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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dione
compound
dihydroquinazolin
butyl
acetamide
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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 diketone derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound taking quinazolinedione as a parent nucleus, a pharmaceutically acceptable salt or hydrate thereof, a preparation method thereof and application of the compound in medicines for treating, preventing and inhibiting diseases mediated by CB2receptors.
Background
The plant cannabis has been used as a medicine for thousands of years, the active ingredients of which are collectively referred to as cannabinoids. In 1964, Gaoni and Mechoulam reported that the main active ingredient of cannabis is Δ9-tetrahydrocannabinol (Δ)9The widely known cannabis receptors at present are mainly of two types, namely the cannabis type I receptor (CB1) and the cannabis type II receptor (CB2), which belong to the rhodopsin-like family of G-protein coupled receptors, have a typical 7-segment α -helical transmembrane structure and are involved in the regulation of various physiological functions in humans, CB1and CB2 have a total amino acid sequence homology of 44% and a relatively conserved transmembrane amino acid sequence of 68%Homology (Pertwe, R.G.Pharmacology of Cannabinoid CB1and CB2Receptors.Pharmacol.Ther.1997,74, 129-180). From a distribution standpoint, CB1 Receptors are mainly distributed in the central nervous system, such as the hippocampus, olfactory region, subcortical networks, etc., and are mainly involved in regulating functions such as cognition, memory, and sensory transmission (Gali e gue, s.; Mary, s.; Marchand, j.; ducssosy, d.; carrierre, d.; Carayon, p.; bouado μ La, m.; Shire, d.; Le Fur, g.; caselas, p.; Expression of central and Peripheral Cannabinoid Receptors in Human Immune Tissues and lei. surgery. eur.j. biochem.1995,232, 54-61); while the CB2receptor is mainly distributed in peripheral tissues, especially immune tissues such as spleen marginal zone, thymus, tonsil, B and T cells, macrophages and the like, and is mainly involved in the regulation of immune function (Di Marzo, V.; et al. the endenanbindin system and its therapy multiplication. Nat. Rev. drug Discov.2004,3, 771-784). The CB1 receptor and the CB2receptor both belong to the Gi/o type G protein-coupled receptors, through which multiple intracellular signal transduction pathways can be activated. CB2receptors inhibit cAMP production, regulate phosphoinositide-3 kinase (PI3K), and ceramide metabolism by inhibiting adenylate cyclase, activating mitogen-activated protein kinase (MAP kinase) channels, and the like.
The basic structures of conventional cannabinoid ligands can be largely divided into the following five classes: 1) by Delta9-THC is a classical cannabinoid represented by a compound of the class extracted from natural plants or structurally modified on the basis of natural products, the polycyclic structure being a common feature thereof; 2) non-classical cannabinoid compounds represented by CP55940, which are mostly derivatives of classical cannabinoids; 3) fatty acid amine compounds represented by endogenous neurotransmitter Ananamide are derivatives of arachidonic acid; 4) aminoalkyl indoles represented by WIN 55212-2; 5) diaryl pyrazoles represented by SR141716A and SR 144528. With the increasingly wide application of new technical means such as high-throughput screening and virtual screening in the field of pharmaceutical chemistry, more and more cannabinoid ligands with novel structures are continuously reported, and the cannabinoid ligands show abundant diversity on chemical structures.
Modern research has shown that cannabinoid receptors are involved in a variety of diseases in humans. The CB1 antagonist can be used for developing new medicines for losing weight, quitting smoking and the like, and the CB2 ligand can be used for treating immune system diseases, inflammation, pain, acute and chronic liver diseases, osteoporosis, atherosclerosis and the like. Since CB1 is mainly located in the central nervous system, its ligands are liable to cause serious central nervous side effects such as hypomnesis, depression, decrease in motor coordination ability, etc. For example rimonabant, an antagonist of CB1, was marketed in europe in 2006 for the treatment of obesity, but rapidly falls off the shelf due to its potential side effects such as depression, anxiety and the like. CB2 is mainly distributed in peripheral systems, avoids the serious central nervous side effect, and becomes a medicinal target with more prospects due to higher safety. Currently, the CB2agonist GW842166X reported by GSK corporation as an analgesic drug has completed three clinical secondary studies, but the efficacy is not ideal (Giblin, G.M.P.; et al discovery of 2- [ (2, 4-dichlorphenyl) amino ] -N- [ (tetrahydro-2H-pyran-4-yl) methyl ] -4- (trifluoromethyl) -5-pyrim dinecarboxamide, a Selective CB2Receptor agonist for the Treatment of inflammation Pain.J.Med.chem.2007,50, 2597-; the CB2agonist S-777469 has also completed clinical phase II studies as a candidate for the treatment of atopic dermatitis (Odan, M., et al, Discovery of S-777469: an organic available CB2agonist as an anti-inflammatory agent, bioorg. Med. chem. Lett.,2012,22, 2803-. The research of the CB2 selective ligand is focused on the preclinical stage and the clinical research stage, and no drug is on the market. Therefore, the discovery of the high-activity and high-selectivity CB2 ligand is of great significance to drug development.
Disclosure of Invention
The invention provides a quinazoline diketone derivative and a pharmaceutically acceptable salt or hydrate thereof, wherein the structure general formula V is as follows:
wherein,
R1、R2、R3、R4each independently selected from hydrogen atom, halogen, C1-C4Straight or branched alkyl, C1-C4Linear or branched alkoxy, hydroxy;
R5is selected from C2-C6Straight chain alkyl radical, with C3-C6Cyclic alkyl, 3-buten-1-yl;
R6is selected from C2-C6Straight or branched alkyl, C3-C6Cycloalkyl radical, with C3-C6A cyclic alkyl, aryl, heteroaryl, heterocyclyl or adamantyl group;
the halogen is fluorine, chlorine, bromine or iodine;
the heteroaryl group is a 5-10 membered aromatic group containing 1-3 heteroatoms, which may be the same or different, selected from N, O and S;
the heterocyclic group is a 4-10 membered nonaromatic group containing 1-3 heteroatoms selected from N, O and S which may be the same or different.
In the compounds of formula V of the present invention and pharmaceutically acceptable salts or hydrates thereof, preferred specific compounds include:
(1) n-tert-butyl-2- (1-cyclopropylmethyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(2)2- (1- (3-buten-1-yl) -5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide
(3) N-tert-butyl-2- (5-methyl-2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(4) N-tert-butyl-2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(5) N-N-butyl-2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(6)2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide
(7) N-tert-butyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(8) N-N-butyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(9) N-cyclohexyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(10) N-tert-butyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(11) N-N-butyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(12) N-cyclohexyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(13) N-tert-butyl-2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(14) N-N-butyl-2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(15)2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide
(16) N-tert-butyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(17) N-N-butyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(18) N-cyclohexyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(19) N-tert-butyl-2- (1-cyclopropylmethyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(20)2- (1- (3-buten-1-yl) -8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide
(21) N-tert-butyl-2- (1-ethyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(22) N-tert-butyl-2- (8-methyl-2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(23) N-tert-butyl-2- (1-N-butyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(24) N-tert-butyl-2- (1-N-pentyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(25) N-N-butyl-2- (8-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(26) N-cyclohexyl-2- (1-N-pentyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(27) N-tert-butyl-2- (8-methyl-2, 4-dione-1-N-hexyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(28) N-tert-butyl-2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(29) N-N-butyl-2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(30)2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide
(31) N-tert-butyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(32) N-N-butyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(33) N-cyclohexyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(34) N-tert-butyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(35) N-N-butyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(36) N-cyclohexyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(37) N-tert-butyl-2- (7-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(38)2- (7-bromo-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide
(39) N-tert-butyl-2- (7-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(40) N-tert-butyl-2- (6-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(41) N-tert-butyl-2- (6-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(42) N-tert-butyl-2- (6-fluoro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(43) N-tert-butyl-2- (6-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(44)2- (6-bromo-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide
(45) N-tert-butyl-2- (2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(46) N-tert-butyl-2- (1-N-butyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(47)2- (1-N-butyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide
(48) N-tert-butyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(49)2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-isopropylacetamide
(50) N-cyclopropyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(51) N-N-butyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(52)2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-isobutylacetamide
(53) N-cyclohexyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(54) N-tert-butyl-2- (1-N-hexyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
And pharmaceutically acceptable salts or hydrates of the above specific compounds.
Specific examples of the "pharmaceutically acceptable salt" in the present specification include salts of the compounds provided by the present invention with organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, and citric acid; or forming salt with inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid, etc.; or a quaternary ammonium salt formed with a haloalkane, said haloalkane being a fluoro, chloro, bromo or iodo alkane.
A second object of the present invention is to provide a process for preparing quinazolinedione derivatives and pharmaceutically acceptable salts or hydrates thereof, wherein the following is a preferred embodiment of the present invention:
(1) reacting a compound shown in the formula I with a compound shown in the formula II to generate a compound shown in the formula III;
(2) reacting the compound shown in the formula VI with the compound shown in the formula III to generate a compound shown in the formula V;
wherein R is1、R2、R3、R4、R5、R6The same as defined in formula V.
(3) Dissolving the compound V in anhydrous methanol, adding a proper amount of organic acid such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid and the like or inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid and the like under ice bath, and spin-drying the solvent to obtain a pharmaceutically acceptable acid addition salt; or dissolving the compound V in absolute ethyl alcohol, adding equivalent sodium hydroxide, potassium iodide and halogenated hydrocarbon such as methyl iodide, heating and refluxing overnight, and recrystallizing and purifying the crude product with acetone to obtain the pharmaceutically acceptable quaternary ammonium salt of the compound V.
(4) Dissolving the compound V in an aqueous acid solution, adding a non-acidic organic solvent into the system, and obtaining a hydrate of the compound V by a crystallization method. Wherein the suitable acid is selected from hydrochloric acid, sulfuric 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; the non-acidic organic solvent is selected from ethanol, methanol, acetonitrile, ethyl acetate, tetrahydrofuran, diethyl ether, petroleum ether, isopropanol, N-butanol, and N, N-dimethylformamide.
In yet another aspect, the invention relates to a process for the preparation of a compound of formula VI by:
(1) the compound of formula VI is prepared as follows:
under the alkaline condition, the compounds A-1 and A-2 are subjected to N-alkylation to obtain an N-substituted compound A-3, and then the N-substituted compound A-3 and cyanic acid generated by thermal decomposition of urea are subjected to ring synthesis at high temperature to form the compound in the formula VI.
Wherein the base is an organic or inorganic base selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, triethylamine, Diisopropylethylamine (DIEA), pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 4-Dimethylaminopyridine (DMAP);
wherein R is1、R2、R3、R4Is a hydrogen atom, R5As defined in claim 1.
