CN107628975B - Lysine derivative histone deacetylases inhibitor and its synthesis and application - Google Patents

Abstract

The invention discloses a kind of lysine derivative histone deacetylases inhibitor, the inhibitor selectivity is high, can be used for strong to Sirtuin selectivity, high-efficiency low-toxicity Sirtuin mechanism type inhibitors antitumor drugs object, raw material is easy to get, at low cost.

Description

Lysine derivative histone deacetylases inhibitor and its synthesis and application

Technical field

The present invention relates to a kind of lysine derivative histone deacetylases inhibitor and its synthesis and application, especially It is a kind of lysine derivative histone deacetylases inhibitor with anti-tumor activity and its synthesis and application.

Background technique

For a long time, people just recognize Mechanisms of Histone Acetylation Modification and chromatin Structure and the close phase of gene transcription regulation It closes.In nucleus, acetylation of histone and DNA methylase inhibitor process are in dynamic equilibrium, and by with opposing activity Acetylation of histone transferase (histone acetyltransferases, HATs) and histon deacetylase (HDAC) (histone Deacetylases, HDACs) regulation jointly.The catalytic activity of HAT is acetyl donor using acetyl coenzyme A, and acetyl group is turned Move on on the epsilon-amino of istone lysine side chain, chromatin made to be in of a relatively loose state, kind state be conducive to transcription because Son, RNA polymerase and other effect proteins it is close, thus the life for promoting genetic transcription and various chromatin dynamic changes to participate in Life process.HDACs combines closely after making DNA methylase inhibitor with negatively charged DNA, chromatin densification curling, certain genes If the transcription of tumor suppressor is suppressed, to induce the generation of tumour.

Have now been found that 18 kinds of mankind's HDACs hypotypes.It is big that two are classified as according to the homology with yeast Rpd3, Hda1 and Sir2 Class: first is that classical HDACs family, including I, II, IV subtribe of HDACs, belong to Zn²⁺Dependent enzyme；Second is that III subtribe of HDACs is Sirtuin family, the Sir2 albumen homology with yeast, belongs to NAD⁺Dependent enzyme.Sirtuin shares 7 families in human body Member is Sirtuin1~7 respectively.

The Sirtuin cellular localization and function (such as table 1) of different subtype are also different, such as: SIRT3, SIRT4 and SIRT5 is located at mitochondria, can adjust a variety of mitochondrial accesses and pressure response, and SIRT2 is located at cytoplasm, SIRT1, SIRT6 and SIRT7 are located at nucleus, can influence chromosome stability and genetic transcription.

SIRT1 can also be transferred in cytoplasm and play a role, such as participate in insulin signaling although being located at nucleus The process of inhibition of access.Each Sirtuin hypotype has its respective enzymatic reaction feature.Second is gone with very strong in SIRT1~3 Acylase activity, and SIRT4~7 item are only able to detect very weak deacetylation enzymatic activity, by the study found that SIRT5 also has Have succinoylated and goes malonyl enzymatic activity, and SIRT4 and SIRT6 also have ADP ribosyltransferase activity, SIRT6, which also has, stronger goes long chain fatty acyl enzymatic activity.The Sirtuins inhibitor reported at present is to pass through height mostly Structure optimization acquisition is carried out after flux screening, selectivity is all relatively low, at high cost.

Therefore, it is all relatively low, at high cost and swollen without resisting to there is selectivity in Sirtuin inhibitor in the prior art The problem of tumor activity.

Summary of the invention

The object of the present invention is to provide a kind of lysine derivative histone deacetylases inhibitor and its synthesis And application, the inhibitor selectivity is high, and it is at low cost, and there is anti-tumor activity, it can be used as Sirtuin inhibitor and preparing Application in anti-tumor drug.

