7-Cyano-8-hydroxyquinoline derivative, method for producing the same, and pharmaceutical use thereof

Abstract

Provided are 7-cyano-8-hydroxyquinoline derivatives, a method for preparing the same, and their pharmaceutical use. Specifically, disclosed are compounds represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and their use in the treatment of infectious diseases or cancers. The compounds have excellent antibacterial, antiviral, and antitumor activities and can be developed as drugs for the treatment of infectious diseases or tumors. The definitions of the groups in general formula (I) are as described. JPEG2025518150000058.jpg34170

Description

Technical Field

[0001] The present invention relates to 7-cyano-8-hydroxyquinoline derivatives, a method for preparing the same, and their pharmaceutical uses.

Background Art

[0002] Nitroxin, chemical name 5-nitro-8-hydroxyquinoline, was developed as an oral antibiotic in the 1960s. It is mainly used for urinary tract infections and has a relatively safe usage history. In addition, recent studies have found that nitroxin can exert a synergistic inhibitory effect on tumor angiogenesis and can also exert an inhibitory effect on the growth of tumor cells. However, the activity of current quinoline derivatives still requires further improvement. Based on this, the applicant has studied 7-cyano-8-hydroxyquinoline derivatives.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0004] The present inventor has conducted a detailed study to design and synthesize a series of 7-cyano-8-hydroxyquinoline derivatives that exhibit excellent antibacterial or antitumor activity and can be developed as drugs for treating infectious diseases or tumors.

Means for Solving the Problems

[0005] The present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0006]

Chemical formula

[0007] Wherein, R 1 is selected from the group consisting of a hydrogen atom, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from the group consisting of a hydrogen atom, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 3 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 4 is selected from the group consisting of a hydrogen atom, halogen, haloalkyl, carboxy, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, thiol, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 5is selected from the group consisting of a hydrogen atom, a halogen, an alkyl, a hydroxy, a haloalkyl, a hydroxyalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a thiol, a nitro, a carboxy, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, provided that R 1 to R 5 are not all hydrogen atoms at the same time.

[0008] In some embodiments, in the compound of formula (I), R 4 is selected from the group consisting of a hydrogen atom, a halogen, a haloC 1~6 alkyl, a carboxy and a hydroxy, preferably selected from the group consisting of a hydrogen atom, a halogen, a haloC 1~6 alkyl and a carboxy, more preferably selected from the group consisting of a hydrogen atom, a bromine atom, a chlorine atom, a trifluoromethyl and a carboxy.

[0009] In some embodiments, in the compound of formula (I), R 3 is selected from the group consisting of a hydrogen atom, a C 1~6 alkyl, a halogen and a hydroxy, preferably a hydrogen atom or a C 1~6 alkyl, more preferably a hydrogen atom or a methyl.

[0010] In some embodiments, in the compound of formula (I), R 1 is selected from the group consisting of a hydrogen atom, a halogen, a C 1~6 alkyl and a hydroxy, preferably a hydrogen atom or a halogen, more preferably a hydrogen atom or a fluorine atom.

[0011] In some embodiments, in the compound of formula (I), R 5 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl and a hydroxy, preferably a hydrogen atom or a halogen, more preferably a hydrogen atom or a chlorine atom.

[0012] In some embodiments, in the compound of formula (I), R2 is selected from the group consisting of a hydrogen atom, a halogen, C 1~6 alkyl and hydroxy, and is preferably a hydrogen atom.

[0013] In some embodiments, the compound of formula (I) is a compound of formula (II),

[0014]

Chemical formula

[0015] wherein, R 1 is a hydrogen atom or a halogen, preferably a hydrogen atom or a fluorine atom, R 3 is a hydrogen atom or C 1~6 alkyl, preferably a hydrogen atom or methyl, R 4 is selected from the group consisting of a hydrogen atom, a halogen, halo C 1~6 alkyl and carboxy, preferably selected from the group consisting of a hydrogen atom, a bromine atom, a chlorine atom, trifluoromethyl and carboxy, R 5 is a hydrogen atom or a halogen, preferably a hydrogen atom or a chlorine atom, provided that not all of R 1 to R 5 are simultaneously hydrogen atoms.

[0016] Typical compounds of formula (I) of the present invention include, but are not limited to, the following compounds.

[0017]

Chemical formula

[0018] The present invention also provides a method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt, comprising the following steps, Method I:

[0019]

Chem.

[0020] The compound of formula (IA) is subjected to a dealkylation reaction in the presence of lithium chloride to form the compound of formula (I), where R 6 is alkyl, preferably C 1~6 alkyl, more preferably methyl, Furthermore,

[0021]

Chem.

[0022] The compound of formula (IB) is reacted with zinc cyanide to form the compound of formula (IA), where X is halogen, preferably a bromine atom or a chlorine atom, Method II:

[0023]

Chem.

[0024] The compound of formula (IC) is reacted with a halogenating reagent to form the compound of formula (I), where the halogenating reagent is selected from the group consisting of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, pyridinium tribromide, copper chloride, and copper iodide, preferably N-chlorosuccinimide or N-bromosuccinimide, and R 4 is halogen, preferably a chlorine atom or a bromine atom, R 1 from R 3 and R 5 are as defined in formula (I).

[0025] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0026] The present invention relates to the use of a compound of formula (I'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for treating an infectious disease or cancer.

[0027]

Chemical formula

[0028] In the formula, R 1 to R 3 and R 5 are as defined in formula (I). R 4 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, and preferably, R 4 is selected from the group consisting of a hydrogen atom, halogen, C 1~6 alkyl, halo C 1~6 alkyl, carboxy and hydroxy. In particular, the compounds of formula (I') include, but are not limited to, the following compounds:

[0029]

Chemical formula

[0030] Here, the infectious disease is preferably a systemic infection, a genital infection or a urinary tract infection. In particular, the infectious disease is caused by Gram-negative bacteria, Gram-positive bacteria, viruses, fungi. More specifically, the Gram-negative bacteria include Escherichia coli, Acinetobacter baumannii and Klebsiella pneumoniae. Escherichia coli is preferably carbapenem-resistant Escherichia coli. Acinetobacter baumannii is preferably carbapenem-resistant Acinetobacter baumannii. The Gram-positive bacteria include Staphylococcus aureus. Staphylococcus aureus is preferably methicillin-resistant Staphylococcus aureus and / or methicillin-sensitive Staphylococcus aureus. The viruses include 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. Here, the cancer is preferably bladder cancer or prostate cancer.

[0031] The pharmaceutical composition of the present invention may be in various conventional dosage forms such as tablets, aqueous suspensions, oily suspensions, dispersible powders, dispersible granules, emulsions, hard capsule agents, soft capsule agents, sterile aqueous solutions for injection, oil-in-water type microemulsions for injection or suppositories. Each of the above dosage forms can be prepared by conventional preparation methods.

[0032] Definition of terms Terms not defined in this specification have meanings generally understood by those skilled in the art. Terms defined in this specification have the meanings described in the description.

[0033] The term "substitution" or "substituent" refers to the replacement of one or more hydrogen atoms by the indicated group. The substitution may be at any position, provided that a stable or chemically feasible chemical substance is formed when the substitution position is not specified.

[0034] The term "any" or "optionally" means that the event or situation described thereafter may occur, but does not necessarily occur, and such a description includes the state in which the event or situation occurs and the state in which the event or situation does not occur.

