WO2021092892A1 - 喹啉或喹唑啉类化合物在制备抗肿瘤药物中的应用 - Google Patents

喹啉或喹唑啉类化合物在制备抗肿瘤药物中的应用 Download PDF

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WO2021092892A1
WO2021092892A1 PCT/CN2019/118783 CN2019118783W WO2021092892A1 WO 2021092892 A1 WO2021092892 A1 WO 2021092892A1 CN 2019118783 W CN2019118783 W CN 2019118783W WO 2021092892 A1 WO2021092892 A1 WO 2021092892A1
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substituted
branched
unsubstituted
compound
cancer
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French (fr)
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杨震
车超
全军民
许正双
洪梅
李勤凯
黄湧
李志明
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北京大学深圳研究生院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the field of organic compounds, in particular to the application of quinoline or quinazoline compounds in the preparation of anti-tumor drugs.
  • Tumor cells are abnormal cells that can reproduce rapidly and have the characteristics of infinite proliferation, transformation and easy metastasis.
  • the energy metabolism of normal cells is mainly completed by the oxidative phosphorylation of glucose in the mitochondria.
  • the energy metabolism of tumor cells is different from that of normal cells.
  • Tumor cells mainly obtain energy to satisfy tumor cells by ingesting a large amount of glucose and carrying out glycolysis (Warburg effect). Growth and proliferation.
  • the glycolysis pathway is the main metabolic pathway in almost all organisms.
  • the expression, activity and regulation of receptors, transport molecules, key enzymes in the glycolysis process play a vital role in the occurrence, development, metastasis and regression of tumors. , Has become the target of new anti-tumor drug research.
  • the candidate drugs that inhibit tumor cell proliferation by inhibiting the glycolytic metabolism of tumor cells are mainly concentrated in thiophene sulfonamides, phenoxyindoles, benzopyrones, benzoindoles and triazopyridazines. Research on ketones. Although progress has been made in the diagnosis and treatment of tumors, there is still a lack of anti-tumor drugs that can effectively block the energy supply of tumor cells from the source.
  • -R 1 , -R 2 , -R 5 are independently selected from -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkylamino, N-alkane
  • N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl One of N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl;
  • -R 3 is selected from -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkylamino, N-alkyl-N-acylamino, pyridyl, One of imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl;
  • -R 4 is an alkyl group or an aryl group.
  • a preparation method of quinoline compounds including the following steps:
  • the nucleophilic substitution reaction between compound A2 and 4-fluoronitrobenzene yields compound A3.
  • the structural formula of compound A2 is The structural formula of the compound A3 is
  • the compound A3 and the compound D are subjected to a condensation cyclization reaction to obtain the compound A4, wherein the structural formula of the compound D is -Y is -R 1 , -R 2 are independently selected from -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkylamino, N-alkyl-N- One of acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl, the structural formula of the compound A4 for
  • the nitro group on the benzene ring of the compound A5 is reduced to an amino group to obtain the compound A6.
  • the structural formula of the compound A6 is And the compound A6 and the compound F undergo a condensation reaction to obtain the quinoline compound, wherein the structure of the compound F is -R 4 is an alkyl group or an aryl group.
  • a preparation method of quinazoline compounds including the following steps:
  • the nucleophilic substitution reaction between compound A2 and 4-fluoronitrobenzene yields compound A3.
  • the structural formula of compound A2 is The structural formula of the compound A3 is The compound A3 is condensed and cyclized with chloroacetaldehyde hydrate to obtain compound B1.
  • the structural formula of compound B1 is The compound B1 is ring-opened to obtain compound B2, and the structural formula of compound B2 is The compound B2 and urea undergo a condensation reaction to obtain compound B3.
  • the structural formula of compound B3 is The compound B3 is chlorinated to obtain compound B4, the structural formula of the compound B4 is
  • compound B5 is an alcohol compound containing -R 3 , and -R 3 is selected from -H, -Cl, -Br, alkyl, and alkoxy Group, aryl, aryloxy, N,N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N- One of alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl, the structural formula of the compound B5 is
  • the nitro group of the compound B6 is reduced to an amino group to obtain the compound B7.
  • the structural formula of the compound B7 is And the compound B7 and the compound F undergo a condensation reaction to obtain the quinazoline compound, wherein the compound F is a carboxylic acid, and the structure of the compound F is -R 4 is an alkyl group or an aryl group.
  • a PFKFB inhibitor includes the above-mentioned quinoline or quinazoline compound.
  • the preparation method of the above-mentioned quinoline or quinazoline compound is simple and convenient, the raw materials are easily obtained, the preparation conditions are not harsh, and the industrial production is easy to realize.
  • the quinoline or quinazoline compound has the following structural formula:
  • -R 1 , -R 2 , -R 5 are independently selected from -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkylamino, N-alkane
  • N-acylamino pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl.
  • -R 3 is selected from -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkylamino, N-alkyl-N-acylamino, pyridyl, One of imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl.
  • -R 4 is an alkyl group or an aryl group.
  • quinoline or quinazoline compound is selected from one of the following structural formulas:
  • PFKFB is an important bifunctional enzyme, consisting of the N-terminal kinase (6-phosphofructo-2-kinase, PFK-2) domain and the C-terminal esterase (fructose-2, 6-biphosphatase, FBPase-2) domain. , which can respectively catalyze the synthesis and hydrolysis of fructose-2,6-bisphosphate (Fructose2,6-bisphosphate, Fru-2,6-BP).
  • Mammalian PFKFB generally has four subtypes: PFKFB1, PFKFB2, PFKFB3 and PFKFB4. Among them, the kinase activity of PFKFB3 is much greater than its esterase activity, and it is more inclined to synthesize Fru-2,6-BP.
  • the preparation method (method A) of quinoline compounds includes the following steps:
  • the compound A1 and Boc anhydride are dissolved in methanol, and triethylamine is added with stirring, and the reaction is stirred at room temperature for 12 to 18 hours. 2mol/L hydrochloric acid solution is added, and purified by separation and purification. Compound A2.
  • compound A1 is 4-aminophenol Its structural formula is, the chemical formula of Boc anhydride is (Boc) 2 O, and the structural formula of compound A2 is
  • the molar ratio of compound A1 to Boc anhydride is 1:1 to 1.2, preferably 1:1.2.
  • the molar ratio of compound A1 to triethylamine is 1:1.5 to 2.3, preferably 1:2.2.
  • the specific method of separation and purification is: ethyl acetate extraction, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product purified by silica gel column chromatography, wherein the eluent is n-hexane And ethyl acetate, the volume ratio of n-hexane to ethyl acetate is 4-8:1) to obtain pure compound A2.
  • reaction formula for preparing compound A2 from compound A1 is as follows:
  • compound A2 can also be purchased from the market.
  • the compound A2 and -fluoronitrobenzene were dissolved in acetonitrile, potassium carbonate was added, and the reaction was stirred at 70°C to 90°C for 18 hours. After extraction, it was concentrated and then dissolved in dichloromethane. With trifluoroacetic acid, the reaction was stirred at room temperature for 6 hours. After the reaction is completed, a saturated aqueous sodium bicarbonate solution is added, and the pure compound A3 is separated and purified.
  • the molar ratio of compound A2 to potassium carbonate is 1:1.5 to 2.5, preferably 1:2.5.
  • the specific method of extraction and concentration is: cooling to room temperature, adding water to dilute the reaction solution, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product.
  • the specific method of separation and purification is: extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo to obtain a crude product that is purified by silica gel column chromatography (eluent: n-hexane/acetic acid Ethyl ester, volume ratio 3-6:1) to obtain pure compound A3.
  • reaction formula for preparing compound A3 from compound A2 and 4-fluoronitrobenzene is as follows:
  • compound A3 and compound D are mixed, a protic acid is added, and the reaction is stirred at 120°C to 140°C for 18 hours. After separation and purification, pure compound A4 is obtained.
  • the structural formula of compound D is -Y- is -R 1 , -R 2 are independently selected from -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkylamino, N-alkyl-N- One of acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl.
  • the structural formula of compound A4 is
  • the protic acid is polyphosphoric acid (PPA), and in other embodiments, it may also be concentrated sulfuric acid.
  • compound D is selected from one of ethyl acetoacetate, ethyl propionylacetate, ethyl butyrylacetate, ethyl acetoacetate isobutyrate, and other aliphatic or aromatic substituted ethyl acetoacetates.
  • the molar ratio of compound A3 to compound D is 1:1.3 to 1.5, preferably 1:1.5.
  • the specific method of separation and purification is: after cooling to room temperature, adding water, filtering and extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating in vacuo, and passing through silica gel column chromatography Purification (eluent dichloromethane/methanol, volume ratio 20-30:1) to obtain pure compound A4. More preferably, the ratio of the added water to the compound A3 is 20 mL: 1.0 mmol.
  • reaction formula for preparing compound A4 from compound A3 and compound D is:
  • compound A4 and compound E are dissolved in acetonitrile, anhydrous potassium carbonate is added, and the reaction is stirred at 80°C to 90°C for 12 hours. After separation and purification, pure compound A5 is obtained.
  • compound E is a halogenated hydrocarbon containing -R 3 , -R 3 selects -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkylamino , N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and one of tetrahydropyrrolyl Species, the structural formula of compound A5 is
  • the compound E is selected from the group consisting of methyl iodide, allyl bromide, propargyl bromide, bromoethane, 1-iodopropane, 1-iodo-2-methylpropane, 1-iodobutane and benzyl bromide One kind.
  • the molar ratio of compound A4 to compound E is 1:1.0 to 1.3, preferably 1:1.2.
  • the molar ratio of compound A4 to anhydrous potassium carbonate is 1:3.0 to 4.0, preferably 1:4.0.
  • the specific method of separation and purification is: cooling to room temperature, diluting with water, filtering, extracting the filtrate with ethyl acetate, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, and vacuum concentration to obtain the crude product through silica gel Purification by column chromatography (eluent: n-hexane/ethyl acetate, volume ratio 5-10:1) to obtain pure compound A5. More preferably, the ratio of water to compound A4 is 15 mL: 1.0 mmol.
  • the anhydrous potassium carbonate can also be replaced by other inorganic bases such as anhydrous sodium carbonate, or can be replaced by organic bases such as triethylamine and pyridine.
  • reaction formula for preparing compound A5 from compound A4 and compound is:
  • the compound A5 is dissolved in an organic solution, a reducing agent is added, and the mixture is stirred at room temperature for 8 hours to 12 hours to separate and purify the pure compound A6.
  • the structural formula of the compound A6 is
  • the organic solvent is a mixed solution of dichloromethane and methanol, the volume ratio of dichloromethane and methanol is 1:1, and the ratio of compound A5 to the mixed solution of dichloromethane and methanol is 1 mmol: 10 mL.
  • the organic solvents methylene chloride and methanol can be replaced by at least one of water or ethanol.
  • the reducing agent is a mixture of zinc powder and ammonium chloride, and the molar ratio of compound A5, zinc powder and ammonium chloride is 1:6.0-8.0:8.0-10.0. Preferably it is 1:8:10.
  • the reducing agent may also be iron powder, palladium-carbon hydrogenation, platinum metal hydrogenation, nickel metal hydrogenation, and other common reducing agents in the art.
  • the method of separation and purification is specifically: filtration through diatomaceous earth, washing with dichloromethane and saturated brine, drying with anhydrous sodium sulfate, and concentration in vacuo to obtain pure compound A6.
  • reaction formula for preparing compound A6 from compound A5 is:
  • the compound A6 and the compound F are dissolved in dichloromethane, a condensing agent is added, and the mixture is stirred at room temperature for 16 hours. After separation and purification, the pure compound A7 is the pure quinoline compound.
  • compound F is -R 4 is an alkyl group or an aryl group.
  • compound F can be various aromatic acids or fatty acids, and compound F can be selected from N-tert-butoxycarbonylproline, N-tert-butoxycarbonylalanine, N-tert-butoxycarbonylvaline, and thiazole-2 -Carboxylic acid, 1H-imidazole-5-carboxylic acid, oxazole-4-carboxylic acid, pyrrole-2-carboxylic acid, indole-2-carboxylic acid, pyridine-2-carboxylic acid, 3-chlorobenzothiophene- One of 2-carboxylic acid, 2-acetoxyacetic acid, 2-bromoacetic acid, 2-chloroacetic acid and trifluoroacetic acid.
  • the molar ratio of compound A6 to compound F is 1:1.0 to 1.2, preferably 1:1.
  • the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride EDCI, and the molar ratio of compound A4 to EDCI is 1:1 to 1.3, preferably 1 :1.2.
  • the condensing agent can also be DCC (1,3-dicyclohexylcarbodiimide), HATU (2-(7-benzotriazole oxide)-N,N,N' , N'-tetramethylurea hexafluorophosphate), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) or DPPA (diphenyl azide phosphate) ).
  • DCC 1,3-dicyclohexylcarbodiimide
  • HATU (2-(7-benzotriazole oxide)-N,N,N' , N'-tetramethylurea hexafluorophosphate
  • BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • DPPA diphenyl azide phosphate
  • the specific method of separation and purification is as follows: dilute with water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify by silica gel column chromatography (the eluent is two Methyl chloride/methanol, volume ratio 20-30:1) to obtain pure compound A7, which is the pure above-mentioned quinoline compound.
  • reaction formula for preparing the above-mentioned quinoline compound from compound A6 is:
  • compound A7 was dissolved in dichloromethane, trifluoroacetic acid was added thereto, stirred at room temperature for 6 hours, sodium bicarbonate aqueous solution was added, and the above-mentioned quinoline compound without tert-butoxycarbonyl group was purified and purified by separation and purification.
  • the ratio of compound A7 to dichloromethane is 1 mmol:5 mL.
  • the ratio of compound A7 to trifluoroacetic acid is 1 mmol: 0.8 mL to 1.2 mL, preferably 1 mmol: 1 mL.
  • the effect of trifluoroacetic acid is to remove the above-mentioned quinoline compounds containing tert-butoxycarbonyl (Boc).
  • the tert-butoxycarbonyl group in other embodiments, trifluoroacetic acid can also be replaced with hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid or formic acid.
  • the specific method of separation and purification is as follows: extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo.
  • the residue obtained is purified by silica gel column chromatography to be pure without The above-mentioned quinoline compounds of tert-butoxycarbonyl.
  • the eluent of silica gel column chromatography is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 5-10:1.
  • reaction formula for removing tert-butoxycarbonyl of compound A7 is as follows:
  • the preparation method of the above-mentioned quinoline compounds is simple and convenient, the raw materials are readily available, the preparation conditions are mild, and the industrial production is easy to realize.
  • the preparation method (method B) of quinazoline compounds according to one embodiment includes the following steps:
  • step S210 According to step S110 of the preparation method A of quinoline compounds, compound A2 is prepared.
  • step S220 According to step S120 of the preparation method A of quinoline compounds, compound A3 is prepared.
  • chloroform hydrate, water, sodium sulfate, compound A3, hydrochloric acid solution (6mL water and 1mL concentrated hydrochloric acid), aqueous hydroxylamine hydrochloride were added sequentially, and the reaction was stirred at 110°C for 2 hours, and the temperature was raised to The reaction was stirred at 130°C for 1h. Then it was cooled to room temperature, filtered, dried, and then gradually added to concentrated sulfuric acid at 50°C, and reacted at 65°C for 2 hours. Cool to room temperature, pour it into crushed ice 10 times the volume of the reactant, filter after 30 minutes, wash with cold water, and dry to obtain compound B1.
  • the molar ratio of compound A3 to chloroform hydrate is 1:1.0 to 1.2, preferably 1:1.1.
  • the molar ratio of compound A3 to sodium sulfate is 1:8.0 to 9.0, preferably 1:8.0.