Or
(2) The compound of formula VI is prepared as follows:
carrying out condensation reaction on the compound A-1 and BTC to obtain a compound A-4, carrying out N alkylation reaction in the presence of sodium hydride to obtain a compound A-5, and reacting with urea at high temperature to form a compound in a formula VI;
wherein R is1、R2、R3、R4、R5As defined in claim 1.
Or
(3) The compound of formula VI is prepared as follows:
after the compound A-1 is chlorinated by thionyl chloride, the compound A-1 reacts with tert-butylamine to obtain a compound shown as a formula A-7; reacting the compound A-7 with ethyl chloroformate or methyl chloroformate to obtain a compound shown in a formula A-8, and performing reflux reaction on the compound A-8 with N, N' -carbonyldiimidazole or potassium hydroxide and ethanol to obtain a compound shown in a formula A-9; in the presence of sodium methoxide, performing N alkylation reaction to obtain a compound shown in a formula A-10; then carrying out reflux reaction under an acidic condition to obtain a compound shown in a formula VI;
wherein R is1、R2、R3、R4、R5The same as defined in formula V.
The third purpose of the invention is to provide the application of the quinazoline diketone derivative and the pharmaceutically acceptable salt or hydrate thereof in preparing the medicines for treating, preventing, relieving and inhibiting diseases mediated by CB2receptors.
The diseases are cancer, inflammation, acquired immunodeficiency syndrome, autoimmune diseases, rheumatism, allergy, pain, acute and chronic liver diseases, osteoporosis, atherosclerosis, multiple sclerosis, neurodegenerative diseases, Alzheimer disease, Parkinson disease and Huntington disease caused by CB2receptor active ligand regulation.
The fourth purpose of the invention is to provide a pharmaceutical composition of quinazoline diketone derivatives and pharmaceutically acceptable salts or hydrates thereof, which can further comprise excipients, diluents and carriers. The compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, polyethylene glycol, propylene glycol, and the like. In general, the solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention. The pharmaceutical compositions of the invention may include one or more compounds of the invention, typically formulated by mixing a compound of the invention, and a pharmaceutically acceptable salt or hydrate thereof, with a carrier, excipient, or diluent. Suitable carriers, excipients or diluents are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, solvents, water and the like. The dosage form of the medicine is solid preparation or liquid preparation, and specifically is tablet, capsule, powder, solution, syrup, suspension or aerosol.
The compound provided by the invention is an active ligand of a novel cannabinoid II-type receptor CB2, and the compound comprises a compound with a structure shown in a general formula V and pharmaceutically acceptable salt or hydrate thereof. The compound is an agonist, a partial agonist, an inverse agonist or an antagonist of cannabis receptor CB2, can be used for preparing medicines for treating, preventing and relieving diseases mediated by CB2receptor, and has good medicine development prospect.
Detailed Description
The invention is further illustrated by reference to examples, which are intended to further illustrate the invention but are not intended to be limiting.
The starting materials, reaction reagents and the like used in the examples of the present invention are commercially available products. Example 55 illustrates a method for preparing a hydrochloride, a quaternary ammonium salt, or a monohydrate of compound 7, to which other compounds can be referred, or other salts can be formed by a method generally used in the art.
Example 1: n-tert-butyl-2- (1-cyclopropylmethyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 1)
a) 2-chloro-N-tert-butylacetamide (Compound 1a)
Tert-butylamine (438.8mg, 6.00mmol), potassium carbonate (995.1mg, 7.20mmol) were placed in 6mL of dichloromethane solution, and chloroacetyl chloride (677.6mg, 6.00mmol) was slowly added dropwise to the above reaction flask under ice bath at room temperature overnight. After the reaction is finished, adding a proper amount of water, extracting by dichloromethane, combining organic phases, washing by saturated saline, drying by anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product which is a white solid. Yield: 74.9 percent; melting point of 81.0-82.1 deg.C.
b) 2-amino-N-tert-butyl-6-methylbenzamide (Compound 1b)
2-amino-6-methylbenzoic acid (800.0mg, 5.29mmol) was placed in a 50mL single neck round bottom flask, N2After replacement, 9.8mL of thionyl chloride is added, reflux reaction is carried out for 3h, then concentration is carried out under vacuum, and then 7.8mL of dry tetrahydrofuran solution is added; the above acid chloride solution in tetrahydrofuran was then added slowly to a solution of tert-butylamine (5.6mL, 52.92mmol) in tetrahydrofuran (7.8mL) at 0 deg.C and allowed to react overnight at room temperature. After the reaction is finished, cooling to room temperature, concentrating the reaction solution to be dry, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out separation and purification by silica gel column chromatography to obtain a white solid. Yield: 72.5 percent; melting point: 102.2-103.2 ℃.
1H NMR(500MHz,CDCl3)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- (tert-butylcarbamoyl) -3-methylphenyl) carbamate (Compound 1c)
Compound 1b (81.7mg, 0.40mmol) was placed in a 10mL single neck round bottom flask, 1mL ethyl chloroformate was added and reacted at 95 ℃ for 3 h. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 70.3 percent; melting point: 129.6-130.3 ℃.
1H NMR(500MHz,CDCl3)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) 3-tert-butyl-5-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 1d)
Compound 1c (100.0mg, 0.48mmol) was dissolved in 4mL of dry tetrahydrofuran solution, and N, N' -carbonyldiimidazole (163.5mg, 1.01mmol) was added thereto, followed by reaction under reflux overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 44.8 percent; melting point: 207.2-108.4 ℃.
1H NMR(500MHz,CDCl3)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) 3-tert-butyl-1-cyclopropylmethyl-5-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 1e)
Compound 1d (40.0mg, 0.17mmol) was dissolved in 2mL of DMF, and sodium methoxide (14.0mg, 0.26mmol) and bromomethylcyclopropane (18. mu.L, 0.19mmol) were added in this order to react at 50 ℃ overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a yellow liquid which is directly used for the next reaction.
f) 1-Cyclopropylmethyl-5-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 1f)
Compound 1e (77.7mg, 0.27mmol) was placed in a 10mL single neck round bottom flask, 2mL of 1, 4-dioxane solution was added and dissolved with magnetic stirring, 1.6mL of 6N HCl solution was added and heated to reflux and monitored by TLC to completion of the reaction. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid with a melting point: 176.7-178.5 ℃.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (1-cyclopropylmethyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 1)
Compound 1f (10.2mg, 0.04mmol) was dissolved in 2mL of DMF solution, potassium carbonate (12.2mg, 0.08mmol) was added, reaction was carried out at 80 ℃ for 30min, compound 1a (7.9mg, 0.05mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 90.8 percent; melting point: 202.1-202.6 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 2: 2- (1- (3-buten-1-yl) -5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide (Compound 2)
a)1- (3-buten-1-yl) -3-tert-butyl-5-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 2a)
Experimental procedure as in example 1 for the preparation of Compound 1e except that 4-bromo-1-butene was used in place of bromomethylcyclopropane, a yellow liquid was obtained and used directly in the next reaction.
b)1- (3-buten-1-yl) -5-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 2b)
Experimental procedure the same procedure used to prepare compound 1f in example 1, except that compound 2a (42.6mg, 0.15mmol) was used in place of compound 1f, to give a white solid. Yield: 42.9 percent; melting point: 167.4-168.8 ℃.
1H NMR(500MHz,CDCl3)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-buten-1-yl) -5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide (Compound 2)
Experimental procedure the same procedure as for the preparation of Compound 1 in example 1 was followed, except that Compound 2b was used in place of Compound 1f, to give a white solid. Yield: 98.7 percent; melting point: 199.9-200.7 ℃.
1H NMR(500M Hz,CDCl3)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)。
Example 3: n-tert-butyl-2- (5-methyl-2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 3)
a) 3-tert-butyl-5-methyl-1-propylquinazoline-2, 4(1H,3H) -dione (Compound 3a)
The experimental procedure was the same as that for the preparation of compound 1e in example 1 except that bromocyclopropane was replaced by n-propyl bromide to give a yellow liquid which was used directly in the next reaction.
b) 5-methyl-1-propylquinazoline-2, 4(1H,3H) -dione (Compound 3b)
Experimental procedure the same procedure used to prepare compound 1f in example 1, except that compound 3a (53.8mg, 0.20mmol) was used in place of compound 1f, to give a white solid. Yield: 70.3 percent; melting point: 183.8-184.8 deg.C.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (5-methyl-2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 3)
Experimental procedure the same procedure as for the preparation of Compound 1 in example 1 was followed, except that Compound 3b was used in place of Compound 1f, to give a white solid. Yield: 92.1 percent; melting point: 212.2-212.6 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 4: n-tert-butyl-2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 4)
a) 5-methyl-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 4a)
2-amino-6-methylbenzoic acid (100.0mg, 0.66mmol) and triphosgene (65.4mg, 0.22mmol) were placed in a 25mL single-neck round-bottom flask, and 3mL of tetrahydrofuran solution was added dropwise slowly and heated to 45-50 ℃ for 3 h. After the reaction is finished, concentrating the solvent, adding n-hexane, separating out solids, filtering and drying to obtain a crude product. Melting point: 209-209.6 ℃.
1H NMR(500MHz,DMSO)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-n-butyl-5-methyl-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 4b)
Compound 4a (204.0mg, 1.15mmol), sodium hydride (55.3mg, 1.38mmol) were placed in a 25mL two-necked flask, N2After displacement, 4mL of dry DMF solution was added and reaction was carried out at room temperature for 1h, followed by addition of n-butyl bromide (148. mu.L, 1.38mmol) and reaction at room temperature overnight. After the reaction is finished, adding a proper amount of ice water, stirring for 10min, and filtering out solids to obtain a crude product.
c) 1-n-butyl-5-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 4c)
Compound 4b (155.8mg, 0.67mmol) was placed in a 10mL single neck round bottom flask, urea (120.3mg, 2.09mmol) was added, and the reaction was allowed to proceed at 200 ℃ for 2 h. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a yellow solid. Yield: 43.7 percent; melting point: 161.3-162 ℃.
d) N-tert-butyl-2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 4)
Compound 4c (19.0mg, 0.08mmol) was dissolved in 2mL of DMF solution, potassium carbonate (21.3mg, 0.15mmol) was added, reaction was carried out at 80 ℃ for 30min, compound 1a (12.7mg, 0.08mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 97.4 percent; melting point: 198.9-199.4 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 5: N-N-butyl-2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 5)
a) 2-chloro-N-N-butylacetamide (Compound 5a)
N-butylamine (585.1mg, 8.00mmol) and potassium carbonate (1.3g, 9.60mmol) were placed in a solution of 8mL of dichloromethane, and chloroacetyl chloride (903.5mg, 8.00mmol) was slowly added dropwise to the above reaction flask under ice-bath at room temperature overnight. After the reaction is finished, adding a proper amount of water, extracting by dichloromethane, combining organic phases, washing by saturated saline solution, drying by anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product which is yellow oily liquid. Yield: 86.1 percent.
b) N-N-butyl-2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 5)
Experimental procedure was the same as the preparation of Compound 4 in example 4, except that Compound 5a was used in place of Compound 1a to obtain
A white solid. Yield: 98 percent; melting point: 185.9-186.4 ℃.