[0035] If any variable element, such as R, appears more than once in the structure of the compound, its definition is independent in each case. For example, if a group is substituted by 0 to 2 R's, the group can optionally be substituted by up to 2 R's, with independent choices for each R.

[0036] The term "alkyl" refers to a saturated, straight-chain or branched-chain 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 or 20) carbon atoms, preferably C 1~10 alkyl, more preferably C 1~6Refers to alkyl. Examples 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-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-3-ethylhexyl, n-decyl, and 3,3-diethylhexyl.

[0037] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least 2 carbon-carbon double bonds, where the carbon-carbon double bonds can be located anywhere in the alkenyl, preferably C 2~5 Refers to alkenyl. Examples of alkenyl include, but are not limited to, -CH=CH 2 , -CH=CH-CH 3 , -CH 2 -CH=CH 2 , -CH=CH-CH 2 -CH 3 , -CH 2 -CH=CH-CH 3 , -CH=CH-CH=CH 2 , -CH=C(CH 3 )-CH 3 and -CH 2 -C(CH 3 )=CH 2 and are not limited thereto.

[0038] The term "alkynyl" has 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon triple bond, where the carbon-carbon triple bond can be located anywhere in the alkynyl, and is a straight-chain or branched-chain monovalent hydrocarbon group, preferably C 2~5 refers to alkynyl. Examples of alkynyl include -C≡CH, -C≡C-CH 3 , -CH 2 -C≡CH, -C≡C-CH 2 -CH 3 , -CH 2 -CH 2 -C≡CH, -CH(CH 3 )C≡CH and -CH 2 -C≡C-CH 3 , but are not limited thereto.

[0039] The term "cycloalkyl" includes two categories, one is the conventional cycloalkyl and the other is the hetero-structured cycloalkyl.

[0040] Conventional cycloalkyl is an aliphatic, saturated or partially unsaturated monovalent cyclic hydrocarbon group having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably conventional C 3~12 cycloalkyl, more preferably conventional C 3~10 cycloalkyl, still more preferably conventional C 3~8 cycloalkyl, and most preferably conventional C 3~6 cycloalkyl. Conventional cycloalkyl optionally contains one or more double bonds or triple bonds.

[0041] Conventional cycloalkyls may be monocyclic cycloalkyls. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Conventional cycloalkyls may also be polycyclic cycloalkyls (e.g., dicycloalkyl and tricycloalkyl), and polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0042] The term "spirocycloalkyl" refers to spirocycloalkyls having 5 to 20 membered rings (e.g., 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered ring, 17-membered ring, 18-membered ring, 19-membered ring, and 20-membered ring), preferably spirocycloalkyls having 6 to 14 membered rings, more preferably spirocycloalkyls having 7 to 10 membered rings. Spirocycloalkyls may be monospirocycloalkyls, dispirocycloalkyls, or polyspirocycloalkyls, preferably monospirocycloalkyls, preferably monospirocycloalkyls of 4-membered ring / 4-membered ring, 4-membered ring / 5-membered ring, 4-membered ring / 6-membered ring, 5-membered ring / 5-membered ring, or 5-membered ring / 6-membered ring. Examples of spirocycloalkyls include, but are not limited to, the following.

[0043] [Chemical formula]

[0044] The term "fused cycloalkyl" refers to a fused cycloalkyl having a 5- to 20-membered ring (e.g., 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered ring, 17-membered ring, 18-membered ring, 19-membered ring, and 20-membered ring), preferably a fused cycloalkyl having a 6- to 14-membered ring, more preferably a fused cycloalkyl having a 7- to 10-membered ring. The fused cycloalkyl may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher fused cycloalkyl, preferably a bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered ring / 5-membered ring or 5-membered ring / 6-membered ring fused cycloalkyl. Examples of the fused cycloalkyl include, but are not limited to, the following.

[0045]

Chem.

[0046] The term "bridged cycloalkyl" refers to a bridged cycloalkyl having a 5- to 20-membered ring (e.g., 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered ring, 17-membered ring, 18-membered ring, 19-membered ring, and 20-membered ring), preferably a bridged cycloalkyl having a 6- to 14-membered ring, more preferably a bridged cycloalkyl having a 7- to 10-membered ring. The bridged cycloalkyl may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Examples of the bridged cycloalkyl include, but are not limited to, the following.

[0047]

Chem.

[0048] The term "heterostructure cycloalkyl" includes monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl that are fused at a bonding point where a corresponding conventional cycloalkyl (i.e., monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl, or bridged cycloalkyl) is located with any one selected from the group consisting of a conventional aryl, a conventional heteroaryl, and a conventional heterocyclyl. Examples of heterostructure cycloalkyl include, but are not limited to, the following.

[0049] [Chemical formula]

[0050] The term "heterocyclyl" includes two categories, one is a conventional heterocyclyl and the other is a heterostructure heterocyclyl.

[0051] 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, wherein one or more ring atoms are replaced by one or more elements selected from the group consisting of nitrogen, oxygen, S, S(O), and S(O) 2 and this replacement does not form -O-O-, -O-S-, or -S-S-, preferably 1 to 4 (e.g., 1, 2, 3, and 4) ring atoms are heteroatoms in a conventional C 3~12 heterocyclyl, more preferably 1 to 3 (e.g., 1, 2, and 3) ring atoms are heteroatoms in a conventional C 3~8 heterocyclyl, most preferably 1 to 2 or 1 to 3 ring atoms are heteroatoms in a conventional C 5~7 heterocyclyl.

[0052] Conventional heterocyclyls may be monocyclic heterocyclyls. Examples of monocyclic heterocyclyls include oxetanyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Preferably, they include 1,2,5-oxadiazolyl, pyranyl, or morpholinyl, but are not limited thereto. Conventional heterocyclyls may also be polycyclic heterocyclyls, and polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0053] The term "spiroheterocyclyl" refers to a spiroheterocyclyl having 5 to 20 members (e.g., 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered ring, 17-membered ring, 18-membered ring, 19-membered ring, and 20-membered ring), preferably a spiroheterocyclyl having 6 to 14 members, and more preferably a heterocyclyl having 7 to 10 members. Spiroheterocyclyls may be monospiroheterocyclyls, dispiroheterocyclyls, or polyspiroheterocyclyls. Preferably, they are monospiroheterocyclyls or dispiroheterocyclyls, and more preferably monospiroheterocyclyls having a 3-membered ring / 6-membered ring, 4-membered ring / 4-membered ring, 4-membered ring / 5-membered ring, 4-membered ring / 6-membered ring, 5-membered ring / 5-membered ring, or 5-membered ring / 6-membered ring. Examples of spiroheterocyclyls include, but are not limited to, the following.

[0054]

Chemical formula

[0055] The term "fused heterocycle" refers to a fused heterocycle having 5 to 20 members (e.g., 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered ring, 17-membered ring, 18-membered ring, 19-membered ring, and 20-membered ring), preferably a fused heterocycle having 6 to 14 members, more preferably a fused heterocycle having 7 to 10 members. The fused heterocycle may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher fused heterocycle, preferably a bicyclic or tricyclic fused heterocycle, more preferably a bicyclic fused heterocycle of 5-membered ring / 5-membered ring or 5-membered ring / 6-membered ring. Examples of the fused heterocycle include, but are not limited to, the following.

