quinolin-6-d-8-ol (117d) (51.0 mg, crude yield 93%).

[0708] Sodium nitrite (75.0 mg, 1.1 mmol) was added to a suspension of crude quinolin-6-d-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 and at room temperature for 18 hours, and then 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 resulting filter cake was washed with methanol (0.5 mL × 2) and evaporated to dryness in vacuo to give 7-nitroquinolin-6-d-8-ol (117) (34.0 mg, 51% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 9.44 (dd, J = 8.8, 1.6 Hz, 1 H), 8.62 (dd, J = 4.0, 1.6 Hz, 1 H), 7.59 (dd, J = 8.6, 4.0 Hz, 1 H), 6.29 (s, 1 H). MS calculated: 191.04; MS found: 192.0 [M+H] + .

[0709] Example 118 Synthesis of 5-chloro-4-(3,3-difluoropiperidin-1-yl)-7-nitroquinolin-8-ol (118)

[0710] [ka]

[0711] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (150.0 mg, 0.51 mmol) and 3,3-difluoroperidin-1-yl) 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 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (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). 1 H NMR (400 MHz, DMSO-d6) δ: 8.44 (d, J = 8 Hz, 1 H), 7.99 (s, 1 H), 7.50 (d, J = 8 Hz, 1 H), 4.13-4.00 (m, 1 H), 3.94-3.83 (m, 1 H), 3.70-3.63 (m, 2 H), 2.30-2.10 (m, 2 H), 2.06-1.96 (m, 1 H), 1.88-1.78 (m, 1 H). MS calculated: 343.05; MS found: 344.0, 346.0 [M+H] + .

[0712] Example 119 Synthesis of 5-chloro-4-(3-fluoropiperidin-1-yl)-7-nitroquinolin-8-ol (119)

[0713] [ka]

[0714] 4,5-Dichloro-7-nitroquinolin-8-ol (29) (104.0 mg, 0.4 mmol) and 3-fluoroperidin-1-yl 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 h, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by reverse-phase high-performance liquid chromatography (chromatography column: Eclipse XDB-C18 (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). 1 H NMR (400 MHz, DMSO-d6) δ: 8.44 (d, J = 8.0 Hz, 1 H), 7.99 (s, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 4.13-4.00 (m, 1 H), 3.94-3.83 (m, 1 H), 3.70-3.63 (m, 3 H), 2.30-2.10 (m, 2 H), 2.06-1.96 (m, 1 H), 1.88-1.78 (m, 1 H). MS calculated: 325.06; MS found: 326.0, 328.0 [M+H] + .

[0715] Example 120 Synthesis of 5-chloro-7-nitroquinolin-4-d-8-ol (120)

[0716] [ka]

[0717] 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 × 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 to 4 / 1) to give 8-methoxyquinoline-4-d (120a) (125.0 mg, 62% yield).

[0718] 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-methoxyquinoline-4-d (120a) (125.0 mg, 0.78 mmol) in dichloromethane (2.0 mL). The reaction solution was warmed to room temperature and stirred for 16 hours. The pH of the aqueous phase was adjusted to approximately 8-9 by slowly adding saturated aqueous sodium carbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 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: dichloromethane / methanol = 100% / 0 to 30 / 1) to give quinolin-4-d-8-ol (120b) (100.0 mg, 88% yield).

[0719] N-chlorosuccinimide (86.8 mg, 0.65 mmol) was added in portions to a solution of quinolin-4-d-8-ol (120b) (100.0 mg, 0.68 mmol) in sulfuric acid (98 wt%) (2.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h and at room temperature for 5 h, and then cooled to 0°C. The pH of the aqueous phase was adjusted to approximately 8 to 9 by slowly adding saturated aqueous sodium carbonate solution. The resulting mixture was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, 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 to 30 / 1) to give 5-chloroquinolin-4-d-8-ol (120c) (86.0 mg, yield 70%).

