CN106432248B - The LSD1 of triazole containing pyrimido inhibitor, preparation method and application - Google Patents
The LSD1 of triazole containing pyrimido inhibitor, preparation method and application Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract
The invention belongs to field of medicinal chemistry, the compound of a kind of triazole structure containing pyrimido, preparation method are disclosed and its with lysine specificity demethylase（Hereinafter referred to as LSD1）As target application in preparation of anti-tumor drugs.The compounds of this invention general formula is as shown in I.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to the compound of pyrimido triazole, their preparation method
It and its is being the application in target anti-tumor drug with istone lysine specificity demethylase (hereinafter referred to as LSD1).
Background technique
Tumour is to seriously endanger human health and be difficult to the disease overcome, and the anti-tumor drug listed at present also has
Very much, but in these drugs still there are some problems, for example toxicity is big, targeting is weak and is easy to produce drug resistance etc..Cause
This, the research and development of new type antineoplastic medicine are particularly important.
Covalent histone modifications are a kind of important epigenetic mode, including acetylation of histone, methylation, phosphorylation
And ubiquitination etc., wherein acetylation and methylation are for more histone modification side in histone modification Mechanism Study
Formula.Histone methylated before 2004 is considered as irreversible, lysine specific histone demethylase (lysine
Specific demethylase 1, LSD1) be first be found can be catalyzed histone H 3 K4me1/2 and H3K9me1/
The specific demethylase of 2 demethylations, to adjust the transcription of downstream target gene.
Expression quantity of the LSD1 in kinds of tumor cells is significantly higher than normal cell, such as neuroblastoma, cancer eye, forefront
Gland cancer, breast cancer, lung cancer, bladder cancer etc..And it is demonstrated experimentally that being reduced by RNAi technology or micromolecular inhibitor in cellular level
LSD1 expression quantity or the activity for reducing LSD1 can inhibit cell Proliferation and induce the expression of some cell differentiation related genes；Small
Also it can inhibit the growth of kinds of tumor cells and solid tumor under the action of molecule monoamine oxidase inhibitors PCPA.Therefore, LSD1
Inhibitor not only serves as the research tool of epigenetics for illustrating biological function, and can be used as epigenetics medicine
Object is used for the prevention and treatment of tumour, has caused the extensive concern of scientific research circle, has become the hot spot of current research.
Meanwhile miazines and triazole heterocycle compound have very extensive bioactivity, such as antiviral, anti-
It is bacterium, anti-inflammatory and antitumor etc..But by new compound of the pyrimidine in conjunction with triazole structure with it is anti-based on LSD1 target spot
The report that function of tumor combines research is less, and therefore, this research has very important value.
Summary of the invention
To develop and use existing clinical medicine resource, it is mother that it is an object of that present invention to provide one kind with pyrimido triazole
The derivative of core, to open up a new way to find a new class of anti-tumor drug based on LSD1 target spot；The present invention is another
One is designed to provide preparation method and its is preparing the application in anti-tumor drug and LSD1 inhibitor.
The general structure of purpose to realize the present invention, pyrimido triazole LSD1 inhibitor of the present invention is as follows：
R in general formula I2For C1-5 alkyl chain (straight chain, branch or ring), In any one；Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, acyl group etc., n=1~6.MsO- is first
Base sulfonic group, TsO- toluenesulfonic acid base；
R1For any one in following group：Its
In, R is halogen, H ,-OH ,-NO2,-OCH3, acyl group etc., n=1~6.
R3For any one of following group：
Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, CF3, C1-4 alkyl or acyl group etc..
Boc- is tertbutyloxycarbonyl.
In general formula I preferably：
R2For C1-5 alkyl chain (straight chain, branch or ring), In any one；Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, acetyl group etc., n=1~2.
R1For any one in following group：
Wherein, n=1-2.
R3For any one of following group：
Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, CF3, C1-4 alkyl or acetyl group etc..
One of more preferable following compound：
R2ForR1ForWhen：
8 R3=4-Cl-Ph-NH-
9 R3=3-Cl-Ph-NH-
10 R3=4-Br-Ph-NH-
11 R3=4-F-Ph-NH-
12 R3=3-CF3-Ph-NH-
13 R3=3,4,5-tri-OMe-Ph-NH-
14 R3=4-Ac-Ph-NH-
15 R3=Bn-NH-
16 R3=4-Me-Bn-NH-
17 R3=4-OH-Bn-NH-
18 R3=4-OMe-Bn-NH-
19
20
24 R3=3-Cl-PhO-
25 R3=4-Cl-PhO-
26 R3=1-naphthalene-O-
27 R3=2-naphthalene-O-
28 R3=4-Me-Ph-S-
29 R3=4-Cl-Ph-S-
30 R3=2-Pyridine-S-；
R2For Bn-, R1ForWhen：
21
22
23
36 R3=2-Pyridine-S-；
Work as R3When=2-Pyridine-S-,
31 R1=Propyl,
32 R1=Propyl,
33 R1=Propyl,
34 R1=Propyl,
35 R1=Propyl, R2=Bn
37 R1=Bn, R2=Bn
The preparation method of pyrimido triazole LSD1 inhibitor of the present invention is mainly made by following steps：
1. the preparation method of general formula 2a~c：
In solvent, compound 1 and bromo-hydrocarbons are stirred to react at room temperature under alkaline matter effect, after reaction,
Filtering is washed, dry, obtains series compound 2.In this reaction, solvent for use can be acetone, methanol, ethyl alcohol, propyl alcohol, isopropyl
One of alcohol, tetrahydrofuran, acetonitrile, water, DMF, methylene chloride, chloroform, dioxane or wherein any or three kinds mixing
Object.Alkaline matter used can be one of triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide.Institute
It states bromo-hydrocarbons and corresponds to R1 substituent group in general formula；
2. the preparation method of general formula 3a~c：
In acetic acid, nitrating agent is added, series compound 2 is then added portionwise, is stirred to react, after reaction,
Enter in water, filter, washs, it is dry, obtain series compound 3.In this reaction, the nitrating agent can be fuming nitric aicd, concentrated nitric acid.
15-60 DEG C of preferable temperature.
3. the preparation method of general formula 4a~c：
In solvent, chlorination reagent is added, series compound 3 is then added portionwise, organic base, back flow reaction, reaction is added dropwise
After, it is cooled to room temperature, hydrolyzes, extracted with organic solvent, wash, neutralize, dry organic phase is up to 4 crude product of series compound
(can directly be carried out in next step without advanced optimizing, sterling can be made through being chromatographed with column).In this reaction, the chlorination examination
Agent can be phosphorus oxychloride, phosphorus pentachloride, and solvent can be toluene, and dioxane, THF, ethyl acetate etc., the organic base can
To be triethylamine, n,N-Dimethylaniline, N, N- diethylaniline or pyridine etc..40~120 DEG C of preferable temperature.
