CN106478639A - The LSD1 inhibitor of pyrimido 1,2,4 triazole, its preparation method and application - Google Patents

The LSD1 inhibitor of pyrimido 1,2,4 triazole, its preparation method and application Download PDF

Info

Publication number
CN106478639A
CN106478639A CN201610801772.4A CN201610801772A CN106478639A CN 106478639 A CN106478639 A CN 106478639A CN 201610801772 A CN201610801772 A CN 201610801772A CN 106478639 A CN106478639 A CN 106478639A
Authority
CN
China
Prior art keywords
compound
reaction
preparation
nmr
dmso
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201610801772.4A
Other languages
Chinese (zh)
Other versions
CN106478639B (en
Inventor
刘宏民
王帅
余斌
赵丽杰
郑甲信
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhengzhou University
Original Assignee
Zhengzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhengzhou University filed Critical Zhengzhou University
Priority to CN201610801772.4A priority Critical patent/CN106478639B/en
Publication of CN106478639A publication Critical patent/CN106478639A/en
Application granted granted Critical
Publication of CN106478639B publication Critical patent/CN106478639B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to medicinal chemistry art, disclose LSD1 inhibitor, its preparation method and the application of pyrimido 1,2,4 triazole.Pyrimido 1,2,4 triazole compound is combined preparation series and has active compound for anti tumor by the present invention with LSD1 compound.Synthetic method is feasible, high income.The general structure of such compound is：R is amino, hydroxyethyl piperazine base, morpholinyl, piperazinyl, para-fluoroaniline base, open-chain crown ether base, anilino- etc..Such compound is applied to istone lysine specificity demethylase（Hereinafter referred to as LSD1）For in the antitumor drug of target, there being preferable activity, it is to open new way for LSD1 for the new type antineoplastic medicine of target spot.