1H NMR(400MHz,CDCl3)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)。
Example 6: 2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide (Compound 6)
a) 2-chloro-N-cyclohexylacetamide (Compound 6a)
Cyclohexylamine (992.0mg, 10.00mmol), potassium carbonate (1.66g, 12.00mmol) were placed in a 10mL dichloromethane solution and chloroacetyl chloride (1.13g, 10.00mmol) was slowly added dropwise to the above reaction flask under ice bath overnight at room temperature. After the reaction is finished, adding a proper amount of water, extracting by dichloromethane, combining organic phases, washing by saturated saline solution, drying by anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product, namely a white solid. Yield: 74.9 percent; the melting point is 103.8-105.9 ℃.
b)2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide (Compound 6)
Experimental procedure was the same as the preparation of Compound 4 in example 4, except that Compound 6a was used in place of Compound 1a to obtain
A white solid. Yield: 97 percent; melting point is 218.2-218.9 ℃.
1H NMR(400MHz,CDCl3)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)。
Example 7: n-tert-butyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 7)
a) 5-methyl-1-n-pentyl-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 7a)
The experimental procedure was the same as that for the preparation of compound 4b in example 4, except that n-pentane bromide was used instead of n-butyl bromide, and the crude product was obtained by suction filtration.
b) 5-methyl-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 7b)
Experimental procedure the same procedure used to prepare Compound 4c in example 4, except that Compound 7a was used in place of 4b, gave a white solid. Yield: 47.9 percent; melting point: 140 ℃ and 141 ℃.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 7)
Compound 7b (13.5mg, 0.05mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.1mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, compound 1a (9.0mg, 0.06mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 87.3 percent; melting point: 192.6-193 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 8: N-N-butyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 8)
Experimental procedure the same procedure as for the preparation of Compound 7 in example 7 was followed, except that Compound 5a was used in place of Compound 1a, to give a white solid. Yield: 95.9 percent; melting point: 163-164.5 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 9: n-cyclohexyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 9)
Experimental procedure the same procedure as for the preparation of Compound 7 in example 7 was followed, except that Compound 6a was used in place of Compound 1a, to give a white solid. Yield: 93 percent; melting point: 192.3-193.2 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 10: n-tert-butyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 10)
a) 1-n-hexyl-5-methyl-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 10a)
The experimental method is the same as the preparation method of the compound 4b in the example 4, except that n-butyl bromide is replaced by n-hexane bromide, and a crude product is obtained by suction filtration.
b) 1-n-hexyl-5-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 10b)
Experimental procedure the same procedure used to prepare Compound 4c in example 4 was followed except that Compound 10a was used in place of Compound 4b to give a white solid. Yield: 35.2 percent.
c) N-tert-butyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 10)
Compound 10b (15.0mg, 0.06mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.9mg, 0.12mmol) was added and reacted at 80 ℃ for 30min, compound 1a (9.5mg, 0.06mmol) was added and reacted at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 78 percent; melting point: 188.1-189 ℃.
1H NMR(400MHz,CDCl3)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)。
Example 11: N-N-butyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 11)
Experimental procedure the same procedure as for the preparation of Compound 10 in example 10 was followed, except that Compound 5a was used in place of Compound 1a, to give a white solid. Yield: 71.7 percent; melting point: 165.1-165.9 ℃.
1H NMR(400MHz,CDCl3)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)。
Example 12: n-cyclohexyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 12)
Experimental procedure the same procedure as for the preparation of Compound 10 in example 10 was followed, except that Compound 6a was used in place of Compound 1a, to give a white solid. Yield: 86.5 percent; melting point: 183.1-184 ℃.
1H NMR(400MHz,CDCl3)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)。
Example 13: n-tert-butyl-2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 13)
a) 5-chloro-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 13a)
2-amino-6-chlorobenzoic acid (500.0mg, 2.91mmol) and triphosgene (288.3mg, 0.97mmol) were placed in a 25mL single-neck round-bottom flask, and 14mL tetrahydrofuran solution was added dropwise slowly and heated to 45-50 ℃ for 3 h. After the reaction is finished, concentrating the solvent, adding n-hexane, separating out solids, filtering, and drying to obtain a crude product which is directly used for the next reaction.
b) 5-chloro-1-n-pentyl-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 13b)
Compound 13a (100.0mg, 0.51mmol), sodium hydride (24.3mg, 0.61mmol) were placed in a 10mL two-necked flask, N2After displacement, 2mL of dry DMF solution was added and reaction was carried out at room temperature for 1h, followed by addition of n-butyl bromide (75. mu.L, 0.61mmol) and reaction at room temperature overnight. After the reaction is finished, adding a proper amount of ice water, stirring for 10min, and filtering out solids to obtain a crude product.
c) 5-chloro-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 13c)
Compound 13b (97.4mg, 0.36mmol) was placed in a 10mL single neck round bottom flask and reacted at 200 ℃ for 2h with urea (65.6mg, 1.09 mmol). After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 43.7 percent; melting point: 130-133.4 ℃.
1H NMR(400MHz,CDCl3)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) N-tert-butyl-2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 13)
Compound 13c (20.0mg, 0.07mmol) was dissolved in 2mL of DMF solution, potassium carbonate (20.7mg, 0.15mmol) was added, reaction was carried out at 80 ℃ for 30min, compound 1a (12.3mg, 0.08mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 99 percent; melting point: 212.6-213.2 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 14: N-N-butyl-2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 14)
Experimental procedure the same procedure as for the preparation of Compound 13 in example 13 was followed, except that Compound 1a was replaced with Compound 5a, to give a white solid. Yield: 90 percent; melting point: 184.2-184.9 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 15: 2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide (Compound 15)
Experimental procedure the same procedure as for the preparation of Compound 13 in example 13 was followed, except that Compound 6a was used in place of Compound 1a, to give a white solid. Yield: 81.3 percent; melting point: 206.2-206.9 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 16: n-tert-butyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 16)
a) 5-methoxy-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 16a)
2-amino-6-methoxybenzoic acid (500.0mg, 2.99mmol) and triphosgene (295.9mg, 1.00mmol) were placed in a 25mL single-neck round-bottom flask, and 14mL tetrahydrofuran solution was slowly added dropwise and heated to 45-50 ℃ for reaction for 3 h. After the reaction is finished, concentrating the solvent, adding n-hexane, separating out solids, filtering, and drying to obtain a crude product which is directly used for the next reaction.
b) 2-amino-N-tert-butyl-6-methoxybenzamide (Compound 16b)
Compound 16a (100.0mg, 0.52mmol) was dissolved in 2mL of DMF, and tert-butylamine (60. mu.L, 0.57mmol) and DMAP (6.3mg, 0.05mmol) were added in this order to react at room temperature overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 38.6 percent; melting point: 94.8-95.2 ℃.
c) 3-tert-butyl-5-methoxyquinazoline-2, 4(1H,3H) -dione (Compound 16c)
Compound 16b (42.2mg, 0.19mmol) was placed in a 10mL single neck round bottom flask, N' -carbonyldiimidazole (64.0mg, 0.39mmol) was added, 1.5mL of dried tetrahydrofuran solution was added, and the reaction was refluxed overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 66.2 percent.
1H NMR(500MHz,DMSO)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) 3-tert-butyl-5-methoxy-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 16d)
Compound 16c (20.0mg, 0.08mmol) was dissolved in 1mL of DMF, and sodium methoxide (6.5mg, 0.12mmol) and n-pentane bromide (15. mu.L, 0.10mmol) were added in this order to react at 50 ℃ overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a yellow liquid which is directly used for the next reaction.
e) 5-methoxy-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 16e)
Compound 16d (13.9mg, 0.04mmol) was placed in a 10mL single neck round bottom flask, 1mL of 1, 4-dioxane solution was added and dissolved with magnetic stirring, 1mL of 6N HCl solution was added and heated to reflux and TLC monitored to completion of the reaction. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid, wherein the yield is as follows: 84.3 percent; HRMS (ESI) m/zcalculated for C14H18N2O3[M+H]+,263.1394；found,263.1351。
f) N-tert-butyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 16)
Compound 16e (9.7mg, 0.04mmol) was dissolved in 1.5mL of DMF solution, potassium carbonate (10.2mg, 0.07mmol) was added, and the reaction was carried out at 80 ℃ for 30min, followed by addition of compound 1a (6.1mg, 0.04mmol) and reaction at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 93.5 percent; melting point: 198.7-199 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 17: N-N-butyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 17)
Experimental procedure the same procedure as for the preparation of Compound 16 in example 16, except that Compound 5a was used in place of Compound 1a, gave a white solid. Yield: 95.8 percent; melting point: 181.8 to 182.4 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 18: n-cyclohexyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 18)
Experimental procedure the same procedure as for the preparation of Compound 16 in example 16, except that Compound 6a was used in place of Compound 1a, gave a white solid. Yield: 91.3 percent; melting point: 206.2-206.9 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 19: n-tert-butyl-2- (1-cyclopropylmethyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 19)
a) 2-amino-N-tert-butyl-3-methylbenzamide (Compound 19a)
2-amino-3-methylbenzoic acid (800.0mg, 5.29mmol) was placed in a 50mL single neck round bottom flask, N2After replacement, 9.8mL of thionyl chloride is added, reflux reaction is carried out for 3h, then concentration is carried out under vacuum, and then 7.8mL of dry tetrahydrofuran solution is added; the above acid chloride solution in tetrahydrofuran was then added slowly to a solution of tert-butylamine (5.6mL, 52.92mmol) in tetrahydrofuran (7.8mL) at 0 deg.C and allowed to react overnight at room temperature. After the reaction is finished, cooling to room temperature, concentrating the reaction solution to be dry, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out separation and purification by silica gel column chromatography to obtain a yellow solid. Yield: 63.7 percent; melting point: 103.6-104.9 ℃.