4. the preparation method of general formula 5a~c：
Series compound 4 is dissolved in the in the mixed solvent of ethyl alcohol and acetic acid, reduced iron powder, temperature rising reflux is then added portionwise
Reaction filters, is spin-dried for solvent, then extracted with organic solvent, washes, and dry organic phase obtains the crude product of series compound 5, pure
Product can be chromatographed through column and are made.
5. the preparation method of general formula 6a~l：
Series compound 5 and aminated compounds are dissolved in solvent, add organic base, back flow reaction, after reaction,
Solvent evaporated, is added ethyl acetate, washing, and dry organic phase obtains the crude product of series compound 6 (without further purification directly
It connects for reacting in next step).In this reaction, reaction solvent for use can be methanol, ethyl alcohol, isopropanol, DMF, dioxane,
THF, acetonitrile etc., the organic base can be triethylamine, pyridine or diisopropylethylamine etc..Preferable reaction temperature is 60~120
℃.The aminated compounds corresponds to R in general formula2Substituent group；
6. the preparation method of general formula 7a~l：
Series compound 6 is dissolved in the mixed liquor of acetic acid and water, the reactant aqueous solution of sodium nitrite is added dropwise under ice bath, instead
After answering, ethyl acetate and water is added, is layered, washes, neutralizes, dry organic phase obtains 7 crude product of series compound, without into
The purifying of one step directly carries out next step reaction.
7. the preparation method of compound 8~23 in general formula：
Series compound 7 and aminated compounds are dissolved in solvent, acid binding agent is added, back flow reaction is steamed after reaction
Dry solvent, is dissolved in ethyl acetate, is washed with water, dry, crosses column, and mobile phase is the petroleum ether and ethyl acetate of different proportion.This is anti-
Ying Zhong, the solvent are methanol, and ethyl alcohol, isopropanol, THF, acetonitrile, DMF, dioxane etc., acid binding agent is triethylamine, pyridine,
Wopropyl ethyl amine etc..Preferable reaction temperature is 20~100 DEG C.
8. the preparation method of compound 24~27 in general formula：
Series compound 7 and phenolic compound are dissolved in solvent, potassium carbonate or potassium carbonate, back flow reaction, reaction is added
After, solvent evaporated is dissolved in ethyl acetate, is washed with water, and dry, crossing column, (mobile phase is the petroleum ether and acetic acid of different proportion
Ethyl ester).In this reaction, the solvent is acetone, acetonitrile, THF, DMF, DMSO etc..Preferable reaction temperature is 20~80 DEG C.
9. the preparation method of compound 28~37 in general formula：
Series compound 7 and sulfhydryl compound are dissolved in solvent, alkali substance reaction is added and is evaporated after reaction
Solvent is dissolved in ethyl acetate, is washed with water, and dries, and (mobile phase is the petroleum ether and acetic acid second of different proportion for column or recrystallization excessively
Ester).In this reaction, the reaction dissolvent is acetonitrile, and ethyl alcohol, methanol, THF, DMF, dioxane etc., alkaline matter used is three
Ethamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate etc..Preferable reaction temperature is 20~80 DEG C.
Step (7), (8), aminated compounds, phenolic compound or sulfhydryl compound correspond to R in general formula described in (9)3It takes
Dai Ji.
Pyrimido triazole derivative of the present invention has well LSD1 by the experiment discovery of LSD1 enzymatic activity
Inhibiting effect.Wherein the activity of most compound is better than positive control tranylcypromine (2-PCPA).Therefore, provided by the invention phonetic
Pyridine and three nitrogen analog derivatives are to develop new type antineoplastic medicine, the drug combination of drug and novel LSD1 inhibitor medicaments to open up
Another effective way, the compounding design of such compound is reasonable, reaction condition is mild, easy to operate, and reaction yield is high, total to receive
Rate is up to 60% or more, as can good market application prospect will be had by being developed into new drug.
Specific embodiment
To better illustrate the invention, special as follows for embodiment：
Embodiment 1 compound 2b, R1The preparation of=Propyl
Barbiturates (3g, 1eq) and triethylamine (2.9ml, 1eq) are added in the methanol of 30ml, are heated to reflux down, slowly
It is added dropwise N-Propyl Bromide (1.8ml, 1eq), continues reflux 1 hour after adding, it is cooling, it filters, obtains 3.7g pink solid compound 2b,
Yield 97%.
Embodiment 2 compound 3b, R1The preparation of=Propyl
Under ice bath, the fuming nitric aicd of 3ml is carefully dissolved in the acetic acid of 6ml, 2.9g compound 2b is then added portionwise, adds
After complete, continue stirring 2 hours, then reaction solution is added in the ice water of 18ml, filter, washing obtains the powdered of kermesinus
Close object 3b, yield 77.5%.
Embodiment 3 compound 4b, R1The preparation of=Propyl
It is dissolved in compound 3b (12.4g, 1eq) in the phosphorus oxychloride of 50ml, DMA (12ml, 1.8eq) is slowly added dropwise, so
After be warming up to reflux, react 5 hours.It is cooled to room temperature, hydrolyzes, then extracted with EA, wash, then is washed with the sodium carbonate liquor of saturation
It washs, to get brown compound 4b crude product 13g, yield 90.2% after organic phase is dry.
Embodiment 4 compound 5b, R1The preparation of=Propyl
Compound 4b (0.5g, 1eq) is dissolved in the methanol of 4ml and the acetic acid of 2ml, reduced iron powder is then added portionwise
(0.3g, 3eq) flows back 2 hours, it is cooled to room temperature, filters, filtrate is evaporated, and ethyl acetate is dissolved in, with the sodium carbonate liquor of saturation
Washing, washing, dry organic phase obtain 0.44g compound 5b crude product, yield 95% after being evaporated.
Embodiment 5 compound 6b, R1=Propyl,Preparation
By compound 5b (3.9g, 1eq), ethanol amine (1.0g, 1eq) and triethylamine (3ml, 1.3eq) are dissolved in ethyl alcohol, are returned
Stream 48 hours, solvent evaporated is dissolved in ethyl acetate, is then neutralized to neutrality with dilute hydrochloric acid, and washing is three times, dry, after being evaporated
Compound 6b crude product directly carries out in next step without further purification.
6 compound 7, R of embodiment1=Propyl,Preparation
The crude product of upper step compound 6b is dissolved in the mixed liquor of acetic acid and water, under 0 DEG C of ice bath, sodium nitrite is added dropwise
The aqueous solution of (1.13g, 1eq) keeps temperature not to be more than 10 DEG C, then proceedes to be stirred to react 1 hour, reaction solution is dissolved in acetic acid
It in ethyl ester, is washed with water three times, is then neutralized to neutrality with the sodium bicarbonate solution of saturation again, wash, dry organic phase, after being evaporated
Compound 7b crude product is obtained, is directly carried out without further purification in next step.