  • the ratio of compound A3 to hydroxylamine hydrochloride is 1 mmol: 3.0 mmol/mL to 3.6 mmol/mL, preferably 1 mmol: 3.3 mmol/mL.
  • reaction formula for preparing compound B1 from compound A3 is as follows:
  • the compound B1 was dissolved in an aqueous sodium hydroxide solution, and hydrogen peroxide was gradually added, and the reaction was stirred at 60° C. for 3 hours. Cool to room temperature, add HCl, adjust the pH of the reaction solution to 2-4, filter, wash with cold water, and dry to obtain compound B2.
  • reaction formula for preparing compound B2 by ring opening of compound B1 is as follows:
  • the compound B2 and urea (urea) are stirred and reacted at 160°C to 170°C for 12 hours to 18 hours. Cool to room temperature, add water, filter, wash with water, and dry to obtain compound B3.
  • the molar ratio of compound B2 to urea is 1:6.0 to 7.0, preferably 1:7.0.
  • reaction formula for preparing compound B3 from compound B2 is as follows:
  • the compound B3, phosphorus pentachloride and phosphorus oxychloride were stirred and reacted at 110°C for 6 hours. Cool to room temperature, add saturated aqueous sodium bicarbonate solution after concentration, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify by silica gel column chromatography (eluent: n-hexane /Ethyl acetate, volume ratio 10-20:1) to obtain pure compound B4.
  • the ratio of compound B3, phosphorus pentachloride and phosphorus oxychloride is 10.0 mmol: 35-45.0 mmol: 8 mL, preferably 10.0 mmol: 40.0 mmol: 8 mL.
  • reaction formula for preparing compound B4 from compound B3 is as follows:
  • compound B4 is dissolved in tetrahydrofuran, triethylamine and compound G are added, and the reaction is stirred at 50°C to 70°C for 12 hours to 16 hours. Cool to room temperature, concentrate and add saturated aqueous sodium bicarbonate solution. Then it was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, volume ratio 5-10: 1) to obtain pure compound B5.
  • compound G is R 3 -OH, and -R 3 is selected from -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkylamino, N- One of alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl, compound The structural formula of B5 is
  • compound G is selected from methanol, ethanol, propanol, butanol, allyl alcohol, isopropanol, isobutanol, pentanol, propargyl alcohol, phenol, 3-chlorophenol, 3-hydroxypyridine and benzyl alcohol One of them.
  • the molar ratio of compound B4 to compound G is 1:1.5 to 2.0, preferably 1:2.0.
  • the molar ratio of compound B4 to triethylamine is 1:1.5 to 2.0, preferably 1:2.0.
  • reaction formula for preparing compound B5 from compound B4 is as follows:
  • compound B5, compound H, and n-butanol are mixed, concentrated hydrochloric acid is added, and the reaction is stirred at 100°C to 110°C for 12 to 16 hours. Cooled to room temperature, concentrated, added water, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate Ester, the volume ratio is 2 ⁇ 4:1) to obtain pure compound B6.
  • compound H is YH, where -Y is Or -OR 5 , -R 1 , -R 2 , -R 5 are each independently selected from -H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N,N-dialkyl Among amino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl
  • the structural formula of compound B6 is
  • the compound H is selected from one of nitrogen-methylpiperazine, morpholine, hexahydropyridine, tetrahydropyrrole, diethylamine, dimethylamine, dipropylamine, methanol and azetidine.
  • nitrogen-methylpiperazine morpholine
  • hexahydropyridine hexahydropyridine
  • tetrahydropyrrole diethylamine
  • dimethylamine dipropylamine
  • methanol and azetidine azetidine.
  • the molar ratio of compound B5 to compound H is 1:1.2 to 1.5, preferably 1:1.5.
  • reaction formula for preparing compound B6 from compound B5 is as follows:
  • compound B6 is dissolved in dichloromethane and methanol mixed in equal proportions, zinc powder and ammonium chloride are added to the above solution, and stirred at room temperature for 8-12 hours. Then, it was filtered through Celite, washed with dichloromethane, and the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound B7.
  • the molar ratio of compound B6, zinc powder and ammonium chloride is 1:6-8:8-10, preferably 1:8:10.
  • reaction formula for preparing compound B7 from compound B6 is as follows:
  • compound F is a carboxylic acid
  • the structure of compound F is -R 4 is an alkyl group or an aryl group.
  • compound B7 and compound F are dissolved in dichloromethane, and the condensing agent EDCI is added thereto, and the reaction solution is stirred and reacted at room temperature for 12 to 16 hours. After separation and purification, the pure compound B8 is obtained, which is the pure above-mentioned quinazoline compound.
  • compound F is various aromatic acids or fatty acids, and further, compound F is selected from N-tert-butoxycarbonylproline, N-tert-butoxycarbonylalanine, N-tert-butoxycarbonylvaline, Thiazole-2-carboxylic acid, 1H-imidazole-5-carboxylic acid, oxazole-4-carboxylic acid, pyrrole-2-carboxylic acid, indole-2-carboxylic acid, pyridine-2-carboxylic acid, 3-chlorobenzene One of thiophene-2-carboxylic acid, 2-acetoxyacetic acid, 2-bromoacetic acid, 2-chloroacetic acid and trifluoroacetic acid.
  • the molar ratio of compound B7 to compound F is 1:1.0 to 1.2, preferably 1:1.0.
  • the molar ratio of compound B7 to the condensing agent is 1:1.1 to 1.3, preferably 1:1.2.
  • the specific method of separation and purification is as follows: add water to the reaction solution, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify by silica gel column chromatography (washing Deliquoring: dichloromethane/methanol, volume ratio 20-30:1), the pure compound is the above-mentioned quinazoline compound.
  • compound B8 was dissolved in dichloromethane, trifluoroacetic acid was added thereto, stirred at room temperature for 6 hours, sodium bicarbonate aqueous solution was added, and the above-mentioned quinazoline compound without tert-butoxycarbonyl group was purified and purified by separation and purification. .
  • the ratio of compound B8 to dichloromethane is 1 mmol:5 mL.
  • the ratio of compound B8 to trifluoroacetic acid is 1 mmol: 0.8 mL to 1.2 mL, preferably 1 mmol: 1.0 mL.
  • the function of trifluoroacetic acid is to remove the above-mentioned quinolines containing tert-butoxycarbonyl (Boc) The tert-butoxycarbonyl group of the compound.
  • trifluoroacetic acid can also be replaced with hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid or formic acid.
  • the specific method of separation and purification is as follows: extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo.
  • the residue obtained is purified by silica gel column chromatography to be pure without The above-mentioned quinoline compounds of tert-butoxycarbonyl.
  • the eluent of silica gel column chromatography is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 10-20:1.
  • reaction formula for removing tert-butoxycarbonyl of compound B8 is as follows:
  • the preparation method of the above-mentioned quinazoline compound is simple and convenient, the raw material is easy to obtain, the preparation condition is mild, and the industrial production is easy to realize.
  • the application also provides an application of a quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt in the preparation of an anti-tumor drug:
  • X is N or CR 9 ;
  • Y is selected from H; -OH; -NH 2 ; halogen; substituted or unsubstituted linear or branched C1-C6 alkyl, substituted or unsubstituted linear or branched C1-C6 alkenyl; substituted or unsubstituted Straight or branched C1-C6 alkynyl; substituted or unsubstituted straight or branched C1-C6 alkoxy; substituted or unsubstituted straight or branched C1-C6 secondary amino, tertiary amino or Quaternary amino group; substituted or unsubstituted linear or branched C1-C6 ester group; substituted or unsubstituted linear or branched C1-C6 amide group; substituted or unsubstituted linear or branched C1-C6 ketone Group; substituted or unsubstituted C1-C10 cycloalkyl; substituted or unsubstituted C1
  • Z is selected from substituted or unsubstituted aryl or heteroaryl; substituted or unsubstituted linear or branched C1-C6 alkyl, substituted or unsubstituted linear or branched C1-C6 alkenyl; substituted or unsubstituted Substituted linear or branched C1-C6 alkynyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from H; halogen; substituted or unsubstituted straight Chain or branched C1-C6 alkyl, substituted or unsubstituted linear or branched C1-C6 alkenyl; substituted or unsubstituted linear or branched C1-C6 alkynyl; substituted or unsubstituted linear or Branched C1-C6 alkoxy; substituted or unsubstituted linear or branched C1-C6 secondary, tertiary or quaternary amino groups; substituted or unsubstituted linear or branched C1-C6 ester groups; Substituted or unsubstituted linear or branched C1-C6 amide group; substituted or unsubstituted linear or branched C1-
  • the tumor is lung cancer, gastric cancer, esophageal cancer, liver cancer, breast cancer, cervical cancer, nasopharyngeal cancer, colon cancer, cardia cancer, liver duct cancer, ovarian cancer, laryngeal cancer, oral cancer, lymphoma, leukemia, One or more of rectal cancer, thyroid cancer, maxillary sinus cancer, craniocerebral glioma, oropharyngeal cancer, and pancreatic cancer.
  • a quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an antitumor drug wherein said Y is Substituted or unsubstituted C1-C10 cycloalkyl; substituted or unsubstituted C1-C10 heterocyclic group.
  • a quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an antitumor drug wherein said Y is A substituted or unsubstituted C1-C10 heterocyclic group, which may be substituted or unsubstituted tetrahydropyrrolyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl , Substituted or unsubstituted piperidinyl.
  • a quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an antitumor drug wherein the substitution or The unsubstituted piperazinyl group is a piperazinyl group with a C1-C6 branched or branched alkyl substituent on N, a piperazinyl group with a C1-C6 branched or branched alkenyl substituent on N, and a piperazinyl group with a C1-C6 branched or branched alkenyl substituent on N.
  • a quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an anti-tumor drug wherein the N is
  • the piperazinyl group having a C1-C6 branched or branched alkenyl substituent is N-methyl-piperazinyl or N-ethyl-piperazinyl.
  • a quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an antitumor drug wherein said Z is Substituted or unsubstituted aryl or heteroaryl, aryl or heteroaryl means a stable 5- or 6-membered monocyclic ring containing 1 to 4 selected from N, O and S, and the remaining ring atoms being carbon ; Or multi-ring.
  • a quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of antineoplastic drugs wherein the heteroaromatic The group is selected from pyridyl, pyranyl, pyrrolyl, furyl, imidazolyl, oxazolyl, isoxazolyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, thiazolyl, Triazolyl, tetrazolyl, quinolinyl, pyrazolyl, benzo[b]phenylthio, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5 ,6,7,8-Tetrahydroisoquinoline.
  • quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an antitumor drug wherein said Z is Phenyl or naphthyl substituted with 1-4 halogens.
  • quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an antitumor drug wherein said Z is Substituted or unsubstituted allyl, substituted or unsubstituted propenyl.
  • quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an anti-tumor drug, wherein the tumor is Lung cancer, colon cancer, breast cancer.
  • quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an anti-tumor drug, wherein the tumor is Non-small cell lung cancer or breast duct cancer.
  • quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an antitumor drug, wherein the tumor is human Tumor.
  • quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an anti-tumor drug, said drug comprising pharmaceutical Acceptable carrier.
  • the pharmaceutical dosage form is Tablets, injections, injection powders, capsules, pills, solid dispersions, sustained-release agents, immediate-release agents, controlled-release agents, embedding agents, aerosols, creams, gels, syrups, patches One or more of agents, solutions, and suspensions.
  • the application also provides a pharmaceutical composition, which comprises a quinoline or quinazoline compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt as shown in the following formula,
  • X is N or CR 9 ;
  • Y is selected from H; -OH; -NH 2 ; halogen; substituted or unsubstituted linear or branched C1-C6 alkyl, substituted or unsubstituted linear or branched C1-C6 alkenyl; substituted or unsubstituted Straight or branched C1-C6 alkynyl; substituted or unsubstituted straight or branched C1-C6 alkoxy; substituted or unsubstituted straight or branched C1-C6 secondary amino, tertiary amino or Quaternary amino group; substituted or unsubstituted linear or branched C1-C6 ester group; substituted or unsubstituted linear or branched C1-C6 amide group; substituted or unsubstituted linear or branched C1-C6 ketone Group; substituted or unsubstituted C1-C10 cycloalkyl; substituted or unsubstituted C1
  • Z is selected from substituted or unsubstituted aryl or heteroaryl; substituted or unsubstituted linear or branched C1-C6 alkyl, substituted or unsubstituted linear or branched C1-C6 alkenyl; substituted or unsubstituted Substituted linear or branched C1-C6 alkynyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from H; halogen; substituted or unsubstituted straight Chain or branched C1-C6 alkyl, substituted or unsubstituted linear or branched C1-C6 alkenyl; substituted or unsubstituted linear or branched C1-C6 alkynyl; substituted or unsubstituted linear or Branched C1-C6 alkoxy; substituted or unsubstituted linear or branched C1-C6 secondary, tertiary or quaternary amino groups; substituted or unsubstituted linear or branched C1-C6 ester groups; Substituted or unsubstituted linear or branched C1-C6 amide group; substituted or unsubstituted linear or branched C1-
  • the preferred dosage ratio of the quinoline or quinazoline compound of the present invention to the second anti-tumor active agent or synergist is 0.1-100:0.1-100; preferably 1-100:0.1-50; more preferably It is 1-100:1-10; more preferably 60-100:1-10; more preferably 60-100:1-5; most preferably 80:2.5.
  • the X is N.
  • the Y is substituted or unsubstituted C1-C10 cycloalkyl; substituted or unsubstituted C1-C10 heterocyclic group.
  • the Y is a substituted or unsubstituted C1-C10 heterocyclic group, which may be substituted or unsubstituted tetrahydropyrrolyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted morpholinyl, substituted Or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl.
  • the substituted or unsubstituted piperazinyl group is a piperazinyl group having a C1-C6 branched or branched alkyl substituent on N, and a C1-C6 branched or branched alkenyl substituent on N Piperazinyl, piperazinyl having C2-C6 branched or branched alkynyl substituents on N, or piperazinyl having C1-C6 branched or branched carbonyl substituents on N.
  • the piperazinyl group having a C1-C6 branched or branched alkenyl substituent on N is N-methyl-piperazinyl or N-ethyl-piperazinyl.
  • the Z is a substituted or unsubstituted aryl or heteroaryl group.
  • the aryl or heteroaryl group means a stable 5 containing 1 to 4 selected from N, O, and S, and the remaining ring atoms are carbon. -Or 6-membered monocyclic ring; or polycyclic ring.
  • the aryl group is phenyl or naphthyl.
  • the heteroaryl group is selected from pyridyl, pyranyl, pyrrolyl, furyl, imidazolyl, oxazolyl, isoxazolyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, Phenylthio, thiazolyl, triazolyl, tetrazolyl, quinolyl, pyrazolyl, benzo[b]phenylthio, isoquinolyl, quinazolinyl, quinoxalinyl, thienyl, Isoindolyl, and 5,6,7,8-tetrahydroisoquinoline.
  • the Z is phenyl or naphthyl substituted with 1-4 halogens.
  • the Z is 3-chloro-phenyl.
  • the Z is substituted or unsubstituted allyl, substituted or unsubstituted propenyl.
  • a pharmaceutical composition as described above wherein the second anti-tumor active agent or synergist is a paclitaxel-type anti-tumor agent.
  • paclitaxel anti-tumor agent is paclitaxel or docetaxel.
  • a pharmaceutical composition as described above is characterized in that the second anti-tumor active agent or synergist is docetaxel.
  • the tumor is selected from lung cancer, gastric cancer, esophageal cancer, liver cancer, breast cancer, cervical cancer, nasopharyngeal cancer, colon cancer, cardia cancer, liver tube cancer, ovarian cancer, laryngeal cancer, oral cavity
  • lung cancer gastric cancer, esophageal cancer, liver cancer, breast cancer, cervical cancer, nasopharyngeal cancer, colon cancer, cardia cancer, liver tube cancer, ovarian cancer, laryngeal cancer, oral cavity
  • cancer lymphoma, leukemia, rectal cancer, thyroid cancer, maxillary sinus cancer, craniocerebral glioma, oropharyngeal cancer, and pancreatic cancer.