Description

The LSD1 inhibitor of pyrimido 1,2,4 triazole, its preparation method and application
Technical field
The invention belongs to medicinal chemistry art is and in particular to the chemical combination of a class pyrimido 1,2,4 triazole structure unit Thing, preparation method and its swell in anti-with istone lysine specificity demethylase (hereinafter referred to as LSD1) as target of preparation Application in tumor medicine.
Background technology
Tumor is seriously to threaten human diseasess, although the antitumor drug of listing is a lot, in these medicines still Come with some shortcomings, such as produce larger toxic and side effects, targeting weak and easy generation drug resistance etc..Targeted drug is not only imitated Fruit is good and side effect is more much smaller than conventional Therapeutic Method, and therefore, its research and development is increasingly taken seriously.
Covalent modification is extremely important in epigenetic, and covalent histone modifications include histone acetylation, acetylation, general Elementization, methylate, at present the acetylation in histone modification mechanism is compared with the research that methylates many.Histone methylated It is considered within 2004 forever irreversible before, LSD1 is to be found reversible catalytic elimination histone H 3 K4 and H3K9 first Single, double methylate, and then adjust the interaction of histone and other albumen.
LSD1 in tumor cell expression apparently higher than normal cell, including carcinoma of prostate, pulmonary carcinoma, breast carcinoma, bladder Cancer, neuroblastoma, cancer eye etc..It is demonstrated experimentally that on the one hand LSD1 expression can be reduced in cellular level by RNAi technology Amount；On the other hand, reduce the activation energy suppression cell proliferation of LSD1 in cellular level using micromolecular inhibitor；Induce one simultaneously The expression of a little cell differentiation related genes.LSD1 inhibitor is used for illustrating the research work of biological function as epigenetics Tool, therefore, it can cause the research boom of scientific circles as the epigenetics medicine for tumor prevention and treatment.
In addition, having been reported confirmation, pyrimido 1,2,4 triazole compounds have extensive biological activity, for example anti-swollen Tumor, antiinflammatory, antiviral and antibacterial etc..But pyrimido 1,2,4 triazole compound is associated with LSD1, and it is anti-swollen to play The report of tumor effect is little, so the direction has very important researching value.
Content of the invention
Purpose of the present invention one side is to provide the preparation method of such compound, and its in LSD1 inhibitor and resists swollen Application in tumor medicine；On the other hand it is that pyrimido 1,2,4 triazole compound is provided, be target spot for finding for LSD1 New type antineoplastic medicine open up new way.
General structure involved in the present invention is：
R is following groups：
The syntheti c route of such pyrimido 1,2,4 triazole compound is as follows：
(1) preparation method of compound 3：
In acetone, by 2- amino -5- sulfydryl -1,2,4- triazoles (1) in the basic conditions with benzyl chloride (2a) or 2- chloromethane Base benzimidazole (2b) reacts, and thin layer chromatography monitors reaction system, and completely, products therefrom is through sucking filtration, column chromatography (dichloro for question response Methane:Methanol=20:1) obtain compound 3a or 3b.Alkali used is one of triethylamine or potassium carbonate, sodium carbonate, reaction temperature 60-70 DEG C of degree.
(2) preparation method of compound 4：
In glacial acetic acid, compound 3 is added in reaction bulb, be subsequently slowly added dropwise ethyl acetoacetate, reaction temperature 110- 120℃.Thin layer chromatography monitors reaction system, and question response completely, system is poured in frozen water, and cleaning is dried, obtains compound 4a Or 4b.
(3) preparation method of compound 5：
Compound 4 is added to reaction bulb, is slowly added dropwise phosphorus oxychloride, reaction temperature 80-90 DEG C.Thin layer chromatography is monitored Reaction system, question response completely, reaction system is slowly added dropwise in frozen water, cleaned, extraction, is dried, sucking filtration, obtains compound 5a or 5b.
(4) preparation method of compound 6：
In ethanol, compound 5 is added after reaction bulb, add R-H, normal-temperature reaction.Thin layer chromatography monitors reaction system, treats Completely, solid separates out, sucking filtration for reaction, and filter cake obtains compound 6.
R group is ibid.
Advantage of the present invention：Pyrimido 1,2,4 triazole compound is combined with LSD1 compound preparation series have anti- Tumor promotion compound.Synthetic method is feasible, high income, and total recovery reaches more than 69%.By such compound can apply to Istone lysine specificity demethylase (hereinafter referred to as LSD1) is in the antitumor drug of target, is to be target for LSD1 The new type antineoplastic medicine of point opens new way.
Specific embodiment
In order to preferably be explained to the present invention, embodiment is as follows：
Embodiment 1
The preparation of compound 3a
By 2- amino -5- sulfydryl -1,2,4- triazoles (1g, 8.61mmoL) and sodium carbonate (1.37g, 12.92mmoL) add After entering to reaction bulb, add 20mL acetone, be slowly added dropwise benzyl chloride (1.13mL, 9.47mmoL) back flow reaction, TLC at 60 DEG C Monitoring reaction.After reaction terminates, direct sucking filtration, filtrate is through column chromatography (dichloromethane：Methanol=20:1) obtain sterling.Yield 67.57%, white solid.1H NMR(400MHz,DMSO-d6)δ7.41-7.18(m,5H),4.34(s,2H).13C NMR (100MHz,DMSO-d6)δ152.19,147.08,136.55,128.79,128.43,127.48,35.41.HRMS(ESI):m/ z calcd for C9H9N4S(M-H)-,205.0548；found,205.0548.
The preparation of compound 4a
Compound 3a (1g, 4.85mmoL) is added to reaction bulb, after adding glacial acetic acid 20mL, is slowly added dropwise acetoacetic acid Ethyl ester (612.57 μ L, 4.85mmoL) is heated to reflux at 120 DEG C, TLC monitoring reaction.After reaction terminates, by reaction system, put into In frozen water, a large amount of white solids are had to separate out, direct sucking filtration obtains white solid.Solid is placed in and 6h is dried in 60 DEG C of baking ovens and obtains sterling Compound 4a.Yield 84.83%, white solid.240-245 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ13.17(s, 1H), 7.44 (d, J=7.1Hz, 2H), 7.32 (t, J=7.3Hz, 2H), 7.26 (d, J=7.2Hz, 1H), 5.80 (s, 1H), 4.43(s,2H),2.29(s,3H).13C NMR(100MHz,DMSO-d6)δ161.92,154.75,151.09,150.63, 137.35,128.77,128.38,127.22,98.46,34.48,18.43.HRMS(ESI):m/z calcd forC13H11N4OS (M-H)-,271.0654；found,271.0660.
The preparation of compound 5a
Compound 4a (1.12g, 4.11mmoL) is added to reaction bulb, is slowly added dropwise 20mL phosphorus oxychloride, at 90 DEG C It is heated to reflux, TLC monitoring reaction.After reaction terminates, reaction system is carefully slowly added dropwise in frozen water, period can release in a large number Heat, having faint yellow solid precipitation is compounds Ⅳ, with dichloromethane extraction, after anhydrous magnesium sulfate is dried 2h, sucking filtration, concentrate Obtain sterling compound 5a.Yield 91.98%, light green solid.HRMS(ESI):m/z calcd for C13H12ClN4S(M- H)-,291.0471；found,291.0463.