[0056]

Chem.

[0057] The term "bridged heterocycle" refers to a bridged heterocycle having 5 to 14 members (e.g., 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, and 14-membered ring), preferably a bridged heterocycle having 6 to 14 members, more preferably a bridged heterocycle having 7 to 10 members. The bridged heterocycle may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged heterocycle, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocycle. Examples of the bridged heterocycle include, but are not limited to, the following.

[0058]

Chem.

[0059] The term "hetero-structured heterocyclyl" includes monocyclic heterocyclyls, spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls, which are fused at the bonding point where the corresponding conventional heterocyclyl (i.e., monocyclic heterocyclyl, spiro heteroalkyl, fused heteroalkyl or bridged heteroalkyl) is located, with any one selected from the group consisting of conventional aryl, conventional heteroaryl and conventional cycloalkyl. Examples of hetero-structured heterocyclyls include, but are not limited to, the following.

[0060]

Chemical formula

[0061] The term "aryl" includes two categories, one is conventional aryl and the other is hetero-structured aryl.

[0062] Conventional aryl refers to aromatic hydrocarbon groups having 6 to 14 members (e.g., 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring and 14-membered ring), preferably conventional C 6~10 aryl, more preferably phenyl, naphthyl, phenanthryl or anthracenyl.

[0063] The term "hetero-structured aryl" includes conventional aryl fused at the bonding point where conventional aryl is located, with any one selected from the group consisting of conventional heteroaryl, conventional heterocyclyl and conventional cycloalkyl. Examples of hetero-structured aryl include, but are not limited to, the following.

[0064]

Chemical formula

[0065] The term "heteroaryl" includes two categories, one is conventional heteroaryl and the other is hetero-structured heteroaryl.

[0066] Conventional heteroaryl refers to an aromatic hydrocarbon group having a 5- to 14-membered ring (e.g., 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, and 14-membered ring), wherein 1 to 4 (e.g., 1, 2, 3, and 4) carbon atoms are replaced by heteroatoms, and the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5 to 10, and it contains 1 to 3 (e.g., 1, 2, and 3) heteroatoms. More preferably, the number of ring atoms is 5 or 6, and it contains 1 to 2 heteroatoms. Examples of conventional heteroaryl include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, and pyrazinyl. Preferably, imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, or thiazolyl, and more preferably, pyrazolyl or thiazolyl, but are not limited thereto.

[0067] The term "heterostructure heteroaryl" includes a conventional heteroaryl fused with any one selected from the group consisting of a conventional aryl, a conventional cycloalkyl, and a conventional heterocyclyl at the bonding point where the conventional heteroaryl is located. Examples of heterostructure heteroaryl include, but are not limited to, the following.

[0068] [Chemical formula]

[0069] 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, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.

[0070] The term "haloalkyl" refers to alkyl substituted by one or more halogens, where alkyl is as defined above.

[0071] The term "haloalkoxy" refers to alkoxy substituted by one or more halogens, where alkoxy is as defined above.

[0072] The term "hydroxy" refers to -OH-.

[0073] The term "halogen" refers to -F, -Cl, -Br or -I.

[0074] The term "amino" refers to -NH 2 -.

[0075] The term "cyano" refers to -CN.

[0076] The term "nitro" refers to -NO 2 -.

[0077] The term "oxo" refers to =O.

[0078] The term "carboxy" refers to -C(=O)OH.

[0079] The term "thiol" refers to -SH.

[0080] The term "alkoxycarbonyl" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where alkyl and cycloalkyl are as defined above.

[0081] The term "acyl" refers to -C(=O)R, where R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0082] Symbol

[0083]

Chem.

[0084] refers to a junction point.

[0085] The term "stereoisomer" refers to isomers generated by different spatial arrangements of atoms within a molecule, which can be classified into two types, cis-trans isomers and enantiomers, and can also be classified into two categories, enantiomers and diastereoisomers. Stereoisomers caused by the rotation of single bonds are called conformational isomers and sometimes rotational isomers. Stereoisomers caused by the bond length, bond angle, double bond, and ring within a molecule are called configurational isomers, and configurational isomers are classified into two categories. Among them, isomers caused by the inability of the double bond or single bond of carbon atoms forming a ring to rotate freely are called geometric isomers and are also known as cis-trans isomers, which are classified into two categories, Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers, and stereoisomers with different optical rotation characteristics caused by the absence of inversion symmetry within the molecule are called optical isomers, which are classified into R configuration and S configuration. The "stereoisomers" described in the present invention can be understood to include one or more of the above-mentioned enantiomers, configurational isomers, and conformational isomers unless otherwise specified.

[0086] The term "pharmaceutically acceptable" means that when used in the preparation of a pharmaceutical composition, the pharmaceutical composition is generally safe, non-toxic, meets biological requirements, and can be tolerated and used as a drug for mammals (e.g., humans).

[0087] The term "pharmaceutically acceptable salt" should be understood to refer to pharmaceutically acceptable salts having the predicted pharmacological activity of the parent compound (i.e., the compound of the formula). Such salts are listed below: (1) An acid addition salt formed with an inorganic acid or an acid addition salt formed with an organic acid; here, the inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; the organic acid may be one or more of formic acid, oxalic acid, succinic acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid; and (2) A salt formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion (e.g., Na + , K + or Li + ), an alkaline earth metal ion (Ca 2+ or Mg 2+ etc.) or an aluminum ion; or a salt formed when coordinated with an organic base or an inorganic base; here, the organic base may be one or more of pyridine, imidazole, pyrazine, indole, purine, a tertiary amine, and aniline, preferably one or more of pyridine, methylpyridine, 4-dimethylaminopyridine, 2-methyl-5-ethylpyridine, triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, and tromethamine; the inorganic base may be one or more of aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0088] The term "isotope derivative" refers to a compound different from the parent compound described herein only in the presence of one or more isotopically enriched atoms. For example, an isotope derivative has a structure represented by a formula where only hydrogen is replaced by "deuterium" or "tritium", and / or fluorine is replaced by 18 F, and carbon is11 C、 13 C or 14 is replaced by C, while the remaining part remains unchanged. The above isotope derivatives can be used as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor research. Deuterium compounds can often retain the same activity as non-deuterium compounds, and when deuterated at specific specific positions, better metabolic stability can be achieved, thereby obtaining certain specific therapeutic advantages (such as an increase in in vivo half-life or a decrease in the required dose, etc.). Therefore, the isotope derivative is preferably a deuterium compound.

[0089] The term "solvate" refers to a substance formed from the parent compound described herein and a suitable solvent. The solvent is preferably water or an organic solvent.

[0090] The term "pharmaceutical composition" refers to a mixture containing a pharmaceutical compound (i.e., one or more compounds of the formulas described herein, its pharmaceutically acceptable salts, its tautomers, its stereoisomers, its enantiomers, its diastereoisomers, its isomer derivatives, its crystalline forms, its solvates, its metabolites and racemates containing it) and a pharmaceutically acceptable excipient.

[0091] The term "pharmaceutically acceptable excipient" is a pharmaceutically acceptable excipient for delivering the pharmaceutical compounds herein. The pharmaceutical composition may contain 0.1% to 99% by weight of the pharmaceutical compound depending on the administration method.