  • quinoline or quinazoline compound, tautomer, stereoisomer, or pharmaceutically acceptable salt as described above in the preparation of an antitumor drug wherein the compound is One or more of the following compounds;
  • a pharmaceutical composition as described above characterized in that the compound is one or more of the following compounds;
  • the stereoisomers of all the above compounds include enantiomers and diastereomers.
  • the present invention is not limited to any specific tautomer, but includes all tautomeric forms.
  • isotopes include those atoms that have the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 11 C, 13 C, and 14 C.
  • Halogen can be F, Cl, Br, I.
  • the present invention also provides a pharmaceutical composition.
  • the compound disclosed herein can be administered as a pure chemical, but is preferably administered as a pharmaceutical composition. Therefore, the present disclosure provides a pharmaceutical composition including a compound or a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may include a compound or salt as the sole active agent, but preferably includes at least one other active agent.
  • the pharmaceutical composition contains about 0.1 mg to about 1000 mg, about 1 mg to about 500 mg, or about 10 mg to about 200 mg of the compound of formula I and optionally about 0.1 mg to about 2000 mg in a unit dosage form. , About 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of other active agents.
  • the compounds disclosed herein can be administered orally, topically, injected, parenterally, by inhalation or spray, sublingually, transdermally, by oral cavity, rectal, as an ophthalmic solution, or by dosage unit formulations containing conventional pharmaceutical carriers.
  • the pharmaceutical composition can be formulated into any medicinal form, such as: injection, injection powder, aerosol, cream, gel, pill, capsule, tablet, syrup, transdermal patch, solution , Suspensions, emulsions, sustained release agents, controlled release agents, immediate release agents, nano formulations, or ophthalmic solutions.
  • Some dosage forms such as tablets and capsules can be subdivided into appropriate dosage unit dosage forms containing appropriate amounts of active ingredients such as effective amounts for the desired purpose.
  • Carriers include excipients and diluents, and must have sufficiently high purity and very low toxicity to make them suitable for administration to the patient to be treated.
  • the carrier may be inert or it may have pharmaceutical benefits on its own. .
  • the types of carriers include, but are not limited to: binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents Agent, and wetting agent.
  • Some carriers can be listed in more than one category.
  • vegetable oils can be used as lubricants in some formulations and as diluents in others.
  • Exemplary pharmaceutical carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils.
  • the compound or salt of the present invention may be the only active agent administered or may be administered in conjunction with other active agents.
  • the compound of the present application can be administered together with another anti-tumor active agent or potentiator.
  • stereoisomers of the present invention are compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space.
  • Alkyl includes both branched and straight chain saturated aliphatic hydrocarbon groups, and has a specified number of carbon atoms, generally 1 to about 12 carbon atoms.
  • the term C1-C6 alkyl as used herein means an alkyl group having 1 to about 6 carbon atoms.
  • a C0-Cn alkyl group is used in conjunction with another group in this article, take (phenyl)C0-C4 alkyl as an example, the designated group, in this case, the phenyl group is through a single covalent bond (C0 ) Is directly bonded or connected through an alkyl chain having the specified number of carbon atoms (in this case, 1 to about 4 carbon atoms).
  • alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.
  • alkenyl refers to straight and branched hydrocarbon chains that include one or more unsaturated carbon-carbon bonds, which can occur at any stable point along the chain.
  • the alkenyl groups described herein generally have 2 to about 12 carbon atoms.
  • Preferred alkenyl groups are lower alkenyl groups, and those alkenyl groups have 2 to about 8 carbon atoms, such as C2-C8, C2-C6, and C2-C4 alkenyl groups.
  • alkenyl groups include ethenyl, propenyl, and butenyl.
  • Alkoxy refers to an alkyl group as defined above having the specified number of carbon atoms connected by an oxygen bridge.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.
  • heterocyclic ring means a 5- to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring containing 1 to about 4 heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon, or Is a 7 to 11 membered saturated ring, partially unsaturated ring, or aromatic heterocyclic ring system and a 10 to 15-membered tricyclic ring system, which contains at least 1 heteroatom selected from the group consisting of N, O and S polycyclic ring systems And each ring in the polycyclic system contains up to about 4 heteroatoms independently selected from N, O, and S.
  • the heterocyclic ring can be attached to a group which is substituted at any heteroatom and carbon atom and results in a stable structure.
  • the heterocyclic ring described herein may be substituted on a carbon or nitrogen atom, as long as the resulting compound is stable.
  • the nitrogen atom in the heterocyclic ring can optionally be quaternized.
  • the total number of heteroatoms in the heterocyclic group is not more than 4 and preferably the total number of S and O atoms in the heterocyclic group is not more than 2, more preferably not more than 1.
  • heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio (benz[b]thiophenyl), isoquinolinyl, quinazolinyl, quinoxalinyl, Thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidine Group, morpholinyl, piperazinyl, piperide
  • Aryl or heteroaryl means a stable 5- or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and the remaining ring atoms are carbon. ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heteroaryl group is not more than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not more than one.
  • the nitrogen atom in the heterocyclic ring can optionally be quaternized.
  • these heteroaryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion with a 5- to 7-membered saturated ring group optionally containing 1 or 2 heteroatoms independently selected from N, O, and S, thereby forming, for example, [1,3]dioxin Azolo[4,5-c]pyridyl.
  • heteroaryl groups include, but are not limited to: pyridinyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl , And 5,6,7,8-tetrahydroisoquinoline.
  • the compound of the present invention has a better inhibitory effect on tumor cells, and the effect is better than the positive control AZ-26, especially in non-small cell lung cancer, colon cancer, and breast cancer.
  • the inhibitory effect is better than the positive control AZ-26, especially in non-small cell lung cancer, colon cancer, and breast cancer.
  • the compound of the present invention has an excellent inhibitory effect on breast cancer solid tumors, and the effect is better than the positive control AZ-26. And it has a synergistic effect in the process of combination with paclitaxel anti-tumor drugs, especially docetaxel, showing a strong anti-tumor effect.
  • the compound of the present invention has excellent anti-tumor activity, and can be used in combination with anti-tumor drugs known in the prior art to achieve synergistic and synergistic effects.
  • Figure 1 Representative compound's inhibitory effect on A549 cells
  • Figure 2 Representative compound's inhibitory effect on HCT116 cells
  • FIG. 1 Representative compound's inhibitory effect on T47D cells
  • Figure 4 Representative compound's inhibitory effect on F26BP levels in A549 cells
  • Figure 5 Representative compound's effect on F26BP levels in HCT116 cells
  • Figure 6 Representative compound's inhibitory effect on F26BP levels in T47D cells
  • Figure 7 Tumor weight statistics in the inhibitory test of compounds on solid tumors in NCG mice.
  • Examples 1-28 the quinoline compound preparation method (Method A) was used to prepare the above-mentioned quinoline compound.
  • the specific parameters of the preparation are shown in Table 1. The specific steps are as follows:
  • Step 1 Dissolve 20.0 mmol 4-aminophenol and 24.0 mmol Boc anhydride in 150 mL methanol, add 44.0 mmol triethylamine under stirring, and stir at room temperature for 18 hours. After the reaction is completed, add 20mL of 2mol/L hydrochloric acid solution, and extract with 3 ⁇ 50mL ethyl acetate. Combine the organic phases and wash with 2 ⁇ 50mL saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo to get the crude product to pass through the silica gel column. Analytical purification (eluent: n-hexane/ethyl acetate, volume ratio 4:1) to obtain pure compound A2.
  • Step 2 Dissolve 12.0mmol of compound A2 and 10.0mmol of 4-fluoronitrobenzene in 50mL of acetonitrile, and add 30.0mmol of potassium carbonate to the above solution, and the reaction mixture was stirred at 90°C for 18 hours. Then it was cooled to room temperature, 40 mL of water was added to dilute the reaction solution, extracted with 3 ⁇ 40 mL of ethyl acetate, the organic phases were combined and washed with 2 ⁇ 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • the crude product was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, 10 mL saturated aqueous sodium bicarbonate solution was added, extracted with 3 ⁇ 20 mL dichloromethane, and the organic phases were combined, washed with 20 mL saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product purified by silica gel column chromatography (washing Deliquoring: n-hexane/ethyl acetate, volume ratio 3:1) to obtain pure compound A3.
  • Step 3 Mix 1.0mmol of compound A3 and compound D (same as D in Table 1) in a three-necked flask, the molar ratio of compound A3 to compound D is C1, add 5g of polyphosphoric acid (PPA), stir and react at 130°C for 18 hour. After cooling to room temperature, add 20 mL of water and filter. The filtrate was extracted with 3 ⁇ 30 mL of ethyl acetate. After the organic phases were combined, they were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product that was purified by silica gel column chromatography. (Eluent: dichloromethane/methanol, volume ratio 20:1) to obtain pure compound A4.
  • PPA polyphosphoric acid
  • Step 4 Dissolve 1.0mmol of compound A4 and compound E (same as E in Table 1) in 8mL of acetonitrile, the molar ratio of compound A4 to compound E is C2, and add 4.0mmol of anhydrous potassium carbonate, and stir the reaction at 90°C. 12 hours.
  • Step 5 Dissolve 1.0 mmol of compound A5 in 10 mL of dichloromethane and methanol mixed in equal proportions, and add zinc powder and ammonium chloride to the above solution.
  • the molar ratio of compound A5, zinc powder and ammonium chloride is C3.
  • the reaction solution was stirred at room temperature for 12 hours. Then it was filtered through Celite, washed with dichloromethane, and the filtrate was washed with 2 ⁇ 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain pure compound A6.
  • Step 6 Dissolve 1.0mmol of compound A6 and compound F (same as F in Table 1) in 8mL of dichloromethane, the molar ratio of compound A6 to compound F is C4, and add 1.2mmol of EDCI to them, and stir at room temperature to react 16 hour. Then 10 mL of water was added, extracted with 3 ⁇ 15 mL of dichloromethane, the organic phases were combined and washed with 2 ⁇ 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue obtained was purified by silica gel column chromatography (eluent : Dichloromethane/methanol, volume ratio 20:1) to obtain pure compound A7, which is the above-mentioned quinoline compound.
  • Step 1 According to the steps 1 and 2 of the preparation method A used in Examples 1 to 31, compound A3 was prepared, and then chloroformaldehyde hydrate (11.0 mmol) and 40 mL of water were added to the flask; then sodium sulfate ( 80.0 mmol), compound A3 (10.0 mmol), hydrochloric acid solution (6 mL of water and 1 mL of concentrated hydrochloric acid), and finally a solution of hydroxylamine hydrochloride (33.0 mmol) dissolved in 10 mL of water.
  • reaction mixture was stirred and reacted at 110°C for 2h, heated to 130°C and stirred for 1h, cooled to room temperature, filtered, dried, and then gradually (added in about 20min) added to 50°C concentrated sulfuric acid (20mL), and reacted at 65°C. 2 hour. Cool to room temperature, pour it into crushed ice 10 times the volume of the reactant, filter after 30 minutes, wash with cold water, and dry to obtain compound B1.
  • Step 2 Dissolve compound B1 (2.0 mmol) in aqueous sodium hydroxide solution (2M, 15 mL), gradually add hydrogen peroxide (2 mL), and stir for reaction at 60° C. for 3 hours. Cool to room temperature, add HCl (6M), adjust the pH of the reaction solution to 2-4, filter, wash with cold water, and dry to obtain compound B2.
  • Step 3 Add compound B2 (5.0 mmol) and urea (35.0 mmol) into the reaction flask, and stir and react at 160°C for 18 hours. Cool to room temperature, add 50 mL of water, filter, wash with water, and dry to obtain compound B3.
  • Step 5 Dissolve compound B4 (2.0mmol) in tetrahydrofuran (8mL), and add triethylamine (4.0mmol) and compound G (same as G in Table 2). The molar ratio of compound B4 to compound G is C5, at 60 The reaction was stirred at °C for 16 hours. Cooled to room temperature, concentrated the solvent, added 10 mL of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (3 ⁇ 20 mL), combined the organic phases, washed with saturated brine (2 ⁇ 20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, volume ratio 5:1) to obtain compound B5.
  • Step 6 Mix compound B5 (1.0 mmol), compound H (same as H in Table 2), and n-butanol (4 mL) in the reaction flask. The molar ratio of compound B5 to compound H is C6. Add concentrated hydrochloric acid (1 drop). The reaction was stirred at 110°C for 16 hours.
  • Step 7 Dissolve compound B6 (1.0mmol) in dichloromethane and methanol (10mL) mixed in equal proportions, and add zinc powder (8.0mmol) and ammonium chloride (10.0mmol) to the above solution.
  • the reaction solution is in Stir at room temperature for 12 hours. Then filtered through Celite, washed with dichloromethane, and the filtrate was washed with saturated brine (2 ⁇ 20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue obtained was the intermediate product B7.
  • Step 8 Dissolve compound B7 (1.0mmol) and compound F (same as F in Table 2) in dichloromethane (8mL), the molar ratio of compound B7 (1.0mmol) and compound F is C7, and add condensate to them The mixture is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride EDCI (1.2 mmol), and the reaction solution is stirred and reacted at room temperature for 16 hours.
  • compound B8 (1.0 mmol) is dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) is added thereto, and the reaction solution is stirred and reacted at room temperature for 6 hours. Then an aqueous sodium bicarbonate solution (10 mL) was added, extracted with dichloromethane (3 ⁇ 15 mL), the organic phases were combined and washed with saturated brine (2 ⁇ 20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the prepared quinoline or quinazoline compound was prepared by using proton nuclear magnetic resonance spectroscopy to determine the structure, or proton nuclear magnetic resonance spectroscopy and high resolution mass spectrometry to determine the structure.
  • the quinoline or quinazoline compound of Examples 1 to 56 was subjected to a PFKFB3 enzyme activity test, which mainly includes two reaction steps, namely
  • Step 1 PFKFB3 catalyzes F6P and ATP to generate F-2,6-BP;
  • Step 2 The produced F-2,6-BP activates PFK1, and PFK1 catalyzes the consumption of NADH.
  • the reaction system of step 1 consists of Buffer A and Buffer B+ or Buffer B-.
  • Buffer A mainly contains enzymes and target products
  • Buffer B+ contains the substrate fructose 6-phosphate (F6P)
  • Buffer B- does not contain the substrate F6P, and is used to detect the reaction background.
  • Buffer A contains DTT (final concentration: 1mM), PFKFB3 (add the appropriate volume according to the enzyme activity) and Mops Buffer, mix and dispense into a labeled Ep tube on ice, 200 ⁇ L/tube .
  • the final concentration of the target product are: 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M,
  • An equal volume of DMSO was added to the negative control group. After mixing, centrifuge and incubate at room temperature for 30 minutes. It is assumed that it takes a certain time for the target product to bind to the enzyme.
  • Buffer B+ and Buffer B- where Buffer B+ contains MgCl 2 (working concentration: 2mM), ATP (working concentration: 50 ⁇ M), F6P (working concentration: 50 ⁇ M) and MOPS buffer; Buffer B- contains MgCl 2 (working concentration) : 2mM), ATP (working concentration: 50 ⁇ M) and MOPS buffer.
  • Buffer B+ or Buffer B- into the corresponding Ep tubes of Buffer A, add 200 ⁇ L of buffer B to each tube, mix and centrifuge and incubate at 37°C for one hour, so that PFKFB3- catalyzes the production of F6P and ATP.