7 compound 8, R of embodiment1=Propyl,R3The preparation of=4-Cl-Ph-NH-
Midbody compound 7b (100mg, 1eq), parachloroanilinum (63mg, 1eq) and triethylamine (37mg, 1eq) are dissolved in
In ethyl alcohol, be heated to reflux a few hours, with TLC (PE/EA) monitor react, after solvent evaporated, be dissolved in ethyl acetate, water
It washes, it is dry, column is crossed, shallow white solid 90mg, yield 60% are obtained.156~157 DEG C of of White solid, Mp1H NMR
(400MHz,DMSO-d6,ppm):δ 11.01 (s, 1H), 7.92-7.94 (d, J=8.8Hz, 2H), 7.44-7.46 (d, J=
8.8Hz, 2H), 4.97-5.00 (t, J=5.8Hz, 1H), 4.55-4.58 (t, J=5.4Hz, 2H), 3.91-3.95 (q, 2H),
3.09-3.13 (t, J=7.2Hz, 2H), 1.68-1.74 (m, 2H), 0.96-1.00 (t, J=7.2Hz, 3H)13C NMR
(100MHz,DMSO-d6,ppm):δ169.70,151.41,150.48,137.84,128.92,128.25,123.70,
123.39,59.27,49.72,32.94,22.96,13.76.HR-MS(ESI):Calcd.C15H17ClN6OS,[M+H]+m/z:
365.0951,found:365.0953.。
8 compound 9, R of embodiment1=Propyl,R3The preparation of=3-Cl-Ph-NH-
3- chloroaniline substitute parachloroanilinum, take the same method of embodiment 7 prepare 9, White solid, Mp154~
155℃.1H NMR(400MHz,DMSO-d6,ppm):δ 11.08 (s, 1H), 8.17 (s, 1H), 7.82-7.84 (d, J=8.4Hz,
1H), 7.40-7.44 (t, J=8Hz, 1H), 7.19-7.21 (d, J=8Hz, 1H), 4.55-4.58 (t, J=5.6Hz, 2H),
3.91-3.94 (t, J=5.6Hz, 2H), 3.13-3.17 (t, J=7.2Hz, 2H), 1.68-1.77 (m, 2H), 0.98-1.01
(t, J=7.2Hz, 3H)13C NMR(100MHz,DMSO-d6,ppm):δ169.70,151.41,150.53,140.40,
133.32,130.68,124.07,123.41,121.50,120.36,59.27,49.74,32.99,22.86,13.72.HR-MS
(ESI):Calcd.C15H17ClN6OS,[M+H]+m/z:365.0951,found:365.0950.。
9 compound 10, R of embodiment1=Propyl,R3The preparation of=4-Br-Ph-NH-
Para-bromoaniline substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 10, Yellow solid, Mp 149
~151 DEG C of1H NMR(400MHz,DMSO-d6,ppm):δ 11.00 (s, 1H), 7.87-7.89 (d, J=8.8Hz, 2H), 7.57-
7.60 (m, 2H), 4.55-4.58 (t, J=5.6Hz, 2H), 3.91-3.94 (t, J=5.6Hz, 2H), 3.09-3.13 (t, J=
7.1Hz, 2H), 1.68-1.74 (m, 2H), 0.96-1.00 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6,δ,
ppm):δ169.70,151.39,150.49,138.27,131.83,124.06,123.41,116.37,59.27,49.72,
32.94,22.96,13.76.HR-MS(ESI):Calcd.C15H17BrN6OS,[M+H]+m/z:409.0446,found:
409.0429.。
10 compound 11, R of embodiment1=Propyl,R3The preparation of=4-F-Ph-NH-
Para-fluoroaniline substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 11, Light yellow solid,
140~141 DEG C of of Mp1H NMR(400MHz,DMSO-d6,ppm):δ 10.92 (s, 1H), 7.87-7.90 (m, 2H), 7.23-
7.27 (m, 2H), 4.98-5.00 (t, J=5.6Hz, 2H), 4.54-4.57 (t, J=5.6Hz, 2H), 3.91-3.95 (q, 2H),
3.08-3.11 (t, J=7.0Hz, 2H), 1.65-1.74 (m, 2H), 0.95-0.99 (t, J=7.4Hz, 3H)13C NMR
(100MHz,DMSO-d6,ppm):δ169.68,151.53,150.44,135.10,124.25,123.30,115.78,
115.57,59.27,49.68,32.91,23.01,13.75.HR-MS(ESI):Calcd.C15H17FN6OS,[M+H]+m/z:
349.1247,found:349.1263.。
11 compound 12, R of embodiment1=Propyl,R3=3-CF3The preparation of-Ph-NH-
3- trifluoromethyl-aniline substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 12, Yellow solid,
151~153 DEG C of of Mp1H NMR(400MHz,DMSO-d6,ppm):δ 11.21 (s, 1H), 8.47 (s, 1H), 8.13-8.15 (d, J
=8.4Hz, 1H), 7.62-7.66 (t, J=7.8Hz, 1H), 7.48-7.50 (d, J=7.6Hz, 1H), 4.98-5.01 (t, J=
5.8Hz, 1H), 4.56-4.59 (t, J=5.4Hz, 2H), 3.91-3.96 (q, 2H), 3.13-3.16 (t, J=7.2Hz, 2H),
1.67-1.72 (q, 2H), 0.95-0.99 (t, J=7.2Hz, 3H)13C NMR(100MHz,DMSO-d6,ppm):δ169.73,
151.48,150.55,139.74,130.26,129.95,129.63,125.49,123.42,120.67,118.20,59.28,
49.75,32.90,22.64,13.62.HR-MS(ESI):Calcd.C16H17F3N6OS,[M+H]+m/z:399.1215,found:
399.1241.。
12 compound 13, R of embodiment1=Propyl,R3The system of=3,4,5-tri-OMe-Ph-NH-
It is standby
3,4, tri- oxygen metlyl-phenylamine of 5- substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 13, White
163~165 DEG C of of solid, Mp1H NMR(400MHz,CDCl3,ppm):δ 8.34 (s, 1H), 7.13 (s, 2H), 4.72-4.75
(t, J=4.8Hz, 2H), 4.38-4.42 (t, J=6.8Hz, 1H), 4.25-4.27 (q, 2H), 3.90 (s, 6H), 3.85 (s,
3H), 3.08-3.12 (t, J=7.2Hz, 2H), 1.73-1.78 (q, 2H), 1.03-1.06 (t, J=7.2Hz, 3H)13C NMR
(100MHz,CDCl3,ppm):δ171.52,153.24,150.62,149.64,134.89,133.58,123.33,98.59,
61.00,60.70,56.18,50.94,33.24,22.30,13.50.HR-MS(ESI):Calcd.C18H24N6O4S,[M+H]+m/
z:421.1658,found:421.1649.。
