CN106928235A - The LSD1 of triazole containing pyrimido inhibitor, its preparation method and application - Google Patents
The LSD1 of triazole containing pyrimido inhibitor, its preparation method and application Download PDFInfo
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- CN106928235A CN106928235A CN201710303272.2A CN201710303272A CN106928235A CN 106928235 A CN106928235 A CN 106928235A CN 201710303272 A CN201710303272 A CN 201710303272A CN 106928235 A CN106928235 A CN 106928235A
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- 0 C*1C(C)(CN(C)c2ccc[o]2)*1 Chemical compound C*1C(C)(CN(C)c2ccc[o]2)*1 0.000 description 2
- UTBVIMLZIRIFFR-UHFFFAOYSA-N CSc1nc2ccccc2[s]1 Chemical compound CSc1nc2ccccc2[s]1 UTBVIMLZIRIFFR-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention belongs to medicinal chemistry art, the compound of a class pyrimido triazole, its preparation method are disclosed and and its with lysine specificity demethylase（Hereinafter referred to as LSD1）Application as target in antineoplastic is prepared.The compounds of this invention formula is as shown in I.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to the compound of pyrimido triazole, their preparation method
And its application in being target antineoplastic with istone lysine specificity demethylase (hereinafter referred to as LSD1).
Background technology
Tumour is serious harm human health and is difficult to the disease for overcoming, and the antineoplastic for having listed at present also has
A lot, but in these medicines or there are problems that, such as toxicity is big, targeting is weak and easy produces 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 patterns, including acetylation of histone, methylate, phosphorylation
And ubiquitination etc., wherein acetylation compares many histone modification sides with methylating to be directed 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, so as 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, prostatitis
Gland cancer, breast cancer, lung cancer, carcinoma of urinary bladder etc..And it is demonstrated experimentally that by RNAi technology or micromolecular inhibitor in cellular level reduction
The activity of LSD1 expression quantity or reduction LSD1 can suppress the expression that cell is bred and induces some cell differentiation related genes；Small
Also the growth of kinds of tumor cells and solid tumor can be suppressed in the presence of molecule MAOI PCPA.Therefore, LSD1
Inhibitor not only serves as the research tool of epigenetics for illustrating biological function, and can be used as epigenetics medicine
Thing is used for the prevention and treatment of tumour, has caused the extensive concern of scientific research circle, the focus as current research.
Meanwhile, such as miazines and triazole heterocycle compound antiviral, anti-with bioactivity widely
Bacterium, anti-inflammatory and antitumor etc..But the new compound that pyrimidine is combined with triazole structure and resisting based on LSD1 target spots
The report that function of tumor combines research is less, therefore such research has very important value.
The content of the invention
It is the existing clinical medicine resource of exploitation, is female present invention aim at a class is provided with pyrimido triazole
The derivative of core, so as to open up a new way to find the new antineoplastic based on LSD1 target spots of a class；It is of the invention another
One purpose is to provide its preparation method and its application in antineoplastic and LSD1 inhibitor is prepared.
To realize the object of the invention, the general structure of pyrimido triazole LSD1 inhibitor of the present invention is as follows：
R in formula I2It is C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, In any one,
Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, C1-4 acyl groups, n=1~6；MsO- is pyrovinic acid base, and TsO- is toluenesulfonic acid
Base；
R1It is any one in following group： C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, hydrogen atom, wherein, X is nitrogen, oxygen or
Person's sulphur atom, R is halogen, H ,-OH ,-NO2,-OCH3, C1-4 acyl groups, n=1~6；
R3For following group any one：
Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, CF3, C1-4 alkyl or C1-4 acyl groups.
In formula I preferably：
R2It is C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, In any one；N=1~3；
R1It is any one in following group：C1-5 straight chain alkane
Base, C1-5 branched alkyls or C3-5 cycloalkyl, hydrogen atom, wherein, X is sulphur atom, n=1~3；R3It is appointing for following group
Meaning one：
Wherein, R is C1-4 alkyl, chlorine, bromine, H.