[0720] Sodium nitrite (99.0 mg, 1.43 mmol) was added to a solution of 5-chloroquinolin-4-d-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 × 2). The resulting filtrate was allowed to stand at room temperature for 16 hours, whereupon a solid precipitated. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with water (0.5 mL × 2) and evaporated to dryness in vacuo to give 5-chloro-7-nitroquinolin-4-d-8-ol (120) (24.0 mg, 22% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 9.13 (d, J = 4.2 Hz, 1H), 8.25 (s, 1H), 7.98 (d, J = 4.2 Hz, 1H). MS calculated: 225.01; MS found: 226.0 [M+H] + .

[0721] Example 121 Synthesis of 5-bromo-7-nitroquinolin-8-ol (121)

[0722] [ka]

[0723] 5-Bromo-2-methoxyaniline (84a) (2.0 g, 9.9 mmol) was added to 40.0 mL of 6.0 M hydrochloric acid at room temperature. The reaction mixture was heated to 110 °C, and then acrolein diethyl acetal (4.88 mL, 30 mmol) was slowly added dropwise and stirred for 6 h. The reaction mixture was cooled to room temperature, and the pH of the aqueous phase was adjusted to approximately 9 to 10 by slowly adding saturated aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate (30.0 mL × 2). 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 (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 5-bromo-8-methoxyquinoline (121a) (0.84 g, 36% yield).

[0724] At 0°C, 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) and stirred for 10 minutes. 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 and at room temperature for 18 hours, then cooled to 0°C. The pH of the aqueous phase was adjusted to approximately 9 to 10 by adding aqueous sodium hydroxide (1.0 M). The resulting mixture was extracted with dichloromethane (10.0 mL × 3). 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 (eluent: petroleum ether / ethyl acetate=4 / 1) to give 5-bromo-8-methoxy-7-nitroquinoline (121b) (60.0 mg, yield 25%).

[0725] At room temperature, 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). 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 × 2) and evaporated to dryness in vacuo to give 5-bromo-7-nitroquinolin-8-ol (121) (40.0 mg, 71% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.69 (d, J = 4.4 Hz, 1H), 8.23 ​​(s, 1 H), 8.21-8.19 (m,1H), 7.68 (dd, J = 8.4, 4.4 Hz, 1 H). MS calculated: 267.95; MS found: 269.0, 271.0 [M+H] + .

[0726] Example 122 Synthesis of 6-fluoro-7-nitroquinolin-8-ol (122)

[0727] [ka]

[0728] 2-Methoxy-3-nitro-4-fluoroaniline (122a) (100.0 mg, 0.537 mmol) was added to 10.0 mL of 6.0 M hydrochloric acid at room temperature. The reaction mixture was heated to 110 °C, and then acrolein diethyl acetal (0.25 mL, 1.61 mmol) was slowly added dropwise and stirred for 2 h. The reaction mixture was coo...

Claims

1. Use of a compound of 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 medicament 【Chemistry 1】 (In the formula, R x are each independently optional and h is each independently 1, 2, or 3; R y is selected from the group consisting of nitro and cyano, and k is 1 or 2; However, all R x but at the same time not H atoms).