13 compound 14, R of embodiment1=Propyl,R3The preparation of=4-Ac-Ph-NH-
4- acetyl group-aniline substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 14, Light yellow
163~164 DEG C of of solid, Mp1H NMR(400MHz,DMSO-d6,ppm):δ 11.20 (s, 1H), 8.08-8.11 (d, J=
8.8Hz, 2H), 7.97-7.99 (d, J=8.8Hz, 2H), 4.99-5.02 (t, J=5.8Hz, 1H), 4.563-4.591 (t, J=
5.6Hz, 2H), 3.92-3.96 (q, 2H), 3.13-3.16 (t, J=7.2Hz, 2H), 2.56 (s, 3H), 1.69-1.78 (m,
2H), 0.99-1.02 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6,ppm):δ196.53,169.27,
150.83,150.11,142.93,131.98,129.04,123.06,120.52,58.77,49.27,32.48,26.46,
22.45,13.27.HR-MS(ESI):Calcd.C17H20N6O2S,[M+Na]+m/z:395.1266,found:395.1265.。
14 compound 15, R of embodiment1=Propyl-,R3The preparation of=Bn-NH-
Benzyl amine substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 15, White solid, Mp139~140
℃.1H NMR(400MHz,CDCl3,ppm):δ 7.31-7.41 (m, 5H), 7.14-7.15 (m, 1H), 4.88-4.90 (d, J=
6Hz, 2H), 4.68-4.70 (t, J=4.6Hz, 2H), 4.45 (m, 1H), 4.16 (m, 2H), 3.10-3.13 (t, J=7.4Hz,
2H), 1.73-1.82 (m, 2H), 1.03-1.07 (t, J=7.2Hz, 3H)13C NMR(100MHz,CDCl3,ppm):δ
171.42,153.23,149.55,137.44,128.79,127.89,127.79,123.30,60.85,51.17,44.68,
33.36,22.71,13.51.HR-MS(ESI):Calcd.C16H20N6OS,[M+H]+m/z:345.1498,found:
345.1484.。
15 compound 16, R of embodiment1=Propyl-,R3The preparation of=4-Me-Bn-NH-
4- Methyl-benzvl amine substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 16, White solid, Mp
154~155 DEG C of1H NMR(400MHz,CDCl3,ppm):δ 7.28-7.30 (d, J=8.0Hz, 2H), 7.16-7.18 (d, J=
7.9Hz, 2H), 4.83-4.85 (d, J=5.6Hz, 2H), 4.68-4.70 (t, J=4.6Hz, 2H), 4.47-4.50 (t, J=
6.4Hz, 1H), 4.14-4.17 (m, 2H), 3.121-3.14 (t, J=7.2Hz, 2H), 2.36 (s, 3H), 1.7-1.82 (m,
2H), 1.06 (t, J=7.4Hz, 3H)13C NMR(100MHz,CDCl3,ppm):δ171.39,153.18,149.51,
137.55,134.37,129.44,127.94,123.31,60.85,51.21,44.46,33.36,22.72,21.14,
13.52.HR-MS(ESI):Calcd.C17H22N6OS,[M+Na]+m/z:381.1473,found:381.1475.。
16 compound 17, R of embodiment1=Propyl-,R3The preparation of=4-OH-Bn-NH-
4- Hydroxy-benzvl amine substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 17, White solid, Mp
198~199 DEG C of1H NMR(400MHz,DMSO-d6,ppm):δ 9.40-9.43 (t, J=6Hz, 1H), 9.31 (s, 1H), 7.15-
7.17 (d, J=8.4Hz, 2H), 6.70-6.72 (d, J=8.4Hz, 2H), 4.94-4.97 (t, J=5.8Hz, 1H), 4.60-
4.62 (d, J=6Hz, 2H), 4.48-4.50 (d, J=5.4Hz, 2H), 3.86-3.91 (m, 2H), 3.05-3.08 (t, J=
7.2Hz, 2H), 1.62-1.70 (m, 2H), 0.93-0.97 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6,
ppm):δ169.58,156.81,153.40,150.04,129.57,129.08,123.21,115.50,59.29,49.51,
43.20,32.90,23.09,13.78.HR-MS(ESI):Calcd.C16H20N6O2S,[M+H]+m/z:361.1447,found:
361.1448.。
17 compound 18, R of embodiment1=Propyl-,R3The preparation of=4-OMe-Bn-NH-
4- methyoxy-benzyl amine substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 18, White solid,
148~149 DEG C of of Mp1H NMR(400MHz,DMSO-d6,ppm):δ 9.45-9.48 (t, J=6Hz, 1H), 7.27-7.29 (d, J
=8.8Hz, 2H), 6.88-6.90 (d, J=8.8Hz, 2H), 4.94-4.97 (t, J=5.8Hz, 1H), 4.64-4.66 (d, J=
6Hz, 2H), 4.48-4.50 (t, J=5.4Hz, 2H), 3.86-3.91 (q, 2H), 3.72 (s, 3H), 3.04-3.07 (t, J=
7.2Hz, 2H), 1.61-1.72 (m, 2H), 0.92-0.96 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6,
ppm):δ169.59,158.74,153.42,150.05,131.35,129.04,123.22,114.28,114.18,59.28,
55.51,49.52,43.11,32.90,23.08,13.78.HR-MS(ESI):Calcd.C17H22N6O2S,[M+H]+m/z:
375.1603,found:375.1608.。
18 compound 19, R of embodiment1=Propyl-,Preparation
Cyclohexylamine substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 19, White solid, Mp81~83
℃.1HNMR(400MHz,CDCl3,ppm):δ 4.69-4.71 (t, J=4.6Hz, 2H), 4.62 (m, 1H), 4.56 (m, 2H),
4.13 (m, 2H), 4.02 (m, 2H), 3.08-3.11 (t, J=7.2Hz, 2H), 1.71-1.84 (m, 8H), 1.05-1.09 (t, J
=7.2Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ169.91,152.16,150.85,123.87,61.13,51.28,
48.56,44.99,33.21,26.43,25.83,24.52,22.77,13.51.HR-MS(ESI):Calcd.C14H22N6OS,[M+
H]+m/z:323.1654,found:323.1653.。
19 compound 20, R of embodiment1=Propyl-,Preparation
1- Benzyl-piperazin amine substitutes parachloroanilinum, and the same method of embodiment 7 is taken to prepare 20, Yellow solid, Mp
115~116 DEG C of1H NMR(400MHz,CDCl3,ppm):δ7.36-7.37(m,4H),7.31-7.33(m,1H),4.70-4.72