[0092] The term "subject" refers to mammals including, for example, camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, rabbit, guinea pig, mouse and primates. In some embodiments, the subject is a human. In some specific embodiments, the subject is a human who is susceptible to cancer or bacterial infection, suspected of having cancer or bacterial infection, or suffering from cancer or bacterial infection.

[0093] The term "treatment" refers to removing a disease, preventing the progression of a disease, delaying the progression of a disease, shortening the duration of symptoms associated with one or more diseases, improving or restoring a measurable parameter associated with at least one disease, or extending the survival period of a subject having the disease.

[0094] The term "effective amount" refers to the amount of a pharmaceutically active ingredient (i.e., a pharmaceutical compound) that elicits a desired effect in a subject. In certain embodiments, one of ordinary skill in the art can determine the selection of an effective amount based on consideration of various factors (e.g., through clinical trials), and the factors include the disease to be treated, the associated symptoms, the route of administration, the severity of the disease, the weight of the patient, the immune status of the patient, and other factors known to one of ordinary skill in the art. The effective amount can be obtained from a dose-response curve derived from an animal model test system and can be determined according to the opinion of a physician and the condition of each patient. The effective amount of the pharmaceutical compound of the present invention may be 0.5 mg / kg to 500 mg / kg, preferably 1 mg / kg to 200 mg / kg, more preferably 10 mg / kg to 100 mg / kg.

[0095] As used herein, the same pharmaceutically active ingredient (referring to a single pharmaceutical compound) or different pharmaceutically active ingredients (two or more pharmaceutical compounds) can be administered once, or divided into multiple low doses and administered at regular time intervals. It should be understood that the exact dosage, duration, and interval of treatment are a function of the disease being treated and can be determined by inference from animal or clinical trial data being used. Administration can include a single administration or multiple administrations over an appropriate time interval. In the present invention, 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, one day and a half, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, one week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, one month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months.

[0096] Each pharmaceutically active ingredient (each pharmaceutical compound) referred to in this specification can be used alone, provided that it does not cause other adverse effects, such as allergic reactions, or can be administered in combination with other active ingredients (referring to compounds other than the pharmaceutical compounds described in this specification). "Combined administration" includes simultaneous or sequential administration of each active compound.

[0097] The term "combined administration" refers to a method of providing two or more active compounds to a subject simultaneously or sequentially for therapeutic purposes. In the case of "combined administration", the time interval between each administration is sufficient to achieve a synergistic effect between the active compounds administered.

[0098] When the term "about" is applied to parameters such as weight, volume, pH, concentration, temperature, etc., it indicates that the parameter can vary within ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when the parameter is not critical, the value is usually given for illustrative purposes only and not for limitation.

Mode for Carrying Out the Invention

[0099] Those skilled in the art will better understand the present invention by reading the following examples. These examples are used only to illustrate the present invention and do not limit the scope of the present invention.

[0100] The compounds of the present invention are prepared by using convenient 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, etc. However, other reaction conditions can also be adopted unless otherwise specified. The optimal conditions may vary depending on the use of specific reactants or solvents, but under normal circumstances, the optimization process and conditions of the reaction can be determined.

[0101] Furthermore, in the present invention, in order to protect specific functional groups from unnecessary reactions, several protecting groups can be used. Suitable protecting groups for various functional groups and their protecting or deprotecting conditions are well known to those skilled in the art. For example, "Protective Groups In Organic Synthesis" by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and cited herein) details the protection or deprotection of a number of protecting groups.

[0102] For the separation and purification of compounds and intermediates, appropriate methods and procedures, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or combinations of the above methods, are employed according to specific requirements. The examples described in the present invention can be referred to for the specific methods used. Of course, other similar separation and purification methods can also be used. They can be characterized using conventional methods (including physical constants and spectral data).

[0103] The method for purity analysis is as follows: Gradient elution is carried out using a Kinetex EVO C18 (50×4.6 mm, 5 μm, 100 Å) column and acetonitrile-water as the mobile phase, at a flow rate of 1.5 mL / min and a detection wavelength of 220 nm.

[0104] The MS determination is carried out using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (photodiode array detector).

[0105] The structure of the compound is determined by hydrogen nuclear magnetic resonance using a model WNMR-I-400 MHz apparatus.

[0106] Fractional liquid chromatography is carried out using an Agilent 1260 Infinity II high-performance liquid chromatography (manufactured by Agilent) with a Daisogel C18 10μm 100A (30mm×250mm) column and acetonitrile-water as the mobile phase.

[0107] Thin-layer chromatography (TCL) for reaction monitoring was carried out using a GF254 silica gel plate from Qingdao Haiyang Chemical, a 0.20mm - 0.25mm silica gel plate, and for separation and purification, a 0.5mm silica gel plate was used.

[0108] Silica gel column chromatography was carried out using silica gel from Qingdao Haiyang with mesh sizes of 100 - 200, 200 - 300, and 300 - 400 as the carrier.

[0109] The known starting materials of the present invention may be synthesized by methods known in the art or purchased from WHmall, Beijing Ouhe, Sigma, J&K Scientific, Yishiming, Shanghai Shuya, Shanghai InnoChem, Energy Chemical, Shanghai Bide and other companies.

[0110] In the examples, unless otherwise specified, all reactions are carried out under a nitrogen atmosphere.

[0111] The nitrogen atmosphere means that the reaction flask is equipped with a nitrogen balloon having a volume of about 1L.

[0112] A reaction solvent, organic solvent, or inert solvent each means that the solvent used does not participate in the reaction under the reaction conditions described, and this includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, and N-methylpyrrolidone (NMP).

[0113] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0114] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as those commonly known to those skilled in the art. Further, any methods and materials similar or equivalent to those described in this specification can be applied to the method of the present invention.

[0115] Unless otherwise specified, the mixing ratio of different solvents is a volume ratio.

Examples

[0116] In the following examples, the related abbreviations have the following meanings: NBS: N-bromosuccinimide NCS: N-chlorosuccinimide NIS: N-iodosuccinimide DPPF: 1,1'-bis(diphenylphosphino)ferrocene.

[0117] Example 1 Synthesis of 5-bromo-7-cyano-8-hydroxyquinoline (1)

[0118]

Chemical formula

[0119] 2-Methoxy-3-bromoaniline (Compound 1a) (5.7 g, 28.5 mmol, 1 equiv) was dissolved in 100 mL of 6 M aqueous hydrochloric acid, and the mixture was heated to reflux. 3,3-Diethoxyprop-1-ene (Compound 1b) (11.1 g, 85.5 mmol, 3 equiv) was added dropwise, and the reaction was carried out for 2 h. The reaction solution was cooled, and the pH was adjusted to neutral using aqueous sodium carbonate solution. The reaction solution was extracted with 30 mL × 2 of dichloromethane. The organic phases were combined and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE:EA = 10:1 to 1:1) to give 800 mg of 7-bromo-8-methoxyquinoline (Compound 1c) as a colorless oil with a purity of 90%.

[0120]

Chemical formula

[0121] 7-Bromo-8-methoxyquinoline (Compound 1c) (400 mg, 1.18 mmol, 1 equiv) was dissolved in 5 mL of anhydrous dimethylformamide, and zinc cyanide (Compound 1d) (110.5 mg, 0.95 mmol, 0.8 equiv) and tetrakis(triphenylphosphine)palladium (68 mg, 0.059 mmol, 0.05 equiv) were added. The reaction system was purged with nitrogen, and the reaction was carried out at 110 °C for 8 h. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE:EA = 10:1 to 0:1) to give 130 mg of 7-cyano-8-methoxyquinoline (Compound 1e) as a white solid with a purity of 90%.

