CN103864680B

CN103864680B - There is the 7-chloro-4-oxo-quinoline derivative of anti-tumor activity

Info

Publication number: CN103864680B
Application number: CN201310652191.5A
Authority: CN
Inventors: 王子厚; 曹日晖; 张晓东; 荣祖元; 陈西敬; 张训缨; 黄汉源; 李忠野; 徐�明; 王忠奎; 李键茹; 任政华
Original assignee: Individual
Current assignee: Individual
Priority date: 2012-12-12
Filing date: 2013-12-05
Publication date: 2015-09-02
Anticipated expiration: 2033-12-05
Also published as: CN103864680A; CN105017145A; CN105017145B

Abstract

The present invention relates to the oxoquinoline derivatives with anti-tumor activity, particularly, the present invention relates to formula I: and pharmacologically acceptable salts, solvate, prodrug, wherein R ¹be selected from hydrogen ,-C _1-6alkyl ,-C _2-6thiazolinyl ,-C _2-6alkynyl ,-C _1-6alkyl-phenyl, wherein said alkyl, thiazolinyl, alkynyl and phenyl can optionally by halogen, nitro, cyano group, hydroxyl ,-C _1-6alkoxyl group, phenyl replace; R ³be selected from hydrogen ,-CONHR ₃₁,-COOR ₃₂, wherein said R ₃₁and R ₃₂independently be selected from-C separately _1-6alkyl and-C _1-6alkylamino, wherein said amino is optionally by 1 ~ 2-C _1-6alkyl replaces; R ⁷be selected from halogen ,-C _1-6alkoxyl group, morpholinyl or piperazinyl.

Description

Chloroxoquinoline derivative with antineoplastic activity

Technical Field

The invention relates to chloroquine derivatives with anti-tumor activity, a preparation method of the chloroquine derivatives and application of the chloroquine derivatives in preparing anti-tumor medicines.

Background

7-chloro-4-oxo-quinoline, commonly known as chloroquine, of the formula: c₉H₆ClNO, molecular weight: 179.6, melting point 282-:

the compound has tautomerism, and the tautomer is 7-chloro-4-hydroxy-quinoline, and the change relationship of the two is as follows:

chloroquine is known to be a new national anticancer drug developed by Jilin Tonghuxing pharmacy limited company, and belongs to the first class of chemical drugs. The medicine is listed in the state 1035 engineering and the state 'nine five' science and technology project; in 2002, 4 months, the product is accepted by the life science and technology development center of Ministry of science and technology; in 2002, 9 months, an invention patent certificate issued by the national intellectual property office is obtained. Two new drug certificates (drug substances and capsules) and two drug registration lots issued by the national drug administration were obtained on 23/4/2003.

As early as 1946, Hammer and Surrey reported the synthesis of 7-chloro-4-hydroxy-quinoline by condensation, ring closure, decarboxylation, etc. reactions using m-chloroaniline and diethyl oxaloacetate as starting materials (J.Am.chem.Soc.68 (1946) 113-116). Subsequently, Roberts and Price reported a synthetic route with higher yield, namely a method for synthesizing 7-chloro-4-hydroxy-quinoline by condensation, ring closure, deacidification and the like by using m-chloroaniline and ethoxymethylene malonate as raw materials, wherein the total yield of three-step reaction is up to 75% (J.Am.chem.Soc.68 (1946) 1204-1208). This method has two advantages over the previous method: (1) the ring closing reaction does not produce 5-chloro substituted isomer; (2) the total yield of the reaction is high. In 2009, Langer et al reported a simpler synthetic route, i.e., m-chloroaniline and isopropylidene malonate were used as raw materials, and 7-chloro-4-hydroxy-quinoline was obtained by two steps of condensation and ring-closing reaction, which has a higher yield for aniline raw materials having symmetrically substituted halogen atoms on the benzene ring, but in this method, 5-substituted isomers were produced for aniline mono-substituted on the benzene ring (Synthesis 1(2009) 69-78).

Chloroquine is currently used for clinical antitumor treatment in the form of oral capsules, and clinical application proves that chloroquine has a wider antitumor spectrum, is more remarkable particularly for advanced breast cancer and non-small cell lung cancer, can obviously prolong the life cycle and improve the life quality, and has the characteristics of slight toxic and side effects, no myelosuppression and immunosuppression effects of common anticancer drugs and convenient taking.

In addition, the curative effect of the chloroquine patient is more obvious when the chloroquine patient receives radiotherapy, and the analysis can have the radiation sensitization effect at the same time.

The anti-tumor action mechanism of chloroquine is that lysosome in cancer cells is enlarged and increased through damaging a DNA template of the cancer cells, so that the lysosome is broken, and various hydrolytic enzymes are released, thereby causing the cancer cells to die by autolysis.

However, chloroquine as a chemical anti-tumor innovative medicine in China has two problems: (1) the solubility of chloroquine raw material medicine in water is very low, so clinically, the chloroquine raw material medicine cannot be administrated in the form of injection. At present, the preparation form of oral capsules is clinically adopted, so that the in-vivo bioavailability and the exertion of the anti-tumor curative effect are limited. Therefore, there is a need to solve the solubility problem of such compounds. (2) At present, the anti-tumor rate of chloroquine to S180 sarcoma and Ehrlich carcinoma solid tumor-bearing mouse models is only about 30%, and the anti-tumor activity of chloroquine needs to be improved.

Therefore, chloroquine is necessary to be used as a precursor to search for a derivative with new biological activity characteristics so as to obtain a new anticancer drug superior to the original drug for clinical application.

Disclosure of Invention

There is still a need to find new chloroquine compounds with anti-tumor activity for clinical application. The invention finds that the compound shown in the general formula I has expected antitumor activity. The present invention has been completed based on this finding.

In a first aspect, the present invention provides a compound of formula I:

and pharmaceutically acceptable salts, solvates, prodrugs thereof, wherein

R¹Selected from hydrogen, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_1-6Alkyl-phenyl, wherein said alkyl, alkenyl, alkynyl and phenyl groups may optionally be substituted by halogen, nitro, cyano, hydroxy, -C_1-6Alkoxy, phenyl substitution;

R³selected from hydrogen, -CONHR₃₁、-COOR₃₂Wherein said R is₃₁And R₃₂Each independently selected from-C_1-6Alkyl and-C_1-6Alkylamino, wherein the amino group is optionally substituted by 1 to 2-C_1-6Alkyl substitution;

R⁷selected from halogen, -C_1-6Alkoxy radical,

A compound according to the first aspect of the invention, wherein R¹Selected from hydrogen, -C_1-6Alkyl, -C_2-6Alkenyl, -C_1-6Alkyl-phenyl, wherein said alkyl, alkenyl and phenyl groups may optionally be substituted by halogen, nitro, cyano, hydroxy, -C_1-6An alkoxy group.

A compound according to the first aspect of the invention, wherein R¹Selected from hydrogen, -C_1-6Alkyl, -C_2-6Alkenyl, -C_1-6Alkyl-phenyl.

A compound according to the first aspect of the invention, wherein R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, allyl, propenyl, benzyl, phenylpropyl, n-butyl.

A compound according to the first aspect of the invention, wherein R³Selected from hydrogen, -CONHR₃₁、-COOR₃₂Wherein said R is₃₁And R₃₂Each independently selected from-C_1-4Alkyl and-C_1-4Alkylamino, wherein the amino group is optionally substituted by 1 to 2-C_1-4Alkyl substitution.

A compound according to the first aspect of the invention, wherein R³Selected from hydrogen, -COO-C_1-4Alkyl, -CONH-C_1-4Alkyl, -CONH-C_1-4alkyl-NH-C_1-4Alkyl, -CONH-C_1-4alkyl-N (C)_1-4Alkyl radical)₂。

A compound according to the first aspect of the invention, wherein R³Selected from hydrogen, -COOCH₂CH₃、-CONH-(CH₂)₂-N(C₂H₅)₂、-CONH-(CH₂)₃-N(C₂H₅)₂、-CONH-(CH₂)₃-NH₂。

A compound according to the first aspect of the invention, wherein R⁷Selected from halogen, -C_1-4Alkoxy radical,

A compound according to the first aspect of the invention, wherein R⁷Selected from fluorine, chlorine, bromine, methoxy,

A compound according to the first aspect of the invention, wherein R¹And R³Not hydrogen at the same time.

A compound according to the first aspect of the invention, with the proviso that: r¹And R³At the same time is hydrogen, and R⁷Is halogen.

A compound according to the first aspect of the invention, which is a compound selected from the group consisting of:

7-fluoro-1-methyl-4-oxo-quinoline,

7-chloro-1-methyl-4-oxo-quinoline,

7-bromo-1-methyl-4-oxo-quinoline,

7-methoxy-1-methyl-4-oxo-quinoline,

7-chloro-1-isopropyl-4-oxo-quinoline,

1-allyl-7-chloro-4-oxo-quinoline,

1-benzyl-7-chloro-4-oxo-quinoline,

7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline,

1-benzyl-7-bromo-4-oxo-quinoline,

7-morpholinyl-4 (1H) oxoquinoline,

1-methyl-7- (4-methylpiperazin-1-yl) -4-oxo-quinoline,

1-benzyl-7-morpholinyl-4-oxo-quinoline,

n- (3- (diethylamino) propyl) -7-fluoro-4 (1H) -oxoquinoline-3-carboxamide,

7-chloro-N- (3- (diethylamino) propyl) -4(1H) -oxoquinoline-3-carboxamide,

7-bromo-N- (3- (diethylamino) propyl) -4(1H) -oxoquinoline-3-carboxamide,

n- (3-diethylamino) propyl-7-methoxy-4- (1H) -oxoquinoline-3-carboxamide,

ethyl 7-chloro-1-methyl-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 1-allyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxylic acid ester,

7-chloro-N- [2- (diethylamino) ethyl ] -1-methyl-4-oxo-quinoline-3-carboxamide,

7-chloro-N- [3- (diethylamino) propyl ] -1-methyl-4-oxo-quinoline-3-carboxamide,

7-chloro-N- [2- (diethylamino) ethyl ] -1-ethyl-4-oxo-quinoline-3-carboxamide,

7-chloro-N- [2- (diethylamino) propyl ] -1-ethyl-4-oxo-quinoline-3-carboxamide,

1-allyl-7-chloro-N- [2- (diethylamino) ethyl ] -4-oxo-quinoline-3-carboxamide,

1-allyl-7-chloro-N- [3- (diethylamino) propyl ] -4-oxoquinoline-3-carboxamide,

1-butyl-7-chloro-N- [2- (diethylamino) ethyl ] -4-oxo-quinoline-3-carboxamide,

1-butyl-7-chloro-N- [3- (diethylamino) propyl ] -4-oxo-quinoline-3-carboxamide,

1-benzyl-7-chloro-N- [2- (diethylamino) ethyl ] -4-oxo-quinoline-3-carboxamide,

1-benzyl-7-chloro-N- [2- (diethylamino) propyl ] -4-oxo-quinoline-3-carboxamide,

7-chloro-N- [3- (diethylamino) propyl ] -1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxamide,

n- (3-aminopropyl) -7-chloro-1-ethyl-4-oxo-quinoline-3-carboxamide,

1-allyl-N- (3-aminopropyl) -7-chloro-4-oxo-quinoline-3-carboxamide,

n- (3-aminopropyl) -1-butyl-7-chloro-4-oxo-quinoline-3-carboxamide,

n- (3-aminopropyl) -7-chloro-1-benzyl-4-oxo-quinoline-3-carboxamide,

n- (3-aminopropyl) -7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxamide,

and pharmaceutically acceptable salts, solvates, prodrugs thereof.

A second aspect of the present invention relates to the use of a compound of formula I according to any one of the first aspect of the present invention, a tautomer, racemate or optical isomer thereof, a pharmaceutically acceptable salt thereof, or solvate thereof, for the preparation of a medicament useful for the prophylaxis or treatment of tumors.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I according to the first aspect of the present invention and a compound of formula II, formula III or a pharmaceutically acceptable salt, solvate, prodrug thereof, as described below, and optionally a pharmaceutically acceptable carrier or excipient. According to this aspect, the present invention also relates to the use of the pharmaceutical composition as a medicament for preventing or treating diseases such as tumor.

In a fifth aspect, the present invention provides a method for the prevention and/or treatment of neoplasms, the method comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of formula I of the first aspect and a compound of formula II, formula III, or a pharmaceutically acceptable salt, solvate, prodrug thereof, as described below.

In a sixth aspect, the present invention provides a process for the preparation of a compound of formula I of the first aspect, or a pharmaceutically acceptable salt, solvate, prodrug thereof, which comprises the steps of:

a) make formulaReacting the compound with diethyl ethoxymethylenemalonate (for example, under heating conditions, such as at 80-120 ℃) to obtain a compound of the formula:

b) adding the compound obtained in the step a) into a suitable solvent (such as diphenyl ether), reacting the mixture under heating (such as boiling or refluxing of the solvent), adding petroleum ether after the reaction is finished, and separating to obtain the compound shown in the formula:

c) adding an aqueous base (e.g., aqueous sodium hydroxide solution, e.g., 5-20% aqueous sodium hydroxide solution) to the compound obtained in step b), heating (e.g., refluxing) for reaction, and acidifying with an acid (e.g., hydrochloric acid, e.g., concentrated hydrochloric acid) after the reaction is completed to obtain a compound of the formula

d) Adding the compound obtained in step c) into a suitable solvent (such as diphenyl ether), reacting the mixture under heating (such as reflux), adding petroleum ether after the reaction is finished, and separating to obtain the 7-substituted-4- (1H) -oxoquinoline compound shown in the following formula:

and

e) dissolving the compound obtained in step d) in a suitable solvent (e.g. DMF), adding NaH and then the haloalkane R¹Y is reacted to give R³The compounds of the present invention having the formula:

wherein,

x represents halogen or-C_1-4An alkoxy group,

y represents a halogen atom or a halogen atom,

R¹is selected from-C_1-6Alkyl, -C_2-6Alkenyl, -C_1-6Alkyl-phenyl radicals, especially for example R¹Selected from methyl, ethyl, propyl, isopropyl, allyl, propenyl, benzyl, phenylpropyl, n-butyl.