(t, J=4.6Hz, 2H), 4.66 (m, 2H), 4.51 (br, 1H), 4.09-4.15 (m, 4H), 3.60 (s, 2H), 3.07-3.11
(t, J=7.2Hz, 2H), 2.58-2.67 (m, 4H), 1.76-1.81 (m, 2H), 1.05-1.08 (t, J=7.4Hz, 3H)13C
NMR(100MHz,CDCl3,ppm):δ170.07,152.29,150.86,137.48,129.20,128.39,127.37,
123.85,62.93,61.10,53.23,52.67,51.28,47.35,43.69,33.21,22.69,13.51.HR-MS
(ESI):Calcd.C20H27N7OS,[M+H]+m/z:414.2076,found:414.2078.。
20 compound 21, R of embodiment1=Propargyl, R2=Bn,Preparation
N-Propyl Bromide is replaced with 3- bromo allyl alkynes, benzyl amine substitutes ethanol amine, and 1- Benzyl-piperazin amine substitutes parachloroanilinum,
The same method of embodiment 7 is taken to prepare 21, Yellow solid, 103~104 DEG C of of Mp1H NMR(400MHz,CDCl3,
ppm):δ7.43-7.45(m,2H),7.32-7.34(m,4H),7.28-7.30(m,4H),5.65(s,2H),4.64(s,2H),
4.06 (s, 2H), 3.89-3.90 (d, J=2.4Hz, 2H), 3.56 (s, 2H), 2.55-2.62 (m, 4H), 2.16 (t, J=
2.6Hz,1H).13C NMR(100MHz,CDCl3,ppm):δ167.84,152.49,150.76,137.48,135.06,
129.18,128.75,128.54,128.35,128.31,127.32,123.82,80.22,70.15,62.91,53.19,
52.70,50.16,47.27,43.70,19.73.HR-MS(ESI):Calcd.C25H25N7S,[M+H]+m/z:456.1970,
found:456.1971.。
21 compound 22, R of embodiment1=Propargyl, R2=Bn,Preparation
N-Propyl Bromide is replaced with 3- bromo propine, benzyl amine substitutes ethanol amine, and 1- tbutyloxycarbonyl-piperazin amine is substituted to chlorobenzene
Amine takes the same method of embodiment 7 to prepare 22, Yellow solid, 128~129 DEG C of of Mp1HNMR(400MHz,CDCl3,
ppm):δ7.44-7.46(m,2H),7.29-7.34(m,3H),5.67(s,1H),4.61(s,2H),4.04(s,2H),3.90-
3.91 (d, J=2.8Hz, 2H), 3.56-3.60 (m, 4H), 2.17-2.18 (t, J=2.8Hz, 1H), 1.49 (s, 9H)13CNMR
(100MHz,CDCl3,ppm):δ168.00,154.58,152.69,150.81,134.95,128.78,128.58,128.38,
123.79,80.41,80.15,70.21,50.26,47.13,43.52,28.40,19.78.HR-MS(ESI):
Calcd.C23H27N7O2S,[M+H]+m/z:466.2025,found:466.2026.。
22 compound 23, R of embodiment1=Propargyl, R2=Bn,Preparation
N-Propyl Bromide is replaced with 3- bromo allyl alkynes, benzyl amine substitutes ethanol amine, and 2- (2- furans _)-ethamine is substituted to chlorobenzene
Amine takes the same method of embodiment 7 to prepare 23, White solid, 192~194 DEG C of of Mp1HNMR(400MHz,CDCl3,
ppm):δ 7.44-7.45 (m, 2H), 7.38 (s, 1H), 7.31-7.34 (m, 3H), 6.54 (t, J=6.0Hz, 1H), 6.33 (s,
2H), 5.67 (s, 2H), 4.85-4.86 (d, J=5.6Hz, 2H), 3.95-3.96 (d, J=2.4Hz, 2H), 2.18-2.20 (t,
J=2.6Hz, 1H)13CNMR(100MHz,DMSO-d6,ppm):δ167.87,152.99,151.44,149.09,142.18,
135.63,128.73,128.34,128.06,122.76,110.51,107.45,80.53,73.00,49.43,36.72,
19.11.HR-MS(ESI):Calcd.C19H16N6OS,[M+Na]+m/z:399.1004,found:399.1006.。
23 compound 24, R of embodiment1=Propyl,R3The preparation of=3-Cl-PhO-
By midbody compound 7b (100mg, 1eq), 3- chlorophenol (47mg, 1eq) and potassium carbonate (51mg, 1eq) are dissolved in
It in acetone, flows back 6 hours, TLC (PE/EA) detects end of reaction, and solvent evaporated is dissolved in ethyl acetate, is washed with water three times, does
It is dry, it crosses column (PE/EA), obtains white solid 70mg, yield 52.6%.143~144 DEG C of of White solid, Mp1HNMR
(400MHz,CDCl3,ppm):δ 7.38-7.42 (t, J=8.0Hz, 1H), 7.31-7.33 (m, 2H), 7.18-7.21 (m, 1H),
4.77-4.80 (t, J=4.8Hz, 2H), 4.19-4.23 (m, 2H), 3.20-3.23 (t, J=6.6Hz, 1H), 2.89-2.93
(t, J=7.4Hz, 1H), 1.58-1.63 (m, 2H), 0.88-0.92 (t, J=7.4Hz, 3H)13CNMR(100MHz,CDCl3,
ppm):δ171.57,159.37,152.75,152.03,134.84,130.35,126.65,123.62,122.57,120.22,
60.78,50.69,33.62,22.67,13.30.HR-MS(ESI):Calcd.C15H16ClN5O2S,[M+Na]+m/z:
388.0611,found:388.0612.。
24 compound 25, R of embodiment1=Propyl,R3The preparation of=4-Cl-PhO-
3- chlorophenol is substituted with 4 chlorophenols, the same method of embodiment 23 is taken to prepare 25, White solid, Mp 153
~155 DEG C of1HNMR(400MHz,DMSO-d6,ppm):δ 7.59-7.61 (d, J=8.8Hz, 2H), 7.45-7.48 (d, J=
8.8Hz, 2H), 4.97-4.50 (t, J=5.8Hz, 1H), 4.64-4.66 (t, J=5.4Hz, 2H), 3.92-3.96 (m, 2H),
2.89-2.93 (t, J=7.2Hz, 1H), 1.51-1.57 (m, 2H), 0.80-0.84 (t, J=7.2Hz, 3H)13CNMR
(100MHz,DMSO-d6,ppm):δ169.26,159.20,152.64,150.17,130.56,129.69,123.90,
123.07,58.79,49.67,32.67,22.38,13.08.HR-MS(ESI):Calcd.C15H16ClN5O2S,[M+Na]+m/z:
388.0611,found:388.0612.