2. 2. The use according to claim 1, which is the use of a compound of formula (IA), 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 medicament. 【Chemistry 2】 (In the formula, R 11 is H atom, halogen, D atom and C 1～6 selected from the group consisting of alkyl; R 12 is a H atom, C 1～6 Alkyl, C 3～8 Cycloalkyl, C 6～14 Aryl, -C(O)-OR 16 , -CH 2 -NR 17 R 18 and -CH 2 -NR 19 R 110 selected from the group consisting of: R 13 is H atom, D atom, C 1～6 Alkyl, halogen, C 1～6 Alkoxy, hydroxy, haloC 1～6 Alkyl, HaloC 1～6 Alkoxy, Cyano, C 3～8 Cycloalkyl, -(CH 2 ) n -3 to 8-membered heterocyclyl, C 6～14 Aryl, 5- to 14-membered heteroaryl, -NR 17 R 18 , -O-(CH 2 ) n -NR 17 R 18 , -O-(CH 2 ) n -R 111 , -(CH=CH) m C(O)-NR 17 R 18 and -(CH=CH) m C(O)-NR 19 R 110 wherein said 3- to 8-membered heterocyclyl is optionally selected from the group consisting of C 1～6 Alkyl, C 1～6 Alkoxy, halogen, haloC 1～6 Alkyl, oxo, -C(O)-NR 17 R 18 , -C(O)-OR 16 , -C(O)-R 16 , -S(O) x R 16 , -O-(CH 2 ) n -R 111 and C 6～14 is further substituted by one or more substituents selected from the group consisting of aryl; R 14 is an H atom, halogen, cyano, C 1～6 Alkyl, C 3～8 Cycloalkyl, HaloC 1～6 Alkyl, Hydroxy C 1～6 Alkyl, -CH 2 -NR 17 R 18 and -CH 2 -NR 19 R 110 selected from the group consisting of: R 15 is H atom, D atom, halogen, C 1～6 Alkyl and -NR 17 R 18 selected from the group consisting of: R 16 is C 1～6 is alkyl; R 17 and R 18 is a H atom, C 1～6 are each independently selected from the group consisting of alkyl and 3- to 8-membered heterocyclyl; R 19 and R 110 together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclyl, which optionally contains, in addition to N, one or more heteroatoms selected from the group consisting of N, O and S, and which is optionally further substituted by one or more oxo groups; R 111 is a halogen, C 3～8 Cycloalkyl, C 6～14 Aryl, HaloC 1～6 Alkyl, C 1～6 Alkyl and C 1～6 selected from the group consisting of alkoxy; m is 1; n is 0, 1, 2 or 3; x is 2).

3. R 11 H atom, F atom, -CH 3 and D atoms; and / or R 12 But H atom, CH 3 , 【Transformation 3】 selected from the group consisting of: and / or R 13 is H atom, -CH 3 , 【Chemistry 4】 , Cl atom, 【Transformation 5】 , Br atom, 【Transformation 6】 ,-AND 3 、 【Transformation 7】 , F atom, 【Transformation 8】 , -OH, 【Chemistry 9】 ,-AND 2 CH 3 、-CF 3 、 【Chemistry 10】 、-CHF 2 、 【Chemistry 11】 and D atoms; and / or R 14 is H atom, I atom, -CH 3 , Cl atom, -CN, F atom, 【Chemistry 12】 , -CHF 2 , -CH 2 selected from the group consisting of OH and Br atoms; and / or R 15 is H atom, -CH 3 , F atom, Br atom, Cl atom, D atom and -NHCH 3 selected from the group consisting of 3. The use according to claim 2.

4. The compound of formula (IA) 【Chemical Engineering 13A】 【Chemistry 13B】 【Chemical 13C】 【13D Transformation】 [Chemical 13E] [Chemical 13F] 4. The use according to claim 2 or 3, selected from the group consisting of:

5. R 11 However, H atoms, halogens, D atoms and C 1 ~C 6 selected from the group consisting of alkyl; R 12 But H atom, C 1 ~C 6 Alkyl or C 3～8 is cycloalkyl; R 13 But H atom, D atom, C 1 ~C 6 Alkyl, halogen, C 1～6 Alkoxy, hydroxy, cyano, haloC 1～6 Alkyl and C 3～8 cycloalkyl; R 14 H atoms, halogens, cyano, haloC 1 ~ 6 Alkyl and C 1 ~C 6 selected from the group consisting of alkyl; R 15 But H atoms, D atoms, halogens, C 1 ~C 6 Alkyl and -NR 17 R 18 selected from the group consisting of: R 17 and R 18 are each independently a H atom or a C 1～6 is alkyl, 2. The use according to claim 1.