The preparation of compound 6a
By compound 5a (150mg, 515.87 μm of oL) and 3,4,5- trimethoxy-anilines (94.51mg, 515.87 μm of oL) Add in reaction bulb, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out. Directly sucking filtration, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6a.White solid.Fusing point：196-207 ℃.Yield 79.12%.1H NMR(400MHz,DMSO-d6) δ 9.95 (s, 1H), 7.48 (d, J=7.2Hz, 2H), 7.32 (t, J =7.4Hz, 2H), 7.26 (d, J=7.2Hz, 1H), 6.76 (s, 2H), 6.40 (s, 1H), 4.54 (s, 2H), 3.78 (s, 6H), 3.69(s,3H),2.40(s,3H).13C NMR(100MHz,DMSO-d6)δ164.46,164.00,155.76,153.24, 145.14,138.02,135.67,132.32,128.90,128.43,127.21,102.55,89.64,60.08,56.02, 34.49,24.66.HRMS(ESI):m/z calcd for C22H22N5O3S(M-H)-,436.1443；found,436.1451.
The preparation of embodiment 2 compound 6b
Compound 5a (150mg, 515.87 μm of oL) is added in reaction bulb, addition 2mL ethanol, Deca excessive ammonia, often Temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains filter cake.Filter cake is placed in 60 After DEG C oven drying 6h pure compound 6b.Yellow solid.Fusing point：196-201℃.Yield 89%.
1H NMR(400MHz,DMSO-d6)δ7.93(s,2H),7.55-7.43(m,2H),7.37-7.28(m,2H),7.24 (dd, J=8.4,6.1Hz, 1H), 6.12 (s, 1H), 4.49 (s, 2H), 2.37 (s, 3H).13C NMR(100MHz,DMSO-d6)δ 164.29,162.84,155.87,147.50,138.07,128.92,128.38,127.16,90.25,34.36, 24.37.HRMS(ESI):m/z calcd for C13H12N5S(M-H)-,270.0813；found,270.0821.
The preparation of embodiment 3 compound 6c
By compound 5a (150mg, 515.87 μm of oL) add reaction bulb, add 2mL ethanol, Deca aniline (70.65 μ L, 773.81 μm of oL), normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains filter Cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6c.White solid.Fusing point：189-192℃.Yield 89%.1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.51-7.44(m,4H),7.36-7.27(m,5H),7.26-7.20(m,1H), 6.30(s,1H),4.54(s,2H),2.51(s,3H).13C NMR(100MHz,CDCl3)δ166.54,164.77,155.92, 144.35,137.57,135.76,130.02,129.11,128.53,127.36,126.92,123.82,89.01,35.80, 25.41.HRMS(ESI):m/z calcd for C19H16N5S(M-H)-,346.1126；found,346.1135.
The preparation of embodiment 4 compound 6d
Compound 5a (150mg, 515.87 μm of oL) and open-chain crown ether (55.28mg, 515.87 μm of oL) are added reaction In bottle, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, Obtain filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6d.White solid.Fusing point：240-247℃.Yield 89%.1H NMR(400MHz,DMSO-d6) δ 11.03 (s, 1H), 7.51 (d, J=6.1Hz, 2H), 7.30 (s, 7H), 6.36 (s, 1H),4.57(s,2H),2.45(s,3H),2.36(s,3H).13C NMR(100MHz,DMSO-d6)δ165.10,159.74, 152.19,146.52,137.51,136.70,132.89,130.08,128.88,128.41,127.29,124.97,90.27, 34.51,21.74,20.54.HRMS(ESI):m/z calcd for C20H18N5S(M-H)-,360.1283；found, 360.1292.
The preparation of embodiment 5 compound 6e
Compound 5a (150mg, 515.87 μm of oL) and para-fluoroaniline (57.32mg, 515.87 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6e.Yellow solid.Fusing point：227-231℃.Yield 92% .1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.49(m,4H),7.41-7.22(m,5H),6.37(s,1H),4.57 (s,2H),2.45(s,3H).13C NMR(100MHz,DMSO-d6)δ165.20,161.90,160.23,159.47,152.44, (J=8Hz), 146.64,137.60,132.00,128.95,128.48,127.50 127.36,116.54 (J=23Hz), 90.38,34.58,22.00.HRMS(ESI):m/z calcd for C19H15FN5S(M-H)-,364.1032；found, 364.1041.
The preparation of embodiment 6 compound 6f
Compound 5a (150mg, 515.87 μm of oL) and para-amino benzoic acid (70.75mg, 515.87 μm of oL) are added anti- Answer in bottle, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly take out Filter, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6f.Yellow solid.Fusing point：186-190℃.Produce Rate：93%.1H NMR(400MHz,DMSO-d6) δ 12.89 (s, 1H), 10.32 (s, 1H), 8.02 (d, J=8.6Hz, 2H), 7.57 (d, J=8.5Hz, 2H), 7.49 (d, J=7.2Hz, 2H), 7.32 (t, J=7.4Hz, 2H), 7.25 (t, J=7.2Hz, 1H),6.62(s,1H),4.56(s,2H),2.44(s,3H).13C NMR(100MHz,DMSO-d6)δ166.69,164.70, 164.32,155.79,143.96,141.24,137.94,130.68,128.89,128.43,127.30,127.23,122.76, 90.48,34.57,24.71.HRMS(ESI):m/z calcd for C20H16N5O2S(M-H)-,390.1025；found, 390.1036.
The preparation of embodiment 7 compound 6g
Compound 5a (150mg, 515.87 μm of oL) and piperazine (88.87mg, 1.03 μm of oL) are added in reaction bulb, adds 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains filter cake.Will Filter cake obtains pure compound 6g after being placed in 60 DEG C of oven drying 6h.Yellow solid.Fusing point：173-176℃.Yield 76%.1H NMR (400MHz,DMSO-d6) δ 7.46 (d, J=7.2Hz, 2H), 7.31 (t, J=7.4Hz, 2H), 7.24 (t, J=7.3Hz, 1H), 6.46 (s, 1H), 4.45 (s, 2H), 3.67 (t, J=4Hz, 4H), 2.86 (m, J=4Hz, 4H), 2.43 (s, 3H).13C NMR (100MHz,DMSO-d6)δ169.05,168.97,162.35,154.11,143.21,134.00,133.57,132.37, 99.52,54.04,50.30,39.61,29.71.HRMS(ESI):m/z calcd for C17H21N6S(M+H)+,341.1548； found,341.1542.
The preparation of embodiment 8 compound 6h
By compound 5a (150mg, 515.87 μm of oL) add reaction bulb, add 2mL ethanol, Deca morpholine (89.89 μ L, 1.03 μm of oL), normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains filter cake. Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6h.White solid.Fusing point：204-207℃.Yield 89%.1H NMR(400MHz,DMSO-d6) δ 7.45 (d, J=7.2Hz, 2H), 7.32 (t, J=7.4Hz, 2H), 7.24 (t, J=7.3Hz, 1H),6.50(s,1H),4.45(s,2H),3.77(s,4H),3.75(s,4H),2.45(s,3H).13C NMR(100MHz, DMSO-d6)δ164.01,163.91,157.00,148.66,137.90,128.73,128.34,127.13,94.33,65.49, s 47.76,34.39,24.48.HRMS(ESI):m/z calcd for C17H20N5OS(M+H)+,342.1389；found, 342.1381.
The preparation of embodiment 8 compound 6i
Compound 5a (150mg, 515.87 μm of oL) is added in reaction bulb, adds 2mL ethanol, Deca hydroxyethyl piperazine (130.79 μ L, 1.03 μm of oL), normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly take out Filter, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6i.Yellow solid.Fusing point：136-142℃.Yield 77%.1H NMR(400MHz,DMSO-d6) δ 7.46 (d, J=7.2Hz, 2H), 7.32 (t, J=7.4Hz, 2H), 7.24 (t, J= 7.3Hz, 1H), 6.48 (s, 1H), 4.48 (s, 1H), 4.45 (s, 2H), 3.75 (d, J=4.5Hz, 4H), 3.55 (d, J= 3.0Hz, 2H), 2.62 (d, J=4.5Hz, 4H), 2.47 (t, J=6.1Hz, 2H), 2.44 (s, 3H).13C NMR(100MHz, DMSO-d6)δ163.89,163.77,157.06,148.64,137.93,128.77,128.33,127.13,94.40,59.98, 58.47,52.44,47.46,34.37,24.46.HRMS(ESI):m/z calcd for C19H25N6OS(M+H)+, 385.1811；found,385.1802.
The preparation of embodiment 9 compound 6j
Compound 5a (150mg, 515.87 μm of oL) and pyrazine hydrazides (75.06mg, 515.87 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6j.Yellow solid.Fusing point：196-200℃.Yield 90% .1H NMR(400MHz,DMSO-d6) δ 11.38 (s, 1H), 10.45 (s, 1H), 9.25 (d, J=1.2Hz, 1H), 8.96 (s, 1H), 8.83 (s, 1H), 7.51 (d, J=7.1Hz, 3H), 7.32 (t, J=7.3Hz, 2H), 7.26 (t, J=7.3Hz, 1H), 6.36(s,1H),4.55(s,2H),2.40(s,3H).13C NMR(100MHz,DMSO-d6)δ148.19,143.96,143.58, 137.91,128.93,128.44,127.25,34.41.HRMS(ESI):m/z calcd for C18H17N8OS(M+H)+, 393.1246；found,393.1235.
The preparation of embodiment 10 compound 6k
Compound 5a (150mg, 515.87 μm of oL) is added in reaction bulb, adds 2mL ethanol, Deca N- (3- aminopropyl) Morpholine (151.83 μ L, 1.03 μm of oL), normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly Connect sucking filtration, obtain filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6k.White solid.Fusing point：193-196℃. Yield 85%.1H NMR(400MHz,DMSO-d6) δ 8.36 (t, J=5.7Hz, 1H), 7.51-7.42 (m, 2H), 7.35-7.28 (m, 2H), 7.27-7.20 (m, 1H), 6.30 (s, 1H), 4.50 (s, 2H), 3.61 (t, J=4.5Hz, 4H), 3.42 (q, J= 6.3Hz,2H),2.45-2.29(m,9H),1.78(m,2H).13C NMR(100MHz,DMSO-d6)δ163.98,163.29, 155.48,146.31,137.87,128.79,128.34,127.12,87.75,65.96,55.93,53.21,40.56, 34.38,24.62,24.38.HRMS(ESI):m/z calcd for C20H27N6OS(M+H)+,399.1967；found, 399.1960.