One of more preferably following compound：
8:R1=propyl-S-,
9:R1=propyl-S-,
10:R1=propyl-S-,
11:R1=propyl-S-,
12:R1=propyl-S-,
13:R1=propyl-S-,
14:R1=propyl-S-,
15:R1=propyl-S-,
16:R1=propyl-S-,
17:R1=propyl-S-,
18:R1=propyl-S-,
19:R1=propyl-S-,
20:R1=propyl-S-,
21:R1=propyl-S-,
The preparation method of pyrimido triazole LSD1 inhibitor of the present invention, is mainly obtained by following steps：
1. the preparation method of formula 2：
In solvent, by compound 1 and bromo-hydrocarbons, under alkaline matter effect, stirring reaction, reacts after terminating at room temperature,
Filtering, washing is dried, and obtains series compound 2.In this reaction, solvent for use can be acetone, methyl alcohol, ethanol, propyl alcohol, isopropyl
One of alcohol, tetrahydrofuran, acetonitrile, water, DMF, dichloromethane, chloroform, dioxane or two or more mixtures.It is used
Alkaline matter can be one kind in triethylamine, diisopropylethylamine, pyridine, NaOH, potassium hydroxide.The bromo-hydrocarbons
R1 substitutions base in correspondence formula；
2. the preparation method of formula 3：
In acetic acid, nitrating agent is added, be then dividedly in some parts series compound 2, stirring reaction is reacted after terminating,
Enter in water, suction filtration, washing is dried, and obtains series compound 3.In this reaction, the nitrating agent selects fuming nitric aicd, concentrated nitric acid.It is excellent
Select 15-60 DEG C of temperature.
3. the preparation method of formula 4：
In solvent, chlorination reagent is added, be then dividedly in some parts series compound 3, organic base, back flow reaction, reaction is added dropwise
After end, it is cooled to room temperature, hydrolyzes, extracted with organic solvent, washing is neutralized, and is dried organic phase and is obtained final product the crude product of series compound 4
(can directly carry out next step without further optimization, sterling can be obtained through with column chromatography).In this reaction, the chlorination examination
Agent can be POCl3, phosphorus pentachloride, and solvent can be toluene, dioxane, THF, ethyl acetate etc., and the organic base can
Being triethylamine, DMA, dimethylacetylamide (DMA), N, N- diethylanilines or pyridine etc..Preferable temperature 40
~120 DEG C.
4. the preparation method of formula 5：
Series compound 4 is dissolved in the mixed solvent of ethanol and acetic acid, reduced iron powder, temperature rising reflux is then dividedly in some parts
Reaction, suction filtration is spin-dried for solvent, then is extracted with organic solvent, and washing dries organic phase, obtains the crude product of series compound 5, pure
Product can be obtained through column chromatography.
5. the preparation method of formula 6：
Series compound 5 and aminated compounds are dissolved in solvent, organic base is added, back flow reaction are reacted after terminating,
Solvent evaporated, adds ethyl acetate, and washing dries organic phase, and the crude product for obtaining series compound 6 is (straight without further purification
Connect for next step reaction).In this reaction, reaction solvent for use can be methyl alcohol, ethanol, isopropanol, DMF, dioxane,
THF, acetonitrile etc., the organic base can be triethylamine, pyridine or diisopropylethylamine etc..Preferable reaction temperature is 60~120
℃.R in described aminated compounds correspondence formula2Substitution base；
6. the preparation method of formula 7：
Series compound 6 is dissolved in the mixed liquor of acetic acid and water, the reactant aqueous solution of natrium nitrosum is added dropwise under ice bath, instead
After should terminating, ethyl acetate and water are added, layering, washing is neutralized, and dries organic phase, the crude product of series compound 7 is obtained, without entering
The purifying of one step directly carries out next step reaction.
7. in formula compound 8~21 preparation method：
Series compound 7 and sulfydryl virtue cyclics are dissolved in solvent, acid binding agent, room temperature or back flow reaction is added,
Reaction terminate after, solvent evaporated is dissolved in ethyl acetate, washes with water, dry, cross post, mobile phase for different proportion petroleum ether and
Ethyl acetate.In this reaction, the solvent is methyl alcohol, ethanol, isopropanol, THF, acetonitrile, DMF, dioxane etc., and acid binding agent is
Triethylamine, pyridine, wopropyl ethyl amine etc..Preferable reaction temperature is 20~100 DEG C.
Pyrimido triazole derivative of the present invention, is tested by LSD1 enzymatic activitys and finds have well to LSD1
Inhibitory action.Therefore, the nitrogen analog derivative of pyrimido three that the present invention is provided is the joint use for developing new type antineoplastic medicine, medicine
Medicine and new LSD1 inhibitor medicaments open another effective way, and the compounding design of such compound is reasonable, reaction condition
Gently, simple to operate, reaction yield is high, and total recovery is up to more than 60%, if being developed into new drug will have good market using preceding
Scape.
Specific embodiment
It is as follows especially exemplified by embodiment in order to be better illustrated to the present invention：
The compound 8, R of embodiment 11=propyl-S-,Preparation
(1) (the R of compound 21=propyl-S-) preparation
Barbiturates (3g, 1eq) and triethylamine (2.9ml, 1eq) are added in the methyl alcohol of 30ml, are heated to reflux down, slowly
N-Propyl Bromide (1.8ml, 1eq) is added dropwise, continues to flow back 1 hour after adding, cooling, suction filtration obtains 3.7g pink solid compound 2b,
Yield 97%.
(2) (the R of compound 31=propyl-S-) preparation
Under ice bath, the fuming nitric aicd of 3ml is carefully dissolved in the acetic acid of 6ml, is then dividedly in some parts 2.9g compound 2b, plus
After complete, continue to stir 2 hours, then reaction solution is added in the frozen water of 18ml, suction filtration, wash, obtain the powdered of kermesinus
Compound 3b, yield 77.5%.
(3) (the R of compound 41=propyl-S-) preparation
Compound 3b (12.4g, 1eq) is dissolved in the POCl3 of 50ml, is slowly added dropwise DMA (12ml, 1.8eq), so
After be warming up to backflow, react 5 hours.It is cooled to room temperature, hydrolyzes, is then extracted with EA, washing, then washed with the sodium carbonate liquor of saturation
Wash, after organic phase is dried, obtain final product brown compound 4b crude product 13g, yield 90.2%.
(4) (the R of compound 51=propyl-S-) preparation
Compound 4b (0.5g, 1eq) is dissolved in the acetic acid of the methyl alcohol of 4ml and 2ml, reduced iron powder is then dividedly in some parts
(0.3g, 3eq), flows back 2 hours, is cooled to room temperature, and suction filtration, filtrate is evaporated, and is dissolved in ethyl acetate, is washed with the sodium carbonate liquor of saturation
Wash, wash, dry organic phase, 0.44g compound 5b crude products, yield 95% are obtained after being evaporated.
(5) (the R of compound 61=propyl-S-,) preparation
By compound 5b (3.9g, 1eq), monoethanolamine (1.0g, 1eq) and triethylamine (3ml, 1.3eq) are dissolved in ethanol, are returned
Stream 48 hours, solvent evaporated is dissolved in ethyl acetate, is then neutralized to neutrality with watery hydrochloric acid, washes three times, dries, after being evaporated
Compound 6b crude products, without further purification, directly carry out next step.
(6) (the R of compound 71=propyl-S-,) preparation
The crude product of upper step compound 6 is dissolved in the mixed liquor of acetic acid and water, under 0 DEG C of ice bath, natrium nitrosum is added dropwise
The aqueous solution of (1.13g, 1eq), keeping temperature is not more than 10 DEG C, then proceedes to stirring reaction 1 hour, and reaction solution is dissolved in into acetic acid
In ethyl ester, wash with water three times, be then neutralized to neutrality with the sodium bicarbonate solution of saturation again, wash, organic phase is dried, after being evaporated
Compound 7b crude products are obtained, it is not purified directly to carry out next step.