The sixth aspect of the present invention also provides a process for the preparation of a compound of formula I of the first aspect, or a pharmaceutically acceptable salt, solvate, prodrug thereof, comprising the steps of:

a) in a suitable solution (e.g. 1, 4-dioxane), in KN [ Si (CH3)₃]₂In the presence ofCompounds with morpholine or NMethylpiperazine (for example under heating, for example under reflux) to give the compounds of the formula:wherein R is¹Is hydrogen or-C_1-6Alkyl radicals such as methyl, R⁷Is composed ofOrOr

b) In a suitable solution (e.g. DMSO) in the presence of cuprous iodide, L-proline, tripotassium phosphateReacting the compound with morpholine (e.g. under heated conditions, such as under reflux conditions) to give a compound of the formula:wherein R is¹is-C_1-6Alkyl-phenyl radicals such as benzyl, R⁷Is composed of

a) reacting ethyl 7-substituted-4 (1H) -oxoquinoline-3-carboxylic acid ester represented by the following formula

Mixing with 3- (diethylamino) propylamine and heating (for example, at 120 to 180 ℃) to react to obtain a compound of the formula:

wherein X is halogen or-C_1-6Alkoxy, for example X is fluorine, chlorine, bromine or methoxy.

a) make formulaThe compound is reacted with a compound of formula R in a suitable solvent (e.g., DMF) in the presence of NaH¹-Y to obtain the compound of formula:

and optionally further to the above-mentioned step of,

b) reacting the compound obtained in step a) with a compound of the formula H₂N-(CH₂)_n-NH₂、H₂N-(CH₂)_n-N(C₂H₅)₂Mixing the diamines and heating (for example, at 120 to 180 ℃) to react the diamines to obtain the compound of the formula:

or

Wherein

Y represents a halogen atom or a halogen atom,

n is 2 or 3, and n is a linear alkyl group,

In the above sixth aspect of the present invention, wherein the symbols are as defined for compounds of formula I in any one of the first aspect of the present invention.

The seventh aspect of the present invention provides a compound represented by the following formula II

And pharmaceutically acceptable salts, solvates, prodrugs thereof, wherein

R⁴Selected from halogen (e.g. chlorine, fluorine, bromine, iodine), -C_1-6Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl), -C_1-6Alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, n-butoxy), -NH-C_1-6alkyl-N (C)_1-4Alkyl radical)₂；

R⁷Selected from halogen (e.g. chlorine, fluorine, bromine, iodine), -C_1-6Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl), -C_1-6Alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, n-butoxy), -C_1-6Alkenyloxy (e.g. ethyleneoxy, propyleneoxy, butyleneoxy), -C_1-6Alkyl-phenyl, -C_1-6Alkyl-halo (e.g., chloro, fluoro, bromo, iodo) phenyl.

A compound according to the seventh aspect of the invention, selected from:

4, 7-dichloro-quinoline,

4-chloro-7-methoxyquinoline,

7-chloro-4-methoxyquinoline,

7-chloro-4-ethoxyquinoline,

7-chloro-4-isopropoxy quinoline,

4, 7-dimethoxy quinoline,

4-ethoxy-7-methoxyquinoline,

4-chloro-7-hydroxyquinoline,

4-chloro-7-ethoxyquinoline,

4-chloro-7-n-butoxyquinoline,

4-chloro-7-n-hexyloxyquinoline,

4-chloro-7-allyloxyquinoline,

4-chloro-7-isopropoxy quinoline,

4-chloro-7-isobutoxyquinoline,

4-chloro-7-benzyloxyquinoline,

4-chloro-7- (4-fluorobenzyloxy) quinoline,

4-chloro-7- (3-phenethyloxy) quinoline,

4-chloro-7- (3-phenylpropoxy) quinoline,

N¹- (7-ethoxyquinolin-4-yl) -N²,N²-diethylethane-1, 2-diamine,

N¹,N¹-diethyl-N²- (7-hexyloxyquinolin-4-yl) ethane-1, 2-diamine,

N¹- (7-allyloxyquinolin-4-yl) -N²,N²-diethylethane-1, 2-diamine,

N¹,N¹-diethyl-N²- (7-isopropoxyquinolin-4-yl) ethane-1, 2-diamine,

N¹- (7-benzyloxy)Quinolinyl-4-yl) -N²,N²-diethylethane-1, 2-diamine,

N¹,N¹-diethyl-N²- (7- (4-fluorobenzyloxy) quinolin-4-yl) ethane-1, 2-diamine,

N¹- (7-ethoxyquinolin-4-yl) -N²,N²-diethylpropane-1, 2-diamine,

N¹- (7-allyloxyquinolin-4-yl) -N²,N²-diethylpropane-1, 2-diamine,

N¹,N¹-diethyl-N²- (7- (4-fluorobenzyloxy) quinolin-4-yl) propane-1, 2-diamine,

and pharmaceutically acceptable salts, solvates, prodrugs thereof.

The eighth aspect of the present invention provides a compound represented by the following formula III

And pharmaceutically acceptable salts, solvates, prodrugs thereof, wherein

Y is1 to 4 groups selected from halogen, e.g. Y is 1-2 groups selected from fluorine, chlorine, bromine, iodine, e.g. Y is 2 chlorine.

A compound according to the eighth aspect of the invention selected from:

5, 8-dichloro-4- (1H) -oxoquinoline, and

6, 8-dichloro-4- (1H) -oxoquinoline,

and pharmaceutically acceptable salts, solvates, prodrugs thereof.

Any aspect of the invention or any one of the aspects having features is equally applicable to any other aspect or any one of the other aspects as long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. In the present invention, for example, reference to "any of the first aspects of the invention" means any sub-aspect of the first aspects of the invention; and in other respects, are referred to in a similar manner and have the same meaning.

Various aspects and features of the disclosure are described further below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

The radical definitions, composition descriptions, instructions for use, etc., which follow for the compounds of formula I, are equally applicable to the compounds of formula II and the compounds of formula III, if no conflict arises.

The terms "halo", "halogen", "Hal" or "halo" as used herein refer to fluoro, chloro, bromo, and iodo.

The terms "alkyl", "alkenyl" and "alkynyl" as used herein have the general meaning well known in the art, and are straight or branched chain hydrocarbyl groups such as, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, allyl, propenyl, propynyl, and the like, and the "alkyl", "alkenyl" and "alkynyl" groups may be collectively referred to as "hydrocarbyl" or "alkanyl". In a preferred embodiment of the present invention, said "hydrocarbyl" means alkyl including alkanyl and cycloalkyl, especially alkanyl such as C1-C6 alkyl.

As used herein, the term "aryl" is for example, but not limited to, phenyl, naphthyl.

As used herein, the phrase "substituted or unsubstituted C1-C6 alkyl" refers to a substituted or unsubstituted alkyl group having the specified number of carbon atoms, examples of which include, but are not limited to: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl, hexyl.

The invention relates to a series of compounds comprising a quinazolinone ring, the quinazolinone ring and the ring atom numbering thereof being indicated in the following order for easy identificationWherein the ring nitrogen atom is in the 1-position and the ring carbon at the oxo group is in the 4-position.

In the present invention, the group "C₁-C₆Alkyl "and" C_1-6Alkyl "both have the same meaning and both represent straight-chain or branched alkyl groups having 1 to 6 carbon atoms. Other situations may be similarly understood.

In the present invention, the group "C_1-6Alkyl "may be selected, for example, from C_1-5Alkyl radical, C_1-4An alkyl group. Likewise, -C_1-6Alkoxy can be selected, for example, from C_1-5Alkoxy radical, C_1-4Alkoxy radical, -C_2-6Alkenyl radicals may be selected, for example, from C_2-5Alkenyl radical, C_2-4Alkenyl, -C_2-6Alkynyl may be selected, for example, from C_2-5Alkynyl, C_2-4Alkynyl.

In the process of the present invention for the synthesis of compounds of formula I, the various starting materials for the reaction are either prepared by methods known in the literature or are commercially available, as known to the person skilled in the art. The intermediates, starting materials, reagents, reaction conditions, etc. used in the above reaction schemes may be appropriately modified according to the knowledge of those skilled in the art. Alternatively, other compounds of formula I not specifically recited herein may also be synthesized by those skilled in the art according to the method of the second aspect of the invention.

According to the invention, pharmaceutically acceptable salts of the compounds of formula I may be acid addition salts or salts with bases. Acid addition salts may be exemplified by inorganic acid salts such as, but not limited to, hydrochloride, sulfate, phosphate, hydrobromide; or organic acid salts such as, but not limited to, acetate, oxalate, citrate, gluconate, succinate, tartrate, p-toluenesulfonate, methanesulfonate, benzoate, lactate and maleate; salts of compounds of formula I with bases may be exemplified by alkali metal salts such as, but not limited to, lithium, sodium and potassium salts; alkaline earth metal salts such as, but not limited to, calcium and magnesium salts; organic base salts such as, but not limited to, diethanolamine salts, choline salts, and the like; or chiral base salts such as, but not limited to, alkylphenylamine salts.

Solvates of the compounds of the invention may be hydrates or contain other crystallization solvents such as alcohols, for example ethanol.

According to the invention, the compounds of the formula I may exist in cis/trans isomers, and the invention relates to the cis form and the trans form and mixtures of these forms. If desired, the single stereoisomers may be prepared by resolution of a mixture according to conventional methods, or by, for example, stereoselective synthesis. The invention also relates to tautomeric forms of the compounds of the formula I, if motorized hydrogen atoms are present.

The present invention therefore also relates to pharmaceutical compositions containing as active ingredient an effective dose of at least one compound of formula I, or a pharmaceutically acceptable salt and/or stereoisomer thereof, together with conventional pharmaceutical excipients or adjuvants. The pharmaceutical compositions according to the invention generally contain 0.1 to 90% by weight of a compound of the formula I and/or a physiologically acceptable salt thereof. The pharmaceutical compositions may be prepared according to methods known in the art. For this purpose, the compounds of the formula I and/or stereoisomers can, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants in a suitable administration form or dosage form for human use.

The compound of formula I or the pharmaceutical composition containing it of the present invention can be administered in unit dosage form, either enterally or parenterally, such as orally, intramuscularly, subcutaneously, intratumorally, nasally, oromucosally, dermally, peritoneally or rectally, etc. The administration dosage forms include tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized powder for injection, etc. Can be common preparation, sustained release preparation, controlled release preparation and various microparticle drug delivery systems. In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. For making the administration units into pills, a wide variety of carriers well known in the art can be used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc. For making the administration unit into a suppository, various carriers well known in the art can be widely used. As examples of the carrier, there may be mentioned, for example, polyethylene glycol, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like. To encapsulate the dosage unit, the active ingredient compound of formula I or a stereoisomer thereof is mixed with the various carriers mentioned above and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. Or making the effective component of formula I or its stereoisomer into microcapsule, suspending in aqueous medium to form suspension, or making into hard capsule or injection. For preparing the administration unit into preparations for injection, such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art can be used, for example, water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, and the like. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added.

In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.

The dosage of a compound of formula I, or an isomer thereof, of the present invention will depend on a number of factors, such as the nature and severity of the condition to be prevented or treated, the sex, age, weight and individual response of the patient or animal, the particular compound used, the route of administration and the number of administrations desired. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g. two, three or four dosage forms.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is common practice in the art to start doses of the compounds at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The compound can be used for preparing antitumor drugs. The tumor includes, but is not limited to, malignant tumors such as melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermoid carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder cancer, head and neck tumor, nasopharyngeal carcinoma, skin cancer and leukemia. The gastric cancer comprises gastric adenocarcinoma; the lung cancer comprises lung adenocarcinoma; the colon cancer comprises colon adenocarcinoma; the ovarian cancer comprises ovarian adenocarcinoma; the renal cancer comprises renal clear cell adenocarcinoma; the leukemia includes acute lymphocytic leukemia, chronic leukemia, and special leukemia.

When used in the above-described therapeutic and/or prophylactic or other therapeutic and/or prophylactic applications, a therapeutically and/or prophylactically effective amount of a compound of the present invention may be employed in pure form, or in the form of a pharmaceutically acceptable ester or prodrug, where such forms are present. Alternatively, the compounds may be administered in a pharmaceutical composition comprising the compound of interest together with one or more pharmaceutically acceptable excipients. The phrase "prophylactically and/or therapeutically effective amount" of a compound of the present invention refers to a sufficient amount of the compound to treat a disorder at a reasonable benefit/risk ratio applicable to any medical prophylaxis and/or treatment. It will be appreciated, however, that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. In general, the dosage of the compounds of formula I of the present invention for use in mammals, especially humans, may be between 0.001 to 1000mg/kg body weight/day, such as between 0.01 to 100mg/kg body weight/day, such as between 0.01 to 10mg/kg body weight/day.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to be limiting in any way.

The following scheme 1 depicts some intermediates for preparing the compounds of the present invention and the general process for preparing some of the compounds of the present invention.

Synthesis scheme 1

General synthetic procedure for compounds 6 a-d:

(1) synthesis of Schiff bases 3 a-d:

the corresponding meta-anilines 1a-d (100mmol) and diethyl ethoxymethylenemalonate 2(23.3g,108mmol) were mixed and stirred at room temperature until the solution was clear. And then heating and stirring the reaction mixed solution at 100 ℃ for 2 hours to react, and directly adding the reaction mixed solution (namely the Schiff base 3a-d) into a next reaction bottle without post-treatment and purification after the reaction is finished.

(2) Oxoquinoline-3-carboxylic acidSynthesis of acid esters 4a-d

Diphenyl ether (100ml) was added to a 250ml round bottom flask and heated to boiling with stirring. And then the Schiff base 3a-d obtained in the previous step is dripped into the boiling diphenyl ether solution when the solution is hot. After the addition, the heating reflux reaction is continued, white solid is separated out from the bottle wall in about 15 minutes, and the solid is full of the whole bottle of solution and gradually turns yellow in about 45 minutes. Stopping the reaction, cooling the reaction liquid to room temperature, adding petroleum ether (100ml) with the temperature of 60-90 ℃ into a reaction bottle, uniformly stirring, filtering, and washing with the petroleum ether to obtain a white solid, namely the intermediate oxoquinoline-3-carboxylic ester 4 a-d.

Ethyl 7-fluoro-4 (1H) -oxoquinoline-3-carboxylic acid ester (4a)

Starting from m-fluoroaniline 1a (100mmol), a white solid (16.9g,72%) was obtained.

Ethyl 7-chloro-4 (1H) -oxoquinoline-3-carboxylic acid ester (4b)

Starting from m-chloroaniline 1b (100mmol), a white solid (19.6g,78%) was obtained.

