CN115197225A - Five-membered heterocyclic quinazolinone compound and preparation method thereof - Google Patents
Five-membered heterocyclic quinazolinone compound and preparation method thereof Download PDFInfo
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- CN115197225A CN115197225A CN202111031025.4A CN202111031025A CN115197225A CN 115197225 A CN115197225 A CN 115197225A CN 202111031025 A CN202111031025 A CN 202111031025A CN 115197225 A CN115197225 A CN 115197225A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention belongs to the technical field of C07D487/00, and particularly relates to a five-membered heterocyclic quinazolinone compound and a preparation method thereof. The invention provides a five-membered heterocyclic quinazolone compound, and the preparation raw materials comprise the five-membered heterocyclic quinazolone compound and the quinazolone compound; the five-membered heterocyclic quinazolinone compound provided by the invention has anti-tumor activity, and can be used for preparing medicines for treating and/or preventing various cancers caused by mutation of SHP2 phosphatase; the five-membered heterocyclic quinazolinone compound provided by the invention is simple in preparation process, and the treatment method is not strictly limited, so that the possibility of applying the compound to large-scale production for preparing medicines is provided, and the compound has extremely high market prospect and application value.
Description
Technical Field
The invention belongs to the technical field of C07D487/00, and particularly relates to a five-membered heterocyclic quinazolinone compound and a preparation method thereof.
Background
Malignant tumor is a very serious disease threatening human life at present, with the development of society and the promotion of industrialization process, the life style is changed, and the morbidity and the mortality of the malignant tumor are increased continuously. Among the worldwide reported number of new cancer patients, the number of new cancer patients in China is the first worldwide, and the number of cancer deaths is also the first worldwide.
In the face of the threat of cancer to human beings at the present stage, researchers are also dedicated to the development of tumor treatment methods, such as surgery, chemotherapy, radiotherapy and the like, which generally have high recurrence rate and various side effects and limited clinical treatment effect. Therefore, the search for novel targeted antitumor drugs based on new action mechanisms and new targets, which have higher selectivity and smaller toxic and side effects, has urgent practical needs.
Chinese patent publication No. CN110256444A discloses a method for synthesizing a benzimidazolone and oxazolinone compound, which aims to solve the problem of easy separation during the synthesis process. And shows excellent effect of SHP2 allosteric inhibition.
Disclosure of Invention
In order to solve the technical problems, the invention provides a five-membered heterocyclic quinazolinone compound, which is prepared from five-membered heterocyclic compounds and quinazolinone compounds as raw materials; the five-membered heterocyclic quinazolinone compound is represented by a structural formula I or a structural formula II;
the structural formula I is as follows:
wherein R is 1 One selected from alkyl heterocyclic amine group, aromatic heterocyclic and alkyl amine group; r is 2 One selected from substituted phenyl groups;
the structural formula II is as follows:
wherein R is 3 One selected from alkyl heterocyclic amine group, fatty amide group and aromatic amide group.
In this application, reference to "amine" is intended to mean the product of substitution of one or more hydrogen atoms in the ammonia molecule with a hydrocarbyl group.
As used herein, "heterocyclic amine" includes nitrogen-containing heterocyclic compounds and amino-substituted heterocyclic compounds;
as used herein, "heterocyclic amine group" refers to a portion of a nitrogen-containing heterocyclic group or amino-substituted heterocyclic compound having a nitrogen atom as a bonding atom, which remains after one amino hydrogen atom is lost.
In the present application, the heterocyclic amine group includes, but is not limited to, a 4-methylpiperazine group, a morpholine group, a thiomorpholine group.
In the present application, the term "aromatic heterocyclic ring" refers to an aromatic compound having a heterocyclic structure, and the term "aromatic heterocyclic group" refers to a portion of the aromatic heterocyclic ring remaining after one aromatic hydrogen atom is lost.
In the present application, the heteroaromatic group includes, but is not limited to, a pyridine group.
In the present application, the "alkylamine" refers to an organic amine having an unsubstituted alkyl group or a substituted alkyl group, and the "alkylamine group" refers to a portion remaining after the alkylamine has lost one amino hydrogen atom.
In the present application, the "substituted benzene" refers to a compound in which a hydrogen atom on the benzene ring is substituted with a substituent; and the "substituted benzene group" means a portion remaining after the substituted benzene has lost one hydrogen atom on the benzene ring.
As used herein, a "substituted phenyl group" includes, but is not limited to, a 4-fluorophenyl group, a 2-chlorophenyl group, and a 4-methoxyphenyl group.
In the present application, the term "fatty amide" refers to a compound in which the nitrogen atom of the amide is replaced with an aliphatic hydrocarbon; the term "aliphatic amide-preventing group" as used herein refers to a moiety in which the carbonyl group of the aromatic amide is not bonded.
As used herein, the fatty amide groups include, but are not limited to, N-cyclopropylcarboxamide groups, N- (2-hydroxyethyl) carboxamide groups, N-benzylcarboxamide groups.
In the present application, the term "aromatic amide" refers to a compound in which the nitrogen atom of the amide is substituted with an aromatic group; the term "aromatic amide" as used herein refers to a moiety in which the carbonyl group of the aromatic amide is not bonded.
As used herein, the aromatic amide group includes, but is not limited to, an N-phenyl carboxamide group, an N- (2-methoxyphenyl) carboxamide group, an N- (4- (trifluoromethyl) phenyl) carboxamide group.
In some preferred embodiments, the heterocyclic amine group contains 1-2 heteroatoms selected from one of N, O, and S.
In some preferred embodiments, the heterocyclic amine comprises pyrrolidine, morpholine, thiomorpholine, 4-methylpiperazine.
In some preferred embodiments, the starting materials for the preparation comprise compound a or compound B;
the compound A is represented by a formula (III), and the formula (III):
wherein R2 is selected from one of substituted phenyl groups;
the compound B is represented by a formula (IV):
wherein R4 is selected from one of aldehyde group or carboxyl.
In some preferred embodiments, R is 2 The substitution position of the group is ortho-position substitution or para-position substitution.
In some preferred embodiments, the five-membered heterocyclic ring is one of imidazole or triazole.
In some preferred embodiments, R is 1 Replacing hydrogen atoms on triazole; said R 3 Replacing one hydrogen atom on the imidazole.
In some of the preferred embodiments of the present invention, the five-membered heterocyclic quinazolinone compound is selected from the group consisting of 4- (2-chlorobenzyl) -1- (morpholinomethyl) - [1,2,4] triazol [4,3-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -1- (pyridin-4-yl) - [1,2,4] triazol [4,3-a ] quinazolin-5 (4H) -one, 4- (4-fluorobenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-fluorobenzyl) -1- (pyrrolidinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, and 4- (4-Fluorobenzyl) -1- (((4-methylpiperazin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, tert-butyl 4- (((4- (4-fluorobenzyl) -5-oxo-4, 5-dihydro- [1,2,4] triazolo [4,3-a ] quinazolin-1-yl) methyl) piperazine-1-carboxylate, 1- ((4- (2-chloroacetyl) piperazin-1-yl) methyl) -4- (4-fluorobenzyl) - [1,2,4] triazolo [4,3-a ] methyl) Quinazolin-5 (4H) -one, 4- (4-fluorobenzyl) -1- ((4- (2-morpholinoacetyl) piperazin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 1- ((4- (cyclopropylsulfonyl) piperazin-1-yl) methyl) -4- (4-fluorobenzyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-fluorobenzyl) -1- (piperidin-1-ylmethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, and pharmaceutically acceptable salts thereof 4- (4-Fluorobenzyl) -) 1- (Thiomorpholinylmethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H, 4- (4-methoxybenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (pyrrolidin-1-ylmethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (((4-methylpiperazin-1-yl) methyl) - [1,2,4] triazolo [4, 4] quinazolin-5 (4H) -one [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- ((((4-methoxybenzyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, tert-butyl 4- (((4- (4-methoxybenzyl) -5-oxo-4, 5-dihydro- [1,2,4] triazolo [4,3-a ] quinazolin-1-yl) methyl) piperazine-1-carboxylate, 1- ((4- (2-chloroacetyl) piperazin-1-yl) methyl) -4- (4-methoxybenzyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, and mixtures thereof 4- (4-methoxybenzyl) -1- ((4- (2-morpholinoacetyl) piperazin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- ((4- (2-pyrrolidineacetyl) piperazin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 1- ((4- (cyclopropylsulfonyl) piperazin-1-yl) methyl) -4- (4-methoxybenzyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (piperidin-1-ylmethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (thiomorpholinylmethyl) - [1,2,4] triazolo [4,3-a ] quinolin-5 (4H), 1- ((4-hydroxypiperidin-1-yl) methyl) -4- (4-methoxybenzyl) - [1,2,4] triazolo [4,3-a ] quinolin-5 (4H) 4- (4-methoxybenzyl) -1- ((4-methylpiperidin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinoline-5 (4H), 4- (4-methoxybenzyl) -1- ((2-methylpiperidin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinoline-5 (4H), 4- (2-chlorobenzyl) -1- ((4-methylpiperadine-5 (4H) Oxazin-1-yl) methyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -1- (pyrrolidin-1-ylmethyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -1- (piperidin-1-ylmethyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -1- (morpholinomethyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, and pharmaceutically acceptable salts thereof 4- (2-chlorobenzyl) -1- (thiomorpholinmethyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (4-methylpiperazine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (morpholine-4-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (pyrrolidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (thiomorpholine-1-carbonyl) Imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (4-methylpiperidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (4-hydroxypiperidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (piperidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, and 4- (2-chlorobenzyl) -2- (2-methylpiperidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (3-methylpiperidine-1-carbonyl) imidazo [1,2-a ] quinazoline, and pharmaceutically acceptable salts thereof tert-butyl 4- (4- (2-chlorobenzyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carbonyl) piperazine-1-carboxylate, 4- (2-chlorobenzyl) -N- (3-methoxyphenyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof, 4- (2-chlorobenzyl) -5-oxo-N- (3- (trifluoromethoxy) phenyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N- (4-fluorophenyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -5-oxo-N- (pyridin-2-ylmethyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof 4- (2-chlorobenzyl) -N- (furan-2-ylmethyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, (S) -4- (2-chlorobenzyl) -5-oxo-N- (1-phenylethyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, (R) -4- (2-chlorobenzyl) -5-oxo-N- (1-phenylethyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -5-oxo-N- (3- (trifluoromethyl) phenyl) -4, 5-bis Hydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -5-oxo-N-phenyl-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N- (2-hydroxyethyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N-cyclopropyl-5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, salts of the corresponding compounds, and salts thereof 4- (2-chlorobenzyl) -N- (2, 4-dimethylphenyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N-cyclohexyl-5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N- (2-methoxyphenyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N- ((2R, 6S) -2, 6-dimethylcyclohexyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, one of N-benzyl-4- (2-chlorobenzyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, and tert-butyl (1- (4- (2-chlorobenzyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carbonyl) piperidin-4-yl) carbamate.
In some preferred embodiments, the starting materials for the preparation of compound a or compound B include the hexacyclic anhydrides.
In some preferred embodiments, the starting material for the preparation of compound a or compound B comprises isatoic anhydride.
The second aspect of the invention provides a preparation method of a five-membered heterocyclic quinazolinone compound, which comprises the following steps:
s1: preparing a compound A or a compound B;
s2: synthesizing a five-membered heterocyclic quinazolinone compound crude product;
s3: and (3) performing side chain splicing on the crude product prepared in the step (S2) to obtain the product.
In some preferred embodiments, when the five-membered heterocycle is triazole, the preparation raw materials comprise: hexacyclic acid anhydride substances, alkaline substances and reducing agents.
In some preferred embodiments, when the five-membered heterocycle is triazole, the preparation raw materials comprise: isatoic anhydride, o-chloroaniline, potassium hydroxide, carbon disulfide, hydrazine hydrate, chloroacetyl chloride, potassium carbonate and morpholine.
In the experimental process, the applicant discovers through a large amount of experimental researches that in the system, the yield of the triazoloquinazolinone compound prepared from the preparation raw materials can be ensured to be more than 50%, the preparation process is simple, the intermediate product can be prepared in the next stage without complex treatment in the preparation process, the complex treatment process is avoided, the cost is saved, the yield is improved, and the specific high economic value and the possibility of large-scale production are realized.
In some preferred embodiments, the synthesis method of the five-membered heterocyclic quinazolinone compound is represented by the following chemical reaction formulas (1) and (2):
in some preferred embodiments, the five-membered heterocyclic quinazolinone compound represented by structural formula II can be obtained by side chain splicing of compound B through substitution reaction, and the specific synthetic route is as follows:
the compound B can be prepared by taking 2H-benzo [ d ] [1,3] oxazine-2, 4 (1H) -diketone as a starting material, and the specific synthetic route is as follows:
to further illustrate the preparation of the triazoloquinazolinones, the preparation will now be described as follows:
(1) In a 500mL single-neck bottle, 50 parts of isatoic anhydride is dissolved in 250 parts of ethyl acetate, and 43.4 parts of o-chlorobenzylamine is added while stirring; after the addition, the reaction was heated to 40 ℃ for 2h, and the progress of the reaction was monitored by TLC; after the reaction is finished, the reaction solution is cooled to room temperature, the solvent ethyl acetate is removed through reduced pressure distillation to obtain a white solid, the white solid is soaked in methanol and stirred, and insoluble impurities are removed through filtration. Adding water into the filtrate, stirring, separating out a solid, performing suction filtration, washing a filter cake for 2 times by using petroleum ether, and performing suction filtration to obtain a crude product compound 2-amino-N- (2-chlorobenzyl) benzamide;
(2) Adding 50 parts of 2-amino-N- (2-chlorobenzyl) benzamide obtained in the step (1) into a 500mL single-mouth bottle, dissolving a compound 2-amino-N- (2-chlorobenzyl) benzamide into 250 parts of ethanol, adding 23.67 parts of potassium hydroxide under the stirring state, slowly dropwise adding 146.02 parts of carbon disulfide, heating the reaction to 55 ℃ after the addition is finished, reacting for 169h, and monitoring the reaction by TLC; after the reaction is finished, cooling the reaction solution to room temperature, separating out a solid, carrying out suction filtration, washing the filter cake once with clear water, washing once with acetone, and carrying out suction filtration to obtain a crude product compound 3- (2-chlorobenzyl) -2-sulfo-2, 3-dihydroquinazoline-4 (1H) -ketone;
(3) And (3) adding 10 parts of crude compound 3- (2-chlorobenzyl) -2-thio-2, 3-dihydroquinazolin-4 (1H) -ketone obtained in the step (2) into a 250mL single-neck bottle, then adding 100 parts of isopropanol into the single-neck bottle, adding 31 parts of hydrazine hydrate under the stirring state, and after the addition is finished, heating the reaction to 90 ℃ for reacting for 16 hours. TLC monitoring reaction, after the reaction is finished, bringing the reaction solution to room temperature, separating out a solid, carrying out suction filtration, washing a filter cake once with clear water, washing once with ethyl acetate, and carrying out suction filtration to obtain a crude product compound (E) -3- (2-chlorobenzyl) -2-hydrazino-2, 3-dihydroquinazolin-4 (1H) -one;
(4) Adding the crude compound (E) -3- (2-chlorobenzyl) -2-hydrazino-2, 3-dihydroquinazoline-4 (1H) -ketone obtained in the step (3) into a 250mL single-mouth bottle, slowly dropwise adding 2.82 parts of chloroacetyl chloride under the condition of ice-bath stirring, reacting for half an hour in ice bath, heating the reaction system to 100 ℃ for reaction for 5 hours, monitoring the reaction by TLC, cooling the reaction liquid to room temperature after the reaction is finished, adding water for quenching reaction, stirring to obtain a solid, performing suction filtration, washing a filter cake twice by using petroleum ether, washing a methyl tert-butyl ether twice, and performing suction filtration to obtain a crude compound 4- (2-chlorobenzyl) -1- (chloromethyl) - [1,2,4] triazolo [4,3-a ] quinazoline-5 (4H) -ketone;
(5) And (3) putting the compound 4- (2-chlorobenzyl) -1- (chloromethyl) - [1,2,4] triazolo [4,3-a ] quinazoline-5 (4H) -ketone prepared in the step (4) into a 100mL single-mouth bottle, dissolving the single-mouth bottle in 20 parts of acetonitrile, adding 0.23 part of potassium carbonate and 0.06 part of morpholine under the stirring state, heating the reaction system to 50 ℃ after the addition is finished, reacting for 4H, monitoring the reaction by TLC, cooling the reaction liquid to room temperature after the reaction is finished, adding water to quench the reaction, stirring out a solid, performing suction filtration, and washing a filter cake twice by using acetone to obtain the compound 4- (2-chlorobenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazoline-5 (4H) -ketone.
In some preferred embodiments, where the five-membered heterocyclic ring is imidazole, the starting materials for the preparation include: compound 1, compound 2, compound 3, p-methoxybenzylamine, potassium carbonate, trifluoroacetic acid, ethyl bromopyruvate, sodium bicarbonate, N-methylpiperazine, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, triethylamine.
The structural formula of the compound 1 is as follows:
the structural formula of the compound 2 is as follows:
the structural formula of the compound 3 is as follows:
to further illustrate the preparation of the imidazoquinazolinones, the preparation is now described as follows:
(1) Placing 15 parts of compound 1 in a 250mL single-neck flask at normal temperature, adding 150 parts of acetonitrile, sequentially adding 8.09 parts of p-methoxybenzylamine and 20.35 parts of potassium carbonate under stirring, heating to 80 ℃, reacting for 8 hours, detecting the reaction by TLC, transferring the reaction solution to normal temperature after the reaction is finished, adding 50 parts of water into the reaction solution after the reaction solution is cooled, extracting twice, collecting filtrate, drying with anhydrous sodium sulfate, and removing the organic solvent by reduced pressure distillation to obtain a crude product; adding 96.64 parts of trifluoroacetic acid into the obtained crude product, heating to 80 ℃, reacting for 24 hours, detecting the reaction by TLC (thin layer chromatography), distilling the reaction solution under reduced pressure after the reaction is finished to remove the trifluoroacetic acid, wherein the residue is a dark green oily substance, adding 50 parts of water into a bottle, stirring to obtain a solid oily substance, performing suction filtration, collecting a filter cake to obtain a green solid crude product, pulping the crude product by methyl tert-butyl ether, purifying, and drying to obtain a light green solid;
(2) And (2) placing 9.5 parts of the light green solid obtained in the step (1) into a 250mL single-neck flask, adding 150 parts of absolute ethyl alcohol into the flask, sequentially adding 12.97 parts of ethyl bromopyruvate and 5.59 parts of sodium bicarbonate under a stirring state, heating to 100 ℃, and reacting for 7 hours. Detecting reaction by TLC, after the reaction is finished, moving the reaction solution to normal temperature, after the reaction solution is cooled to room temperature, carrying out suction filtration on the reaction solution, collecting a filter cake to obtain a crude product which is an off-white solid, pulping and purifying the solid by using acetone, and drying to obtain a white solid; placing 10.0 parts of white solid in a 100mL single-neck flask, adding 50 parts of 1mol/L sodium hydroxide aqueous solution into the flask, heating to 100 ℃, detecting reaction by TLC, moving the reaction solution to normal temperature after the reaction is finished, cooling the reaction solution to room temperature, filtering out insoluble substances in the reaction solution, discarding, treating the water layer with 1mol/L HCl aqueous solution until the pH value is 1-2, filtering, washing the filter cake with clear water, collecting the filter cake, pulping and purifying the filter cake with acetone, and drying to obtain white solid;
(3) Under normal temperature conditions, 0.2 part of the white solid obtained in step 2 was placed in a 50mL single-neck flask, 15 parts of N, N-dimethylformamide was added to the flask, 0.12 part of N-methylpiperazine, 0.35 part of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, and 0.11 part of triethylamine were sequentially added under stirring, and then reacted at normal temperature for 2 hours. And detecting the reaction by TLC, adding water into the reaction solution after the reaction is finished, stirring for 10min, performing suction filtration, collecting a filter cake, pulping and purifying the filter cake by using acetone, and drying to obtain the compound 4- (2-chlorobenzyl) -2- (4-methylpiperazine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one.
In the present application, according to the synthesis methods of the compounds 4- (2-chlorobenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one (A1) and 4- (2-chlorobenzyl) -2- (4-methylpiperazine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one (E1), the compounds i (triazoloquinazolinone core compound) and II (imidazoquinazolinone compound) can be prepared, respectively, and the core compounds are spliced by side chain modification to prepare the compounds shown in examples A1-A2, B1-B9, C1-C15, D1-D5, and E1-E27, which are specifically shown in the following table 1:
table 1:
the third aspect of the invention provides a pharmaceutical composition, and the preparation raw materials comprise a five-membered heterocyclic quinazolinone compound and at least one of a carrier, a diluent and an excipient.
Has the advantages that: the five-membered heterocyclic quinazolinone compound prepared by the invention has the following advantages:
1. the five-membered heterocyclic quinazolinone compound provided by the invention has anti-tumor activity, and can be used for preparing medicines for treating and/or preventing various cancers caused by mutation of SHP2 phosphatase;
2. the five-membered heterocyclic quinazolinone compound provided by the invention is particularly applied to medicaments for treating melanoma, lung cancer, leukemia, neuroblastoma and breast cancer;
3. the five-membered heterocyclic quinazolinone compound provided by the invention is simple in preparation process, and the treatment method is not strictly limited, so that the possibility of applying the five-membered heterocyclic quinazolinone compound to large-scale production and preparation of medicines is provided, and the five-membered heterocyclic quinazolinone compound has extremely high market prospect and application value.
Detailed Description
Examples
Example 1
A triazolo-quinazolinone compound is prepared from the following raw materials: isatoic anhydride, o-chloroaniline, potassium hydroxide, carbon disulfide, hydrazine hydrate, chloroacetyl chloride, potassium carbonate and morpholine.
A preparation method of a triazoloquinazolinone compound comprises the following steps:
(1) In a 500mL single-neck flask, 50 parts of isatoic anhydride is dissolved in 250 parts of ethyl acetate, and 43.4 parts of o-chlorobenzylamine is added while stirring; after the addition, the reaction was heated to 40 ℃ for 2h, and the progress of the reaction was monitored by TLC; after the reaction is finished, the reaction solution is cooled to room temperature, the solvent ethyl acetate is removed through reduced pressure distillation to obtain a white solid, the white solid is soaked and stirred by methanol, and insoluble impurities are removed through filtration. Adding water into the filtrate, stirring, separating out solid, performing suction filtration, washing a filter cake for 2 times by using petroleum ether, and performing suction filtration to obtain a crude product compound 2-amino-N- (2-chlorobenzyl) benzamide;
(2) Adding 50 parts of 2-amino-N- (2-chlorobenzyl) benzamide obtained in the step (1) into a 500mL single-neck bottle, dissolving a compound 2-amino-N- (2-chlorobenzyl) benzamide into 250 parts of ethanol, adding 23.67 parts of potassium hydroxide under a stirring state, slowly dropwise adding 146.02 parts of carbon disulfide, heating the reaction to 55 ℃ after the addition is finished, reacting for 169h, and monitoring the reaction by TLC; after the reaction is finished, cooling the reaction solution to room temperature, separating out a solid, carrying out suction filtration, washing the filter cake once with clear water, washing once with acetone, and carrying out suction filtration to obtain a crude product compound 3- (2-chlorobenzyl) -2-sulfo-2, 3-dihydroquinazoline-4 (1H) -ketone;
(3) And (3) adding 10 parts of crude compound 3- (2-chlorobenzyl) -2-thio-2, 3-dihydroquinazolin-4 (1H) -ketone obtained in the step (2) into a 250mL single-neck bottle, then adding 100 parts of isopropanol into the single-neck bottle, adding 31 parts of hydrazine hydrate under the stirring state, and after the addition is finished, heating the reaction to 90 ℃ for reacting for 16 hours. Monitoring the reaction by TLC, after the reaction is finished, bringing the reaction solution to room temperature, separating out a solid, performing suction filtration, washing a filter cake once by using clear water, washing once by using ethyl acetate, and performing suction filtration to obtain a crude product compound (E) -3- (2-chlorobenzyl) -2-hydrazino-2, 3-dihydroquinazolin-4 (1H) -one;
(4) Adding the crude compound (E) -3- (2-chlorobenzyl) -2-hydrazino-2, 3-dihydroquinazoline-4 (1H) -ketone obtained in the step (3) into a 250mL single-mouth bottle, slowly dropwise adding 2.82 parts of chloroacetyl chloride under the condition of ice bath stirring, reacting for half an hour under ice bath, heating the reaction system to 100 ℃ for reacting for 5 hours, monitoring the reaction by TLC, cooling the reaction liquid to room temperature after the reaction is finished, adding water for quenching reaction, stirring to obtain a solid, performing suction filtration, washing a filter cake twice by using petroleum ether, washing twice by using methyl tert-butyl ether, and performing suction filtration to obtain a crude compound 4- (2-chlorobenzyl) -1- (chloromethyl) - [1,2,4] triazolo [4,3-a ] quinazoline-5 (4H) -ketone;
(5) And (3) putting the compound 4- (2-chlorobenzyl) -1- (chloromethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -ketone prepared in the step (4) into a 100mL single-mouth bottle, dissolving the single-mouth bottle in 20 parts of acetonitrile, adding 0.23 part of potassium carbonate and 0.06 part of morpholine under the stirring state, heating the reaction system to 50 ℃ after the completion of the addition, reacting for 4H by TLC, cooling the reaction liquid to room temperature after the reaction is finished, adding water to quench the reaction, stirring out a solid, performing suction filtration, and washing a filter cake twice by acetone to obtain the compound 4- (2-chlorobenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -ketone.
The nuclear magnetism and the yield are measured by adopting an Inova-400MHz nuclear magnetic resonance instrument and an Agilent 1100 LC-MS:
and (3) measuring results: 1 H NMR(400MHz,DMSO-d6)δ8.31(d,J＝8.4Hz,1H),8.28(d,J＝7.9Hz,1H),8.01(t,J＝7.4Hz,1H),7.65(t,J＝7.5Hz,1H),7.53(d,J＝7.9Hz,1H),7.31(t,J＝7.1Hz,1H),7.20(d,J＝6.9Hz,2H),5.42(s,2H),4.02(s,2H),3.57(s,4H),2.54(s,4H).m.p：213～215℃。HRMS(ESI-MS)m/z：410.13681[M+H] + 。
the yield is as follows: 65.2 percent.
Example 2
An imidazoquinazolinone compound is prepared from the following raw materials: compound 1, compound 2, compound 3, p-methoxybenzylamine, potassium carbonate, trifluoroacetic acid, ethyl bromopyruvate, sodium bicarbonate, N-methylpiperazine, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, triethylamine.
The structural formula of the compound 1 is as follows:
the structural formula of the compound 2 is as follows:
the structural formula of the compound 3 is as follows:
a preparation method of an imidazoquinazolinone compound comprises the following steps:
(1) Placing 15 parts of compound 1 in a 250mL single-neck flask at normal temperature, adding 150 parts of acetonitrile, sequentially adding 8.09 parts of p-methoxybenzylamine and 20.35 parts of potassium carbonate under stirring, heating to 80 ℃, reacting for 8 hours, detecting the reaction by TLC, transferring the reaction solution to normal temperature after the reaction is finished, adding 50 parts of water into the reaction solution after the reaction solution is cooled, extracting twice, collecting filtrate, drying with anhydrous sodium sulfate, and removing the organic solvent by reduced pressure distillation to obtain a crude product; adding 96.64 parts of trifluoroacetic acid into the obtained crude product, heating to 80 ℃, reacting for 24 hours, detecting the reaction by TLC (thin layer chromatography), distilling the reaction solution under reduced pressure after the reaction is finished to remove the trifluoroacetic acid, wherein the residue is a dark green oily substance, adding 50 parts of water into a bottle, stirring to obtain a solid oily substance, performing suction filtration, collecting a filter cake to obtain a green solid crude product, pulping the crude product by methyl tert-butyl ether, purifying, and drying to obtain a light green solid;
(2) Under the condition of normal temperature, 9.5 parts of the light green solid (compound 2) obtained in the step 1 are placed in a 250mL single-neck flask, 150 parts of absolute ethyl alcohol is added into the flask, 12.97 parts of ethyl bromopyruvate and 5.59 parts of sodium bicarbonate are sequentially added under the stirring state, the temperature is raised to 100 ℃, and the reaction is carried out for 7 hours. Detecting reaction by TLC, after the reaction is finished, moving the reaction solution to normal temperature, after the reaction solution is cooled to room temperature, carrying out suction filtration on the reaction solution, collecting a filter cake to obtain a crude product which is an off-white solid, pulping and purifying the solid by using acetone, and drying to obtain a white solid; placing 10.0 parts of white solid in a 100mL single-neck flask, adding 50 parts of 1mol/L sodium hydroxide aqueous solution into the flask, heating to 100 ℃, detecting reaction by TLC, moving the reaction solution to normal temperature after the reaction is finished, cooling the reaction solution to room temperature, filtering out insoluble substances in the reaction solution, discarding, treating the water layer with 1mol/L HCl aqueous solution until the pH value is 1-2, filtering, washing the filter cake with clear water, collecting the filter cake, pulping and purifying the filter cake with acetone, and drying to obtain white solid;
(3) 0.2 part of the white solid (compound 3) obtained in step 2 was placed in a 50mL single-neck flask at normal temperature, 15 parts of N, N-dimethylformamide was added to the flask, and 0.12 part of N-methylpiperazine, 0.35 part of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, and 0.11 part of triethylamine were sequentially added under stirring, followed by reaction at normal temperature for 2 hours. And detecting the reaction by TLC, adding water into the reaction solution after the reaction is finished, stirring for 10min, performing suction filtration, collecting a filter cake, pulping and purifying the filter cake by using acetone, and drying to obtain the compound 4- (2-chlorobenzyl) -2- (4-methylpiperazine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one.
The nuclear magnetism and the yield are measured by adopting an Inova-400MHz nuclear magnetic resonance instrument and an Agilent 1100 LC-MS:
and (3) measuring results:
compound 1: 1 H NMR(400MHz,CDCl3)δ8.25(d,J＝7.9Hz,1H),7.79(t,J＝7.7Hz,1H),7.61(d,J＝8.2Hz,1H),7.53-7.42(m,2H),7.33(dt,J＝20.8,7.4Hz,2H),7.23(s,1H),5.49(s,2H),3.59(s,2H)。
m.p.:218℃； 1 H NMR(400MHz,CDCl3)δ8.50(d,J＝7.9Hz,1H),8.18(s,1H),7.88(t,J＝7.7Hz,1H),7.69(d,J＝8.2Hz,1H),7.58(t,J＝7.6Hz,1H),7.44(d,J＝7.8Hz,1H),7.24(t,J＝7.0Hz,1H),7.20–7.15(m,2H),5.70(s,2H),4.18(s,2H),3.80(s,2H),2.50(s,2H),2.40(s,2H),2.36(s,3H)；MS(ESI-MS)m/z:435.15,436.66635[M+H] + 。
the yield is as follows: 61 percent.
In the present application, according to the synthesis methods of the compounds 4- (2-chlorobenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one (A1) and 4- (2-chlorobenzyl) -2- (4-methylpiperazine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one (E1), the compounds i (triazoloquinazolinone core compounds) and II (imidazoquinazolinone compounds) can be prepared respectively, and the core compounds are spliced by side chain modification to prepare the compounds shown in examples A1-A2, B1-B9, C1-C15, D1-D5 and E1-E27.
Performance evaluation:
1. the compound prepared by the application takes SHP244 as a positive control and SHP2 as a target protein, and the enzyme activity inhibition rate of part of target compounds is detected under the conditions of the molar concentration of 100 and 200 mu M respectively.
The test experiment procedure was as follows:
1. preparation of the experiment:
(1) Positive control and target compound solution: the positive control SHP244 and the compound from the example preparation, each 5mg, were dissolved in 200. Mu.L DMSO to form a stock solution, which was stored in a refrigerator at 4 ℃ until use. Diluting with phosphate buffer solution to desired concentration before use;
(2) Phosphate Buffered Saline (PBS): dissolving PBS powder with ultrapure water, adjusting the PH to about 7-8, sterilizing with high-pressure steam, filtering with a 0.22 mu m microporous filter membrane, and storing at 4 ℃ for later use.
(3) 2P-IRS-1 polypeptide solution: preparing 2P-IRS-1 polypeptide into a solution with the molar concentration of 0.5 mu M by using a PBS buffer solution;
(4) bpV solution: the bpV (CAS: 42494-73-5) is prepared into solution with the molar concentration of 160 mu M by PBS buffer solution;
(5) SHP2 enzyme solution: preparing SHP2 enzyme into a solution with the molar concentration of 0.5nM by using a PBS buffer solution, and using the solution as it is;
(6) Difmuup solution: diFMUP (CAS: 214491-43-7) was made into a solution of 0.5nM molarity in PBS buffer;
2. setting a group:
the total volume of the experimental system is set to be 25 mu L at room temperature, and the enzyme activity test experiment is carried out in a 96-hole cell culture plate.
The grouping situation is as follows: (1) normal group (enzyme only); (2) Administration of the target compound (addition of enzyme, addition of target compound); (3) Positive controls were administered (enzyme plus positive control).
3. And (3) experimental operation:
add 5. Mu.L each of the prepared target compound solution and positive control solution to the test plate, 2 duplicate wells for each solution at each concentration, then add 5. Mu.L SHP2 enzyme solution (0.5 nM molarity), shake the test plate gently to mix the solutions, incubate at room temperature for 10min, add 5. Mu.L 2P-IRS-1 polypeptide solution (0.5. Mu.M molarity), react for 30min, add 5. Mu.L metabolic substrate DiFMUP solution (0.5 nM molarity), incubate for 30min, add 5. Mu.L bpV solution (160. Mu.M molarity) to quench the reaction. And (3) measuring the absorbance value (A value) of each hole of the fluorescent signal at the excitation wavelength of 340nm and the emission wavelength of 450nm by using a microplate reader, and calculating the enzyme activity inhibition rate according to the average value of the absorbance of each group of 2 multiple holes:
enzyme activity inhibition (%) = (normal well a value-administration well a value)/normal well a value × 100%
The activity data are shown in Table 2.
Table 2: inhibition of SHP2 protein by test compounds at 100. Mu.M and 200. Mu.M concentrations
The performance test results show that the compound prepared by the invention has certain inhibitory activity on SHP2 phosphatase.
2. The compound prepared by the invention takes melanoma cells A375 as a test cell line, SHP244 and Sorafenib as positive controls, and the MTT method is adopted to determine the in vitro inhibition rate of the cells of the target compound at the molar concentration of 100 mu M and the administration time of 72h. The in vitro inhibitory rate of human melanoma cell a375 is shown in table 3.
1. Preparation before experiment:
(1) Positive control and target compound solutions: positive controls SHP244, sorafenib and the compound prepared herein were each dissolved in 5mg of DMSO (200. Mu.L) to stock solutions, filtered through a 0.22 μm microporous membrane, and stored at 4 ℃ for further use. Diluted to the desired concentration with 90% DMEM high sugar medium just before use.
(2) Complete medium: 90% DMEM high-glucose medium +10% fetal bovine serum +1% penicillin-streptomycin solution.
(3) Phosphate Buffered Saline (PBS): dissolving PBS powder with ultrapure water, adjusting the PH to about 7-8, sterilizing with high-pressure steam, filtering with a 0.22 mu m microporous filter membrane, and storing at 4 ℃ for later use.
(4) And (3) cell culture: placing human melanoma cells A375 in complete medium, placing at a volume fraction of 5% CO 2 The cells are cultured in a cell incubator at 37 ℃ and can be used when the cells are in the logarithmic growth phase.
(5) MTT solution: dissolving MTT in PBS buffer solution to obtain solution with mass concentration of 5mg/mL, filtering with 0.22 μm microporous membrane, storing at 4 deg.C in dark place, and mixing.
2. Primary screening experiment for cell proliferation inhibition:
the experiments were performed in the following groups:
(1) Normal group (DMEM high glucose medium added);
(2) Target compound administration group (target compound addition, molarity of 100. Mu.M or 200. Mu.M);
(3) Positive control administration group: group I (plus SHP244, 100. Mu.M molarity) and group II (plus Sorafenib, 100. Mu.M molarity).
Uniformly seeding the cells in logarithmic growth phase in 96-well plates (105/well), placing in a volume fraction of 5% 2 Culturing at 37 deg.C for 12h in incubator. After cell adherence, the administration is carried out in 3 duplicate wells per group, put at a volume fraction of 5% 2 Culturing for 72h at 37 ℃ in an incubator. Removing all the well solutions, adding DMEM high sugar medium 100 μ L per well, adding 20 μ L MTT solution (at a mass concentration of 5 mg/mL) in the dark, placing again at a volume fraction of 5% CO 2 Culturing in an incubator at 37 ℃ for 4h in the dark. The absorbance value (A value) of each well was measured at a wavelength of 490nm using a microplate reader, and the cell proliferation inhibition rate was calculated from the average value of the absorbance of 3 duplicate wells per group:
cell growth inhibition ratio (%) = 1-dose well A value/normal well A value × 100%
The data on the inhibition rate of cell proliferation are shown in Table 4.
Table 3:
| compound (I) | Inhibition rate/%) | Molar concentration/. Mu.M | Compound (I) | Inhibition rate/%) | Molar concentration/. Mu.M |
| A1 | -- | 200 | D5 | -- | 100 |
| A2 | 21.19 | 200 | E1 | 17.60 | 100 |
| B1 | -- | 200 | E2 | 16.81 | 100 |
| B2 | -- | 200 | E3 | 15.04 | 100 |
| B3 | -- | 200 | E4 | 15.92 | 100 |
| B4 | 7.36 | 200 | E5 | -- | 100 |
| B5 | -- | 200 | E6 | -- | 100 |
| B6 | -- | 200 | E7 | -- | 100 |
| B7 | 17.95 | 200 | E8 | -- | 100 |
| B8 | 5.45 | 100 | E9 | -- | 100 |
| B9 | -0.30 | 100 | E10 | 24.42 | 100 |
| C1 | -- | 200 | E11 | 24.08 | 100 |
| C2 | 24.34 | 200 | E12 | 20.14 | 100 |
| C3 | --- | 200 | E12 | 11.23 | 100 |
| C4 | 7.53 | 200 | E14 | 20.61 | 100 |
| C5 | -- | 200 | E15 | 21.89 | 100 |
| C6 | -- | 200 | E16 | 18.13 | 100 |
| C7 | 16.90 | 200 | E17 | 27.93 | 100 |
| C8 | -- | 200 | E18 | 20.14 | 100 |
| C9 | 24.34 | 200 | E19 | 16.82 | 100 |
| C10 | 29.60 | 100 | E20 | 14.98 | 100 |
| C11 | 24.15 | 100 | E21 | 15.23 | 100 |
| C12 | 18.70 | 100 | E22 | 12.47 | 100 |
| C13 | 16.05 | 100 | E23 | 5.02 | 100 |
| C14 | 7.65 | 100 | E24 | 22.09 | 100 |
| C15 | 0.30 | 100 | E25 | 24.77 | 100 |
| D1 | 76.15 | 100 | E26 | 12.22 | 100 |
| D2 | -- | 100 | E27 | 20.59 | 100 |
| D3 | -- | 100 | SHP244 | 13.81 | 100 |
| D4 | -- | 100 | Sorafenib | 14.79 | 100 |
The performance test results show that: the compound prepared by the invention has certain inhibitory activity on melanoma cells A375.
Claims (10)
1. A five-membered heterocyclic quinazolinone compound is characterized in that the preparation raw materials comprise the five-membered heterocyclic compound and the quinazolinone compound; the five-membered heterocyclic quinazolinone compound is represented by a structural formula I or a structural formula II;
the structural formula I is as follows:
wherein R is 1 One selected from alkyl heterocyclic amine group, aromatic heterocyclic and alkyl amine group; r 2 One selected from substituted phenyl groups;
the structural formula II is as follows:
wherein R is 3 One selected from alkyl heterocyclic amine group, fatty amide group and aromatic amide group.
2. The five-membered heterocycloquinazolinone compound according to claim 1, wherein said heterocyclylamine group contains 1-2 heteroatoms, and said heteroatoms are selected from one of N, O and S.
3. The five-membered heterocyclic quinazolinone compound according to claim 1, wherein the starting material comprises compound a or compound B;
the compound A is represented by a formula (III), and the formula (III):
wherein R is 2 One selected from substituted phenyl groups;
the compound B is represented by a formula (IV):
wherein R is 4 Is selected from one of aldehyde group or carboxyl group.
4. The five-membered heterocycloquinazolinone compound according to claim 1 or 3, wherein R is 2 The substitution position of the group is ortho-position substitution or para-position substitution.
5. The five-membered heterocycloquinazolinone compound according to claim 1, wherein the five-membered heterocycle is one of imidazole or triazole.
6. The five-membered heterocycloquinazolinone compound according to claim 5, wherein R is 1 Replacing hydrogen atoms on triazole; r is as described 3 Replacing one hydrogen atom on the imidazole.
7. The five-membered heterocycloquinazolinone compound according to claim 1, wherein, the five-membered heterocyclic quinazoline ketone compound is selected from 4- (2-chlorobenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -1- (pyridine-4-yl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-fluorobenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, and pharmaceutically acceptable salts thereof 4- (4-Fluorobenzyl) -1- (pyrrolidinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-fluorobenzyl) -1- (((4-methylpiperazin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, tert-butyl 4- (((4- (4-fluorobenzyl) -5-oxo-4, 5-dihydro- [1,2,4] triazolo [4,3-a ] quinazolin-1-yl) methyl) piperazine-1-carboxylate, 1- ((4- (2-chloroacetyl) piperazin-1-yl) methyl) -4- (4- Fluorobenzyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-fluorobenzyl) -1- ((4- (2-morpholinoacetyl) piperazin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 1- ((4- (cyclopropylsulfonyl) piperazin-1-yl) methyl) -4- (4-fluorobenzyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-fluorobenzyl) -1- (piperidin-1-ylmethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, and methods of making and using the same 4- (4-Fluorobenzyl) -) 1- (Thiomorpholinylmethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H, 4- (4-methoxybenzyl) -1- (morpholinomethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (pyrrolidin-1-ylmethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (((4-methylpiperazin-1-yl-methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (((4-methylpiperazin-1-one -yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- ((((4-methoxybenzyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, tert-butyl 4- (((4- (4-methoxybenzyl) -5-oxo-4, 5-dihydro- [1,2,4] triazolo [4,3-a ] quinazolin-1-yl) methyl) piperazine-1-carboxylate, methods of making and using the same 1- ((4- (2-chloroacetyl) piperazin-1-yl) methyl) -4- (4-methoxybenzyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- ((4- (2-morpholinoacetyl) piperazin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- ((4- (2-pyrrolidinoacetyl) piperazin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, and, 1- ((4- (Cyclopropylsulfonyl) piperazin-1-yl) methyl) -4- (4-methoxybenzyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (piperidin-1-ylmethyl) - [1,2,4] triazolo [4,3-a ] quinazolin-5 (4H) -one, 4- (4-methoxybenzyl) -1- (thiomorpholinylmethyl) - [1,2,4] triazolo [4,3-a ] quinolin-5 (4H); and methods of use thereof 1- ((4-Hydroxypiperidin-1-yl) methyl) -4- (4-methoxybenzyl) - [1,2,4] triazolo [4,3-a ] quinoline-5 (4H), 4- (4-methoxybenzyl) -1- ((4-methylpiperidin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinoline-5 (4H), 4- (4-methoxybenzyl) -1- ((2-methylpiperidin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] quinoline -5 (4H), 4- (2-chlorobenzyl) -1- ((4-methylpiperazin-1-yl) methyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -1- (pyrrolidin-1-ylmethyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -1- (piperidin-1-ylmethyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -1- (morpholinomethyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, a 4- (2-chlorobenzyl) -1- (thiomorpholinylmethyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (4-methylpiperazine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (morpholine-4-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (pyrrolidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -ketones, 4- (2-chlorobenzyl) -2- (thiomorpholine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -ones, 4- (2-chlorobenzyl) -2- (4-methylpiperidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -ones, 4- (2-chlorobenzyl) -2- (4-hydroxypiperidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -ones, 4- (2-chlorobenzyl) -2- (piperidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -ones, and 4- (2-chlorobenzyl) -2- (2-methylpiperidine-1-carbonyl) imidazo [1,2-a ] quinazolin-5 (4H) -one, 4- (2-chlorobenzyl) -2- (3-methylpiperidine-1-carbonyl) imidazo [1,2-a ] quinazoline, tert-butyl 4- (4- (2-chlorobenzyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carbonyl) piperazine-1-carboxylate, 4- (2-chlorobenzyl) -N- (3-methoxyphenyl) -5-oxo-4, 5-dihydroimid-idine Azolo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -5-oxo-N- (3- (trifluoromethoxy) phenyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N- (4-fluorophenyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -5-oxo-N- (pyridin-2-ylmethyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, and pharmaceutically acceptable salts thereof 4- (2-chlorobenzyl) -N- (furan-2-ylmethyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, (S) -4- (2-chlorobenzyl) -5-oxo-N- (1-phenylethyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, (R) -4- (2-chlorobenzyl) -5-oxo-N- (1-phenylethyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -5-oxo-N- (3-chlorobenzyl) -5-oxo-N- (1-phenylethyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide - (trifluoromethyl) phenyl) -4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -5-oxo-N-phenyl-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof 4- (2-chlorobenzyl) -N- (2-hydroxyethyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N-cyclopropyl-5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof 4- (2-chlorobenzyl) -N- (2, 4-dimethylphenyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N-cyclohexyl-5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N- (2-methoxyphenyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N- ((2R, 6S) -2, 6-dimethylcyclohexyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, 4- (2-chlorobenzyl) -N- ((2R, 6-dimethylcyclohexyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, N-benzyl-4- (2-chlorobenzyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carboxamide, tert-butyl (1- (4- (2-chlorobenzyl) -5-oxo-4, 5-dihydroimidazo [1,2-a ] quinazoline-2-carbonyl) piperidin-4-yl) carbamate.
8. The five-membered heterocycloquinazolinone compound according to claim 3, wherein the starting material for preparing compound A or compound B comprises a hexacyclic anhydride.
9. A process for the preparation of five-membered heterocycloquinazolinones according to any of claims 3 to 8, comprising the steps of:
s1: preparing a compound A or a compound B;
s2: synthesizing a five-membered heterocyclic quinazolinone compound crude product;
s3: and (3) performing side chain splicing on the crude product prepared in the step (S2) to obtain the product.
10. A pharmaceutical composition, characterized in that raw materials for preparation comprise the five-membered heterocyclic quinazolinone compound according to any one of claims 1 to 8 and at least one of carrier, diluent and excipient.
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| WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
| WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
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| WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
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