(7) preparation of compound 8
By midbody compound 7b (100mg, 1eq), mercaptobenzothiazoler (61mg, 1eq) and triethylamine (37mg, 1eq)
It is dissolved in ethanol, is heated to a few hours of flowing back, monitored with TLC (PE/EA) and reacted, terminate rear solvent evaporated, is dissolved in ethyl acetate,
Washing, dries, and crosses post, obtains white solid 89mg, yield 60%.1HNMR(400MHz,DMSO-d6,ppm):δ8.23-8.25(d,
J=7.6Hz, 1H), 8.10-8.12 (d, J=8.0Hz, 1H), 7.55-7.63 (m, 2H), 4.95-4.97 (t, J=5.8Hz,
1H), 4.64-4.67 (t, J=5.4Hz, 2H), 3.92-3.96 (m, 2H), 2.95-2.99 (t, J=7.0Hz, 2H), 1.48-
1.57 (m, 2H), 0.77-0.80 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6,ppm):δ169.45,
159.12,155.22,152.07,149.55,137.35,131.15,127.31,126.72,123.39,122.66,59.26,
50.35,33.09,22.33,13.44.。
The compound 9, R of embodiment 21=propyl-S-,Preparation
The aminoethyle alcohol of mesyl chloride protection replaces monoethanolamine, takes the same method of embodiment 7 to prepare 9.1HNMR
(400MHz,CDCl3,ppm):δ 8.12-8.14 (d, J=8.0Hz, 1H), 7.97-7.99 (d, J=7.6Hz, 1H), 7.55-
7.59 (m, 1H), 7.49-7.53 (m, 1H), 4.95-4.97 (t, J=5.2Hz, 2H), 4.79-4.81 (t, J=5.2Hz, 2H),
3.00 (s, 3H), 1.57-1.62 (m, 2H), 0.85-0.89 (t, J=7.4Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ
171.34,160.36,154.99,152.17,149.24,137.33,131.06,126.62,126.08,123.47,121.31,
65.21,46.06,37.95,33.50,22.17,13.26..Yield 70%.
The compound 10, R of embodiment 31=propyl-S-,'s
Prepare
The aminoethyle alcohol of benzoyl protection replaces monoethanolamine, takes the same method of embodiment 7 to prepare 10.1HNMR
(400MHz,CDCl3,ppm):δ 8.11-8.13 (d, J=8.0Hz, 1H), 7.96-7.98 (d, J=7.6Hz, 1H), 7.91-
7.94 (m, 2H), 7.54-7.58 (m, 2H), 7.48-7.52 (m, 1H), 7.40-7.44 (m, 2H), 5.02-5.05 (t, J=
5.2Hz, 2H), 4.83-4.85 (t, J=5.2Hz, 2H), 2.87-2.90 (t, J=7.2Hz, 2H), 1.50-1.59 (m, 2H),
0.83-0.86 (t, J=7.4Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ171.04,166.04,160.02,
155.33,152.08,149.33,137.23,133.37,131.01,129.75,129.20,128.50,126.57,125.99,
123.40,121.26,62.34,46.12,33.32,22.12,13.27..Yield 63%.
The compound 11, R of embodiment 41=propyl-S-,
Preparation
Replace monoethanolamine with sweet glycol amine, take the same method of embodiment 7 to prepare 11.1HNMR(400MHz,CDCl3,
ppm):δ 8.08-8.10 (d, J=8.0Hz, 1H), 7.94-7.96 (d, J=8.0Hz, 1H), 7.52-7.56 (m, 1H), 7.45-
7.49 (m, 1H), 4.78-4.81 (t, J=5.2Hz, 2H), 4.03-4.06 (t, J=5.2Hz, 2H), 3.65 (m, 2H), 3.58-
3.60 (t, J=4.2Hz, 2H), 2.91-2.95 (t, J=7.4Hz, 2H), 1.52-1.58 (m, 2H), 0.80-0.84 (t, J=
7.4Hz,3H).13CNMR(100MHz,CDCl3,ppm):δ170.83,160.15,155.16,152.20,149.21,137.36,
131.09,126.58,126.04,123.45,121.28,72.57,68.65,61.61,46.90,33.47,22.19,
13.24..Yield 65%.