Technical solution of the present invention: a kind of lysine derivative histone deacetylases inhibitor, the inhibitor Structural formula are as follows:

The R₁: it is benzyloxycarbonyl group, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethyl silicane ethoxy carbonyl Base, trichloro-ethoxycarbonyl, phthalyl, p-toluenesulfonyl, replaces benzenesulfonyl, trifluoroacetyl at first (second) oxygen carbonyl Base, pivaloyl group, benzoyl, trityl, 2,4- dimethoxy-benzyl, to methoxy-benzyl, benzyl；

The R₂: be alkoxy, unsaturated alkoxy, aralkoxy, benzyloxy, substituted benzyloxy, two benzyloxies, 4- pyridomethoxy, tri-chloroethoxy base, methyl thio ethyoxyl, tolysulfonyl ethyoxyl, p-nitrophenyl thio ethoxy, Front three (second) base siloxy, tert-butoxy, anilino-, benzamido group, alpha substituted benzylamine base；

The R₃: alkylamino radical, anilino-, substituted anilinic, benzamido group, the alpha substituted benzylamine base, 2- of amino, 1-13 carbon Tarine base or 2- nitro ethylamino-；

The X: being S, O or NH；

The Y: being CH₂Or NH；

The Z: being S or O.

A kind of synthetic method of lysine derivative histone deacetylases inhibitor above-mentioned, by following routes into Row synthesis:

The R₁, R₂,R₃, the X and R in claim 1₁, R₂,R₃, X is identical.

3. a kind of synthesis side of lysine derivative histone deacetylases inhibitor as described in claim 1 Method is synthesized by following routes:

The R₁, R₂,R₃, the X and R in claim 1₁, R₂,R₃, X is identical.

A kind of lysine derivative histone deacetylases inhibitor as claimed in any one of claims 1-3 Using as Sirtuin inhibitor application in preparation of anti-tumor drugs.

Compared with prior art, the present invention is to synthesize a variety of lysine analogues using acylated lysine or polypeptide and make For the inhibitor with histon deacetylase (HDAC) related disease, the inhibitor has inhibitor effect to Sirtuin, moreover, Synthesis material of the present invention is cheap, and cost is relatively low, selectivity is strong, and anti-tumor activity is obvious, can be used for strong to Sirtuin selectivity, high Imitate the Sirtuin inhibitors antitumor drugs object of low toxicity.

Specific embodiment

The utility model is further described below with reference to embodiment, but is not intended as the foundation to invention limitation.

Embodiment 1:

A kind of lysine derivative histone deacetylases inhibitor: its general formula are as follows:

Its synthetic method are as follows:

Synthetic schemes 1:

X is S or O or NH in general formula (I)；Y is CH₂；Z is S or O；R₁For benzyloxycarbonyl group, fluorenylmethyloxycarbonyl；R₂For methoxy Base, anilino-, specific synthetic route are as follows:

Synthetic schemes 2:

X is S or O or NH in general formula (I)；Y is NH；Z is S or O；R₁For benzyloxycarbonyl group, fluorenylmethyloxycarbonyl；R₂For methoxyl group, Anilino-；Specific synthetic route are as follows:

The specific synthesis step of II class compound of general formula

Wherein, the definition of R is shown in Table 1.

Specific synthesis step and preparation method:

1, the synthetic route of compound 2:

The preparation method of compound 2: taking the eggplant-shape bottle of 250ml, weighs DMAP (5mg), the addition tert-butyl alcohol (25ml, 273mmol), pyridine (25ml) dissolves；It sets and stirs 5min in ice bath, 4- chlorobutanoylchloride (8.3ml, 74mmol), ice is slowly added dropwise The reaction was continued in bath 30min, removes ice bath, reacts 1h at room temperature, and solvent under reduced pressure in reaction system is steamed to the greatest extent, ethyl acetate is used (500ml) extraction, uses saturated sodium bicarbonate (100ml, x2) respectively, and saturated salt solution (100ml, x2) is washed；Collected organic layer is used Anhydrous sodium sulfate is dry, is concentrated to get brown oil product, compound 2 (20g, yield 95%)；¹H-NMR(400MHz, CDCl₃)δ(ppm):3.58(t,2H)；2.40(t,2H)；2.06(m,2H)；1.45(s,9H).¹³C-NMR(100MHz, CDCl₃):172.5,81.1,44.8,33.1,28.6,28.4.