  • F-2,6-BP One hour later, add KOH 40 ⁇ L/tube (KOH storage concentration is 1M) to the Ep tube to stop the reaction, mix well and centrifuge and place on ice.
  • the reaction system of step two includes NADH (final concentration: 0.2mM), DTT (final concentration: 5mM), F6P (final concentration: 1mM), MgCl 2 (final concentration: 2mM), Aldolase (final concentration: 0.7U/mL) , GDH (final concentration: 0.45U/mL), TIM (final concentration: 0.6U/mL), PFK1 final concentration: 0.033 ⁇ g/ ⁇ L) and Tris-HCl buffer.
  • step 2 Prepare the reaction solution of step 2 above, mix well, and dispense into the labeled Ep tubes, 450 ⁇ L/tube.
  • Add the reaction solution of step 1 after termination to the reaction solution of step 2 add 6 ⁇ L to each tube, mix and centrifuge.
  • Transfer the above reaction solution to a 96-well plate, 150 ⁇ L/well add 2 replicate wells to each sample.
  • use a discharge gun to add PPi-Na with a storage concentration of 25 mM, 3 ⁇ L/well to the 96-well plate.
  • a microplate reader to detect the NADH consumption rate, measure the Mean V value, and use the GraphPad Prism 5 software to calculate the IC50 of the target product.
  • Example IC50( ⁇ M) Example IC50( ⁇ M) 2 1.67 35 1.09 3 0.37 36 0.48 4 1.59 37 0.35 5 0.32 38 0.69 6 0.68 39 0.48 7 0.51 40 0.32 8 0.49 41 0.88 9 0.49 42 0.72 10 0.91 43 0.50 11 0.68 44 1.11 12 0.68 45 0.33 13 1.22 46 0.72 14 0.48 47 0.47 29 1.20 48 1.94 30 0.94 49 0.77 33 3.89 50 0.99 34 1.42 51 1.58
  • the quinoline or quinazoline compound prepared according to the preparation method A and the preparation method B has a good inhibitory effect on the kinase activity of the PFKFB3 enzyme.
  • the synthesis of Fru-2,6-BP is blocked, thereby inhibiting the activity of PFK-1, thereby inhibiting the glycolytic metabolism of tumor cells, so that the energy required for the proliferation and growth of tumor cells is supplied and received limit.
  • Example 58 Representative compound's anti-proliferative activity on tumor cell lines
  • AZ-26 was used as a positive control to study the anti-tumor activity of self-made compounds.
  • the three representative cell lines selected are: A549 (human non-small cell lung cancer cells), HCT116 (human colon cancer cells) and T-47D (human breast tube cancer cells).
  • the following 3 representative compounds were selected from various active inhibitors with different chemical structures for testing: YZ-429, YZ-443, YZ-421.
  • the above representative compounds have a significant inhibitory effect on the enzymatic activity of PFKFB3 in in vitro experiments.
  • the MTT method was used to further verify its anti-proliferation effect on the above three types of tumor cells.
  • the main points of the MTT experiment method are as follows: tumor cells in the logarithmic growth phase are seeded in a 96-well cell culture plate so that the number of cells added to each well is 2000, and each experimental group is set up with 5 replicate wells. After culturing for 48 hours, add 10 uL of DMSO solution containing different concentrations of drugs to each well. After 4h, add DMSO, shake on a shaker to fully dissolve the crystals, and measure the absorbance at 490nm with a microplate reader.
  • Figure 1 to Figure 3 show the half-inhibitory concentrations of three compounds on the proliferation of three tumor cells.
  • AZ-26 significantly inhibited the proliferation rate of three kinds of tumor cells.
  • the test results show that the three self-made representative compounds also have a significant inhibitory effect on the proliferation of tumor cells.
  • the compounds YZ429 and YZ443 both showed strong inhibitory activity.
  • the three compounds all showed superior or close to AZ-26 cell proliferation inhibitory activity, among which compounds YZ429 and YZ443 had stronger inhibitory effects.
  • compound YZ443 has stronger inhibitory effect than the positive control drug.
  • the three representative compounds all show good anti-tumor activity.
  • Example 59 Representative compound reduces the level of PFKFB3 product F26BP in tumor cells
  • Cell F26BP content determination-reaction principle extract F26BP contained in tumor cells, activate PFK enzyme in vitro, PFK enzyme converts the substrate F6P into product F16BP, which consumes NADH.
  • the effects of the three representative self-made compounds on the F26BP levels of the three tumor cells are shown in Figure 4 to Figure 6.
  • the three compounds have inhibitory effects on F26BP levels, and YZ4433 has a stronger inhibitory effect, which is consistent with the results of the cell proliferation inhibition experiment.
  • the three compounds all showed inhibitory effects in HCT116 cells, among which YZ421 and YZ4433 had more significant inhibitory effects, which was also consistent with the results of cell proliferation inhibition experiments. And for T47D cells 3 compounds have a good inhibitory effect.
  • Compound YZ-443 2HCl compound, which is pale yellow-white crystalline substance, easily soluble in water. The purity is not less than 96% and contains 10-20% HCI.
  • Taxotere Docetaxel injection (hereinafter referred to as docetaxel), 0.5ml: 20mg, imported from Sanofi (Hangzhou) Pharmaceutical Co., Ltd., product batch number 7F159B.
  • docetaxel stock solution for test docetaxel (20mg, dissolved in 0.5ml polysorbate 80), add its own solvent (the main component is absolute ethanol) to prepare a uniform concentration of 13mg/ml
  • the solution should be stored in a refrigerator at 4°C as a stock solution. Before use, take an appropriate amount of stock solution and put it at room temperature before use.
  • Cell line The human breast cancer MDA-MB-231 cell line is derived from American Type Culture Collection (ATCC).
  • YZ-443 ⁇ 2HCl A qualitative experiment on the effect of YZ-443 ⁇ 2HCl on MDA-MB-231 breast cancer solid tumors in NCG female mice was carried out.
  • the experimental groups are as follows: intragastric administration, YZ-443 (high, medium, and low dose) group, docetaxel (high and low dose) group, combined medication group (YZ-443 and docetaxel combined)
  • the test ends when the compound administration group has a tendency to suppress tumors.
  • the dosage of YZ-443 is divided into 20mg/kg ⁇ BW, 40mg/kg ⁇ BW and 80mg/kg ⁇ BW.
  • the YZ-443 compound high-dose group (80mg/kg ⁇ BW), the YZ-443 compound middle-dose group (40mg/kg ⁇ BW), and the YZ-443 compound low-dose group (20mg/kg ⁇ BW) showed a tendency to suppress tumors.
  • the tumor weight in the high-dose docetaxel group (10mg/kg ⁇ BW) was significantly reduced, and the difference was extremely significant (p ⁇ 0.01); the low-dose docetaxel group (2.5mg/kg ⁇ BW) )
  • the combination group YZ-443 compound 80 mg/kg ⁇ BW + docetaxel 2.5 mg/kg ⁇ BW
  • the tumor weight was significantly reduced, and the difference was significant (p ⁇ 0.05).
  • YZ-443 compound is administered alone at the doses of 80mg/kg ⁇ BW, 40mg/kg ⁇ BW, 20mg/kg ⁇ BW, compared with the negative control group, there is a tendency to suppress tumors; YZ-443 When the compound is used in combination with a dose of 80 mg/kg ⁇ BW and a dose of 2.5 mg/kg ⁇ BW of docetaxel, there is a tendency to suppress tumors and is statistically significant, indicating that the YZ-443 compound has a synergistic effect on docetaxel.

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Abstract

一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其对于肿瘤具有较好的抑制效果，且与紫杉醇类抗肿瘤药物联合给药，具有协同作用。。

Description

喹啉或喹唑啉类化合物在制备抗肿瘤药物中的应用 技术领域
本发明涉及有机化合物领域，特别是涉及喹啉或喹唑啉类化合物在制备抗肿瘤药物中的应用。
背景技术
肿瘤细胞是能快速繁殖再生的异常细胞，具有无限增殖、可转化和易转移的特点。正常细胞的能量代谢主要通过葡萄糖在线粒体内进行氧化磷酸化来完成，肿瘤细胞的能量代谢不同于正常细胞，肿瘤细胞主要通过大量摄取葡萄糖并进行糖酵解(Warburg效应)来获取能量满足肿瘤细胞的生长及增殖。酵解途径是几乎所有生物中主要的代谢途径，糖酵解过程中的受体、转运分子、关键酶的表达、活性及调控对肿瘤的发生、发展、转移及消退起着至关重要的作用，已成为新的抗肿瘤药物研究的靶点。
目前，通过抑制肿瘤细胞的糖酵解代谢来抑制肿瘤细胞增殖的候选药物主要集中在噻吩磺酰胺类、苯氧吲哚类、苯并吡喃酮类、苯并吲哚类以及三唑哒嗪酮类的研究。尽管在肿瘤的诊断和治疗中取得进展，但仍然缺乏有效从源头上阻断肿瘤细胞能量供给的抗肿瘤药物。
发明内容
基于此，有必要提供一种能够从源头上阻断肿瘤细胞能量供给的喹啉或喹唑啉类化合物及其制备方法和应用。
一种喹啉或喹唑啉类化合物，具有如下结构式：
Figure PCTCN2019118783-appb-000001
其中，当-X-为-CH-时，-Y为
Figure PCTCN2019118783-appb-000002
当-X-为-N-时，-Y为
Figure PCTCN2019118783-appb-000003
或-O-R 5，
-R 1、-R 2、-R 5分别独立选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种；
-R 3选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种；
-R 4为烷基或芳基。
在其中一个实施例中，具有如下结构式：
Figure PCTCN2019118783-appb-000004
Figure PCTCN2019118783-appb-000005
在其中一个实施例中，具有如下结构式：
Figure PCTCN2019118783-appb-000006