The preparation of embodiment 11 compound 6L
Compound 5a (150mg, 515.87 μm of oL) is added in reaction bulb, adds 2mL ethanol, Deca 1- (3- aminopropan Base) imidazoles (77.97 μ L, 619.05 μm of oL), normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, there are a large amount of solid analysis Go out.Directly sucking filtration, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6L.White solid.Fusing point：209- 213℃.Yield 91%.1H NMR(400MHz,DMSO-d6) δ 8.23 (t, J=6.0Hz, 1H), 7.67 (s, 1H), 7.52-7.42 (m,2H),7.31(m,2H),7.25(m,1H),7.22(s,1H),6.91(s,1H),6.20(s,1H),4.50(s,2H),4.06 (t, J=7.0Hz, 2H), 3.33 (m, 2H), 2.41 (s, 3H), 2.06 (p, J=6.9Hz, 2H).13C NMR(100MHz,DMSO- d6)δ163.96,163.39,155.52,146.23,137.96,137.25,128.83,128.32,127.11,119.25, 87.79,43.48,34.39,29.69,24.61.HRMS(ESI):m/z calcd for C19H22N7S(M+H)+,380.1657； found,380.1649.
The preparation of embodiment 12 compound 6m
Compound 5a (150mg, 515.87 μm of oL) and potassium tert-butoxide (86.83mg, 773.81 μm of oL) are added reaction bulb In, add 2mL ethanol, Deca 1- (2- ethoxy) pyrrolidine (90.48 μ L, 773.81 μm of oL), normal-temperature reaction, TLC monitoring is anti- Should carry out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains Pure compound 6m.Yellow solid.Fusing point：197-200.Yield 69%.1H NMR(400MHz,CDCl3)δ7.51-7.42(m, 2H), 7.32-7.25 (m, 2H), 7.25-7.19 (m, 1H), 6.25 (s, 1H), 4.53 (s, 2H), 4.49 (t, J=6.1Hz, 2H), 3.09 (t, J=6.1Hz, 2H), 2.75-2.63 (m, 4H), 2.62 (s, 3H), 1.90-1.76 (m, 4H).13C NMR (100MHz,CDCl3)δ167.76,166.15,157.16,154.17,137.49,129.17,128.48,127.32,90.14, 70.10,54.76,53.78,35.69,29.70,25.49,23.61.HRMS(ESI):m/z calcd for C19H24N5OS(M+ H)+,370.1702；found,370.1695.
The preparation of embodiment 13 compound 6n
Compound 5a (150mg, 515.87 μm of oL) is added in reaction bulb, adds 2mL ethanol, Deca 3- aminopropanol (47.33 μ L, 619.05 μm of oL), normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly Sucking filtration, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6n.White solid.Fusing point：199-203℃.Produce Rate 74%.1H NMR(400MHz,DMSO-d6) δ 8.07 (t, J=6.0Hz, 1H), 7.47 (d, J=7.2Hz, 2H), 7.31 (t, J =7.3Hz, 2H), 7.25 (d, J=7.2Hz, 1H), 6.29 (s, 1H), 4.62 (t, J=4.9Hz, 1H), 4.49 (s, 2H), 3.51(m,2H),3.42(m,2H),2.41(s,3H),1.84–1.69(m,2H).13C NMR(100MHz,DMSO-d6)δ 163.94,163.35,155.52,146.28,137.96,128.85,128.32,127.10,87.71,58.25,34.38, 31.22,24.62.HRMS(ESI):m/z calcd for C16H20N5OS(M+H)+,330.1389；found,330.1379.
The preparation of embodiment 14 compound 6o
Compound 5a (150mg, 515.87 μm of oL) and 4- piperidinyl piperidine (104.18mg, 619.05 μm of oL) are added anti- Answer in bottle, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly take out Filter, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6o.Yellow solid.Fusing point：186-189℃.Yield 71%.1H NMR(400MHz,CDCl3) δ 7.44 (d, J=7.2Hz, 2H), 7.28 (d, J=7.0Hz, 2H), 7.21 (t, J= 7.3Hz, 1H), 6.03 (s, 1H), 4.47 (s, 2H), 3.14 (s, 1H), 2.97 (m, 6H), 2.50 (s, 3H), 2.29 (d, J= 12.0Hz,2H),2.00-1.83(m,6H),1.58(s,2H).13C NMR(100MHz,CDCl3)δ165.89,164.46, 157.48,148.64,137.57,128.99,128.52,127.34,94.52,62.96,50.00,47.14,35.57, 26.18,25.11,23.89,23.17.HRMS(ESI):m/z calcd for C23H31N6S(M+H)+,423.2331；found, 423.2323.
The preparation of embodiment 15 compound 6p
Compound 5a (150mg, 515.87 μm of oL) and tryptamines (101.17mg, 631.43 μm of oL) are added in reaction bulb, Add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains filter Cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6p.White solid.Fusing point：203-207℃.Yield 90%.1H NMR(400MHz,DMSO-d6) δ 10.83 (s, 1H), 8.13 (t, J=6.1Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 7.46 (d, J=7.1Hz, 2H), 7.38-7.28 (m, 3H), 7.23 (m, 2H), 7.07 (t, J=8,4.0Hz, 1H), 6.98 (t, J= 7.4Hz, 1H), 6.18 (s, 1H), 4.49 (s, 2H), 3.65 (m, 2H), 3.06 (t, J=7.2Hz, 2H), 2.32 (s, 3H) .13CNMR(100MHz,DMSO-d6)δ163.91,163.17,146.23,137.95,136.15,128.83,128.33, 127.11,123.03,120.90,118.21,118.10,111.28,110.90,87.84,42.18,34.37,24.49, 24.43,13.99.HRMS(ESI):m/z calcd for C23H23N6S(M+H)+,415.1705；found,415.1696.
The preparation of embodiment 16 compound 6q
Compound 5a (150mg, 515.87 μm of oL) and thiosemicarbazides (47.01mg, 515.87 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6q.Yellow solid.Fusing point：227-231℃.Yield 92% .1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.78(s,1H),8.15(s,1H),7.91(s,1H),7.49(d,J =7.3Hz, 2H), 7.31 (t, J=7.3Hz, 2H), 7.25 (t, J=7.3Hz, 1H), 6.09 (s, 1H), 4.51 (s, 2H), 2.45(s,3H).13C NMR(100MHz,DMSO-d6)δ182.14,164.60,163.82,155.69,147.09,138.02, 128.84,128.31,127.10,88.32,34.25,24.64.HRMS(ESI):m/z calcd for C14H14N7S2(M- H)-,344.0752；found,344.0760.
The preparation of embodiment 17 compound 6r
Using embodiment 1 methods described prepare compound 5b.
Compound 4b (1.12g, 4.11mmoL) is added to reaction bulb, is slowly added dropwise 20mL phosphorus oxychloride, at 90 DEG C It is heated to reflux, TLC monitoring reaction.After reaction terminates, reaction system is carefully slowly added dropwise in frozen water, period can release in a large number Heat, having faint yellow solid precipitation is compounds Ⅳ, with dichloromethane extraction, after anhydrous magnesium sulfate is dried 2h, sucking filtration, concentrate Obtain sterling compound 5b.Yield 91.98%, yellow solid.HRMS(ESI):m/z calcd for C14H12ClN6S(M-H)-, 331.0533；found,331.0524.
Compound 5b (150mg, 453.45 μm of oL) and aniline (42.23mg, 453.45 μm of oL) are added in reaction bulb, plus Enter 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains filter cake. Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6r.White solid.Fusing point：180-191℃.Yield 79%.1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H), 7.50 (m, 6H), 7.33 (d, J=7.0Hz, 1H), 7.18 (dd, J= 6.0,3.1Hz,2H),6.34(s,1H),4.79(s,2H),2.38(s,3H).13C NMR(100MHz,DMSO-d6)δ164.03, 163.80,155.80,150.66,144.94,136.53,129.48,126.12,124.44,122.01,114.75,89.29, 28.00,24.60.HRMS(ESI):m/z calcd for C20H16N7S(M-H)-,386.1188；found,386.1196.
The preparation of embodiment 18 compound 6s
Compound 5b (150mg, 453.45 μm of oL) and para-totuidine (48.59mg, 453.45 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6s.White solid.Fusing point：240-247℃.Yield 86% .1H NMR(400MHz,DMSO-d6) δ 11.41 (s, 1H), 7.79 (s, 2H), 7.53 (s, 2H), 7.37 (t, J=6.7Hz, 4H), 6.37(s,1H),5.09(s,2H),2.41(s,3H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ163.37, 152.43,150.23,146.66,136.98,132.59,130.62,130.10,125.96,125.35,125.17,113.96, 90.51,25.10,21.51,20.64.HRMS(ESI):m/z calcd for C21H18N7S(M-H)-,400.1344；found, 400.1352.
The preparation of embodiment 19 compound 6t
Compound 5b (150mg, 453.45 μm of oL) and para-fluoroaniline (50.39mg, 453.45 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6t.White solid.Fusing point：207-215℃.Yield 91% .1H NMR(400MHz,DMSO-d6) δ 7.63 (dd, J=6.0,3.1Hz, 2H), 7.49 (dd, J=8.8,4.9Hz, 2H), 7.40-7.25(m,4H),6.27(s,1H),4.88(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ 164.13,163.35,161.32,158.90,155.72,150.82,145.29,134.10 (J=248Hz), 127.05 (J= 9Hz), 123.35,116.30 (J=22Hz), 114.48,89.29,27.21,24.54.HRMS (ESI):m/z calcd for C20H15FN7S(M-H)-,404.1094；found,404.1102.
The preparation of embodiment 20 compound 6u