Ethyl 7-bromo-4 (1H) -oxoquinoline-3-carboxylic acid ester (4c)

Starting from m-bromoaniline 1c (100mmol), a white solid was obtained (22.2g,75%).

Ethyl 7-methoxy-4 (1H) -oxoquinoline-3-carboxylic acid ester (4d)

Starting from 3-methoxyaniline, 1d (100mmol), a white solid was obtained (16.3g,66%).

(3) Synthesis of oxoquinoline-3-carboxylic acid 5a-d

The oxoquinoline-3-carboxylic acid ester 4a-d (20mmol) obtained in the previous step was charged into a round-bottomed flask, followed by addition of a 10% NaOH solution (150ml), and heated under reflux for 1 hour with stirring. And cooling the reaction solution to room temperature, adding 500ml of water to dilute the reaction solution, adjusting the pH value to 6.0 by using concentrated hydrochloric acid, separating out a light yellow solid, filtering, fully washing by using water, and drying to obtain a white solid, namely the intermediate oxoquinoline-3-carboxylic acid 5 a-d.

7-fluoro-4 (1H) -oxoquinoline-3-carboxylic acid (5a) gave a white solid (4.1g,98%).

7-chloro-4 (1H) -oxoquinoline-3-carboxylic acid (5b) gave a white solid (4.3g,97%).

7-bromo-4 (1H) -oxoquinoline-3-carboxylic acid (5c) gave a white solid (5.2g,98%).

7-methoxy-4 (1H) -oxoquinoline-3-carboxylic acid (5d) gave a white solid (4.2g,96%).

(4) Synthesis of 7-substituted-4- (1H) -oxoquinoline 6a-d

The corresponding intermediate oxoquinoline-3-carboxylic acid 5a-d (16.0g) obtained in the previous step was mixed with diphenyl ether (100ml), and the mixture was heated under reflux. The carboxylic acid does not dissolve first. As the temperature increases, the insoluble solids gradually decrease with the generation of a large number of bubbles. Heating and refluxing the mixture for about 30 minutes to react, stopping the reaction when no bubbles are generated, and cooling the reaction liquid to room temperature to precipitate off-white solid. Adding 60-90 deg.C petroleum ether (100ml), stirring well, and filtering to obtain white solid.

7-fluoro-4 (1H) -oxoquinoline (6a)

A white solid (1.5g,92%) was obtained. ESI-MS M/z164[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆):11.75(1H,s),8.07-8.13(1H,m),7.88(1H,d,J=7.2Hz),7.23-7.27(1H,m),7.13-7.17(1H,m),6.02(1H,d,J=7.2Hz).

7-chloro-4 (1H) -oxoquinoline (6b)

A white solid (1.5g,86%) was obtained. ESI-MS M/z180[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆):11.75(1H,s),8.03(1H,d,J=8.7Hz),7.88(1H,d,J=7.2Hz),7.55(1H,d,J=2.1Hz),7.28(1H,dd,J=8.7Hz,J=2.1Hz),6.02(1H,d,J=7.2Hz).

7-bromo-4 (1H) -oxoquinoline (6c)

A white solid (2.0g,88%) was obtained. ESI-MS M/z224[ M ]]⁺.¹H NMR(300MHz,DMSO-d₆):11.75(1H,s),7.95(1H,d,J=8.7Hz),7.88(1H,d,J=7.5Hz),7.71(1H,d,J=1.8Hz),7.41(1H,dd,J=8.7Hz,J=2.1Hz),6.02(1H,d,J=7.5Hz).¹³C NMR(75MHz,CDCl₃)177.1,141.6,140.6,128.0,126.8,125.7,125.2,121.1,110.0.

7-methoxy-4 (1H) -oxoquinoline (6d)

A white solid (1.6g, 86%) was obtained. ESI-MS M/z176[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆):11.63(1H,s),7.93(1H,d,J=8.7Hz),7.76(1H,d,J=7.5Hz),6.91(1H,d,J=2.4Hz),6.88(1H,dd,J=8.7Hz,J=2.4Hz)5.91(1H,d,J=7.5Hz),3.83(3H,s).

General synthesis process for compounds 7a to 7i of the invention:

7-substituted-4- (1H) -oxoquinoline (10mmol) was dissolved in DMF (60ml), stirred at room temperature to clear, added with 60% NaH (0.8g,20mmol), stirred at room temperature for 5min, added with the corresponding alkyl halide (15-25mmol), stirred at room temperature for reaction, and checked by TLC. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate (150 ml. times.3), and the organic phases were combined, washed with water, and washed with saturated brine. Acidifying the organic phase with concentrated hydrochloric acid (pH 1-2), concentrating under reduced pressure until the organic phase is nearly dry, carrying water with absolute ethyl alcohol for 2 times, and recrystallizing the residue with acetone. And filtering to obtain yellow solid. Dissolving the yellow solid in water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and recrystallizing the residue with diethyl ether or diethyl ether/petroleum ether to obtain the target product 7 a-i. Wherein

Example 1: preparation of 7-fluoro-1-methyl-4-oxo-quinoline (Compound 7a)

Starting from 7-fluoro-4 (1H) -oxoquinoline 6a (5.0mmol) and iodomethane (7.5 mmol). A white solid (0.86g,86%) was obtained. ESI-MS M/z178[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.40-8.45(1H,m),7.47(1H,d,J=7.5Hz),7.00-7.11(2H,m),6.20(1H,d,J=7.5Hz),3.74(3H,s).

Example 2: preparation of 7-chloro-1-methyl-4-oxo-quinoline (Compound 7b)

Starting from 7-chloro-4 (1H) -oxoquinoline 6b (5.0mmol) and iodomethane (7.5 mmol). A white solid (0.67g,69%) was obtained, mp233-234 ℃. ESI-MS M/z194[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.30(1H,d,J=8.7Hz),7.43(1H,d,J=7.8Hz),7.34(1H,d,J=1.8Hz),7.28(1H,dd,J=8.7Hz,J=1.8Hz),6.18(1H,d,J=7.8Hz),3.74(3H,s).¹³CNMR(75MHz,CDCl₃)177.6(C=O),144.1,141.4,138.8,128.8,125.5,124.5,115.4,110.8,41.0.

Example 3: preparation of 7-bromo-1-methyl-4-oxo-quinoline (Compound 7c)

Starting from 7-bromo-4 (1H) -oxoquinoline 6c (5.0mmol) and iodomethane (7.5 mmol). A white solid (1.0g,88%) was obtained. ESI-MS M/z239[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.27(1H,d,J=8.7Hz),7.44-7.54(3H,m),6.23(1H,d,J=7.8Hz),3.76(3H,s).¹³C NMR(75MHz,CDCl₃)176.5,146.1,128.5,128.4,127.1,126.6,126.0,120.0,109.9,40.8.

Example 4: preparation of 7-methoxy-1-methyl-4-oxo-quinoline (Compound 7d)

Starting from 7-methoxy-4 (1H) -oxoquinoline 6d (5.0mmol) and iodomethane (7.5 mmol). A white solid (0.76g,80%) was obtained. Mp179-180 ℃. ESI-MS M/z190[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆):8.31(1H,d,J=8.7Hz),7.40(1H,d,J=7.5Hz),6.94(1H,dd,J=8.7Hz,J=1.8Hz),6.66(1H,s),6.15(1H,d,J=7.5Hz),3.91(3H,s),3.71(3H,s).¹³C NMR(75MHz,CDCl₃)176.4,162.8,145.4,142.9,128.0,121.2,113.4,109.1,99.2,56.4,40.9.

Example 5: preparation of 7-chloro-1-isopropyl-4-oxo-quinoline (Compound 7e)

Starting from 7-chloro-4 (1H) -oxoquinoline 6b (5.0mmol) and 2-bromopropane (20mmol), a white solid was obtained (0.75g, 68%). ESI-MS M/z222[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):9.08(1H,d,J=6.9Hz),8.28-8.32(2H,m),7.82(1H,dd,J=9.0Hz,J=2.1Hz),7.54(1H,d,J=6.9Hz),5.20-5.32(1H,m),1.49(3H,s),1.47(3H,s).¹³CNMR(75MHz,CDCl₃)167.5(C=O),147.9,139.8,139.5,129.7,125.9,119.9,119.8,104.2,76.1,22.0.

Example 6: preparation of 1-allyl-7 chloro-4-oxo-quinoline (Compound 7f)

Starting from 7-chloro-4 (1H) -oxoquinoline 6b (5.0mmol) and allyl bromide (7.5mmol), a white solid was obtained (0.9g, 82%). ESI-MS M/z220[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.32(1H,d,J=8.4Hz),7.46(1H,d,J=7.8Hz),7.26-7.32(2H,m),6.23(1H,d,J=7.8Hz),5.90-6.03(1H,m),5.09-5.34(2H,m),4.64-4.67(2H,m).¹³CNMR(75MHz,CDCl₃)177.5(C=O),143.6,140.8,138.6,130.9,128.7,125.6,124.4,119.0,115.8,111.0,55.2.

Example 7: preparation of 1-benzyl-7-chloro-4-oxo-quinoline (Compound 7g)

Starting from 7-chloro-4 (1H) -oxoquinoline 6b (5.0mmol) and benzyl bromide (7.5mmol), a white solid was obtained (0.95g, 70%). Mp202-203 ℃. ESI-MS M/z270[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.34(1H,d,J=9.0Hz),7.58(1H,d,J=7.8Hz),7.25-7.36(5H,m),7.12(2H,d，J=6.9Hz),6.30(1H,d,J=7.8Hz),5.27(2H,s).¹³C NMR(75MHz,CDCl₃)177.6(C=O),144.1,141.0,138.7,134.7,129.5,128.8,128.7,126.3,125.8,124.6,116.0,111.1,56.7.

Example 8: preparation of 7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline (Compound 7h)

Starting from 7-chloro-4 (1H) -oxoquinoline 6b (5.0mmol) and 1- (3-bromopropyl) benzene (25mmol), a yellow oil (1.0g, 68%) was obtained. ESI-MS M/z298[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.35(1H,d,J=8.7Hz),7.40(1H,d,J=7.8Hz),7.18-7.34(7H,m),6.22(1H,d,J=7.8Hz),4.03(2H,t,J=7.5Hz),2.74(2H,t,J=7.5Hz),2.16-2.26(2H,m).¹³C NMR(75MHz,CDCl₃)177.5(C=O),143.6,140.5,139.8,138.7,129.0,128.5,126.9,125.8,124.4,115.3,110.8,52.6,32.8,30.1.

Example 9: preparation of 1-benzyl-7-bromo-4-oxo-quinoline (Compound 7i)

Starting from 7-bromo-4 (1H) -oxoquinoline 6c (5.0mmol) a and benzyl bromide (7.5mmol), a white solid was obtained (1.32g, 84%). ESI-MS M/z315[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.29(1H,d,J=8.7Hz),7.56(1H,d,J=7.8Hz),7.32-7.48(5H,m),7.13-7.16(2H,m),6.31(1H,d,J=7.8),5.26(2H,s).¹³C NMR(75MHz,CDCl₃)177.1,144.0,141.1,134.7,129.5,128.9,128.7,127.3,126.4,126.2,119.1,111.2,111.1,56.6.

The following scheme 2 depicts some intermediates for preparing the compounds of the present invention and the general methods for preparing some of the compounds of the present invention.

Scheme 2:

example 10: synthesis of 7-morpholinyl-4 (1H) -oxoquinoline (Compound 15)

A50 ml round bottom flask was charged with 1, 4-dioxane (6ml), morpholine (0.21ml, 2.4mmol), KN [ Si (CH3)₃]₂(2.64ml, 2.4mmol) and 7-bromo-4 (1H) -oxoquinoline (0.45g, 2mmol), after addition, the chamberStirring for 5 minutes while warming, then refluxing in oil bath at 100 ℃, tracking and detecting by TLC, after the reaction is finished, cooling the reaction solution to room temperature, adding 20ml of water to terminate the reaction, adjusting the pH value to 6.0, concentrating under reduced pressure until the reaction is dry, carrying out anhydrous ethanol with water for 3 times, carrying out silica gel column chromatography on the residue, and carrying out dichloromethane: methanol 10: 1, a yellow oil (0.16g, 35%) was obtained. ESI-MS M/z230.8[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆):11.38(1H,s),7.88(1H,d,J=7.2Hz),7.69-7.73(1H,m),7.02(1H,dd,J=7.2Hz,1.2Hz),6.71(1H,s),5.87(1H,d,J=7.2Hz),3.73(4H,t,J=4.5Hz),3.20(4H,t,J=4.5Hz).¹³C NMR(75MHz,CDCl₃)177.1,153.8,142.3,139.4,126.6,119.3,113.4,108.9,100.1,66.7,48.2.

Example 11: synthesis of 1-methyl-7- (4-methylpiperazin-1-yl) -4-oxo-quinoline (Compound 16)

A50 ml round bottom flask was charged with 1, 4-dioxane (12ml), N-methylpiperazine (0.4ml, 3.6mmol), KN [ Si (CH3)₃]₂(4ml, 3.64mmol) and 7-bromo-1-methyl-4 (1H) -oxoquinoline (0.48g, 2mmol), after addition, vacuum was immediately applied, after application, N was immediately charged₂The extraction was repeated 4 times for 1 minute each time. The reaction mixture was then placed in a 100 ℃ oil bath at reflux for about 15 hours and checked by TLC. After the reaction, cooling the reaction solution to room temperature, adding 5ml of water to terminate the reaction, concentrating under reduced pressure to dryness, dissolving the reaction residue with methanol, filtering to remove insoluble substances, concentrating the filtrate to dryness, performing silica gel column chromatography, and performing dichloromethane: methanol 30: 1 wash to give a yellow oil (0.16g, 31%). ESI-MS M/z257.9[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆):8.25(1H,d,J=9.0Hz),7.36(1H,d,J=7.5Hz),6.99(1H,dd,J=9.0Hz,2.1Hz),6.49(1H,d,J=2.1Hz),6.13(1H,d,J=7.5Hz),3.70(3H,s),3.38(4H,t,J=4.8Hz),2.59(4H,t,J=4.8Hz),2.36(3H,s).¹³C NMR(75MHz,CDCl₃)177.1,153.8,142.3,139.4,126.6,119.3,113.4,108.9,100.1,66.7,48.2.