25 compound 26, R of embodiment1=Propyl,R3The preparation of=1-naphthalene-O-
3- chlorophenol is substituted with 1- naphthols, the same method of embodiment 23 is taken to prepare 26, White solid, Mp 124
~125 DEG C of1HNMR(400MHz,CDCl3,ppm):δ7.83-7.93(m,3H),7.51-7.56(m,2H),7.44-7.48(m,
1H), 7.39-7.41 (d, J=7.2Hz, 1H), 4.79-4.81 (t, J=5.0Hz, 2H), 4.20-4.24 (m, 2H), 3.31-
3.34 (t, J=6.4Hz, 1H), 2.55-2.59 (t, J=7.4Hz, 2H), 1.19-1.28 (m, 2H), 0.56-0.60 (t, J=
7.4Hz,3H).13CNMR(100MHz,CDCl3,ppm):δ171.66,160.28,152.85,147.89,134.79,128.05,
126.89,126.68,126.64,126.58,125.38,123.71,121.51,118.22,60.84,50.73,33.47,
22.60,13.09.HR-MS(ESI):Calcd.C19H19N5O2S,[M+Na]+m/z:404.1157,found:404.1155..
26 compound 27, R of embodiment1=Propyl,R3The preparation of=2-naphthalene-O-
With beta naphthal substitute 3- chlorophenol, take the same method of embodiment 23 prepare 27, White solid, Mp127~
128℃.1HNMR(400MHz,CDCl3,ppm):δ 7.89-7.94 (m, 2H), 7.84-7.86 (m, 1H), 7.73-7.74 (d, J=
2.0Hz, 1H), 7.52-7.54 (m, 2H), 7.39-7.42 (m, 1H), 4.79-4.81 (t, J=4.8Hz, 2H), 4.20-4.24
(m, 2H), 3.33-3.36 (t, J=6.5Hz, 1H), 2.79-2.83 (t, J=7.4Hz, 2H), 1.47-1.53 (m, 2H),
0.66-0.70 (t, J=7.4Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ171.62,159.97,152.67,
149.35,133.81,131.70,129.51,127.86,127.75,126.76,126.04,123.87,121.22,118.80,
60.83,50.76,33.54,22.67,13.11.HR-MS(ESI):Calcd.C19H19N5O2S,[M+Na]+m/z:404.1157,
found:404.1155。
27 compound 28, R of embodiment1=Propyl,R3The preparation of=4-Me-Ph-S-
3- chlorophenol is substituted with 4- methylphenyl-thiophenol, the same method of embodiment 23 is taken to prepare 28, Orange
107~108 DEG C of of solid, Mp1HNMR(400MHz,CDCl3,ppm):δ 7.50-7.52 (d, J=8.4Hz, 2H), 7.27-
7.29 (d, J=8.0Hz, 2H), 4.72-4.74 (t, J=4.8Hz, 2H), 4.14-4.18 (m, 2H), 3.34-3.37 (t, J=
6.6Hz, 1H), 2.75-2.79 (t, J=7.2Hz, 2H), 2.43 (s, 3H), 1.43-1.49 (m, 2H), 0.82-0.86 (t, J=
7.4Hz,3H).13CNMR(100MHz,CDCl3,ppm):δ170.34,165.08,148.66,140.43,135.96,131.63,
130.15,122.00,60.81,50.58,33.44,22.53,21.43,13.28.HR-MS(ESI):Calcd.C16H19N5OS2,
[M+Na]+m/z:384.0929,found:384.0931.。
28 compound 29, R of embodiment1=Propyl,R3The preparation of=4-Cl-Ph-S-
3- chlorophenol is substituted with the chloro- phenyl of 4--thiophenol, the same method of embodiment 23 is taken to prepare 29, White
114~115 DEG C of of solid, Mp1HNMR(400MHz,CDCl3,ppm):δ 7.56-7.58 (d, J=8.4Hz, 2H), 7.45-
7.47 (d, J=8.8Hz, 2H), 4.73-4.75 (t, J=5.0Hz, 2H), 4.15-4.19 (m, 2H), 3.18-3.22 (t, J=
6.4Hz, 1H), 2.78-2.82 (t, J=7.4Hz, 2H), 1.47-1.53 (m, 2H), 0.88-0.91 (t, J=7.2Hz, 3H)
.13CNMR(100MHz,CDCl3,ppm):δ170.55,164.02,148.77,137.32,136.73,131.54,129.63,
124.05,60.79,50.57,33.50,22.41,13.31.HR-MS(ESI):Calcd.C15H16ClN5OS2,[M+Na]+m/z:
404.0382,found:404.0381.。
29 compound 30, R of embodiment1=Propyl,R3The preparation of=2-Pyridine-S-
With 2- pyridine -- thiophenol substitutes 3- chlorophenol, and the same method of embodiment 23 is taken to prepare 30, Yellow sticky
oil.1H NMR(400MHz,CDCl3,ppm):δ8.68-8.69(m,1H),7.80-7.82(m,2H),7.38-7.42(m,1H),
4.71-4.74 (t, J=5.0Hz, 2H), 4.16-4.18 (t, J=5.0Hz, 2H), 2.84-2.87 (t, J=7.2Hz, 2H),
1.52-1.61 (m, 2H), 0.90-0.93 (t, J=7.2Hz, 3H)13C NMR(100MHz,CDCl3,ppm):δ170.48,
163.72,150.80,150.02,148.92,137.34,131.72,131.38,124.17,60.68,50.43,33.42,
22.28,13.34.HR-MS(ESI):Calcd.C14H16N6OS2,[M+H]+m/z:349.0905,found:349.0902.。
30 compound 31, R of embodiment1=Propyl,R3The preparation of=2-Pyridine-S-
Ethanol amine is substituted with isobutyl amine, the same method of embodiment 29 is taken to prepare 31, Yellow oil.1H NMR
(400MHz,Chloroform-d)δ8.69-8.71(m,1H),7.79-7.85(m,2H),7.38-7.42(m,1H),4.36-
4.38 (d, J=7.2Hz, 2H), 2.85-2.89 (t, J=7.2Hz, 2H), 2.38-2.45 (m, 1H), 1.54-1.60 (m, 2H),
0.95-0.96 (d, J=6.8Hz, 6H), 0.90-0.94 (t, J=7.4Hz, 3H)13C NMR(100MHz,CDCl3,ppm):δ
170.03,163.18,150.77,150.18,148.99,137.27,131.50,131.35,124.07,53.94,33.37,
29.00,22.41,19.96,13.41.HR-MS(ESI):Calcd.C16H20N6S2,[M+H]+m/z:361.1269,found:
361.1268.。
31 compound 32, R of embodiment1=Propyl,R3The preparation of=2-Pyridine-S-
Ethanol amine is substituted with cyclohexylamine, the same method of embodiment 29 is taken to prepare 32, Yellow sticky oil.1H
NMR(400MHz,Chloroform-d)δ8.68–8.70(m,1H),7.78–7.84(m,2H),7.37-7.41(m,1H),
5.21-5.28 (m, 1H), 2.87-2.91 (t, J=7.2Hz, 2H), 2.23-2.28 (m, 4H), 2.00-2.04 (m, 2H),
1.75-1.80 (m, 2H), 1.56-1.62 (m, 2H), 0.91-0.95 (t, J=7.4Hz, 3H)13C NMR(100MHz,CDCl3,
ppm):δ169.51,163.12,150.72,150.35,148.43,137.24,132.00,131.23,124.02,59.25,
33.37,32.46,24.55,22.43,13.41.HR-MS(ESI):Calcd.C17H20N6S2,[M+H]+m/z:373.1269,
found:373.1271.。
32 compound 33, R of embodiment1=Propyl,R3The preparation of=2-Pyridine-S-