6. The compound of formula (IA) 【Chemical 14A】 【Chemical 14B】 6. The use according to claim 5, selected from the group consisting of:

7. R 11 is an H atom; R 12 is H atom or C 3～8 is cycloalkyl; R 13 But H atom, halo C 1～6 Alkyl and C 3～8 cycloalkyl; R 14 is a H atom or a halogen; R 15 H atoms, halogens and -NR 17 R 18 selected from the group consisting of: R 17 and R 18 are each independently a H atom or a C 1～6 is alkyl, 6. Use according to claim 1 or 5.

8. The compound of formula (IA) 【Chemistry 15】 is selected from the group consisting of: 【Chemistry 16】 8. The use according to any one of claims 2 to 7, selected from the group consisting of:

9. 2. The use according to claim 1, which is the use of a compound of formula (IB), 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 medicament. 【Chemistry 17】 (In the formula, R 21 represents a hydrogen atom, halogen, cyano, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR a , -NR a R b , -OR a and -S(O) p R a wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted with one or more groups selected from Q; R 22 is selected from the group consisting of a hydrogen atom, halogen, alkyl, and cycloalkyl; R 23 is selected from the group consisting of a hydrogen atom, halogen, and alkyl; R 24 represents a hydrogen atom, halogen, alkyl, -C(O)OR a and -C(O)NR a R b and R a and R b is a hydrogen atom, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkyl-C 1 ~C 6 are each independently selected from the group consisting of alkyl; R 25 is selected from the group consisting of a hydrogen atom, halogen, and alkyl; R a and R b are each independently selected from the group consisting of a hydrogen atom, alkyl, and cycloalkyl; 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 )(CH 2 ) q R d and; R c and R d are each independently selected from the group consisting of a hydrogen atom, alkyl, aryl, and heteroaryl, each of which is optionally further substituted with alkoxy; Or R c and R d together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl, which optionally contains, in addition to N, one or more heteroatoms selected from the group consisting of N and O; p is 1 or 2; q is an integer from 0 to 6; However, R 21 , R 22 , R 23 , R 24 and R 25 is not a hydrogen atom at the same time).