Figure PCTCN2019118783-appb-000007
在其中一个实施例中，具有如下结构式：
Figure PCTCN2019118783-appb-000008
Figure PCTCN2019118783-appb-000009
在其中一个实施例中，具有如下结构式：
Figure PCTCN2019118783-appb-000010
Figure PCTCN2019118783-appb-000011
一种喹啉类化合物的制备方法，包括以下步骤：
将化合物A2与4-氟硝基苯发生亲核取代反应，得化合物A3，所述化合物A2的结构式为
Figure PCTCN2019118783-appb-000012
所述化合物A3的结构式为
Figure PCTCN2019118783-appb-000013
将所述化合物A3与化合物D进行缩合环化反应，得化合物A4，其中所述 化合物D的结构式为
Figure PCTCN2019118783-appb-000014
-Y为
Figure PCTCN2019118783-appb-000015
-R 1、-R 2分别独立选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种，所述化合物A4的结构式为
Figure PCTCN2019118783-appb-000016
将所述化合物A4与化合物E发生取代反应，得到化合物A5，其中所述化合物E为含有-R 3的卤代烃，-R 3选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种，所述化合物A5的结构式为
Figure PCTCN2019118783-appb-000017
将所述化合物A5苯环上的硝基还原成氨基，得到化合物A6，所述化合物A6的结构式为
Figure PCTCN2019118783-appb-000018
及所述化合物A6与化合物F发生缩合反应，得所述喹啉类化合物，其中所述化合物F的结构为
Figure PCTCN2019118783-appb-000019
-R 4为烷基或芳基。
一种喹唑啉类化合物的制备方法，包括以下步骤：
将化合物A2与4-氟硝基苯发生亲核取代反应，得化合物A3，所述化合物A2的结构式为
Figure PCTCN2019118783-appb-000020
所述化合物A3的结构式为
Figure PCTCN2019118783-appb-000021
将所述化合物A3与水合三氯乙醛缩合环化，得化合物B1，将所述化合物B1的结构式为
Figure PCTCN2019118783-appb-000022
将所述化合物B1开 环，得到化合物B2，所述化合物B2的结构式为
Figure PCTCN2019118783-appb-000023
将所述化合物B2与尿素发生缩合反应，得化合物B3，所述化合物B3的结构式为
Figure PCTCN2019118783-appb-000024
将所述化合物B3氯化，得到化合物B4，所述化合物B4的结构式为
Figure PCTCN2019118783-appb-000025
将所述化合物B4与化合物G发生取代反应，得化合物B5，其中所述化合物G为含有-R 3的醇类化合物，-R 3选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种，所述化合物B5的结构式为
Figure PCTCN2019118783-appb-000026
将所述化合物B5与化合物H发生取代反应，得化合物B6，其中所述化合物H的结构式为Y-H，其中-Y为
Figure PCTCN2019118783-appb-000027
或-O-R 5，-R 1、-R 2、-R 5分别独立选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种，所述化合物B6的结构式为
Figure PCTCN2019118783-appb-000028
将所述化合物B6的硝基还原成氨基，得化合物B7，所述化合物B7的结构 式为
Figure PCTCN2019118783-appb-000029
及所述化合物B7与化合物F发生缩合反应，得所述喹唑啉类化合物，其中所述化合物F为羧酸，化合物F的结构为
Figure PCTCN2019118783-appb-000030
-R 4为烷基或芳基。
上述的喹啉或喹唑啉类化合物在PFKFB抑制剂中的应用。
一种PFKFB抑制剂，包括上述的喹啉或喹唑啉类化合物。
上述的喹啉或喹唑啉类化合物在制备抗肿瘤的药物中的应用。
实验结果表明，上述的喹啉或喹唑啉类化合物能够抑制肿瘤细胞中PFKFB(6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶，6-phosphofructo-2-kinase/fructose-2,6-biphosphatase)的活性，有效阻断的糖酵解过程中关键酶的激活，从而从肿瘤细胞的能量源头阻断其能量供给，为肿瘤疾病的有效治疗提供了一个新的药物，同时也为抗肿瘤新药研发提供了新的思路。
上述的喹啉或喹唑啉类化合物的制备方法简便易行，原料易得，制备条件不苛刻，易实现工业生产。
具体实施方式
为了便于理解本发明，下面主要结合喹啉或喹唑啉类化合物及其制备方法和应用，对本发明进行更全面的描述。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使本发明公开内容更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
一实施方式喹啉或喹唑啉类化合物，具有如下结构式：
Figure PCTCN2019118783-appb-000031
其中，当-X-为-CH-时，-Y为
Figure PCTCN2019118783-appb-000032
当-X-为-N-时，-Y为
Figure PCTCN2019118783-appb-000033
或-O-R 5，
-R 1、-R 2、-R 5分别独立选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种。
-R 3选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种。
-R 4为烷基或芳基。
具体地，该喹啉或喹唑啉类化合物，选自如下结构式中的一种：
Figure PCTCN2019118783-appb-000034
Figure PCTCN2019118783-appb-000035
Figure PCTCN2019118783-appb-000036
Figure PCTCN2019118783-appb-000037
Figure PCTCN2019118783-appb-000038
及
Figure PCTCN2019118783-appb-000039
PFKFB是一种重要的双功能酶，由N端的激酶(6-phosphofructo-2-kinase，PFK-2)结构域和C端的酯酶(fructose-2,6-biphosphatase，FBPase-2)结构域构成，能够分别催化果糖-2,6-二磷酸(Fructose2,6-bisphosphate，Fru-2,6-BP)的合成与水解反应。哺乳动物的PFKFB一般有4种亚型：PFKFB1、PFKFB2、PFKFB3和PFKFB4。其中PFKFB3的激酶活性远大于其酯酶活性，更倾向于合成Fru-2,6-BP。
实验结果表明，上述的喹啉或喹唑啉类化合物可有效抑制肿瘤细胞中PFKFB的活性，特别是能够有效抑制PFKFB3的激酶活性，从而降低Fru-2,6-BP水平。而在糖酵解过程中，由于限速酶6-磷酸果糖-1-激酶(6-phosphofructo-2-kinase，PFK-1)活性受到ATP、ADP、AMP、Fru-2,6-BP的调控，其中，Fru-2,6-BP是最强激活剂。因此抑制Fru-2,6-BP即能够有效抑制PFK-1的活性，抑制肿瘤细胞糖酵解代谢，使得肿瘤细胞的增殖及生长所需的能量供受限，从源头上阻断肿瘤细胞能量供给。上述的喹啉或喹唑啉类化合物可为肿瘤疾病的有效治疗提供了一个新的途径，同时也为抗肿瘤新药研发提供了新的思路。
一实施方式的喹啉类化合物的制备方法(方法A)，包括以下步骤：
S110、将化合物A1与Boc酸酐反应，得化合物A2。
在其中一个实施例中，将化合物A1和Boc酸酐溶于甲醇中，并在搅拌下加入三乙胺，室温搅拌反应12小时～18小时，加入2mol/L的盐酸溶液，经分离纯化得纯净的化合物A2。
具体地，化合物A1为4-氨基苯酚
Figure PCTCN2019118783-appb-000040
其结构式为，Boc酸酐的化学式为(Boc) 2O，化合物A2的结构式为
Figure PCTCN2019118783-appb-000041
具体地，化合物A1与Boc酸酐的摩尔比为1:1～1.2，优选的1:1.2。
具体地，化合物A1与三乙胺的摩尔比为1:1.5～2.3，优选为1:2.2。
具体地，分离纯化的具体方法为：乙酸乙酯萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩得粗产物通过硅胶柱层析纯化，其中洗 脱液为正己烷和乙酸乙酯，正己烷与乙酸乙酯的体积比为4～8:1)，得到纯净的化合物A2。
具体地，由化合物A1制备化合物A2的反应式如下：
Figure PCTCN2019118783-appb-000042
当然在其他实施方式中，化合物A2也可以从市场购得。
S120、化合物A2与4-氟硝基苯发生亲核取代反应，得化合物A3。
在其中一个实施例中，将化合物A2与-氟硝基苯溶于乙腈中，加入碳酸钾，在70℃～90℃搅拌反应18小时后，经萃取浓缩之后再溶于二氯甲烷中，加入三氟乙酸，室温搅拌反应6小时。反应完毕后加入饱和碳酸氢钠水溶液，经分离纯化的纯净的化合物A3。
具体地，4-氟硝基苯的结构式为
Figure PCTCN2019118783-appb-000043
化合物A3的结构式为
Figure PCTCN2019118783-appb-000044
具体地，化合物A2与碳酸钾的摩尔比为1:1.5～2.5，优选为1:2.5。
具体地，萃取浓缩的具体方法为：冷却至室温，加入水稀释反应液，用乙酸乙酯萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗产物。
具体地，分离纯化的具体方法为：二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩得粗产物通过硅胶柱层析纯化(洗脱液正己烷/乙酸乙酯，体积比3～6:1)，得到纯净的化合物A3。
具体地，由化合物A2与4-氟硝基苯制备化合物A3的反应式如下：
Figure PCTCN2019118783-appb-000045
S130、将化合物A3与化合物D进行反应，得到化合物A4。
在其中一个实施例中，将化合物A3与化合物D混合，加入质子酸，在120℃～140℃搅拌反应18小时，分离纯化后得纯净的化合物A4。
具体地，化合物D的结构式为
Figure PCTCN2019118783-appb-000046
-Y-为
Figure PCTCN2019118783-appb-000047
-R 1、-R 2分别独立选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种，化合物A4的结构式为
Figure PCTCN2019118783-appb-000048
在本实施方式中，质子酸为多聚磷酸(PPA)，在其他实施方式中，还可以是浓硫酸。
进一步地，化合物D选自乙酰乙酸乙酯、丙酰乙酸乙酯，丁酰乙酸乙酯，异丁酸乙酰乙酸乙酯，及其他脂肪族或芳香族取代的乙酰乙酸乙酯中的一种。
化合物A3与化合物D的摩尔比为：1:1.3～1.5，优选为1:1.5。
具体地，分离纯化的具体方法为：冷却至室温后，加入水，过滤后用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后通过硅胶柱层析纯化(洗脱液二氯甲烷/甲醇，体积比20～30:1)得到纯净的化合物A4。更进一步优选的，加入水与化合物A3的比例为20mL:1.0mmol。
具体地，由将化合物A3与化合物D制备化合物A4的反应式为：
Figure PCTCN2019118783-appb-000049
S140、将化合物A4与化合物E发生取代反应，得到化合物A5。
在其中一个实施例中，将化合物A4与化合物E溶于乙腈中，加入无水碳酸 钾，在80℃～90℃搅拌反应12小时，分离纯化后得纯净的化合物A5。
具体地，化合物E为含有-R 3的卤代烃，-R 3选择-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种，化合物A5的结构式为
Figure PCTCN2019118783-appb-000050
具体地，化合物E选自碘甲烷、烯丙基溴、炔丙基溴、溴乙烷、1-碘丙烷、1-碘-2-甲基丙烷、1-碘丁烷及苄基溴中的一种。
化合物A4与化合物E的摩尔比为：1:1.0～1.3，优选为1:1.2。
化合物A4与无水碳酸钾的摩尔比为：1:3.0～4.0，优选为1:4.0。
具体地，分离纯化的具体方法为：冷却至室温，加入水稀释，过滤，滤液用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩得粗产物通过硅胶柱层析纯化(洗脱液为正己烷/乙酸乙酯，体积比5～10:1)得到纯净的化合物A5。更进一步优选的，水与化合物A4的比例为15mL:1.0mmol。
具体地，在其他实施方式中，无水碳酸钾还可以被其他如无水碳酸钠的无机碱替代，也可以被如三乙胺、吡啶等有机碱替代。
也可以是有机碱：三乙胺、吡啶等
在本实施方式中，由将化合物A4及化合物制备化合物A5的反应式为：
Figure PCTCN2019118783-appb-000051
S150、将化合物A5苯环上的硝基还原成氨基，得到化合物A6。
在其中一个实施例中，将化合物A5溶于有机溶液中，加入还原剂，在室温搅拌8小时～12小时，分离纯化得纯净的化合物A6，化合物A6的结构式为
Figure PCTCN2019118783-appb-000052
本实施方式中，有机溶剂为二氯甲烷及甲醇的混合溶液，二氯甲烷和甲醇的体积比为1:1，化合物A5与二氯甲烷和甲醇混合液的比例为1mmol:10mL。当然，在其他实施例中，有机溶剂二氯甲烷和甲醇可以被水或乙醇中的至少一种替代。
本实施方式中，还原剂为锌粉和氯化铵的混合物，化合物A5、锌粉及氯化铵的摩尔比为：1:6.0～8.0:8.0～10.0。优选为1:8:10。在其他实施例中，还原剂还可以是铁粉、钯碳加氢、铂金属加氢或镍金属加氢等本领域常见的还原剂。
具体地，分离纯化的方法具体为：硅藻土过滤，经二氯甲烷及饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得纯净的化合物A6。
具体地，在本实施方式中，由化合物A5制备化合物A6的反应式为：
Figure PCTCN2019118783-appb-000053
S160、化合物A6与化合物F发生缩合反应，得上述喹啉类化合物。
在其中一个实施例中，将化合物A6与化合物F溶于二氯甲烷中，加入缩合剂，在室温下搅拌16h，经分离纯化得纯净的化合物A7即为纯净的上述喹啉类化合物。
具体地，化合物F的结构为
Figure PCTCN2019118783-appb-000054
-R 4为烷基或芳基。进一步地，化合物 F可以为各种芳香酸或脂肪酸，化合物F选N-叔丁氧羰基脯氨酸、N-叔丁氧羰基丙氨酸、N-叔丁氧羰基缬氨酸、噻唑-2-羧酸、1H-咪唑-5-羧酸、恶唑-4-羧酸、吡咯-2-羧酸、吲哚-2-羧酸、吡啶-2-羧酸、3-氯苯并噻吩-2-羧酸、2-乙酰氧基乙酸、2-溴乙酸、2-氯乙酸及三氟乙酸中的一种。
具体地，化合物A6与化合物F的摩尔比为1:1.0～1.2，优选为1:1。
在本实施方式中，缩合剂是1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐EDCI，化合物A4与EDCI的摩尔比为1:1～1.3，优选为1:1.2，在其他实施方式中，缩合剂还可以是DCC(1,3-二环己基碳二亚胺)、HATU(2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、BOP(苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐)或DPPA(叠氮磷酸二苯酯)。
具体地，分离纯化的具体方法为：加入水稀释，二氯甲烷萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后通过硅胶柱层析纯化(洗脱液为二氯甲烷/甲醇，体积比20～30:1)，得到纯净的化合物A7即为纯净的上述的喹啉类化合物。
具体地，由化合物A6制备上述的喹啉类化合物的反应式为：
Figure PCTCN2019118783-appb-000055
当化合物F为N-叔丁氧羰基脯氨酸时，所得的化合物A7还需要进行脱叔丁氧羰基。
具体地，将化合物A7溶于二氯甲烷中，并向其中加入三氟乙酸，室温搅拌6小时，加入碳酸氢钠水溶液，分离纯化得纯净的不含叔丁氧羰基的上述喹啉类化合物。
具体地，化合物A7与二氯甲烷的比例为1mmol:5mL。
具体地，化合物A7与三氟乙酸(TFA)的比例为1mmol:0.8mL～1.2mL，优选为1mmol:1mL三氟乙酸作用是脱去含有叔丁氧羰基(Boc)的上述喹啉类化合物的叔丁氧羰基，在其他实施例中，三氟乙酸还可以用盐酸、氢溴酸、对甲苯磺酸或甲酸替代。
具体地，分离纯化的具体方法为：二氯甲烷萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化的到纯净的不含叔丁氧羰基的上述喹啉类化合物。其中，硅胶柱层析的洗脱液为二氯甲烷及甲醇的混合液，二氯甲烷及甲醇的体积比为5～10:1。
具体地，化合物A7脱叔丁氧羰基的反应式如下：
Figure PCTCN2019118783-appb-000056
上述的喹啉类化合物的制备方法简便易行，原料易得，制备条件温和，易实现工业生产。
一实施方式的喹唑啉类化合物的制备方法(方法B)，包括以下步骤：
S210、按照喹啉类化合物的制备方法A的步骤S110，制得化合物A2。
S220、按照喹啉类化合物的制备方法A的步骤S120，制得化合物A3。
S230、将化合物A3与水合三氯乙醛胺缩合环化，得化合物B1，化合物B1的结构式为
Figure PCTCN2019118783-appb-000057
在其中一个实施例中，依次加入水合三氯乙醛、水、加入硫酸钠、化合物A3、盐酸溶液(6mL水与1mL浓盐酸配置)、盐酸羟胺水溶液，在110℃搅拌反应2小时，升温至130℃搅拌反应1h。然后冷却至室温、过滤、干燥后逐渐加入至50℃的浓硫酸中，在65℃反应2小时。冷却至室温，并倒入相当于反应 物体积10倍的碎冰中，30min后过滤，用冷水洗涤、干燥得化合物B1。
具体地，化合物A3与水合三氯乙醛的摩尔比为1:1.0～1.2，优选为1:1.1。化合物A3与硫酸钠的摩尔比为1:8.0～9.0，优选为1:8.0。化合物A3与盐酸羟胺的比例为1mmol:3.0mmol/mL～3.6mmol/mL，优选为1mmol:3.3mmol/mL。
具体地，在本实施方式中，由化合物A3制备化合物B1的反应式如下：
Figure PCTCN2019118783-appb-000058
S230、将化合物B1开环，得到化合物B2，化合物B2的结构式为