The compound 12, R of embodiment 51=propyl-S-,System
It is standby
The sweet glycol amine protected with p-toluenesulfonyl replaces monoethanolamine, takes the same method of embodiment 7 to prepare 12.1H
NMR(400MHz,CDCl3,ppm):δ 8.10-8.12 (d, J=8.0Hz, 1H), 7.95-7.97 (d, J=7.6Hz, 1H),
7.73-7.75 (d, J=8.4Hz, 2H), 7.53-7.57 (m, 1H), 7.46-7.50 (m, 1H), 7.32-7.34 (d, J=
8.4Hz, 2H), 4.70-4.73 (t, J=5.6Hz, 2H), 4.05-4.08 (t, J=4.6Hz, 2H), 3.99-4.02 (t, J=
5.6Hz, 2H), 3.64-3.66 (t, J=4.6Hz, 2H), 2.96-3.00 (t, J=7.2Hz, 2H), 2.44 (s, 3H), 1.56-
1.64 (m, 2H), 1.24-1.28 (t, J=7.2Hz, 3H)13C NMR(100MHz,CDCl3,ppm):δ170.72,159.91,
155.39,152.15,149.21,144.94,137.30,131.03,129.88,127.90,126.54,125.97,123.42,
121.26,68.88,68.86,68.55,68.41,46.49,33.47,22.21,13.27..Yield 72%.
The compound 13, R of embodiment 61=propyl-S-,Preparation
Replace monoethanolamine with chaff amine, take the same method of embodiment 7 to prepare 13.1HNMR(400MHz,CDCl3,ppm):δ
8.08-8.10 (d, J=8.0Hz, 1H), 7.94-7.96 (d, J=8.0Hz, 1H), 7.52-7.56 (m, 1H), 7.46-7.49
(m, 1H), 7.36-7.37 (d, J=1.2Hz, 1H), 6.48-6.49 (d, J=3.2Hz, 1H), 6.35-6.36 (m, 1H), 5.76
(s, 2H), 3.00-3.03 (t, J=7.4Hz, 2H), 1.61-1.66 (m, 2H), 0.89-0.93 (t, J=7.4Hz, 3H)
.13CNMR(100MHz,CDCl3,ppm):δ170.86,159.80,155.56,151.99,148.69,147.10,143.40,
137.14,130.94,126.51,125.90,123.33,121.24,110.77,110.26,43.34,33.45,22.24,
13.36..Yield 61%.
The compound 14, R of embodiment 71=propyl-S-,Preparation
Replace monoethanolamine with isopropylamine, take the same method of embodiment 7 to prepare 14.1HNMR(400MHz,CDCl3,
ppm):δ 8.10-8.12 (d, J=8.4Hz, 1H), 7.96-7.98 (d, J=8.0Hz, 1H), 7.53-7.57 (m, 1H), 7.47-
7.50 (m, 1H), 5.17-5.23 (m, 1H), 3.01-3.05 (t, J=7.2Hz, 2H), 1.74-1.76 (d, J=6.8Hz, 6H),
1.61-1.70 (m, 2H), 0.90-0.94 (t, J=7.4Hz, 3H)13CNMR(100MHz,CDCl3,ppm):δ169.85,
159.59,155.77,151.99,148.24,137.14,131.41,126.50,125.87,123.31,121.24,51.52,
33.43,22.28,21.94,13.35..Yield 60%.
The compound 15, R of embodiment 81=propyl-S-,Preparation
Replace mercaptobenzothiazoler with mercaptobenzoxazole, take the same method of embodiment 7 to prepare 15.1HNMR
(400MHz,DMSO-d6,ppm):δ 7.92-7.94 (d, J=8.0Hz, 1H), 7.86-7.88 (d, J=8.0Hz, 1H), 7.56-
7.60 (m, 1H), 7.50-7.54 (m, 1H), 4.95 (br, 1H), 4.61-4.63 (t, J=5.4Hz, 2H), 3.89-3.93 (m,
2H), 2.76-2.79 (t, J=7.2Hz, 2H), 1.33-1.42 (m, 2H), 0.67-0.71 (t, J=7.4Hz, 3H)13CNMR
(100MHz,DMSO-d6,ppm):δ169.51,160.03,153.67,152.79,149.94,141.77,131.46,
127.52,125.78,120.93,111.76,59.23,50.35,33.13,22.10,13.22..Yield 66%.
