CN105541806A - Barbiturate compound, preparing method and application thereof - Google Patents

Barbiturate compound, preparing method and application thereof Download PDF

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CN105541806A
CN105541806A CN201511003646.6A CN201511003646A CN105541806A CN 105541806 A CN105541806 A CN 105541806A CN 201511003646 A CN201511003646 A CN 201511003646A CN 105541806 A CN105541806 A CN 105541806A
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compound
methyl
pyrimidine
triketone
dmso
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查晓明
蓝斐
徐思远
周忱
徐云根
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China Pharmaceutical University
Fudan University
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China Pharmaceutical University
Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/62—Barbituric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/66—Thiobarbituric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a barbiturate compound, a preparing method and application thereof. Specifically, the invention relates to the compound as shown in formula I, and a medicinal usage thereof as a selective LSD1 reversible inhibitor, particular to the application in preparing of antitumor medicine. A test shows that the compound in formula I can efficiently reversibly inhibit LSD1 activity, and has a weak inhibition action for homologous proteins MAO-A and MAO-B, can intensively induce differentiation of leukemia cell NB4 and obviously enhance the methylation level of primers H3K4me1 and H3K4me2 of the LSD1.

Description

Barbituric acid compounds, preparation method and application thereof
Technical field
The invention belongs to medicinal chemistry art, be specifically related to barbituric acid compounds, preparation method and the medicinal use as istone lysine specificity demethylase 1 inhibitor thereof, particularly preparing the application in antitumor drug.
Background technology
Large quantity research shows, generation, the development of tumour are not only relevant with genetic gene mutation, and closely related with epigenetic regulation.2004, Shi Yang group of Harvard University has found first istone lysine specificity demethylase 1 (LysineSpecificDemethylase1, LSD1), specify that methylating and there is running balance between demethylation of histone first, regulated and controled by ZNFN3A1 and histone demethylase respectively, this finds the frontier (Cell, 2004 that open histone modification mechanism and drug research thereof, 119,941-953).LSD1 is a kind of flavin adenine dinucleotide (flavinadeninedinucleotide, FAD) demethylase relied on, belong to amino group enzyme family, with monoamine oxidase (monoamineoxidase, MAO) there is homology, and mixture can be formed with CoREST, BHC80, HDAC1/2 etc., remove the 4th Methionin (histone3lysine4 of H3, H3K4) monomethyl or two methyl, cause the suppression of genetic transcription; What is interesting is when LSD1 and androgen receptor or estrogen receptor in conjunction with time can participate in removing the monomethyl of the 9th Methionin (histone3lysine9, H3K9) of histone H 3 or two methyl, cause the activation of genetic transcription.In addition, LSD1 can also with the generation effects such as nonhistones p53, DNMT1, affect generation and development (Nature, 2007,449,105-108 of tumour; Mol.Cell.Biol.2008,28,5139-5146).
Research finds, LSD1 is high expression level in the kinds of tumors such as leukemia, mammary cancer, bladder cancer, prostate cancer and liver cancer, to the differentiation of tumour, propagation, transfer and invasion and attack, there is vital role (Nat.Rev.DrugDiscov.2014,12,917-930).Therefore, LSD1 inhibitor has potential antitumor action.According to the difference of chemical structure and binding mode, LSD1 inhibitor can be divided into irreversible and reversible two class.In irreversible LSD1 inhibitor, most study is tranylcypromine class, the tranylcypromine in its structure and FAD covalent attachment, thus irreversibly suppresses LSD1 active.But can not get rid of the possibility of the enzyme effect relied on other (even potential is still undiscovered) LSD1 homology enzymes or FAD, this genotoxic potential based on covalent attachment mechanism of action makes LSD1 irreversible inhibitor there is greater risk.Reversible LSD1 inhibitor comprises peptide class, polyamines class and other micromolecular compounds (ExpertOpin.Ther.Targets, 2012,16,1239-1249), but have that restraining effect is strong, selectivity is not high and to problems such as the specificity of LSD1 are not strong.Therefore, find that selectivity is strong, the LSD1 reversible inhibitor of high-efficiency low-toxicity is one of new way for the treatment of malignant tumor.
Summary of the invention
Technical problem to be solved by this invention is for the pharmacological agent of disease such as tumor disease, nerve degenerative diseases and the virus disease of LSD1 mediation provides a kind of selection newly.
The invention discloses a class barbituric acid compounds, this compounds has the structure as shown in general formula I:
Wherein, R 1, R 2, R 3represent any one in hydrogen, amino, hydroxyl, halogen, carboxyl, trifluoromethyl, methyl, methoxyl group, ethyl, oxyethyl group, sec.-propyl, nitro or cyano group; R 4representative in any one, wherein R 5represent any one in mono-substituted hydroxyl, amino, methyl, methoxyl group or halogen, or any two in disubstituted hydroxyl, amino, methyl, methoxyl group or halogen, or in trisubstituted hydroxyl, amino, methyl, methoxyl group or halogen any three.
Wherein, as the preferred compound in the present invention, R 1, R 2, R 3represent any one of hydrogen, amino, halogen, trifluoromethyl, methyl, methoxyl group or nitro; X represention oxygen atom or sulphur atom; R 4representative in any one.
In the present invention, more preferred compound is:
Another object of the present invention there is provided the preparation method of formula I, comprises the following steps:
(1) when X is O, formula I is prepared by the method described in reaction formula one:
A. the aniline 1 of potassium cyanate and aniline or replacement is obtained by reacting the carbamide compounds 2 of replacement in the mixing solutions of acetic acid and water, and temperature of reaction is zero degree to 60 DEG C, preferentially adopts zero degree to room temperature as temperature of reaction;
B. compound 2 and diethyl malonate reflux and are obtained by reacting sulfo-veronal compound 3 under basic conditions; Highly basic used is the one in sodium ethylate, sodium methylate, sodium hydride, sodium tert-butoxide, potassium ethylate, sodium hydroxide, potassium hydroxide, preferentially adopts sodium ethylate; The solvent adopted is ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, benzene, dimethylbenzene, dioxane, N, the mixture of a kind of or above-mentioned solvent in dinethylformamide, methyl-sulphoxide, preferentially adopts ethanol;
C. compound 3 obtains formula I with the fragrant formaldehyde reaction of fragrant formaldehyde or replacement.The solvent adopted is the mixture of a kind of or above-mentioned solvent in ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, 1,2-ethylene dichloride, chloroform, dioxane, DMF, methyl-sulphoxide, preferentially adopts ethanol; The temperature adopted is room temperature to 140 DEG C, preferential employing room temperature to 80 DEG C.
Reaction formula one
(2) when X is S, formula I is prepared by the method described in reaction formula two:
A. ammonium thiocyanate and Benzoyl chloride are obtained by reacting isothiocyanic acid benzoic ether in acetone soln, then obtain compound 4 with aniline 1 heating reflux reaction of aniline or replacement;
B. compound 4 is removed benzoyl protecting group through hydrolysis and is obtained substituting thioureido 5, and reagent used is the aqueous sodium hydroxide solution of 5%-10%, and temperature of reaction is room temperature to 100 DEG C, preferential employing 60 DEG C to 90 DEG C;
C. compound 5 and diethyl malonate reflux and are obtained by reacting sulfo-veronal compound 6 under basic conditions, highly basic used is the one in sodium ethylate, sodium methylate, sodium hydride, sodium tert-butoxide, potassium ethylate, sodium hydroxide, potassium hydroxide, preferentially adopts sodium ethylate; The solvent adopted is ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, benzene, dimethylbenzene, dioxane, N, the mixture of a kind of or above-mentioned solvent in dinethylformamide, methyl-sulphoxide, preferentially adopts ethanol;
D. compound 6 obtains formula I with the fragrant formaldehyde condensation of fragrant formaldehyde or replacement, the solvent adopted is ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, 1,2-ethylene dichloride, chloroform, dioxane, N, the mixture of a kind of or above-mentioned solvent in dinethylformamide, methyl-sulphoxide, preferentially adopts ethanol; The temperature adopted is room temperature to 140 DEG C, preferential employing room temperature to 80 DEG C.