Compound 5b (150mg, 453.45 μm of oL) and parachloroanilinum (57.85mg, 453.45 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6u.White solid.Fusing point：213-217℃.Yield 81% .1H NMR(400MHz,DMSO-d6) δ 7.79 (dd, J=6.1,3.1Hz, 2H), 7.54 (m, 6H), 6.45 (s, 1H), 5.07 (s, 2H),2.39(s,3H).13C NMR(100MHz,DMSO-d6)δ163.11,161.84,153.87,150.47,145.79, 134.79,131.02,130.63,129.53,126.89,125.94,113.95,90.39,25.12,22.77.HRMS(ESI): m/z calcd for C20H15ClN7S(M-H)-,420.0798；found,420.0808.
The preparation of embodiment 21 compound 6v
Compound 5b (150mg, 453.45 μm of oL) and para-bromoaniline (131.05mg, 453.45 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6v.White solid.Fusing point：289-292℃.Yield 78% .1H NMR(400MHz,DMSO-d6) δ 12.43 (s, 1H), 10.18 (s, 1H), 7.66 (d, J=8.7Hz, 2H), 7.55-7.46 (m, 2H), 7.42 (d, J=8.7Hz, 2H), 7.15 (dd, J=6.0,3.2Hz, 2H), 6.42 (s, 1H), 4.77 (s, 2H), 2.40(s,3H).13C NMR(100MHz,DMSO-d6)δ164.24,164.06,155.84,150.61,144.67,136.19, 132.38,126.38,121.74,118.26,89.70,28.34,24.66.HRMS(ESI):m/z calcd for C20H16BrN7S(M-H)-,400.1344；found,400.1352.
The preparation of embodiment 22 compound 6w
By compound 5b (150mg, 453.45 μm of oL) with to 3,4,5- trimethoxy-anilines (83.08mg, 453.45 μ MoL) add in reaction bulb, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, there are a large amount of solid analysis Go out.Directly sucking filtration, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6w.White solid.Fusing point：228- 235℃.Yield 88%.1H NMR(400MHz,DMSO-d6) δ 7.80 (dd, J=6.2,3.1Hz, 2H), 7.53 (dd, J=6.2, 3.1Hz,2H),6.84(s,2H),6.52(s,1H),5.08(s,2H),3.81(s,6H),3.72(s,3H),2.41(s,3H) .13C NMR(100MHz,DMSO-d6)δ163.05,153.24,150.54,145.99,136.19,131.32,130.66, 125.93,113.97,103.01,90.51,60.09,56.07,25.16,22.84.HRMS(ESI):m/z calcd forC23H22N7O3S(M-H)-,476.1505；found,476.1513.
The preparation of embodiment 23 compound 6x
Add reaction by compound 5b (150mg, 453.45 μm of oL) with to cyano-aniline (53.57mg, 453.45 μm of oL) In bottle, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, Obtain filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6x.White solid.Fusing point：236-239℃.Yield 89%.1H NMR(400MHz,DMSO-d6) δ 7.96 (d, J=8.6Hz, 2H), 7.83-7.70 (m, 4H), 7.51 (dd, J= 6.1,3.1Hz,2H),6.68(s,1H),5.08(s,2H),2.42(s,3H).13C NMR(100MHz,DMSO-d6)δ163.02, 154.48,150.51,144.49,140.88,133.59,130.55,125.86,124.23,118.54,113.88,107.87, 91.25,25.04,23.34.HRMS(ESI):m/z calcd for C21H15N8S(M-H)-,411.1140；found, 411.1149.
The preparation of embodiment 24 compound 6y
Compound 5b (150mg, 453.45 μm of oL) and para-amino benzoic acid (62.19mg, 453.45 μm of oL) are added anti- Answer in bottle, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly take out Filter, obtains filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6y.White solid.Fusing point：230-235℃.Yield 85%.1H NMR(400MHz,DMSO-d6) δ 8.05 (d, J=8.5Hz, 2H), 7.80 (dd, J=6.1,3.1Hz, 2H), 7.66 (d, J=8.5Hz, 2H), 7.52 (dd, J=6.1,3.1Hz, 2H), 6.63 (s, 1H), 5.09 (s, 2H), 2.42 (s, 3H).13C NMR(100MHz,DMSO-d6)δ166.64,163.04,162.70,154.38,150.60,145.01,140.26,130.67, 130.64,128.25,125.94,123.94,113.96,90.88,25.15,23.25.HRMS(ESI):m/z calcd for C21H16N7O2S(M-H)-,430.1086；found,430.1094.
The preparation of embodiment 25 compound 6z
Compound 5b (150mg, 453.45 μm of oL) and pyrazine hydrazides (62.64mg, 453.45 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6z.Green solid.Fusing point：187-191℃.Yield 94% .1H NMR(400MHz,DMSO-d6) δ 11.47 (s, 1H), 9.26 (d, J=1.2Hz, 1H), 8.98 (d, J=2.4Hz, 1H), 8.85(s,1H),7.78(m,2H),7.60-7.40(m,2H),6.38(s,1H),5.04(s,2H),2.38(s,3H).13C NMR (100MHz,DMSO-d6)δ164.27,163.20,162.69,155.63,150.72,148.17,147.17,143.93, 143.80,143.56,131.14,125.60,113.98,89.05,25.54,24.33.HRMS(ESI):m/z calcd for C19H15N10OS(M-H)-,431.1151；found,431.1161.
The preparation of embodiment 26 compound 6aa
Compound 5b (150mg, 453.45 μm of oL) and lenalidomide (136.30mg, 453.45 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6aa.Pink solid.Fusing point：270-276℃.Yield 94%.1H NMR(400MHz,DMSO-d6) δ 11.07 (s, 1H), 7.91-7.67 (m, 5H), 7.54 (dd, J=5.8,2.9Hz, 2H), 6.26-6.02 (m, 1H), 5.20 (dd, J=13.1,4.8Hz, 1H), 5.07 (s, 2H), 4.58 (d, J=17.6Hz, 1H),4.51((m,2H),3.03-2.83(m,1H),2.60(m,1H),2.35(s,3H),2.31-2.16(m,1H),2.03(s, 1H).13C NMR(100MHz,DMSO-d6)δ172.84,170.90,167.41,163.11,162.10,154.05,150.46, 146.06,138.88,133.73,131.08,130.67,130.26,129.86,125.95,122.69,113.91,90.26, 51.49,45.78,31.09,25.17,22.88,22.63.HRMS(ESI):m/z calcd for C27H22N9O3S(M-H)-, 552.1566；found,552.1578.
The preparation of embodiment 27 compound 6ab
Compound 5b (150mg, 453.45 μm of oL) and aminoglutethimide (62.19mg, 453.45 μm of oL) are added reaction bulb In, add 2mL ethanol, normal-temperature reaction, TLC monitoring reaction is carried out.After reaction terminates, a large amount of solids are had to separate out.Directly sucking filtration, obtains Filter cake.Filter cake is placed in after 60 DEG C of oven drying 6h and obtains pure compound 6ab.White solid.Fusing point：212-218℃.Yield 82%.1H NMR(400MHz,DMSO-d6) δ 10.96 (s, 1H), 7.81 (dd, J=6.2,3.2Hz, 2H), 7.54 (m, 4H), 7.45 (d, J=8.6Hz, 2H), 6.49 (s, 1H), 5.09 (s, 2H), 2.54 (s, 1H), 2.41 (s, 4H), 2.26 (m, 2H), 2.02-1.82 (m, 2H), 0.82 (t, J=7.3Hz, 3H).13C NMR(100MHz,DMSO-d6)δ175.49,172.69, 162.87,162.30,154.25,150.59,138.21,134.75,130.62,127.40,125.86,124.84,113.91, 90.06,50.03,32.00,29.07,26.01,25.11,23.14,8.92.HRMS(ESI):m/z calcd for C27H25N8O2S(M-H)-,525.1821；found,525.1831.
Application examples 1LSD1 inhibitory activity measures
1. experimental technique：
Sample is synthesized above compound, purification obtains；Stock sample solution：Weigh 1-2mg sample in 1.5mL EP Guan Zhong, is configured to the solution that concentration is 20mM, 4 DEG C of preservations with DMSO, in experimentation, desired concn is diluted with DMSO.To treat Test sample product and LSD1 albumen, after incubated at room, add LSD1 substrate H3K4me2 incubation reaction, add fluorescent dye afterwards Amplex and horseradish peroxidase HRP incubated at room, set exciting light 530nm in microplate reader, and launching light 590nm is glimmering to detect Light numerical value:
Result of the test SPSS computed in software IC50Value is as follows：
The mensure of application examples 2 tumor cytotoxicity
1. experimental technique：
Sample is the above-claimed cpd of synthesis, purification obtains；Stock sample solution：Weigh 1-2mg sample and be placed in 1.5mL EP Guan Zhong, is then configured to, with DMSO, the solution that concentration is 10mM, 4 DEG C preserve placement, and experiment desired concn utilizes culture medium to dilute.
2. screen：
Take the logarithm the cell of trophophase, after digestion counts, adjust cell density with culture medium, with 4000-8000 cell/ Hole is seeded in 96 orifice plates, every hole 100 μ L, after culture 24h, discards culture medium, the medicine that addition culture medium has diluted, each Concentration sets 3 multiple holes, separately sets blank control group and positive controls.After medicine effect 72h, every hole adds 20 μ L MTT solution, After continuing culture 4h, suck liquid, add the DMSO of 150 μ L, shaken well, at microplate reader 490nm, detect absorbance, calculate Suppression ratio, computing formula is as follows：Suppression ratio (%)=(blank group absorbance-administration group absorbance/blank group absorbance Value) × 100%
3. experimental result
Suppression ratio under the conditions of being 10 μM in table, is IC in bracket50Unit is (μM).
MGC-803 is gastric carcinoma cells
EC-109 is human esophagus cancer cell
A549 is human lung carcinoma cell
PC-9 is human lung carcinoma cell.