Example 12: 1-benzyl-Synthesis of 7-morpholinyl-4-oxo-quinoline (Compound 17):

in a 50ml round bottom flask were added 7-bromo-1-benzyl-4 (1H) -oxoquinoline (0.64g, 2mmol), cuprous iodide (0.05g), L-proline (0.05g,1mmol), tripotassium phosphate (0.42g, 2mmol), morpholine (0.2ml, 1.5mmol) and DMSO (1.5ml) in that order, after addition, the reaction was carried out in an oil bath at 90 ℃ and followed by TLC. After the reaction, 0.5ml of ammonia water was added to terminate the reaction, followed by addition of 10ml of water and 20ml of dichloromethane, separation of the organic phase, extraction of the aqueous phase with dichloromethane twice, combination of the organic phases, washing with water, washing with saturated saline, and drying with anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness, and performing silica gel column chromatography on the residue, wherein the dichloromethane content is as follows: methanol 100: 1 as eluent, to give a yellow oil (0.26g, 40%). ESI-MS M/z320.9[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆):8.28(1H,d,J=9.0Hz),7.53(1H,d,J=7.8Hz),7.29-7.34(3H,m),7.14-7.17(1H,m),6.93(1H,dd,J=9.0Hz,2.1Hz),6.42(1H,d,J=2.1Hz),6.24(1H,d,J=7.8Hz),5.23(2H,s),3.78(4H,t,J=4.8Hz),3.12(4H,t,J=4.8Hz).¹³C NMR(75MHz,CDCl₃)177.8,153.8,143.6,141.9,135.6,129.4,128.4,128.2,126.3,120.4,113.0,110.2,99.3,66.7,57.0,48.2.

The following scheme 3 depicts some intermediates for preparing the compounds of the present invention and the general methods for preparing some of the compounds of the present invention.

Scheme 3:

general Synthesis Process for Compounds 18a-d

Ethyl 7-substituted-4 (1H) -oxoquinoline-3-carboxylic acid ester (5.0mmol) and 3- (diethylamino) propylamine (5.0ml) were mixed and reacted by microwave heating at 150 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, 100mL of water was added to the reaction mixture, dichloromethane extraction (50mL × 3) was performed, organic phases were combined, washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, silica gel column chromatography, dichloromethane: methanol 50: 1 is eluent to obtain the target product.

Example 13: preparation of N- (3- (diethylamino) propyl) -7-fluoro-4 (1H) -oxoquinoline-3-carboxamide (Compound 18a)

Ethyl 7-fluoro-4 (1H) -oxoquinoline-3-carboxylic acid ester 4a (5.0mmol) was used as starting material to give a white solid (0.72,45%). ESI-MS M/z320[ M + H ],]⁺.¹H NMR(300MHz,CDCl₃)10.45(s,1H),8.82(s,1H),8.35-8.40(m,1H),7.23-7.27(m,1H),7.08-7.14(m,1H),3.56(q,J=5.1Hz,2H),2.53-2.60(m,6H),1.78-1.88(m,2H),1.02(t,J=6.9Hz,6H).¹³CNMR(75MHz,CDCl₃)176.6,166.4,163.4,144.6,141.8,129.1,123.8,114.2,111.3,104.8,50.5,47.0,38.0,27.4,11.6.

example 14: preparation of 7-chloro-N- (3- (diethylamino) propyl) -4(1H) -oxoquinoline-3-carboxamide (Compound 18b)

Ethyl 7-chloro-4 (1H) -oxoquinoline-3-carboxylic acid ester 4b (5.0mmol) was used as starting material to give a white solid (0.87g,52%). ESI-MS M/z336[ M + H ],]⁺.¹H NMR(300MHz,CDCl₃)10.48(s,1H),8.84(s,1H),8.34(d,J=8.7Hz,1H),7.63(d,J=1.5Hz,1H),7.36(dd,J=8.7,1.5Hz,1H),3.55(q,J=5.1Hz,2H),2.58-2.65(m,6H),1.78-1.94(m,2H),1.07(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)176.7,166.4,144.6,140.9,138.8,127.9,125.8,125.4,118.9,111.5,50.5,47.1,38.1,27.4,11.6.

example 15: preparation of 7-bromo-N- (3- (diethylamino) propyl) -4(1H) -oxoquinoline-3-carboxamide (Compound 18c)

Ethyl 7-bromo-4 (1H) -oxoquinoline-3-carboxylic acid ester 4c (5.0mmol) was used as starting material to give a white solid (0.93,49%). ESI-MS M/z380[ M + H ],]⁺.¹H NMR(300MHz,CDCl₃)10.52(s,1H),8.84(s,1H),8.26(d,J=8.7Hz,1H),7.81(d,J=1.5Hz,1H),7.51(dd,J=8.7,1.5Hz,1H),3.56(q,J=5.1Hz,2H),2.58-2.65(m,6H),1.82-1.91(m,2H),1.06(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)176.8,166.5,144.5,141.1,128.6,127.9,127.2,125.8,122.1,111.5,50.6,47.1,38.1,27.4,11.7.

example 16: preparation of N- (3-diethylamino) propyl-7-methoxy-4- (1H) -oxoquinoline-3-carboxamide (Compound 18d)

Ethyl 7-methoxy-4 (1H) -oxoquinoline-3-carboxylic acid ester 4d (5.0mmol) was used as starting material to give a white solid (0.96g,58%). ESI-MSm/z332[ M + H ]/]⁺.¹H NMR(300MHz,CDCl₃)10.50(s,1H),8.78(s,1H),8.30(d,J=9.0Hz,1H),7.00(dd,J=9.0,1.8Hz,1H),6.91(d,J=1.8Hz,1H),3.89(s,3H),3.54(q,J=5.4Hz,2H),2.51-2.59(m,6H),1.78-1.87(m,2H),1.02(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)176.6,166.3,162.9,143.1,141.1,127.6,120.7,115.8,110.8,99.7,55.6,50.3,46.7,37.8,27.2,11.4.

The following scheme 4 depicts some intermediates for preparing the compounds of the present invention and a general method for preparing some of the compounds of the present invention.

Scheme 4:

general synthetic process for compounds 19a-f

Ethyl 7-chloro-4 (1H) -oxoquinoline-3-carboxylate 4b (2.51g,10mmol) and DMF (50ml) were added to a 100ml round bottom flask and stirred at room temperature for 10 minutes followed by the addition of 60% NaH (0.8g,20mmol), stirring at room temperature for 15 minutes, followed by the addition of the corresponding haloalkane (15-30mmol), stirring at room temperature for the reaction, and follow-up by TLC. After the reaction, pouring the reaction mixture into water, extracting with ethyl acetate, combining organic phases, washing with water, and washing with saturated brine. Acidifying the organic phase with concentrated hydrochloric acid, concentrating under pressure to dryness, adding anhydrous ethanol with water for 3 times, recrystallizing with acetone, and filtering to obtain yellow solid. Dissolving the yellow solid in water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, performing silica gel column chromatography, and eluting with ethyl acetate/petroleum ether =2:1 to obtain the target product.

Example 17: preparation of Ethyl 7-chloro-1-methyl-4-oxo-quinoline-3-carboxylic acid ester (Compound 19a)

Using methyl iodide (15mmol) as the starting material, white solid (1.7g,65%). ESI-MS M/z288[ M + Na ]. The]⁺.¹H NMR(300MHz,CDCl₃)8.42-8.45(m,2H),7.38-7.41(m,2H),4.39(q,J=7.2Hz,2H),3.86(s,3H),1.42(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)172.9,164.9,151.2,141.3,138.2,128.8,127.1,125.8,117.7,110.8,60.6,41.8,15.1.

Example 18: preparation of Ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ester (Compound 19b)

Iodothane (15mmol) was used as the starting material to give a white solid (1.9g,69%). ESI-MS M/z302[ M + Na ]. The]⁺.¹H NMR(300MHz,CDCl₃)8.44-8.47(m,2H),7.25-7.43(m,2H),4.39(q,J=7.2Hz,2H),4.21(q,J=7.2Hz,2H),1.56(t,J=7.2Hz,3H),1.41(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)173.5,165.2,148.9,139.4,139.1,129.5,127.5,125.5,115.8,111.5,61.1,49.2,14.7.

Example 19: preparation of Ethyl 1-allyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester (Compound 19c)

Allyl bromide (15mmol) was used as starting material to give a white solid (2.2g,75%). ESI-MS M/z314[ M + Na ]. The]⁺.¹H NMR(300MHz,CDCl₃)8.48(s,1H),8.42(d,J=8.7Hz,1H),7.34-7.39(m,2H),5.94-5.07(m,1H),5.40(d,J=10.5Hz,1H),5.20(d,J=17.1Hz,1H),4.79(m,2H),4.38(q,J=6.9Hz,2H),1.41(t,J=6.9Hz,3H).¹³C NMR(75MHz,CDCl₃)173.8,165.2,149.7,140.0,139.2,130.5,129.4,127.3,125.8,119.8,116.5,111.6,61.2,56.2,14.8.

Example 20: preparation of Ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester (Compound 19d)

Starting from n-butyl iodide (30mmol), a white solid (1.9g,62%). ESI-MS M/z330[ M + Na ]]⁺.¹HNMR(300MHz,DMSO-d₆):8.62(s,1H),8.17(d,J=8.7Hz,1H),7.87(d,J=1.8Hz,1H),7.47(dd,J=8.7Hz,1.8Hz,1H),4.33(t,J=7.2Hz,2H),4.20(q,J=7.2Hz,2H),1.64-1.73(m,2H),1.24-1.34(m,5H),0.88(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)172.8,165.0,150.5,140.3,138.4,129.2,127.5,125.8,117.4,111.1,60.7,53.3,31.3,19.9,15.1,14.3.

Example 21: preparation of Ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester (Compound 19e)

Benzyl bromide (15mmol) was used as starting material to give a white solid (2.9g,85%). ESI-MS M/z364[ M + Na ]. The]⁺.¹H NMR(300MHz,DMSO-d₆):8.54(s,1H),8.43(d,J=8.1Hz,1H),7.30-7.38(m,5H),7.14-7.18(m,2H),5.34(s,2H),4.38(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)173.6,165.0,150.0,140.1,139.1,134.0,129.5,129.4,128.8,127.5,126.4,125.7,116.7,111.7,61.1,57.5,14.8.

Example 22: preparation of Ethyl 7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxylic acid ester (Compound 19f)

1- (3-bromopropyl) benzene (50mmol) is taken as a raw material to obtain a white solid (2.4)_g,65%).ESI-MS m/z392[M+Na]⁺.¹HNMR(300MHz,CDCl₃)8.44(d,J=8.7Hz,1H),8.37(s,1H),7.43-7.15(m,7H),4.40(q,J=7.2Hz,2H),4.10(t,J=7.2Hz,2H),2.77(t,J=7.2Hz,2H),2.32–2.20(m,2H),1.42(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)173.2,164.9,149.1,139.2,139.1,138.8,129.4,128.6,128.1,127.9,127.3,126.5,125.3,115.3,111.2,60.8,52.9,32.3,29.6,14.4.

The following general synthetic procedures depict general methods for preparing compounds 20a-k and 21a-e of the present invention.

1-substituted ethyl 7-chloro-4 (1H) -oxoquinoline-3-carboxylate (5.0mmol) and the corresponding diamine (5.0ml) were mixed and reacted by microwave heating at 150 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, 100mL of water was added to the reaction mixture, dichloromethane extraction (50mL × 3) was performed, organic phases were combined, washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, silica gel column chromatography, dichloromethane: methanol 50: 1 is eluent to obtain the target product.

Example 23: preparation of 7-chloro-N- [2- (diethylamino) ethyl]-1-methyl-4-oxo-quinoline-3-carboxamide (Compound 20a)

Starting from ethyl 7-chloro-1-methyl-4-oxo-quinoline-3-carboxylate 19a (5.0mmol) and N, N-diethylethylenediamine (5.0ml), gave a white solid (1.1g,68%). ESI-MS M/z336[ M + H ] -]⁺.¹H NMR(300MHz,CDCl₃)9.92(s,1H),8.73(s,1H),8.45(d,J=8.4Hz,1H),7.43-7.50(m,2H),3.91(s,3H),3.55(q,J=6.3Hz,2H),2.61-2.67(m,6H),1.79-1.91(m,2H),1.08(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)176.0,164.6,148.8,140.7,139.5,129.1,126.3,125.9,116.0,112.7,52.1,47.5,41.8,37.7,12.2.

Example 24: preparation of 7-chloro-N- [3- (diethylamino) propyl]-1-methyl-4-oxo-quinoline-3-carboxamide (Compound 20b)

Starting from ethyl 7-chloro-1-methyl-4-oxo-quinoline-3-carboxylic acid ester 19a (5.0mmol) and 3- (diethylamino) propylamine (5.0ml)Feed to give a white solid (0.9g,54%). ESI-MS M/z350[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃)9.92(s,1H),8.73(s,1H),8.45(d,J=8.7Hz,1H),7.43-7.50(m,2H),3.91(s,3H),3.55(q,J=6.3Hz,2H),2.61-2.67(m,6H),1.79-1.91(m,2H),1.08(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)176.1,164.6,148.9,140.7,139.6,129.0,125.9,116.0,112.7,50.6,47.1,41.8,38.0,27.4,11.9.

Example 25: preparation of 7-chloro-N- [2- (diethylamino) ethyl]-1-Ethyl-4-oxo-quinoline-3-carboxamide (Compound 20c)

Starting from ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylate 19b (5.0mmol) and N, N-diethylethylenediamine (5.0ml) was obtained a white solid (1.0g,58%). ESI-MS M/z350[ M + H ]. The results are obtained]⁺.¹H NMR(300MHz,CDCl₃)9.95(s,1H),8.77(s,1H),8.44(d,J=8.4Hz,1H),7.50(d,J=1.5Hz，1H),7.43(d,J=8.4Hz,1.5Hz,1H),4.29(q,J=7.2Hz,2H),3.55(q,J=6.6Hz,2H),2.82(t,J=6.9Hz,2H),2.64(q,J=7.2Hz,4H),1.57(t,J=7.2Hz,3H),1.10(t,J=7.2Hz,6H).¹³CNMR(75MHz,CDCl₃)175.9,164.7,147.6,139.6,139.4,129.3,126.6,125.6,115.7,112.9,52.1,49.3,47.5,37.7,14.8,12.3.