Reaction formula two
Another object of the present invention discloses formula I and pharmaceutical salts thereof as the application of LSD1 inhibitor in disease treatment.Described disease, comprises tumor disease, nerve degenerative diseases and virus disease.Described tumor disease, comprises leukemia, prostate cancer, mammary cancer, bladder cancer, lung cancer, liver cancer, skin carcinoma, colorectal cancer, lymphatic cancer, ovarian cancer or carcinoma of testis.Described leukemia, comprises acute lymphoblastic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia and chronic monocytic leukemia.
Experimental result shows, potent suppression LSD1 is active for formula I energy of the present invention, it act as reversible, and it is very weak to the restraining effect of homologous protein MAO-A and MAO-B, the differentiation of energy induced strong Leukemia cells NB4, significantly promotes the methylation level of LSD1 substrate H3K4me1 and H3K4me2 simultaneously.
Compared with existing LSD1 inhibitor, formula I of the present invention has following advantages: (1) structure is different from existing LSD1 inhibitor, is particularly different from tranylcypromine class LSD1 inhibitor; (2) good LSD1 reversible inhibit activities, is significantly better than tranylcypromine class LSD1 inhibitor Tranylcypromine; (3) to homologous protein MAO-A/B, there is selectivity.Therefore, can be used as selectivity LSD1 reversible inhibitor for the preparation of antitumor drug.
The invention has the beneficial effects as follows: creatively demonstrate formula I by experiment as potent, reversible, the purposes of selectivity LSD1 inhibitor in medicine, the application especially in oncotherapy.
Accompanying drawing explanation
Fig. 1 represents the reversible experiment of I-30 to LSD1.
Fig. 2 represents I-10, I-11, I-12 and I-15 impact on NB4 cytodifferentiation.
Fig. 3 represents I-20, I-22, I-30 and I-32 impact on NB4 cytodifferentiation.
Fig. 4 represents I-10, I-12, I-15, I-20, I-22, I-30 and I-32 impact on substrate H3K4me1 and H3K4me2 level.
Embodiment
Be described above the universal method preparing the compounds of this invention.There is provided the following example in order to illustrate the present invention further, instead of limiting the scope of the invention.
Embodiment 1
(E/Z) preparation of-5-((1H-indoles-2-base) methylene radical)-1-(4-bromophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-1)
(1) indoles-2-formaldehyde
Add indole-2-carboxylic acid 805.8mg (5mmol) in 100mL eggplant-shape bottle, add THF30mL.Stir in ice bath while slowly add LiAlH 4379.5mg (10mmol).Stirring at room temperature 14h to TLC detection reaction terminates.Add saturated NH 4cl solution, extraction into ethyl acetate organic layer 3 times.With brine It, merge organic layer, anhydrous sodium sulfate drying.Decompression is spin-dried for solvent and obtains yellow crude indoles-2-methyl alcohol 441.5mg, yield 60%.Next step reaction is directly carried out without the need to purifying.
Crude product indoles-2-methyl alcohol 441.5mg (3mmol) is dissolved in 20mLCH 2cl 2, add activation MnO 21.74g (20mmol), stirring at room temperature 18h to TLC detection reaction terminates.Add diluted ethyl acetate reaction solution, diatomite filtration.Collect filtrate, pressure reducing and steaming solvent, through rapid column chromatography (developping agent sherwood oil: ethyl acetate=10: 3) obtain yellow solid 311.4mg, yield 71.5%. 1HNMR(300MHz，DMSO-d 6)δ11.95(s，1H，-N H-)，9.85(s，1H，-C HO)，7.75(d，J＝8.1Hz，1H，Ar H)，7.46(d，J＝8.3Hz，1H，Ar H)，7.39(s，1H，-C H-)，7.33(t，J＝7.2Hz，1H，Ar H)，7.11(t，J＝7.2Hz，1H，Ar H).
(2) 1-(4-bromophenyl) urea
Para-bromoaniline 1.72g (0.01mol) is dissolved in the mixing solutions of 4.8mL acetic acid and 9.6mL water, slowly adds the potassium cyanate aqueous solution (1.62g, 0.02mol are dissolved in 9mL water).Reaction one hour after white precipitate occurs, filtration washing obtains white solid 1.90g, productive rate 88.4%.Column chromatography for separation (sherwood oil: ethyl acetate=3: 1) obtain white solid 1.65g, yield 76.7%. 1HNMR(300MHz，DMSO-d 6)δ8.91(s，1H，-N H-)，7.65(d，J＝8.3Hz，2H，Ar H)，7.51(d，J＝8.4Hz，2H，Ar H)，5.83(s，2H，-N H 2).
(3) 1-(4-bromophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Add 60mL ethanol in 100mL eggplant-shape bottle, 0.46g sodium (20mmol) section adds.Stirring at room temperature is dissolved completely to sodium, adds 1-(4-bromophenyl) urea (2.15g, 10mmol) successively, and diethyl malonate (1.52mL, 10mmol) heating reflux reaction 35h to TLC detection reaction terminates.Decompression is spin-dried for solvent, resistates is dissolved in the sodium hydroxide solution (20mL) of 1mol/L, extraction into ethyl acetate (20mL × 3), aqueous phase layer 1mol/L hydrochloric acid adjusts pH to 1, white precipitate is separated out, filter, through rapid column chromatography (developping agent methylene dichloride: methyl alcohol=50: 1) obtain white solid 1.67g, productive rate 59.0%. 1HNMR(300MHz，DMSO-d 6)δ11.51(s，1H，-N H-)，7.67(d，J＝8.3Hz，2H，Ar H)，7.21(d，J＝8.4Hz，2H，Ar H)，3.72(s，2H，-C H 2-).
(4) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-(4-bromophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-1)
By 1-(4-bromophenyl) pyrimidine-(2,4,6 (1H, 3H, 5H)-triketone (1.42g, 5mmol) be dissolved in 20mL dehydrated alcohol, room temperature adds indoles-2-formaldehyde (0.73g, 5mmol), room temperature is cooled to after back flow reaction 1h, filter to obtain crude product, and obtain yellow solid (I-1) 1.72g with water recrystallization, productive rate 81.5%.M.p.＞300℃. 1HNMR(300MHz，DMSO-d 6)δ12.45(s，1H，indole-N H-)，12.08(s，1H，indole-N H-)，11.87(s，1H，-N H-)，11.74(s，1H，-N H-)，8.41(s，1H，-C H-)，8.35(s，1H，-C H-)，7.75-7.68(m，9H，Ar H)，7.40-7.31(m，6H，Ar H)，7.17-7.09(m，3H，Ar H).HRMSm/z([M+H] +)calcdforC 19H 12BrN 3O 3：410.0135；found：410.0128.
Embodiment 2
(E/Z) preparation of-5-((1H-indoles-2-base) methylene radical)-1-(4-chloro-phenyl-) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-2)
(1) 1-(4-chloro-phenyl-) urea
Reference example 1 take p-Chlorobenzoic acid amide as Material synthesis 1-(4-chloro-phenyl-) urea, productive rate 72.3%. 1HNMR(300MHz，DMSO-d 6)δ8.78(s，1H，-N H-)，7.71(d，J＝8.4Hz，2H，Ar H)，7.38(d，J＝8.4Hz，2H，Ar H)，5.93(s，2H，-N H 2).
(3) 1-(4-chloro-phenyl-) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1 is Material synthesis 1-(4-chloro-phenyl-) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone with 1-(4-chloro-phenyl-) urea, yield 52.0%. 1HNMR(300MHz，DMSO-d 6)δ11.51(s，1H，-N H-)，7.54(d，J＝8.4Hz，2H，Ar H)，7.09(d，J＝8.4Hz，2H，Ar H)，3.72(s，2H，-C H 2-).