[0122]

Chemical formula

[0123] 7-Cyano-8-methoxyquinoline (Compound 1e) (120 mg, 1.43 mmol, 1 equiv) was dissolved in 5 mL of anhydrous dimethylformamide, and NBS (506 mg, 2.86 mmol, 2 equiv) was added. The reaction was carried out at room temperature for 8 h, and 20 mL of water was added. The precipitated solid was filtered and dried to obtain 100 mg of 5-bromo-7-cyano-8-methoxyquinoline (Compound 1f) as a white solid with a purity of 90%.

[0124]

Chemical formula

[0125] 5-Bromo-7-cyano-8-methoxyquinoline (Compound 1f) (100 mg, 0.38 mmol, 1 equiv) was dissolved in 5 mL of dimethylformamide, and 200 mg of lithium chloride was added. The reaction was carried out at 80 °C for 1 h, and 20 mL of water was added. The pH was adjusted to neutral, and the reaction solution was extracted with 5 mL × 2 of dichloromethane. The organic phases were combined, and the crude product was purified by preparative HPLC to obtain 8.8 mg of 5-bromo-7-cyano-8-hydroxyquinoline (Compound 1) as a white solid with a purity of 97%. MS calculated values: 247.96, 249.96; MS measured values: 249.0, 250.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.10 (d, J = 4 Hz, 1H), 8.56 (d, J = 8 Hz, 1H), 8.13 (s, 1H), 7.93 (dd, J = 4 Hz, J = 8 Hz, 1H).

[0126] Example 2 Synthesis of 5-trifluoromethyl-7-cyano-8-hydroxyquinoline (2)

[0127]

Chemical formula

[0128] 2-Methoxy-5-trifluoromethylaniline (Compound 2a) (5 g, 26.16 mmol, 1 equiv) was dissolved in 50 mL of 3 M aqueous hydrochloric acid and heated to reflux. 3,3-Diethoxyprop-1-ene (Compound 1b) (17.1 g, 130.8 mmol, 5 equiv) was added dropwise, and the reaction was carried out for 3 h. The reaction solution was cooled, and the pH was adjusted to neutral using an aqueous sodium carbonate solution. The reaction solution was extracted with 50 mL × 2 of dichloromethane. The organic phases were combined and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE:EA = 10:1~0:1) to give 3.1 g of 5-trifluoromethyl-8-methoxyquinoline (Compound 2b) as a colorless oil with a purity of 90%.

[0129]

Chem.

[0130] 5-Trifluoromethyl-8-methoxyquinoline (Compound 2b) (3.1 g, 13.6 mmol, 1 equiv) was dissolved in 30 mL of dimethylformamide, and NBS (4.84 g, 27.2 mmol, 2 equiv) was added. The reaction was carried out at room temperature for 3 h. The reaction solution was diluted with 50 mL of water, extracted with 50 mL of dichloromethane, and separated into two phases. The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (eluent: PE:EA = 10:1~0:1) to give 1.2 g of 5-trifluoromethyl-7-bromo-8-methoxyquinoline (Compound 2c) as a pale red liquid with a purity of 90%.

[0131]

Chem.

[0132] 5-Trifluoromethyl-7-bromo-8-methoxyquinoline (Compound 2c) (1.2 g, 3.92 mmol, 1 equiv) was dissolved in 20 mL of anhydrous dimethylformamide, and zinc cyanide (Compound 1d) (917.3 mg, 7.84 mmol, 2 equiv) and tetrakis(triphenylphosphine)palladium (226 mg, 0.196 mmol, 0.05 equiv) were added. The reaction system was purged with nitrogen, and the reaction was carried out at 110 °C for 8 h. The reaction solution was diluted with 50 mL of water and extracted with 25 mL×2 of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 900 mg of crude 5-trifluoromethyl-7-cyano-8-methoxyquinoline (Compound 2d).

[0133] [Chemical formula]

[0134] 5-Trifluoromethyl-7-cyano-8-methoxyquinoline (Compound 2d) (900 mg, 3.58 mmol, 1 equiv) was dissolved in 10 mL of dimethylformamide, and 767 mg of lithium chloride was added. The reaction was carried out at 80 °C for 2 h, and 50 mL of water was added. The pH was adjusted to neutral, and the reaction solution was extracted with 25 mL×2 of dichloromethane. The organic phases were combined, concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE:EA = 10:1~0:1) to obtain 220 mg of a product (having a purity of 80%). The product was purified by preparative HPLC to obtain 32 mg of 5-trifluoromethyl-7-cyano-8-hydroxyquinoline (Compound 2) as a white solid with a purity of 96%. MS calculated value: 238.04; MS measured value: 239.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.13 (d, J = 4Hz,1H), 8.50 (d, J = 8Hz,1H), 8.22 (s, 1H), 7.99 (dd, J = 4Hz, J = 8Hz,1H).

[0135] Example 3 Synthesis of 4-Methyl-7-cyano-8-hydroxyquinoline (3)

[0136] [Chemical formula]

[0137] 2-Amino-6-bromophenol (Compound 3a) (5 g, 26.6 mmol, 1 equivalent) was dissolved in 100 mL of 1 M aqueous hydrochloric acid and heated under reflux. 4-Hydroxy-2-butanone (Compound 3b) (7 g, 79.8 mmol, 3 equivalents) was added dropwise, and the reaction was carried out for 2 hours. The reaction solution was cooled, and the pH was adjusted to neutral using an aqueous sodium carbonate solution. The reaction solution was extracted with 50 mL × 2 of ethyl acetate and concentrated to obtain 7 g of crude 4-methyl-7-bromo-8-hydroxyquinoline (Compound 3c) as a red solid.

[0138] [Chemical formula]

[0139] 4-Methyl-7-bromo-8-hydroxyquinoline (Compound 3c) (7 g, 29.2 mmol, 1 equivalent) was dissolved in 70 mL of dimethylformamide solution, and potassium carbonate (6 g, 43.8 mmol, 1.5 equivalents) and methyl iodide (6.3 g, 43.8 mmol, 1.5 equivalents) were added. The reaction was carried out at room temperature for 3 hours. The reaction solution was diluted with 150 mL of water, extracted with 50 mL × 2 of ethyl acetate, and separated into two phases. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE / EA = 10:1 to 1:1) to obtain 2 g of the product 4-methyl-7-bromo-8-methoxyquinoline (Compound 3d) as a red liquid.

[0140] [Chemical formula]

[0141] 4-Methyl-7-bromo-8-methoxyquinoline (Compound 3d) (2 g, 7.88 mmol, 1 equiv), zinc cyanide (Compound 1d) (900 mg, 3.94 mmol, 0.5 equiv), Pd 2 (dba) 3 (226 mg, 0.394 mmol, 0.05 equiv) and DPPF (220 mg, 0.394 mmol, 0.05 equiv) were dissolved in 20 mL of dimethylformamide. The reaction system was purged with nitrogen, and the reaction was carried out at 100 °C for 10 hours. The reaction solution was diluted with 50 mL of water and extracted with 20 mL×2 of ethyl acetate to separate into two phases. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE / EA = 10:1~1:1) to obtain 800 mg of 4-methyl-7-cyano-8-methoxyquinoline (Compound 3e) as a red oil with a purity of 80%.