Claims (4)

1. pyrimido 1, the LSD1 inhibitor of 2,4 triazoles is it is characterised in that its general structure such as formula I or formula II：
R is one of following groups：
2. prepare the method for the LSD1 inhibitor of pyrimido 1,2,4 triazole as claimed in claim 1 it is characterised in that It is achieved by the steps of：
(1) preparation method of compound 3：
In acetone, by 2- amino -5- sulfydryl -1,2,4- triazoles (1) in the basic conditions with benzyl chloride (2a) or 2- chloromethylbenzene And imidazoles (2b) reacts at 60-70 DEG C, thin layer chromatography monitors reaction system, and completely, products therefrom is through sucking filtration, post layer for question response Analyse to obtain compound 3a or 3b；Alkali used is one of triethylamine or potassium carbonate, sodium carbonate；
(2) preparation method of compound 4：
In glacial acetic acid, compound 3a or 3b is added in reaction bulb, is subsequently slowly added dropwise ethyl acetoacetate, reaction temperature 110- 120 DEG C, thin layer chromatography monitors reaction system, and question response completely, system is poured in frozen water, through sucking filtration, cleans, is dried, obtains Compound 4a or 4b；
(3) preparation method of compound 5：
Compound 4a or 4b is added to reaction bulb, is slowly added dropwise phosphorus oxychloride, reaction temperature 80-90 DEG C, thin layer chromatography is supervised Measured reaction system, question response completely, reaction system is slowly added dropwise in frozen water, cleaned, extraction, is dried, sucking filtration, obtains chemical combination Thing 5a or 5b；
(4) preparation method of compound 6：
In ethanol, compound 5a or 5b is added after reaction bulb, adds R-H, normal-temperature reaction, thin layer chromatography monitors reaction system, Completely, solid separates out question response, sucking filtration, and filter cake obtains compound 6,
R group is with claim 1.
3. application in preparing medicine for the LSD1 inhibitor of pyrimido 1,2,4 triazole as claimed in claim 1, its It is characterised by, be used for the antitumor with istone lysine specificity demethylase as target for the preparation as active component In medicine.
4. application in preparing medicine for the LSD1 inhibitor of pyrimido 1,2,4 triazole as claimed in claim 3, its It is characterised by, described antitumor drug is anti-gastric cancer, the esophageal carcinoma or lung-cancer medicament.
CN201610801772.4A 2016-09-05 2016-09-05 LSD1 inhibitor, preparation method and the application of 1,2,4-triazole of pyrimido Active CN106478639B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610801772.4A CN106478639B (en) 2016-09-05 2016-09-05 LSD1 inhibitor, preparation method and the application of 1,2,4-triazole of pyrimido