1H NMR(500MHz,CDCl3)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) 3-tert-butyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 19b)
Compound 19a (100.0mg, 0.48mmol) was dissolved in 4mL of dry DMF solution, and N, N' -carbonyldiimidazole (163.5mg, 1.01mmol) was added thereto, followed by reaction under reflux overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 90.2 percent; melting point: 194 ℃ and 195 ℃.
c) 3-tert-butyl-1-cyclopropylmethyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 19c)
Compound 19b (40.0mg, 0.17mmol) was dissolved in 2mL of DMF, and sodium methoxide (14.0mg, 0.26mmol) and bromomethylcyclopropane (18. mu.L, 0.19mmol) were added in this order to react at 50 ℃ overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a yellow liquid which is directly used for the next reaction.
d) 1-Cyclopropylmethyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 19d)
Compound 19c (67.3mg, 0.24mmol) was placed in a 10mL single neck round bottom flask, 2mL of 1, 4-dioxane solution was added and dissolved with magnetic stirring, 1.6mL of 6N HCl solution was added and heated to reflux and monitored by TLC to completion. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 21.6 percent; melting point: 177.9-179.2 ℃.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (1-cyclopropylmethyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 19)
Compound 19d (9.0mg, 0.04mmol) was dissolved in 2mL of DMF solution, potassium carbonate (10.8mg, 0.08mmol) was added, reaction was carried out at 80 ℃ for 30min, and compound 1a (6.4mg, 0.04mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 87.3 percent; melting point: 200.5-201 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 20: 2- (1- (3-buten-1-yl) -8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide (Compound 20)
a)1- (3-buten-1-yl) -3-tert-butyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 20a)
Experimental procedure as for the preparation of compound 19c in example 19, except that 4-bromo-1-butene was used in place of bromomethylcyclopropane, a colorless liquid was obtained and used directly in the next reaction.
b)1- (3-buten-1-yl) -8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 20b)
Experimental procedure the same procedure used to prepare compound 19d in example 19, except that compound 20a was used in place of compound 19c, gave a white solid. Yield: 27.3 percent; melting point: 139.3 to 140.3 ℃.
1H NMR(500MHz,CDCl3)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-buten-1-yl) -8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide (Compound 20)
Experimental procedure the same procedure used to prepare Compound 19 in example 19, except that Compound 20b was used in place of Compound 19d, gave a white solid. Yield: 93.8 percent; melting point: 204.6-205.9 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 21: n-tert-butyl-2- (1-ethyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 21)
a) 3-tert-butyl-1-ethyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (compound 21a)
The experimental procedure was the same as that used for the preparation of compound 19c in example 19 except that bromoethane was used instead of bromomethylcyclopropane to give a colorless liquid which was used directly in the next reaction.
b) 1-Ethyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 21b)
Experimental procedure the same procedure used to prepare compound 19d in example 19, except that compound 21a was used in place of compound 19c, gave a white solid. Yield: 90.9 percent; melting point: 200.7-201.4 ℃.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (1-ethyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 21)
Experimental procedure the same procedure used to prepare Compound 19 in example 19, except that Compound 21b was used in place of Compound 19d, gave a white solid. Yield: 96.8 percent; melting point: 204.3-204.7 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 22: n-tert-butyl-2- (8-methyl-2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 22)
a) 3-tert-butyl-8-methyl-1-n-propylquinazoline-2, 4(1H,3H) -dione (Compound 22a)
The experimental procedure was the same as that used in the preparation of compound 19c of example 19 except that bromocyclopropane was replaced with n-propyl bromide to give a colorless liquid which was used directly in the next reaction.
b) 8-methyl-1-n-propylquinazoline-2, 4(1H,3H) -dione (Compound 22b)
Experimental procedure the same procedure used to prepare compound 19d in example 19, except that compound 22a was used in place of compound 19c, gave a white solid. Yield: 28%; melting point: 169-169.8 ℃.
c) N-tert-butyl-2- (8-methyl-2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 22)
Experimental procedure the same procedure used to prepare Compound 19 in example 19, except that Compound 22b was used in place of Compound 19d, gave a white solid. Yield: 92.2 percent; melting point: 204.0-204.9 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 23: n-tert-butyl-2- (1-N-butyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 23)
a) 3-tert-butyl-1-n-butyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 23a)
The experimental procedure was the same as that used in the preparation of compound 19c of example 19 except that n-butyl bromide was used instead of bromomethylcyclopropane to give a colorless liquid which was used directly in the next reaction.
b) 1-n-butyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 23b)
Experimental procedure the same procedure used to prepare compound 19d in example 19, except that compound 23a was used in place of compound 19c, gave a white solid. Yield: 42.3 percent; melting point: 124.4-125 ℃.
c) N-tert-butyl-2- (1-N-butyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 23)
Experimental procedure the same procedure used to prepare Compound 19 in example 19, except that Compound 23b was used in place of Compound 19d, gave a white solid. Yield: 81 percent; melting point: 206.0-206.9 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 24: n-tert-butyl-2- (1-N-pentyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 24)
a) 3-tert-butyl-8-methyl-1-n-pentylquinazoline-2, 4(1H,3H) -dione (compound 24a)
The experimental procedure was the same as that used for the preparation of compound 19c in example 19, except that bromomethylcyclopropane was replaced with n-pentane bromide to give a colorless liquid which was used directly in the next reaction.
b) 8-methyl-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 24b)
Experimental procedure the same procedure used to prepare compound 19d in example 19, except that compound 24a was used in place of compound 19c, gave a white solid. Yield: 50.3 percent; melting point: 125.6-127 ℃.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (1-N-pentyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 24)
Experimental procedure the same procedure used to prepare Compound 19 in example 19, except that Compound 24b was used in place of Compound 19d, gave a white solid. Yield: 98.2 percent; melting point: 182.5-183.4 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 25: N-N-butyl-2- (8-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 25)
Experimental procedure the same procedure used to prepare Compound 19 in example 19, except that Compound 24b was used instead of Compound 19d and Compound 5a was used instead of Compound 1a, respectively, gave a white solid. Yield: 98.4 percent; melting point: 164-164.7 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 26: n-cyclohexyl-2- (1-N-pentyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 26)
Experimental procedure the same procedure used to prepare Compound 19 in example 19, except that Compound 24b was used instead of Compound 19d and Compound 6a was used instead of Compound 1a, respectively, gave a white solid. Yield: 90.1 percent; melting point: 187.3-188 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 27: n-tert-butyl-2- (8-methyl-2, 4-dione-1-N-hexyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 27)
a) 3-tert-butyl-1-n-hexyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (compound 27a)
The experimental procedure was the same as that for the preparation of compound 19c in example 19 except that bromon-hexane was used instead of bromomethylcyclopropane to obtain a colorless liquid which was used directly in the next reaction.
b) 1-n-hexyl-8-methyl-quinazoline-2, 4(1H,3H) -dione (Compound 27b)
Experimental procedure the same procedure used to prepare compound 19d in example 19, except that compound 27a was used in place of compound 19c, gave a white solid. Yield: 31.9 percent; melting point: 119.6-120.4 ℃.
c) N-tert-butyl-2- (8-methyl-2, 4-dione-1-N-hexyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 27)
Experimental procedure the same procedure used to prepare Compound 19 in example 19, except that Compound 27b was used in place of Compound 19d, gave a white solid. Yield: 94.9 percent; melting point: 173.5-174.5 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 28: n-tert-butyl-2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-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) was placed in a 50mL single neck round bottom flask, N2After replacement, 8.6mL of thionyl chloride is added, reflux reaction is carried out for 3h, then concentration is carried out under vacuum, and 6.9mL of dry tetrahydrofuran solution is added; the above acid chloride solution in tetrahydrofuran was then added slowly to a solution of tert-butylamine (5.0mL, 46.63mmol) in tetrahydrofuran (6.9mL) at 0 deg.C and allowed to react overnight at room temperature. After the reaction is finished, cooling to room temperature, concentrating the reaction solution to be dry, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out separation and purification by silica gel column chromatography to obtain a yellow solid. Yield: 87 percent; melting point: 98-98.8 ℃.
1H NMR(500MHz,CDCl3)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) 3-tert-butyl-8-chloroquinazoline-2, 4(1H,3H) -dione (Compound 28b)
Compound 28a (100.0mg, 0.44mmol) was dissolved in 4mL of dry DMF solution, and N, N' -carbonyldiimidazole (148.8mg, 0.92mmol) was added thereto, followed by reaction under reflux overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 25.5 percent; melting point: 162 ℃ and 163 ℃.
c) 3-tert-butyl-8-chloro-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 28c)
Compound 28b (83.0mg, 0.33mmol) was dissolved in 2mL of DMF, and sodium methoxide (35.5mg, 0.66mmol) and n-pentane bromide (49. mu.L, 0.39mmol) were added in this order to react at 50 ℃ overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a yellow liquid which is directly used for the next reaction.
d) 8-chloro-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 28d)
Compound 28c (74.9mg, 0.23mmol) was placed in a 10mL single neck round bottom flask, 2mL of 1, 4-dioxane solution was added and dissolved with magnetic stirring, 1.6mL of 6N HCl solution was added and heated to reflux and monitored by TLC to completion. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 37.6 percent; melting point: 191.6 to 192 ℃.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 28)
Compound 28d (10.0mg, 0.04mmol) was dissolved in 2mL of DMF solution, potassium carbonate (10.4mg, 0.07mmol) was added, reaction was carried out at 80 ℃ for 30min, and compound 1a (6.2mg, 0.04mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 57 percent; melting point: 169.6-170.2 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 29: N-N-butyl-2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 29)
Experimental procedure the same procedure used to prepare Compound 28 in example 28 was followed, except that Compound 5a was used in place of Compound 1a to give a white solid. Yield: 47.9 percent; melting point: 160.6-161 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 30: 2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide (Compound 30)
Experimental procedure the same procedure used to prepare Compound 28 in example 28 was followed, except that Compound 6a was used in place of Compound 1a to give a white solid. Yield: 98 percent; melting point: 189.6-190.2 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 31: n-tert-butyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 31)
a) 8-methoxy-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 31a)
2-amino-3-methoxybenzoic acid (500.0mg, 2.99mmol) and triphosgene (295.9mg, 1.00mmol) were placed in a 50mL single-neck round-bottom flask, and 14mL tetrahydrofuran solution was slowly added dropwise and heated to 45-50 ℃ for reaction for 3 h. After the reaction is finished, concentrating the solvent, adding n-hexane, separating out solids, filtering, and drying to obtain a crude product which is directly used for the next reaction.
b) 8-methoxy-1-n-pentyl-1H-benzo [ d ] [1,3] oxazine-2, 4-dione (Compound 31b)
Compound 31a (300.0mg, 1.55mmol), sodium hydride (74.5mg, 1.86mmol) were placed in a 25mL two-necked flask, N2After displacement, 4mL of dry DMF solution was added and reaction was carried out at room temperature for 1h, followed by addition of n-butyl bromide (230. mu.L, 1.86mmol) and reaction at room temperature overnight. After the reaction is finished, adding a proper amount of ice water, stirring for 10min, and filtering out solids to obtain a crude product.
c) 8-methoxy-1-pentylquinazoline-2, 4(1H,3H) -dione (Compound 31c)
Compound 31b (200.0mg, 0.76mmol) was placed in a 10mL single neck round bottom flask, urea (136.9mg, 2.28mmol) was added, and the reaction was carried out at 200 ℃ for 2 h. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a yellow solid, wherein the yield is as follows: 29.1 percent.