Example 26: preparation of 7-chloro-N- [2- (diethylamino) propyl]-1-Ethyl-4-oxo-quinoline-3-carboxamide (Compound 20d)

Starting from ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylate 19b (5.0mmol) and 3- (diethylamino) propylamine (5.0ml), this gave ESI-MS M/z364[ M + H/M ] 364 as a white solid (1.06g,57%)]⁺.¹H NMR(300MHz,CDCl₃)9.92(s,1H),8.77(s,1HH),8.45(d,J=8.7Hz,1H),7.51(d,J=1.8Hz,1H),7.43(dd,J=8.7,1.8Hz,1H),4.28(q,J=7.2Hz,2H),3.49(q,J=6.9Hz,2H),2.54(m,6H),1.86-1.74(m,2H),1.57(t,J=7.2Hz,3H),1.04(t,J=7.2Hz,6H).¹³CNMR(75MHz,CDCl₃)176.0,164.6,147.7,139.5,129.3,126.6,125.7,115.7,112.9,50.7,49.4,47.2,38.0,27.6,14.9,12.1.

Example 27: preparation of 1-allyl-7-chloro-N- [2- (diethylamino) ethyl]-4-oxo-quinoline-3-carboxamide (Compound 20e)

Starting from ethyl 1-allyl-7-chloro-4-oxo-quinoline-3-carboxylate 19c (5.0mmol) and N, N-diethylethylenediamine (5.0ml) was obtained a white solid (0.96g,53%). ESI-MS M/z362[ M + H ] -]⁺.¹H NMR(300MHz,CDCl₃)10.00(s,1H),8.75(s,1H),8.44(d,J=8.7Hz,1H),7.46(d,J=1.5Hz,1H),7.42(dd,J=8.7,1.5Hz,1H),5.94-6.07(m,1H),5.40(d,J=10.2Hz,1H),5.20(d,J=17.1Hz,1H),4.81-4.84(m,2H),3.64(q,J=6.6Hz,2H),2.82(t,J=6.6Hz,2H),2.74(q,J=6.9Hz,4H),1.17(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)176.0,164.6,148.3,140.1,139.4,130.3,129.1,126.4,125.8,119.9,116.4,112.9,56.2,52.1,47.5,37.8.12.2.

Example 28: preparation of 1-allyl-7-chloro-N- [3- (diethylamino) propyl]-4-oxoquinoline-3-carboxamide (Compound 20f)

Ethyl 1-allyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19c (5.0mmol) and 3- (diethylamino) propylamine (5.0ml) were used as starting materials to give a white solid (1.24g,66%). ESI-MS M/z376[ M + H ] -]⁺.¹H NMR(300MHz,CDCl₃)9.91(s,1H),8.76(s,1H),8.45(d,J=8.7Hz,1H),7.46(d,J=1.8Hz,1H),7.40-7.44(m,1H),5.94-6.07(m,1H),5.40(d,J=10.5Hz,1H),5.20(d,J=17.1Hz,1H),4.81-4.83(m,2H),3.50(q,J=6.6Hz,2H),2.56-2.63(m,6H),1.79-1.89(m,2H),1.08(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)171.4,159.8,143.4,135.4,134.7,125.5,124.4,121.7,121.1,115.3,111.7,108.3,51.5,46.0,42,5,33.3,22.8,7.4.

Example 29: preparation of 1-butyl-7-chloro-N- [2- (diethylamino) ethyl]-4-oxo-quinoline-3-carboxamide (Compound 20g)

Starting from ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylate 19d (5.0mmol) and N, N-diethylethylenediamine (5.0ml), gave white solid (1.23g,65%). ESI-MS M/z378[ M + H ]. The results are shown in FIGS]⁺.¹H NMR(300MHz,CDCl₃)9.96(s,1H),8.72(s,1H),8.46(d,J=8.7Hz,1H),7.49(d,J=1.5Hz,1H),7.43(dd,J=8.7,1.5Hz,1H),4.20(t,J=7.2Hz,2H),3.58(q,J=6.6Hz,2H),2.73(t,J=6.6Hz,2H),2.66(q,J=6.9Hz,4H),1.84-1.94(m,2H),1.40-1.52(m,2H),1.10(t,J=7.2Hz,6H),1.01(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)175.9,164.7,148.2,139.9,139.4,129.4,126.7,125.7,115.8,112.7,54.3,52.2,47.6,37.8,31.2,20.3,13.9,12.3.

Example 30: preparation of 1-butyl-7-chloro-N- [3- (diethylamino) propyl group]-4-oxo-quinoline-3-carboxamide (Compound 20h)

Starting from ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylate 19d (5.0mmol) and 3- (diethylamino) propylamine (5.0ml), a white solid was obtained (1.22g,63%). ESI-MS M/z392[ M + H ] M/z392]⁺.¹H NMR(300MHz,CDCl₃)9.96(s,1H),8.72(s,1H),8.45(d,J=8.7Hz,1H),7.49(d,J=1.5Hz,1H),7.43(dd,J=8.7,1.5Hz,1H),4.21(t,J=7.5Hz,2H),3.50(q,J=6.6Hz,2H),2.65-2.71(m,6H),1.84-1.94(m,4H),1.40-1.52(m,2H),1.13(t,J=7.2Hz,6H),1.02(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)176.0,164.6,148.2,139.9.139.4,129.3,126.6,125.7,115.9,112.7,54.3,50.8,47.2,38.1,31.2,27.6,20.3,14.0,12.1.

Example 31: preparation of 1-benzyl-7-chloro-N- [2- (diethylamino) ethyl]-4-oxo-quinoline-3-carboxamide (Compound 20i)

Ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylate 19e (5mmol) and N, N-diethylethylenediamine (5.0ml) as starting materials gave white solid (1.4g,68%). ESI-MS M/z412[ M + H ],]⁺.¹H NMR(300MHz,CDCl₃)9.94(s,1H),8.88(s,1H),8.45(d,J=9.0Hz,1H),7.32-7.39(m,5H),7.15-7.17(m,2H),5.40(s,2H),3.57(q,J=6.6Hz,2H),2.72(t,J=6.6Hz,2H),2.63(q,J=7.2Hz,4H),1.09(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)176.1,164.6,148.9,140.2,139.4,134.0,129.6,129.2,128.9,126.7,126.4,125.6,116.7,113.0,57.852.1,47.6,37.8,12.3.

example 32: preparation of 1-benzyl-7-chloro-N- [2- (diethylamino) propyl]-4-oxo-quinoline-3-carboxamide (Compound 2)0j)

Ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylate 19e (5mmol) and 3- (diethylamino) propylamine (5.0ml) as starting materials gave white solid (1.2g,56%). ESI-MS M/z426[ M + H ] -]⁺.¹H NMR(300MHz,DMSO-d₆):10.04(s,1H),8.85(1H,s),8.41(d,J=9.0Hz,1H),7.34-7.40(m,5H),7.14-7.16(m,2H),5.42(s,2H),3.55(q,J=6.3Hz,2H),2.90-3.01(m,6H),1.82-1.87(m,2H),1.29(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)176.2,164.5,149.0,140.2,139.5,133.9,129.6,129.2,129.0,126.6,126.4,125.9,116.7,113.0,57.9,50.7,47.2,38.1,27.5,12.0.

Example 33: preparation of 7-chloro-N- [3- (diethylamino) propyl]-1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxamide (Compound 20k)

Ethyl 7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxylic acid ester 19f (5.0mmol) and 3- (diethylamino) propylamine (5.0ml) were used as starting materials to give a white solid (1.4g,63%). ESI-MS M/z454[ M + H/z ]]⁺.¹H NMR(300MHz,CDCl₃)9.91(s,1H),8.71(s,1H),8.43(d,J=8.7Hz,1H),7.40(d,J=8.7Hz,1H),7.37-7.17(m,6H),4.17(t,J=7.2Hz,2H),3.48(q,J=6.6Hz,2H),2.78(t,J=7.2Hz,2H),2.53-2.60(m,6H),2.19-2.30(m,2H),1.76-1.86(m,2H),1.05(t,J=7.2Hz,6H).¹³C NMR(75MHz,CDCl₃)175.6,164.2,147.8,139.4,139.1,128.9,128.7,128.1,126.5,126.2,125.4,115.4,112.3,53.1,50.3,46.8,37.6,32.4,30.0,27.0,11.6.

Examples34: preparation of N- (3-aminopropyl) -7-chloro-1-ethyl-4-oxo-quinoline-3-carboxamide (Compound 21a)

Ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ester 19b (5.0mmol) and 1, 3-propanediamine (5.0ml) were used as starting materials to give a white solid (0.9g,60%). ESI-MS M/z308[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃)9.95(s,1H),8.77(s,1H),8.44(d,J=8.7Hz,1H),7.51(s,1H),7.43(d,J=8.7Hz,1H),4.29(q,J=7.2Hz,2H),3.55(q,J=6.3Hz,2H),2.82(t,J=6.9Hz,2H),1.72-1.92(m,2H),1.57(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)176.0,164.9,147.7,139.6,129.2,126.5,125.8,115.8,112.7,49.4,39.7,36.7,33.7,14.9.

Example 35: preparation of 1-allyl-N- (3-aminopropyl) -7-chloro-4-oxo-quinoline-3-carboxamide (Compound 21b)

Ethyl 1-allyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19c (5.0mmol) and 1, 3-propanediamine (5.0ml) were used as starting materials to give a white solid (0.9g,58%). ESI-MS M/z320[ M + H ]. The results are obtained]⁺.¹H NMR(300MHz,CDCl₃)9.91(s,1H),8.75(s,1H),8.43(d,J=8.7Hz,1H),7.41-7.48(m,2H),5.94-6.07(m,1H),5.39(d,J=10.5Hz,1H),5.19(d,J=17.1Hz,1H),4.82-4.84(m,2H),3.55(q,J=6.6Hz,2H),2.82(t,J=6.9Hz,2H),1.69-1.81(m,2H).¹³C NMR(75MHz,CDCl₃)176.1,165.0,164.8,148.5,140.3,140.1,139.5,130.3,129.0,126.4,125.9,120.0,116.5,112.7,56.3,39.6,36.8,33.5.

Example 36: preparation of N- (3-aminopropyl) -1-butyl-7-chloro-4-oxo-quinoline-3-carboxamide (Compound 21c)

Ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19d (5.0mmol) and 1, 3-propanediamine (5.0ml) were used as starting materials to give a white solid (1.2g,70%). ESI-MS M/z336[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃)9.98(s,1H),8.74(s,1H),8.46(d,J=8.7Hz,1H),7.51(d,J=1.8Hz,1H),7.44(dd,J=8.7,1.8Hz,1H),4.23(t,J=7.5Hz,2H),3.52(q,J=6.6Hz,2H),2.78(t,J=6.3Hz,2H),1.80-1.91(m,4H),1.40-1.52(m,2H),1.03(t,J=7.2Hz,3H).¹³C NMR(75MHz,CDCl₃)176.1,165.7,148.5,139.7.139.3,128.9,126.2,125.6,115.8,111.6,54.1,38.0,36.1,30.9,27.9,19.9,13.6.

Example 37: preparation of N- (3-aminopropyl) -7-chloro-1-benzyl-4-oxo-quinoline-3-carboxamide (Compound 21d)

Ethyl 7-chloro-1-benzyl-4-oxo-quinoline-3-carboxylic acid ester 19e (5.0mmol) and 1, 3-propanediamine (5.0ml) were used as starting materials to give a white solid (1.1g,62%). ESI-MS M/z370[ M + H ]. The results are shown in FIGS]⁺.¹H NMR(300MHz,DMSO-d₆):9.95(s,1H),8.89(s,1H),8.43(d,1H,J=9.3Hz),7.34-7.40(m,5H),7.14-7.16(m,2H),5.42(s,2H),3.56(q,J=6.6Hz,2H),2.84(t,J=6.6Hz2H),1.84-1.88(m,2H).¹³C NMR(75MHz,CDCl₃)176.2,164.7,148.9,140.1,139.4,133.7,129.5,129.0,128.9,126.5,126.2,125.8,116.5,112.7,57.6,39.5,36.5,33.4.

Example 38: preparation of N- (3-aminopropyl) -7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxamide (Compound 21e)

Ethyl 7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxylic acid ester 19f (5.0mmol) and 1, 3-propanediamine (5.0ml) were used as starting materials to give a white solid (0.9g,45%). ESI-MS M/z398[ M + H ] M/z398 (M + H)]⁺.¹H NMR(300MHz,CDCl₃)9.97(s,1H),8.71(s,1H),8.43(d,J=8.7Hz,1H),7.45-7.38(m,1H),7.38-7.14(m,6H),4.18(t,J=7.2Hz,2H),3.57(q,J=6.9Hz,2H),2.85(t,J=6.6Hz,2H),2.79(t,J=7.2Hz,2H),2.34–2.20(m,2H),1.76–1.88(m,2H).¹³C NMR(75MHz,CDCl₃)175.6,164.5,147.8,139.4,139.1,128.8,128.7,128.1,126.5,126.2,125.5,115.4,112.2,53.2,39.3,36.4,33.3,32.4,30.0.

The following scheme 5 generally depicts the preparation of compound 8_aAnd compound 8b and compound 9_aTo 9_eThe synthesis process of (1).

Scheme 5:

general synthetic procedure for compounds 8 a-b: 7-chloro-4- (1H) -oxoquinoline 6b or 7-methoxy-4- (1H) -oxoquinoline 6d (10mmol) was added to a round-bottom flask followed by POCl₃(20ml), the mixture was heated under reflux for 1 h. Cooling the reaction solution and replenishing POCl₃(10ml), the reaction was continued under reflux for 1 h. After the reaction, the reaction solution was cooled to room temperature. Slowly pouring the reaction solution into ice water (violent heat release), adjusting the pH value of the sodium hydroxide solution to 9.0, separating out white flocculent solid, filtering, washing with water, and drying (easy sublimation) to obtain the off-white solid.

Example 39: preparation of 4, 7-dichloroquinoline (Compound 8a)

Starting from 7-chloro-4 (1H) -oxoquinoline 6b (10mmol), a white solid was obtained (1.68g, 85%). ESI-MS M/z197[ M ]]⁺.¹HNMR(300MHz,CDCl₃):8.74(1H,d,J=4.8Hz),8.09-8.15(2H,m),7.54-7.58(1H,m),7.45(1H,d,J=4.8Hz).¹³C NMR(75MHz,CDCl₃)151.0,149.4,142.8,136.7,128.8(2C),125.7,125.1,121.6.