[0142]

Chem.

[0143] 4-Methyl-7-cyano-8-methoxyquinoline (Compound 3e) (800 mg, 4 mmol, 1 equiv) was dissolved in 10 mL of dimethylformamide, and 200 mg of lithium chloride was added. The reaction was carried out at 100 °C for 2 hours, and 50 mL of water was added. The pH was adjusted to neutral, and the product was precipitated, filtered, and dried to obtain a crude product, which was triturated twice with 20 mL of methanol / 15 mL of dichloromethane to obtain 23.7 mg of 4-methyl-7-cyano-8-hydroxyquinoline (Compound 3) as an off-white solid with a purity of 98%. MS calculated value: 184.06; MS measured value: 185.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ8.86 (d,J=8Hz,1H), 7.69 (d,J=12Hz,1H),7.63 (dd, J=4Hz, 1H), 7.58 (dd, J=8Hz,1H),2.71(s,3H).

[0144] Example 4 Synthesis of 2-Fluoro-7-cyano-8-hydroxyquinoline (4)

[0145] [Chemical formula]

[0146] 7-Cyano-8-methoxyquinoline (Compound 4a) (150 mg, 0.815 mmol, 1 equivalent) was dissolved in 17 mL of anhydrous acetonitrile, and silver difluoride (708 mg, 4.8 mmol, 6 equivalents) was added. The reaction was carried out at room temperature for 1 hour, and the reaction solution was filtered. The filtrate was concentrated to obtain 100 mg of crude 2-fluoro-7-cyano-8-methoxyquinoline (Compound 4b).

[0147] [Chemical formula]

[0148] 2-Fluoro-7-cyano-8-methoxyquinoline (Compound 4b) (100 mg, 0.54 mmol, 1 equivalent) was dissolved in 5 ml of dimethylformamide, and 228 mg of lithium chloride was added. The reaction was carried out at 80 °C for 2 hours, and the reaction solution was concentrated. The obtained crude product was purified by preparative HPLC to obtain 12 mg of 2-fluoro-7-cyano-8-hydroxyquinoline (Compound 4) as a yellow-green solid with a purity of 96%. MS calculated value: 188.0; MS measured value: 189.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6): δ8.30~8.37 (m,1H), 7.70~7.75 (m,1H), 7.63 (dd, J=4Hz, J=8Hz,1H), 7.37 (dd, J=8Hz,1H).

[0149] Example 5 Synthesis of 4-Methyl-5-chloro-7-cyano-8-hydroxyquinoline (5)

[0150] [Chemical formula]

[0151] 4-Methyl-7-cyano-8-hydroxyquinoline (Compound 3) (300 mg, 1.62 mmol, 1 equiv) was dissolved in 10 mL of dimethylformamide, and NCS (425 mg, 3.2 mmol, 2 equiv) was added. The reaction was carried out at room temperature for 30 minutes. The reaction solution was diluted with 30 mL of water and extracted with 15 mL×2 of dichloromethane. The organic phases were combined, dried, filtered, and the filtrate was concentrated. The obtained crude product was purified by preparative HPLC to give 155 mg of 4-methyl-5-bromo-7-cyano-8-hydroxyquinoline (Compound 5) as a pale yellow solid with a purity of 98%. MS calculated value: 218.02; MS measured value: 219.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ8.85 (d, J=4Hz,1H), 7.84 (s, 1H), 7.66 (d, J=8Hz, 1H), 3.01(s,3H).

[0152] Example 6 Synthesis of 4-Methyl-5-bromo-7-cyano-8-hydroxyquinoline (6)

[0153]

Chemical formula

[0154] 4-Methyl-7-cyano-8-hydroxyquinoline (Compound 3) (300 mg, 1.62 mmol, 1 equiv) was dissolved in 10 mL of dimethylformamide, and NBS (569 mg, 3.2 mmol, 2 equiv) was added. The reaction was carried out at room temperature for 30 minutes. The reaction solution was diluted with 50 mL of water and extracted with 15 mL×2 of dichloromethane. The organic phases were combined, dried, filtered, and the filtrate was concentrated. The obtained crude product was triturated with 30 mL of methanol / 5 mL of dichloromethane to give 105 mg of 4-methyl-5-bromo-7-cyano-8-hydroxyquinoline (Compound 6) as a pale yellow solid with a purity of 97%. MS calculated values: 261.97, 263.97; MS measured values: 263.0, 265.0 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6): δ8.85 (d, J = 4Hz, 1H), 8.06 (s, 1H), 7.69 (d, J = 8Hz, 1H), 3.01(s, 3H).

[0155] Example 7 Synthesis of 5,6-dichloro-7-cyano-8-hydroxyquinoline (7)

[0156]

Chemical Structure

[0157] 5 g of 2-nitro-4,5-dichlorophenol (Compound 7a) was dissolved in 50 mL of tetrahydrofuran, and 500 mg of wet palladium carbon was added. The reaction system was equipped with a hydrogen balloon and the reaction was carried out for 8 hours. The reaction solution was filtered and the filtrate was concentrated to obtain 4.7 g of the product 2-amino-4,5-dichlorophenol (Compound 7b).

[0158]

Chemical Structure

[0159] 2-Amino-4,5-dichlorophenol (Compound 7b) (4.7 g, 26.5 mmol, 1 equivalent) was dissolved in 100 mL of 1M aqueous hydrochloric acid solution and heated to reflux. 3,3-Diethoxyprop-1-ene (Compound 1b) (10 g, 79.7 mmol, 3 equivalents) was added dropwise and the reaction was carried out for 1 hour. The reaction solution was cooled, the pH was adjusted to neutral with aqueous sodium carbonate solution, and the reaction solution was extracted with 30 mL × 2 of dichloromethane. The organic phases were combined and concentrated to obtain 3.5 g of crude 5,6-dichloro-8-hydroxyquinoline (Compound 7c) as a black solid.

[0160]

Chemical Structure

[0161] 5,6-Dichloro-8-hydroxyquinoline (Compound 7c) (3.5 g, 16.3 mmol, 1 equiv) was dissolved in 50 mL of dimethylformamide, and NBS (2.9 g, 16.3 mmol, 1.0 equiv) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was diluted with 100 mL of water and extracted with 50 mL × 2 of dichloromethane, and separated into two phases. The organic phases were combined, dried, then filtered and concentrated to obtain 4 g of crude 5,6-dichloro-7-bromo-8-hydroxyquinoline (Compound 7d) as a yellow solid.

[0162]

Chemical formula

[0163] 5,6-Dichloro-7-bromo-8-hydroxyquinoline (Compound 7d) (4 g, 13.7 g, 1 equiv) was dissolved in 40 mL of dimethylformamide solution, and potassium carbonate (1.89 g, 13.6 mmol, 1 equiv) and methyl iodide (1.94 g, 13.6 mmol, 1 equiv) were added. The reaction was carried out at room temperature for 3 hours. The reaction solution was diluted with 150 mL of water and extracted with 50 mL × 2 of dichloromethane, and separated into two phases. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE / EA = 10:1~2:1) to obtain 400 mg of the product 5,6-dichloro-7-bromo-8-methoxyquinoline (Compound 7e) as a pale yellow solid with a purity of 90%.