(4) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-(4-chloro-phenyl-) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-2)
Reference example 1, be Material synthesis I-2 with 1-(4-chloro-phenyl-) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 87.0%, M.p. > 250 DEG C. 1hNMR (300MHz, DMSO-d 6) δ 12.46 (s, 1H, indole-N h-), 12.08 (s, 1H, indole-N h-), 11.87 (s, 1H ,-N h-), 11.75 (s, 1H ,-N h-), 8.42 (s, 1H ,-C h-), 8.35 (s, 1H ,-C h-), 7.75-7.70 (m, 6H, Ar h), 7.60-7.55 (m, 4H, Ar h), 7.47-7.32 (m, 6H, Ar h), 7.32-7.09 (m, 2H, Ar h) .HRMSm/z ([M+H] +) calcdforC 19h 12clN 3o 3: 364.0494; Found:364.0497.
Embodiment 3
(E/Z) preparation of-5-((1H indoles-2-base) methylene radical)-1-(3-nitrophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-3)
(1) 1-(3-nitrophenyl) urea
Reference example 1 take m-nitraniline as Material synthesis 1-(3-nitrophenyl) urea, yield 63.0%. 1HNMR(300MHz，DMSO-d 6)δ8.91(s，1H，-N H-)，8.35(s，1H，Ar H)，7.95(m，2H，Ar H)，7.59(t，J＝8.4Hz，1H，Ar H)，5.90(s，2H，-N H 2).
(3) 1-(3-nitrophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1 is Material synthesis 1-(3-nitrophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone with 1-(3-nitrophenyl) urea, yield 50.2%. 1HNMR(300MHz，DMSO-d 6)δ11.61(s，1H，-N H-)，8.29(d，J＝6.8Hz，1H，Ar H)，8.2(s，1H，Ar H)，7.82-7.75(m，2H，Ar H)，3.76(s，2H，-C H 2-).
(4) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-(3-nitrophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-3)
Reference example 1, be Material synthesis I-3 with 1-(3-nitrophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 87.3%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.45(s，1H，indole-N H-)，12.03(s，1H，indole-N H-)，11.96(s，1H，-N H-)，11.83(s，1H，-N H-)，8.44(s，1H，-C H-)，8.43(s，1H，-C H-)，8.37-8.33(m，4H，Ar H)，8.33-7.48(m，9H，Ar H)，7.44-7.17(m，3H，Ar H)，7.15-7.08(m，2H，Ar H).MS(m/z)：377.4([M+H] +).HRMSm/z([M+H] +)calcdforC 19H 12N 4O 5：377.088；found：377.0889.
Embodiment 4
(E/Z) preparation of-5-((1H-indoles-2-base) methylene radical)-1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-4)
(1) 1-(4-tolyl) urea
Reference example 1 take open-chain crown ether as Material synthesis 1-(4-tolyl) urea, yield 90.0%. 1HNMR(300MHz，DMSO-d 6)δ8.82(s，1H，-N H-)，7.32(d，J＝8.4Hz，2H，Ar H)，7.08(d，J＝8.4Hz，2H，Ar H)，5.71(s，2H，-N H 2)，2.38(s，3H，-C H 3).
(3) 1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1 is Material synthesis 1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone with 1-(4-tolyl) urea, yield 66.5%. 1HNMR(300MHz，DMSO-d 6)δ11.44(s，1H，-N H-)，7.25(d，J＝8.0Hz，2H，Ar H)，7.09(d，J＝8.0Hz，2H，Ar H)，3.71(s，2H，-C H 2)，2.34(s，3H，-C H 3).
(4) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-4)
Reference example 1, be Material synthesis I-4 with 1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 90.0%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.47(s，1H，indole-N H-)，12.11(s，1H，indole-N H-)，11.81(s，1H，-N H-)，11.68(s，1H，-N H-)，8.40(s，1H，-C H-)，8.34(s，1H，-C H-)，7.73-7.72(m，6H，Ar H)，7.69-7.08(m，12H，Ar H)，2.38(s，3H，-C H 3-)，2.37(s，3H，-C H 3-).MS(m/z)：346.4([M+H] +).HRMSm/z([M+H] +)calcdforC 20H 16N 3O 3：346.1186；found：346.1188.
Embodiment 5
(E/Z) preparation of-5-((1H-indoles-2-base) methylene radical)-1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-5)
(1) 1-(4-trifluoromethyl) urea
Reference example 1 take p-trifluoromethylaniline as Material synthesis 1-(4-trifluoromethyl) urea, yield 84.8%. 1HNMR(300MHz，DMSO-d 6)δ8.71(s，1H，-N H-)，7.56(d，J＝8.4Hz，2H，Ar H)，7.45(d，J＝8.4Hz，2H，Ar H)，5.71(s，2H，-N H 2).
(3) 1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1 is Material synthesis 1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone with 1-(4-trifluoromethyl) urea, yield 60.6%. 1HNMR(300MHz，DMSO-d 6)δ11.57(s，1H，-N H-)，7.87(d，J＝8.4Hz，2H，Ar H)，7.50(d，J＝8.4Hz，2H，Ar H)，3.75(s，2H，-C H 2).
(4) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-5)
Reference example 1, be Material synthesis I-5 with 1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 93.2%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.46(s，1H，indole-N H-)，12.05(s，1H，indole-N H-)，11.92(s，1H，-N H-)，11.79(s，1H，-N H-)，8.43(s，1H，-C H-)，8.36(s，1H，-C H-)，7.93-7.86(m，4H，Ar H)，7.76-7.60(m，10H，Ar H)，7.44-7.17(m，2H，Ar H)，7.15-7.09(m，2H，Ar H).HRMSm/z([M+Na] +)calcdforC 20H 12F 3N 3O 3：422.0723；found：422.0725.
Embodiment 6
(E/Z) preparation of-5-((1H-indoles-2-base) methylene radical)-1-(2-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-6)
(1) 1-(2-tolyl) urea
Reference example 1 take o-toluidine as Material synthesis 1-(2-tolyl) urea, yield 92.0%. 1HNMR(300MHz，DMSO-d 6)δ8.65(s，1H，-N H-)，7.29-7.20(m，3H，Ar H)，7.08(t，J＝8.4Hz，1H，Ar H)，6.19(s，2H，-N H 2)，2.21(s，3H，-C H 3).
(3) 1-(2-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1 is Material synthesis 1-(2-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone with 1-(2-tolyl) urea.Yield 75.2%. 1HNMR(300MHz，DMSO-d 6)δ11.42(s，1H，-N H-)，7.65-7.05(m，4H，Ar H)，3.90(d，J＝20.9Hz，1H，-C H 2-)，3.68(d，J＝20.8Hz，1H，-C H 2-)，2.12(s，3H，-C H 3).
(4) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-(2-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-6)
Reference example 1, be Material synthesis I-6 with 1-(2-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 82.0%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.47(s，1H，indole-N H-)，12.08(s，1H，indole-N H-)，11.88(s，1H，-N H-)，11.76(s，1H，-N H-)，8.43(s，1H，-C H-)，8.36(s，1H，-C H-)，7.75-7.70(m，6H，Ar H)，7.43-7.29(m，10H，Ar H)，7.17-7.08(m，2H，Ar H)，2.14(s，3H，-C H 3-)，2.11(s，3H，-C H 3-).HRMS(ESI)：m/z[M+H]+calcdforC 20H 15N 3O 3：346.1186；found：346.1194.
Embodiment 7
(E/Z) preparation of-5-((1H-indoles-2-base) methylene radical)-1-(3-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-7)
(1) 1-(3-trifluoromethyl) urea
Reference example 1 take 3-Aminotrifluorotoluene as Material synthesis 1-(3-trifluoromethyl) urea, yield 75.0%. 1HNMR(300MHz，DMSO-d 6)δ8.98(s，1H，-N H-)，7.92(s，1H，Ar H)，7.56-7.40(m，3H，Ar H)，6.05(s，2H，-N H 2).