10. R 21 is as defined in claim 9, wherein the halogen is chlorine or fluorine; and / or R 21 is as defined in claim 9, and said alkyl is C 1 ~C 6 alkyl; 1 ~C 6 C alkyl is preferably substituted by halogen 1 ~C 6 Alkyl, more preferably -CF 3 , -CHF 2 or -CH 2 F, even more preferably -CF 3 and; and / or R 21 is as defined in claim 9, and said alkenyl is C 2 ~C 6 alkenyl; preferably, 2 ~C 6 The alkenyl is alkenyl 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 )(CH 2 ) q R d and R c and R d is as defined in claim 9; more preferably, said C 2 ~C 6 alkenyl is -CH=CH-COOH, [Chemistry 18] and; and / or R 21 is as defined in claim 9, and said cycloalkyl is C 3 ~C 10 Cycloalkyl, preferably C 3 ~C 6 Cycloalkyl, more preferably unsubstituted C 3 ~C 6 cycloalkyl, even more preferably unsubstituted cyclopropyl, unsubstituted cyclopentyl or unsubstituted cyclohexyl; and / or R 21 is as defined in claim 9, and said heterocyclyl is C 4 ~C 7 heterocyclyl; preferably, 4 ~C 7 Heterocyclyl is a nitrogen-containing C 4 ~C 7 heterocyclyl; more preferably, 4 ~C 7 Heterocyclyl is -NR e R f and R e and R f together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl, said nitrogen-containing heterocyclyl optionally containing, in addition to N, one or more heteroatoms selected from the group consisting of N and O, said nitrogen-containing heterocyclyl optionally being further substituted by one or more groups selected from Q, and Q being C 1 ~C 6 Alkyl, oxo or C 1 ~C 6 alkoxycarbonyl, 1 ~C 6 The alkyl is preferably methyl, and 1 ~C 6 The alkoxycarbonyl is preferably —C(O)OCH 2 CH 3 and even more preferably, 4 ~C 7 Heterocyclyl is 【Chemistry 19】 and; and / or R 21 is as defined in claim 9, and said aryl is C 6 ~C 10 aryl, preferably unsubstituted phenyl; and / or R 21 is as defined in claim 9, wherein said heteroaryl is a 5- to 10-membered heteroaryl, preferably unsubstituted or C 1 ~C 6 Pyridyl, pyrazolyl or imidazolyl substituted by alkyl, more preferably 【Chemistry 20】 and; and / or R 21 is as defined in claim 9, and said -C(O)OR c Medium, R g But C 1 ~C 6 alkyl; preferably —C(O)OR c But -C(O)OCH 2 CH 3 and; and / or R 21 is as defined in claim 9, and said -NR a R b But -NH 2 or -N(CH 3 ) 2 and; and / or R 21 is as defined in claim 9, and said -OR a But, -OCH 3 and; and / or R 21 is as defined in claim 9, and said -S(O) p R a But -S(O) 2 CH 3 and; and / or R 22 is as defined in claim 9, wherein the halogen is fluorine or chlorine; and / or R 22 is as defined in claim 9, and said alkyl is C 1 ~C 6 alkyl, preferably methyl; and / or R 22 is as defined in claim 9, and said cycloalkyl is C 1 ~C 6 cycloalkyl, preferably cyclopropyl; and / or R 23 is as defined in claim 9, wherein the halogen is fluorine or chlorine; and / or R 23 is as defined in claim 9, and said alkyl is C 1 ~C 6 alkyl, preferably methyl; and / or R 24 is as defined in claim 9, wherein the halogen is fluorine or chlorine; and / or R 24 is as defined in claim 9, and said alkyl is C 1 ~C 6 alkyl, preferably methyl; and / or R 24 is as defined in claim 9, and said -C(O)OR a R a is alkyl or cycloalkyl, and the alkyl is C 1 ~C 6 alkyl, preferably ethyl; said cycloalkyl is C 1 ~C 6 cycloalkyl, preferably methylcyclopropyl or cyclohexyl; and / or R 24 is as defined in claim 9, and said —C(O)NR a R b R a and R b are each independently alkyl, and the alkyl is C 1 ~C 6 alkyl, preferably ethyl, methyl or isopropyl; and / or R 25 is as defined in claim 9, wherein the halogen is fluorine or chlorine; and / or R 25 is as defined in claim 9, and said alkyl is C 1 ~C 6 alkyl, preferably methyl; However, R 21 , R 22 , R 23 , R 24 and R 25 But at the same time, it is not a hydrogen atom.

10. The use according to claim 9.

11. The compound of formula (IB) 【Chemical Engineering 21A】 【Chemical 21B】 11. The use according to claim 9 or 10, selected from the group consisting of:

12. R 21 But hydrogen atoms, halogens, cyano, C 1 ~C 6 Alkyl, 4-8 membered heterocyclyl, haloC 1 ~C 6 Alkyl, -C(O)OR a and C 3 ~C 6 cycloalkyl; R 22 is hydrogen atom, halogen and C 1 ~C 6 selected from the group consisting of alkyl; R 23 is hydrogen atom, halogen and C 1 ~C 6 selected from the group consisting of alkyl; R 24 However, hydrogen atoms, halogens, C 1 ~C 6 Alkyl and -C(O)OR a and R a is a hydrogen atom, C 1 ~C 6 Alkyl and C 3 ~C 6 cycloalkyl; R 25 is hydrogen atom, halogen and C 1 ~C 6 selected from the group consisting of alkyl; However, R 21 , R 22 , R 23 , R 24 and R 25 But at the same time, it is not a hydrogen atom.

10. The use according to claim 9.

13. The compound of formula (IB) 【Chemistry 22】 13. The use according to claim 12, selected from the group consisting of:

14. R 21 is a hydrogen atom, 4- to 8-membered heterocyclyl, haloC 1 ~C 6 Alkyl, -C(O)OR a and C 3 ~C 6 cycloalkyl; R 22 is a hydrogen atom; R 23 is a hydrogen atom; R 24 is a hydrogen atom or -C(O)OR a and; R 25 is a hydrogen atom; R a is a hydrogen atom or C 1 ~C 6 is alkyl, 13. Use according to claim 9 or 12.