Figure PCTCN2019118783-appb-000059
在其中一个实施例中，将化合物B1溶解于氢氧化钠水溶液，逐渐加入双氧水，于60℃搅拌反应3h。冷却至室温，加入HCl，调节反应液pH到2-4，过滤，用冷水洗涤，干燥得化合物B2。
具体地，由化合物B1开环制备化合物B2的反应式如下：
Figure PCTCN2019118783-appb-000060
S240、将化合物B2与尿素发生缩合反应，得化合物B3，化合物B3的结构式为
Figure PCTCN2019118783-appb-000061
在其中一个实施例中，将化合物B2和尿素(urea)在160℃～170℃条件下搅拌反应12小时～18小时。冷却至室温，加入水，过滤，用水洗涤，干燥得化合物B3。
具体地，化合物B2与尿素的摩尔比为1:6.0～7.0，优选为1:7.0。
具体地，由化合物B2制备化合物B3的反应式如下：
Figure PCTCN2019118783-appb-000062
S250、将化合物B3氯化，得到化合物B4，化合物B4的结构式为
Figure PCTCN2019118783-appb-000063
在其中一个实施例中，将化合物B3、五氯化磷和三氯氧磷在110℃搅拌反应6小时。冷却至室温，浓缩后加入饱和碳酸氢钠水溶液，经乙酸乙酯萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后通过硅胶柱层析纯化(洗脱液正己烷/乙酸乙酯，体积比10～20:1)，得到纯净的化合物B4。
具体地，化合物B3、五氯化磷及三氯氧磷的比例为10.0mmol：35～45.0mmol：8mL，优选为10.0mmol：40.0mmol：8mL。
具体地，由化合物B3制备化合物B4的反应式如下：
Figure PCTCN2019118783-appb-000064
S260、将化合物B4与化合物G发生取代反应，得化合物B5。
在其中一个实施例中，将化合物B4溶于四氢呋喃中，并加入三乙胺和化合物G，50℃～70℃搅拌反应12小时～16小时。冷却至室温，浓缩后加入饱和碳酸氢钠水溶液。然后用乙酸乙酯萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后通过硅胶柱层析纯化(洗脱液：正己烷/乙酸乙酯，体积比5～10:1)，得到纯净的化合B5。
具体地，化合物G为R 3-OH，-R 3选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N-烷基哌嗪基、哌啶基和四氢吡咯基中的一种，化合物B5的结构式为
Figure PCTCN2019118783-appb-000065
进一步地，化合物G选自甲醇、乙醇、丙醇、丁醇、烯丙醇、异丙醇、异丁醇、戊醇、炔丙醇、苯酚、3-氯苯酚、3-羟基吡啶及苄醇中的一种。
具体地，化合物B4与化合物G的摩尔比为1:1.5～2.0，优选为1:2.0。化合物B4与三乙胺的摩尔比为1:1.5～2.0，优选为1:2.0。
具体地，由化合物B4制备化合物B5的反应式如下：
Figure PCTCN2019118783-appb-000066
S270、将化合物B5与化合物H发生取代反应，得化合物B6。
在其中一个实施例中，将化合物B5、化合物H、正丁醇混合，加入浓盐酸，100℃～110℃搅拌反应12小时～16小时。冷却至室温，浓缩，加入水，经用乙酸乙酯萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后通过硅胶柱层析纯化(洗脱液正己烷/乙酸乙酯，体积比2～4:1)，得到纯净的化合物B6。
具体地，化合物H为Y-H，其中-Y为
Figure PCTCN2019118783-appb-000067
或-O-R 5，-R 1、-R 2、-R 5分别独立选自-H、-Cl、-Br、烷基、烷氧基、芳基、芳氧基、N,N-二烷基氨基、N-烷基-N-酰基氨基、吡啶基、咪唑基、吡唑基、呋喃基、吡咯基、吗啉基、N- 烷基哌嗪基、哌啶基和四氢吡咯基中的一种，化合物B6的结构式为
Figure PCTCN2019118783-appb-000068
具体地，化合物H选自氮-甲基哌嗪、吗啉、六氢吡啶、四氢吡咯，二乙基胺，二甲基胺，二丙基胺、甲醇及氮杂环丁烷中的一种。
具体地，化合物B5与化合物H的摩尔比为1:1.2～1.5，优选为1:1.5。
具体地，由化合物B5制备化合物B6的反应式如下：
Figure PCTCN2019118783-appb-000069
S280、将化合物B6的硝基还原成氨基，得化合物B7，化合物B7的结构式为
Figure PCTCN2019118783-appb-000070
在其中一个实施例中，将化合物B6溶于等比例混合的二氯甲烷和甲醇中，并向上述溶液中加入锌粉和氯化铵，在室温搅拌8小时～12小时。然后硅藻土过滤，用二氯甲烷洗涤，滤液用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后得化合物B7。
具体地，化合物B6、锌粉及氯化铵的摩尔比为1:6～8:8～10，优选为1:8:10。
具体地，由化合物B6制备化合物B7的反应式如下：
Figure PCTCN2019118783-appb-000071
S290、化合物B7与化合物F发生缩合反应，得上述的喹唑啉类化合物。
其中化合物F为羧酸，化合物F的结构为
Figure PCTCN2019118783-appb-000072
-R 4为烷基或芳基。
在其中一个实施例中，将化合物B7和化合物F溶于二氯甲烷中，并向其中加入缩合剂EDCI，反应液在室温搅拌反应12小时～16小时。分离纯化后得纯净的化合物B8，即为纯净的上述的喹唑啉类化合物。
具体地，化合物F为各种芳香酸或脂肪酸，进一步地，化合物F选自N-叔丁氧羰基脯氨酸、N-叔丁氧羰基丙氨酸、N-叔丁氧羰基缬氨酸、噻唑-2-羧酸、1H-咪唑-5-羧酸、恶唑-4-羧酸、吡咯-2-羧酸、吲哚-2-羧酸、吡啶-2-羧酸、3-氯苯并噻吩-2-羧酸、2-乙酰氧基乙酸、2-溴乙酸、2-氯乙酸及三氟乙酸中的一种。
具体地，化合物B7与化合物F的摩尔比为1:1.0～1.2，优选为1:1.0。化合物B7与缩合剂的摩尔比为1:1.1～1.3，优选为1:1.2。
具体地，分离纯化的具体方法为：向反应液中加入水，用二氯甲烷萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩后通过硅胶柱层析纯化(洗脱液：二氯甲烷/甲醇，体积比20～30:1)，得纯净的化合物即为上述的喹唑啉类化合物。
当化合物F为N-叔丁氧羰基脯氨酸时，所得的化合物B8还需要进行脱叔丁氧羰基。
具体地，将化合物B8溶于二氯甲烷中，并向其中加入三氟乙酸，室温搅拌6小时，加入碳酸氢钠水溶液，分离纯化得纯净的不含叔丁氧羰基的上述喹唑啉类化合物。
具体地，化合物B8与二氯甲烷的比例为1mmol:5mL。
具体地，化合物B8与三氟乙酸(TFA)的比例为1mmol:0.8mL～1.2mL，优选为1mmol:1.0mL，三氟乙酸作用是脱去含有叔丁氧羰基(Boc)的上述喹啉类化合物的叔丁氧羰基。在其他实施例中，三氟乙酸还可以用盐酸、氢溴酸、对 甲苯磺酸或甲酸替代。
具体地，分离纯化的具体方法为：二氯甲烷萃取，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化的到纯净的不含叔丁氧羰基的上述喹啉类化合物。其中，硅胶柱层析的洗脱液为二氯甲烷及甲醇的混合液，二氯甲烷及甲醇的体积比为10～20:1。
具体地，化合物B8脱叔丁氧羰基的反应式如下：
Figure PCTCN2019118783-appb-000073
上述的喹唑啉类化合物的制备方法简便易行，原料易得，制备条件温和，易实现工业生产。
本申请还提供了一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用：
Figure PCTCN2019118783-appb-000074
其中
X为N或C-R 9；
Y选自H；-OH；-NH 2；卤素；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；取代或未取代的直链或支链C1-C6烷氧基；取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基；取代或未取代的直链或支链C1-C6酯基；取代或未取代的直链或支链C1-C6酰胺基；取代或未取代的直链或支链C1-C6酮 基；取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基；取代或未取代的C1-C10芳基或杂芳基；
Z选自取代或未取代的芳基或杂芳基；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12各自独立的选自H；卤素；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；取代或未取代的直链或支链C1-C6烷氧基；取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基；取代或未取代的直链或支链C1-C6酯基；取代或未取代的直链或支链C1-C6酰胺基；取代或未取代的直链或支链C1-C6酮基；取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基；取代或未取代的C1-C10芳基或杂芳基；
优选的，所述肿瘤为肺癌、胃癌、食道癌、肝癌、乳腺癌、宫颈癌、鼻咽癌、结肠癌、贲门癌、肝管癌、卵巢癌、喉癌、口腔癌、淋巴癌、白血病、直肠癌、甲状腺癌、上颌窦癌、颅脑胶质瘤、口咽癌、胰腺癌中的一种或多种。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述X为N。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Y为取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Y为取代或未取代的C1-C10杂环基，其可以为取代或未取代的四氢吡咯基、取代或未取代的 四氢呋喃基、取代或未取代的吗啉基、取代或未取代的哌嗪基、取代或未取代的哌啶基。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述取代或未取代的哌嗪基为N上具有C1-C6支链或支链烷基取代基的哌嗪基、N上具有C1-C6支链或支链烯基取代基的哌嗪基、N上具有C2-C6支链或支链炔基取代基的哌嗪基、或N上具有C1-C6支链或支链羰基取代基的哌嗪基。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述N上具有C1-C6支链或支链烯基取代基的哌嗪基为N-甲基-哌嗪基或N-乙基-哌嗪基。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Z为取代或未取代的芳基或杂芳基，芳基或杂芳基表示包含选自N、O和S的1至4个、并且剩余环原子为碳的稳定的5-或6-元单环；或多环。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述芳基为苯基或萘基。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述杂芳基选自吡啶基、吡喃基、吡咯基、呋喃基、咪唑基、噁唑基、异噁唑基、吲哚基、嘧啶基、哒嗪基、吡嗪基、苯硫基、噻唑基、三唑基、四唑基、喹啉基、吡唑基、苯并[b]苯硫基、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、和5,6,7,8-四氢异喹啉。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Z为具有1-4个卤素取代的苯基或萘基。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Z为3-氯-苯基。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Z为取代或未取代的烯丙基、取代或未取代的丙烯基。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述肿瘤为肺癌、结肠癌、乳腺癌。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述肿瘤为非小细胞肺癌或乳腺管癌。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述肿瘤为人肿瘤。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，所述药物包含药学上可接受的载体。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，所述药物剂型为片剂、注射液、注射粉针剂、胶囊剂、丸剂、固体分散体、缓释剂、速释剂、控释剂、埋入剂、气雾剂、乳膏剂、凝胶剂、糖浆剂、贴剂、溶液剂、混悬剂中的一种 或多种。
本申请还提供一种药物组合物，其中包含如下式所示喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐，
Figure PCTCN2019118783-appb-000075
其中
X为N或C-R 9；
Y选自H；-OH；-NH 2；卤素；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；取代或未取代的直链或支链C1-C6烷氧基；取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基；取代或未取代的直链或支链C1-C6酯基；取代或未取代的直链或支链C1-C6酰胺基；取代或未取代的直链或支链C1-C6酮基；取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基；取代或未取代的C1-C10芳基或杂芳基；
Z选自取代或未取代的芳基或杂芳基；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12各自独立的选自H；卤素；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；取代或未取代的直链或 支链C1-C6烷氧基；取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基；取代或未取代的直链或支链C1-C6酯基；取代或未取代的直链或支链C1-C6酰胺基；取代或未取代的直链或支链C1-C6酮基；取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基；取代或未取代的C1-C10芳基或杂芳基；
和第二抗肿瘤活性剂或增效剂。
优选的本发明的喹啉或喹唑啉类化合物与第二抗肿瘤活性剂或增效剂的用量比为0.1-100:0.1-100；优选的为1-100:0.1-50；更优选的为1-100:1-10；更优选的为60-100:1-10；更优选的为60-100:1-5；最优选的为80:2.5。
优选的，所述X为N。
优选的，所述Y为取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基。
优选的，所述Y为取代或未取代的C1-C10杂环基，其可以为取代或未取代的四氢吡咯基、取代或未取代的四氢呋喃基、取代或未取代的吗啉基、取代或未取代的哌嗪基、取代或未取代的哌啶基。
优选的，所述取代或未取代的哌嗪基为N上具有C1-C6支链或支链烷基取代基的哌嗪基、N上具有C1-C6支链或支链烯基取代基的哌嗪基、N上具有C2-C6支链或支链炔基取代基的哌嗪基、或N上具有C1-C6支链或支链羰基取代基的哌嗪基。
优选的，所述N上具有C1-C6支链或支链烯基取代基的哌嗪基为N-甲基-哌嗪基或N-乙基-哌嗪基。
优选的，所述Z为取代或未取代的芳基或杂芳基，芳基或杂芳基表示包含选自N、O和S的1至4个、并且剩余环原子为碳的稳定的5-或6-元单环；或多环。
优选的，所述芳基为苯基或萘基。
优选的，所述杂芳基选自吡啶基、吡喃基、吡咯基、呋喃基、咪唑基、噁唑基、异噁唑基、吲哚基、嘧啶基、哒嗪基、吡嗪基、苯硫基、噻唑基、三唑基、四唑基、喹啉基、吡唑基、苯并[b]苯硫基、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、和5,6,7,8-四氢异喹啉。
优选的，所述Z为具有1-4个卤素取代的苯基或萘基。
优选的，所述Z为3-氯-苯基。
优选的，所述Z为取代或未取代的烯丙基、取代或未取代的丙烯基。
优选的，如上所述的一种药物组合物，其中第二抗肿瘤活性剂或增效剂为紫杉醇类抗肿瘤剂。
优选的，如上所述的一种药物组合物，其中紫杉醇类抗肿瘤剂为紫杉醇或多西他赛。
优选的，如上所述的一种药物组合物，其特征在于第二抗肿瘤活性剂或增效剂为多西他赛。
优选的，如上所述的一种药物组合物在制备抗肿瘤药物中的应用。
优选的，如上所述的应用，所述肿瘤选自肺癌、胃癌、食道癌、肝癌、乳腺癌、宫颈癌、鼻咽癌、结肠癌、贲门癌、肝管癌、卵巢癌、喉癌、口腔癌、淋巴癌、白血病、直肠癌、甲状腺癌、上颌窦癌、颅脑胶质瘤、口咽癌、胰腺癌中的一种或多种。
优选的，如上所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述化合物为如下化合物的一个或多个；
Figure PCTCN2019118783-appb-000076
优选的，如上所述的一种药物组合物，其特征在于所述化合物为如下化合物的一个或多个；
Figure PCTCN2019118783-appb-000077
上述所有化合物的立体异构体包括对映异构体、非对映异构体。
上述所有化合物在化合物以不同互变异构形式存在的情况下，本发明不限于任一种具体互变异构体，而是包括所有的互变异构体形式。
上述所有化合物包括具有在化合物中出现的原子的所有可能的同位素的化合物。同位素包括具有相同原子序数但是不同质量数的那些原子。通过一般实 例，在没有限制的情况下，氢的同位素包括氚和氘，并且碳的同位素包括 11C、 13C和 14C。
卤素可以为F、Cl、Br、I。
本发明还提供了一种药物组合物，本文中公开的化合物可以以纯化学品给予，但优选作为药物组合物给予。因此，本公开提供了包括化合物或药用盐连同至少一种药用载体的药物组合物。药物组合物可以包含化合物或盐作为唯一的活性剂，但是优选包含至少一种其他活性剂。在某些实施方式中，药物组合物是在单位剂型中包含约0.1mg至约1000mg、约1mg至约500mg、或约10mg至约200mg的式I的化合物以及可选的约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg、或约200mg至约600mg的其他活性剂的口服剂型。
本文中公开的化合物可以以包含常规药用载体的剂量单位制剂口服、局部、注射、非肠道、通过吸入或喷雾、舌下、透皮、通过口腔给予、直肠、作为眼用溶液、或通过其它方式来给予。可以将药物组合物配制成任何药用形式，如：注射液、注射粉针剂、气雾剂、乳膏剂、凝胶剂、丸剂、胶囊剂、片剂、糖浆剂、透皮贴剂、溶液剂、混悬剂、乳剂、缓释剂、控释剂、速释剂、纳米制剂、或眼用溶液。诸如片剂和胶囊剂的一些剂型可以再分成包含诸如达到期望目的的有效量的适当量活性组分的适当剂量单位剂型。