(2) 1-(3-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1 is Material synthesis 1-(3-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone with 1-(3-trifluoromethyl) urea, productive rate 64.7%.1HNMR(300MHz，DMSO-d6)611.59(s，1H，-N H-)，7.82-7.67(m，3H，Ar H)，7.57(d，J＝7.5Hz，1H，Ar H)，3.74(s，2H，-C H2-).
(3) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-(3-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-7)
Reference example 1, be Material synthesis I-7 with 1-(3-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 82.4%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.45(s，1H，indole-N H-)，12.03(s，1H，indole-N H-)，11.92(s，1H，-N H-)，11.79(s，1H，-N H-)，8.43(s，1H，-C H-)，8.36(s，1H，-C H-)，7.90-7.70(m，14H，Ar H)，7.44-7.32(m，2H，Ar H)，7.14-7.09(m，2H，Ar H).HRMSm/z([M+Na] +)calcdforC 20H 12F 3N 3O 3：422.0723；found：422.0733.
Embodiment 8
(E/Z) preparation of-5-((1H-indoles-2-base) methylene radical)-1-phenyl pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-8)
(1) 1-phenylurea
Reference example 1 take aniline as Material synthesis 1-phenylurea, yield 77.2%. 1HNMR(300MHz，DMSO-d 6)δ8.57(s，1H，-N H-)，7.49-7.40(m，3H，Ar H)，7.23(d，J＝7.3Hz，2H，Ar H)，5.72(s，2H，-N H 2).
(3) 1-phenyl pyrimidine-2,4,6 (1H, 3H, 5H)-triketones
Reference example 1, with 1-phenylurea for Material synthesis 1-phenyl pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield 55.3%. 1HNMR(300MHz，DMSO-d 6)δ11.47(s，1H，-N H-)，7.49-7.40(m，3H，Ar H)，7.23(d，J＝7.3Hz，2H，Ar H)，3.72(s，2H，-C H 2-).
(4) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-phenyl pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-8)
Reference example 1, be Material synthesis I-8 with 1-phenyl pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 75.4%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.45(s，1H，indole-N H-)，12.09(s，1H，indole-N H-)，11.84(s，1H，-N H-)，11.71(s，1H，-N H-)，8.42(s，1H，-C H-)，8.35(s，1H，-C H-)，7.76-7.69(m，6H，Ar H)，7.54-7.33(m，12H，Ar H)，7.17-7.08(m，2H，Ar H).HRMSm/z([M+Na] +)calcdforC 19H 13N 3O 3：354.0849；found：354.0854.
Embodiment 9
(E/Z) preparation of-5-((1H-indoles-2-base) methylene radical)-1-(4-cyano-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-9)
(1) 1-(4-cyano-phenyl) urea
Reference example 1, with to cyano-aniline for Material synthesis 1-(4-cyano-phenyl) urea, yield 77.6%. 1HNMR(300MHz，DMSO-d 6)δ8.81(s，1H，-N H-)，7.82(d，J＝8.4Hz，2H，Ar H)，7.61(d，J＝8.4Hz，2H，Ar H)，5.99(s，2H，-N H 2).
(3) 1-(4-cyano-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1 is Material synthesis 1-(4-cyano-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone with 1-(4-cyano-phenyl) urea, yield 55.3%. 1HNMR(300MHz，DMSO-d 6)δ11.59(s，1H，-N H-)，7.96(d，J＝8.4Hz，2H，Ar H)，7.48(d，J＝8.3Hz，2H，Ar H)，3.75(s，2H，-C H 2-).
(4) (E/Z)-5-((1H-indoles-2-base) methylene radical)-1-(4-cyano-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-9)
Reference example 1, be Material synthesis I-9 with 1-(4-cyano-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 73.5%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.44(s，1H，indole-N H-)，12.02(s，1H，indole-N H-)，11.93(s，1H，-N H-)，11.80(s，1H，-N H-)，8.43(s，1H，-C H-)，8.36(s，1H，-C H-)，8.03-7.98(m，4H，Ar H)，7.76-7.59(m，10H，Ar H)，7.41-7.32(m，2H，Ar H)，7.17-7.11(m，2H，Ar H).HRMS(ESI)：m/z[M+H] +calcdforC 20H 12N 4O 3：355.0837；found：355.084.
Embodiment 10
(E/Z) preparation of-5-(3,4-dihydroxy-benzene methylene radical)-1-(3-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-10)
Reference example 1, be Material synthesis I-10 with 1-(3-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 86.2%.M.p.235-236℃. 1HNMR(300MHz，DMSO-d 6)δ11.62(s，1H，-N H-)，11.54(s，1H，-N H-)，10.42(s，2H，-O H)，9.50(s，2H，-O H)，8.23(m，2H，-C H-，2H，Ar H)，7.81-7.60(m，10H，Ar H)，6.87(s，1H，Ar H)，6.84(s，1H，Ar H).HRMSm/z：([M+Na] +)calcdforC 18H 11F 3N 2O 5：415.0512；found：415.0512.
Embodiment 11
(E/Z) preparation of-1-(4-chloro-phenyl-)-5-(3,4-dihydroxy-benzene methylene radical) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-11)
Reference example 1, be Material synthesis I-11 with 1-(4-chloro-phenyl-) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 77.9%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.58(s，1H，-N H-)，11.48(s，1H，-N H-)，10.40(s，2H，-O H)，9.50(s，2H，-O H)，8.23-8.15(m，2H，-C H-，2H，Ar H)，7.59-7.52(m，6H，Ar H)，7.37(d，J＝7.8Hz，4H，Ar H)，6.86(s，1H，Ar H)，6.83(s，1H，Ar H).HRMSm/z：([M+H] +)calcdforC 17H 11ClN 2O 5：359.0429；found：359.0428.
Embodiment 12
(E/Z) (I-12) preparation of-1-(4-bromophenyl)-5-(3,4-dihydroxy-benzene methylene radical) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1, so that 1-(4-bromophenyl) pyrimidine-(2,4,6 (1H, 3H, 5H)-triketones are Material synthesis I-12, and yield is 74.3%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.57(s，1H，-N H)，11.46(s，1H，-N H)，10.42(s，2H，-O H)，9.50(s，2H，-O H)，8.22-8.15(m，2H，-C H-，2H，Ar H)，7.68-7.56(m，6H，Ar H)，7.30(d，J＝8.1Hz，4H，Ar H)，6.86(s，1H，Ar H)，6.83(s，1H，Ar H).HRMSm/z：([M+H] +)calcdforC 17H 11BrN 2O 5：402.9924；found：402.9931.
Embodiment 13
(E/Z) preparation of-1-(4-p-methoxy-phenyl)-5-(3,4-dihydroxy-benzene methylene radical) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-13)
(1) 1-(4-p-methoxy-phenyl) urea
Reference example 1 take P-nethoxyaniline as Material synthesis 1-(4-p-methoxy-phenyl) urea, yield 80.0%. 1HNMR(300MHz，DMSO-d 6)δ8.79(s，1H，-N H-)，7.27(d，J＝8.3Hz，2H，Ar H)，6.92(d，J＝8.4Hz，2H，Ar H)，5.78(s，2H，-N H 2)，3.79(s，3H，-OC H 3).
(3) 1-(4-p-methoxy-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone
Reference example 1 is Material synthesis 1-(4-p-methoxy-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone with 1-(4-p-methoxy-phenyl) urea, yield 66.2%. 1HNMR(300MHz，DMSO-d 6)δ11.42(s，1H，-N H-)，7.14(d，J＝8.4Hz，2H，Ar H)，7.00(d，J＝8.3Hz，2H，Ar H)，3.79(s，3H，-OC H 3)，3.71(s，2H，-C H 2-).
(4) (E/Z)-1-(4-p-methoxy-phenyl)-5-(3,4-dihydroxy-benzene methylene radical) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-13)
Reference example 1, be Material synthesis I-13 with 1-(4-p-methoxy-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 74.6%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.51(s，1H，-N H-)，11.40(s，1H，-N H-)，10.39(s，2H，-OH)，9.51(s，2H，-O H)，8.25-8.15(m，2H，-C H-，2H，Ar H)，7.67-7.56(m，2H，Ar H)，7.25-7.20(m，4H，Ar H)，7.02-6.98(m，4H，Ar H)，6.88-6.83(m，2H，Ar H)，3.80(s，6H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 18H 14N 2O 6：355.0925；found：355.0925.