d) N-tert-butyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 31)
Compound 31c (20.4mg, 0.08mmol) was dissolved in 2mL of DMF solution, potassium carbonate (21.5mg, 0.16mmol) was added, reaction was carried out at 80 ℃ for 30min, compound 1a (12.8mg, 0.09mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 84.9 percent; melting point: 189-189.4 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 32: N-N-butyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 32)
Experimental procedure the same procedure used to prepare Compound 31 in example 31 was followed, except that Compound 5a was used in place of Compound 1a, to give a white solid. Yield: 81.9 percent; melting point: 165.5-166 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 33: n-cyclohexyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 33)
Experimental procedure the same procedure used to prepare Compound 31 in example 31 was followed, except that Compound 6a was used in place of Compound 1a, to give a white solid. Yield: 93.7 percent; melting point: 210.8-211 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 34: n-tert-butyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 34)
a) 2-amino-N-tert-butyl-4, 5-dimethoxybenzamide (Compound 34a)
2-amino-4, 5-dimethoxybenzoic acid (500.0mg, 2.54mmol) was placed in a 25mL single neck round bottom flaskIn, N2After replacement, adding 4.7mL of thionyl chloride, carrying out reflux reaction for 3h, then concentrating the mixture under vacuum to dryness, and adding 3.8mL of dry tetrahydrofuran solution; the above acid chloride solution in tetrahydrofuran was then added slowly to a solution of tert-butylamine (2.7mL, 25.36mmol) in tetrahydrofuran (3.8mL) at 0 deg.C and allowed to react overnight at room temperature. After the reaction is finished, cooling to room temperature, concentrating the reaction solution to be dry, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out separation and purification by silica gel column chromatography to obtain a white solid. Yield: 72.5 percent.
1H NMR(500MHz,CDCl3)6.79(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- (tert-butylcarbamoyl) -4, 5-methoxyphenyl) carbamate (compound 34b)
Compound 34a (211.2mg, 0.84mmol) was placed in a 10mL single neck round bottom flask, 2.1mL ethyl chloroformate was added and reacted at 95 ℃ for 3 h. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 79.1 percent; melting point: 105.5-106.5 ℃.
1H NMR(500MHz,CDCl3)10.53(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) 3-tert-butyl-6, 7-dimethoxyquinazoline-2, 4(1H,3H) -dione (compound 34c)
Compound 34b (120.0mg, 0.37mmol) was dissolved in 2mL of ethanol solution, followed by addition of potassium hydroxide (166.1mg, 2.96mmol) and reaction under reflux for 9 h. After the reaction is finished, concentrating to be dry, adding a small amount of hydrosolvent, acidifying by using 1M HCl, separating out solid, and filtering to obtain a yellow solid crude product.
1H NMR(500MHz,CDCl3)10.31(s,1H),7.41(s,1H),6.47(s,1H),3.93(s,3H),3.91(s,3H),1.81(s,9H)。
d) 3-tert-butyl-6, 7-dimethoxy-1-n-pentylquinazoline-2, 4(1H,3H) -dione (compound 34d)
Compound 34c (67.3mg, 0.24mmol) was dissolved in 2mL of DMF, and sodium methoxide (26.1mg, 0.48mmol) and n-pentane bromide (45. mu.L, 0.36mmol) were added in this order to react at 50 ℃ overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a colorless liquid which is directly used for the next reaction.
e)6, 7-dimethoxy-1-n-pentylquinazoline-2, 4(1H,3H) -dione (compound 34e)
Compound 34d (43.5mg, 0.12mmol) was placed in a 10mL single neck round bottom flask, 2mL of 1, 4-dioxane solution was added and dissolved with magnetic stirring, 1.6mL of 6N HCl solution was added and heated to reflux and monitored by TLC to completion of the reaction. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 82.2 percent; melting point: 195.1-196.3 ℃.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 34)
Compound 34e (10.0mg, 0.03mmol) was dissolved in 2mL of DMF solution, potassium carbonate (9.5mg, 0.07mmol) was added and reacted at 80 ℃ for 30min, compound 1a (5.6mg, 0.04mmol) was added and reacted at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 93.5 percent; melting point: 172.2-174.2 ℃.
1H NMR(500MHz,CDCl3)7.60(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)。
Example 35: N-N-butyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 35)
Experimental procedure the same procedure as for the preparation of compound 34 in example 34 was followed, except that compound 1a was replaced with compound 5a to obtain a white solid. Yield: 93.5 percent; melting point: 149.6-150.6 ℃.
1H NMR(500MHz,CDCl3)7.59(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)。
Example 36: n-cyclohexyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 36)
Experimental procedure the same procedure as for the preparation of compound 34 in example 34 was followed, except that compound 6a was used instead of compound 1a, to give a white solid. Yield: 99.3 percent; melting point: 174.5 to 175.9 ℃.
1H NMR(500MHz,CDCl3)7.60(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)。
Example 37: n-tert-butyl-2- (7-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-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) was placed in a 25mL single neck round bottom flask, N2After replacement, adding 5.4mL of thionyl chloride, carrying out reflux reaction for 3h, then concentrating the mixture under vacuum to dryness, and adding 4.3mL of dry tetrahydrofuran solution; the above acid chloride solution in tetrahydrofuran was then added slowly to a solution of tert-butylamine (3.1mL, 29.14mmol) in tetrahydrofuran (4.3mL) at 0 deg.C and allowed to react overnight at room temperature. After the reaction is finished, cooling to room temperature, concentrating the reaction solution to be dry, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out separation and purification by silica gel column chromatography to obtain a white solid. Yield: 72.8 percent; melting point: 111.3-112.8 ℃.
b) Methyl (2- (tert-butylcarbamoyl) -5-chlorophenyl) carbamate (Compound 37b)
Compound 37a (200.0mg, 0.88mmol) was dissolved in 1, 4-dioxane (882. mu.L) and 1M NaOH (882. mu.L), methyl chloroformate (75. mu.L, 0.97mmol) was added, and the reaction was carried out at room temperature for 30 min. After the reaction is finished, pouring the mixture into 1M HCl solution, separating out solid, and filtering to obtain white solid which is directly used for the next reaction.
1H NMR(500MHz,CDCl3)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) 3-tert-butyl-7-chloroquinazoline-2, 4(1H,3H) -dione (Compound 37c)
Compound 37b (126.7mg, 0.44mmol) was dissolved in 2.2mL of ethanol solution, and potassium hydroxide (249.7mg, 4.45mmol) was added thereto, followed by reaction under reflux overnight. After the reaction is finished, concentrating to be dry, adding a small amount of hydrosolvent, acidifying by using 1M HCl, separating out solid, and filtering to obtain a yellow solid crude product.
1H NMR(500MHz,CDCl3)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) 3-tert-butyl-7-chloro-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 37d)
Compound 37c (47mg, 0.19mmol) was dissolved in 2mL of DMF, and sodium methoxide (20.1mg, 0.37mmol) and n-pentane bromide (28. mu.L, 0.22mmol) were added in this order to react at 50 ℃ overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a colorless liquid which is directly used for the next reaction.
e) 7-chloro-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 37e)
Compound 37d (45.6mg, 0.14mmol) was placed in a 10mL single neck round bottom flask, 2mL of 1, 4-dioxane solution was added and dissolved with magnetic stirring, 1.8mL of 6N HCl solution was added and heated to reflux and monitored by TLC until the reaction was complete. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 48.8 percent; melting point: 157.2-158.5 ℃.
1H NMR(500MHz,CDCl3)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) N-tert-butyl-2- (7-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 37)
Compound 37e (10.0mg, 0.04mmol) was dissolved in 2mL of DMF solution, potassium carbonate (10.4mg, 0.07mmol) was added, reaction was carried out at 80 ℃ for 30min, and compound 1a (6.2mg, 0.04mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 97.5 percent; melting point: 157.9-159.2 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 38: 2- (7-bromo-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide (Compound 38)
a) 2-amino-4-bromo-N-tert-butylbenzamide (Compound 38a)
2-amino-4-bromobenzoic acid (500.0mg, 2.31mmol) was placed in a 25mL single neck round bottom flask, N2After replacement, adding 4.3mL of thionyl chloride, carrying out reflux reaction for 3h, then concentrating the mixture under vacuum to dryness, and adding 3.4mL of dry tetrahydrofuran solution; the above acid chloride solution in tetrahydrofuran was then added slowly to a solution of tert-butylamine (2.5mL, 23.14mmol) in tetrahydrofuran (3.4mL) at 0 deg.C and allowed to react overnight at room temperature. After the reaction is finished, cooling to room temperature, concentrating the reaction solution to be dry, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out separation and purification by silica gel column chromatography to obtain a white solid. Yield: 48.5 percent; melting point: 114.8-116.2 ℃.
b) Ethyl (5-bromo-2- (tert-butylcarbamoyl) phenyl) carbamate (compound 38b)
Compound 38a (100.0mg, 0.88mmol) was dissolved in 1, 4-dioxane (882. mu.L) and 1M NaOH (882. mu.L), methyl chloroformate (75. mu.L, 0.97mmol) was added and reacted at room temperature for 30 min. After the reaction is finished, pouring the mixture into 1M HCl solution, separating out solid, and filtering to obtain white solid which is directly used for the next reaction.
Compound 38a (100.0mg, 0.37mmol) was placed in a 10mL single neck round bottom flask, 1.0mL ethyl chloroformate was added and reacted at 95 ℃ for 3 h. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 93.8 percent; melting point: 150-151.5 ℃.
1H NMR(500MHz,CDCl3)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-butylquinazoline-2, 4(1H,3H) -dione (Compound 38c)
Compound 38b (112.5mg, 0.34mmol) was dissolved in 1.7mL of ethanol solution, and potassium hydroxide (191.8mg, 3.42mmol) was added thereto, followed by reaction under reflux overnight. After the reaction is finished, concentrating to be dry, adding a small amount of hydrosolvent, acidifying by using 1M HCl, separating out solid, and filtering to obtain a yellow solid crude product.
1H NMR(500MHz,CDCl3)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) 7-bromo-3-tert-butyl-1-n-pentylquinazoline-2, 4(1H,3H) -dione (compound 38d)
Compound 38c (46mg, 0.15mmol) was dissolved in 2mL of DMF, and sodium methoxide (16.7mg, 0.31mmol) and n-pentane bromide (23. mu.L, 0.19mmol) were added in this order to react at 50 ℃ overnight. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a colorless liquid which is directly used for the next reaction.
e) 7-bromo-1-n-pentylquinazoline-2, 4(1H,3H) -dione (compound 38e)
Compound 38d (45.4mg, 0.12mmol) was placed in a 10mL single neck round bottom flask, 2mL of 1, 4-dioxane solution was added and dissolved with magnetic stirring, 1.8mL of 6N HCl solution was added and heated to reflux and monitored by TLC to completion. After the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing and rotary-steaming to remove an organic solvent, and separating and purifying by silica gel column chromatography to obtain a white solid. Yield: 49.1 percent; melting point: 141.4-142.6 ℃.