载体包括赋形剂和稀释剂，并且必须具有足够高的纯度和十分低的毒性以使它们适于被给予待治疗的患者。载体可以是惰性的或其可以本身具有药用益处。。
载体的种类包括但不限于：粘合剂、缓冲剂、着色剂、稀释剂、崩解剂、乳化剂、调味剂、助流剂、滑润剂、防腐剂、稳定剂、表面活性剂、制片剂、以及润湿剂。一些载体可以列在多于一种的类别中，如：植物油可以在一些制剂中用作滑润剂并在其他制剂中用作稀释剂。示例性药用载体包括糖、淀粉、纤维素、西黄蓍胶粉(powdered tragacanth)、麦芽、明胶、滑石和植物油。
本发明的化合物或盐可以是被给予的唯一活性剂或可以连同其他活性剂被给予。例如，本申请的化合物可以连同另一抗肿瘤活性剂或增效剂一起给予。
本发明的“立体异构体”是具有相同化学组成但原子或基团在空间中的排布不同的化合物。
“烷基”包括支链和直链饱和脂肪族烃基两者，并具有指定数量的碳原子数量，一般1至约12个碳原子。如在本文中使用的术语C1-C6烷基表示具有1至约6个碳原子的烷基。当本文中结合另一基团使用C0-Cn烷基时，以(苯基)C0-C4烷基为例，指定的基团，在这种情况下，苯基是通过单个共价键(C0)直接键合或通过具有指定的碳原子数(在这种情况下，1至约4个碳原子)的烷基链连接。烷基的实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、3-甲基丁基、叔丁基、正戊基、和仲戊基。
“烯基”指包括一个或多个不饱和的碳-碳键的直链和支链烃链，碳-碳键可以出现在沿着链的任一稳定点。本文中所述的烯基通常具有2至约12个碳原子。优选烯基是低级烯基，那些烯基具有2至约8个碳原子，如：C2-C8、C2-C6、和C2-C4烯基。烯基的实例包括乙烯基、丙烯基、和丁烯基。
“烷氧基”是指具有通过氧桥连接的指定数量的碳原子的如上所定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、3-己氧基、和3-甲基戊氧基。
术语“杂环”表示5-至8-元饱和环、部分不饱和环、或包含选自N、O和S的1至约4个杂原子且剩余的环原子是碳的芳族环，或是7至11元饱和环、部分不饱和环、或芳族杂环系统和10至15-元三环系统，该系统包含选自N、O和S的多环系统中的至少1个杂原子并且在多环系统中的各环中包含独立地选自N、O和S的至多约4个杂原子。除非另外指明，否则杂环可以连接至它在任何杂原子和碳原子处取代并且产生稳定结构的基团。当指明时，本文中所述的杂环可以在碳或氮原子上被取代，只要得到的化合物是稳定的。可以可选地季铵化杂环中的氮原子。优选杂环基中杂原子的总数不大于4而且优选杂环基中S和O原子的总数不大于2，更优选不大于1。杂环基的实例包括：吡啶基、吲哚基、嘧啶基、哒嗪基(pyridizinyl)、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、三唑基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基(benz[b]thiophenyl)、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、二氢异吲哚基、5,6,7,8-四氢异喹啉、吡啶基、嘧啶基、呋喃基、噻吩基、 吡咯基、吡唑基、吡咯烷基、吗啉基、哌嗪基、哌啶基、和吡咯烷基。
“芳基或杂芳基”表示包含选自N、O和S的1至4个、或优选1至3个杂原子并且剩余环原子为碳的稳定的5-或6-元单环或多环。当杂芳基中S和O原子的总数超过1时，这些杂原子不彼此邻近。优选杂芳基中S和O原子的总数不大于2。尤其优选杂芳基中S和O原子的总数不大于1。可以可选地季铵化杂环中的氮原子。当指明时，这些杂芳基还可以用碳或非碳原子或基团取代。这种取代可以包括与可选地包含独立地选自N、O和S的1或2个杂原子的5至7-元饱和的环基的稠合，从而形成例如[1,3]二噁唑并[4,5-c]吡啶基。杂芳基的实例包括但不限于：吡啶基、吲哚基、嘧啶基、哒嗪基、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、三唑基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、和5,6,7,8-四氢异喹啉。
通过测试化合物的抗肿瘤活性，发现本发明的化合物对于肿瘤细胞具有较好的抑制效果，效果优于阳性对照AZ-26，尤其是在非小细胞肺癌、结肠癌、乳腺癌中均取得了优异的抑制效果。
在乳腺癌实体瘤测试过程中，本发明化合物对于乳腺癌实体瘤具有优异的抑制效果，效果优于阳性对照AZ-26。且在与紫杉醇类抗肿瘤药物，尤其是多西他赛联合用药过程中产生了协同作用，显示了较强的抗肿瘤效果。
由此可见，本发明的化合物具有优异的抗肿瘤活性，且可以与现有技术已知的抗肿瘤药物联合使用，实现增效和协同作用。
附图说明
图1：代表化合物对A549细胞的抑制作用；
图2：代表化合物对HCT116细胞的抑制作用；
图3：代表化合物对T47D细胞的抑制作用；
图4：代表化合物对A549细胞中F26BP水平的抑制作用；
图5：代表化合物对HCT116细胞中F26BP水平的影响；
图6：代表化合物对T47D细胞中F26BP水平的抑制作用；
图7：化合物对NCG小鼠实体瘤的抑制试验瘤重统计。
下面为具体实施例。
实施例1～56
实施例1～28采用喹啉类化合物的制备方法(方法A)制备得上述喹啉类化合物。制备的具体参数见表1，具体步骤如下：
步骤一、将20.0mmol 4-氨基苯酚和24.0mmol Boc酸酐溶于150mL甲醇，并在搅拌下加入44.0mmol三乙胺，室温搅拌反应18小时。反应完毕后加入20mL的2mol/L的盐酸溶液，并用3×50mL乙酸乙酯萃取，合并有机相后用2×50mL饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩得粗产物通过硅胶柱层析纯化(洗脱液：正己烷/乙酸乙酯，体积比4:1)，得到纯净的化合物A2。
步骤二、将12.0mmol化合物A2和10.0mmol 4-氟硝基苯溶于50mL乙腈中，并向上述溶液中加入30.0mmol碳酸钾，反应混合物在90℃搅拌反应18小时。然后冷却至室温，加入40mL水稀释反应液，用3×40mL乙酸乙酯萃取，合并有机相后用2×50mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗产物。将粗产物溶于5mL二氯甲烷，加入1mL三氟乙酸，室温搅拌反应6小时。反应完毕后加入10mL饱和碳酸氢钠水溶液，用3×20mL二氯甲烷萃取，合并有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩得粗产物通过硅胶柱层析纯化(洗脱液：正己烷/乙酸乙酯，体积比3:1)，得到纯净的化合物A3。
步骤三、将1.0mmol化合物A3和化合物D(同表1中的D)混合于三口烧瓶中，化合物A3和化合物D的摩尔比为C1，加入5g多聚磷酸(PPA)，130℃搅拌反应18小时。冷却至室温后，加入20mL水，过滤，滤液用3×30mL乙酸乙酯萃取，合并有机相后，用30mL饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩得粗产物通过硅胶柱层析纯化(洗脱液：二氯甲烷/甲醇，体积比20:1)，得到 纯净的化合物A4。
步骤四、将1.0mmol化合物A4和化合物E(同表1中的E)溶于8mL乙腈，化合物A4和和化合物E法人摩尔比为C2，并加入4.0mmol无水碳酸钾，在90℃搅拌反应12小时。冷却至室温，加入15mL水，过滤，滤液用3×20mL乙酸乙酯萃取，合并有机相后，用20mL饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩得粗产物通过硅胶柱层析纯化(洗脱液：正己烷/乙酸乙酯，体积比5:1)，得到纯净的化合物A5。
步骤五、将1.0mmol化合物A5溶于10mL等比例混合的二氯甲烷和甲醇中，并向上述溶液中加入锌粉和氯化铵，化合物A5、锌粉和氯化铵的摩尔比为C3。反应液在室温搅拌12小时。然后硅藻土过滤，用二氯甲烷洗涤，滤液用2×20mL饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得到纯净的化合物A6。
步骤六、将1.0mmol化合物A6和化合物F(同表1中的F)溶于8mL二氯甲烷中，化合物A6和化合物F的摩尔比为C4，并向其中加入1.2mmol EDCI，室温搅拌反应16小时。然后加入10mL水，用3×15mL二氯甲烷萃取，合并有机相后用2×20mL饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化(洗脱液：二氯甲烷/甲醇，体积比20:1)得到纯净的化合物A7，即为上述喹啉类化合物。
当化合物F为N-叔丁氧羰基脯氨酸时，需要进行脱Boc保护基，具体为：将1.0mmol化合物A7溶于5mL二氯甲烷中，并向其中加入1mL三氟乙酸，反应液在室温搅拌反应6小时。然后加入碳酸氢钠水溶液(10mL)，用3×15mL二氯甲烷萃取，合并有机相后用2×20mL饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化(洗脱液：二氯甲烷/甲醇＝10:1)得到脱Boc保护基的上述喹啉类化合物。 表1
Figure PCTCN2019118783-appb-000078
Figure PCTCN2019118783-appb-000079
实施例29～56采用喹唑啉类化合物的制备方法(方法B)制备得上述喹唑啉类化合物，制备参数见表2，具体步骤如下：
步骤一、按照实施例1～31采用的制备方法A中的步骤一及步骤二制备得化合物A3，然后在烧瓶中加入水合三氯乙醛(11.0mmol)，40mL水；然后依次加入硫酸钠(80.0mmol)，化合物A3(10.0mmol)，盐酸溶液(6mL水与1mL浓盐酸配置)，最后加入盐酸羟胺(33.0mmol)溶于10mL水中制成的溶液。反应混合液在110℃搅拌反应2h，升温至130℃搅拌反应1h，冷却至室温，过滤，干燥后逐渐(约在20min加完)加入到50℃浓硫酸(20mL)中，于65℃反应2小时。冷却至室温，并倒入相当于反应物体积10倍的碎冰中，30min后过滤，用冷水洗涤，干燥得化合物B1。
步骤二、将化合物B1(2.0mmol)溶解于氢氧化钠水溶液(2M，15mL)，逐渐加入双氧水(2mL)，于60℃搅拌反应3h。冷却至室温，加入HCl(6M)，调节反应液pH到2-4，过滤，用冷水洗涤，干燥得化合物B2。
步骤三、将化合物物B2(5.0mmol)和尿素(35.0mmol)加入反应瓶，在160℃搅拌反应18小时。冷却至室温，加入50mL水，过滤，用水洗涤，干燥得化合物B3。
步骤四、将化合物B3(10.0mmol)、五氯化磷(40.0mmol)和三氯氧磷(8mL)加入到反应烧瓶，在110℃搅拌反应6小时。冷却至室温，浓缩溶剂，加入20mL饱和碳酸氢钠水溶液，用乙酸乙酯(3×20mL)萃取，合并有机相后用饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化(洗脱液：正己烷/乙酸乙酯＝10:1)得到中间产物B4。
步骤五、将化合物B4(2.0mmol)溶于四氢呋喃(8mL)，并加入三乙胺(4.0mmol)和化合物G(同表2中G)，化合物B4与化合物G的摩尔比为C5，在60℃搅拌反应16小时。冷却至室温，浓缩溶剂，加入10mL饱和碳酸氢钠水溶液，用乙酸乙酯(3×20mL)萃取，合并有机相后用饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化(洗脱液：正己烷/乙酸乙酯，体积比5:1)得到化合物B5。
步骤六、将化合物B5(1.0mmol)、化合物H(同表2中H)和正丁醇(4mL)混合于反应烧瓶，化合物B5于化合物H的摩尔比为C6，加入浓盐酸(1滴)，在110℃搅拌反应16小时。冷却至室温，浓缩溶剂，加入10mL水，用乙酸乙酯(3×20mL)萃取，合并有机相后用饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化(洗脱液：正己烷/乙酸乙酯，体积比2:1)得到化合物B6。
步骤七、将化合物B6(1.0mmol)溶于等比例混合的二氯甲烷和甲醇(10mL)中，并向上述溶液中加入锌粉(8.0mmol)和氯化铵(10.0mmol)，反应液在室温搅拌12小时。然后硅藻土过滤，用二氯甲烷洗涤，滤液用饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物即为中间产物B7。
步骤八、将化合物B7(1.0mmol)和化合物F(同表2中的F)溶于二氯甲烷(8mL)，化合物B7(1.0mmol)和化合物F的摩尔比为C7，并向其中加入缩合剂1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐EDCI(1.2mmol)，反应液在室温搅拌反应16小时。然后向反应液中加入水(10mL)，用二氯甲烷(3×15mL)萃取，合并有机相后用饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化(洗脱液：二氯甲烷/甲醇，体积比20:1)得到化合物B8，即为纯净的上述喹唑啉类化合物。
当化合物为N-叔丁氧羰基脯氨酸时，将化合物B8(1.0mmol)溶于二氯甲烷(5mL)，并向其中加入三氟乙酸(1mL)，反应液在室温搅拌反应6小时。然后加入碳酸氢钠水溶液(10mL)，用二氯甲烷(3×15mL)萃取，合并有机相后用饱和食盐水(2×20mL)洗涤，无水硫酸钠干燥，真空浓缩，得到的残留物通过硅胶柱层析纯化(洗脱液：二氯甲烷/甲醇，体积比10:1)得到纯净的不含叔丁羰基的上述喹唑啉类化合物。
表2
实施例 G H F C5 C6 C7
29 丁醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.5 1:1.2 1:1
30 丁醇 吗啉 N-叔丁氧羰基脯氨酸 1:1.5 1:1.2 1:1.1
31 丁醇 氮-甲基哌嗪 乙酸 1:1.5 1:1.3 1:1.2
32 丁醇 吗啉 乙酸 1:1.6 1:1.2 1:1
33 甲醇 甲醇 N-叔丁氧羰基脯氨酸 1:1.6 1:1.4 1:1.1
34 甲醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.6 1:15 1:1.2
35 乙醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.6 1:1.3 1:1
36 丙醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.7 1:1.3 1:1.1
37 烯丙醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.7 1:1.3 1:1.2
38 异丙醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.7 1:1.4 1:1
39 异丁醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.7 1:1.5 1:1.1
40 戊醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.8 1:1.2 1:1.2
41 炔丙醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.8 1:1.3 1:1.2
42 甲醇 吗啉 N-叔丁氧羰基脯氨酸 1:1.8 1:1.5 1:1
43 烯丙醇 吗啉 N-叔丁氧羰基脯氨酸 1:1.8 1:1.3 1:1.1
44 丁醇 吗啉 N-叔丁氧羰基脯氨酸 1:1.8 1:1.4 1:1.2
45 3-氯苯酚 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.9 1:1.2 1:1
46 3-羟基吡啶 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.9 1:1.3 1:1.1
47 苄醇 氮-甲基哌嗪 N-叔丁氧羰基脯氨酸 1:1.9 1:1.4 1:1.2
48 丁醇 二乙基胺 N-叔丁氧羰基脯氨酸 1:1.9 1:1.5 1:1
49 丁醇 氮杂环丁烷 N-叔丁氧羰基脯氨酸 1:1.9 1:1.5 1:1.1
50 丁醇 四氢吡咯 N-叔丁氧羰基脯氨酸 1:1.9 1:1.4 1:1.2
51 丁醇 六氢吡啶 N-叔丁氧羰基脯氨酸 1:2.0 1:1.2 1:1
52 烯丙醇 氮-甲基哌嗪 1H-咪唑-5-羧酸 1:2.0 1:1.3 1:1.1
53 烯丙醇 氮-甲基哌嗪 吡咯-2-羧酸 1:2.0 1:1.4 1:1.2
54 烯丙醇 氮-甲基哌嗪 2-溴乙酸 1:2.0 1:1.5 1:1
55 烯丙醇 氮-甲基哌嗪 2-氯乙酸 1:2.0 1:1.5 1:1.1
56 烯丙醇 氮-甲基哌嗪 三氟乙酸 1:2.0 1:1.5 1:1.2
制备所得的上述喹啉或喹唑啉类化合物采用核磁共振氢谱测定结构，或核磁共振氢谱和高分辨质谱测定结构，结果如表3所示。
表3
Figure PCTCN2019118783-appb-000080
Figure PCTCN2019118783-appb-000081
Figure PCTCN2019118783-appb-000082
Figure PCTCN2019118783-appb-000083
Figure PCTCN2019118783-appb-000084
Figure PCTCN2019118783-appb-000085
Figure PCTCN2019118783-appb-000086
Figure PCTCN2019118783-appb-000087
Figure PCTCN2019118783-appb-000088
Figure PCTCN2019118783-appb-000089
Figure PCTCN2019118783-appb-000090
Figure PCTCN2019118783-appb-000091
Figure PCTCN2019118783-appb-000092
Figure PCTCN2019118783-appb-000093
实施例57 PFKFB3酶活性测试
将实施例1～56的喹啉或喹唑啉类化合物进行PFKFB3酶活性测试，该测试主要包含两个反应步骤，即
步骤一：PFKFB3催化F6P和ATP生成F-2,6-BP；步骤二：产生的F-2,6-BP激活PFK1，PFK1催化消耗NADH，用酶标仪检测NADH含量变化，根据NADH 的含量定量PFKFB3酶的活性。
步骤一的反应体系由Buffer A和Buffer B+或Buffer B-组成。其中，Buffer A：主要含有酶及目标产物；Buffer B+：含底物6-磷酸果糖(F6P)；Buffer B-：不含底物F6P，用于检测反应背景。
配制一定量的Buffer A，Buffer A包含DTT(终浓度：1mM)，PFKFB3(根据酶活加入适量体积)和Mops Buffer，混匀后分装到标记好的冰置的Ep管中，200μL/管。向Ep管中分别加入4μL稀释好的梯度浓度的目标产物，目标产物的终浓度分别为：30μM、10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM，阴性对照组加入等体积的DMSO。混匀后离心，室温孵育30分钟，假设目标产物与酶结合需要一定时间。