Embodiment 14
(E/Z) preparation of-5-(3,4-dihydroxy-benzene methylene radical)-1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-14)
Reference example 1, be Material synthesis I-14 with 1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 64.9%.M.p.229-230℃. 1HNMR(300MHz，DMSO-d 6)δ11.49(s，2H，-N H-)，10.31(s，2H，-O H)，9.46(s，2H，-O H)，8.21-8.18(m，2H，-C H-，2H，Ar H)，7.61-7.57(m，2H，Ar H)，7.27-7.16(m，8H，Ar H)，6.85(s，1H，Ar H)，6.82(s，1H，Ar H)，2.36(s，3H，-C H 3)，2.32(s，3H，-C H 3).HRMSm/z：([M+H] +)calcdforC 18H 14N 2O 5：339.0975；found：339.0982.
Embodiment 15
(E/Z) preparation of-5-(3,4-dihydroxy-benzene methylene radical)-1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-15)
Reference example 1, be Material synthesis I-15 with 1-(4-(trifluoromethyl) phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 73.8%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.64(s，1H，-N H-)，11.53(s，1H，-N H-)，10.45(s，2H，-O H)，9.51(s，2H，-O H)，8.25-8.16(m，2H，-C H-，2H，Ar H)，7.87(d，J＝7.9Hz，4H，Ar H)，7.67-7.58(m，6H，Ar H)，6.89(s，1H，Ar H)，6.83(s，1H，Ar H).HRMS(m/z)：([M+H] +)calcdforC 18H 11F 3N 2O 5：393.0693；found：393.0693.
Embodiment 16
(E/Z) preparation of-5-(3,4-dihydroxy-benzene methylene radical)-1-(4-cyano-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-16)
Reference example 1, be Material synthesis I-16 with 1-(4-cyano-phenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 87.3%.M.p.229-230℃. 1HNMR(300MHz，DMSO-d 6)δ11.64(s，1H，-N H-)，11.53(s，1H，-N H-)，10.42(s，2H，-O H)，9.51(s，2H，-O H)，8.25-8.16(m，2H，-C H-，2H，Ar H)，7.98-7.95(m，4H，Ar H)，7.67-7.56(m，6H，Ar H)，6.89(s，1H，Ar H)，6.82(s，1H，Ar H).HRMSm/z：([M+H] +)calcdforC 18H 11N 3O 5：350.0771；found：350.0774.
Embodiment 17
(E/Z) preparation of-5-(3,4-dihydroxy-benzene methylene radical)-1-phenyl pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-17)
Reference example 1, be Material synthesis I-17 with 1-phenyl pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 76.1%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.56(s，1H，-N H)，11.45(s，1H，-N H)，10.39(s，2H，-OH)，9.51(s，2H，-O H)，8.26-8.16(m，2H，-C H-，2H，Ar H)，7.66-7.32(m，12H，Ar H)，6.88(s，1H，Ar H)，6.83(s，1H，Ar H).HRMSm/z：([M+H] +)calcdforC 17H 12N 2O 5：325.0819；found：325.0825.
Embodiment 18
(E/Z) preparation of-5-(3,4-dihydroxy-benzene methylene radical)-1-(2-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-18)
Reference example 1, be Material synthesis I-18 with 1-(2-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 71.6%.M.p.229-230℃. 1HNMR(300MHz，DMSO-d 6)δ11.58(s，1H，-N H)，11.47(s，1H，-N H)，10.35(s，2H，-O H)，9.49(s，2H，-O H)，8.24(s，2H，-C H)，8.17(s，2H，Ar H)，7.67-7.56(m，2H，Ar H)，7.35-7.27(m，8H，Ar H)，6.91(s，1H，Ar H)，6.83(s，1H，Ar H)，2.09(s，6H，-C H 3).HRMSm/z：([M+H] +)calcdforC 18H 14N 2O 5：339.0975；found：339.0971.
Embodiment 19
(E/Z) preparation of-5-(3-phenol methylene)-1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-19)
Reference example 1, be Material synthesis I-19 with 1-(4-tolyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 70.1%.M.p.249-250℃. 1HNMR(300MHz，DMSO-d 6)δ11.68(s，1H，-N H)，11.54(s，1H，-N H)，9.71(s，1H，-O H)，9.65(s，1H，-O H)，8.28(s，1H，-C H-)，8.21(s，1H，-C H-)，7.63(s，2H，Ar H)，7.45-7.17(m，12H，Ar H)，6.97-6.91(m，2H，Ar H)，2.36(s，6H，-C H 3).HRMSm/z：([M+H] +)calcdforC 18H 14N 2O 4：323.1026；found：323.1034.
Embodiment 20
(E/Z) preparation of-1-(4-bromophenyl)-5-(4-hydroxy 3-methoxybenzene methylene radical) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-20)
Reference example 1, be Material synthesis I-20 with 1-(4-bromophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 69.5%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.62(s，1H，-N H-)，11.51(s，1H，-N H-)，10.59(s，1H，-O H)，10.56(s，1H，-O H)，8.47(s，1H，-C H-)，8.34(s，1H，-C H-)，8.25(s，1H，Ar H)，8.24(s，1H，Ar H)，7.91-7.79(m，2H，Ar H)，7.69-7.66(m，4H，Ar H)，7.33-7.29(m，4H，Ar H)，6.93-6.87(m，2H，Ar H)，3.84(s，3H，-OC H 3)，3.76(s，3H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 18H 13BrN 2O 5：417.0081；found：417.0089.
Embodiment 21
(E/Z) preparation of-1-(4-bromophenyl)-5-(3-hydroxyl-4-methoxybenzylidene) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-21)
Reference example 1, be Material synthesis I-21 with 1-(4-bromophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 78.4%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.63(s，1H，-N H)，11.52(s，1H，-N H)，9.45(s，1H，-O H)，9.43(s，1H，-O H)，8.26(s，1H，-C H-)，8.18(s，1H，-C H-)，8.14(s，2H，Ar H)，7.75-7.64(m，6H，Ar H)，7.33-7.28(m，4H，Ar H)，7.10-7.03(m，2H，Ar H)，3.90(s，3H，-OC H 3)，3.87(s，3H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 18H 13BrN 2O 5：417.0081；found：417.0086.
Embodiment 22
(E/Z) preparation of-1-(4-bromophenyl)-5-(4-hydroxyl-3,5-dimethoxybenzyliden) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-22)
Reference example 1, be Material synthesis I-22 with 1-(4-bromophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 88.1%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.65(s，1H，-N H)，11.54(s，1H，-N H)，10.06(s，2H，-O H)，8.38(s，1H，-C H-)，8.28(s，1H，-C H-)，8.01(s，2H，Ar H)，7.94(s，2H，Ar H)，7.68(d，J＝8.2Hz，4H，Ar H)，7.34-7.30(m，4H，Ar H)，3.84(s，6H，-OC H 3)，3.78(s，6H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 19H 15BrN 2O 6：447.0186；found：447.0189.
Embodiment 23
(E/Z) preparation of-1-(4-bromophenyl)-5-(2,3,4-trimethoxy α-tolylene) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-23)
Reference example 1, be Material synthesis I-23 with 1-(4-bromophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 89.1%, M.p. > 250 DEG C. 1hNMR (300MHz, DMSO-d 6) δ 11.66 (s, 1H ,-N h-), 11.51 (s, 1H ,-N h-), 8.58 (s, 1H ,-C h-), 8.54 (s, 1H ,-C h-), 8.35 (d, J=9.2Hz, 1H, Ar h), 8.15 (d, J=9.2Hz, 1H, Ar h), 7.69-7.65 (m, 4H, Ar h), 7.31-7.28 (m, 4H, Ar h), 6.95 (d, J=9.6Hz, 1H, Ar h), 6.85 (d, J=9.3Hz, 1H, Ar h), 3.93 (s, 3H ,-OC h 3), 3.91 (s, 3H ,-OC h 3), 3.88 (s, 3H ,-OC h 3), 3.87 (s, 3H ,-OC h 3), 3.78 (s, 3H ,-OC h 3), 3.76 (s, 3H ,-OC h 3) .HRMSm/z:([M+H] +) calcdforC 20h 17brN 2o 6: 461.0341; Found:461.0347.