Example 40: preparation of 4-chloro-7-methoxyquinoline (Compound 8b)

Starting from 7-methoxy-4 (1H) -oxoquinoline 6d (10mmol), a white solid was obtained (1.7g, 88%). ESI-MS M/z194[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.67(1H,d,J=4.8Hz),8.09(1H,d,J=9.0Hz),7.42(1H,d,J=2.4Hz),7.33(1H,d,J=4.8Hz),7.28(1H,dd,J=9.0Hz,J=2.4Hz),3.97(3H,s).¹³C NMR(75MHz,CDCl₃)161.3,151.0,150.2,142.4,125.3,121.7,120.8,119.3,107.7,55.9.

Example 41: preparation of 7-chloro-4-methoxyquinoline (Compound 9a)

Anhydrous methanol (50ml) was added to a 100ml round bottom flask followed by metallic sodium (1.05g,50mmol) and after the metallic sodium disappeared, 4, 7-dichloro-quinoline (10mmol) was added and heated under reflux for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the remaining methanol was distilled off under reduced pressure to obtain a white solid, and 50ml of water was added to the bottle, filtered, washed with water, and dried to obtain an off-white solid (1.66g, 84%). ESI-MS M/z194[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.71(1H,d,J=5.1Hz),8.09(1H,d,J=8.7Hz),7.99(1H,d,J=2.1Hz),7.40(1H,dd，J=8.7Hz,J=2.1Hz),6.70(1H,d,J=5.1Hz),4.03(3H,s).¹³C NMR(75MHz,CDCl₃)162.4,152.7,149.7,135.8,128.0,126.7,123.6,120.0,100.6,56.1.

Example 42: preparation of 7-chloro-4-ethoxyquinoline (Compound 9b)

Anhydrous ethanol (50ml) was added to a 100ml round bottom flask followed by metallic sodium (1.05g,50mmol) and after the metallic sodium disappeared, 4, 7-dichloro-quinoline (10mmol) was added and heated under reflux for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the remaining ethanol was distilled off under reduced pressure to obtain a white solid, and 50ml of water was added to the bottle, filtered, washed with water, and dried to obtain an off-white solid (1.8g, 87%). ESI-MS M/z208[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.68(1H,d,J=5.1Hz),8.11(1H,d,J=9.0Hz),7.98(1H,d,J=2.1Hz),7.39(1H,dd，J=8.7Hz,J=2.1Hz),6.67(1H,d,J=5.1Hz),4.21(2H,q，J=6.9Hz),1.54(3H,t，J=7.2Hz).¹³C NMR(75MHz,CDCl₃)161.7,152.6,149.8,135.7,128.0,126.5,123.7,120.0,101.1,64.6,14.8.

Example 43: preparation of 7-chloro-4-isopropoxyquinoline (Compound 9c)

Isopropanol (50ml) was added to a 100ml round bottom flask followed by sodium metal (1.0)5g,50mmol), after the sodium metal disappeared, 4, 7-dichloro-quinoline (10mmol) was added and heated under reflux for 8 h. TLC tracking detection, after the reaction is finished, cooling the reaction solution to room temperature, distilling off residual isopropanol under reduced pressure to obtain yellow oily matter, adding water (50ml) into the residue, extracting with dichloromethane three times, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, performing silica gel column chromatography, eluting with dichloromethane/methanol =200:1, and concentrating under reduced pressure to dryness to obtain yellow oily matter (1.51g, 68%). ESI-MS M/z222[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.68(1H,d,J=5.1Hz),8.12(1H,d,J=8.7Hz),7.98(1H,d,J=2.1Hz),7.41(1H,dd，J=8.7Hz,J=2.1Hz),6.69(1H,d,J=5.1Hz),4.78-4.86(1H,m),1.50(3H,s)，1.48(3H,s).¹³C NMR(75MHz,CDCl₃)160.8,152.5,150.1,135.7,127.9,126.4,123.9,120.7,101.8,71.3,22.1.

Example 44: preparation of 4, 7-Dimethoxyquinoline (Compound 9d)

Methanol (50ml) was added to a 100ml round bottom flask followed by metallic sodium (1.05g,50mmol) and, after the metallic sodium had disappeared, 4-chloro-7-methoxyquinoline (10mmol) was added and heated under reflux for 8 h. TLC, after the reaction was complete, the reaction mixture was cooled to room temperature, the remaining methanol was evaporated under reduced pressure to give a yellow oil, water (50ml) was added to the residue, extracted three times with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, chromatographed on silica gel column, eluted with petroleum ether/acetone ═ 4:1, and concentrated to dryness under reduced pressure to give a white solid (1.66g, 88%). ESI-MS M/z190[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.63(1H,d,J=5.1Hz),8.04(1H,d,J=9.0Hz),7.34(1H,d,J=2.4Hz),7.12(1H,dd,J=9.0Hz,J=2.4Hz),6.60(1H,d,J=5.1Hz),4.00(3H,s),3.93(3H,s).¹³C NMR(75MHz,CDCl₃)162.3,160.9,151.8,151.1,123.1,118.3,116.1,107.3,98.9,55.7,55.6.

Example 45: preparation of 4-ethoxy-7-methoxyquinoline (Compound 9e)

Anhydrous ethanol (50ml) was added to a 100ml round-bottom flask, followed by addition of metallic sodium (1.05g,50mmol), and after the metallic sodium disappeared, 4-chloro-7-methoxyquinoline (10mmol) was added, and heated under reflux for 2 h. After the reaction, the reaction mixture was cooled to room temperature, the remaining ethanol was evaporated under reduced pressure, 50ml of water was added to the residue, extraction was performed with ethyl acetate (100ml × 3), the organic phases were combined, washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to give a pale yellow oil, subjected to silica gel column chromatography, eluted with petroleum ether/acetone ═ 4:1, and concentrated to dryness under reduced pressure to give a white solid (1.58g, 78%). ESI-MS M/z204[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):8.60(1H,d,J=5.4Hz),8.06(1H,d,J=9.3Hz),7.33(1H,d,J=2.4Hz),7.11(1H,dd,J=9.3Hz,J=2.4Hz),6.56(1H,d,J=5.4Hz),4.20(2H,q,J=6.9Hz),3.92(3H,s),1.54(3H,t,J=6.9Hz).¹³C NMR(75MHz,CDCl₃)161.6,160.9,151.8,151.2,123.3,118.1,116.1,107.2,99.4,64.1,55.6,14.7.

The following scheme 6 generally depicts the synthetic procedures for preparing compounds 12a and 12b and compounds 13, 14.

Scheme 6:

example 46: preparation of 5, 8-dichloro-4- (1H) -oxoquinoline (Compound 13)

Isopropylidene malonate (4.32g, 30mmol) and trimethyl orthoformate (53g, 500mmol) were mixed and heated under reflux for 2h, then the reaction was cooled to room temperature, 2, 5-dichloroaniline (3.24g, 20mmol) was added and the reaction mixture was heated under reflux for 2 h. And cooling the reaction liquid to room temperature, separating out white crystals, filtering, and washing with methanol to obtain a white solid.

The white solid was mixed with diphenyl ether (40ml) and heated under reflux for 1 h. Cooling the reaction solution toAt room temperature, 50ml of petroleum ether was added, stirred well and filtered to obtain 3.0g of a brown solid. Silica gel column chromatography, dichloromethane/methanol = 25: 1 to give compound 13 as a white solid (2.5g, 69%). ESI-MS M/z215[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):11.23(1H,s),7.71-7.75(2H,m),7.26(1H,d,J=7.2Hz),6.08(1H,d,J=7.2Hz).

Example 47: preparation of 6, 8-dichloro-4- (1H) -oxoquinoline (Compound 14)

Isopropylidene malonate (4.32g, 30mmol) and trimethyl orthoformate (53g, 500mmol) were mixed and heated under reflux for 2h, then the reaction was cooled to room temperature, 3, 4-dichloroaniline (3.24g, 20mmol) was added and the reaction mixture was heated under reflux for 2 h. And cooling the reaction liquid to room temperature, separating out white crystals, filtering, and washing with methanol to obtain a white solid.

The white solid was mixed with diphenyl ether (40ml) and heated under reflux for 1 h. The reaction solution was cooled to room temperature, 50ml of petroleum ether was added thereto, and after stirring, filtration was carried out to obtain 3.0g of a brown solid. Recrystallization from methanol gave compound 14 as a white solid (2.6g, 72%). ESI-MS M/z215[ M + H ]]⁺.¹H NMR(300MHz,CDCl₃):11.54(1H,s),7.96-7.99(2H,m),7.85(1H,d,J=6.9Hz),6.13(1H,d,J=6.9Hz).

Scheme 7:

example 48: preparation of 4-chloro-7-hydroxyquinoline (Compound 22)

4-chloro-7-methoxyquinoline 8b (3.86g,20mmol), 40% HBr (30mL) and acetic anhydride (20mL) were mixed and heated to reflux, followed by TLC detection, and after completion of the reaction, the reaction was cooled to room temperature. The reaction was then diluted with 100mL of water, adjusted to pH 6.0 with 20% NaOH solution and a large amount of solid precipitated, filtered, washed with water and dried to give an off-white solid (3.53g, 98.6%).

Example 49: preparation of 4-chloro-7-ethoxyquinoline (Compound 23a)

A100 ml round bottom flask was charged with 4-chloro-7-hydroxyquinoline (0.72g,4mmol), DMF (10ml) and 60% NaH (0.4g,10mmol), stirred at room temperature for 15min, added 1-bromoethane (20mmol) and allowed to continue the reaction, followed by TLC. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 200/1) to obtain a pale yellow solid (0.56g, yield 67.2%). Mp70-71 ℃ MS (ESI) M/z (M + H)⁺207.8.¹H NMR(300MHz,CDCl₃)8.66(d,J=4.7Hz,1H,ArH),8.09(d,J=9.2Hz,1H,ArH),7.39(d,J=1.8Hz,1H,ArH),7.32(d,J=4.7Hz,1H,ArH),7.29–7.20(m,1H,ArH),4.19(q,J=6.9Hz,2H,CH₂),1.50(t,J=7.0Hz,3H,CH₃).¹³C NMR(75MHz,CDCl₃)160.3,150.6,149.8,142.0,124.9,121.2,120.7,118.8,107.8,63.7,14.6.

Example 50: preparation of 4-chloro-7-n-butoxyquinoline (Compound 23b)

In a 100ml round bottom flask were placed 4-chloro-7-hydroxyquinoline (0.89g,5mmol), acetone (40ml) and anhydrous K₂CO₃(2.0g) was stirred at reflux for 15min at room temperature, followed by addition of iodine to characterize butane (20mmol) and detection by TLC. After the reaction was completed, acetone was distilled off under reduced pressure, 150mL of water was added, ethyl acetate was extracted, the organic phases were combined, concentrated hydrochloric acid was added for acidification, anhydrous ethanol was used for water-carrying to give a yellow oil, acetone was recrystallized to precipitate white crystals, which were alkalinized after filtration to give a white solid (0.57g, yield 47.6%). Mp37-38 ℃ MS (ESI) M/z (M + H)⁺236.1.¹H NMR(300MHz,CDCl₃)8.65(d,J=4.8Hz,1H,ArH),8.08(d,J=9.2Hz,1H,ArH),7.39(d,J=1.9Hz,1H,ArH),7.31(d,J=4.8Hz,1H,ArH),7.29–7.23(m,1H,ArH),4.12(t,J=6.5Hz,2H,CH₂CH₂CH₂CH₃),1.92–1.79(m,2H,CH₂CH₂CH₂CH₃),1.62–1.47(m,2H,CH₂CH₂CH₂CH₃),1.00(t,J=7.3Hz,3H,CH₂CH₂CH₂CH₃).¹³C NMR(75MHz,CDCl₃)160.5,150.7,149.8,142.0,124.9,121.2,120.8,118.8,108.0,68.0,31.0,19.2,13.8.

Example 50: preparation of 4-chloro-7-n-hexyloxyquinoline (Compound 23c)

A100 ml round bottom flask was charged with 4-chloro-7-hydroxyquinoline (0.36g,2mmol), DMF (10ml) and 60% NaH (0.2g,5mmol), stirred at room temperature for 10min, reacted further with bromoisobutane (3.5mmol) and checked by TLC follow-up. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 200/1) to obtain a yellow oil (0.22g, yield 68.0%). MS (ESI) M/z (M + H) +263.9.¹H NMR(300MHz,CDCl₃)8.65(d,J=4.8Hz,1H,ArH),8.07(d,J=9.2Hz,1H,ArH),7.38(d,J=2.4Hz,1H,ArH),7.30(d,J=4.8Hz,1H,ArH),7.26(dd,J=9.1,2.5Hz,1H,ArH),4.11(t,J=6.5Hz,2H,OCH₂(CH₂)₄CH₃),1.94–1.79(m,1H,OCH₂CH₂(CH₂)₃CH₃),1.49(dd,J=14.4,7.2Hz,2H,O(CH₂)₂CH₂(CH₂)₂CH₃),1.37(dt,J=7.1,4.7Hz,4H,O(CH₂)₃CH₂CH₂CH₃),0.91(t,J=6.9Hz,3H,CH₃).¹³C NMR(75MHz,CDCl₃)160.7,150.8,149.9,142.2,125.0,121.3,121.0,118.9,108.1,68.4,31.6,29.0,25.8,22.7,14.1.

Example 50: preparation of4-chloro-7-allyloxyquinoline (Compound 23d)

In a 100ml round bottom flask was added 4-chloro-7-hydroxyquinoline (0.36g,2mmol), DMF (10ml) and 60% NaH (0.2g,5mmol), stirred at room temperature for 10min, added 1-bromoallyl propane (3.5mmol) and allowed to continue the reaction for follow-up by TLC. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 200/1) to obtain a pale yellow solid (0.37g, yield 78.4%). Mp36-37 ℃ MS (ESI) M/z (M + H)⁺219.8.¹H NMR(300MHz,CDCl₃)8.66(d,J=4.6Hz,1H,ArH),8.09(d,J=9.1Hz,1H,ArH),7.41(s,1H,ArH),7.29(dd,J=15.9,6.2Hz,2H,ArH),6.10(ddt,J=15.9,10.4,5.3Hz,1H,CH₂=CH),5.48(d,J=17.2Hz,1H,CH₂=CH),5.34(d,J=10.4Hz,1H,CH₂=CH),4.69(d,J=4.8Hz,2H,OCH₂).¹³C NMR(75MHz,CDCl₃)159.9,150.5,149.9,142.1,132.2,125.1,121.4,120.8,119.0,118.1,108.4,68.9.

Example 50: preparation of 4-chloro-7-isopropoxyquinoline (compound 23e)

4-chloro-7-hydroxyquinoline (0.36g,2mmol), DMF (10ml) and 60% NaH (0.2g,5mmol) were added to a 100ml round bottom flask, stirred at room temperature for 10min, added 1-bromoisopropane (3.5mmol) and reacted further, followed by TLC for 24 h. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 200/1) to obtain a pale yellow solid (0.28g, yield 54.6%). Mp65-66 ℃ MS (ESI) M/z (M + H)⁺221.8.¹H NMR(300MHz,CDCl₃)8.65(d,J=4.7Hz,1H,ArH),8.08(d,J=9.2Hz,1H,ArH),7.39(s,1H,ArH),7.30(d,J=4.7Hz,1H,ArH),7.27–7.20(m,1H,ArH),4.82–4.67(m,1H,CH),1.43(d,J=6.0Hz,6H,CH₃).¹³C NMR(75MHz,CDCl₃)159.3,150.5,149.7,142.1,125.0,121.5,121.0,118.7,108.8,70.2,21.7.

Example 50: preparation of 4-chloro-7-isobutoxyquinoline (Compound 23f)

4-chloro-7-hydroxyquinoline (0.36g,2mmol), DMF (10ml) and 60% NaH (0.2g,5mmol) were added to a 100ml round bottom flask, stirred at room temperature for 10min, added bromoisobutane (3.5mmol) and allowed to continue the reaction for 8h with TLC follow-up. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 200/1) to obtain a white solid (0.26g, yield 88.7%). Mp57-58 ℃ MS (ESI) M/z (M + H)⁺235.8.¹H NMR(300MHz,CDCl₃)8.65(d,J=4.8Hz,1H,ArH),8.09(d,J=9.2Hz,1H,ArH),7.38(d,J=2.4Hz,1H,ArH),7.31(d,J=4.8Hz,1H,ArH),7.28(dd,J=9.2,2.4Hz,1H,ArH),3.88(d,J=6.5Hz,2H,CH₂),2.18(dp,J=13.3,6.6Hz,1H,CH),1.07(d,J=6.7Hz,6H,CH₃).¹³CNMR(75MHz,CDCl₃)160.7,150.8,149.9,142.2,125.0,121.3,121.0,118.9,108.1,74.7,28.1,19.3.

Example 50: preparation of 4-chloro-7-benzyloxyquinoline (Compound 23g)

A100 mL round bottom flask was charged with 4-chloro-7-hydroxyquinoline (0.89g,5mmol), acetone (40mL), benzyl bromide (7.5mmol) and anhydrous K₂CO₃(2.0g), the reaction was stirred at room temperature and checked by TLC. After the reaction was completed, acetone was distilled off under reduced pressure, 150mL of water was added, extraction was performed with ethyl acetate, the organic phases were combined, concentrated hydrochloric acid was added for acidification, anhydrous ethanol was used for water-carrying to obtain a dark oil, acetone was recrystallized, crystals were precipitated, and basification was performed after filtration to obtain a white solid (0.63g, yield 46.8%). Mp87-88 ℃ MS (ESI) M/z (M + H)⁺269.8.¹HNMR(300MHz,CDCl₃)8.67(d,J=4.7Hz,1H,ArH),8.12(d,J=9.2Hz,1H,ArH),7.52–7.30(m,8H,ArH),5.21(s,2H,CH₂).¹³C NMR(75MHz,CDCl₃)160.2,150.7,150.0,142.2,135.9,128.5,128.1,127.5,125.2,121.6,120.9,119.2,108.7,70.3.

Example 50: preparation of 4-chloro-7- (4-fluorobenzyloxy) quinoline (Compound 23h)

4-chloro-7-hydroxyquinoline (0.36g,2mmol), DMF (15ml) and 60% NaH (0.2g,5mmol) were added to a 100ml round bottom flask, stirred at room temperature for 10min, then 4-fluorobenzyl chloride (3.5mmol) was added and the reaction continued with TLC follow-up. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, acidified by adding concentrated hydrochloric acid, and absolute ethanol brought water to give a yellow oil, recrystallized from ethyl acetate to precipitate pale yellow crystals, filtered and alkalified to give a yellow solid (0.57g, 89.2% yield). Mp98-99 deg.C, MS (ESI) M/z (M + H)⁺287.9.¹H NMR(300MHz,CDCl₃)8.67(d,J=4.8Hz,1H,ArH),8.12(d,J=9.2Hz,1H,ArH),7.49–7.42(m,3H,ArH),7.36–7.30(m,2H,ArH),7.08(t,J=8.7Hz,2H,ArH),5.17(s,2H,CH₂).¹³C NMR(75MHz,CDCl₃)162.4(d,J=246.4Hz),159.9,150.6,150.0,142.2,131.7(d,J=2.2Hz),129.4(d,J=8.1Hz),125.2,121.6,120.8,119.2,115.44(d,J=21.5Hz),108.6,69.5.

Example 50: preparation of 4-chloro-7- (3-phenethyloxy) quinoline (Compound 23i)

In a 100ml round bottom flask was added 4-chloro-7-hydroxyquinoline (0.36g,2mmol), DMF (10ml) and 60% NaH (0.2g,5mmol), stirred at room temperature for 10min, added 1-bromo 2-phenylethane (3.5mmol) and allowed to continue the reaction, followed by TLC. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 200/1) to obtain a pale yellow solid (0.14g, yield 23.3%). Mp84-85 ℃ MS (ESI) M/z (M + H)⁺283.8.¹H NMR(300MHz,CDCl₃)8.64(d,J=4.0Hz,1H,ArH),8.07(d,J=9.1Hz,1H,ArH),7.40(s,1H,ArH),7.36–7.19(m,7H,ArH),4.34(t,J=6.7Hz,2H,OCH₂CH₂),3.18(t,J=6.7Hz,2H,OCH₂CH₂).¹³C NMR(75MHz,CDCl₃)160.1150.6,149.8,142.0,137.7,128.7,128.3,126.4,124.9,121.3,120.7,118.9,108.1,68.7,35.4.

Example 50: preparation of 4-chloro-7- (3-phenylpropyloxy) quinoline (Compound 23j)

4-chloro-7-hydroxyquinoline (0.45g,2.5mmol) and DMF (15ml) were added to a 100ml round bottom flask and stirred at room temperature for 10min, then 60% NaH (0.2g,5mmol) was added and stirred at room temperature for 10min, and 1-bromo 3-phenylpropane (5mmol) was added and the reaction continued with TLC follow-up. After the reaction, pouring the reaction mixture into water, extracting with ethyl acetate, combining organic phases, concentrating under reduced pressure to dryness to obtain yellow oily matter, adding concentrated hydrochloric acid for acidification to obtain white solid, and adding 20mL of acetone/petroleum ether to obtain a solution of 3: 1 to give a solid which was then basified to give white crystals (0.03g, 53.6% yield). Mp51-52 ℃ MS (ESI) M/z (M + H)⁺297.9.¹H NMR(300MHz,CDCl₃)8.64(d,J=4.3Hz,1H,ArH),8.08(d,J=9.1Hz,1H,ArH),7.36(s,1H,ArH),7.33–7.15(m,7H,ArH),4.10(t,J=6.0Hz,2H,OCH₂CH₂CH₂),2.84(t,J=7.4Hz,2H,OCH₂CH₂CH₂),2.26–2.10(m,2H,OCH₂CH₂CH₂).¹³C NMR(75MHz,CDCl₃)160.4150.6,149.8,142.0,140.9,128.2(C=2),125.8,124.9,121.3,120.7,118.9,108.0,67.2,32.1,30.5.

Scheme 8:

example 51: preparation of N ¹ - (7-ethoxyquinolin-4-yl) -N ² ,N ² Diethyl ethane-1, 2-diamine (Compound 24a)

A100 mL flask was charged with compound 23a (0.35g,1.7mmol) and N, N-diethylethylenediamine (4mL), heated to reflux for 3.5h and monitored by TLC follow-up. After the reaction, about 100mL of water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) to obtain a pale yellow solid (0.36g, yield 73.7%). Mp84-85 ℃ MS (ESI) M/z (M + H)⁺287.9.¹H NMR(300MHz,CDCl₃)8.44(d,J=5.2Hz,1H,ArH),7.61(d,J=9.1Hz,1H,ArH),7.28(s,1H,ArH)),7.04(d,J=9.0Hz,1H,ArH),6.25(d,J=5.3Hz,1H,ArH),5.98(s,1H,NH),4.13(q,J=6.9Hz,2H,OCH₂CH₃),3.20(dd,J=10.1,5.1Hz,2H,NHCH₂CH₂),2.75(t,J=5.8Hz,2H,NHCH₂CH₂),2.56(q,J=7.0Hz,4H,N(CH₂CH₃)₂),1.46(t,J=6.9Hz,1H,OCH₂CH₃),1.04(t,J=7.1Hz,6H,N(CH₂CH₃)₂).¹³C NMR(75MHz,CDCl₃)159.2,151.1,150.0,149.7,120.6,116.9,113.2,108.5,97.8,63.3,50.6,46.4,39.7,14.7,12.0.

Example 52: preparation of N ¹ ,N ¹ -diethyl-N ² - (7-hexyloxyquinolin-4-yl) ethane-1, 2-diamine (Compound 24b)

A100 mL flask was charged with 23c (0.53g,2mmol) and N, N-diethylethylenediamine (4mL), heated to reflux for 3.5h, and monitored by TLC follow-up. After completion of the reaction, about 100mL of water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) to obtain a yellow solid (0.59g, yield 85.4%). Mp92-93 ℃ MS (ESI) M/z (M + H)⁺344.0.¹H NMR(300MHz,CDCl₃)8.43(d,J=5.3Hz,1H,ArH),7.61(d,J=9.1Hz,1H,ArH),7.28(d,J=2.0Hz,1H,ArH),7.04(dd,J=9.0,2.2Hz,1H,ArH),6.26(d,J=5.3Hz,1H,ArH),5.98(s,1H,NH),4.06(t,J=6.5Hz,2H,OCH₂(CH₂)₄CH₃),3.22(dd,J=10.3,5.4Hz,2H,NHCH₂CH₂),2.77(t,J=5.8Hz,2H,NHCH₂CH₂),2.57(q,J=7.0Hz,4H,N(CH₂CH₃)₂),1.89-1.76(m,2H,OCH₂CH₂(CH₂)₃CH₃),1.54-1.42(m,2H,O(CH₂)₂CH₂(CH₂)₂CH₃),1.34(d,J=3.5Hz,4H,O(CH₂)₃(CH₂)₂CH₃,1.05(t,J=7.1Hz,6H,N(CH₂CH₃)₂),0.90(t,J=6.5Hz,3H,O(CH₂)₅CH₃).¹³C NMR(75MHz,CDCl₃)159.5,151.1,145.0,149.8,120.6,117.1,113.2,108.6,97.8,68.0,50.7,46.5,39.8,31.6,29.1,25.8,22.6,14.1,12.1.

Example 53: preparation of N ¹ - (7-allyloxyquinolin-4-yl) -N ² ,N ² Diethyl ethane-1, 2-diamine (Compound 24c)

A100 mL flask was charged with 23d (0.33g,1.5mmol) and N, N-diethylethylenediamine (4mL), heated to reflux for 4h, and monitored by TLC follow-up. After completion of the reaction, about 100mL of water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) to obtain a white solid (0.36g, yield 79.8%). MS (ESI) M/z (M + H)⁺300.1.¹H NMR(300MHz,CDCl₃)8.43(d,J=5.3Hz,1H,ArH),7.62(d,J=9.1Hz,1H,ArH),7.30(d,J=2.1Hz,1H,ArH),7.08(dd,J=9.2,1.9Hz,1H,ArH),6.28(d,J=5.3Hz,1H,ArH),6.09(ddd,J=15.8,10.5,5.2Hz,1H,CH₂=CH),5.97(s,1H,NH),5.46(d,J=17.2Hz,1H,CH₂=CH),5.31(d,J=10.5Hz,1H,CH₂=CH),4.65(d,J=5.0Hz,2H,OCH₂CH=CH₂),3.25(dd,J=10.6,5.4Hz,2H,NHCH₂CH₂),2.80(t,J=5.8Hz,2H,NHCH₂CH₂),2.59(q,J=7.1Hz,4H,(CH₂CH₃)₂),1.07(t,J=7.1Hz,6H,(CH₂CH₃)₂).¹³C NMR(75MHz,CDCl₃)158.4,150.4,149.5,149.3,132.2,120.8,117.1,116.3,113.1,108.2,97.2,68.1,50.3,46.0,39.5,11.4.

Example 54: preparation of N ¹ ,N ¹ -diethyl-N ² - (7-Isopropoxyquinolin-4-yl) ethane-1, 2-diamine (Compound 24d)

A100 mL flask was charged with 23e (0.20g,0.9mmol) and N, N-diethylethylenediamine (4mL), heated to reflux for 5h, and monitored by TLC follow-up. After completion of the reaction, about 100mL of water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) to obtain a yellow oil (0.12g, yield 10.9%). MS (ESI) M/z (M + H)⁺302.1.¹H NMR(300MHz,CDCl₃)8.42(d,J=5.3Hz,1H,ArH),7.61(d,J=9.1Hz,1H,ArH),7.29(d,J=2.0Hz,1H,ArH),7.01(dd,J=9.1,2.1Hz,1H,ArH),6.26(d,J=5.3Hz,1H,ArH),5.99(s,1H,NH),4.80–4.62(m,1H,OCH(CH₃)₂),3.24(dd,J=10.5,5.3Hz,2H,NHCH₂CH₂),2.79(t,J=5.9Hz,2H,NHCH₂CH₂),2.58(q,J=7.1Hz,4H,N(CH₂CH₃)₂),1.40(d,J=6.0Hz,6H,OCH(CH₃)₂),1.06(t,J=7.1Hz,6H,N(CH₂CH₃)₂).¹³C NMR(75MHz,CDCl₃)158.2,150.7,149.8,149.7,120.8,117.7,113.1,109.5,97.6,69.7,50.7,46.4439.8,21.8,12.0.