1H NMR(500MHz,CDCl3)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-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide (Compound 38)
Compound 38e (10.0mg, 0.03mmol) was dissolved in 2mL of DMF solution, potassium carbonate (8.88mg, 0.06mmol) was added, and the reaction was carried out at 80 ℃ for 30min, followed by addition of compound 1a (5.3mg, 0.04mmol) and reaction at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 97.6 percent; melting point: 166.4-167.6 ℃.
1H NMR(500MHz,CDCl3)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)。
Example 39: n-tert-butyl-2- (7-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 39)
a) 4-methyl-2- (n-pentylamino) benzoic acid (Compound 39a)
2-amino-4-methylbenzoic acid (907.2mg, 6.0mmol) was dissolved in 18mL of acetonitrile and 6mL of water, anhydrous potassium carbonate (1.82g, 6.0mmol) and potassium iodide (99.6mg, 0.6mmol) were sequentially added, and after stirring at room temperature for half an hour, n-pentane bromide (744. mu.L, 6.0mmol) was added, followed by heating and refluxing for 24 hours. After the reaction is finished, the reaction product is cooled to room temperature, the solvent acetonitrile is removed through rotary evaporation as much as possible, 10mL of water is added, ethyl acetate is used for extraction, the combined organic phase is washed by saturated saline solution, dried by anhydrous magnesium sulfate, and subjected to reduced pressure distillation to obtain a crude product. And (4) separating and purifying by column chromatography to obtain a yellow solid. Yield: 23.2 percent; melting point: 138.2-139.1 ℃.
b) 7-methyl-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 39b)
Compound 39a (305.1mg, 1.38mmol) was placed in a reaction flask, added with urea (331.2mg, 5.51mmol), and heated to 200 ℃ without solvent for 1 h. After the reaction is finished, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product. Separating and purifying by column chromatography to obtain white solid. Yield: 21.0 percent; melting point: 130.8-131.9 ℃.
c) N-tert-butyl-2- (7-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 39)
Compound 39b (24.6mg, 0.10mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.2mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, and Compound 1a (15.0mg, 0.10mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 90.4 percent; melting point: 136.4-137.5 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 40: n-tert-butyl-2- (6-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 40)
a) 5-methyl-2- (n-pentylamino) benzoic acid (Compound 40a)
2-amino-5-methylbenzoic acid (907.2mg, 6.0mmol) was dissolved in 18mL of acetonitrile and 6mL of water, anhydrous potassium carbonate (1.82g, 6.0mmol) and potassium iodide (99.6mg, 0.6mmol) were sequentially added, and after stirring at room temperature for half an hour, n-pentane bromide (744. mu.L, 6.0mmol) was added, followed by heating and refluxing for 24 hours. After the reaction is finished, the reaction product is cooled to room temperature, the solvent acetonitrile is removed through rotary evaporation as much as possible, 10mL of water is added, ethyl acetate is used for extraction, the combined organic phase is washed by saturated saline solution, dried by anhydrous magnesium sulfate, and subjected to reduced pressure distillation to obtain a crude product. And (4) separating and purifying by column chromatography to obtain a yellow solid. Yield: 19.1 percent; melting point: 128.1-129.4 ℃.
b) 6-methyl-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 40b)
Compound 39a (250.3mg, 1.13mmol) was placed in a reaction flask, added with urea (271.7mg, 4.52mmol), and heated to 200 ℃ without solvent for 1 h. After the reaction is finished, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product. Separating and purifying by column chromatography to obtain white solid. Yield: 51.7 percent; melting point: 107.5-109 ℃.
c) N-tert-butyl-2- (6-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 40)
Compound 40b (24.6mg, 0.10mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.2mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, compound 1a (15.0mg, 0.10mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 90.1 percent; melting point: 186.4-187.7 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 41: n-tert-butyl-2- (6-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 41)
a) 5-methoxy-2- (n-pentylamino) benzoic acid (Compound 41a)
2-amino-5-methoxybenzoic acid (835.8mg, 5.0mmol) was dissolved in 18mL of acetonitrile and 6mL of water, anhydrous potassium carbonate (1.52g, 11.0mmol) and potassium iodide (83.0mg, 0.5mmol) were sequentially added, and after stirring at room temperature for half an hour, n-pentane bromide (620. mu.L, 5.0mmol) was added, followed by heating and refluxing for 24 hours. After the reaction is finished, the reaction product is cooled to room temperature, the solvent acetonitrile is removed through rotary evaporation as much as possible, 10mL of water is added, ethyl acetate is used for extraction, the combined organic phase is washed by saturated saline solution, dried by anhydrous magnesium sulfate, and subjected to reduced pressure distillation to obtain a crude product. And (4) separating and purifying by column chromatography to obtain a yellow solid. Yield: 24.9 percent; melting point: 100.3-101.5 ℃.
b) 6-methoxy-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 41b)
Compound 40a (295.4mg, 1.24mmol) was placed in a reaction flask, added with urea (299.1mg, 4.98mmol) and heated to 200 ℃ without solvent for 1 h. After the reaction is finished, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product. Separating and purifying by column chromatography to obtain white solid. Yield: 67.9 percent; melting point: 172.9-173.9 ℃.
c) N-tert-butyl-2- (6-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 41)
Compound 41b (26.2mg, 0.10mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.2mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, and Compound 1a (15.0mg, 0.10mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 82%; melting point: 142.8-143.8 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 42: n-tert-butyl-2- (6-fluoro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 42)
a) 5-fluoro-2- (n-pentylamino) benzoic acid (Compound 42a)
2-amino-5-fluorobenzoic acid (930.8mg, 6.0mmol) was dissolved in 18mL of acetonitrile and 6mL of water, anhydrous potassium carbonate (1.82g, 13.2mmol) and potassium iodide (99.6mg, 0.6mmol) were sequentially added, and after stirring at room temperature for half an hour, n-pentane bromide (744. mu.L, 6.0mmol) was added, followed by heating and refluxing for 24 hours. After the reaction is finished, the reaction product is cooled to room temperature, the solvent acetonitrile is removed through rotary evaporation as much as possible, 10mL of water is added, ethyl acetate is used for extraction, the combined organic phase is washed by saturated saline solution, dried by anhydrous magnesium sulfate, and subjected to reduced pressure distillation to obtain a crude product. And (4) separating and purifying by column chromatography to obtain a yellow solid. Yield: 19.1 percent; melting point: 80.5-82 ℃.
b) 6-fluoro-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 42b)
Compound 41a (256.0mg, 1.14mmol) was placed in a reaction flask, added with urea (273.0mg, 4.55mmol), and heated to 200 ℃ without solvent for 1 h. After the reaction is finished, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product. Separating and purifying by column chromatography to obtain white solid. Yield: 51.5 percent; melting point: 140.7-141.8 ℃.
c) N-tert-butyl-2- (6-fluoro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 42)
Compound 42b (25.0mg, 0.10mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.2mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, compound 1a (15.0mg, 0.11mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 90.3 percent; melting point: 180.8-182.3 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 43: n-tert-butyl-2- (6-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 43)
a) 5-chloro-2- (n-pentylamino) benzoic acid (Compound 43a)
2-amino-5-chlorobenzoic acid (1.03g, 6.0mmol) was dissolved in 18mL of acetonitrile and 6mL of water, anhydrous potassium carbonate (1.82g, 13.2mmol) and potassium iodide (99.6mg, 0.6mmol) were sequentially added, and after stirring at room temperature for half an hour, n-pentane bromide (893. mu.L, 7.2mmol) was added, followed by heating and refluxing for 24 hours. After the reaction is finished, the reaction product is cooled to room temperature, the solvent acetonitrile is removed through rotary evaporation as much as possible, 10mL of water is added, ethyl acetate is used for extraction, the combined organic phase is washed by saturated saline solution, dried by anhydrous magnesium sulfate, and subjected to reduced pressure distillation to obtain a crude product. And (4) separating and purifying by column chromatography to obtain a yellow solid. Yield: 8.2 percent; melting point: 114.7-116.1 ℃.
b) 6-chloro-1-n-pentylquinazoline-2, 4(1H,3H) -dione (Compound 43b)
Compound 43a (118.6mg, 0.49mmol) was placed in a reaction flask, added with urea (117.9mg, 1.96mmol) and heated to 200 ℃ without solvent for 1 h. After the reaction is finished, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product. Separating and purifying by column chromatography to obtain white solid. Yield: 51.3 percent; melting point: 146.7-148 ℃.
c) N-tert-butyl-2- (6-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 43)
Compound 43b (21.3mg, 0.08mmol) was dissolved in 2mL of DMF solution, and potassium carbonate (12.2mg, 0.09mmol) was added and reacted at 80 ℃ for 30min, and Compound 1a (12.0mg, 0.08mmol) was added and reacted at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 99.3 percent; melting point: 172.2-173.3 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 44: 2- (6-bromo-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide (Compound 44)
a) 5-bromo-2- (n-pentylamino) benzoic acid (Compound 44a)
2-amino-5-bromobenzoic acid (1.08g, 5.0mmol) was dissolved in 18mL of acetonitrile and 6mL of water, anhydrous potassium carbonate (1.52g, 11.0mmol) and potassium iodide (83.0mg, 0.5mmol) were added in this order, and after stirring at room temperature for half an hour, n-pentane bromide (620. mu.L, 5.0mmol) was added, followed by heating and refluxing for 24 hours. After the reaction is finished, the reaction product is cooled to room temperature, the solvent acetonitrile is removed through rotary evaporation as much as possible, 10mL of water is added, ethyl acetate is used for extraction, the combined organic phase is washed by saturated saline solution, dried by anhydrous magnesium sulfate, and subjected to reduced pressure distillation to obtain a crude product. And (4) separating and purifying by column chromatography to obtain a yellow solid. Yield: 9.8 percent; melting point: 131.8-132.9 ℃.
b) 6-bromo-1-n-pentylquinazoline-2, 4(1H,3H) -dione (compound 44b)
Compound 44a (139.5mg, 0.49mmol) was placed in a reaction flask, added with urea (117.1mg, 1.95mmol) and heated to 200 ℃ without solvent for 1 h. After the reaction is finished, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product. Separating and purifying by column chromatography to obtain white solid. Yield: 51.3 percent; melting point: 138.6-139.5 ℃.