Embodiment 24
(E/Z) preparation of-1-(4-bromophenyl)-5-(3,4-dimethoxybenzyliden) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-24)
Reference example 1, be Material synthesis I-24 with 1-(4-bromophenyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 80.5%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.66(s，1H，-N H)，11.56(s，1H，-N H)，8.39(s，1H，-C H-)，8.37(s，1H，-C H-)，8.29(s，1H，Ar H)，8.19(s，1H，Ar H)，7.96-7.90(m，2H，Ar H)，7.67(d，J＝7.9Hz，4H，Ar H)，7.33-7.28(m，4H，Ar H)，7.15-7.08(m，2H，Ar H)，3.90(s，3H，-OC H 3)，3.87(s，3H，-OC H 3)，3.83(s，3H，-OC H 3)，3.74(s，3H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 19H 15BrN 2O 5：431.0237；found：431.024.
Embodiment 25
(E/Z) preparation of-1-(4-trifluoromethyl)-5-(3-methoxyl group-4-phenol methylene) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-25)
Reference example 1, be Material synthesis I-25 with 1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 64.1%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.66(s，1H，-N H-)，11.56(s，1H，-N H-)，10.57(s，1H，-O H)，8.48-7.48(m，16H，Ar H)，6.88(s，1H，Ar H)，3.83(s，3H，-OC H 3)，3.75(s，3H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 19H 13F 3N 2O 5：407.0849；found：407.0853.
Embodiment 26
(E/Z) preparation of-1-(4-trifluoromethyl)-5-(3-hydroxyl-4-methoxybenzylidene) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-26)
Reference example 1, be Material synthesis I-26 with 1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 78.5%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.68(s，1H，-N H-)，11.58(s，1H，-N H-)，9.46(s，1H，-OH)，9.43(s，1H，-O H)，8.28(s，1H，-C H-)，8.20(s，1H，-C H-)，8.15(s，2H，Ar H)，7.88-7.86(m，4H，Ar H)，7.76-7.58(m，6H，Ar H)，7.10-7.03(m，2H，Ar H)，3.90(s，3H，-OC H 3)，3.87(s，3H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 19H 13F 3N 2O 5：407.0849；found：407.0851.
Embodiment 27
(E/Z) preparation of-1-(4-trifluoromethyl)-5-(4-hydroxyl-3,5-dimethoxybenzyliden) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-27)
Reference example 1, be Material synthesis I-27 with 1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 86.1%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.68(s，1H，-N H-)，11.57(s，1H，-N H-)，10.03(s，2H，-O H)，8.39(s，1H，-C H-)，8.29(s，1H，-C H-)，8.01-7.86(m，8H，Ar H)，7.60(s，4H，Ar H)，3.84(s，6H，-OC H 3)，3.77(s，6H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 20H 15F 3N 2O 6：437.0955；found：437.0946.
Embodiment 28
(E/Z) preparation of-1-(4-trifluoromethyl)-5-(3,4-dimethoxybenzyliden) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone (I-28)
Reference example 1, be Material synthesis I-28 with 1-(4-trifluoromethyl) pyrimidine-2,4,6 (1H, 3H, 5H)-triketone, yield is 80.7%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ11.70(s，1H，-N H-)，11.60(s，1H，-N H-)，8.39(s，2H，-C H-)，8.29(s，1H，Ar H)，8.14(s，1H，Ar H)，7.97-7.86(m，6H，Ar H)，7.63-7.58(m，4H，Ar H)，7.15-7.07(m，2H，Ar H)，3.90(s，6H，-OC H 3)，3.74(s，6H，-OC H 3).HRMSm/z：([M+H] +)calcdforC 20H 15F 3N 2O 5：421.0905；found：421.0904.
Embodiment 29
(E/Z) preparation of-1-(4-bromophenyl)-5-((1H-indoles-2-base) methylene radical)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone (I-29)
(1) N-((4-bromophenyl) thiocarbamoyl) benzamide
Ammonium thiocyanate 0.76g (0.012mol) is added in 30mL acetone solution in 100mL eggplant type bottle, slowly add 1.41g Benzoyl chloride (0.01mol) wherein, heating is stopped after reflux 15min, add rapidly para-bromoaniline 1.55g (0.009mol) and the 30min that refluxes, then pour into rapidly in trash ice, vigorous stirring, generate a large amount of precipitation, filter, successively use water, water: the mixed solution of methyl alcohol (v: v, 1: 1) washs to obtain white solid 2.68g, productive rate 88.9%, without the need to purifying, directly throw next step.
(2) 1-(4-bromophenyl) thiocarbamide
The aqueous sodium hydroxide solution of 5% is heated to 85 DEG C; add N-((4-bromophenyl) thiocarbamoyl) benzamide; stirring reaction 12min; reaction solution is poured in the hydrochloric acid ice aqueous solution of 5%; adjust pH to 8 by saturated solution of sodium carbonate, filter and obtain yellow solid, washing; filter residue is through rapid column chromatography (developping agent v: v, methylene dichloride: methyl alcohol=30: 1) obtain white solid 1.62g. productive rate 87.5%. 1HNMR(DMSO-d 6)δ12.91(s，1H，-N H-)，7.71(d，J＝8.3Hz，2H，Ar H)，7.54(d，J＝8.4Hz，2H，Ar H)，8.83(s，2H，-N H 2).
(3) 1-(4-bromophenyl)-2-sulfo-dihydroxy-pyrimidine-4,6 (1H, 5H)-diketone
Add 60mL ethanol in 100mL eggplant-shape bottle, 0.46g sodium (20mmol) section adds.Stirring at room temperature is until sodium dissolves completely.Add 1-(4-bromophenyl) thiocarbamide 2.31g (10mmol) successively, diethyl malonate 1.52mL (10mmol) heating reflux reaction 25h, until TLC detection reaction terminates.Decompression is spin-dried for solvent, and residual residue is dissolved in 20mL1M sodium hydroxide solution, crosses and filters insoluble impurities, and filtrate is with 20mL extraction into ethyl acetate three times.Water layer 1M hydrochloric acid soln adjusts pH to 1, and white precipitate is separated out, and filter, filter residue obtains yellow solid 1.78g through ethyl alcohol recrystallization, productive rate 49.5%. 1HNMR(300MHz，DMSO-d 6)δ12.67(s，1H，-N H-)，7.62(d，J＝8.4Hz，2H，Ar H)，7.14(d，J＝8.4Hz，2H，Ar H)，5.09(s，2H，-C H 2-).
(4) (E/Z)-1-(4-bromophenyl)-5-((1H-indoles-2-base) methylene radical)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone (I-29)
1-(4-bromophenyl)-2-sulfo-dihydroxy-pyrimidine-4,6 (1H, 5H)-diketone (1.49g, 5mmol) and 20mL dehydrated alcohol are joined in 50ml eggplant-shape bottle.Disposablely in room temperature add 2-indolecarboxaldehyde (726mg, 5mmol).Heating reflux reaction 1h.Reaction solution is cooled to room temperature, and the sedimentation and filtration of generation, obtains red solid I-291.87g, yield 87.6%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.78(s，1H，indole-N H-)，12.66(s，1H，indole-N H-)，10.98(s，1H，-N H-)，10.72(s，1H，-N H-)，8.19(s，1H，Ar H)，7.90(s，1H，Ar H)，7.66-7.61(m，5H，Ar H)，7.45-7.25(m，8H，Ar H)，7.15-7.08(m，5H，Ar H).HRMSm/z：([M-H] +)calcdforC 19H 12BrN 3O 2S：423.9761；found：423.9767.