[0164]

Chemical formula

[0165] 5,6-Dichloro-7-bromo-8-methoxyquinoline (Compound 7e) (400 mg, 1.31 mmol, 1 equiv), zinc cyanide (Compound 1d) (75 mg, 0.65 mmol, 0.5 equiv), Pd 2 (dba) 3(75 mg, 0.13 mmol, 0.1 equiv) and DPPF (72 mg, 0.13 mmol, 0.1 equiv) were dissolved in 10 mL of dimethylformamide. The reaction system was purged with nitrogen, and the reaction was carried out at 90 °C for 8 hours. The reaction solution was diluted with 50 mL of water and extracted with 30 mL × 2 of ethyl acetate, and separated into two phases. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE / EA = 10:1~1:1) to obtain 200 mg of crude 5,6-dichloro-7-cyano-8-methoxyquinoline (Compound 7f) as a white solid.

[0166]

Chemical Structure

[0167] 5,6-Dichloro-7-cyano-8-methoxyquinoline (Compound 7f) (200 mg, 0.8 mmol, 1 equiv) was dissolved in 3 mL of dimethylformamide, and 100 mg of lithium chloride was added. The reaction was carried out at 100 °C for 1 hour, and the reaction solution was concentrated. The obtained crude product was purified by preparative HPLC to obtain 36 mg of 5,6-dichloro-7-cyano-8-hydroxyquinoline (Compound 7) as a white solid with a purity of 98%. MS calculated value: 237.97; MS measured value: 239.0 [M+H]+. 1 1H NMR (400 MHz, DMSO-d6): δ 9.10 (d, J = 4 Hz, 1H), 8.62 (d, J = 8 Hz, 1H), 7.97 (dd, J = 4 Hz, J = 8 Hz, 1H).

[0168] Example 8 Synthesis of 7-Cyano-8-hydroxyquinoline-5-carboxylic Acid (8)

[0169]

Chemical Structure

[0170] 8-Hydroxyquinoline (Compound 8a) (10 g, 68.6 mmol, 1 equiv) and NIS (18.6 g, 82.6 mmol, 1.2 equiv) were dissolved in 200 mL of chloroform. The reaction was carried out at 40 °C for 20 h, and the reaction solution was filtered. 100 mL of the filtrate was washed twice with a 5% aqueous sodium thiosulfate solution and separated into two phases. The organic phase was concentrated to obtain a crude product, which was triturated with 50 mL of methanol / 50 mL of water and filtered. The filter cake was dried to obtain 12 g of the product 7-iodo-8-hydroxyquinoline (Compound 8b).

[0171]

Chemical formula

[0172] 7-Iodo-8-hydroxyquinoline (Compound 8b) (12 g, 44.3 mmol, 1 equiv) was dissolved in 180 mL of dimethylformamide, and NBS (9.4 g, 55.3 mmol, 1.2 equiv) was added. The reaction was carried out at room temperature for 1 h, and the reaction solution was filtered. The filter cake was washed with water and dried to obtain 13 g of crude 5-bromo-7-iodo-8-hydroxyquinoline (Compound 8c) as a yellow solid.

[0173]

Chemical formula

[0174] 5-Bromo-7-iodo-8-hydroxyquinoline (Compound 8c) (13 g, 37.2 mmol, 1 equiv) was dissolved in 150 mL of dimethylformamide solution, and potassium carbonate (7.7 g, 55.8 mmol, 1.5 equiv) and methyl iodide (7.7 g, 44.7 mmol, 1.2 equiv) were added. The reaction was carried out at room temperature for 2 hours. The reaction solution was diluted with 200 mL of water and extracted with 50 mL × 2 of dichloromethane, and separated into two phases. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product, which was purified twice by silica gel column chromatography (eluent: PE / EA = 10:1~1:1) to obtain 3.7 g of the product 5-bromo-7-iodo-8-methoxyquinoline (Compound 8d) as a pale yellow solid.

[0175]

Chem.

[0176] 5-Bromo-7-iodo-8-methoxyquinoline (Compound 8d) (3.7 g, 10.2 mmol, 1 equiv), zinc cyanide (Compound 1d) (599 mg, 5.1 mmol, 0.5 equiv), Pd 2 (dba) 3 (281 mg, 0.51 mmol, 0.05 equiv) and DPPF (276 mg, 0.51 mmol, 0.05 equiv) were dissolved in 40 mL of dimethylformamide. The reaction system was purged with nitrogen, and the reaction was carried out at 100 °C for 10 hours. The reaction solution was diluted with 50 mL of water and extracted with 20 mL × 2 of ethyl acetate, and separated into two phases. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE / EA = 10:1~1:1) to obtain 1.4 g of the product 5-bromo-7-cyano-8-methoxyquinoline (Compound 8e) as a white solid with a purity of 90%.

[0177]

Chem.

[0178] Compound 8e (200 mg, 0.763 mmol, 1 equiv) was dissolved in 5 mL of anhydrous tetrahydrofuran. The reaction mixture was purged with nitrogen and cooled to -78 °C. n-Butyllithium (1 M, 1 mmol, 1.3 equiv) was added and the mixture was stirred for 10 minutes. Small pieces of dry ice were added and the reaction was carried out for 5 minutes. The reaction was quenched by adding 2 mL of water and the reaction solution was concentrated to obtain 250 mg of crude 7-cyano-8-methoxyquinoline-5-carboxylic acid (Compound 8f).

[0179]

Chemical Structure

[0180] 7-Cyano-8-methoxyquinoline-5-carboxylic acid (Compound 8f) (200 mg, 0.93 mmol, 1 equiv) was dissolved in 3 mL of dimethylformamide and 100 mg of lithium chloride was added. The reaction was carried out at 100 °C for 2 hours and the reaction solution was concentrated. The obtained crude product was purified by preparative HPLC to obtain 40 mg of the product 7-cyano-8-hydroxyquinoline-5-carboxylic acid (Compound 8) as a yellow solid with a purity of 98%. MS calculated value: 214.18; MS measured value: 215.1 MS [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 10.1(s, 1H), 9.58 (d,J=4Hz,1H),9.27 (d,J=4Hz,1H), 7.86(dd, J=4Hz, J=8Hz,1H), 7.71(s,1H).

[0181] Example 9 Synthesis of 5-Chloro-7-cyano-8-hydroxyquinoline (9) NBS in Example 1 was replaced with NCS in an equimolar ratio, and the other reaction steps were the same as in Example 1, and as a result, 5-chloro-7-cyano-8-hydroxyquinoline (Compound 9) was obtained. MS calculated value: 184.06; MS measured value: 185.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6): δ 8.67 (d, J = 4.3 Hz, 1H), 8.34 (dd, J = 8.4, 1.5 Hz), 7.68 (dd, 8.4, 4.3 Hz, 1H), 7.44 (s, 1H).