The compound 16, R of embodiment 91=propyl-S-,Preparation
Replace mercaptobenzothiazoler with mercaptopyrimidine, take the same method of embodiment 7 to prepare 16.1HNMR(400MHz,
DMSO-d6,ppm):δ 8.85-8.86 (d, J=4.8Hz, 2H), 7.58-7.60 (t, J=4.8Hz, 1H), 4.98 (br, 1H),
4.62-4.65 (t, J=5.4Hz, 2H), 3.93-3.94 (m, 2H), 3.02-3.04 (t, J=7.0Hz, 2H), 1.58-1.67
(m, 2H), 0.91-0.95 (t, J=7.2Hz, 3H)13CNMR(100MHz,DMSO-d6,ppm):δ169.52,165.21,
160.78,159.51,149.96,132.73,121.32,59.19,50.28,33.14,22.38,13.63..Yield 71%.
The compound 17, R of embodiment 101=propyl-S-,Preparation
With 2- sulfydryl -1,3,4- thiadiazoles replace mercaptobenzothiazoler, take the same method of embodiment 7 to prepare
17.1HNMR(400MHz,DMSO-d6,ppm):δ 9.96 (s, 1H), 4.94-4.97 (t, J=6.0Hz, 1H), 4.65-4.67 (t,
J=5.4Hz, 2H), 3.92-3.96 (m, 2H), 3.03-3.07 (t, J=7.2Hz, 2H), 1.58-1.67 (m, 2H), 0.93-
0.97 (t, J=7.4Hz, 3H)13CNMR(100MHz,DMSO-d6,ppm):δ169.48,159.38,158.04,155.12,
149.59,131.18,59.25,50.38,33.12,22.36,13.63..Yield 70%.
The compound 18, R of embodiment 111=propyl-S-,Preparation
With 2- amino -5- sulfydryl -1,3,4- thiadiazoles replace mercaptobenzothiazoler, take the same method system of embodiment 7
Standby 18.1H NMR(400MHz,DMSO-d6,ppm):δ 7.79 (s, 1H), 4.90-4.93 (t, J=5.8Hz, 1H), 4.62-4.64
(t, J=5.4Hz, 2H), 3.90-3.94 (m, 2H), 3.03-3.07 (t, J=7.2Hz, 2H), 1.58-1.67 (m, 2H),
0.94-0.97 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6,ppm):δ173.62,168.96,160.34,
149.11,138.42,130.82,58.77,49.78,32.78,22.13,13.09..Yield 65%.
The compound 19, R of embodiment 121=propyl-S-,Preparation
With 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles replace mercaptobenzothiazoler, take the same method system of embodiment 7
Standby 19.1H NMR(400MHz,CDCl3) δ 7.29 (d, J=1.2Hz, 1H), 7.25 (d, J=1.3Hz, 1H), 4.71-4.73 (m,
2H), 4.17 (m, 2H), 3.73 (s, 3H), 2.89-2.93 (m, 2H), 1.62-1.65 (m, 2H), 0.97-1.00 (t, J=
7.4Hz,3H).13C NMR(100MHz,CDCl3)δ174.95,167.39,154.15,136.25,136.12,135.73,
129.97,64.56,54.53,38.84,38.15,27.01,18.12..Yield 69%.
The compound 20, R of embodiment 131=propyl-S-,Preparation
Replace mercaptobenzothiazoler with 2- thyroidans, take the same method of embodiment 7 to prepare 20.1H NMR
(400MHz,CDCl3) δ 8.02 (d, J=3.4Hz, 1H), 7.68 (d, J=3.4Hz, 1H), 4.74-4.77 (m, 2H), 4.17-
4.21 (m, 2H), 2.97-3.00 (t, J=6.7Hz, 2H), 1.64-1.69 (m, 2H), 0.98-1.02 (t, J=7.3Hz, 3H)
.13C NMR(100MHz,CDCl3)δ170.27,160.66,152.04,149.15,143.59,131.03,125.00,59.98,
49.91,33.32,22.23,13.37..Yield 62%.
The compound 21, R of embodiment 141=propyl-S-,Preparation
Replace mercaptobenzothiazoler with methimazole, take the same method of embodiment 7 to prepare 21,1H NMR(400MHz,
CDCl3) δ 7.29 (d, J=1.2Hz, 1H), 7.25 (d, J=1.3Hz, 1H), 4.71-4.73 (m, 2H), 4.17 (m, 2H),
3.73 (s, 3H), 2.89-2.93 (d, J=7.2Hz, 2H), 1.62-1.65 (m, 2H), 0.97-1.00 (t, J=7.4Hz, 3H)
.13C NMR(100MHz,CDCl3)δ174.95,167.39,154.15,136.25,136.12,135.73,129.97,64.56,
54.53,38.84,38.15,27.01,18.12..Yield 68%.
The LSD1 inhibitory activity of the above-claimed cpd of embodiment 15 is determined：
1. experimental technique：
Above-claimed cpd of the sample synthesized by embodiment, purifying and obtain；Stock sample solution：3-5mg samples are weighed to be placed in
In 1.5mL EP pipes, be then configured to the solution that concentration is 20mM with DMSO, 4 DEG C preserve and place, during experiment according to needed for concentration
Diluted with DMSO.By testing sample and LSD1 albumen in after incubation at room temperature, addition LSD1 reaction substrates H3K4me2 is simultaneously incubated anti-
Should, it is eventually adding fluorescent dye Amplex and HRPO HRP incubations at room temperature, the exciting light 530nm on ELIASA, transmitting
Light 590nm detects fluorescence values:
Result of the test calculates IC using SPSS softwares50Value.
Experimental result is as follows.
The inhibitory activity data of 1. above-claimed cpds of Table, 8~21 couples of LSD1:
Claims (5)
1. the LSD1 of triazole containing pyrimido inhibitor, it is characterised in that with structure described in formula I,
In formula I, R2It is C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, In any one,
Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, C1-4 acyl groups, n=1~6；MsO- is pyrovinic acid base, and TsO- is toluenesulfonic acid
Base；
R1It is any one in following group：
C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, hydrogen atom, wherein, X is nitrogen, oxygen or sulphur atom, and R is halogen
Element, H ,-OH ,-NO2,-OCH3, C1-4 acyl groups, n=1~6；
R3For following group any one：
Wherein, R is halogen, H ,-OH ,-NO2,-OCH3, CF3, C1-4 alkyl or
C1-4 acyl groups.
2. the LSD1 inhibitor of triazole containing pyrimido as claimed in claim 1, it is characterised in that
In formula I preferably：
R2It is C1-5 straight chained alkyls, C1-5 branched alkyls or C3-5 cycloalkyl, In any one；N=1~3；
R1It is any one in following group：C1-5 straight chained alkyls,
C1-5 branched alkyls or C3-5 cycloalkyl, hydrogen atom, wherein, X is sulphur atom, n=1~3；R3It is any one for following group
It is individual：
Wherein, R is C1-4 alkyl, chlorine, bromine, H.