Embodiment 30
(E/Z) preparation of-1-(4-bromophenyl)-5-(3,4-dihydroxy-benzene methylene radical)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone (I-30)
With reference to embodiment 29, be Material synthesis I-30 with 1-(4-bromophenyl)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone, yield 75.9%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.16(s，2H，-N H-)，10.59(s，2H，-O H)，9.59(s，2H，-O H)，8.28(s，2H，-C H-)，8.22(s，2H，Ar H)，7.67-7.64(m，6H，Ar H)，7.28-7.26(m，4H，Ar H)，6.86(d，J＝8.4Hz，2H，Ar H).HRMSm/z：([M+H] +)calcdforC 17H 11BrN 2O 4S：418.9696；found：418.9683.
Embodiment 31
(E/Z) preparation of-1-(4-trifluoromethyl)-5-((1H-indoles-2-base) methylene radical)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone (I-31)
(1) N-((4-trifluoromethyl) thiocarbamoyl) benzamide
With reference to embodiment 29, take p-trifluoromethylaniline as Material synthesis N-((4-trifluoromethyl) thiocarbamoyl) benzamide, productive rate 78.1%. 1HNMR(300MHz，DMSO-d 6)δ12.83(s，1H，-N H-)，9.10(s，1H，-N H-)，7.92(t，J＝8.6Hz，4H，Ar H)，7.69-7.66(m，3H，Ar H)，7.57(t，J＝7.9Hz，2H，Ar H).
(2) 1-(4-trifluoromethyl) thiocarbamide
With reference to embodiment 29, be Material synthesis 1-(4-trifluoromethyl) thiocarbamide with N-((4-trifluoromethyl) thiocarbamoyl) benzamide, productive rate 87.5%. 1HNMR(DMSO-d 6)δ12.91(s，1H，-N H-)，7.71(d，J＝8.3Hz，2H，Ar H)，7.54(d，J＝8.4Hz，2H，Ar H)，8.83(s，2H，-N H 2).
(3) 1-(4-trifluoromethyl)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone
With reference to embodiment 29, be Material synthesis 1-(4-trifluoromethyl)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone with 1-(4-trifluoromethyl) thiocarbamide, productive rate 37.5%. 1HNMR(300MHz，DMSO-d 6)δ9.05(s，1H，-N H-)，7.65(d，J＝8.4Hz，2H，Ar H)，7.57(d，J＝8.3Hz，2H，Ar H)，6.09(s，2H，-C H 2-).
(4) (E/Z)-1-(4-trifluoromethyl)-5-((1H-indoles-2-base) methylene radical)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone (I-31)
With reference to embodiment 29, be Material synthesis I-31 with 1-(4-trifluoromethyl)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone, yield 65.6%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.85(s，1H，indole-N H-)，12.79(s，1H，indole-N H-)，10.99(s，1H，-N H-)，10.75(s，1H，-N H-)，8.20(s，1H，-C H-)，8.08(s，1H，-C H-)，7.94-7.80(m，6H，Ar H)，7.61-7.33(m，10H，Ar H)，7.11(s，2H，Ar H).HRMSm/z：([M+H] +)calcdforC 20H 12F 3N 3O 2S：416.0675；found：416.0667.
Embodiment 32
(E/Z) preparation of-1-(4-trifluoromethyl)-5-(3,4-dihydroxy-benzene methylene radical)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone (I-32)
With reference to embodiment 29, be Material synthesis I-32 with 1-(4-trifluoromethyl)-2-sulfo-dihydro-pyrimidin-4,6 (1H, 5H)-diketone, yield 54.3%.M.p.＞250℃. 1HNMR(300MHz，DMSO-d 6)δ12.69(s，1H，-N H-)，12.62(s，1H，-N H-)，10.69(s，2H，-O H)，9.59(s，2H，-O H)，8.27(s，2H，-C H-)，7.85-7.57(m，11H，Ar H)，7.38(m，1H，Ar H)，6.92-6.85(m，2H，Ar H).HRMSm/z：([M+H] +)calcdforC 18H 11F 3N 2O 4S：409.0464；found：409.0456.
Embodiment 33
Compound in embodiment 1-32 is active to the vitro inhibition of LSD1
Experimental technique: it is active that peroxidase conjugate measures LSD1 (EnzoLifeSciences).Testing compound is dissolved in DMSO, to join in the reaction buffer of LSD1 (50mMTris-hydrochloric acid, pH value be 7.5 and 1%DMSO), incubated at room temperature 15 minutes.Add substrate (histone H 3 (1-21aa) K4me2 peptide (AnaSpecInc.) of 10 μMs), provocative reaction, and incubated at room 60 minutes.Then horseradish peroxidase (Sigma) that final concentration is 0.1 unit/mL and 10 μMs are added ultraRed (LifeTechnologies) termination reaction, finally to use in microplate reader 30min every 5min in 535nM excitation wavelength, 590nM transmitted wave strong point fluorescence intensity.Inhibiting rate %=[(100% active group-blank group)-(to be measured group-blank group)]/(100% active group-blank group) × 100%, and use GrapgPadPrism4 processing data.
The inhibit activities of a table 132 Compound ira vitro LSD1
Experimental result shows, above-mentioned 32 embodiment compounds (I-1 ~ I-32) all have significant external LSD1 inhibit activities, are better than positive control drug benzyl ring propylamine (Tranylcypromine, TCPA).
Embodiment 34
The vitro inhibition of Compound I-30 couples of MAO-A and MAO-B is active
Experimental technique: use MAO luminescent activity test kit (Promega), test compounds is dissolved in DMSO, add containing MAO-A/MAO-B enzyme 10nM (ActiveMotif), (100mMHEPES in the buffer system of substrate (test kit provides) 4 μMs, pH7.5,5% glycerine), room temperature lucifuge hatches 1 hour.The fluorescein of reaction volume such as to add, lucifuge is reacted 30 minutes, uses Gen5 microplate reader (BioTek) to read flat light emission.Inhibiting rate=[(100% active group-blank group)-(to be measured group-blank group)]/(100% active group-blank group) × 100%, and use GrapgPadPrism4 processing data.
Table 2.I-30 is active to the vitro inhibition of MAO-A and MAO-B
Result shows, the restraining effect of I-30 to homologous protein MAO-A and MAO-B of LSD1 is very weak, and compared with the inhibit activities of LSD1, its selectivity coefficient is respectively 577.8 and 603.9 times, illustrates that I-30 has significant selective inhibitory to LSD1.
Embodiment 35
Adopt Endpoint Dilution Method test compounds I-30 to the external reversible inhibition of LSD1.
Experimental technique: Max control group uses DMSO and LSD1 enzyme, and experimental group gets 10 times of IC 50the enzyme of the compound of concentration and 100 times of concentration, Min control group uses DMSO and damping fluid, hatches 15 minutes, obtains compound-enzyme mixture.Compound-enzyme complex is diluted 100 times, room temperature enzyme reaction 60 minutes.Add substrate (histone H 3 (1-21) K4me2 peptide (AnaSpec) of 10 μMs), provocative reaction, and room temperature lucifuge hatches 60 minutes.EnSpire is used to read fluorescence intensity.Reversible active %=([experimental group fluorescence intensity]-[Min control group fluorescence intensity])/([Max control group fluorescence intensity]-[Min control group fluorescence intensity]) × 100%
Result such as Fig. 1 shows, and I-30 and LSD1 mixture is after 100 times of dilutions, and the activity of 98% still can be recovered, and illustrates that I-30 and LSD1 is Non-covalent binding, reversible inhibition LSD1.
Embodiment 36
FACS method is adopted to investigate embodiment to the impact of leukemia cytodifferentiation.