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610801772.4A CN106478639B (en) 2016-09-05 2016-09-05 LSD1 inhibitor, preparation method and the application of 1,2,4-triazole of pyrimido

Publications (2)

Publication Number Publication Date
CN106478639A true CN106478639A (en) 2017-03-08
CN106478639B CN106478639B (en) 2018-09-18

Family

ID=58273579

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610801772.4A Active CN106478639B (en) 2016-09-05 2016-09-05 LSD1 inhibitor, preparation method and the application of 1,2,4-triazole of pyrimido

Country Status (1)

Country Link
CN (1) CN106478639B (en)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106928235A (en) * 2017-05-03 2017-07-07 郑州大学 The LSD1 of triazole containing pyrimido inhibitor, its preparation method and application
CN107033148A (en) * 2017-05-03 2017-08-11 郑州大学 Triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor, its preparation method and application
CN107936022A (en) * 2017-11-30 2018-04-20 郑州大学 Xanthine LSD1 inhibitor and its preparation method and application
WO2018083189A1 (en) 2016-11-03 2018-05-11 Oryzon Genomics, S.A. Biomarkers for determining responsiveness to lsd1 inhibitors
CN109180684A (en) * 2018-09-28 2019-01-11 郑州大学 A kind of double aryl class compounds and preparation method thereof
CN109265462A (en) * 2018-10-31 2019-01-25 郑州大学 1,2,4-triazole compound of pyrimido and its preparation method and application
CN109293664A (en) * 2018-11-14 2019-02-01 郑州大学 Pyrimido 1,2,4- triazole hydrazine class compound and its preparation method and application
WO2019025588A1 (en) 2017-08-03 2019-02-07 Oryzon Genomics, S.A. Methods of treating behavior alterations
CN109516990A (en) * 2017-09-19 2019-03-26 天津药物研究院有限公司 Pyrimido triazole compound, preparation method and use
WO2020188090A1 (en) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Methods of treating borderline personality disorder
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
CN113185512A (en) * 2021-05-17 2021-07-30 桂林医学院 5-aminopyrimidino [4,5-b ] quinoline compound and preparation method and application thereof
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors
US11992531B2 (en) 2016-05-10 2024-05-28 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
WO2024110649A1 (en) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors and menin inhibitors for treating cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3969639A1 (en) 2019-05-13 2022-03-23 Ecolab Usa Inc. 1,2,4-triazolo[1,5-a] pyrimidine derivative as copper corrosion inhibitor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1423266A (en) * 1972-06-07 1976-02-04 Icn Pharmaceuticals 2-substituted thio-s-triazolo-1,5-a pyrimidines
WO2014119752A1 (en) * 2013-01-31 2014-08-07 三井化学アグロ株式会社 Condensed cyclic pyrimidine compound, and noxious organism control agent comprising same
CN104119280A (en) * 2014-06-27 2014-10-29 郑州大学 Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, and preparation methods and applications of pyrimidine derivatives
CN105272985A (en) * 2014-06-24 2016-01-27 珠海联邦制药股份有限公司 Triazolo[4,5-d]pyrimidine compound and synthesis method, application and composition thereof
CN105555788A (en) * 2013-09-06 2016-05-04 豪夫迈·罗氏有限公司 Novel triazolo[4,5-d]pyrimidine derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1423266A (en) * 1972-06-07 1976-02-04 Icn Pharmaceuticals 2-substituted thio-s-triazolo-1,5-a pyrimidines
WO2014119752A1 (en) * 2013-01-31 2014-08-07 三井化学アグロ株式会社 Condensed cyclic pyrimidine compound, and noxious organism control agent comprising same
CN105555788A (en) * 2013-09-06 2016-05-04 豪夫迈·罗氏有限公司 Novel triazolo[4,5-d]pyrimidine derivatives
CN105272985A (en) * 2014-06-24 2016-01-27 珠海联邦制药股份有限公司 Triazolo[4,5-d]pyrimidine compound and synthesis method, application and composition thereof
CN104119280A (en) * 2014-06-27 2014-10-29 郑州大学 Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, and preparation methods and applications of pyrimidine derivatives