15. The compound of formula (IB) 【Chemistry 23】 15. The use according to any one of claims 9 to 14, selected from the group consisting of:

16. 2. The use according to claim 1, wherein the compound is a compound of formula (IC), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: 【Chemistry 24】 (In the formula, R 31 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 32 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 33 is selected from the group consisting of a hydrogen atom, alkyl, halogen, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 34 is selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, carboxy, hydroxy, 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, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; However, R 31 , R 32 , R 33 , R 34 and R 35 is not a hydrogen atom at the same time).

17. R 34 However, hydrogen atoms, halogens, C 1～6 Alkyl, HaloC 1～6 is selected from the group consisting of alkyl, carboxy and hydroxy, and is preferably a hydrogen atom, a halogen, C 1～6 Alkyl, HaloC 1～6 17. The use according to claim 16, wherein the alkyl group is selected from the group consisting of alkyl and carboxy, more preferably selected from the group consisting of hydrogen, bromine, chlorine, methyl, trifluoromethyl and carboxy.

18. R 33 is a hydrogen atom, C 1～6 Alkyl, halogen and hydroxy, preferably a hydrogen atom or C 1～6 18. Use according to claim 16 or 17, wherein the alkyl is selected from the group consisting of an alkyl, more preferably a hydrogen atom or a methyl.

19. The compound of formula (IC) 【Chemistry 25】 and preferably selected from the group consisting of 【Chemistry 26】 19. The use according to any one of claims 16 to 18, selected from the group consisting of:

20. 20. The use according to any one of claims 1 to 19, wherein the antiviral agent is used in a mammal, preferably in a human.

21. 21. The use according to any one of claims 1 to 20, wherein the virus is a 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. 22. The use according to any one of claims 1 to 21, wherein the daily dose of the compound of formula (I) is between 0.01 mg and 1000 mg per kilogram of body weight, preferably between 0.1 mg and 500 mg per kilogram of body weight.

23. 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 the group consisting of acyclovir, valacyclovir, zidovudine, ganciclovir, penciclovir, famciclovir, foscarnet, ribavirin, lamivudine, amantadine, IFNα, cidofovir and rimantadine.

24. 24. The use according to any one of claims 1 to 23, wherein the medicament is in the following dosage forms: oral liquid, suspension, powder, granules, tablet, capsule, pill, emulsion, syrup, aerosol or injection.

25. 25. The use according to any one of claims 1 to 24, wherein the medicament is administered via oral, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, sublingual, intranasal, intracerebral, intraventricular, intrathecal, intravaginal, rectal, inhalable or topical route.

26. 20. A method for preventing or treating a viral infection, comprising administering to a subject a therapeutically effective amount of an 8-hydroxyquinoline derivative as defined in any one of claims 1 to 19, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof.

27. 20. A method for preventing or treating a viral infection in a mammal, the method comprising administering to a subject a therapeutically effective amount of an 8-hydroxyquinoline derivative as defined in any one of claims 1 to 19, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, wherein the mammal is preferably a human.

28. 1. A method for in vitro disinfection, comprising: contacting the environment or object to be treated with an effective amount of an 8-hydroxyquinoline derivative, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, or an isotopic derivative thereof as defined in any one of claims 1 to 19. A method comprising:

29. 29. The method of any one of claims 26 to 28, wherein the virus is a 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. 20. A pharmaceutical composition for treating a viral infection, comprising an 8-hydroxyquinoline derivative as defined in any one of claims 1 to 19, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.

31. 20. A pharmaceutical composition for treating a viral infection in a mammal, comprising an 8-hydroxyquinoline derivative as defined in any one of claims 1 to 19, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.

32. 32. The pharmaceutical composition of claim 30 or 31, wherein the virus is a 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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