Experimental technique: get and be in exponential growth NB4 cell in good condition, centrifugal, change to fresh culture, make cell count maintain 2 × 10 5individual/mL.Get 24 orifice plates, every hole adds 1mL cell suspension, adds testing compound, positive control and the DMSO negative control of different concns (0,1.2 μM, 2.5 μMs, 5.0 μMs), puts 37 degree of constant temperature 5%CO 2cultivate 48 hours in incubator.Draw cell suspension, centrifugal, clean one time with PBS, add the CD11b antibody diluent of band FITC mark, incubated at room 15 minutes.The optimized parameter of debugging flow cell sorter, makes more than 90% cell all drop in observation area, reads fluorescence intensity, is background, obtains per-cent and the histogram of CD11b positive cell group with blank.
On the impact that I-10, I-11, I-12 and I-15 tetra-compounds adopt FACS method investigation embodiment to break up Leukemia cells NB4, with LSD1 irreversible inhibitor benzyl ring propylamine (TCPA, IC 50=3600nM) and LSD1 irreversible inhibitor RN-1 (IC 50=8nM) be contrast, as shown in Figure 2, after 5 μMs of mass action 48h, I-10, I-12 and I-15 all have comparatively obvious differentiation-inducing activity, and wherein I-15 effect is best, differentiation rate 32.1%, are better than RN-1.
On the impact that I-20, I-22, I-30 and I-32 tetra-compounds adopt FACS method investigation embodiment to break up Leukemia cells NB4, as Fig. 3 display, I-30 has significant inducing leukemia cell NB4 differentiation capability, when concentration is 2.5 and 5 μMs, differentiation rate is respectively 42.0% and 55.5%, I-20 has faint Differentiation, and I-22 and I-32 effect is not obvious.
Embodiment 37
To the detection of substrate H3K4me1 and H3K4me2 methylation level
By testing compound effect 293T cell after 24 hours, Westernblot method detects the level of itself H3K4me1 and H3K4me2, judges testing compound how to disturb LSD1 activity.
Experimental technique: get the 293T cell that growth conditions is good, count with after 0.25% tryptic digestion, make cell count maintain 2 × 10 5individual/mL.Get 24 orifice plates, every hole adds 1mL cell suspension, adds the test medicine of different concns (0,2.5 μM, 5.0 μMs, 10 μMs), positive control and DMSO negative control, puts 37 degree of constant temperature 5%CO 2cultivate 24 hours in incubator.After 0.25% trypsin digestion and cell, be transferred to EP pipe, with the cracking of SDS protein lysate after PBS cleans one time, high-temperature denatured.WesternBlot method detects LSD1 substrate H3K4me1 and the change of H3K4me2 expression level.
By the methylation level of testing compound effect 293T cell detection substrate H3K4me1 and H3K4me2 after 24 hours, judge how testing compound disturbs LSD1 enzymic activity.As Fig. 4 display, it is the most remarkable that I-30 affects the modification effect that methylates, the methylation level of H3K4me1 and H3K4me2 can be caused to rise simultaneously, it should be noted that, I-30 not only just obviously raises H3K4me2 2.5 μMs time, 10 μMs time, significantly improve the level of H3K4me1 especially, this also may be the mechanism that its short differentiation effect is better than other compounds.I-20 and I-22 is comparatively obvious for the impact of H3K4me2 level.

Claims (8)

1. barbituric acid compounds, is characterized in that, it is the compound shown in general formula I and pharmaceutical salts thereof:
Wherein, R 1, R 2, R 3represent any one in hydrogen, amino, hydroxyl, halogen, carboxyl, trifluoromethyl, methyl, methoxyl group, ethyl, oxyethyl group, sec.-propyl, nitro or cyano group; X represention oxygen atom or sulphur atom; R 4representative in any one, wherein, R 5represent any one in mono-substituted hydroxyl, amino, methyl, methoxyl group or halogen, or any two in disubstituted hydroxyl, amino, methyl, methoxyl group or halogen, or in trisubstituted hydroxyl, amino, methyl, methoxyl group or halogen any three.
2. barbituric acid compounds according to claim 1, is characterized in that:
R 1, R 2, R 3represent any one of hydrogen, amino, halogen, trifluoromethyl, methyl, methoxyl group or nitro; X represention oxygen atom or sulphur atom; R 4representative in any one.
3. barbituric acid compounds according to claim 1 and 2, is characterized in that, described compound is:
4. the preparation method of barbituric acid compounds according to claims 1 to 3 any one, is characterized in that, comprise the following steps:
(1) when X is O, formula I is prepared by the method described in reaction formula one:
A. the aniline 1 of potassium cyanate and aniline or replacement is obtained by reacting the carbamide compounds 2 of replacement in the mixing solutions of acetic acid and water, and temperature of reaction is zero degree to 60 DEG C;
B. compound 2 and diethyl malonate reflux and are obtained by reacting veronal compound 3 under basic conditions;
Wherein, described highly basic is the one in sodium ethylate, sodium methylate, sodium hydride, sodium tert-butoxide, potassium ethylate, sodium hydroxide or potassium hydroxide; The solvent adopted is ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, 1, the mixture of a kind of or above-mentioned solvent arbitrary proportion in 2-ethylene dichloride, chloroform, toluene, benzene, dimethylbenzene, dioxane, DMF, methyl-sulphoxide;
C. compound 3 obtains formula I with the fragrant formaldehyde reaction of fragrant formaldehyde or replacement;
Wherein, the solvent adopted is the mixture of a kind of or above-mentioned solvent arbitrary proportion in ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, 1,2-ethylene dichloride, chloroform, dioxane, DMF, methyl-sulphoxide; The temperature adopted is room temperature to 140 DEG C;
(2) when X is S, formula I is prepared by the method described in reaction formula two:
A. ammonium thiocyanate and Benzoyl chloride are obtained by reacting isothiocyanic acid benzoic ether in acetone soln, then obtain compound 4 with aniline 1 heating reflux reaction of aniline or replacement;
B. compound 4 is removed benzoyl protecting group through hydrolysis and is obtained substituting thioureido 5, and reagent used is the aqueous sodium hydroxide solution of 5%-10%, and temperature of reaction is room temperature to 100 DEG C;
C. compound 5 and diethyl malonate reflux and are obtained by reacting sulfo-veronal compound 6 under basic conditions;
Wherein, described highly basic is the one in sodium ethylate, sodium methylate, sodium hydride, sodium tert-butoxide, potassium ethylate, sodium hydroxide or potassium hydroxide; The solvent adopted is ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, 1, the mixture of a kind of or above-mentioned solvent arbitrary proportion in 2-ethylene dichloride, chloroform, toluene, benzene, dimethylbenzene, dioxane, DMF, methyl-sulphoxide;
D. compound 6 obtains formula I with the fragrant formaldehyde condensation of fragrant formaldehyde or replacement;
Wherein, the solvent adopted is the mixture of a kind of or above-mentioned solvent arbitrary proportion in ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, 1,2-ethylene dichloride, chloroform, dioxane, DMF, methyl-sulphoxide; The temperature adopted is room temperature to 140 DEG C;
5. as the application of barbituric acid compounds as described in any one in claims 1 to 3, it is characterized in that, compound shown in described general formula I and pharmaceutical salts thereof are as the application of istone lysine specificity demethylase 1 inhibitor in disease therapy.
6. the application of barbituric acid compounds according to claim 5, it is characterized in that, described disease comprises tumor disease, nerve degenerative diseases and virus disease.
7. the application of barbituric acid compounds according to claim 6, it is characterized in that, described tumor disease comprises leukemia, prostate cancer, mammary cancer, bladder cancer, lung cancer, liver cancer, skin carcinoma, colorectal cancer, lymphatic cancer, ovarian cancer or carcinoma of testis.
8. the application of barbituric acid compounds according to claim 7, it is characterized in that, described leukemia comprises acute lymphoblastic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia and chronic monocytic leukemia.
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WO2024110649A1 (en) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors and menin inhibitors for treating cancer

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WO2024110649A1 (en) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors and menin inhibitors for treating cancer

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