c)2- (6-bromo-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide (Compound 44)
Compound 44b (31.1mg, 0.10mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.2mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, and compound 1a (15.0mg, 0.10mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 88.1 percent; melting point: 178.4-179.2 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 45: n-tert-butyl-2- (2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 45)
a)2- (n-propylamino) benzoic acid (Compound 45a)
Anthranilic acid (960.0g, 7.0mmol) was dissolved in 18mL of acetonitrile and 6mL of water, anhydrous potassium carbonate (2.13g, 15.4mmol) and potassium iodide (116.2mg, 0.7mmol) were added in this order, and after stirring at room temperature for half an hour, n-propyl bromide (636. mu.L, 7.0mmol) was added, followed by heating and refluxing for 24 hours. After the reaction is finished, the reaction product is cooled to room temperature, the solvent acetonitrile is removed through rotary evaporation as much as possible, 10mL of water is added, ethyl acetate is used for extraction, the combined organic phase is washed by saturated saline solution, dried by anhydrous magnesium sulfate, and subjected to reduced pressure distillation to obtain a crude product. And (4) separating and purifying by column chromatography to obtain a yellow solid. Yield: 22.4 percent; melting point: 109.6-110.7 ℃.
b) 1-n-propylquinazoline-2, 4(1H,3H) -dione (Compound 45b)
Compound 45a (280.0mg, 1.56mmol) was placed in a reaction flask, added with urea (375.3mg, 6.25mmol) and heated to 200 ℃ without solvent for 1 h. After the reaction is finished, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, and distilling under reduced pressure to obtain a crude product. Separating and purifying by column chromatography to obtain white solid. Yield: 35.8 percent; melting point: 172.4-173.8 ℃.
c) N-tert-butyl-2- (2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 45)
Compound 45b (20.4mg, 0.10mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.2mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, and compound 1a (15.0mg, 0.10mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 90.7 percent; melting point: 238.6-239.9 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 46: n-tert-butyl-2- (1-N-butyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 46)
a)2- (n-butylamino) benzoic acid (Compound 46a)
Experimental procedure the same procedure used to prepare Compound 45a in example 45, except that n-butyl bromide was used in place of n-propyl bromide, gave a yellow solid. Yield: 21.4 percent; melting point: 74.9-76.7 ℃.
b) 1-n-butylquinazoline-2, 4(1H,3H) -dione (Compound 46b)
Experimental procedure the same procedure used to prepare Compound 45b in example 45 was followed, except that Compound 46a was used in place of Compound 45a to give a white solid. Yield: 38.5 percent; melting point: 126.5-127.3 ℃.
c) N-tert-butyl-2- (1-N-butyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 46)
Compound 46b (21.8mg, 0.10mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.2mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, and compound 1a (15.0mg, 0.10mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 88.4 percent; melting point: 230.3-231.1 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 47: 2- (1-N-butyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide (Compound 47)
Experimental procedure the same procedure used to prepare Compound 46 in example 46, except that Compound 6a was used in place of Compound 1a, gave a white solid. Yield: 96.8 percent; melting point: 224.4-225.4 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 48: n-tert-butyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 48)
a)2- (n-pentylamino) benzoic acid (Compound 48a)
The experimental procedure was the same as that used in the preparation of compound 45a in example 45, except that n-propyl bromide was replaced with n-pentane bromide to give a yellow solid. Yield: 20.3 percent; melting point: 67.0-68.1 ℃.
b) 1-n-butylquinazoline-2, 4(1H,3H) -dione (Compound 46b)
Experimental procedure the same procedure used to prepare Compound 45b in example 45, except that Compound 48a was used in place of Compound 45a, gave a white solid. Yield: 33.8 percent; melting point: 114.5-115.9 ℃.
c) N-tert-butyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 48)
Compound 48b (23.2mg, 0.10mmol) was dissolved in 2mL of DMF solution, potassium carbonate (15.2mg, 0.11mmol) was added, reaction was carried out at 80 ℃ for 30min, and compound 1a (15.0mg, 0.10mmol) was added, and reaction was carried out at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 76.7 percent; melting point: 213.4-214.2 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 49: 2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-isopropylacetamide (Compound 49)
a) 2-chloro-N-isopropylacetamide (Compound 49a)
Isopropylamine (236.4mg, 4.0mmol) was dissolved in 4mL of dichloromethane, anhydrous potassium carbonate (663.4mg, 4.8mmol) was added, the flask was placed in an ice bath, chloroacetyl chloride (451.8mg, 4.0mmol) was added slowly via the addition funnel, and the reaction was stirred at room temperature overnight. After the reaction, 10mL of ice water was added to quench the reaction, dichloromethane was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure without further purification to give a white solid. Yield: 70.3 percent; melting point: 58.6-59.4 ℃.
b)2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-isopropylacetamide (Compound 49)
Experimental procedure the same procedure used to prepare Compound 48 in example 48, except that Compound 49a was used in place of Compound 1a, gave a white solid. Yield: 99.3 percent; melting point: 213.8-215.6 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 50: n-cyclopropyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 50)
a) 2-chloro-N-cyclopropylacetamide (Compound 50a)
Cyclopropylamine (228.4mg, 4.0mmol) was dissolved in 4mL of dichloromethane, anhydrous potassium carbonate (663.4mg, 4.8mmol) was added, the flask was placed in an ice bath, chloroacetyl chloride (451.8mg, 4.0mmol) was added slowly via the addition funnel, and the reaction was stirred at room temperature overnight. After the reaction, 10mL of ice water was added to quench the reaction, dichloromethane was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure without further purification to give a white solid. Yield: 74.8 percent; melting point: 81.6-83.2 ℃.
b) N-cyclopropyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 50)
Experimental procedure the same procedure used to prepare Compound 48 in example 48, except that Compound 50a was used in place of Compound 1a, gave a white solid. Yield: 98.7 percent; melting point: 195.2-196.9 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 51: N-N-butyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 51)
Experimental procedure the same procedure used to prepare Compound 48 in example 48, except that Compound 5a was used in place of Compound 1a, gave a white solid. Yield: 92.8 percent; melting point: 181.3 to 182.7 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 52: 2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-isobutylacetamide (Compound 52)
a) 2-chloro-N-isobutylacetamide (Compound 52a)
Isobutylamine (292.6mg, 4.0mmol) was dissolved in 4mL of dichloromethane, anhydrous potassium carbonate (663.4mg, 4.8mmol) was added, the flask was placed in an ice bath, chloroacetyl chloride (451.8mg, 4.0mmol) was slowly added through the dropping funnel, and the reaction was stirred at room temperature overnight. After the reaction, 10mL of ice water was added to quench the reaction, dichloromethane was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure without further purification to give a white solid. Yield: 73.1 percent; melting point: 32.2-22.4 ℃.
b)2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-isobutylacetamide (Compound 52)
Experimental procedure the same procedure used to prepare Compound 48 in example 48, except that Compound 52a was used in place of Compound 1a, gave a white solid. Yield: 85.8 percent; melting point: 185.9-186.9 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 53: n-cyclohexyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 53)
Experimental procedure the same procedure used to prepare Compound 48 in example 48, except that Compound 6a was used in place of Compound 1a, gave a white solid. Yield: 94.5 percent; melting point: 211.7-212.5 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 54: n-tert-butyl-2- (1-N-hexyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 54)
a)2- (n-hexylamino) benzoic acid (Compound 54a)
The experimental procedure was the same as that used in the preparation of compound 45a in example 45, except that n-propyl bromide was replaced with n-hexane bromide to give a yellow solid. Yield: 16.9 percent; melting point: 57.3-58.7 ℃.
b) 1-n-hexylquinazoline-2, 4(1H,3H) -dione (compound 54b)
Experimental procedure the same procedure used to prepare Compound 45b in example 45 was followed, except that Compound 54a was used in place of Compound 45a, to give a white solid. Yield: 16 percent; melting point: 85.1-86.7 ℃.
c) N-tert-butyl-2- (1-N-hexyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide (Compound 54)
Compound 54b (19.7mg, 0.08mmol) was dissolved in 2mL of DMF solution, and potassium carbonate (12.2mg, 0.09mmol) was added and reacted at 80 ℃ for 30min, and Compound 1a (12.0mg, 0.08mmol) was added and reacted at 80 ℃ overnight. After the reaction is finished, cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, washing an organic layer with saturated sodium chloride, drying with anhydrous magnesium sulfate, decompressing, carrying out rotary evaporation to remove an organic solvent, and carrying out silica gel column chromatography separation and purification to obtain a white solid. Yield: 87.6 percent; melting point: 194.9-195.9 ℃.
1H NMR(CDCl3,500MHz):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)。
Example 55: preparation of hydrochloride 7A, quaternary ammonium salt 7B and monohydrate 7C of Compound 7
a) Preparation of hydrochloride salt 7A of Compound 7
At room temperature, compound 7(35.9mg, 0.1mmol) was dissolved in anhydrous methanol (1mL), and a saturated methanolic hydrogen chloride solution (2mL) was slowly added dropwise under ice bath, after the solvent was evaporated under reduced pressure, ether was added with stirring to precipitate a white solid, which was filtered and washed with ether to obtain hydrochloride 7A of compound 7 as a white solid, 38.0mg, yield: 96 percent.
ESI-MS:m/z 360.22[M+]
b) Preparation of Quaternary ammonium salt 7B of Compound 7
Compound 7(35.9mg, 0.1mmol) was dissolved in absolute ethanol (1mL) at room temperature, and an equivalent amount of sodium hydroxide, potassium iodide and methyl iodide were added, and after heating under reflux overnight, the solvent was dried under reduced pressure, and the crude product was purified by recrystallization from acetone to give quaternary ammonium salt 7B of compound 7 as a white solid 20mg, yield: 38.8 percent.
ESI-MS:m/z 388.26[M+]
c) Preparation of monohydrate 7C of Compound 7
At room temperature, compound 7(35.9mg, 0.1mmol) was dissolved in 1N HCl solution, petroleum ether was slowly added dropwise with stirring until the solution became cloudy, and left at room temperature until no crystals precipitated, and filtered to give monohydrate 7C of compound 7.
Elem.Anal.:C,63.64％；H,8.28％；N,11.13％；O,16.95％。
According to analogous procedures described in this example, pharmaceutically acceptable salts or hydrates of compound V of the present invention may be prepared, including salts with organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, etc.; or forming salt with inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid, etc.; or a quaternary ammonium salt formed with a haloalkane, said haloalkane being a fluoro, chloro, bromo or iodo alkane.
Example 56: pharmaceutical composition
Compound 7A 20g
140g of starch
Microcrystalline cellulose 60g
According to the conventional operation method, the 3 substances are physically and uniformly mixed and then are filled into a gelatin capsule to obtain 1000 capsules.
Example 57: pharmaceutical composition
Compound 7A 50g
Starch 400g
Microcrystalline cellulose 200g
According to the conventional operation method, the 3 substances are physically and uniformly mixed and then are filled into a gelatin capsule to obtain 1000 capsules.