Example 55: preparation of N ¹ - (7-benzyloxyquinolin-4-yl) -N ² ,N ² Diethyl ethane-1, 2-diamine (Compound 24e)

A100 mL flask was charged with 23g (0.12g,0.4mmol) and N, N-diethylethylenediamine (2mL), heated to reflux for 2.5h, and monitored by TLC follow-up. After completion of the reaction, anhydrous ethanol was added, the amine was distilled off at high temperature under reduced pressure, and silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) was carried out to obtain a pale yellow solid (0.09g, yield 57.7%). Mp93-94 ℃ MS (ESI) M/z (M + H)⁺349.9.¹H NMR(300MHz,CDCl₃)8.44(d,J=4.7Hz,1H,ArH),7.63(d,J=9.0Hz,1H,ArH),7.47(d,J=7.3Hz,2H,ArH),7.34(dd,J=13.5,7.7Hz,4H,ArH),7.13(d,J=9.0Hz,1H,ArH),6.28(d,J=5.1Hz,1H,ArH),5.99(s,1H,NH),5.17(s,2H,OCH₂),3.25(d,J=4.7Hz,2H,NHCH₂CH₂),2.80(t,J=5.4Hz,2H,NHCH₂CH₂),2.59(_q,J=6.8Hz,4H,N(CH₂CH₃)₂),1.07(t,J=6.9Hz,6H,N(CH₂CH₃)₂).¹³C NMR(75MHz,CDCl₃)159.1,151.1,149.9,136.5,128.4,127.9,127.5,120.9,117.1,113.6,109.6,109.2,105.24,98.0,70.0,50.8,46.5,39.8,12.1.

Example 56: preparation of N ¹ ,N ¹ -diethyl-N ² - (7- (4-Fluorobenzyloxy) quinolin-4-yl) ethane-1, 2-diamine (Compound 24f)

A100 mL flask was charged with 23h (0.14g,0.5mmol) and N, N-diethylethylenediamine (4mL), heated to reflux for 3h, and monitored by TLC follow-up. After completion of the reaction, about 100mL of water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) to obtain a white solid (0.10g, yield 55.9%). Mp67-68 ℃ MS (ESI) M/z (M + H) +367.7.¹H NMR(300MHz,CDCl₃)8.44(d,J=5.3Hz,1H,ArH),7.63(d,J=9.1Hz,1H,ArH),7.42(dd,J=8.3,5.5Hz,2H,ArH),7.36(d,J=2.4Hz,1H,ArH),7.10(dd,J=9.1,2.5Hz,1H,ArH),7.04(t,J=8.6Hz,2H,ArH),6.27(d,J=5.3Hz,1H,ArH),5.99(d,J=2.5Hz,1H,NH),5.11(s,2H,OCH₂),3.23(dd,J=10.4,5.4Hz,2H,NHCH₂CH₂),2.78(t,J=5.9Hz,2H,NHCH₂CH₂),2.58(q,J=7.1Hz,4H,NCH₂CH₃),1.06(t,J=7.1Hz,6H,NCH₂CH₃).¹³C NMR(75MHz,CDCl₃)162.32(d,J=246.0Hz),159.0,151.0,149.9,149.8,132.3,129.32(d,J=7.9Hz),121.0,117.0,115.33(d,J=21.5Hz),113.6,109.1,98.0,69.3,50.8,46.6,39.9,12.1.

Scheme 9:

example 57: preparation of N ¹ - (7-ethoxyquinolin-4-yl) -N ² ,N ² -Diethylpropane-1, 2-diamine (Compound 25a)

A100 mL flask was charged with 23a (0.31g,1.5mmol) and 3-diethylaminopropylamine (4mL), heated to reflux for 4.5h, and checked by TLC follow-up. After completion of the reaction, about 100mL of water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) to obtain a yellow oil (0.34g, yield 75.2%). MS (ESI) M/z (M + H)⁺302.1.¹H NMR(400MHz,CDCl₃)8.41(d,J=5.3Hz,1H,ArH),7.83(s,1H,NH),7.64(d,J=9.1Hz,1H,ArH),7.30(s,1H,ArH),7.02(d,J=9.1Hz,1H,ArH),6.23(d,J=5.3Hz,1H,ArH),4.16(q,J=6.9Hz,2H,CH₂CH₃),3.38(d,J=4.5Hz,2H,NCH₂),2.65(dt,J=14.1,6.1Hz,6H,CH₂N(CH₂CH₃)₂),1.97–1.83(m,2H,NHCH₂CH₂CH₂),1.47(t,J=6.8Hz,3H,CH₂CH₃),1.09(t,J=7.0Hz,6H,N(CH₂CH₃)₂).¹³C NMR(100MHz,CDCl₃)159.0,150.5,150.3,149.5,121.4,116.0,113.1,107.8,96.5,62.9,52.5,46.4,43.5.

Example 58: preparation of N ¹ - (7-allyloxyquinolin-4-yl) -N ² ,N ² -Diethylpropane-1, 2-diamine (Compound 25b)

A100 mL flask was charged with 23d (0.33g,2mmol) and 3-diethylaminopropylamine (4mL), heated to reflux for 2.5h, and checked by TLC. After completion of the reaction, about 100mL of water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) to obtain a yellow oil (0.15g, yield 31.9%). MS (ESI) M/z (M + H)⁺313.9.¹H NMR(300MHz,CDCl₃)8.40(d,J=5.3Hz,1H,ArH),7.83(s,1H,NH),7.64(d,J=9.1Hz,1H,ArH),7.03(dd,J=9.1,1.6Hz,1H,ArH),6.20(d,J=5.4Hz,1H,ArH),6.08(ddd,J=21.5,10.4,5.2Hz,1H,CH=CH₂),5.45(d,J=17.2Hz,1H,CH=CH₂),5.29(d,J=10.5Hz,1H,CH=CH₂),4.63(d,J=5.2Hz,2H,OCH₂),3.34(d,J=3.9Hz,2H,NCH₂(CH₂)₂),2.61(dd,J=13.9,6.7Hz,6H,CH₂N(CH₂CH₃)₂),1.94–1.81(m,2H,NCH₂CH₂CH₂),1.07(t,J=7.1Hz,6H,N(CH₂CH₃)₂).¹³C NMR(75MHz,CDCl₃)158.8,151.0,150.5,149.8,132.8,121.7,117.7,116.5,113.6,108.7,97.0,68.7,53.4,47.0,44.4,24.5,11.6.

Example 59: preparation of N ¹ ,N ¹ -diethyl-N ² - (7- (4-Fluorobenzyloxy) quinolin-4-yl) propane-1, 2-diamine (Compound 25c)

A100 mL flask was charged with 23h (0.29g,1mmol) and 3-diethylaminopropylamine (4mL), heated to reflux for 1.5h, and checked by TLC. After the reaction, about 100mL of water is added, ethyl acetate is used for extraction,the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (mobile phase: dichloromethane/methanol = 100/1) to obtain a yellow oil (0.26g, yield 67.5%). MS (ESI) M/z (M + H)⁺382.4.¹H NMR(300MHz,CDCl₃)8.41(d,J=5.2Hz,1H,ArH),7.83(s,1H,NH),7.66(d,J=9.1Hz,1H,ArH),7.45-7.36(m,2H,ArH),7.34(s,1H,ArH),7.13-6.95(m,3H,ArH),6.20(d,J=5.1Hz,1H,ArH),5.08(s,2H,OCH₂),3.32(s,2H,NHCH₂(CH₂)₂),2.67-2.53(m,6H,CH₂N(CH₂CH₃)₂),1.84(s,2H,NHCH₂CH₂CH₂),1.06(t,J=6.8Hz,6H,N(CH₂CH₃)₂).¹³C NMR(75MHz,CDCl₃)162.0(d,J=245.7Hz),158.6,151.0,150.3,149.7,132.11(d,J=2.0Hz),129.0(d,J=8.0Hz),121.7,116.1,115.0(d,J=21.4Hz),113.6,108.8,96.8,68.9,53.0,46.7,44.1,24.3,11.4.

Experimental example 1: in vitro antitumor Activity test

The oxoquinoline derivative is used for preparing pharmacological research of the application of the cancer treatment drug. All tested compounds were prepared in hydrochloride form before testing, with cisplatin, a clinically common antitumor drug, as a positive control.

Cell lines such as a laryngeal cancer cell line (Hep-2), a breast cancer cell line (MCF-7), a gastric cancer cell line (BGC-823), a liver cancer cell line (HepG2), a colon cancer cell line (HCT-8), a cervical cancer cell line (Hela) and a prostate cancer cell line (PC-3) are selected respectively and tested by adopting an MTT method. The specific method comprises respectively culturing the cell lines with good growth state and logarithmic growth phase at 5 × 10⁴Inoculating to 96-well plate at a concentration of 160 μ l/well, culturing in an incubator containing 5% CO2 at 37 deg.C for 24 hr, discarding the old solution, replacing with fresh culture solution, adding sterilized oxoquinoline derivative, culturing for 48 hr, discarding the culture solution, adding 20ul RPMI-1640 culture solution containing 5mg/ml MTT to each well, culturing for 4 hr, carefully removing the supernatant, and adding 200 μ l DMS to each wellO, shaking for about 10min to dissolve the precipitate, and then detecting the OD value with a microplate reader at 490 nm. Cell viability was determined for each sample concentration using the following formula: survival% (% OD of sample group/OD of control group × 100%). Plotting cell viability against log drug concentration and determining IC for each sample by plotting₅₀Values, results are given in the table below.

In vitro anti-tumor results (IC) of oxoquinoline derivatives of the invention₅₀,μM^a)

^a IC₅₀Values represent the drug concentration required to inhibit tumor cell growth by 50%.

^bThe tumor cell lines include human laryngeal cancer cell line (Hep-2), breast cancer cell line (MCF-7), gastric cancer cell line (BGC-823), liver cancer cell line (HepG2), colon cancer cell line (HCT-8), cervical cancer cell line (Hela), and prostate cancer cell line (PC-3).

^cEach value in the table represents the average of the results of three replicates.

Claims

1. A compound of formula I:

I

and pharmaceutically acceptable salts thereof, wherein

R¹Is selected from-C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_1-6Alkyl-phenyl, wherein said alkyl, alkenyl, alkynyl and phenyl groups may optionally be substituted by halogen, nitro, cyano, nitro-phenyl, or by a pharmaceutically acceptable salt thereof,Hydroxy, -C_1-6Alkoxy, phenyl substitution;

R⁷selected from halogen, -C_1-6Alkoxy radical,、、；

And is

When R is¹When it is methyl, R³Is not hydrogen.

2. The compound of claim 1, wherein R¹Is selected from-C_1-6Alkyl, -C_2-6Alkenyl, -C_1-6Alkyl-phenyl.

3. The compound of claim 1, wherein R¹Selected from ethyl, propyl, isopropyl, allyl, propenyl, benzyl, phenylpropyl, n-butyl.

4. The compound of claim 1, wherein R³Selected from hydrogen, -COO-C_1-4Alkyl, -CONH-C_1-4Alkyl, -CONH-C_1-4alkyl-NH-C_1-4Alkyl, -CONH-C_1-4alkyl-N (C)_1-4Alkyl radical)₂。

5. The compound of claim 1, wherein R3 is selected from the group consisting of hydrogen, -COOCH₂CH₃、-CONH-(CH₂)₂-N(C₂H₅)₂、-CONH-(CH₂)₃-N(C₂H₅)₂、-CONH-(CH₂)₃-NH₂。

6. The compound of claim 1, wherein R⁷Selected from halogen, -C_1-4Alkoxy radical,、、。

7. The compound of claim 1, wherein R⁷Selected from fluorine, chlorine, bromine, methoxy,、。

8. The compound according to any one of claims 1 to 4, which is a compound selected from the group consisting of:

7-chloro-1-isopropyl-4-oxo-quinoline,

1-allyl-7-chloro-4-oxo-quinoline,

1-benzyl-7-chloro-4-oxo-quinoline,

7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline,

1-benzyl-7-bromo-4-oxo-quinoline,

1-benzyl-7-morpholinyl-4-oxo-quinoline,

n- (3- (diethylamino) propyl) -7-fluoro-4 (1H) -oxoquinoline-3-carboxamide,

7-chloro-N- (3- (diethylamino) propyl) -4(1H) -oxoquinoline-3-carboxamide,

7-bromo-N- (3- (diethylamino) propyl) -4(1H) -oxoquinoline-3-carboxamide,

n- (3-diethylamino) propyl-7-methoxy-4- (1H) -oxoquinoline-3-carboxamide,

ethyl 7-chloro-1-methyl-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 1-allyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester,

ethyl 7-chloro-1- (3-phenylpropyl) -4-oxo-quinoline-3-carboxylic acid ester,

7-chloro-N- [2- (diethylamino) ethyl ] -1-methyl-4-oxo-quinoline-3-carboxamide,

7-chloro-N- [2- (diethylamino) ethyl ] -1-ethyl-4-oxo-quinoline-3-carboxamide,

7-chloro-N- [2- (diethylamino) propyl ] -1-ethyl-4-oxo-quinoline-3-carboxamide,

1-allyl-7-chloro-N- [2- (diethylamino) ethyl ] -4-oxo-quinoline-3-carboxamide,

1-allyl-7-chloro-N- [3- (diethylamino) propyl ] -4-oxoquinoline-3-carboxamide,

1-butyl-7-chloro-N- [2- (diethylamino) ethyl ] -4-oxo-quinoline-3-carboxamide,

1-butyl-7-chloro-N- [3- (diethylamino) propyl ] -4-oxo-quinoline-3-carboxamide,

1-benzyl-7-chloro-N- [2- (diethylamino) ethyl ] -4-oxo-quinoline-3-carboxamide,

n- (3-aminopropyl) -7-chloro-1-ethyl-4-oxo-quinoline-3-carboxamide,

1-allyl-N- (3-aminopropyl) -7-chloro-4-oxo-quinoline-3-carboxamide,

n- (3-aminopropyl) -1-butyl-7-chloro-4-oxo-quinoline-3-carboxamide,

n- (3-aminopropyl) -7-chloro-1-benzyl-4-oxo-quinoline-3-carboxamide,

and pharmaceutically acceptable salts thereof.

9. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in the prevention or treatment of tumours.

10. The use according to claim 9, wherein the tumor is selected from the group consisting of melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermoid cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder cancer, head and neck tumors, nasopharyngeal cancer, skin cancer malignancies and leukemia; the gastric cancer comprises gastric adenocarcinoma; the lung cancer comprises lung adenocarcinoma; the colon cancer comprises colon adenocarcinoma; the ovarian cancer comprises ovarian adenocarcinoma; the renal cancer comprises renal clear cell adenocarcinoma; the leukemia includes acute lymphocytic leukemia, chronic leukemia, and special leukemia.

11. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or excipient.