配制Buffer B+和Buffer B-，其中，Buffer B+包含MgCl 2(工作浓度：2mM)、ATP(工作浓度：50μM)、F6P(工作浓度：50μM)和MOPS buffer；Buffer B-包含MgCl 2(工作浓度：2mM)、ATP(工作浓度：50μM)和MOPS buffer。将配制好的Buffer B+或Buffer B-混匀后分装到上述Buffer A对应Ep管中，每管加缓冲液B 200μL，混匀离心后37℃孵育一小时，使PFKFB3-催化F6P和ATP生成F-2,6-BP。一小时后，向Ep管中加入KOH 40μL/管(KOH的储存浓度为1M)终止反应，混匀离心后冰上放置。
步骤二的反应体系包含NADH(终浓度：0.2mM)、DTT(终浓度：5mM)、F6P(终浓度：1mM)、MgCl 2(终浓度：2mM)、Aldolase(终浓度：0.7U/mL)、GDH(终浓度：0.45U/mL)、TIM(终浓度：0.6U/mL)、PFK1终浓度：0.033μg/μL)和Tris-HCl缓冲液。
配制上述步骤二的反应液，混匀后分装到标记好的Ep管中，450μL/管。向步骤二的反应液中加入终止后的步骤一的反应液，每管加6μL，混匀离心。将上述反应液转移到96孔板中，150μL/孔，每个样品加2个复孔。然后用排枪向96孔板中加入储存浓度为25mM的PPi-Na，3μL/孔。加完后，用酶标仪检测NADH消耗速率，测得Mean V数值，用GraphPad Prism 5软件计算目标产物的IC50。
部分实施例的目标产物的IC50如表4所示。
表4
实施例 IC50(μM) 实施例 IC50(μM)
2 1.67 35 1.09
3 0.37 36 0.48
4 1.59 37 0.35
5 0.32 38 0.69
6 0.68 39 0.48
7 0.51 40 0.32
8 0.49 41 0.88
9 0.49 42 0.72
10 0.91 43 0.50
11 0.68 44 1.11
12 0.68 45 0.33
13 1.22 46 0.72
14 0.48 47 0.47
29 1.20 48 1.94
30 0.94 49 0.77
33 3.89 50 0.99
34 1.42 51 1.58
由表4可以看出，按照制备方法A和制备方法B制备的喹啉或喹唑啉类化合物对PFKFB3酶的激酶活性具有良好的抑制作用。PFKFB3酶的激酶活性被抑制之后，Fru-2,6-BP的合成受阻，从而抑制PFK-1的活性，进而抑制肿瘤细胞糖酵解代谢，使得肿瘤细胞的增殖及生长所需的能量供受限。
实施例58 代表化合物对肿瘤细胞系的抗增殖活性
选取在世界范围内发病率和死亡率极高的三种肿瘤作为代表，以AZ-26为阳性对照，研究自制化合物的抗肿瘤活性。选取的3种代表细胞系分别为：A549(人非小细胞肺癌细胞)、HCT116(人结肠癌细胞)和T-47D(人乳腺管癌细胞)。 从各类化学结构不同的活性抑制剂中选出以下3种代表性的化合物进行测试：YZ-429、YZ-443、YZ-421。以上代表化合物在体外实验中，对PFKFB3的酶活性有显著的抑制作用，在细胞学研究中，采用MTT法进一步验证其对以上3种肿瘤细胞的抗增殖作用。
MTT实验方法的要点如下：采用对数生长期的肿瘤细胞，接种于96孔细胞培养板中，使每孔加入的细胞数为2000个，每个实验组设置5个复孔。培养48h后，每孔加入含有不同浓度药物的DMSO溶液10uL。4h后用加入DMSO，在摇床上震荡充分溶解结晶后，用酶标仪在490nm处测定吸光度。
表5 化合物结构式
Figure PCTCN2019118783-appb-000094
图1-图3为3种化合物对3种肿瘤细胞增殖的半数抑制浓度。AZ-26作为阳性对照药物，明显抑制了3种肿瘤细胞的增殖速度。检测结果显示，3种自制的代表化合物也对肿瘤细胞的增殖均具备显著的抑制作用。对于A549和T47D细胞，化合物YZ429和YZ443都表现出了很强的抑制活性。对于HCT116细胞，3种化合物均表现出了优于或接近AZ-26的细胞增殖抑制活性，其中化合物YZ429、YZ443的抑制作用更强。对于3种肿瘤细胞，化合物YZ443都比阳性对照药物的抑制作用更强。综上所述，3种代表化合物均显示了良好的抗肿瘤活性。
实施例59 代表化合物降低了肿瘤细胞中PFKFB3产物F26BP的水平
细胞F26BP含量测定--反应原理：提取肿瘤细胞内含有的F26BP，在体外激活PFK酶，PFK酶将底物F6P转化为产物F16BP，消耗NADH。
细胞F26BP含量测定--技术方法：
取对数生长期的肿瘤细胞，接种于六孔培养板中，保证每孔的细胞数一致。当细胞密度达到80％左右时，采用换液的方式加入不同浓度的自制化合物。在药物处理4h后收集细胞，提取细胞F26BP。按以下方法收集细胞和制备样品，将1M NaOH用ddH2O各稀释成0.05M和0.1M，置于冰上预冷。以六孔板为例，每孔加入0.05M NaOH溶液150ul，用细胞刮收集细胞，再加入0.1M NaOH溶液150ul终止反应。将样品置于80℃热击5min，于4℃用14000rpm离心20min，收集上清进行测定。
然后配制如下反应体系：在50mM Tris-HCl(PH 7.5)缓冲液中，加入以下终浓度的试剂，0.2mM NADH，5mM DTT，1mM F6P，2mM MgCl2，0.7U/ml Aldolase，0.45U/ml GDH，0.6U/ml TIM，最后加入提取自发芽荷兰土豆的催化酶PPi-PFK 0.067ug/ul。将以上反应液混匀后加入微孔测量板，每孔加入150ul，再加入上一步骤获得的细胞提取液6ul并混匀，最后以0.5mM PPi-Na启动反应。用BioTek公司的Synergy H1Hybrid Reader酶标仪进行检测，反应温度为37℃，检测波长为340nM，测定反应速率Mean V。
3种代表自制化合物分别对三种肿瘤细胞F26BP水平的影响如图4-图6所 示。在A549细胞中，3种化合物对细胞F26BP水平均有抑制作用，其中YZ4433的抑制作用更强，这与细胞增殖抑制实验的结果吻合。在HCT116细胞中3化合物均显示抑制作用，其中YZ421、YZ4433的抑制作用更显著，这也和细胞增殖抑制实验的结果一致。而对于T47D细胞3化合物都有较好的抑制效果。
实施例60 抑制NCG小鼠MDA-MB-231乳腺癌实体瘤
化合物：YZ-443 2HCl化合物，呈淡黄白色结晶状物，易溶于水。纯度不低于96％，含10～20％HCI。
阳性对照药物：泰索帝
Figure PCTCN2019118783-appb-000095
多西他赛注射液(以下简称多西他赛)，0.5ml：20mg，赛诺菲(杭州)制药有限公司进口分装，产品批号7F159B。
试剂配制
(1)试验用YZ-443·2HCl化合物样品贮备液配制：加入灭菌注射用水，配制成5mg/ml浓度的圴匀溶液。该溶液呈淡黄色，放冰箱4℃保存，作贮备液。临用时取适量贮备液放至室温后使用。
(2)试验用YZ-443·2HCl化合物样品稀释液配制：根据试验需要，试验时分别取贮备液，用灭菌注射用水配制成4mg/ml、2.5mg/ml、2mg/ml、1.5mg/ml、1.25mg/ml、1mg/ml、0.625mg/ml、0.5mg/ml、0.25mg/ml浓度的稀释液，上述溶液临用前新鲜配制。
(3)试验用多西他赛贮备液配制：多西他赛(20mg，溶于0.5ml聚山梨酯80)，加入自带溶剂(主要成分为无水乙醇)配制成13mg/ml浓度的均匀溶液，放冰箱4℃保存，作贮备液。临用时取适量贮备液放至室温后使用。
(4)试验用多西他赛稀释液配制：根据试验需要，试验时分别取贮备液，用0.9％氯化钠注射液配制成2.5mg/ml、0.625mg/ml浓度的稀释液，上述溶液临用前新鲜配制。
5、细胞系：人乳腺癌MDA-MB-231细胞系来源于American Type Culture Collection(ATCC)。
6、实验动物
(1)SPF级NCG小鼠(NOD-Prkdcem26Cd52Il2rgem26Cd22/Nju小鼠)， 雌性，4-8周龄，购买自南京大学-南京生物医药研究院，实验动物生产许可证编号：SCXK(苏)2015-0001。
(2)SPF级NIH小鼠，雌性，17-20g，购买自北京维通利华实验动物技术有限公司，实验动物生产许可证编号：SCXK(京)2016-0006。
开展了YZ-443·2HCl对NCG雌性小鼠MDA-MB-231乳腺癌实体瘤作用的定性试验。实验分组如下：灌胃给药，设YZ-443(高、中、低剂量)组、多西他赛(高、低剂量)组、联合用药组(YZ-443与多西他赛联用)和对照组，在化合物给药组有抑制肿瘤趋势时结束试验。YZ-443用药剂量分为20mg/kg·BW、40mg/kg·BW和80mg/kg·BW。
表6 YZ-443·2HCl经灌胃给药抑制NCG雌性小鼠乳腺癌实体瘤试验瘤重分析
Figure PCTCN2019118783-appb-000096
注：与对照组瘤重比较：*p＜0.05，**p＜0.01
上表和图7结合可以看出：
YZ-443化合物高剂量组(80mg/kg·BW)、YZ-443化合物中剂量组(40mg/kg·BW)、YZ-443化合物低剂量组(20mg/kg·BW)存在抑瘤趋势。多西他赛高剂量组(10mg/kg·BW)与对照组相比，瘤重明显减小，其差异极显著 (p<0.01)；多西他赛低剂量组(2.5mg/kg·BW)存在抑瘤趋势，但与对照组瘤重相比，其差异没有统计学意义；联合用药组(YZ-443化合物80mg/kg·BW+多西他赛2.5mg/kg·BW)与对照组相比，瘤重明显减小，其差异显著(p<0.05)。
在灌胃给药时，YZ-443化合物按80mg/kg·BW、40mg/kg·BW、20mg/kg·BW剂量单独给药时，与阴性对照组相比，有抑瘤趋势；YZ-443化合物按80mg/kg·BW剂量与多西他赛2.5mg/kg·BW剂量联合应用时，有抑瘤趋势，且具有统计学意义，表明YZ-443化合物对多西他赛存在增效作用。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (24)

  1. 一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用：
    Figure PCTCN2019118783-appb-100001
    其中
    X为N或C-R 9；
    Y选自H；-OH；-NH 2；卤素；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；取代或未取代的直链或支链C1-C6烷氧基；取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基；取代或未取代的直链或支链C1-C6酯基；取代或未取代的直链或支链C1-C6酰胺基；取代或未取代的直链或支链C1-C6酮基；取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基；取代或未取代的C1-C10芳基或杂芳基；
    Z选自取代或未取代的芳基或杂芳基；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12各自独立的选自H；卤素；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；取代或未取代的直链或支链C1-C6烷氧基；取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺 基；取代或未取代的直链或支链C1-C6酯基；取代或未取代的直链或支链C1-C6酰胺基；取代或未取代的直链或支链C1-C6酮基；取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基；取代或未取代的C1-C10芳基或杂芳基；
    所述肿瘤为肺癌、胃癌、食道癌、肝癌、乳腺癌、宫颈癌、鼻咽癌、结肠癌、贲门癌、肝管癌、卵巢癌、喉癌、口腔癌、淋巴癌、白血病、直肠癌、甲状腺癌、上颌窦癌、颅脑胶质瘤、口咽癌、胰腺癌中的一种或多种。
  2. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述X为N。
  3. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Y为取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基。
  4. 如权利要求3所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Y为取代或未取代的C1-C10杂环基，其可以为取代或未取代的四氢吡咯基、取代或未取代的四氢呋喃基、取代或未取代的吗啉基、取代或未取代的哌嗪基、取代或未取代的哌啶基。
  5. 如权利要求4所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述取代或未取代的哌嗪基为N上具有C1-C6支链或支链烷基取代基的哌嗪基、N上具有C1-C6支链或支链烯基取代基的哌嗪基、N上具有C2-C6支链或支链炔基取代基的哌嗪基、或N上具有C1-C6支链或支链羰基取代基的哌嗪基。
  6. 如权利要求5所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述N上具有C1-C6 支链或支链烯基取代基的哌嗪基为N-甲基-哌嗪基或N-乙基-哌嗪基。
  7. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Z为取代或未取代的芳基或杂芳基，芳基或杂芳基表示包含选自N、O和S的1至4个、并且剩余环原子为碳的稳定的5-或6-元单环；或多环。
  8. 如权利要求7所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述芳基为苯基或萘基。
  9. 如权利要求7所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述杂芳基选自吡啶基、吡喃基、吡咯基、呋喃基、咪唑基、噁唑基、异噁唑基、吲哚基、嘧啶基、哒嗪基、吡嗪基、苯硫基、噻唑基、三唑基、四唑基、喹啉基、吡唑基、苯并[b]苯硫基、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、和5,6,7,8-四氢异喹啉。
  10. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Z为具有1-4个卤素取代的苯基或萘基。
  11. 如权利要求10所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述Z为3-氯-苯基。
  12. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述肿瘤为肺癌、结肠癌、乳腺癌。
  13. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述肿瘤为非小细胞肺癌或乳腺管癌。
  14. 如权利要求1-13任一项所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述肿瘤为人肿瘤。
  15. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，所述药物包含药学上可接受的载体。
  16. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，所述药物剂型为片剂、注射液、注射粉针剂、胶囊剂、丸剂、固体分散体、缓释剂、速释剂、控释剂、埋入剂、气雾剂、乳膏剂、凝胶剂、糖浆剂、贴剂、溶液剂、混悬剂中的一种或多种。
  17. 一种药物组合物，其中包含如下式所示喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐，
    Figure PCTCN2019118783-appb-100002
    其中
    X为N或C-R 9；
    Y选自H；-OH；-NH 2；卤素；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；取代或未取代的直链或支链C1-C6烷氧基；取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基；取代或未取代的直链或支链C1-C6酯基；取代或未取代的直链或支链C1-C6酰胺基；取代或未取代的直链或支链C1-C6酮基；取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基；取代或未取代的C1-C10芳基或杂芳基；
    Z选自取代或未取代的芳基或杂芳基；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12各自独立的选自H；卤素；取代或未取代的直链或支链C1-C6烷基、取代或未取代的直链或支链C1-C6烯基；取代或未取代的直链或支链C1-C6炔基；取代或未取代的直链或支链C1-C6烷氧基；取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基；取代或未取代的直链或支链C1-C6酯基；取代或未取代的直链或支链C1-C6酰胺基；取代或未取代的直链或支链C1-C6酮基；取代或未取代的C1-C10环烷基；取代或未取代的C1-C10杂环基；取代或未取代的C1-C10芳基或杂芳基；和第二抗肿瘤活性剂或增效剂。
  18. 如权利要求17所述的一种药物组合物，其中第二抗肿瘤活性剂或增效剂为紫杉醇类抗肿瘤剂。
  19. 如权利要求18所述的一种药物组合物，其中紫杉醇类抗肿瘤剂为紫杉醇或多西他赛。
  20. 如权利要求17-19任一项所述的一种药物组合物，其特征在于第二抗肿 瘤活性剂或增效剂为多西他赛。
  21. 权利要求17-20任一项所述的一种药物组合物在制备抗肿瘤药物中的应用。
  22. 如权利要求21所述的应用，所述肿瘤选自肺癌、胃癌、食道癌、肝癌、乳腺癌、宫颈癌、鼻咽癌、结肠癌、贲门癌、肝管癌、卵巢癌、喉癌、口腔癌、淋巴癌、白血病、直肠癌、甲状腺癌、上颌窦癌、颅脑胶质瘤、口咽癌、胰腺癌中的一种或多种。
  23. 如权利要求1所述的一种喹啉或喹唑啉类化合物、互变异构体、立体异构体、或药学上可接受的盐在制备抗肿瘤药物中的应用，其中所述化合物为如下化合物的一个或多个；
    Figure PCTCN2019118783-appb-100003
  24. 如权利要求17-19任一项所述的一种药物组合物，其特征在于所述化合物为如下化合物的一个或多个；
    Figure PCTCN2019118783-appb-100004
    Figure PCTCN2019118783-appb-100005
PCT/CN2019/118783 2019-11-15 2019-11-15 喹啉或喹唑啉类化合物在制备抗肿瘤药物中的应用 WO2021092892A1 (zh)

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