Example 58: pharmacological test example-Calcium flux screening model (Calcium current assay)
Cannabis receptors, when activated, result in the inhibition of intracellular calcium flux. However, after the G protein G alpha 16 is transferred, the calcium flux in cells is activated, and other physiological functions are not affected. By establishing cell lines co-transformed with CB1and G a 16, CB2 and G a 16, respectively, such that activation of the receptor results in activation of the G a 16 protein, which in turn activates phospholipase c (plc) to produce IP3 and DAG, IP3 can bind to the IP3 receptor on the intracellular endoplasmic reticulum, thereby resulting in release of intracellular calcium. Therefore, the determination of the change in intracellular calcium can be used as a method for detecting the activation state of CB1and CB 2. Fluo-4/AM is a calcium fluorescent probe indicator used for measuring calcium ions, is used as a nonpolar fat-soluble compound, and after entering cells, under the action of cell lipolytic enzyme, an AM group is dissociated to release Fluo-4; since Fluo-4 is a polar molecule and does not readily pass through a lipid bilayer membrane, it can retain Fluo-4 in the cell for a long period of time. The level of activation of the G alpha protein may ultimately be reflected by measuring the amount of photons excited. According to the principle, a calcium flux screening model is established.
The experimental method comprises the following steps: cells were transfected with human cannabis receptors (hCB1, hCB2) and G alpha 16 at the same time, and stably transfected cell lines CHO-hCB1-G alpha 16 and CHO-hCB2-G alpha 16 were established by antibiotic selection. An appropriate concentration of CHO/CB2-G alpha 16 or CHO/CB1-G alpha 16 (about 2 ten thousand per well) was applied to a 96-well plate 24 hours before detection, so that about 4 to 6 ten thousand cells per well were detected. The cells were incubated overnight, the culture medium was removed after cell attachment, and incubated with 2. mu. mol/L fluo-4AM dye in an incubator at 37 ℃ for 50 minutes. After excess dye was aspirated, cells were washed once with Hanks' Balanced Salt Solution (HBSS) buffer. In the antagonistic mode, cells are incubated for 10 minutes at room temperature by HBSS buffer solution containing positive control or a compound to be detected or negative control containing DMSO, 25 mu L of agonist is automatically added into a reaction system by a FlexStation detector, and the change of the fluorescence intensity of the dye caused by the change of the intracellular calcium ion current is detected in real time. In the excitation mode, cells are incubated for 10 minutes by HBSS buffer solution at room temperature, HBSS buffer solution containing positive control or a compound to be detected or negative control DMSO is automatically added into a reaction system by a FlexStation detector, and the change of the fluorescence intensity of the dye caused by the change of the intracellular calcium ion current is detected in real time. The inhibition rate or relative activation rate value of the tested compound can be obtained.
The inhibition rate is (peak of calcium flux of negative control-peak of calcium flux of test compound)/(peak of calcium flux of negative control-peak of calcium flux of positive control) × 100%.
Relative agonism ratio (peak calcium flux of test compound-peak calcium flux of negative control)/(peak calcium flux of positive control-peak calcium flux of negative control) × 100%.
Half inhibitory concentration IC of the compounds was performed in the above manner50Or half effective amount of EC50The determination of (2) was mainly obtained by making response rate and dose curves, selecting a total of eight dose concentrations of 100. mu.M, 10. mu.M, 1. mu.M, 100nM, 10nM, 1nM, 100pM, 0, the calcium flux assay was performed according to the experimental procedure described above, with each concentration being determined in triplicate, i.e., using 8-gradient 3-well plates. Data were analyzed using GraphPad Prism software. Fitting dose-dependent curves of the test compounds by non-linear regression and calculating IC50Or EC50。
TABLE 1 in vitro Activity data for quinazolinedione derivatives
The experimental results show that: the compound of the invention generally shows higher calcium flow activity and good selectivity to human hemp receptor CB2, and simultaneously, the compound R of the invention1、R2、R3And R4The difference in groups has an important effect on the activity of the compounds, and the difference in substituents can cause the compounds to exhibit agonistic or inverse agonistic activity. In general, the compound is a specific agonist or inverse agonist of the cannabis receptor CB2, and has better drug development prospect.

Claims (9)

1. A quinazoline diketone derivative and a pharmaceutically acceptable salt or hydrate thereof are characterized in that the structural general formula V is as follows:
wherein,
R1、R2、R3、R4each independently selected from hydrogen atom, halogen, C1-C4A straight or branched alkyl group,C1-C4Linear or branched alkoxy, hydroxy;
R5is selected from C2-C6Straight chain alkyl radical, with C3-C6Cyclic alkyl, 3-buten-1-yl;
R6is selected from C2-C6Straight or branched alkyl, C3-C6Cycloalkyl radical, with C3-C6A cyclic alkyl, aryl, heteroaryl, heterocyclyl or adamantyl group;
the halogen is fluorine, chlorine, bromine or iodine;
the heteroaryl group is a 5-10 membered aromatic group containing 1-3 heteroatoms, which may be the same or different, selected from N, O and S;
the heterocyclic group is a 4-10 membered nonaromatic group containing 1-3 heteroatoms selected from N, O and S which may be the same or different.
2. A quinazolinedione derivative and pharmaceutically acceptable salts or hydrates thereof according to claim 1, wherein said derivative is selected from the group consisting of:
(1) n-tert-butyl-2- (1-cyclopropylmethyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(2)2- (1- (3-buten-1-yl) -5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide
(3) N-tert-butyl-2- (5-methyl-2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(4) N-tert-butyl-2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(5) N-N-butyl-2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(6)2- (1-N-butyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide
(7) N-tert-butyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(8) N-N-butyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(9) N-cyclohexyl-2- (5-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(10) N-tert-butyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(11) N-N-butyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(12) N-cyclohexyl-2- (1-N-hexyl-5-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(13) N-tert-butyl-2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(14) N-N-butyl-2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(15)2- (5-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide
(16) N-tert-butyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(17) N-N-butyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(18) N-cyclohexyl-2- (5-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(19) N-tert-butyl-2- (1-cyclopropylmethyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(20)2- (1- (3-buten-1-yl) -8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide
(21) N-tert-butyl-2- (1-ethyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(22) N-tert-butyl-2- (8-methyl-2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(23) N-tert-butyl-2- (1-N-butyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(24) N-tert-butyl-2- (1-N-pentyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(25) N-N-butyl-2- (8-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(26) N-cyclohexyl-2- (1-N-pentyl-8-methyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(27) N-tert-butyl-2- (8-methyl-2, 4-dione-1-N-hexyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(28) N-tert-butyl-2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(29) N-N-butyl-2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(30)2- (8-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide
(31) N-tert-butyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(32) N-N-butyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(33) N-cyclohexyl-2- (8-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(34) N-tert-butyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(35) N-N-butyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(36) N-cyclohexyl-2- (6, 7-dimethoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(37) N-tert-butyl-2- (7-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(38)2- (7-bromo-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide
(39) N-tert-butyl-2- (7-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(40) N-tert-butyl-2- (6-methyl-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(41) N-tert-butyl-2- (6-methoxy-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(42) N-tert-butyl-2- (6-fluoro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(43) N-tert-butyl-2- (6-chloro-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(44)2- (6-bromo-2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-tert-butylacetamide
(45) N-tert-butyl-2- (2, 4-dione-1-N-propyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(46) N-tert-butyl-2- (1-N-butyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(47)2- (1-N-butyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) -N-cyclohexylacetamide
(48) N-tert-butyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(49)2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-isopropylacetamide
(50) N-cyclopropyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(51) N-N-butyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(52)2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) -N-isobutylacetamide
(53) N-cyclohexyl-2- (2, 4-dione-1-N-pentyl-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
(54) N-tert-butyl-2- (1-N-hexyl-2, 4-dione-1, 2-dihydroquinazolin-3 (4H) -yl) acetamide
And hydrates of the above specific compounds.
3. The quinazoline dione derivative and the pharmaceutically acceptable salt or hydrate thereof according to claim 1, wherein the pharmaceutically acceptable salt is a salt of the compound represented by the general formula V with an organic acid selected from propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid and citric acid; or forming a salt with an inorganic acid selected from hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, and hydrobromic acid; or a quaternary ammonium salt formed with a haloalkane, said haloalkane being a fluoro, chloro, bromo or iodo alkane.
4. A process for preparing a quinazolinedione derivative and pharmaceutically acceptable salts or hydrates thereof according to claim 1, which comprises the steps of:
(1) reacting a compound shown in the formula I with a compound shown in the formula II to generate a compound shown in the formula III;
(2) reacting the compound shown in the formula VI with the compound shown in the formula III to generate a compound shown in the formula V;
wherein R is1、R2、R3、R4、R5、R6As defined in claim 1.
5. The process of claim 4, wherein the compound of formula VI is prepared by:
under the alkaline condition, carrying out N-alkylation on the compounds A-1 and A-2 to obtain an N-substituted compound A-3, and then carrying out ring synthesis with cyanic acid generated by thermal decomposition of urea at high temperature to form a compound in a formula VI;
wherein the base is an organic or inorganic base selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, triethylamine, Diisopropylethylamine (DIEA), pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 4-Dimethylaminopyridine (DMAP);
wherein R is1、R2、R3、R4Is a hydrogen atom, R5As defined in claim 1.
6. The process of claim 4, wherein the compound of formula VI is prepared by:
carrying out condensation reaction on the compound A-1 and BTC to obtain a compound A-4, carrying out N alkylation reaction in the presence of sodium hydride to obtain a compound A-5, and reacting with urea at high temperature to form a compound in a formula VI;
wherein R is1、R2、R3、R4、R5As defined in claim 1.
7. The process of claim 4, wherein the compound of formula VI is prepared by:
after the compound A-1 is chlorinated by thionyl chloride, the compound A-1 reacts with tert-butylamine to obtain a compound shown as a formula A-7; reacting the compound A-7 with ethyl chloroformate or methyl chloroformate to obtain a compound shown in a formula A-8, and performing reflux reaction on the compound A-8 with N, N' -carbonyldiimidazole or potassium hydroxide and ethanol to obtain a compound shown in a formula A-9; in the presence of sodium methoxide, performing N alkylation reaction to obtain a compound shown in a formula A-10; then carrying out reflux reaction under an acidic condition to obtain a compound shown in a formula VI;
wherein R is1、R2、R3、R4、R5As defined in claim 1.
8. The use of a quinazolinedione derivative according to claim 1, or a pharmaceutically acceptable salt or hydrate thereof, for the preparation of a medicament for the treatment, prevention, alleviation or inhibition of diseases mediated by the CB2 receptor.
9. The use according to claim 8, wherein said diseases are caused by modulation of CB2receptor active ligands and relate to cancer, inflammation, acquired immunodeficiency syndrome, autoimmune diseases, rheumatic diseases, allergy, pain, acute and chronic liver diseases, osteoporosis, atherosclerosis, multiple sclerosis, neurodegenerative diseases, alzheimer's disease, parkinson's disease, 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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