3. the LSD1 inhibitor of triazole containing pyrimido as claimed in claim 1, it is characterised in that：It is preferred that following compound it
One：
8:R1=propyl-S-,
9:R1=propyl-S-,
10:R1=propyl-S-,
11:R1=propyl-S-,
12:R1=propyl-S-,
13:R1=propyl-S-,
14:R1=propyl-S-,
15:R1=propyl-S-,
16:R1=propyl-S-,
17:R1=propyl-S-,
18:R1=propyl-S-,
19:R1=propyl-S-,
20:R1=propyl-S-,
21:R1=propyl-S-,
4. the method for preparing the LSD1 inhibitor of triazole containing pyrimido as described in claim 1 is required, it is characterised in that：It is logical
Cross following steps synthesis：
(1) preparation method of formula 2：
In solvent, by compound 1 and bromo-hydrocarbons, under alkaline matter effect, stirring reaction, after reaction terminates, filters at room temperature,
Washing, dries, and obtains series compound 2；Solvent for use select acetone, methyl alcohol, ethanol, propyl alcohol, isopropanol, tetrahydrofuran, acetonitrile,
One of water, DMF, dichloromethane, chloroform, dioxane or two or more mixtures；Alkaline matter used select triethylamine,
One kind in diisopropylethylamine, pyridine, NaOH, potassium hydroxide；R1 substitution bases in the bromo-hydrocarbons correspondence formula；
(2) preparation method of formula 3：
In acetic acid, nitrating agent is added, be then dividedly in some parts series compound 2, stirring reaction after reaction terminates, pours into water
In, suction filtration, washing is dried, and obtains series compound 3；The nitrating agent selects fuming nitric aicd or concentrated nitric acid；
(3) preparation method of formula 4：
In solvent, chlorination reagent is added, be then dividedly in some parts series compound 3, organic base is added dropwise, back flow reaction, reaction terminates
Afterwards, it is cooled to room temperature, hydrolyzes, extracted with organic solvent, washing is neutralized, and is dried organic phase and is obtained final product series compound 4；The chlorination
Reagent selects POCl3, phosphorus pentachloride；Solvent selects toluene, dioxane, THF, ethyl acetate；The organic base select triethylamine,
DMA, N, N- diethylanilines, dimethylacetylamide or pyridine；
(4) preparation method of formula 5：
Series compound 4 is dissolved in the mixed solvent of ethanol and acetic acid, reduced iron powder is then dividedly in some parts, temperature rising reflux is anti-
Should, suction filtration is spin-dried for solvent, then is extracted with organic solvent, and washing dries organic phase, obtains series compound 5；
(5) preparation method of formula 6：
Series compound 5 and aminated compounds are dissolved in solvent, organic base is added, back flow reaction after reaction terminates, is evaporated
Solvent, adds ethyl acetate, and washing dries organic phase, obtains series compound 6；Solvent for use selects methyl alcohol, ethanol, isopropanol,
DMF, dioxane, THF, acetonitrile；The organic base selects triethylamine, pyridine or diisopropylethylamine；Described aminated compounds
R in correspondence formula2Substitution base；
(6) preparation method of formula 7：
Series compound 6 is dissolved in the mixed liquor of acetic acid and water, the reactant aqueous solution of natrium nitrosum, reaction knot are added dropwise under ice bath
Shu Hou, adds ethyl acetate and water, and layering, washing is neutralized, and dries organic phase, obtains series compound 7；
(7) in formula compound 8~21 preparation method：
Series compound 7 and sulfydryl virtue cyclics are dissolved in solvent, acid binding agent, room temperature or back flow reaction is added, instead
After should terminating, solvent evaporated is dissolved in ethyl acetate, washes with water, dries, and crosses post；The solvent be methyl alcohol, ethanol, isopropanol,
THF, acetonitrile, DMF, dioxane；Acid binding agent is triethylamine, pyridine, wopropyl ethyl amine.
5. the LSD1 inhibitor of triazole containing pyrimido as described in one of claim 1-3 in medicine preparation should
With, it is characterised in that：The targeting antitumor lead compounds of LSD1 are based on as preparing.
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| WO2019025588A1 (en) | 2017-08-03 | 2019-02-07 | Oryzon Genomics, S.A. | Methods of treating behavior alterations |
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| WO2020188089A1 (en) | 2019-03-20 | 2020-09-24 | Oryzon Genomics, S.A. | Methods of treating attention deficit hyperactivity disorder using kdm1a inhibitors such as the compound vafidemstat |
| WO2021004610A1 (en) | 2019-07-05 | 2021-01-14 | Oryzon Genomics, S.A. | Biomarkers and methods for personalized treatment of small cell lung cancer using kdm1a inhibitors |
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| WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
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