Ethanol amine is substituted with 2- (2- thiophene) ethamine, the same method of embodiment 29 is taken to prepare 33, Yellow sticky
oil.1H NMR(400MHz,CDCl3,ppm):δ8.69-8.70(m,1H),7.78-7.84(m,2H),7.38-7.41(m,1H),
7.12-7.14 (dd, 1H), 6.86-6.89 (m, 1H), 6.76-6.77 (d, J=3.4Hz, 1H), 4.79-4.83 (t, J=
7.3Hz, 2H), 3.53-3.57 (t, J=7.3Hz, 2H), 2.84-2.88 (t, J=7.2Hz, 2H), 1.54-1.59 (m, 2H),
0.91-0.95 (t, J=7.3Hz, 3H)13C NMR(100MHz,CDCl3,ppm):δ170.23,163.23,150.75,
150.06,148.78,138.64,137.29,131.52,131.34,127.06,125.94,124.48,124.10,48.05,
33.36,29.59,22.37,13.44.HR-MS(ESI):Calcd.C18H18N6S3,[M+H]+m/z:415.0833,found:
415.0832.。
33 compound 34, R of embodiment1=Propyl,R3The preparation of=2-Pyridine-S-
Ethanol amine is substituted with 2-furylamines, the same method of embodiment 29 is taken to prepare 34, Yellow semi-
solid.1H NMR(400MHz,Chloroform-d)δ8.68-8.69(m,1H),7.77–7.82(m,2H),7.37-7.40
(m, 1H), 7.35 (m, 1H), 6.45-6.46 (d, J=3.3Hz, 1H), 6.33-6.34 (m, 1H), 5.71 (s, 2H), 2.88-
2.91 (t, J=7.2Hz, 2H), 1.56-1.62 (m, 2H), 0.92-0.95 (t, J=7.4Hz, 3H)13C NMR(100MHz,
CDCl3,ppm):δ170.54,163.39,150.78,150.15,148.62,147.30,143.26,137.29,131.56,
131.28,124.10,110.70,110.07,43.13,33.41,22.37,13.44.HR-MS(ESI):
Calcd.C17H16N6OS2,[M+H]+m/z:385.0905,found:385.0901.。
34 compound 35, R of embodiment1=Propyl, R2=Bn, R3The preparation of=2-Pyridine-S-
Ethanol amine is substituted with benzylamine, the same method of embodiment 29 is taken to prepare 35, Yellow oil.1H NMR
(400MHz,Chloroform-d)δ8.67-8.68(m,1H),7.76-7.82(m,2H),7.36–7.41(m,3H),7.30-
7.34 (m, 3H), 5.71 (s, 2H), 2.87-2.91 (t, J=7.2Hz, 2H), 1.55-1.61 (m, 2H), 0.91-0.95 (t, J
=7.3Hz, 3H)13C NMR(101MHz,CDCl3)δ170.37,163.33,150.74,150.18,148.63,137.26,
134.48,131.66,131.21,128.84,128.53,128.41,124.05,50.52,33.37,22.37,13.45.HR-
MS(ESI):Calcd.C19H18N6S2,[M+H]+m/z:395.1113,found:395.1111.。
35 compound 36, R of embodiment1=Propargyl, R2=Bn, R3The preparation of=2-Pyridine-S-
Bromo propane is substituted with 3- bromo propine, the same method of embodiment 34 is taken to prepare 36, Yellow semi-
solid.1H NMR(400MHz,Chloroform-d)δ8.67-8.69(m,1H),7.78-7.84(m,2H),7.38-7.44
(m, 3H), 7.29-7.35 (m, 3H), 5.73 (s, 2H), 3.67 (d, J=2.6Hz, 2H), 2.13-2.14 (t, J=2.7Hz,
1H).13C NMR(101MHz,CDCl3)δ168.06,163.90,150.80,149.83,148.52,137.37,134.32,
131.80,131.37,128.88,128.60,128.53,124.20,79.25,70.76,50.67,19.84.HR-MS(ESI):
Calcd.C19H14N6S2,[M+Na]+m/z:413.0619,found:413.0619.。
36 compound 37, R of embodiment1=Bn, R2=Bn, R3The preparation of=2-Pyridine-S-
Bromo propane is substituted with benzyl bromide, the same method of embodiment 34 is taken to prepare 37, White solid.1H NMR
(400MHz,Chloroform-d)δ8.62-8.64(m,1H),7.78-7.80(m,1H),7.68-7.73(m,1H),7.36-
7.38(m,2H),7.30-7.33(m,4H),7.25-7.26(m,5H),5.72(s,2H),4.20(s,2H).13C NMR
(101MHz,CDCl3)δ169.66,163.64,150.72,150.04,148.59,137.24,136.99,134.44,
131.75,131.18,128.90,128.78,128.55,128.50,128.34,127.29,124.10,50.53,
35.66.HR-MS(ESI):Calcd.C23H18N6S2,[M+H]+m/z:443.1113,found:443.1115.。
The LSD1 inhibitory activity of 37 above compound of embodiment measures：
1. experimental method：
Sample is above compound synthesized by embodiment, purifies and obtain；Stock sample solution：3-5mg sample is weighed to be placed in
In 1.5mL EP pipe, the solution that concentration is 20mM then is configured to DMSO, and 4 DEG C of preservations are placed, according to required concentration when experiment
It is diluted with DMSO.By sample to be tested and LSD1 albumen after incubation at room temperature, LSD1 reaction substrate H3K4me2 is added and is incubated for anti-
It answers, is eventually adding fluorescent dye Amplex and horseradish peroxidase HRP incubation at room temperature, the exciting light 530nm in microplate reader, transmitting
Light 590nm detects fluorescence values:
Test result calculates IC using SPSS software50Value.
Experimental result is as follows.
Table 1. the compounds of this invention, 8~23 pairs of LSD1 inhibiting rates:Amido replaces
Table 2. the compounds of this invention, 24~30 pairs of LSD1 inhibiting rates:Phenolic group replaces
Table 3. the compounds of this invention, 30~37 pairs of LSD1 inhibiting rates:Sulfhydryl heterocycle replaces
Claims (4)
1. the LSD1 inhibitor of triazole containing pyrimido, it is characterised in that：With structure described in general formula I,
It is selected in general formula I：
R2For C1-5 straight chained alkyl, branched alkyl or naphthenic base, In any one；Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, acetyl group, n=1~2；
R1For any one in following group：
Wherein, n=1-2；
R3For any one of following group：
Wherein, R H ,-OH ,-NO2,-OCH3, CF3, C1-4 alkyl or acetyl group.