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
PAUL T. P. BEDINGFIELD ET AL.: ""Factors Influencing the Specificity of Inhibitor Binding to the Human and Malaria Parasite Dihydroorotate Dehydrogenases"", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
THOMAS NOVINSON ET AL.: ""2-(Alkylthio)-1,2,4-triazolo[1,5-a] pyrimidines as Adenosine Cyclic 3’,5’-Monophosphate Phosphodiesterase Inhibitors with Potential as New Cardiovascular Agents"", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
徐莉 等: ""三唑并嘧啶类衍生物的合成及生物活性研究"", 《化学研究与应用》 *
林选福 等: ""2-苄硫(砜)基-5-甲基-7-取代苄氧基-1,2,4-三唑并[1,5-a]嘧啶类衍生物的合成及抑菌活性研究"", 《有机化学》 *
鲍小平 等: ""7-位含1,3,4-噁二唑硫醚单元的新型1,2,4-三唑并[1,5-a]嘧啶类衍生物的合成及其生物活性研究"", 《有机化学》 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11992531B2 (en) 2016-05-10 2024-05-28 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
WO2018083189A1 (en) 2016-11-03 2018-05-11 Oryzon Genomics, S.A. Biomarkers for determining responsiveness to lsd1 inhibitors
CN106928235A (en) * 2017-05-03 2017-07-07 郑州大学 The LSD1 of triazole containing pyrimido inhibitor, its preparation method and application
CN107033148A (en) * 2017-05-03 2017-08-11 郑州大学 Triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor, its preparation method and application
CN107033148B (en) * 2017-05-03 2018-10-26 郑州大学 Triazole containing pyrimido-mercapto tetrazole class LSD1 inhibitor, preparation method and application
WO2019025588A1 (en) 2017-08-03 2019-02-07 Oryzon Genomics, S.A. Methods of treating behavior alterations
CN109516990A (en) * 2017-09-19 2019-03-26 天津药物研究院有限公司 Pyrimido triazole compound, preparation method and use
CN107936022A (en) * 2017-11-30 2018-04-20 郑州大学 Xanthine LSD1 inhibitor and its preparation method and application
CN109180684A (en) * 2018-09-28 2019-01-11 郑州大学 A kind of double aryl class compounds and preparation method thereof
CN109265462A (en) * 2018-10-31 2019-01-25 郑州大学 1,2,4-triazole compound of pyrimido and its preparation method and application
CN109293664B (en) * 2018-11-14 2020-06-02 郑州大学 Pyrimido 1,2, 4-triazole hydrazine compounds and preparation method and application thereof
CN109293664A (en) * 2018-11-14 2019-02-01 郑州大学 Pyrimido 1,2,4- triazole hydrazine class compound and its preparation method and application
WO2020188090A1 (en) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Methods of treating borderline personality disorder
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
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
CN113185512A (en) * 2021-05-17 2021-07-30 桂林医学院 5-aminopyrimidino [4,5-b ] quinoline compound and preparation method and application thereof
CN113185512B (en) * 2021-05-17 2023-05-05 桂林医学院 5-aminopyrimido [4,5-b ] quinoline compound and preparation method and application thereof
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors
WO2024110649A1 (en) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors and menin inhibitors for treating cancer

Also Published As

Publication number Publication date
CN106478639B (en) 2018-09-18

Similar Documents

Publication Publication Date Title
CN106478639B (en) LSD1 inhibitor, preparation method and the application of 1,2,4-triazole of pyrimido
EP1787991B1 (en) PYRROLO[2,3-c]PYRIDINE COMPOUND, PROCESS FOR PRODUCING THE SAME, AND USE
EA022339B1 (en) Indoles as respiratory syncytial virus antiviral agents
WO2000050395A1 (en) Sulfonamide-containing indole compounds
CN107474011A (en) A kind of the stibazole class LSD1 inhibitor of 2 phenyl 4, its preparation method and application
CN102850283B (en) Triazolyl-containing amino-dithio formic ether compound as well as preparation method and application of compound
CN113861215B (en) Selective copper ion chelating agent, preparation method thereof and application thereof in colorectal cancer
CN104812761A (en) Bis-beta-carboline compound and preparation method, pharmaceutical composition and use thereof
CN115772110B (en) Method for preparing potassium ion competitive blocker non-surafaxin intermediate
WO2023086341A1 (en) Inhibitors of kras
CN111484491A (en) Substituted pyrido-cyclic compounds, process for their preparation and their use
CN103508930B (en) Two (aminodithioformic acid)-1,3-propylene diester compounds and synthetic method, pharmaceutical composition and purposes
CN108997320A (en) A kind of fluorine-containing substituted benzimidazole derivative and application
KR20050009751A (en) Prodrugs of imidazole derivatives, for use as proton pump inhibitors in the treatment of e.g. peptic ulcers
CN116444501A (en) Quinazoline derivative, preparation method thereof, pharmaceutical composition and application
CN116903585A (en) Oxo-pyridine derivative and application thereof in medicine
EA007226B1 (en) Imidazoquinoline derivatives
CN112279834B (en) FGFR4 inhibitor, preparation method, pharmaceutical composition and application thereof
CN102115469A (en) Preparation method for indoline-2-one derivative and application of same
CN110590640B (en) Indirubin derivative and application thereof as CDK/HDAC dual-target inhibitor
CN111875583A (en) Triazole derivative and preparation method and application thereof
CN102850397A (en) Multi-target antitumor compounds and preparation method and application thereof
JP2018502138A (en) MAP4K4 (HGK) inhibitor
CN112745309A (en) Chromone 3-position nitric oxide donor derivative and preparation method and application thereof
CN106928224A (en) Indoles Sophoridine derivative and preparation method thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant