CN106146414A - Quinazoline diones analog derivative and its production and use - Google Patents

Quinazoline diones analog derivative and its production and use Download PDF

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Publication number
CN106146414A
CN106146414A CN201610541963.1A CN201610541963A CN106146414A CN 106146414 A CN106146414 A CN 106146414A CN 201610541963 A CN201610541963 A CN 201610541963A CN 106146414 A CN106146414 A CN 106146414A
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compound
diketone
dihydroquinazoline
acetamide
pentyl
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陈建忠
谢欣
钱海燕
韩爽
王志龙
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Zhejiang University ZJU
Shanghai Institute of Materia Medica of CAS
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Zhejiang University ZJU
Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms

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Abstract

The present invention provides a kind of new quinazoline diones analog derivative and its production and use, compound that this compounds includes having structure shown in formula V and pharmaceutically acceptable salt thereof or hydrate.The compound that the present invention provides is the active ligand of novel cannabinoids II receptor CB2, can prepare treatment, prevent and alleviate by the medicine of the receptor-mediated disease of CB2.Described medicine is the agonist of cannabinoid CB2 receptor, partial agonist, inverse agonist or antagonist.General structure V is:

Description

Quinazoline diones analog derivative and its production and use
Technical field
The invention belongs to pharmaceutical technology field, more particularly to a kind of compound with quinazoline diones as parent nucleus and Pharmaceutically-acceptable salts or hydrate, its preparation method and this compounds are being treated, are being prevented and suppress receptor-mediated by CB2 Disease medicine in application.
Background technology
Cannabis plant is used as medicine the history of thousands of years, and its active component is referred to as cannabinoid.1964, It is Δ that Gaoni and Mechoulam reports Fructus Cannabis main active9-tetrahydrocannabinol (Δ9-THC), subsequently it is carried out Separate and structural identification, indicate mankind's beginning for cannabinoid modern study.Cannabinoid is in human body Mainly act on Cannabined receptor.Two types, i.e. Fructus Cannabis I receptor is mainly had at present by the cannabinoid receptors that people are generally known (CB1) and Fructus Cannabis II receptor (CB2), both belong to the rhodopsin sample family of G-G-protein linked receptor together, have typical 7 sections The transmembrane structure of alpha-helix, and participate in the regulation of human body different physiological roles.The whole amino acid sequence homology of CB1 and CB2 Being 44%, relatively conservative cross-film region amino acid sequence has homology (Pertwee, the R.G.Pharmacology of of 68% Cannabinoid CB1and CB2Receptors.Pharmacol.Ther.1997,74,129-180).From distribution, CB1 receptor is distributed mainly on central nervous system, such as hippocampus, olfactory region, substantia nigra pars reticulata etc., is primarily involved in regulation and recognizes Know, remember and function (Galiegue, the S. such as sensory transmission；Mary,S.；Marchand,J.；Dussossoy,D.；Carriè re,D.；Carayon,P.；BouaboμLa,M.；Shire,D.；Le Fur,G.；Casellas,P.,Expression of Central and Peripheral Cannabinoid Receptors in Human Immune Tissues and Leukocyte Subpopulations.Eur.J.Biochem.1995,232,54-61)；And outside CB2 receptor is distributed mainly on Week organizes, and especially immuning tissue, such as splenic marginal zones, thymus, tonsil, B and T cell, macrophage etc., is primarily involved in exempting from Regulation (Di Marzo, the V. of epidemic disease function；et al.The endocannabinoid system and its therapeutic exploitation.Nat.Rev.Drug Discov.2004,3,771-784).CB1 receptor and CB2 receptor broadly fall into Gi/o type G protein coupled receptor, can activate signal transduction pathway in cell multiplex by this kind of receptor.CB2 receptor can be by suppression gland Thuja acid cyclase, activation Mitogen-actived protein kinase (map kinase) passage etc. suppress the generation of cAMP, regulation phosphatidyl Inositol-3 kinases (PI3K) and ceramide metabolism.
The basic structure of tradition cannabinoid ligand can be divided mainly into following five classes: 1) with Δ9-THC is the classical big of representative Fiber crops chlorins compound, this compounds is the cannabinoid extracted from natural plants or enters on the basis of natural product Row structure of modification and obtain, multiring structure is its common trait；2) the non-classical Cannabinoids compound with CP55940 as representative, This compounds mostly is the derivant of classical Cannabinoids；3) fatty acid with endogenous neurotransmitter Ananamide as representative Aminated compounds, for arachidonic derivant；4) the amino alkyl indole compounds with WIN55212-2 as representative；5) with SR141716A and SR144528 is the diaryl pyrazole azole compounds of representative.Along with the new skill such as high flux screening and virtual screening Art means are increasingly extensive in the application of medicinal chemistry art, and the cannabinoid ligand of more and more novel structures is constantly reported, Abundant multiformity is shown in chemical constitution.
Modern study shows that the multiple disease of Cannabined receptor and human body is relevant.CB1 antagonist can be used for losing weight, smoking cessation etc. is new The exploitation of medicine, the part of CB2 then can be used for treating disease of immune system and inflammation, pain, acute and chronic hepatitis, osteoporosis, moving The diseases such as pulse atherosclerosis.Owing to CB1 is predominantly located at central nervous system, its part easily causes serious nervus centralis pair to make With, such as degradation under hypomnesis, depression, sports coordination ability.Such as Rimonabant, it is the antagonist of a CB1, Within 2006, list in Europe, be used for treating obesity, but the undercarriage rapidly owing to it may cause the side effect such as depression, anxiety. And CB2 is distributed mainly on peripheral-system, it is to avoid this serious nervus centralis side effect, because of the safety that it is higher, form It it is the drugable target of a more prospect.At present, GSK company the CB2 agonist GW842166X reported is as analgesic Complete three clinical second phase researchs, but drug effect unsatisfactory (Giblin, G.M.P.；et al.Discovery of 2-[(2,4- Dichlorophenyl)amino]-N-[(tetrahydro-2H-pyran-4-yl)methyl]-4- (trifluoromethyl)-5-pyrimi dinecarboxamide,a Selective CB2Receptor Agonist for the Treatment of Inflammatory Pain.J.Med.Chem.2007,50,2597-2600)；CB2 is exciting Agent S-777469 has completed clinical second phase research (Odan, M., et the most as the drug candidate being used for treating atopic dermatitis al.,Discovery of S-777469:an orally available CB2agonist as an antipruritic agent.Bioorg.Med.Chem.Lett.,2012,22,2803-2806).Collect more than the research of CB2 selective ligands now In at preclinical phase and clinical investigation phase, there is no marketed drug.Consequently found that high activity, high selective CB2 part pair Significant in medicament research and development.
Summary of the invention
First purpose of the present invention be to provide a kind of quinazoline diones analog derivative and pharmaceutically acceptable salt thereof or Hydrate, its general structure V is:
Wherein,
R1、R2、R3、R4It is each independently selected from hydrogen atom, halogen, C1-C4Straight or branched alkyl, C1-C4Straight or branched Alkoxyl, hydroxyl；
R5Selected from C2-C6Straight chained alkyl, with C3-C6The alkyl of ring, 3-butene-1-base；
R6Selected from C2-C6Straight or branched alkyl, C3-C6Cyclic hydrocarbon radical, with C3-C6The alkyl of ring, aryl, heteroaryl, Heterocyclic radical or adamantyl；
Described halogen is fluorine, chlorine, bromine or iodine；
Described heteroaryl is containing 1-3 the identical or different heteroatomic 5-10 unit armaticity base in N, O and S Group；
Described heterocyclic radical is containing 1-3 the identical or different heteroatomic 4-10 unit nonaro-maticity in N, O and S Group.
Include at the compounds of formula V of the present invention and pharmaceutically acceptable salt thereof or hydrate, preferably particular compound:
(1) the N-tert-butyl group-2-(1-ring the third methyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(2) 2-(1-(3-butene-1-yl)-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) the tertiary fourth of-N- Yl acetamide
(3) the N-tert-butyl group-2-(5-methyl-2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(4) the N-tert-butyl group-2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(5) N-normal-butyl-2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(6) 2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetyl Amine
(7) the N-tert-butyl group-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(8) N-normal-butyl-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(9) N-cyclohexyl-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(10) the N-tert-butyl group-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(11) N-normal-butyl-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(12) N-cyclohexyl-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(13) the N-tert-butyl group-2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(14) N-normal-butyl-2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(15) 2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide
(16) the N-tert-butyl group-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(17) N-normal-butyl-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(18) N-cyclohexyl-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(19) the N-tert-butyl group-2-(1-ring the third methyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(20) 2-(1-(3-butene-1-yl)-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-uncle Butyl acetamide
(21) the N-tert-butyl group-2-(1-ethyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(22) the N-tert-butyl group-2-(8-methyl-2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(23) the N-tert-butyl group-2-(1-normal-butyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(24) the N-tert-butyl group-2-(1-n-pentyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(25) N-normal-butyl-2-(8-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(26) N-cyclohexyl-2-(1-n-pentyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(27) the N-tert-butyl group-2-(8-methyl-2,4-diketone-1-n-hexyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(28) the N-tert-butyl group-2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(29) N-normal-butyl-2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(30) 2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide
(31) the N-tert-butyl group-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(32) N-normal-butyl-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(33) N-cyclohexyl-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(34) the N-tert-butyl group-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide
(35) N-normal-butyl-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide
(36) N-cyclohexyl-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide
(37) the N-tert-butyl group-2-(7-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(38) 2-(7-bromo-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group acetamide
(39) the N-tert-butyl group-2-(7-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(40) the N-tert-butyl group-2-(6-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine
(41) the N-tert-butyl group-2-(6-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(42) the N-tert-butyl group-2-(6-fluoro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(43) the N-tert-butyl group-2-(6-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(44) 2-(6-bromo-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group acetamide
(45) the N-tert-butyl group-2-(2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(46) the N-tert-butyl group-2-(1-normal-butyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(47) 2-(1-normal-butyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide
(48) the N-tert-butyl group-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(49) 2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-isopropyl acetamide
(50) N-cyclopropyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(51) N-normal-butyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(52) 2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-isobutyl group acetamide
(53) N-cyclohexyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(54) the N-tert-butyl group-2-(1-n-hexyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
And the above-mentioned the most acceptable salt of particular compound or hydrate.
What described in this specification, " pharmaceutically acceptable salt " was concrete enumerates compound provided by the present invention and third The organic acid such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid are formed Salt；Or form salt with the mineral acid such as hydrochloric acid, phosphoric acid, sulphuric acid, Fluohydric acid., hydrobromic acid；Or with alkyl halide formed quaternary ammonium salt, described halogen Alkane is that fluorine, chlorine, bromine or iodine are for alkane.
Second object of the present invention is to provide a kind of quinazoline diones analog derivative and pharmaceutically-acceptable salts thereof or water The preparation method of compound, is presented herein below a preferred embodiment of the present invention:
(1) compound of formula I and Formula II compound react generation formula III compound；
(2) Formula IV compound reacts production V compound with formula III compound；
Wherein, R1、R2、R3、R4、R5、R6Identical with the definition in formula V.
(3) compound V is dissolved in absolute methanol, add under ice bath appropriate acid such as propanoic acid, oxalic acid, malonic acid, succinic acid, The organic acid such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, or hydrochloric acid, phosphoric acid, sulphuric acid, Fluohydric acid., hydrogen bromine The mineral acids such as acid, are spin-dried for solvent, obtain its pharmaceutically acceptable acid addition salts；Or compound V is dissolved in dehydrated alcohol, add equivalent Sodium hydroxide, potassium iodide and halogenated hydrocarbons such as iodomethane, heated overnight at reflux, crude product obtains chemical combination through acetone recrystallization purification The most acceptable quaternary ammonium salt of thing V.
(4) compound V is dissolved in aqueous acid, in this system, adds nonacid organic solvent, by crystallization side Method obtains the hydrate of compound V.The most suitable acid selected from hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, acetic acid, hydrobromic acid, nitric acid, Formic acid, tartaric acid, benzoic acid, phenylacetic acid, maleic acid, oxalic acid, trifluoroacetic acid；Nonacid organic solvent is selected from ethanol, methanol, second Nitrile, ethyl acetate, oxolane, ether, petroleum ether, isopropanol, n-butyl alcohol, N,N-dimethylformamide.
Further aspect of the present invention relates to the preparation method of a kind of Formula IV compound, is realized by following steps:
(1) Formula IV compound prepares as follows:
Under the conditions of alkalescence, compound A-1 and A-2 is obtained N-substituted compound A-3 through N-alkylation, more at high temperature, The cyanic acid thermally decomposed to generate with carbamide carries out cyclization formation Formula IV compound.
Wherein, described alkali is organic base or inorganic base, selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, first Sodium alkoxide, Sodium ethylate, sodium hydride, triethylamine, diisopropylethylamine (DIEA), pyridine, 1,8-diazabicylo [5.4.0] 11 Carbon-7-alkene (DBU) or DMAP (DMAP)；
Wherein, R1、R2、R3、R4For hydrogen atom, R5Identical with the definition in claim 1.
Or
(2) Formula IV compound prepares as follows:
Compound A-1 and BTC condensation reaction obtain compound A-4, in the presence of sodium hydride, obtain through N alkylated reaction Compound A-5, more at high temperature, form Formula IV compound with urea reaction；
Wherein, R1、R2、R3、R4、R5Identical with the definition in claim 1.
Or
(3) Formula IV compound prepares as follows:
Compound A-1, after thionyl chloride chloro, reacts with tert-butylamine and obtains formula A-7 compound；Compound A-7 and chloromethane Formula A-8 compound is obtained after acetoacetic ester or methylchloroformate reaction, then through N, N'-carbonyl dimidazoles or potassium hydroxide, second Alcohol reflux reacts to obtain formula A-9 compound；In the presence of Feldalat NM, obtain formula A-10 compound through N alkylated reaction；Again in acidity Under the conditions of back flow reaction obtain Formula IV compound；
Wherein, R1、R2、R3、R4、R5Identical with the definition in formula V.
Third object of the present invention be to provide a kind of quinazoline diones analog derivative and pharmaceutically acceptable salt thereof or Hydrate treats, prevents, alleviates and suppresses to apply in the medicine by the receptor-mediated disease of CB2 in preparation.
Described disease be by CB2 receptor active part regulate cause cancer, inflammation, acquired immune deficiency syndrome (AIDS), Autoimmune disease, rheumatism, allergy, pain, acute and chronic hepatitis, osteoporosis, atherosclerosis, multiple firmly Change disease, neurodegenerative diseases, Alzheimer, parkinson, Huntington's disease.
Fourth object of the present invention be to provide a kind of quinazoline diones analog derivative and pharmaceutically acceptable salt thereof or The pharmaceutical composition of hydrate, and can further include excipient, diluent and carrier.The compound of the present invention can be with the most molten Agent and with pharmaceutically acceptable solvent (such as water, ethanol, Polyethylene Glycol, propylene glycol etc.) solvation presented in.Logical Often, for the purpose of the present invention, it is believed that the form of solvation is equal to unsolvated form.The pharmaceutical composition of the present invention can Including the compound of one or more present invention, typical formula is the compound by the mixing present invention and pharmaceutically can connect The salt or the hydrate that are subject to are prepared with supporting agent, excipient or diluent.Suitable supporting agent, excipient or diluent are this areas Known to technical staff, including such as carbohydrate, wax, water solublity and/or expansiveness polymer, hydrophilic or hydrophobic The property material such as material, gelatin, solvent, water.The dosage form of described medicine selects solid preparation or liquid preparation, concrete for tablet, Capsule, powder, solution, syrup, suspensoid or aerosol.
The compound that the present invention provides is the active ligand of novel cannabinoids II receptor CB2, and this compounds includes tool There are the compound of structure shown in formula V and pharmaceutically acceptable salt thereof or hydrate.The compounds of this invention is cannabinoid receptors CB2 Agonist, partial agonist, inverse agonist or antagonist, treatment can be prepared, prevent and alleviate by the receptor-mediated disease of CB2 Sick medicine, has good drug development prospect.
Detailed description of the invention
The present invention is further described in conjunction with the embodiments, and the purpose of specific embodiment is to further illustrate present invention But do not mean that and limit the invention.
In the specific embodiment of the invention, the initial feed of use, reaction reagent etc. are commercially available prod.Embodiment 55 is enumerated The hydrochlorate of compound 7, quaternary ammonium salt, the preparation method of monohydrate, other compounds are referred to the method, it is also possible to adopt Other salt is formed by method commonly used in the art.
The embodiment 1:N-tert-butyl group-2-(1-ring the third methyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 1)
A) 2-chloro-N-tert-butyl group acetamide (compound 1a)
By tert-butylamine (438.8mg, 6.00mmol), it is molten that potassium carbonate (995.1mg, 7.20mmol) is placed in 6mL dichloromethane In liquid, under ice bath, chloracetyl chloride (677.6mg, 6.00mmol) is slowly dropped in above-mentioned reaction bulb, ambient temperature overnight.Reaction After end, adding suitable quantity of water, dichloromethane extracts, and merging organic facies saturated aqueous common salt washing, anhydrous magnesium sulfate are dried, and decompression is steamed Evaporate that to obtain thick product be white solid.Yield: 74.9%；Fusing point: 81.0-82.1 DEG C.
B) 2-Amino-N-tert-butyl-6-methyl benzamide (compound 1b)
2-amino-6-ar-Toluic acid (800.0mg, 5.29mmol) is placed in 50mL single necked round bottom flask, N2Displacement After, adding 9.8mL thionyl chloride, back flow reaction 3h, then do in reduced under vacuum, the oxolane that addition 7.8mL is dried is molten Liquid；The tetrahydrofuran solution of above-mentioned acyl chlorides is slowly added at 0 DEG C the oxolane of tert-butylamine (5.6mL, 52.92mmol) again In solution (7.8mL), room temperature reaction is overnight.After reaction terminates, after being cooled to room temperature, reactant liquor is concentrated to dryness, and adds suitable quantity of water, Ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, warp Silica gel column chromatography separating-purifying, obtains white solid.Yield: 72.5%；Fusing point: 102.2-103.2 DEG C.
1H NMR(500MHz,CDCl3) δ 7.02 (t, J=8.0Hz, 1H), 6.57 (d, J=7.5Hz, 1H), 6.53 (d, J =8.0Hz, 1H), 5.63 (s, 1H), 4.08 (s, 2H), 2.33 (s, 3H), 1.48 (s, 9H).
C) ethyl (2-(t-Butylcarbamoyl)-3-aminomethyl phenyl) carbamate (compound 1c)
Compound 1b (81.7mg, 0.40mmol) is placed in 10mL single necked round bottom flask, adds 1mL ethyl chloroformate, 95 DEG C of reaction 3h.After reaction terminates, adding suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, anhydrous sulfur Acid magnesium is dried, and vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 70.3%；Molten Point: 129.6-130.3 DEG C.
1H NMR(500MHz,CDCl3) δ 7.75 (d, J=8.0Hz, 1H), 7.49 (s, 1H), 7.25 (t, J=8.0Hz, 1H), 6.93 (d, J=7.5Hz, 1H), 5.68 (s, 1H), 4.22-4.18 (q, 2H), 2.38 (s, 3H), 1.47 (s, 9H), 1.30 (t, J=7.0Hz, 3H).
D) the 3-tert-butyl group-5-methylquinazolin-2,4 (1H, 3H)-diketone (compound 1d)
Compound 1c (100.0mg, 0.48mmol) is dissolved in the tetrahydrofuran solution that 4mL is dried, adds N, N'-carbonyl Base diimidazole (163.5mg, 1.01mmol), back flow reaction is overnight.After reaction terminates, adding suitable quantity of water, ethyl acetate extracts, and has Machine layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, separates through silica gel column chromatography and carries Pure, obtain white solid.Yield: 44.8%；Fusing point: 207.2-108.4 DEG C.
1H NMR(500MHz,CDCl3) δ 9.67 (s, 1H), 7.37 (t, J=8.0Hz, 1H), 6.94 (d, J=7.5Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 2.69 (s, 3H), 1.77 (s, 9H).
E) the 3-tert-butyl group-1-Cvclopropvlmethvl-5-methylquinazolin-2,4 (1H, 3H)-diketone (compound 1e)
Compound 1d (40.0mg, 0.17mmol) is dissolved in 2mL DMF, be sequentially added into Feldalat NM (14.0mg, 0.26mmol), bromomethyl cyclopropane (18 μ L, 0.19mmol), 50 DEG C reaction overnight.After reaction terminates, add appropriate water, second Acetoacetic ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silicon Plastic column chromatography separating-purifying, obtains yellow liquid, is directly used in next step reaction.
F) 1-Cvclopropvlmethvl-5-methylquinazolin-2,4 (1H, 3H)-diketone (compound 1f)
Compound 1e (77.7mg, 0.27mmol) is placed in 10ml single necked round bottom flask, adds 2mL Isosorbide-5-Nitrae-dioxy six Ring solution, magnetic agitation dissolving, add 1.6mL 6N HCl solution, be heated to reflux, TLC monitoring to reaction is completely.Reaction knot Shu Hou, adds appropriate water, and ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, decompression rotation Organic solvent is evaporated off, through silica gel column chromatography separating-purifying, obtains white solid, fusing point: 176.7-178.5 DEG C.
1H NMR(500MHz,CDCl3) δ 8.55 (s, 1H), 7.54 (t, J=7.5Hz, 1H), 7.24 (d, J=8.5Hz, 1H), 7.05 (d, J=7.5Hz, 1H), 4.04 (d, J=7.0Hz, 2H), 2.83 (s, 3H), 1.21-1.27 (m, 1H), 0.57- 0.54(m,4H)。
G) the N-tert-butyl group-2-(1-ring the third methyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine (compound 1)
Compound 1f (10.2mg, 0.04mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (12.2mg, 0.08mmol), 80 DEG C of reaction 30min, add compound 1a (7.9mg, 0.05mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 90.8%；Fusing point: 202.1- 202.6℃。
1H NMR(500MHz,CDCl3) δ 7.51 (t, J=8.0Hz, 1H), 7.22 (d, J=8.5Hz, 1H), 7.03 (d, J =7.5Hz, 1H), 5.56 (s, 1H), 4.63 (s, 2H), 4.08 (d, J=7.0Hz, 2H), 2.81 (s, 3H), 1.37 (s, 9H), 1.26-1.21(m,1H),0.55-0.52(m,4H)。
Embodiment 2:2-(1-(3-butene-1-yl)-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)- N-tert-butyl group acetamide (compound 2)
A) 1-(3-butene-1-yl)-3-tert-butyl group-5-methylquinazolin-2,4 (1H, 3H)-diketone (compound 2a)
Experimental technique, with the preparation method of compound 1e in embodiment 1, simply instead of bromomethyl ring with the bromo-1-butylene of 4- Propane, obtains yellow liquid, is directly used in next step reaction.
B) 1-(3-butene-1-yl)-5-methylquinazolin-2,4 (1H, 3H)-diketone (compound 2b)
Experimental technique is with the preparation method of compound 1f in embodiment 1, simply with compound 2a (42.6mg, 0.15mmol) Instead of compound 1f, obtain white solid.Yield: 42.9%；Fusing point: 167.4-168.8 DEG C.
1H NMR(500MHz,CDCl3) δ 8.42 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.05 (d, J=7.5Hz, 1H), 5.92-5.84 (m, 1H), 5.15-5.10 (m, 2H), 4.20-4.16 (m, 2H), 2.82 (s,3H),2.52-2.47(m,2H)。
C) 2-(1-(3-butene-1-yl)-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) the tertiary fourth of-N- Yl acetamide (compound 2)
Experimental technique, with the preparation method of compound 1 in embodiment 1, simply instead of compound 1f with compound 2b, To white solid.Yield: 98.7%；Fusing point: 199.9-200.7 DEG C.
1H NMR(500M Hz,CDCl3) δ 7.50 (t, J=8.5Hz, 1H), 7.07 (d, J=8.5Hz, 1H), 7.03 (d, J =7.5Hz, 1H), 5.91-5.83 (m, 1H), 5.55 (s, 1H), 5.15-5.09 (m, 2H), 4.62 (s, 2H), 4.20 (t, J= 8.0Hz,2H),2.80(s,3H),2.52-2.47(q,2H),1.37(s,9H)。
The embodiment 3:N-tert-butyl group-2-(5-methyl-2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 3)
A) the 3-tert-butyl group-5-methyl isophthalic acid-propyl group quinazoline-2,4 (1H, 3H)-diketone (compound 3a)
Experimental technique, with the preparation method of compound 1e in embodiment 1, simply instead of bromomethyl ring with n-propyl bromide Propane, obtains yellow liquid, is directly used in next step reaction.
B) 5-methyl isophthalic acid-propyl group quinazoline-2,4 (1H, 3H)-diketone (compound 3b)
Experimental technique is with the preparation method of compound 1f in embodiment 1, simply with compound 3a (53.8mg, 0.20mmol) Instead of compound 1f, obtain white solid.Yield: 70.3%；Fusing point: 183.8-184.8 DEG C.
1H NMR(500MHz,CDCl3) δ 8.46 (s, 1H), 7.52 (t, J=7.5Hz, 1H), 7.07 (d, J=8.5Hz, 1H), 7.04 (d, J=7.5Hz, 1H), 4.06 (t, J=7.5Hz, 2H), 2.82 (s, 3H), 1.79-1.75 (m, 2H), 1.04 (t, J=7.0Hz, 3H).
C) the N-tert-butyl group-2-(5-methyl-2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 3)
Experimental technique, with the preparation method of compound 1 in embodiment 1, simply instead of compound 1f with compound 3b, To white solid.Yield: 92.1%；Fusing point: 212.2-212.6 DEG C.
1H NMR(500MHz,CDCl3) δ 7.49 (t, J=8.0Hz, 1H), 7.05 (d, J=8.5Hz, 1H), 7.01 (d, J =7.5Hz, 1H), 5.57 (s, 1H), 4.62 (s, 2H), 4.08 (t, J=7.5Hz, 2H), 2.80 (s, 3H), 1.79-1.74 (m, 2H), 1.37 (s, 9H), 1.02 (t, J=7.5Hz, 3H).
The embodiment 4:N-tert-butyl group-2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 4)
A) 5-methyl isophthalic acid H-benzo [d] [1,3] piperazine-2,4-diketone (compound 4a)
By 2-amino-6-ar-Toluic acid (100.0mg, 0.66mmol), triphosgene (65.4mg, 0.22mmol) as In 25mL single necked round bottom flask, then it is slowly added dropwise into 3mL tetrahydrofuran solution, is heated to 45-50 DEG C, react 3h.Reaction terminates After, concentrated solvent, add normal hexane, separate out solid and filter, be dried to obtain crude product.Fusing point: 209-209.6 DEG C.
1H NMR (500MHz, DMSO) δ 11.60 (s, 1H), 7.55 (t, J=7.5Hz, 1H), 7.04 (d, J=6.5Hz, 1H), 6.98 (d, J=7.5Hz, 1H), 2.58 (s, 3H).
B) 1-normal-butyl-5-methyl isophthalic acid H-benzo [d] [1,3] piperazine-2,4-diketone (compound 4b)
Compound 4a (204.0mg, 1.15mmol), sodium hydride (55.3mg, 1.38mmol) are placed in 25mL two-neck bottle, N2After displacement, add the DMF solution that is dried of 4mL, after room temperature reaction 1h, add bromination of n-butane (148 μ L, 1.38mmol), room temperature reaction is overnight.After reaction terminates, adding appropriate frozen water, stir 10min, sucking filtration goes out solid and obtains crude product.
C) 1-normal-butyl-5-methylquinazolin-2,4 (1H, 3H)-diketone (compound 4c)
Compound 4b (155.8mg, 0.67mmol) is placed in 10mL single necked round bottom flask, addition carbamide (120.3mg, 2.09mmol), 2h is reacted in 200 DEG C.After reaction terminates, being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, organic layer Washing with saturated sodium-chloride, anhydrous magnesium sulfate is dried again, and vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, Obtain yellow solid.Yield: 43.7%；Fusing point: 161.3-162 DEG C.
D) the N-tert-butyl group-2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 4)
Compound 4c (19.0mg, 0.08mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (21.3mg, 0.15mmol), 80 DEG C of reaction 30min, add compound 1a (12.7mg, 0.08mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 97.4%；Fusing point: 198.9-199.4℃。
1H NMR(500MHz,CDCl3) δ 7.49 (t, J=8.0Hz, 1H), 7.06 (d, J=8.5Hz, 1H), 7.02 (d, J =7.5Hz, 1H), 5.55 (s, 1H), 4.63 (s, 2H), 4.12 (t, J=7.5Hz, 2H), 2.80 (s, 3H), 1.74-1.68 (m, 2H), 1.48-1.43 (m, 2H), 1.37 (s, 9H), 0.99 (t, J=7.5Hz, 3H).
Embodiment 5:N-normal-butyl-2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 5)
A) 2-chloro-N-normal-butyl acetamide (compound 5a)
By n-butylamine (585.1mg, 8.00mmol), potassium carbonate (1.3g, 9.60mmol) is placed in 8mL dichloromethane solution In, under ice bath, chloracetyl chloride (903.5mg, 8.00mmol) is slowly dropped in above-mentioned reaction bulb, ambient temperature overnight.Reaction knot Shu Hou, adds appropriate water, and dichloromethane extracts, and merging organic facies saturated aqueous common salt washing, anhydrous magnesium sulfate are dried, and decompression is steamed Evaporate that to obtain thick product be yellow oily liquid.Yield: 86.1%.
B) N-normal-butyl-2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 5)
Experimental technique, with the preparation method of compound 4 in embodiment 4, simply instead of compound 1a with compound 5a, Arrive
White solid.Yield: 98%；Fusing point: 185.9-186.4 DEG C.
1H NMR(400MHz,CDCl3) δ 7.50 (t, J=8.0Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 7.02 (d, J =7.6Hz, 1H), 5.79 (s, 1H), 4.70 (s, 2H), 4.12 (t, J=7.6Hz, 2H), 3.31-3.26 (q, 2H), 2.80 (s, 3H), 1.73-1.70 (m, 2H), 1.52-1.43 (m, 4H), 1.37-1.32 (m, 2H), 0.99 (t, J=7.2Hz, 3H), 0.91 (t, J=7.2Hz, 3H).
Embodiment 6:2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl Acetamide (compound 6)
A) 2-chloro-N-cyclohexyl acetamide (compound 6a)
By cyclohexylamine (992.0mg, 10.00mmol), it is molten that potassium carbonate (1.66g, 12.00mmol) is placed in 10mL dichloromethane In liquid, under ice bath, chloracetyl chloride (1.13g, 10.00mmol) is slowly dropped in above-mentioned reaction bulb, ambient temperature overnight.Reaction knot Shu Hou, adds appropriate water, and dichloromethane extracts, and merging organic facies saturated aqueous common salt washing, anhydrous magnesium sulfate are dried, and decompression is steamed Evaporate and obtain thick product white solid.Yield: 74.9%；Fusing point: 103.8-105.9 DEG C.
B) 2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide (compound 6)
Experimental technique, with the preparation method of compound 4 in embodiment 4, simply instead of compound 1a with compound 6a, Arrive
White solid.Yield: 97%；Fusing point: 218.2-218.9 DEG C.
1H NMR(400MHz,CDCl3) δ 7.49 (t, J=8.0Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 7.02 (d, J =7.2Hz, 1H), 5.62 (d, J=7.2Hz, 1H), 4.68 (s, 2H), 4.12 (t, J=7.6Hz, 2H), 3.83-3.78 (m, 1H),2.80(s,3H),1.95-1.93(m,2H),1.73-1.67(m,4H),1.61-1.58(m,1H),1.48-1.42(m, 2H), 1.36-1.30 (m, 2H), 1.19-1.14 (m, 3H), 0.99 (t, J=7.2Hz, 3H).
The embodiment 7:N-tert-butyl group-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 7)
A) 5-methyl isophthalic acid-n-pentyl-1H-benzo [d] [1,3] piperazine-2,4-diketone (compound 7a)
Experimental technique, with the preparation method of compound 4b in embodiment 4, simply instead of the positive fourth of bromo with bromo pentane Alkane, sucking filtration obtains crude product.
B) 5-methyl isophthalic acid-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 7b)
Experimental technique simply instead of 4b with compound 7a with the preparation method of compound 4c in embodiment 4, obtains white Solid.Yield: 47.9%；Fusing point: 140-141 DEG C.
1H NMR(500MHz,CDCl3) δ 8.77 (s, 1H), 7.52 (t, J=8.0Hz, 1H), 7.07 (d, J=8.5Hz, 1H), 7.04 (d, J=7.5Hz, 1H), 4.09 (t, J=7.5Hz, 2H), 2.82 (s, 3H), 1.76-1.70 (m, 2H), 1.43- 1.40 (m, 4H), 0.93 (t, J=7.0Hz, 3H).
C) the N-tert-butyl group-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 7)
Compound 7b (13.5mg, 0.05mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.1mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (9.0mg, 0.06mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 87.3%；Fusing point: 192.6- 193℃。
1H NMR(500MHz,CDCl3) δ 7.49 (t, J=8.0Hz, 1H), 7.06 (d, J=8.5Hz, 1H), 7.02 (d, J =7.5Hz, 1H), 5.55 (s, 1H), 4.63 (s, 2H), 4.11 (t, J=7.5Hz, 2H), 2.80 (s, 3H), 1.76-1.70 (m, 2H), 1.41-1.39 (m, 4H), 1.37 (s, 9H), 0.92 (t, J=7.0Hz, 3H).
Embodiment 8:N-normal-butyl-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 8)
Experimental technique, with the preparation method of compound 7 in embodiment 7, simply instead of compound 1a with compound 5a, To white solid.Yield: 95.9%；Fusing point: 163-164.5 DEG C.
1H NMR(500MHz,CDCl3) δ 7.50 (t, J=8.0Hz, 1H), 7.07 (d, J=8.5Hz, 1H), 7.03 (d, J =7.5Hz, 1H), 5.80 (s, 1H), 4.71 (s, 2H), 4.11 (t, J=8.0Hz, 2H), 3.31-3.27 (q, 2H), 2.80 (s, 3H),1.75-1.70(m,3H),1.53-1.47(m,2H),1.41-1.39(m,4H),1.37-1.33(m,2H),0.94-0.90 (m,6H)。
Embodiment 9:N-cyclohexyl-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 9)
Experimental technique, with the preparation method of compound 7 in embodiment 7, simply instead of compound 1a with compound 6a, To white solid.Yield: 93%；Fusing point: 192.3-193.2 DEG C.
1H NMR(500MHz,CDCl3) δ 7.49 (t, J=8.0Hz, 1H), 7.06 (d, J=8.5Hz, 1H), 7.02 (d, J =7.5Hz, 1H), 5.68 (s, 1H), 4.68 (s, 2H), 4.10 (t, J=7.5Hz, 2H), 3.81-3.78 (m, 1H), 2.80 (s, 3H),1.95-1.93(m,2H),1.74-1.68(m,4H),1.61-1.58(m,1H),1.40-1.39(m,4H),1.36-1.30 (m, 2H), 1.19-1.12 (m, 3H), 0.92 (t, J=7.0Hz, 3H).
The embodiment 10:N-tert-butyl group-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 10)
A) 1-n-hexyl-5-methyl isophthalic acid H-benzo [d] [1,3] piperazine-2,4-diketone (compound 10a)
Experimental technique, with the preparation method of compound 4b in embodiment 4, simply instead of the positive fourth of bromo with bromo normal hexane Alkane, sucking filtration obtains crude product.
B) 1-n-hexyl-5-methylquinazolin-2,4 (1H, 3H)-diketone (compound 10b)
Experimental technique simply instead of compound 4b with compound 10a with the preparation method of compound 4c in embodiment 4, To white solid.Yield: 35.2%.
C) the N-tert-butyl group-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 10)
Compound 10b (15.0mg, 0.06mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.9mg, 0.12mmol), 80 DEG C of reaction 30min, add compound 1a (9.5mg, 0.06mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 78%；Fusing point: 188.1-189 ℃。
1H NMR(400MHz,CDCl3) δ 7.49 (t, J=8.0Hz, 1H), 7.05 (d, J=8.4Hz, 1H), 7.01 (d, J =7.6Hz, 1H), 5.55 (s, 1H), 4.62 (s, 2H), 4.10 (t, J=7.6Hz, 2H), 2.80 (s, 3H), 1.73-1.68 (m, 2H), 1.42-1.40 (m, 2H), 1.37 (s, 9H), 1.34-1.28 (m, 4H), 0.90 (t, J=5.6Hz, 3H).
Embodiment 11:N-normal-butyl-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 11)
Experimental technique, with the preparation method of compound 10 in embodiment 10, simply instead of compound 1a with compound 5a, Obtain white solid.Yield: 71.7%；Fusing point: 165.1-165.9 DEG C.
1H NMR(400MHz,CDCl3) δ 7.50 (t, J=8.0Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 7.02 (d, J =7.2Hz, 1H), 5.82 (s, 1H), 4.70 (s, 2H), 4.10 (t, J=7.6Hz, 2H), 3.31-3.26 (q, 2H), 2.80 (s, 3H),1.72-1.70(m,2H),1.51-1.48(m,2H),1.42-1.40(m,2H),1.33-1.30(m,6H),0.93-0.89 (m,6H)。
Embodiment 12:N-cyclohexyl-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 12)
Experimental technique, with the preparation method of compound 10 in embodiment 10, simply instead of compound 1a with compound 6a, Obtain white solid.Yield: 86.5%；Fusing point: 183.1-184 DEG C.
1H NMR(400MHz,CDCl3) δ 7.50 (t, J=8.0Hz, 1H), 7.06 (d, J=8.8Hz, 1H), 7.02 (d, J =7.6Hz, 1H), 5.61 (d, J=7.2Hz, 1H), 4.68 (s, 2H), 4.10 (t, J=7.6Hz, 2H), 3.83-3.78 (m, 1H),2.80(s,3H),1.95-1.93(m,2H),1.72-1.68(m,5H),1.42-1.40(m,2H),1.34-1.30(m, 6H), 1.19-1.11 (m, 3H), 0.90 (t, J=5.6Hz, 3H).
The embodiment 13:N-tert-butyl group-2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 13)
A) 5-chloro-1H-benzo [d] [1,3] piperazine-2,4-diketone (compound 13a)
By 2-amino-6-chlorobenzoic acid (500.0mg, 2.91mmol), triphosgene (288.3mg, 0.97mmol) as In 25mL single necked round bottom flask, then it is slowly added dropwise into 14mL tetrahydrofuran solution, is heated to 45-50 DEG C, react 3h.Reaction terminates After, concentrated solvent, add normal hexane, separate out solid and filter, be dried to obtain crude product, be directly used in next step reaction.
B) 5-chloro-1-n-pentyl-1H-benzo [d] [1,3] piperazine-2,4-diketone (compound 13b)
Compound 13a (100.0mg, 0.51mmol), sodium hydride (24.3mg, 0.61mmol) are placed in 10mL two-neck bottle In, N2After displacement, add the DMF solution that is dried of 2mL, after room temperature reaction 1h, add bromination of n-butane (75 μ L, 0.61mmol), room temperature reaction is overnight.After reaction terminates, adding appropriate frozen water, stir 10min, sucking filtration goes out solid and obtains crude product.
C) 5-chloro-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 13c)
Compound 13b (97.4mg, 0.36mmol) is placed in 10mL single necked round bottom flask, addition carbamide (65.6mg, 1.09mmol), 2h is reacted in 200 DEG C.After reaction terminates, being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, organic layer Washing with saturated sodium-chloride, anhydrous magnesium sulfate is dried again, and vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, Obtain white solid.Yield: 43.7%；Fusing point: 130-133.4 DEG C.
1H NMR(400MHz,CDCl3) δ 8.83 (s, 1H), 7.54 (t, J=8.4Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.13 (d, J=8.8Hz, 1H), 4.09 (t, J=7.6Hz, 2H), 1.73-1.70 (m, 2H), 1.42-1.38 (m, 4H), 0.93 (t, J=6.0Hz, 3H).
D) the N-tert-butyl group-2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 13)
Compound 13c (20.0mg, 0.07mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (20.7mg, 0.15mmol), 80 DEG C of reaction 30min, add compound 1a (12.3mg, 0.08mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 99%；Fusing point: 212.6-213.2℃。
1H NMR(500MHz,CDCl3) δ 7.51 (t, J=8.5Hz, 1H), 7.25 (d, J=7.5Hz, 1H), 7.12 (dd, J =1.0Hz, J=9.0Hz, 1H), 5.52 (s, 1H), 4.63 (s, 2H), 4.12-4.09 (m, 2H), 1.74-1.71 (m, 2H), 1.41-1.38 (m, 4H), 1.37 (s, 9H), 0.92 (t, J=7.0Hz, 3H).
Embodiment 14:N-normal-butyl-2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 14)
Experimental technique, with the preparation method of compound 13 in embodiment 13, simply instead of compound 1a with compound 5a, Obtain white solid.Yield: 90%；Fusing point: 184.2-184.9 DEG C.
1H NMR(500MHz,CDCl3) δ 7.53 (t, J=8.5Hz, 1H), 7.27 (d, J=7.5Hz, 1H), 7.14 (d, J =8.5Hz, 1H), 5.71 (s, 1H), 4.71 (s, 2H), 4.12 (t, J=7.5Hz, 2H), 3.32-3.28 (q, 2H), 1.76- 1.70(m,2H),1.54-1.48(m,2H),1.42-1.39(m,4H),1.38-1.33(m,2H),0.95-0.91(m,6H)。
Embodiment 15:2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl Acetamide (compound 15)
Experimental technique, with the preparation method of compound 13 in embodiment 13, simply instead of compound 1a with compound 6a, Obtain white solid.Yield: 81.3%；Fusing point: 206.2-206.9 DEG C.
1H NMR(500MHz,CDCl3) δ 7.52 (t, J=8.5Hz, 1H), 7.26 (d, J=7.5Hz, 1H), 7.13 (d, J =8.0Hz, 1H), 5.64 (d, J=7.5Hz, 1H), 4.69 (s, 2H), 4.11 (t, J=7.5Hz, 2H), 3.81-3.75 (m, 1H),1.96-1.93(m,2H),1.74-1.68(m,4H),1.62-1.59(m,1H),1.42-1.39(m,4H),1.36-1.30 (m, 2H), 1.20-1.12 (m, 3H), 0.93 (t, J=7.0Hz, 3H).
The embodiment 16:N-tert-butyl group-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 16)
A) 5-methoxyl group-1H-benzo [d] [1,3] piperazine-2,4-diketone (compound 16a)
By 2-amino-6-methoxybenzoic acid (500.0mg, 2.99mmol), triphosgene (295.9mg, 1.00mmol) extremely In 25mL single necked round bottom flask, then it is slowly added dropwise into 14mL tetrahydrofuran solution, is heated to 45-50 DEG C, react 3h.Reaction knot Shu Hou, concentrated solvent, add normal hexane, separate out solid and filter, be dried to obtain crude product, be directly used in next step reaction.
B) 2-Amino-N-tert-butyl-6-methoxy benzamide (compound 16b)
Compound 16a (100.0mg, 0.52mmol) is dissolved in 2mL DMF solution, be sequentially added into tert-butylamine (60 μ L, 0.57mmol), DMAP (6.3mg, 0.05mmol), room temperature reaction is overnight.After reaction terminates, add appropriate water, ethyl acetate Extraction, organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silica gel column layer Analysis separating-purifying, obtains white solid.Yield: 38.6%；Fusing point: 94.8-95.2 DEG C.
C) the 3-tert-butyl group-5-methoxyquinazoline hydrochloride-2,4 (1H, 3H)-diketone (compound 16c)
Compound 16b (42.2mg, 0.19mmol) is placed in 10mL single necked round bottom flask, adds N, N'-carbonyl diurethane miaow Azoles (64.0mg, 0.39mmol), adds the tetrahydrofuran solution that 1.5mL is dried, and back flow reaction is overnight.After reaction terminates, cold But to room temperature, adding suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, decompression Rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 66.2%.
1H NMR (500MHz, DMSO) δ 10.82 (s, 1H), 7.44 (t, J=8.5Hz, 1H), 6.67 (d, J=8.0Hz, 1H), 6.62 (dd, J=1.0Hz, J=8.5Hz, 1H), 3.80 (s, 3H), 1.60 (s, 9H).
D) the 3-tert-butyl group-5-methoxyl group-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 16d)
Compound 16c (20.0mg, 0.08mmol) is dissolved in 1mL DMF, be sequentially added into Feldalat NM (6.5mg, 0.12mmol), bromo pentane (15 μ L, 0.10mmol), 50 DEG C reaction overnight.After reaction terminates, add appropriate water, acetic acid Ethyl ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silica gel Column chromatography for separation purifies, and obtains yellow liquid, is directly used in next step reaction.
E) 5-methoxyl group-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 16e)
Compound 16d (13.9mg, 0.04mmol) is placed in 10mL single necked round bottom flask, adds 1mL Isosorbide-5-Nitrae-dioxy six Ring solution, magnetic agitation dissolving, add 1mL 6N HCl solution, be heated to reflux, TLC monitoring to reaction is completely.Reaction terminates After, adding appropriate water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, vacuum rotary steam Remove organic solvent, through silica gel column chromatography separating-purifying, obtain white solid, yield: 84.3%；HRMS(ESI):m/z calculated for C14H18N2O3[M+H]+,263.1394；found,263.1351.
F) the N-tert-butyl group-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine (compound 16)
Compound 16e (9.7mg, 0.04mmol) is dissolved in 1.5mL DMF solution, addition potassium carbonate (10.2mg, 0.07mmol), 80 DEG C of reaction 30min, add compound 1a (6.1mg, 0.04mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 93.5%；Fusing point: 198.7- 199℃。
1H NMR(500MHz,CDCl3) δ 7.55 (t, J=8.5Hz, 1H), 6.77 (d, J=8.5Hz, 1H), 6.72 (d, J =8.5Hz, 1H), 5.50 (s, 1H), 4.61 (s, 2H), 4.09 (t, J=8.0Hz, 2H), 3.97 (s, 3H), 1.76-1.71 (m, 2H), 1.41-1.38 (m, 4H), 1.35 (s, 9H), 0.92 (t, J=7.0Hz, 3H).
Embodiment 17:N-normal-butyl-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 17)
Experimental technique, with the preparation method of compound 16 in embodiment 16, simply instead of compound 1a with compound 5a, Obtain white solid.Yield: 95.8%；Fusing point: 181.8-182.4 DEG C.
1H NMR(500MHz,CDCl3) δ 7.56 (t, J=8.5Hz, 1H), 6.77 (d, J=8.5Hz, 1H), 6.72 (d, J =8.5Hz, 1H), 5.89 (d, J=4.5Hz, 1H), 4.68 (s, 2H), 4.07 (t, J=7.5Hz, 2H), 3.96 (s, 3H), 3.27-3.23(q,2H),1.73-1.70(m,2H),1.50-1.44(m,2H),1.40-1.37(m,4H),1.36-1.30(m, 2H),0.93-0.87(m,6H)。
Embodiment 18:N-cyclohexyl-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 18)
Experimental technique, with the preparation method of compound 16 in embodiment 16, simply instead of compound 1a with compound 6a, Obtain white solid.Yield: 91.3%；Fusing point: 206.2-206.9 DEG C.
1H NMR(500MHz,CDCl3) δ 7.56 (t, J=7.5Hz, 1H), 6.78 (d, J=8.5Hz, 1H), 6.72 (d, J =8.5Hz, 1H), 5.64 (s, 1H), 4.67 (s, 2H), 4.08 (t, J=8.0Hz, 2H), 3.96 (s, 3H), 3.80-3.74 (m, 1H),1.94-1.91(m,2H),1.74-1.66(m,4H),1.60-1.57(m,1H),1.41-1.38(m,4H),1.36-1.29 (m, 2H), 1.17-1.09 (m, 3H), 0.92 (t, J=6.5Hz, 3H).
The embodiment 19:N-tert-butyl group-2-(1-ring the third methyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 19)
A) 2-Amino-N-tert-butyl-3-methyl benzamide (compound 19a)
2-amino-3-ar-Toluic acid (800.0mg, 5.29mmol) is placed in 50mL single necked round bottom flask, N2Displacement After, adding 9.8mL thionyl chloride, back flow reaction 3h, then do in reduced under vacuum, the oxolane that addition 7.8mL is dried is molten Liquid；The tetrahydrofuran solution of above-mentioned acyl chlorides is slowly added at 0 DEG C the oxolane of tert-butylamine (5.6mL, 52.92mmol) again In solution (7.8mL), room temperature reaction is overnight.After reaction terminates, after being cooled to room temperature, reactant liquor is concentrated to dryness, and adds suitable quantity of water, Ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, warp Silica gel column chromatography separating-purifying, obtains yellow solid.Yield: 63.7%；Fusing point: 103.6-104.9 DEG C.
1H NMR(500MHz,CDCl3) δ 7.16 (d, J=8.0Hz, 1H), 7.11 (d, J=7.0Hz, 1H), 6.59 (t, J =7.5Hz, 1H), 5.86 (s, 1H), 5.46 (br s, 2H), 2.17 (s, 3H), 1.47 (s, 9H).
B) the 3-tert-butyl group-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 19b)
Compound 19a (100.0mg, 0.48mmol) is dissolved in the DMF solution that 4mL is dried, adds N, N'-carbonyl diurethane Imidazoles (163.5mg, 1.01mmol), back flow reaction is overnight.After reaction terminates, adding suitable quantity of water, ethyl acetate extracts, organic layer Washing with saturated sodium-chloride, anhydrous magnesium sulfate is dried again, and vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, Obtain white solid.Yield: 90.2%；Fusing point: 194-195 DEG C.
C) the 3-tert-butyl group-1-ring the third methyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 19c)
Compound 19b (40.0mg, 0.17mmol) is dissolved in 2mL DMF, be sequentially added into Feldalat NM (14.0mg, 0.26mmol), bromomethyl cyclopropane (18 μ L, 0.19mmol), 50 DEG C reaction overnight.After reaction terminates, add appropriate water, second Acetoacetic ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silicon Plastic column chromatography separating-purifying, obtains yellow liquid, is directly used in next step reaction.
D) 1-ring the third methyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 19d)
Compound 19c (67.3mg, 0.24mmol) is placed in 10mL single necked round bottom flask, adds 2mL Isosorbide-5-Nitrae-dioxy six Ring solution, magnetic agitation dissolving, add 1.6mL 6N HCl solution, be heated to reflux, TLC monitoring to reaction is completely.Reaction knot Shu Hou, adds appropriate water, and ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, decompression rotation Organic solvent is evaporated off, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 21.6%；Fusing point: 177.9-179.2 ℃。
1H NMR(500MHz,CDCl3) δ 8.36 (s, 1H), 8.12 (dd, J=1.5Hz, J=8.0Hz, 1H), 7.49 (dd, J=1.0Hz, J=7.5Hz, 1H), 7.20 (t, J=8.0Hz, 1H), 4.26 (d, J=7.0Hz, 2H), 2.67 (s, 3H), 1.01-0.98(m,1H),0.47-0.44(m,2H),0.35-0.32(m,2H)。
E) the N-tert-butyl group-2-(1-ring the third methyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine (compound 19)
Compound 19d (9.0mg, 0.04mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (10.8mg, 0.08mmol), 80 DEG C of reaction 30min, add compound 1a (6.4mg, 0.04mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 87.3%；Fusing point: 200.5-201 ℃。
1H NMR(500MHz,CDCl3) δ 8.13 (dd, J=1.5Hz, J=7.5Hz, 1H), 7.46 (dd, J=0.5Hz, J =7.5Hz, 1H), 7.17 (t, J=7.5Hz, 1H), 5.55 (s, 1H), 4.63 (s, 2H), 4.27 (d, J=7.0Hz, 2H), 2.64(s,3H),1.36(s,9H),1.01-0.98(m,1H),0.46-0.42(m,2H),0.32-0.29(m,2H)。
Embodiment 20:2-(1-(3-butene-1-yl)-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)- N-tert-butyl group acetamide (compound 20)
A) 1-(3-butene-1-yl)-3-tert-butyl group-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 20a)
Experimental technique, with the preparation method of compound 19c in embodiment 19, simply instead of bromomethyl with the bromo-1-butylene of 4- Cyclopropane, obtains colourless liquid, is directly used in next step reaction.
B) 1-(3-butene-1-yl)-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 20b)
Experimental technique, with the preparation method of compound 19d in embodiment 19, simply instead of compound with compound 20a 19c, obtains white solid.Yield: 27.3%；Fusing point: 139.3-140.3 DEG C.
1H NMR(500MHz,CDCl3) δ 8.76 (s, 1H), 8.11 (dd, J=1.5Hz, J=8.0Hz, 1H), 7.49 (dd, J=1.0Hz, J=7.5Hz, 1H), 7.20 (t, J=7.5Hz, 1H), 5.77-5.69 (m, 1H), 5.03-5.00 (m, 1H), 4.95-4.91 (m, 1H), 4.39 (t, J=7.5Hz, 2H), 2.61 (s, 3H), 2.41-2.36 (m, 2H).
C) 2-(1-(3-butene-1-yl)-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) the tertiary fourth of-N- Yl acetamide (compound 20)
Experimental technique, with the preparation method of compound 19 in embodiment 19, simply instead of compound with compound 20b 19d, obtains white solid.Yield: 93.8%；Fusing point: 204.6-205.9 DEG C.
1H NMR(500MHz,CDCl3) δ 8.12 (dd, J=1.5Hz, J=8Hz, 1H), 7.46 (dd, J=1.0Hz, J= 7.5Hz, 1H), 7.17 (t, J=7.5Hz, 1H), 5.76-5.68 (m, 1H), 5.55 (s, 1H), 5.02-4.95 (m, 2H), 4.62 (s, 2H), 4.36 (t, J=7.5Hz, 2H), 2.60 (s, 3H), 2.44-2.39 (q, 2H), 1.37 (s, 9H).
The embodiment 21:N-tert-butyl group-2-(1-ethyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 21)
A) the 3-tert-butyl group-1-ethyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 21a)
Experimental technique, with the preparation method of compound 19c in embodiment 19, simply instead of bromomethyl ring third with bromoethane Alkane, obtains colourless liquid, is directly used in next step reaction.
B) 1-ethyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 21b)
Experimental technique, with the preparation method of compound 19d in embodiment 19, simply instead of compound with compound 21a 19c, obtains white solid.Yield: 90.9%；Fusing point: 200.7-201.4 DEG C.
1H NMR(500MHz,CDCl3) δ 8.57 (s, 1H), 8.12 (dd, J=1.5Hz, J=8.0Hz, 1H), 7.50 (dd, J=1.0Hz, J=7.5Hz, 1H), 7.19 (t, J=7.5Hz, 1H), 4.34-4.30 (q, 2H), 2.66 (s, 3H), 1.34 (t, J =7.0Hz, 3H).
C) the N-tert-butyl group-2-(1-ethyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 21)
Experimental technique, with the preparation method of compound 19 in embodiment 19, simply instead of compound with compound 21b 19d, obtains white solid.Yield: 96.8%；Fusing point: 204.3-204.7 DEG C.
1H NMR(500MHz,CDCl3) δ 8.12 (dd, J=1.0Hz, J=8.0Hz, 1H), 7.46 (d, J=6.5Hz, 1H), 7.15 (t, J=7.5Hz, 1H), 5.57 (s, 1H), 4.63 (s, 2H), 4.32-4.28 (q, 2H), 2.63 (s, 3H), 1.37 (s, 9H), 1.34 (t, J=7.0Hz, 3H).
The embodiment 22:N-tert-butyl group-2-(8-methyl-2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 22)
A) the 3-tert-butyl group-8-methyl isophthalic acid-n-pro-pyl quinazoline-2,4 (1H, 3H)-diketone (compound 22a)
Experimental technique, with the preparation method of compound 19c in embodiment 19, simply instead of bromomethyl with n-propyl bromide Cyclopropane, obtains colourless liquid, is directly used in next step reaction.
B) 8-methyl isophthalic acid-n-pro-pyl quinazoline-2,4 (1H, 3H)-diketone (compound 22b)
Experimental technique, with the preparation method of compound 19d in embodiment 19, simply instead of compound with compound 22a 19c, obtains white solid.Yield: 28%；Fusing point: 169-169.8 DEG C.
C) the N-tert-butyl group-2-(8-methyl-2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 22)
Experimental technique, with the preparation method of compound 19 in embodiment 19, simply instead of compound with compound 22b 19d, obtains white solid.Yield: 92.2%；Fusing point: 204.0-204.9 DEG C.
1H NMR(500MHz,CDCl3) δ 8.12 (dd, J=0.5Hz, J=7.5Hz, 1H), 7.45 (d, J=7.0Hz, 1H), 7.16 (t, J=8.0Hz, 1H), 5.67 (s, 1H), 4.62 (s, 2H), 4.24 (t, J=7.5Hz, 2H), 2.60 (s, 3H), 1.71-1.67 (m, 2H), 1.37 (s, 9H), 0.89 (t, J=7.5Hz, 3H).
The embodiment 23:N-tert-butyl group-2-(1-normal-butyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 23)
A) the 3-tert-butyl group-1-normal-butyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 23a)
Experimental technique, with the preparation method of compound 19c in embodiment 19, simply instead of bromomethyl with bromination of n-butane Cyclopropane, obtains colourless liquid, is directly used in next step reaction.
B) 1-normal-butyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 23b)
Experimental technique, with the preparation method of compound 19d in embodiment 19, simply instead of compound with compound 23a 19c, obtains white solid.Yield: 42.3%；Fusing point: 124.4-125 DEG C.
C) the N-tert-butyl group-2-(1-normal-butyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 23)
Experimental technique, with the preparation method of compound 19 in embodiment 19, simply instead of compound with compound 23b 19d, obtains white solid.Yield: 81%；Fusing point: 206.0-206.9 DEG C.
1H NMR(500MHz,CDCl3) δ 8.12 (dd, J=1.5Hz, J=8.0Hz, 1H), 7.45 (dd, J=1.0Hz, J =7.5Hz, 1H), 7.16 (t, J=8.0Hz, 1H), 5.54 (s, 1H), 4.63 (s, 2H), 4.28 (t, J=7.5Hz, 2H), 2.60 (s, 3H), 1.66-1.63 (m, 2H), 1.37 (s, 3H), 1.33-1.28 (m, 2H), 0.91 (t, J=7.5Hz, 3H).
The embodiment 24:N-tert-butyl group-2-(1-n-pentyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 24)
A) the 3-tert-butyl group-8-methyl isophthalic acid-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 24a)
Experimental technique, with the preparation method of compound 19c in embodiment 19, simply instead of bromomethyl with bromo pentane Cyclopropane, obtains colourless liquid, is directly used in next step reaction.
B) 8-methyl isophthalic acid-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 24b)
Experimental technique, with the preparation method of compound 19d in embodiment 19, simply instead of compound with compound 24a 19c, obtains white solid.Yield: 50.3%；Fusing point: 125.6-127 DEG C.
1H NMR(500MHz,CDCl3) δ 8.73 (s, 1H), 8.12 (dd, J=1.5Hz, J=8.0Hz, 1H), 7.49- 7.47 (m, 1H), 7.19 (t, J=8.0Hz, 1H), 4.27 (t, J=7.5Hz, 2H), 2.62 (s, 3H), 1.64-1.61 (m, 2H), 1.35-1.25 (m, 4H), 0.88 (t, J=7.0Hz, 3H).
C) the N-tert-butyl group-2-(1-n-pentyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 24)
Experimental technique, with the preparation method of compound 19 in embodiment 19, simply instead of compound with compound 24b 19d, obtains white solid.Yield: 98.2%；Fusing point: 182.5-183.4 DEG C.
1H NMR(500MHz,CDCl3) δ 8.12 (dd, J=1.0Hz, J=8.0Hz, 1H), 7.45 (d, J=7.0Hz, 1H), 7.16 (t, J=7.5Hz, 1H), 5.56 (s, 1H), 4.63 (s, 2H), 4.26 (t, J=8.0Hz, 2H), 2.60 (s, 3H), 1.67-1.64 (m, 2H), 1.37 (s, 9H), 1.32-1.26 (m, 4H), 0.87 (t, J=7.0Hz, 3H).
Embodiment 25:N-normal-butyl-2-(8-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 25)
Experimental technique, with the preparation method of compound 19 in embodiment 19, simply instead of chemical combination with compound 24b respectively Thing 19d, compound 5a instead of compound 1a, obtain white solid.Yield: 98.4%；Fusing point: 164-164.7 DEG C.
1H NMR(500MHz,CDCl3) δ 8.12 (d, J=7.5Hz, 1H), 7.46 (d, J=7.5Hz, 1H), 7.17 (t, J =7.5Hz, 1H), 5.81 (s, 1H), 4.70 (s, 2H), 4.26 (t, J=7.5Hz, 2H), 3.31-3.27 (q, 2H), 2.61 (s, 3H), 1.70-1.65 (m, 2H), 1.53-1.47 (m, 2H), 1.37-1.26 (m, 6H), 0.91 (t, J=7.5Hz, 3H), 0.87 (t, J=7.0Hz, 3H).
Embodiment 26:N-cyclohexyl-2-(1-n-pentyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 26)
Experimental technique, with the preparation method of compound 19 in embodiment 19, simply instead of chemical combination with compound 24b respectively Thing 19d, compound 6a instead of compound 1a, obtain white solid.Yield: 90.1%；Fusing point: 187.3-188 DEG C.
1H NMR(500MHz,CDCl3) δ 8.12 (d, J=7.5Hz, 1H), 7.46 (d, J=7.0Hz, 1H), 7.17 (t, J =7.5Hz, 1H), 5.63 (d, J=5.0Hz, 1H), 4.67 (s, 2H), 4.26 (t, J=8.0Hz, 2H), 3.83-3.77 (m, 1H),2.61(s,3H),1.95-1.93(m,2H),1.71-1.63(m,6H),1.36-1.26(m,6H),1.19-1.12(m, 3H), 0.87 (t, J=7.0Hz, 3H).
The embodiment 27:N-tert-butyl group-2-(8-methyl-2,4-diketone-1-n-hexyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 27)
A) the 3-tert-butyl group-1-n-hexyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 27a)
Experimental technique, with the preparation method of compound 19c in embodiment 19, simply instead of bromomethyl with bromo normal hexane Cyclopropane, obtains colourless liquid, is directly used in next step reaction.
B) 1-n-hexyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (compound 27b)
Experimental technique, with the preparation method of compound 19d in embodiment 19, simply instead of compound with compound 27a 19c, obtains white solid.Yield: 31.9%；Fusing point: 119.6-120.4 DEG C.
C) the N-tert-butyl group-2-(8-methyl-2,4-diketone-1-n-hexyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 27)
Experimental technique, with the preparation method of compound 19 in embodiment 19, simply instead of compound with compound 27b 19d, obtains white solid.Yield: 94.9%；Fusing point: 173.5-174.5 DEG C.
1H NMR(500MHz,CDCl3) δ 8.12 (dd, J=1.0Hz, J=7.5Hz, 1H), 7.45 (d, J=6.5Hz, 1H), 7.16 (t, J=7.5Hz, 1H), 5.56 (s, 1H), 4.63 (s, 2H), 4.26 (t, J=7.5Hz, 2H), 2.60 (s, 3H), 1.66-1.62 (m, 2H), 1.37 (s, 9H), 1.29-1.26 (m, 6H), 0.85 (t, J=6.5Hz, 3H).
The embodiment 28:N-tert-butyl group-2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 28)
A) 2-Amino-N-tert-butyl-3-chlorobenzamide (compound 28a)
2-amino-3-chlorobenzoic acid (800.0mg, 4.66mmol) is placed in 50mL single necked round bottom flask, N2After displacement, Add 8.6mL thionyl chloride, back flow reaction 3h, then do in reduced under vacuum, add the tetrahydrofuran solution that 6.9mL is dried； The oxolane that the tetrahydrofuran solution of above-mentioned acyl chlorides is slowly added at 0 DEG C tert-butylamine (5.0mL, 46.63mmol) again is molten In liquid (6.9mL), room temperature reaction is overnight.After reaction terminates, after being cooled to room temperature, reactant liquor is concentrated to dryness, and adds suitable quantity of water, second Acetoacetic ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silicon Plastic column chromatography separating-purifying, obtains yellow solid.Yield: 87%；Fusing point: 98-98.8 DEG C.
1H NMR(500MHz,CDCl3) δ 7.32 (dd, J=1.5Hz, J=8.0Hz, 1H), 7.19 (dd, J=1.0Hz, J =8.0Hz, 1H), 6.58 (t, J=8.0Hz, 1H), 5.91 (br s, 2H), 5.84 (s, 1H), 1.47 (s, 9H).
B) the 3-tert-butyl group-8-chloro-quinazoline-2,4 (1H, 3H)-diketone (compound 28b)
Compound 28a (100.0mg, 0.44mmol) is dissolved in the DMF solution that 4mL is dried, adds N, N'-carbonyl diurethane Imidazoles (148.8mg, 0.92mmol), back flow reaction is overnight.After reaction terminates, adding suitable quantity of water, ethyl acetate extracts, organic layer Washing with saturated sodium-chloride, anhydrous magnesium sulfate is dried again, and vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, Obtain white solid.Yield: 25.5%；Fusing point: 162-163 DEG C.
C) the 3-tert-butyl group-8-chloro-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 28c)
Compound 28b (83.0mg, 0.33mmol) is dissolved in 2mL DMF, be sequentially added into Feldalat NM (35.5mg, 0.66mmol), bromo pentane (49 μ L, 0.39mmol), 50 DEG C reaction overnight.After reaction terminates, add appropriate water, acetic acid Ethyl ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silica gel Column chromatography for separation purifies, and obtains yellow liquid, is directly used in next step reaction.
D) 8-chloro-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 28d)
Compound 28c (74.9mg, 0.23mmol) is placed in 10mL single necked round bottom flask, adds 2mL Isosorbide-5-Nitrae-dioxy six Ring solution, magnetic agitation dissolving, add 1.6mL 6N HCl solution, be heated to reflux, TLC monitoring to reaction is completely.Reaction knot Shu Hou, adds appropriate water, and ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, decompression rotation Organic solvent is evaporated off, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 37.6%；Fusing point: 191.6-192 DEG C.
1H NMR(500MHz,CDCl3) δ 8.75 (s, 1H), 8.20 (d, J=8.0Hz, 1H), 7.72 (d, J=8.0Hz, 1H), 7.20 (t, J=7.5Hz, 1H), 4.48 (t, J=7.5Hz, 2H), 1.84-1.78 (m, 2H), 1.37-1.32 (m, 4H), 0.91 (t, J=7.0Hz, 3H).
E) the N-tert-butyl group-2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 28)
Compound 28d (10.0mg, 0.04mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (10.4mg, 0.07mmol), 80 DEG C of reaction 30min, add compound 1a (6.2mg, 0.04mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 57%；Fusing point: 169.6-170.2 ℃。
1H NMR(500MHz,CDCl3) δ 8.20 (d, J=7.0Hz, 1H), 7.69 (d, J=7.5Hz, 1H), 7.17 (t, J =8.0Hz, 1H), 5.51 (s, 1H), 4.62 (s, 2H), 4.45 (t, J=8.0Hz, 2H), 1.87-1.81 (m, 2H), 1.37 (s, 9H), 1.37-1.34 (m, 4H), 0.90 (t, J=7.0Hz, 3H).
Embodiment 29:N-normal-butyl-2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 29)
Experimental technique, with the preparation method of compound 28 in embodiment 28, simply instead of compound 1a with compound 5a, Obtain white solid.Yield: 47.9%；Fusing point: 160.6-161 DEG C.
1H NMR(500MHz,CDCl3) δ 8.20 (dd, J=1.0Hz, J=8.0Hz, 1H), 7.70 (dd, J=1.5Hz, J =8.0Hz, 1H), 7.19 (t, J=7.5Hz, 1H), 5.71 (s, 1H), 4.69 (s, 2H), 4.45 (t, J=8.0Hz, 2H), 3.32-3.28(q,2H),1.88-1.82(m,2H),1.54-1.48(m,2H),1.38-1.32(m,6H),0.94-0.89(m, 6H)。
Embodiment 30:2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl Acetamide (compound 30)
Experimental technique, with the preparation method of compound 28 in embodiment 28, simply instead of compound 1a with compound 6a, Obtain white solid.Yield: 98%；Fusing point: 189.6-190.2 DEG C.
1H NMR(500MHz,CDCl3) δ 8.20 (d, J=8.0Hz, 1H), 7.69 (d, J=7.5Hz, 1H), 7.18 (t, J =8.0Hz, 1H), 5.59 (s, 1H), 4.67 (s, 2H), 4.45 (t, J=8.0Hz, 2H), 3.80-3.79 (m, 1H), 1.95 (m, 2H),1.85-1.83(m,2H),1.72-1.69(m,2H),1.60(s,1H),1.37-1.32(m,6H),1.20-1.13(m, 3H), 0.90 (t, J=7.0Hz, 3H).
The embodiment 31:N-tert-butyl group-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 31)
A) 8-methoxyl group-1H-benzo [d] [1,3] piperazine-2,4-diketone (compound 31a)
By 2-amino-3-methoxybenzoic acid (500.0mg, 2.99mmol), triphosgene (295.9mg, 1.00mmol) extremely In 50mL single necked round bottom flask, then it is slowly added dropwise into 14mL tetrahydrofuran solution, is heated to 45-50 DEG C, react 3h.Reaction knot Shu Hou, concentrated solvent, add normal hexane, separate out solid and filter, be dried to obtain crude product, be directly used in next step reaction.
B) 8-methoxyl group-1-n-pentyl-1H-benzo [d] [1,3] piperazine-2,4-diketone (compound 31b)
Compound 31a (300.0mg, 1.55mmol), sodium hydride (74.5mg, 1.86mmol) are placed in 25mL two-neck bottle In, N2After displacement, add the DMF solution that is dried of 4mL, after room temperature reaction 1h, add bromination of n-butane (230 μ L, 1.86mmol), room temperature reaction is overnight.After reaction terminates, adding appropriate frozen water, stir 10min, sucking filtration goes out solid and obtains crude product.
C) 8-methoxyl group-1 n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 31c)
Compound 31b (200.0mg, 0.76mmol) is placed in 10mL single necked round bottom flask, addition carbamide (136.9mg, 2.28mmol), 2h is reacted in 200 DEG C.After reaction terminates, being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, organic layer Washing with saturated sodium-chloride, anhydrous magnesium sulfate is dried again, and vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, Obtain yellow solid, yield: 29.1%.
D) the N-tert-butyl group-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine (compound 31)
Compound 31c (20.4mg, 0.08mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (21.5mg, 0.16mmol), 80 DEG C of reaction 30min, add compound 1a (12.8mg, 0.09mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 84.9%；Fusing point: 189- 189.4℃。
1H NMR(500MHz,CDCl3) δ 7.86 (dd, J=1.5Hz, J=7.5Hz, 1H), 7.20-7.16 (m, 2H), 5.58 (s, 1H), 4.63 (s, 2H), 4.36 (t, J=7.5Hz, 2H), 3.91 (s, 3H), 1.79-1.73 (m, 2H), 1.36 (s, 9H), 1.36-1.33 (m, 4H), 0.91 (t, J=7.0Hz, 3H).
Embodiment 32:N-normal-butyl-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 32)
Experimental technique, with the preparation method of compound 31 in embodiment 31, simply instead of compound 1a with compound 5a, Obtain white solid.Yield: 81.9%；Fusing point: 165.5-166 DEG C.
1H NMR(500MHz,CDCl3) δ 7.87 (d, J=7.0Hz, 1H), 7.21-7.17 (m, 2H), 5.85 (s, 1H), 4.71 (s, 2H), 4.36 (t, J=8.0Hz, 2H), 3.92 (s, 3H), 3.30-3.26 (q, 2H), 1.79-1.73 (m, 2H), 1.52-1.46(m,2H),1.38-1.32(m,6H),0.93-0.89(m,6H)。
Embodiment 33:N-cyclohexyl-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 33)
Experimental technique, with the preparation method of compound 31 in embodiment 31, simply instead of compound 1a with compound 6a, Obtain white solid.Yield: 93.7%；Fusing point: 210.8-211 DEG C.
1H NMR(500MHz,CDCl3) δ 7.87 (dd, J=2.5Hz, J=7.0Hz, 1H), 7.21-7.16 (m, 2H), 5.69 (d, J=7.5Hz, 1H), 4.69 (s, 2H), 4.36 (t, J=7.5Hz, 2H), 3.92 (s, 3H), 3.82-3.76 (m, 1H),1.95-1.92(m,2H),1.79-1.74(m,3H),1.71-1.67(m,2H),1.61-1.58(m,1H),1.38-1.33 (m, 5H), 1.19-1.11 (m, 3H), 0.92 (t, J=7.0Hz, 3H).
The embodiment 34:N-tert-butyl group-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 34)
A) 2-Amino-N-tert-butyl-4,5-dimethoxybenzarnide (compound 34a)
By 2-amino-4,5-dimethoxybenzoic acid (500.0mg, 2.54mmol) is placed in 25mL single necked round bottom flask, N2After displacement, add 4.7mL thionyl chloride, back flow reaction 3h, then do in reduced under vacuum, add the tetrahydrochysene that 3.8mL is dried Tetrahydrofuran solution；The tetrahydrofuran solution of above-mentioned acyl chlorides is slowly added at 0 DEG C the four of tert-butylamine (2.7mL, 25.36mmol) again In hydrogen tetrahydrofuran solution (3.8mL), room temperature reaction is overnight.After reaction terminates, after being cooled to room temperature, reactant liquor is concentrated to dryness, and adds Suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic Solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 72.5%.
1H NMR(500MHz,CDCl3)δ6.79(s,1H),6.19(s,1H),5.82(s,1H),4.68(br s,2H), 3.83(s,3H),3.80(s,3H),1.44(s,9H)。
B) ethyl (2-(t-Butylcarbamoyl)-4,5-methoxyphenyl) carbamate (compound 34b)
Compound 34a (211.2mg, 0.84mmol) is placed in 10mL single necked round bottom flask, adds 2.1mL chloro-carbonic acid second Ester, 95 DEG C of reaction 3h.After reaction terminates, adding suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, nothing Water magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 79.1%；Fusing point: 105.5-106.5 DEG C.
1H NMR(500MHz,CDCl3)δ10.53(s,1H),8.09(s,1H),6.81(s,1H),5.79(s,1H), 4.23-4.19 (q, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 1.48 (s, 9H), 1.32 (t, J=7.5Hz, 3H).
C) the 3-tert-butyl group-6,7-dimethoxyquinazoline-2,4 (1H, 3H)-diketone (compound 34c)
Compound 34b (120.0mg, 0.37mmol) is dissolved in 2mL ethanol solution, adds potassium hydroxide (166.1mg, 2.96mmol), back flow reaction 9h.After reaction terminates, it is concentrated to dryness, adds a small amount of aqueous solvent, and sour with 1M HCl Separate out solid sucking filtration after change, obtain crude yellow solid.
1H NMR(500MHz,CDCl3)δ10.31(s,1H),7.41(s,1H),6.47(s,1H),3.93(s,3H),3.91 (s,3H),1.81(s,9H)。
D) the 3-tert-butyl group-6,7-dimethoxy-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 34d)
Compound 34c (67.3mg, 0.24mmol) is dissolved in 2mL DMF, be sequentially added into Feldalat NM (26.1mg, 0.48mmol), bromo pentane (45 μ L, 0.36mmol), 50 DEG C reaction overnight.After reaction terminates, add appropriate water, acetic acid Ethyl ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silica gel Column chromatography for separation purifies, and obtains colourless liquid, is directly used in next step reaction.
E) 6,7-dimethoxy-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 34e)
Compound 34d (43.5mg, 0.12mmol) is placed in 10mL single necked round bottom flask, adds 2mL Isosorbide-5-Nitrae-dioxy six Ring solution, magnetic agitation dissolving, add 1.6mL 6N HCl solution, be heated to reflux, TLC monitoring to reaction is completely.Reaction knot Shu Hou, adds appropriate water, and ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, decompression rotation Organic solvent is evaporated off, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 82.2%；Fusing point: 195.1-196.3 ℃。
1H NMR(500MHz,CDCl3) δ 8.40 (s, 1H), 7.59 (s, 1H), 6.63 (s, 1H), 4.09 (t, J=7.5Hz, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 1.80-1.74 (m, 2H), 1.44-1.42 (m, 4H), 0.95 (t, J=7.0Hz, 3H)。
F) the N-tert-butyl group-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 34)
Compound 34e (10.0mg, 0.03mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (9.5mg, 0.07mmol), 80 DEG C of reaction 30min, add compound 1a (5.6mg, 0.04mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 93.5%；Fusing point: 172.2- 174.2℃。
1H NMR(500MHz,CDCl3)δ7.60(s,1H),6.60(s,1H),5.56(s,1H),4.65(s,2H),4.10 (t, J=7.5Hz, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 1.77-1.74 (m, 2H), 1.43-1.40 (m, 4H), 1.37 (s, 9H), 0.93 (t, J=7.0Hz, 3H).
Embodiment 35:N-normal-butyl-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 35)
Experimental technique, with the preparation method of compound 34 in embodiment 34, simply instead of compound 1a with compound 5a, Obtain white solid.Yield: 93.5%；Fusing point: 149.6-150.6 DEG C.
1H NMR(500MHz,CDCl3)δ7.59(s,1H),6.60(s,1H),5.84(s,1H),4.72(s,2H),4.09 (t, J=7.5Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.30-3.26 (q, 2H), 1.74-1.77 (m, 2H), 1.53- 1.47(m,2H),1.41-1.40(m,4H),1.38-1.32(m,2H),0.94-0.89(m,6H)。
Embodiment 36:N-cyclohexyl-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 36)
Experimental technique, with the preparation method of compound 34 in embodiment 34, simply instead of compound 1a with compound 6a, Obtain white solid.Yield: 99.3%；Fusing point: 174.5-175.9 DEG C.
1H NMR(500MHz,CDCl3)δ7.60(s,1H),6.61(s,1H),5.66(s,1H),4.70(s,2H),4.10 (t, J=8.0Hz, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 3.80-3.78 (m, 1H), 1.95-1.93 (m, 2H), 1.77- 1.68(m,4H),1.61-1.58(m,1H),1.42-1.40(m,4H),1.35-1.30(m,2H),1.19-1.12(m,3H), 0.93 (t, J=7.0Hz, 3H).
The embodiment 37:N-tert-butyl group-2-(7-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 37)
A) 2-Amino-N-tert-butyl-4-chlorobenzamide (compound 37a)
2-amino-4-chlorobenzoic acid (500.0mg, 2.91mmol) is placed in 25mL single necked round bottom flask, N2After displacement, Add 5.4mL thionyl chloride, back flow reaction 3h, then do in reduced under vacuum, add the tetrahydrofuran solution that 4.3mL is dried； The oxolane that the tetrahydrofuran solution of above-mentioned acyl chlorides is slowly added at 0 DEG C tert-butylamine (3.1mL, 29.14mmol) again is molten In liquid (4.3mL), room temperature reaction is overnight.After reaction terminates, after being cooled to room temperature, reactant liquor is concentrated to dryness, and adds suitable quantity of water, second Acetoacetic ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silicon Plastic column chromatography separating-purifying, obtains white solid.Yield: 72.8%；Fusing point: 111.3-112.8 DEG C.
B) methyl (2-(t-Butylcarbamoyl)-5-chlorphenyl) carbamate (compound 37b)
Compound 37a (200.0mg, 0.88mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (882 μ L) and 1M NaOH (882 μ L) In, add methylchloroformate (75 μ L, 0.97mmol), room temperature reaction 30min.After reaction terminates, pour in 1M HCl solution, analysis Go out solid to filter, obtain white solid, be directly used in next step reaction.
1H NMR(500MHz,CDCl3) δ 10.57 (s, 1H), 8.44 (d, J=2.0Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 6.97 (dd, J=2.0Hz, J=8.5Hz, 1H), 5.92 (s, 1H), 3.78 (s, 3H), 1.47 (s, 9H).
C) the 3-tert-butyl group-7-chloro-quinazoline-2,4 (1H, 3H)-diketone (compound 37c)
Compound 37b (126.7mg, 0.44mmol) is dissolved in 2.2mL ethanol solution, adds potassium hydroxide (249.7mg, 4.45mmol), back flow reaction is overnight.After reaction terminates, it is concentrated to dryness, adds a small amount of aqueous solvent, and use 1M HCl Separate out solid sucking filtration after acidifying, obtain crude yellow solid.
1H NMR(500MHz,CDCl3) δ 10.26 (s, 1H), 7.95 (d, J=8.5Hz, 1H), 7.13 (dd, J=2.0Hz, J=8.5Hz, 1H), 7.00 (d, J=1.5Hz, 1H), 1.80 (s, 9H).
D) the 3-tert-butyl group-7-chloro-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 37d)
Compound 37c (47mg, 0.19mmol) is dissolved in 2mL DMF, be sequentially added into Feldalat NM (20.1mg, 0.37mmol), bromo pentane (28 μ L, 0.22mmol), 50 DEG C reaction overnight.After reaction terminates, add appropriate water, acetic acid Ethyl ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silica gel Column chromatography for separation purifies, and obtains colourless liquid, is directly used in next step reaction.
E) 7-chloro-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 37e)
Compound 37d (45.6mg, 0.14mmol) is placed in 10mL single necked round bottom flask, adds 2mL Isosorbide-5-Nitrae-dioxy six Ring solution, magnetic agitation dissolving, add 1.8mL 6N HCl solution, be heated to reflux, TLC monitoring to reaction is completely.Reaction knot Shu Hou, adds appropriate water, and ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, decompression rotation Organic solvent is evaporated off, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 48.8%；Fusing point: 157.2-158.5 ℃。
1H NMR(500MHz,CDCl3) δ 8.62 (s, 1H), 8.15 (d, J=8.0Hz, 1H), 7.24 (dd, J=1.5Hz, J =8.0Hz, 1H), 7.19 (d, J=2.0Hz, 1H), 4.06 (t, J=8.0Hz, 2H), 1.77-1.71 (m, 2H), 1.44-1.41 (m, 4H), 0.95 (t, J=7.0Hz, 3H).
F) the N-tert-butyl group-2-(7-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 37)
Compound 37e (10.0mg, 0.04mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (10.4mg, 0.07mmol), 80 DEG C of reaction 30min, add compound 1a (6.2mg, 0.04mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 97.5%；Fusing point: 157.9- 159.2℃。
1H NMR(500MHz,CDCl3) δ 8.15 (d, J=8.5Hz, 1H), 7.20 (dd, J=0.5Hz, J=8.5Hz, 1H), 7.17 (s, 1H), 5.55 (s, 1H), 4.64 (s, 2H), 4.07 (t, J=7.5Hz, 2H), 1.74-1.70 (m, 2H), 1.43-1.40 (m, 4H), 1.37 (s, 9H), 0.94 (t, J=7.0Hz, 3H).
Embodiment 38:2-(7-bromo-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group Acetamide (compound 38)
A) 2-amino-4-bromo-N-t-butylbenzamide (compound 38a)
2-amino-4-bromobenzoic acid (500.0mg, 2.31mmol) is placed in 25mL single necked round bottom flask, N2After displacement, Add 4.3mL thionyl chloride, back flow reaction 3h, then do in reduced under vacuum, add the tetrahydrofuran solution that 3.4mL is dried； The oxolane that the tetrahydrofuran solution of above-mentioned acyl chlorides is slowly added at 0 DEG C tert-butylamine (2.5mL, 23.14mmol) again is molten In liquid (3.4mL), room temperature reaction is overnight.After reaction terminates, after being cooled to room temperature, reactant liquor is concentrated to dryness, and adds suitable quantity of water, second Acetoacetic ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silicon Plastic column chromatography separating-purifying, obtains white solid.Yield: 48.5%；Fusing point: 114.8-116.2 DEG C.
B) ethyl (5-bromo-2-(t-Butylcarbamoyl) phenyl) carbamate (compound 38b)
Compound 38a (100.0mg, 0.88mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (882 μ L) and 1M NaOH (882 μ L) In, add methylchloroformate (75 μ L, 0.97mmol), room temperature reaction 30min.After reaction terminates, pour in 1M HCl solution, analysis Go out solid to filter, obtain white solid, be directly used in next step reaction.
Compound 38a (100.0mg, 0.37mmol) is placed in 10mL single necked round bottom flask, adds 1.0mL chloro-carbonic acid second Ester, 95 DEG C of reaction 3h.After reaction terminates, adding suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, nothing Water magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 93.8%；Fusing point: 150-151.5 DEG C.
1H NMR(500MHz,CDCl3) δ 10.44 (s, 1H), 8.62 (s, 1H), 7.22 (d, J=8.5Hz, 1H), 7.11 (dd, J=1.5Hz, J=8.0Hz, 1H), 5.93 (s, 1H), 4.24-4.20 (q, 2H), 1.47 (s, 9H), 1.33 (t, J= 7.0Hz,3H)。
C) 7-bromo-3-tert-butyl group quinazoline-2,4 (1H, 3H)-diketone (compound 38c)
Compound 38b (112.5mg, 0.34mmol) is dissolved in 1.7mL ethanol solution, adds potassium hydroxide (191.8mg, 3.42mmol), back flow reaction is overnight.After reaction terminates, it is concentrated to dryness, adds a small amount of aqueous solvent, and use 1M HCl Separate out solid sucking filtration after acidifying, obtain crude yellow solid.
1H NMR(500MHz,CDCl3) δ 10.07 (s, 1H), 7.87 (d, J=8.5Hz, 1H), 7.29 (dd, J=1.5Hz, J=8.5Hz, 1H), 7.17 (d, J=1.5Hz, 1H), 1.80 (s, 9H).
D) the 7-bromo-3-tert-butyl group-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 38d)
Compound 38c (46mg, 0.15mmol) is dissolved in 2mL DMF, be sequentially added into Feldalat NM (16.7mg, 0.31mmol), bromo pentane (23 μ L, 0.19mmol), 50 DEG C reaction overnight.After reaction terminates, add appropriate water, acetic acid Ethyl ester extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and vacuum rotary steam removes organic solvent, through silica gel Column chromatography for separation purifies, and obtains colourless liquid, is directly used in next step reaction.
E) 7-bromo-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 38e)
Compound 38d (45.4mg, 0.12mmol) is placed in 10mL single necked round bottom flask, adds 2mL Isosorbide-5-Nitrae-dioxy six Ring solution, magnetic agitation dissolving, add 1.8mL 6N HCl solution, be heated to reflux, TLC monitoring to reaction is completely.Reaction knot Shu Hou, adds appropriate water, and ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, decompression rotation Organic solvent is evaporated off, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 49.1%；Fusing point: 141.4-142.6 ℃。
1H NMR(500MHz,CDCl3) δ 8.46 (s, 1H), 8.07 (d, J=8.5Hz, 1H), 7.40 (dd, J=1.5Hz, J =8.5Hz, 1H), 7.36 (d, J=1.5Hz, 1H), 4.06 (t, J=7.5Hz, 3H), 1.76-1.70 (m, 2H), 1.44-1.41 (m, 4H), 0.95 (t, J=7.0Hz, 3H).
F) 2-(7-bromo-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group acetamide (compound 38)
Compound 38e (10.0mg, 0.03mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (8.88mg, 0.06mmol), 80 DEG C of reaction 30min, add compound 1a (5.3mg, 0.04mmol), 80 DEG C of reactions are overnight.After reaction terminates, Being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is dried, and subtracts Pressure rotation is evaporated off organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 97.6%；Fusing point: 166.4- 167.6℃。
1H NMR(500MHz,CDCl3) δ 8.07 (d, J=8.5Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.34 (s, 1H), 5.53 (s, 1H), 4.63 (s, 2H), 4.07 (t, J=8.0Hz, 2H), 1.75-1.71 (m, 2H), 1.43-1.40 (m, 4H), 1.37 (s, 9H), 0.94 (t, J=7.0Hz, 3H).
The embodiment 39:N-tert-butyl group-2-(7-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 39)
A) 4-methyl-2-(n-pentyl amino) benzoic acid (compound 39a)
2-amino-4-ar-Toluic acid (907.2mg, 6.0mmol) is dissolved in 18mL acetonitrile and 6mL water, is sequentially added into Anhydrous potassium carbonate (1.82g, 6.0mmol), potassium iodide (99.6mg, 0.6mmol), add bromo positive penta after half an hour is stirred at room temperature Alkane (744 μ L, 6.0mmol), heating reflux reaction 24h.Reaction is cooled to room temperature after terminating, and rotation as far as possible is evaporated off solvent second Nitrile, adds 10mL water, and ethyl acetate extracts, and merges organic facies and is dried through saturated aqueous common salt washing, anhydrous magnesium sulfate, decompression distillation Obtain crude product.Through column chromatographic isolation and purification, obtain yellow solid.Yield: 23.2%；Fusing point: 138.2-139.1 DEG C.
B) 7-methyl isophthalic acid-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 39b)
Take compound 39a (305.1mg, 1.38mmol) in reaction bulb, add carbamide (331.2mg, 5.51mmol), nothing 200 DEG C of reaction 1h it are heated under solvent condition.Reaction is cooled to room temperature after terminating, add 10mL water, and ethyl acetate extracts, and merges Organic facies is washed through saturated aqueous common salt, anhydrous magnesium sulfate is dried, and crude product is distilled to obtain in decompression.Through column chromatographic isolation and purification, obtain White solid.Yield: 21.0%；Fusing point: 130.8-131.9 DEG C.
C) the N-tert-butyl group-2-(7-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 39)
Compound 39b (24.6mg, 0.10mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.2mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (15.0mg, 0.10mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 90.4%；Fusing point: 136.4-137.5℃。
1H NMR(CDCl3, 500MHz): δ 8.08 (d, J=8.0Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 6.95 (s, 1H), 5.68 (s, 1H), 4.64 (s, 2H), 4.08 (t, J=7.0Hz, 2H), 2.47 (s, 3H), 1.75-1.69 (m, 2H), 1.41-1.35 (m, 13H), 0.92 (t, J=7.0Hz, 3H).
The embodiment 40:N-tert-butyl group-2-(6-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 40)
A) 5-methyl-2-(n-pentyl amino) benzoic acid (compound 40a)
2-amino-5-ar-Toluic acid (907.2mg, 6.0mmol) is dissolved in 18mL acetonitrile and 6mL water, is sequentially added into Anhydrous potassium carbonate (1.82g, 6.0mmol), potassium iodide (99.6mg, 0.6mmol), add bromo positive penta after half an hour is stirred at room temperature Alkane (744 μ L, 6.0mmol), heating reflux reaction 24h.Reaction is cooled to room temperature after terminating, and rotation as far as possible is evaporated off solvent second Nitrile, adds 10mL water, and ethyl acetate extracts, and merges organic facies and is dried through saturated aqueous common salt washing, anhydrous magnesium sulfate, decompression distillation Obtain crude product.Through column chromatographic isolation and purification, obtain yellow solid.Yield: 19.1%；Fusing point: 128.1-129.4 DEG C.
B) 6-methyl isophthalic acid-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 40b)
Take compound 39a (250.3mg, 1.13mmol) in reaction bulb, add carbamide (271.7mg, 4.52mmol), nothing 200 DEG C of reaction 1h it are heated under solvent condition.Reaction is cooled to room temperature after terminating, add 10mL water, and ethyl acetate extracts, and merges Organic facies is washed through saturated aqueous common salt, anhydrous magnesium sulfate is dried, and crude product is distilled to obtain in decompression.Through column chromatographic isolation and purification, obtain White solid.Yield: 51.7%；Fusing point: 107.5-109 DEG C.
C) the N-tert-butyl group-2-(6-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 40)
Compound 40b (24.6mg, 0.10mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.2mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (15.0mg, 0.10mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 90.1%；Fusing point: 186.4-187.7℃。
1H NMR(CDCl3, 500MHz): δ 8.01 (d, J=1.0Hz, 1H), 7.46 (dd, J=8.5,1.5Hz, 1H), 7.07 (d, J=8.5Hz, 1H), 5.69 (s, 1H), 4.65 (s, 2H), 4.07 (t, J=8.0Hz, 2H), 2.38 (s, 3H), 1.74-1.68 (m, 2H), 1.41-1.35 (m, 13H), 0.91 (t, J=7.0Hz, 3H).
The embodiment 41:N-tert-butyl group-2-(6-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)- Base) acetamide (compound 41)
A) 5-methoxyl group-2-(n-pentyl amino) benzoic acid (compound 41a)
2-amino-5-methoxybenzoic acid (835.8mg, 5.0mmol) is dissolved in 18mL acetonitrile and 6mL water, adds successively Enter Anhydrous potassium carbonate (1.52g, 11.0mmol), potassium iodide (83.0mg, 0.5mmol), after half an hour is stirred at room temperature, add bromo Pentane (620 μ L, 5.0mmol), heating reflux reaction 24h.Reaction is cooled to room temperature after terminating, and rotation as far as possible is evaporated off solvent Acetonitrile, adds 10mL water, and ethyl acetate extracts, and merges organic facies and is dried through saturated aqueous common salt washing, anhydrous magnesium sulfate, and decompression is steamed Evaporate to obtain crude product.Through column chromatographic isolation and purification, obtain yellow solid.Yield: 24.9%；Fusing point: 100.3-101.5 DEG C.
B) 6-methoxyl group-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 41b)
Take compound 40a (295.4mg, 1.24mmol) in reaction bulb, add carbamide (299.1mg, 4.98mmol), nothing 200 DEG C of reaction 1h it are heated under solvent condition.Reaction is cooled to room temperature after terminating, add 10mL water, and ethyl acetate extracts, and merges Organic facies is washed through saturated aqueous common salt, anhydrous magnesium sulfate is dried, and crude product is distilled to obtain in decompression.Through column chromatographic isolation and purification, obtain White solid.Yield: 67.9%；Fusing point: 172.9-173.9 DEG C.
C) the N-tert-butyl group-2-(6-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetyl Amine (compound 41)
Compound 41b (26.2mg, 0.10mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.2mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (15.0mg, 0.10mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 82%；Fusing point: 142.8- 143.8℃。
1H NMR(CDCl3, 500MHz): δ 7.65 (d, J=8.0Hz, 1H), 7.25 (dd, J=9.0,3.0Hz, 1H), 7.12 (d, J=9.5Hz, 1H), 5.66 (s, 1H), 4.66 (s, 2H), 4.07 (t, J=7.5Hz, 2H), 3.85 (s, 3H), 1.74-1.68 (m, 2H), 1.40-1.33 (m, 13H), 0.91 (t, J=7.0Hz, 3H).
The embodiment 42:N-tert-butyl group-2-(6-fluoro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 42)
A) the fluoro-2-of 5-(n-pentyl amino) benzoic acid (compound 42a)
2-amino-5-fluorobenzoic acid (930.8mg, 6.0mmol) is dissolved in 18mL acetonitrile and 6mL water, is sequentially added into nothing Aqueous carbonate potassium (1.82g, 13.2mmol), potassium iodide (99.6mg, 0.6mmol), add bromo positive penta after half an hour is stirred at room temperature Alkane (744 μ L, 6.0mmol), heating reflux reaction 24h.Reaction is cooled to room temperature after terminating, and rotation as far as possible is evaporated off solvent second Nitrile, adds 10mL water, and ethyl acetate extracts, and merges organic facies and is dried through saturated aqueous common salt washing, anhydrous magnesium sulfate, decompression distillation Obtain crude product.Through column chromatographic isolation and purification, obtain yellow solid.Yield: 19.1%；Fusing point: 80.5-82 DEG C.
B) 6-fluoro-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 42b)
Take compound 41a (256.0mg, 1.14mmol) in reaction bulb, add carbamide (273.0mg, 4.55mmol), nothing 200 DEG C of reaction 1h it are heated under solvent condition.Reaction is cooled to room temperature after terminating, add 10mL water, and ethyl acetate extracts, and merges Organic facies is washed through saturated aqueous common salt, anhydrous magnesium sulfate is dried, and crude product is distilled to obtain in decompression.Through column chromatographic isolation and purification, obtain White solid.Yield: 51.5%；Fusing point: 140.7-141.8 DEG C.
C) the N-tert-butyl group-2-(6-fluoro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 42)
Compound 42b (25.0mg, 0.10mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.2mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (15.0mg, 0.11mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 90.3%；Fusing point: 180.8-182.3℃。
1H NMR(CDCl3, 500MHz): δ 7.88 (dd, J=8.0,3.0Hz, 1H), 7.41-7.37 (m, 1H), 7.16 (dd, J=9.5,4.0Hz, 1H), 5.63 (s, 1H), 4.64 (s, 2H), 4.09 (t, J=7.5Hz, 2H), 1.74-1.68 (m, 2H), 1.41-1.36 (m, 13H), 0.91 (t, J=7.0Hz, 3H).
The embodiment 43:N-tert-butyl group-2-(6-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) Acetamide (compound 43)
A) the chloro-2-of 5-(n-pentyl amino) benzoic acid (compound 43a)
2-amino-5-chlorobenzoic acid (1.03g, 6.0mmol) is dissolved in 18mL acetonitrile and 6mL water, is sequentially added into anhydrous Potassium carbonate (1.82g, 13.2mmol), potassium iodide (99.6mg, 0.6mmol), add bromo pentane after half an hour is stirred at room temperature (893 μ L, 7.2mmol), heating reflux reaction 24h.Reaction is cooled to room temperature after terminating, and rotation as far as possible is evaporated off solvent acetonitrile, Adding 10mL water, ethyl acetate extracts, and merges organic facies and is dried through saturated aqueous common salt washing, anhydrous magnesium sulfate, and decompression is distilled Crude product.Through column chromatographic isolation and purification, obtain yellow solid.Yield: 8.2%；Fusing point: 114.7-116.1 DEG C.
B) 6-chloro-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 43b)
Take compound 43a (118.6mg, 0.49mmol) in reaction bulb, add carbamide (117.9mg, 1.96mmol), nothing 200 DEG C of reaction 1h it are heated under solvent condition.Reaction is cooled to room temperature after terminating, add 10mL water, and ethyl acetate extracts, and merges Organic facies is washed through saturated aqueous common salt, anhydrous magnesium sulfate is dried, and crude product is distilled to obtain in decompression.Through column chromatographic isolation and purification, obtain White solid.Yield: 51.3%；Fusing point: 146.7-148 DEG C.
C) the N-tert-butyl group-2-(6-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 43)
Compound 43b (21.3mg, 0.08mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (12.2mg, 0.09mmol), 80 DEG C of reaction 30min, add compound 1a (12.0mg, 0.08mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 99.3%；Fusing point: 172.2-173.3℃。
1H NMR(CDCl3, 500MHz): δ 8.17 (s, 1H), 7.59 (dd, J=9.0,2.0Hz, 1H), 7.13 (d, J= 9.0Hz, 1H), 5.60 (s, 1H), 4.64 (s, 2H), 4.08 (t, J=8.0Hz, 2H), 1.73-1.68 (m, 2H), 1.40-1.36 (m, 13H), 0.91 (t, J=7.0Hz, 3H).
Embodiment 44:2-(6-bromo-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group Acetamide (compound 44)
A) the bromo-2-of 5-(n-pentyl amino) benzoic acid (compound 44a)
2-amino-5-bromobenzoic acid (1.08g, 5.0mmol) is dissolved in 18mL acetonitrile and 6mL water, is sequentially added into anhydrous Potassium carbonate (1.52g, 11.0mmol), potassium iodide (83.0mg, 0.5mmol), add bromo pentane after half an hour is stirred at room temperature (620 μ L, 5.0mmol), heating reflux reaction 24h.Reaction is cooled to room temperature after terminating, and rotation as far as possible is evaporated off solvent acetonitrile, Adding 10mL water, ethyl acetate extracts, and merges organic facies and is dried through saturated aqueous common salt washing, anhydrous magnesium sulfate, and decompression is distilled Crude product.Through column chromatographic isolation and purification, obtain yellow solid.Yield: 9.8%；Fusing point: 131.8-132.9 DEG C.
B) 6-bromo-1-n-pentyl quinazoline-2,4 (1H, 3H)-diketone (compound 44b)
Take compound 44a (139.5mg, 0.49mmol) in reaction bulb, add carbamide (117.1mg, 1.95mmol), nothing 200 DEG C of reaction 1h it are heated under solvent condition.Reaction is cooled to room temperature after terminating, add 10mL water, and ethyl acetate extracts, and merges Organic facies is washed through saturated aqueous common salt, anhydrous magnesium sulfate is dried, and crude product is distilled to obtain in decompression.Through column chromatographic isolation and purification, obtain White solid.Yield: 51.3%；Fusing point: 138.6-139.5 DEG C.
C) 2-(6-bromo-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group acetamide (compound 44)
Compound 44b (31.1mg, 0.10mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.2mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (15.0mg, 0.10mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 88.1%；Fusing point: 178.4-179.2℃。
1H NMR(CDCl3, 500MHz): δ 8.31 (d, J=2.0Hz, 1H), 7.72 (dd, J=9.0,2.5Hz, 1H), 7.07 (d, J=9.0Hz, 1H), 5.64 (s, 1H), 4.63 (s, 2H), 4.07 (t, J=7.5Hz, 2H), 1.73-1.67 (m, 2H), 1.39-1.33 (m, 13H), 0.91 (t, J=7.0Hz, 3H).
The embodiment 45:N-tert-butyl group-2-(2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 45)
A) 2-(n-pro-pyl amino) benzoic acid (compound 45a)
Ortho-aminobenzoic acid (960.0g, 7.0mmol) is dissolved in 18mL acetonitrile and 6mL water, is sequentially added into Carbon Dioxide Potassium (2.13g, 15.4mmol), potassium iodide (116.2mg, 0.7mmol), add n-propyl bromide (636 after half an hour is stirred at room temperature μ L, 7.0mmol), heating reflux reaction 24h.Reaction is cooled to room temperature after terminating, and rotation as far as possible is evaporated off solvent acetonitrile, adds 10mL water, ethyl acetate extracts, and merges organic facies and is dried through saturated aqueous common salt washing, anhydrous magnesium sulfate, and decompression distills slightly to produce Thing.Through column chromatographic isolation and purification, obtain yellow solid.Yield: 22.4%；Fusing point: 109.6-110.7 DEG C.
B) 1-n-pro-pyl quinazoline-2,4 (1H, 3H)-diketone (compound 45b)
Take compound 45a (280.0mg, 1.56mmol) in reaction bulb, add carbamide (375.3mg, 6.25mmol), nothing 200 DEG C of reaction 1h it are heated under solvent condition.Reaction is cooled to room temperature after terminating, add 10mL water, and ethyl acetate extracts, and merges Organic facies is washed through saturated aqueous common salt, anhydrous magnesium sulfate is dried, and crude product is distilled to obtain in decompression.Through column chromatographic isolation and purification, obtain White solid.Yield: 35.8%；Fusing point: 172.4-173.8 DEG C.
C) the N-tert-butyl group-2-(2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 45)
Compound 45b (20.4mg, 0.10mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.2mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (15.0mg, 0.10mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 90.7%；Fusing point: 238.6-239.9℃。
1H NMR(CDCl3, 500MHz): δ 8.23 (dd, J=7.5,1.5Hz, 1H), 7.68-7.65 (m, 1H), 7.24 (t, J=7.5Hz, 1H), 7.19 (d, J=8.5Hz, 1H), 5.60 (s, 1H), 4.66 (s, 2H), 4.09 (t, J=7.5Hz, 2H), 1.81-1.73 (m, 2H), 1.36 (s, 9H), 1.03 (t, J=7.5Hz, 3H).
The embodiment 46:N-tert-butyl group-2-(1-normal-butyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 46)
A) 2-(n-butylamino) benzoic acid (compound 46a)
Experimental technique, with the preparation method of compound 45a in embodiment 45, simply just instead of bromo with bromination of n-butane Propane, obtains yellow solid.Yield: 21.4%；Fusing point: 74.9-76.7 DEG C.
B) 1-normal-butyl quinazoline-2,4 (1H, 3H)-diketone (compound 46b)
Experimental technique, with the preparation method of compound 45b in embodiment 45, simply instead of compound with compound 46a 45a, obtains white solid.Yield: 38.5%；Fusing point: 126.5-127.3 DEG C.
C) the N-tert-butyl group-2-(1-normal-butyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 46)
Compound 46b (21.8mg, 0.10mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.2mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (15.0mg, 0.10mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 88.4%；Fusing point: 230.3-231.1℃。
1H NMR(CDCl3, 500MHz): δ 8.23 (dd, J=8.0Hz, J=1.5Hz, 1H), 7.69-7.65 (m, 1H), 7.24 (t, J=7.5Hz, 1H), 7.20 (d, J=8.5Hz, 1H), 5.56 (s, 1H), 4.66 (s, 2H), 4.13 (t, J= 7.5Hz, 2H), 1.76-1.69 (m, 2H), 1.50-1.43 (m, 2H), 1.37 (s, 9H), 0.99 (t, J=7.5Hz, 3H).
Embodiment 47:2-(1-normal-butyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide (compound 47)
Experimental technique, with the preparation method of compound 46 in embodiment 46, simply instead of compound 1a with compound 6a, Obtain white solid.Yield: 96.8%；Fusing point: 224.4-225.4 DEG C.
1H NMR(CDCl3, 500MHz): δ 8.23 (dd, J=8.0Hz, J=1.5Hz, 1H), 7.70-7.66 (m, 1H), 7.25 (t, J=7.5Hz, 1H), 7.20 (d, J=8.5Hz, 1H), 5.66 (s, 1H), 4.71 (s, 2H), 4.13 (t, J= 7.5Hz,2H),3.83-3.76(m,1H),1.96-1.93(m,2H),1.76-1.67(m,4H),1.62-1.58(m,1H), 1.50-1.42 (m, 2H), 1.39-1.30 (m, 2H), 1.20-1.12 (m, 3H), 1.00 (t, J=7.5Hz, 3H).
The embodiment 48:N-tert-butyl group-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 48)
A) 2-(n-pentyl amino) benzoic acid (compound 48a)
Experimental technique, with the preparation method of compound 45a in embodiment 45, simply just instead of bromo with bromo pentane Propane, obtains yellow solid.Yield: 20.3%；Fusing point: 67.0-68.1 DEG C.
B) 1-normal-butyl quinazoline-2,4 (1H, 3H)-diketone (compound 46b)
Experimental technique, with the preparation method of compound 45b in embodiment 45, simply instead of compound with compound 48a 45a, obtains white solid.Yield: 33.8%；Fusing point: 114.5-115.9 DEG C.
C) the N-tert-butyl group-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 48)
Compound 48b (23.2mg, 0.10mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (15.2mg, 0.11mmol), 80 DEG C of reaction 30min, add compound 1a (15.0mg, 0.10mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 76.7%；Fusing point: 213.4-214.2℃。
1H NMR(CDCl3, 500MHz): δ 8.23 (dd, J=8.0Hz, J=1.5Hz, 1H), 7.69-7.65 (m, 1H), 7.24 (t, J=7.5Hz, 1H), 7.19 (d, J=8.5Hz, 1H), 5.56 (s, 1H), 4.66 (s, 2H), 4.12 (t, J= 7.5Hz, 2H), 1.77-1.73 (m, 2H), 1.42-1.39 (m, 4H), 1.37 (s, 9H), 0.93 (t, J=7.0Hz, 3H).
Embodiment 49:2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-isopropyl acetamide (compound 49)
A) 2-chloro-N-isopropyl acetamide (compound 49a)
2-aminopropane. (236.4mg, 4.0mmol) is dissolved in 4mL dichloromethane, addition Anhydrous potassium carbonate (663.4mg, 4.8mmol), reaction bulb is placed in ice bath, chloracetyl chloride (451.8mg, 4.0mmol) is slowly added to through Dropping funnel, room Temperature stirring reaction is overnight.After reaction terminates, adding 10mL frozen water cancellation reaction, dichloromethane extracts, and merges organic facies through saturated Brine It, anhydrous magnesium sulfate are dried, and decompression distillation, without being further purified, obtains white solid.Yield: 70.3%；Molten Point: 58.6-59.4 DEG C.
B) 2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-isopropyl acetamide (compound 49)
Experimental technique, with the preparation method of compound 48 in embodiment 48, simply instead of compound 1a with compound 49a, Obtain white solid.Yield: 99.3%；Fusing point: 213.8-215.6 DEG C.
1H NMR(CDCl3, 500MHz): δ 8.22 (dd, J=7.5,1.5Hz, 1H), 7.69-7.65 (m, 1H), 7.24 (t, J=7.5Hz, 1H), 7.19 (d, J=8.5Hz, 1H), 5.71 (d, J=7.5Hz, 1H), 4.70 (s, 2H), 4.12-4.06 (m, 3H), 1.77-1.71 (m, 2H), 1.43-1.37 (m, 4H), 1.16 (d, J=6.5Hz, 6H), 0.92 (t, J=7.0Hz, 3H).
Embodiment 50:N-cyclopropyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 50)
A) 2-chloro-N-cyclopropylacetyl amine (compound 50a)
Cyclopropylamine (228.4mg, 4.0mmol) is dissolved in 4mL dichloromethane, addition Anhydrous potassium carbonate (663.4mg, 4.8mmol), reaction bulb is placed in ice bath, chloracetyl chloride (451.8mg, 4.0mmol) is slowly added to through Dropping funnel, room Temperature stirring reaction is overnight.After reaction terminates, adding 10mL frozen water cancellation reaction, dichloromethane extracts, and merges organic facies through saturated Brine It, anhydrous magnesium sulfate are dried, and decompression distillation, without being further purified, obtains white solid.Yield: 74.8%；Molten Point: 81.6-83.2 DEG C.
B) N-cyclopropyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 50)
Experimental technique, with the preparation method of compound 48 in embodiment 48, simply instead of compound 1a with compound 50a, Obtain white solid.Yield: 98.7%；Fusing point: 195.2-196.9 DEG C.
1H NMR(CDCl3, 500MHz): δ 8.22 (dd, J=8.0,1.5Hz, 1H), 7.69-7.66 (m, 1H), 7.24 (t, J=8.0Hz, 1H), 7.19 (d, J=7.5Hz, 1H), 6.13 (s, 1H), 4.69 (s, 2H), 4.10 (t, J=7.5Hz, 2H), 2.74-2.71 (m, 2H), 1.76-1.70 (m, 2H), 1.41-1.39 (m, 4H), 0.93 (t, J=7.0Hz, 3H), 0.75-0.71 (m,2H),0.55-0.52(m,2H)。
Embodiment 51:N-normal-butyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 51)
Experimental technique, with the preparation method of compound 48 in embodiment 48, simply instead of compound 1a with compound 5a, Obtain white solid.Yield: 92.8%；Fusing point: 181.3-182.7 DEG C.
1H NMR(CDCl3, 500MHz): δ 8.22 (d, J=8.0Hz, 1H), 7.69-7.65 (m, 1H), 7.24 (t, J= 7.5Hz, 1H), 7.19 (d, J=7.5Hz, 1H), 5.95 (s, 1H), 4.73 (s, 2H), 4.10 (t, J=8.0Hz, 2H), 3.28 (q, J=6.5Hz, 2H), 1.76-1.70 (m, 2H), 1.52-1.46 (m, 2H), 1.43-1.37 (m, 4H), 1.36-1.30 (m, 2H),0.93-0.88(m,6H)。
Embodiment 52:2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-isobutyl group acetamide (compound 52)
A) 2-chloro-N-isobutyl group acetamide (compound 52a)
Isobutyl amine (292.6mg, 4.0mmol) is dissolved in 4mL dichloromethane, addition Anhydrous potassium carbonate (663.4mg, 4.8mmol), reaction bulb is placed in ice bath, chloracetyl chloride (451.8mg, 4.0mmol) is slowly added to through Dropping funnel, room Temperature stirring reaction is overnight.After reaction terminates, adding 10mL frozen water cancellation reaction, dichloromethane extracts, and merges organic facies through saturated Brine It, anhydrous magnesium sulfate are dried, and decompression distillation, without being further purified, obtains white solid.Yield: 73.1%；Molten Point: 32.2-22.4 DEG C.
B) 2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-isobutyl group acetamide (compound 52)
Experimental technique, with the preparation method of compound 48 in embodiment 48, simply instead of compound 1a with compound 52a, Obtain white solid.Yield: 85.8%；Fusing point: 185.9-186.9 DEG C.
1H NMR(CDCl3, 500MHz): δ 8.22 (dd, J=8.0,1.5Hz, 1H), 7.69-7.66 (m, 1H), 7.24 (t, J=7.5Hz, 1H), 7.19 (d, J=8.5Hz, 1H), 6.00 (t, J=5.0Hz, 1H), 4.75 (s, 2H), 4.10 (t, J= 7.5Hz, 2H), 3.11 (t, J=6.5Hz, 2H), 1.81-1.70 (m, 3H), 1.43-1.37 (m, 4H), 0.93-0.90 (m, 9H)。
Embodiment 53:N-cyclohexyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 53)
Experimental technique, with the preparation method of compound 48 in embodiment 48, simply instead of compound 1a with compound 6a, Obtain white solid.Yield: 94.5%；Fusing point: 211.7-212.5 DEG C.
1H NMR(CDCl3, 500MHz): δ 8.23 (dd, J=8.0Hz, J=1.5Hz, 1H), 7.69-7.66 (m, 1H), 7.24 (t, J=7.5Hz, 1H), 7.20 (d, J=8.5Hz, 1H), 5.68 (d, J=7.5Hz, 1H), 4.71 (s, 2H), 4.11 (t, J=7.5Hz, 2H), 3.82-3.76 (m, 1H), 1.96-1.93 (m, 2H), 1.76-1.67 (m, 5H), 1.62-1.58 (m, 1H), 1.42-1.39 (m, 3H), 1.36-1.30 (m, 2H), 1.19-1.12 (m, 3H), 0.93 (t, J=7.0Hz, 3H).
The embodiment 54:N-tert-butyl group-2-(1-n-hexyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 54)
A) 2-(n-hexyl amino) benzoic acid (compound 54a)
Experimental technique, with the preparation method of compound 45a in embodiment 45, simply just instead of bromo with bromo normal hexane Propane, obtains yellow solid.Yield: 16.9%；Fusing point: 57.3-58.7 DEG C.
B) 1-n-hexyl quinazoline-2,4 (1H, 3H)-diketone (compound 54b)
Experimental technique, with the preparation method of compound 45b in embodiment 45, simply instead of compound with compound 54a 45a, obtains white solid.Yield: 16%；Fusing point: 85.1-86.7 DEG C.
C) the N-tert-butyl group-2-(1-n-hexyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide (compound 54)
Compound 54b (19.7mg, 0.08mmol) is dissolved in 2mL DMF solution, addition potassium carbonate (12.2mg, 0.09mmol), 80 DEG C of reaction 30min, add compound 1a (12.0mg, 0.08mmol), 80 DEG C of reactions are overnight.Reaction terminates After, it being cooled to room temperature, add suitable quantity of water, ethyl acetate extracts, and organic layer washs with saturated sodium-chloride again, and anhydrous magnesium sulfate is done Dry, vacuum rotary steam removes organic solvent, through silica gel column chromatography separating-purifying, obtains white solid.Yield: 87.6%；Fusing point: 194.9-195.9℃。
1H NMR(CDCl3, 500MHz): δ 8.23 (dd, J=8.0,1.5Hz, 1H), 7.69-7.65 (m, 1H), 7.24 (t, J=7.5Hz, 1H), 7.19 (d, J=8.5Hz, 1H), 5.62 (s, 1H), 4.66 (s, 2H), 4.11 (t, J=7.5Hz, 2H), 1.76-1.69 (m, 2H), 1.44-1.39 (m, 2H), 1.36-1.32 (m, 13H), 0.90 (t, J=7.0Hz, 3H).
Embodiment 55: the hydrochlorate 7A of compound 7, quaternary ammonium salt 7B and the preparation of monohydrate 7C
A) preparation of the hydrochlorate 7A of compound 7
Under room temperature, compound 7 (35.9mg, 0.1mmol) is dissolved in absolute methanol (1mL), be slowly added dropwise under ice bath into Saturated hydrogen chloride methanol solution (2mL), after removing solvent under reduced pressure, stirring adds ether, separates out white solid, filters, ether Washing, the hydrochlorate 7A obtaining compound 7 is white solid 38.0mg, yield: 96%.
ESI-MS:m/z 360.22[M+]
B) preparation of the quaternary ammonium salt 7B of compound 7
Under room temperature, compound 7 (35.9mg, 0.1mmol) is dissolved in dehydrated alcohol (1mL), adds the hydrogen-oxygen of equivalent Changing sodium, potassium iodide and iodomethane, after heated overnight at reflux, decompression is spin-dried for solvent, crude product acetone recrystallization purification The quaternary ammonium salt 7B of compound 7 is white solid 20mg, yield: 38.8%.
ESI-MS:m/z 388.26[M+]
C) preparation of the monohydrate 7C of compound 7
Under room temperature, compound 7 (35.9mg, 0.1mmol) is dissolved in 1N HCl solution, under stirring, is slowly added dropwise petroleum ether To solution turned cloudy, ambient temperatare is put to separating out without crystal again, is filtrated to get the monohydrate 7C of compound 7.
Elem.Anal.:C, 63.64%；H, 8.28%；N, 11.13%；O, 16.95%.
According to similar approach described in the present embodiment, can be used for preparing the compounds of this invention V pharmaceutically acceptable salt or water Compound, including with propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid etc. The salt that organic acid is formed；Or form salt with the mineral acid such as hydrochloric acid, phosphoric acid, sulphuric acid, Fluohydric acid., hydrobromic acid；Or with alkyl halide formed Quaternary ammonium salt, described alkyl halide is that fluorine, chlorine, bromine or iodine are for alkane.
Embodiment 56: pharmaceutical composition
Compound 7A 20g
Starch 140g
Microcrystalline Cellulose 60g
Operational approach routinely, after uniform for above-mentioned 3 kinds of material physical mixed, load in gelatine capsule, obtains 1000 Capsule.
Embodiment 57: pharmaceutical composition
Compound 7A 50g
Starch 400g
Microcrystalline Cellulose 200g
Operational approach routinely, after uniform for above-mentioned 3 kinds of material physical mixed, load in gelatine capsule, obtains 1000 Capsule.
Embodiment 58: Pharmacological examples Example calcium current screening model (Calcium current assay)
After cannabinoid receptors is activated, the suppression of intracellular calcium current can be caused.But after proceeding to G-protein G 16, show as swashing Calcium current in living cells, other physiologic function is unaffected.Respectively by set up corotation CB1 and G 16, CB2 and G 16 thin Born of the same parents are so that receptor can cause the activation of G 16 albumen after being activated, and then activates phospholipase C (PLC) generation IP3 and DAG, IP3 can be combined by the IP3 receptor in intracellular endoplasmic reticulum, thus causes the release of cellular calcium.Therefore, the change of cellular calcium is measured Can be as the method for detection CB1 and the CB2 state of activation.Fluo-4/AM is that a kind of calcium fluorescent probe indicator is for measuring calcium Ion, as nonpolar fat-soluble compound, after entrance cell under the effect of cell lipolytic enzyme, AM group dissociates, and disengages Fluo-4；Owing to Fluo-4 is polar molecule, not easily passing through bimolecular lipid membrane, it can make Fluo-4 be retained in cell for a long time In.The level that G albumen is activated may finally be reflected by the amount of the photon that measurement is excited.According to this principle, it is established that Calcium current screening model.
Experimental technique: employment source cannabinoid receptors (hCB1, hCB2) and G 16 transfectional cell simultaneously, is built by antibiotic-screening Vertical stably transfected cell line CHO-hCB1-G 16 and CHO-hCB2-G 16.Detect the CHO/CB2-of debita spissitudo in first 24 hours G 16 or CHO/CB1-G 16 (about 20,000/hole) is in 96 porocyte plates so that during detection the cell in every hole about 4-6 ten thousand/ Hole.Overnight incubation, removes culture fluid, with 2 μm ol/L fluo-4AM dyestuff constant-temperature incubations in 37 DEG C of incubators after cell attachment 50 minutes.After sucking excess dye, cell Hanks ' Balanced Salt Solution (HBSS) buffer solution is once. In antagonist mode, cell is with containing positive control or testing compound or the negative control HBSS buffer incubated at room containing DMSO 10 minutes, FlexStation detector automatically 25 μ L agonist are joined in reaction system, detect intracellular calcium ion in real time The dye fluorescence Strength Changes that rheology causes.In activation pattern, cell HBSS buffer incubated at room 10 minutes, by HBSS buffer containing positive control or testing compound or negative control DMSO is joined by FlexStation detector automatically In reaction system, the dye fluorescence Strength Changes that detection intracellular calcium ion rheology causes in real time.Available testing compound Suppression ratio or relatively exciting ratio value.
Suppression ratio=(the calcium current peak value of the calcium current peak value-testing compound of negative control)/(calcium current peak of negative control The calcium current peak value of value-positive control) × 100%.
Relatively exciting ratio=(the calcium current peak value of the calcium current peak value-negative control of testing compound)/(calcium of positive control The calcium current peak value of stream peak value-negative control) × 100%.
In aforementioned manners compound is carried out half-inhibition concentration IC50Or median effective dose EC50Mensuration, mainly pass through Make response rate and dose curve obtain, altogether have chosen 100 μMs, 10 μMs, 1 μM, 100nM, 10nM, 1nM, 100pM, 0 these eight Dose concentration, calcium current detection is carried out according to above-mentioned experimental procedure, each concentration parallel assay three times, i.e. with the 8 multiple orifice plates of gradient 3. Data GraphPad Prism software analysis.With the dose-response curve of the method matching detection compound of nonlinear regression also Calculate IC50Or EC50。
Table 1 quinazoline diones analog derivative external activity data
Experimental result illustrates: the compounds of this invention people source cannabinoid receptors CB2 common manifestation is gone out higher calcium current activity and Well selectivity, meanwhile, the compounds of this invention R1、R2、R3And R4The difference of group has important shadow to the activity of compound Ringing, the difference of substituent group may result in compound and shows agonist activity or reverse agonist activity.The most apparently, chemical combination of the present invention Thing is specific agonist or the inverse agonist of cannabinoid receptors CB2, has preferable drug development prospect.

Claims (9)

1. a quinazoline diones analog derivative and pharmaceutically acceptable salt thereof or hydrate, it is characterised in that general structure V As follows:
Wherein,
R1、R2、R3、R4It is each independently selected from hydrogen atom, halogen, C1-C4Straight or branched alkyl, C1-C4Straight or branched alcoxyl Base, hydroxyl；
R5Selected from C2-C6Straight chained alkyl, with C3-C6The alkyl of ring, 3-butene-1-base；
R6Selected from C2-C6Straight or branched alkyl, C3-C6Cyclic hydrocarbon radical, with C3-C6The alkyl of ring, aryl, heteroaryl, heterocyclic radical Or adamantyl；
Described halogen is fluorine, chlorine, bromine or iodine；
Described heteroaryl is containing 1-3 the identical or different heteroatomic 5-10 unit aromatic radical in N, O and S；
Described heterocyclic radical is containing 1-3 the identical or different heteroatomic 4-10 unit nonaro-maticity base in N, O and S Group.
A kind of quinazoline diones analog derivative the most according to claim 1 and pharmaceutically acceptable salt thereof or hydrate, It is characterized in that, selected from following compound:
(1) the N-tert-butyl group-2-(1-ring the third methyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(2) 2-(1-(3-butene-1-yl)-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group second Amide
(3) the N-tert-butyl group-2-(5-methyl-2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(4) the N-tert-butyl group-2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(5) N-normal-butyl-2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(6) 2-(1-normal-butyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide
(7) the N-tert-butyl group-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(8) N-normal-butyl-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(9) N-cyclohexyl-2-(5-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(10) the N-tert-butyl group-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(11) N-normal-butyl-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(12) N-cyclohexyl-2-(1-n-hexyl-5-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(13) the N-tert-butyl group-2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(14) N-normal-butyl-2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(15) 2-(5-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide
(16) the N-tert-butyl group-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(17) N-normal-butyl-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(18) N-cyclohexyl-2-(5-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(19) the N-tert-butyl group-2-(1-ring the third methyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(20) 2-(1-(3-butene-1-yl)-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group Acetamide
(21) the N-tert-butyl group-2-(1-ethyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(22) the N-tert-butyl group-2-(8-methyl-2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(23) the N-tert-butyl group-2-(1-normal-butyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(24) the N-tert-butyl group-2-(1-n-pentyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(25) N-normal-butyl-2-(8-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(26) N-cyclohexyl-2-(1-n-pentyl-8-methyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(27) the N-tert-butyl group-2-(8-methyl-2,4-diketone-1-n-hexyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(28) the N-tert-butyl group-2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(29) N-normal-butyl-2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(30) 2-(8-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide
(31) the N-tert-butyl group-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(32) N-normal-butyl-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(33) N-cyclohexyl-2-(8-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(34) the N-tert-butyl group-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(35) N-normal-butyl-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(36) N-cyclohexyl-2-(6,7-dimethoxy-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) second Amide
(37) the N-tert-butyl group-2-(7-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(38) 2-(7-bromo-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group acetamide
(39) the N-tert-butyl group-2-(7-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(40) the N-tert-butyl group-2-(6-methyl-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(41) the N-tert-butyl group-2-(6-methoxyl group-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(42) the N-tert-butyl group-2-(6-fluoro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(43) the N-tert-butyl group-2-(6-chloro-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(44) 2-(6-bromo-2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-tert-butyl group acetamide
(45) the N-tert-butyl group-2-(2,4-diketone-1-n-pro-pyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(46) the N-tert-butyl group-2-(1-normal-butyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(47) 2-(1-normal-butyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl)-N-cyclohexyl acetamide
(48) the N-tert-butyl group-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(49) 2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-isopropyl acetamide
(50) N-cyclopropyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(51) N-normal-butyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(52) 2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl)-N-isobutyl group acetamide
(53) N-cyclohexyl-2-(2,4-diketone-1-n-pentyl-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
(54) the N-tert-butyl group-2-(1-n-hexyl-2,4-diketone-1,2-dihydroquinazoline-3 (4H)-yl) acetamide
And the hydrate of above-mentioned particular compound.
A kind of quinazoline diones analog derivative the most according to claim 1 and pharmaceutically acceptable salt thereof or hydrate, It is characterized in that, described pharmaceutically acceptable salt is the compound that represents of formula V and propanoic acid, oxalic acid, malonic acid, succinum The salt that organic acid described in acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid is formed；Or with hydrochloric acid, phosphoric acid, Mineral acid described in sulphuric acid, Fluohydric acid., hydrobromic acid forms salt；Or with alkyl halide formed quaternary ammonium salt, described alkyl halide is fluorine, chlorine, bromine Or alkane iodide.
4. a kind of quinazoline diones analog derivative described in claim 1 and pharmaceutically acceptable salt thereof or the preparation of hydrate Method, it is characterised in that realized by following steps:
(1) compound of formula I and Formula II compound react generation formula III compound；
(2) Formula IV compound reacts production V compound with formula III compound；
Wherein, R1、R2、R3、R4、R5、R6Identical with the definition in claim 1.
Preparation method the most according to claim 4, it is characterised in that Formula IV compound prepares as follows:
Under the conditions of alkalescence, compound A-1 and A-2 is obtained N-substituted compound A-3 through N-alkylation, more at high temperature, with urine The cyanic acid that element thermally decomposes to generate carries out cyclization and forms Formula IV compound；
Wherein, described alkali is organic base or inorganic base, selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, Feldalat NM, Sodium ethylate, sodium hydride, triethylamine, diisopropylethylamine (DIEA), pyridine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene Or DMAP (DMAP) (DBU)；
Wherein, R1、R2、R3、R4For hydrogen atom, R5Identical with the definition in claim 1.
Preparation method the most according to claim 4, it is characterised in that Formula IV compound prepares as follows:
Compound A-1 and BTC condensation reaction obtain compound A-4, in the presence of sodium hydride, obtain chemical combination through N alkylated reaction Thing A-5, more at high temperature, form Formula IV compound with urea reaction；
Wherein, R1、R2、R3、R4、R5Identical with the definition in claim 1.
Preparation method the most according to claim 4, it is characterised in that Formula IV compound prepares as follows:
Compound A-1, after thionyl chloride chloro, reacts with tert-butylamine and obtains formula A-7 compound；Compound A-7 and chloro-carbonic acid second Obtain formula A-8 compound after ester or methylchloroformate reaction, then return through N, N '-carbonyl dimidazoles or potassium hydroxide, ethanol Stream reacts to obtain formula A-9 compound；In the presence of Feldalat NM, obtain formula A-10 compound through N alkylated reaction；Again at acid condition Lower back flow reaction obtains Formula IV compound；
Wherein, R1、R2、R3、R4、R5Identical with the definition in claim 1.
A kind of quinazoline diones analog derivative the most according to claim 1 and pharmaceutically acceptable salt or hydrate thereof exist Preparation treats, prevents, alleviates and suppresses to apply in the medicine by the receptor-mediated disease of CB2.
Application the most according to claim 8, it is characterised in that described disease is caused by the regulation of CB2 receptor active part Disease, relate to cancer, inflammation, acquired immune deficiency syndrome (AIDS), autoimmune disease, rheumatism, allergy, pain, Acute and chronic hepatitis, osteoporosis, atherosclerosis, multiple sclerosis, neurodegenerative diseases, Alzheimer, handkerchief Gold Sen Shi is sick, Huntington's disease.
CN201610541963.1A 2016-07-07 2016-07-07 Quinazoline diones analog derivative and its production and use Pending CN106146414A (en)

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