[0182] Biological assay Test Example 1. Inhibitory Activity Assay of the Compounds of the Present Invention in Bacteria 1. Test drug Compounds of the examples of the present invention 2. Test bacteria The test bacteria were 2 strains of carbapenem-resistant Escherichia coli (18-W09-093 and 18-W18-070), 2 strains of carbapenem-resistant Acinetobacter baumannii (18-W15-036 and 18-W13-081), 1 strain of methicillin-resistant Staphylococcus aureus (19-W03-012), and 1 strain of methicillin-sensitive Staphylococcus aureus (19-W01-012). These were clinically isolated, and duplicate strains isolated from the same patient were excluded. Furthermore, there were 3 quality control strains, namely, Escherichia coli ATCC 25922, Acinetobacter baumannii ATCC 19606, and Staphylococcus aureus ATCC 29213. All of the above strains were supplied by Shanghai GenoMatrix Medical Laboratory Co., Ltd. 3. Test method for drug susceptibility The MIC of the compounds of the present invention in clinically isolated strains was assayed by the microdilution method according to the relevant documents of the Clinical and Laboratory Standards Institute (CLSI) of the United States. 3.1 Preparation of antibacterial drugs: All of the compounds of the present invention were dissolved in DMSO. The drug concentration ranged from 128 mg / L to 0.06 mg / L. 3.2 Culture medium: Cation-adjusted Mueller-Hinton liquid medium (CAMHB) was used. 3.3 Bacterial inoculum: An isolated pure culture of the test bacteria cultured overnight was adjusted to a 0.5 McFarland turbidity by direct colony suspension and 100-fold dilution, and the final inoculum was 10 5 CFU / mL. 3.4 Culture conditions: The bacteria were cultured for 20 hours in air at 35 ± 2°C. 4. Reading and interpretation of results The results of the drug susceptibility test were interpreted according to the criteria of CLSI M100-ED29:2019. 5. Result statistics Statistical analysis of the results of the drug susceptibility test was performed using WHONET version 5.6 software. The inhibitory MIC values of the compounds of the present invention against various bacteria are shown in Table 1 below.

[0183] [Table 1]

[0184] Here, Compound A is

[0185] [Chemical formula]

[0186] and is synthesized according to the literature (Fiedler, H. (1960). Synthese von Methyl-8-hydroxy-chinolin-aldehyden. Archiv Der Pharmazie, 293(6), 609-621. doi:10.1002 / ardp.19602930606).

[0187] From the data in the above table, it can be seen that the compounds of the present invention have excellent antibacterial activity against Gram-negative bacteria such as Escherichia coli and Acinetobacter baumannii, and Gram-positive bacteria such as Staphylococcus aureus. Therefore, the compounds of the present invention can treat infectious diseases caused by Gram-negative bacteria or Gram-positive bacteria.

[0188] Although specific embodiments of the present invention have been described as above, those skilled in the art should understand that these are merely illustrative examples, and the protection scope of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, and all of these changes and modifications are included within the protection scope of the present invention.

Claims

1. A compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof: 【Chemical Formula 1】 (wherein, R 1 is selected from the group consisting of a hydrogen atom, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, R 2 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl, a hydroxy, a haloalkyl, a hydroxyalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a thiol, a nitro, a carboxy, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, R 3 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 4 is selected from the group consisting of a hydrogen atom, halogen, haloalkyl, carboxy, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, thiol, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, R 5 is selected from the group consisting of a hydrogen atom, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, thiol, nitro, carboxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, However, R 1 to R 5 are not all hydrogen atoms at the same time).

2. R 4 is selected from the group consisting of a hydrogen atom, a halogen, a haloC 1～6 alkyl, carboxy and hydroxy, preferably selected from the group consisting of a hydrogen atom, a halogen, a haloC 1～6 alkyl and carboxy, more preferably selected from the group consisting of a hydrogen atom, a bromine atom, a chlorine atom, trifluoromethyl and carboxy, the compound of formula (I) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof.

3. R 3 is selected from the group consisting of a hydrogen atom, C 1～6 alkyl, halogen and hydroxy, preferably a hydrogen atom or C 1～6 alkyl, more preferably a hydrogen atom or methyl, the compound of formula (I) according to claim 1 or 2, its stereoisomers, or a pharmaceutically acceptable salt thereof.

4. R 1 is selected from the group consisting of a hydrogen atom, a halogen, C 1～6 alkyl and hydroxy, preferably a hydrogen atom or a halogen, more preferably a hydrogen atom or a fluorine atom, a compound of formula (I) according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. R 5 The compound of formula (I) according to any one of claims 1 to 4, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of a hydrogen atom, a halogen, an alkyl, and a hydroxy, preferably a hydrogen atom or a halogen, more preferably a hydrogen atom or a chlorine atom.

6. R 2 is selected from the group consisting of a hydrogen atom, a halogen, C 1～6 alkyl and hydroxy, preferably a hydrogen atom, a compound of formula (I) according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. A compound of formula (II), its stereoisomers, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] (wherein, R 1 is a hydrogen atom or a halogen, preferably a hydrogen atom or a fluorine atom, and R 3 is a hydrogen atom or C 1～6 alkyl, preferably a hydrogen atom or methyl, R 4 is selected from the group consisting of a hydrogen atom, a halogen, halo C 1～6 alkyl and carboxy, preferably selected from the group consisting of a hydrogen atom, a bromine atom, a chlorine atom, trifluoromethyl and carboxy, R 5 is a hydrogen atom or a halogen, preferably a hydrogen atom or a chlorine atom, However, R 1 to R 5 are not all hydrogen atoms at the same time) The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 6, wherein...

8. 【Fig. 3】 The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 7, selected from the group consisting of...

9. A method for preparing a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 8, comprising the following steps: Method I: [Chemical Formula 4] A step of subjecting the compound of formula (IA) to a dealkylation reaction in the presence of lithium chloride to form the compound of formula (I), wherein R 6 is alkyl, preferably C 1～6 alkyl, more preferably methyl, step Furthermore, 【Chemical Formula 5】 A step of reacting a compound of formula (IA) with zinc cyanide to form a compound of formula (IA), wherein X is a halogen, preferably a bromine atom or a chlorine atom. Method II: ​ A step of reacting a compound of formula (IA) with a halogenating reagent to form a compound of formula (IA), wherein the halogenating reagent is selected from the group consisting of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, pyridinium tribromide, copper(II) chloride and copper(II) iodide, preferably N-chlorosuccinimide or N-bromosuccinimide, and R 4 is a halogen, preferably a chlorine atom or a bromine atom, the step comprising R 1 from R 3 and R 5 is as defined in claim 1, method

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 8, and one or more pharmaceutically acceptable excipients.

11. Use of a compound of formula (I'), its stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for treating an infectious disease or cancer, 【Chemical Formula 7】 (wherein R 1 to R 3 and R 5 are as defined in claim 1, R 4 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl, a haloalkyl, a carboxy, a hydroxy, a hydroxyalkyl, an alkoxy, a haloalkoxy, an amino, a thiol, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, and preferably, R 4 is a hydrogen atom, a halogen, C 1～6 alkyl, halo C 1～6 alkyl, carboxy and hydroxy (selected from the group consisting of) The infectious disease is preferably a systemic infection, a genital infection or a urinary tract infection. In particular, the infectious disease is caused by Gram-negative bacteria, Gram-positive bacteria, viruses, or fungi. More specifically, the Gram-negative bacteria include Escherichia coli, Acinetobacter baumannii and Klebsiella pneumoniae. Escherichia coli is preferably carbapenem-resistant Escherichia coli. Acinetobacter baumannii is preferably carbapenem-resistant Acinetobacter baumannii. The Gram-positive bacteria include Staphylococcus aureus. Staphylococcus aureus is preferably methicillin-resistant Staphylococcus aureus and / or methicillin-susceptible Staphylococcus aureus. The viruses include 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. The cancer is preferably bladder cancer or prostate cancer, for use.

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