2. 1,2,3- triazole derivatives of pyrimido as described in claim 1, it is characterised in that：Select one of following compound：
Work as R3When=2-Pyridine-S-,
31 R1=Propyl,
32 R1=Propyl,
33 R1=Propyl,
34 R1=Propyl,
35 R1=Propyl, R2=Bn
37 R1=Bn, R2=Bn.
3. preparation such as claim 1 requires the preparation method of 1,2, the 3- triazole LSD1 inhibitor Han pyrimido,
It is characterized in that：Include following synthesis step：
(1) preparation method of general formula 2a~c：
In solvent, compound 1 and bromo-hydrocarbons are stirred to react at room temperature under alkaline matter effect, after reaction, filtering,
Washing, it is dry, obtain series compound 2；Solvent for use select acetone, methanol, ethyl alcohol, propyl alcohol, isopropanol, tetrahydrofuran, acetonitrile,
Water, DMF, methylene chloride, chloroform or dioxane；Alkaline matter used selects triethylamine, diisopropylethylamine, pyridine, hydrogen-oxygen
Change one of sodium, potassium hydroxide；The bromo-hydrocarbons corresponds to R1 substituent group in general formula；
(2) preparation method of general formula 3a~c：
In acetic acid, nitrating agent is added, series compound 2 is then added portionwise, is stirred to react, after reaction, pours into water
In, it filters, washs, it is dry, obtain series compound 3；The nitrating agent selects concentrated nitric acid；
(3) preparation method of general formula 4a~c：
In solvent, chlorination reagent is added, series compound 3 is then added portionwise, organic base, back flow reaction is added dropwise, reaction terminates
Afterwards, it is cooled to room temperature, hydrolyzes, extracted with organic solvent, wash, neutralize, dry organic phase is up to series compound 4；The chlorination
Reagent selects phosphorus oxychloride, phosphorus pentachloride；Solvent selects toluene, dioxane, THF, ethyl acetate；The organic base select triethylamine,
N,N-Dimethylaniline, N, N- diethylaniline or pyridine；
(4) preparation method of general formula 5a~c：
Series compound 4 is dissolved in the in the mixed solvent of ethyl alcohol and acetic acid, reduced iron powder is then added portionwise, temperature rising reflux is anti-
It answers, filters, be spin-dried for solvent, then extracted with organic solvent, wash, dry organic phase obtains series compound 5；
(5) preparation method of general formula 6a~l：
Series compound 5 and aminated compounds are dissolved in solvent, organic base is added, back flow reaction is evaporated after reaction
Solvent, is added ethyl acetate, washing, and dry organic phase obtains series compound 6；Solvent for use selects methanol, ethyl alcohol, isopropanol,
DMF, dioxane, THF, acetonitrile；The organic base selects triethylamine, pyridine or diisopropylethylamine；The aminated compounds
R in corresponding general formula2Substituent group；
(6) preparation method of general formula 7a~l：
Series compound 6 is dissolved in the mixed liquor of acetic acid and water, the reactant aqueous solution of sodium nitrite, reaction knot are added dropwise under ice bath
Ethyl acetate and water is added in Shu Hou, is layered, and washes, and neutralizes, and dry organic phase obtains series compound 7；
(7) in general formula compound 8~23 preparation method：
Series compound 7 and aminated compounds are dissolved in solvent, acid binding agent is added, back flow reaction is evaporated molten after reaction
Agent is dissolved in ethyl acetate, is washed with water, dry, crosses column；The solvent is methanol, ethyl alcohol, isopropanol, THF, acetonitrile, DMF, dioxy
Six rings；Acid binding agent is triethylamine, pyridine, wopropyl ethyl amine；
(8) in general formula compound 24~27 preparation method：
Series compound 7 and phenolic compound are dissolved in solvent, potassium carbonate or potassium carbonate, back flow reaction, reaction, which is added, to be terminated
Afterwards, solvent evaporated is dissolved in ethyl acetate, is washed with water, dry, crosses column；The solvent is acetone, acetonitrile, THF, DMF, DMSO；
(9) in general formula compound 28~37 preparation method：
Series compound 7 and sulfhydryl compound are dissolved in solvent, alkali substance reaction is added, after reaction, solvent evaporated,
It is dissolved in ethyl acetate, is washed with water, it is dry, cross column or recrystallization；The reaction dissolvent be acetonitrile, ethyl alcohol, methanol, THF, DMF,
Dioxane；Alkaline matter used is triethylamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate；
Step (7), (8), aminated compounds, phenolic compound or sulfhydryl compound correspond to R in general formula described in (9)3Substituent group.
4. 1,2,3- triazole derivative the answering in medicine preparation containing pyrimido as described in one of claim 1-2
With, it is characterised in that：As preparation based on the targeting antitumor lead compound of LSD1.
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| CN107033148B (en) * | 2017-05-03 | 2018-10-26 | 郑州大学 | Triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor, preparation method and application |
| CN106928235A (en) * | 2017-05-03 | 2017-07-07 | 郑州大学 | The LSD1 of triazole containing pyrimido inhibitor, its preparation method and application |
| WO2019025588A1 (en) | 2017-08-03 | 2019-02-07 | Oryzon Genomics, S.A. | Methods of treating behavior alterations |
| CN109516990B (en) * | 2017-09-19 | 2021-06-01 | 天津药物研究院有限公司 | Pyrimidotriazole compounds, preparation method and application thereof |
| CN107936022A (en) * | 2017-11-30 | 2018-04-20 | 郑州大学 | Xanthine LSD1 inhibitor and its preparation method and application |
| CN108101926B (en) * | 2018-02-07 | 2019-12-13 | 郑州大学 | Pyrimido five-membered heterocyclic compound containing quinolinone, preparation method and application thereof |
| SG11202109159VA (en) | 2019-03-20 | 2021-10-28 | Oryzon Genomics Sa | Methods of treating borderline personality disorder |
| EP3941465A1 (en) | 2019-03-20 | 2022-01-26 | Oryzon Genomics, S.A. | Methods of treating attention deficit hyperactivity disorder using kdm1a inhibitors such as the compound vafidemstat |
| JP2022546908A (en) | 2019-07-05 | 2022-11-10 | オリゾン・ゲノミクス・ソシエダッド・アノニマ | Biomarkers and methods for personalized treatment of small cell lung cancer using KDM1A inhibitors |
| EP4319732A1 (en) | 2021-04-08 | 2024-02-14 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for treating myeloid cancers |
| WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
| WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
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