2, the synthetic route of compound 3:

The preparation method of compound 3:

Compound 2 obtained above is dissolved in THF (150ml), is added NaI (60g, 400mmol), 80 DEG C of conditions are next time Stream reaction four days, TLC monitors fully reacting, and solvent under reduced pressure in reaction system is steamed to the greatest extent, is extracted with ethyl acetate (400ml, x2), Distilled water (100ml, x2) is used again, saturated salt solution (100ml, x2) is washed, and organic phase is dry with anhydrous sodium sulfate, is concentrated to get palm fibre Dark oil compound, i.e. compound 3 (17.8g, yield 89%).¹H-NMR(400MHz,CDCl₃)δ(ppm):3.23(t, 2H)；2.34(t,2H)；2.07(m,2H)；1.40(s,9H).¹³C-NMR(100MHz,CDCl₃):173.2,81.0,44.6, 35.1,28.9,6.0.

3, the synthetic route of compound 4:

The preparation method of compound 4: taking 250ml eggplant-shape bottle to dry, and is added cysteine (6g, 49mmol), and methanol is added (40ml) stirs degassing (logical nitrogen) 10min, and NaOH (55ml, 2mol) is added under ice bath keeps cysteine dissolution complete；Once Property compound 3 obtained above is added, reaction overnight, is then added 2mol HCl (10ml) and adjusts PH~7, will be in reaction system Solvent under reduced pressure steams to the greatest extent, and light yellow oil is obtained after concentration and recovery, light yellow solid Compound is obtained with acetone recrystallization, that is, changes It closes object 4 (17g, yield 95%).¹H-NMR(400MHz,DMSO-d)δ(ppm):2.97(dd,1H)；2.70(dd,1H)； 2.51(t,2H)；2.29(t,2H)；1.72(m,2H)；1.38(s,9H).

¹³C-NMR(100MHz,DMSO-d):175.2,172.6,80.2,53.9,34.0,33.2,30.6,28.1,24.7.

4, the synthetic route of compound 5:

The preparation method of compound 5: compound 4 is taken to use 10%Na₂CO₃Completely, Cbz-Cl is added under ice bath in (13ml) dissolution The mixed liquor of (1.4ml, 8.3mmol) and THF (7ml), room temperature reaction is overnight.Then PH 4 is adjusted with 10% citric acid (20ml) ~5, solvent under reduced pressure in reaction system is steamed to the greatest extent, is then extracted with methylene chloride (300, x2), with saturated common salt aqueous solution (100ml, x2) is washed, and organic phase is dry with anhydrous sodium sulfate, and the isolated yellow oily of silica gel column chromatography after solvent is removed under reduced pressure Compound, i.e. compound 5 (0.2g, yield 10%)；¹H-NMR (400MHz, DMSO-d) δ (ppm): 7.31~7.23 (m, 5H), 4.97 (s, 2H), 4.03 (m, 2H), 2.85~2.80 (m, 1H), 2.67~2.61 (m, 1H), 2.47~2.43 (m, 2H), 2.20 (m, 2H), 1.67~1.62 (m, 2H), 1.32~1.16 (s, 9H)

¹³C-NMR(100MHz,DMSO-d):175.9,173.1,155.9,136.1,129.0,124.2,119.6,77.3, 77.0,76.6,50.9,37.7,33.9,32.6,29.0,28.4,27.9,25.4.

HR-MS m/z 397.1559 C₁₉H₂₇NO₆S,[M+Na]⁺420.1467

5, the synthetic route of compound 6:

The preparation method of compound 6: taking compound 5 obtained above in eggplant-shape bottle, and THF (3.5ml), which is added, keeps its molten Then DIEA (673 μ l, 4mmol) is added in solution, aniline (367 μ l, 4mmol) stirs 5min, is added by the dissolved DCC of THF (840mg, 4mmol) reaction is overnight；Then solvent is removed under reduced pressure, is extracted with ethyl acetate (200ml, x2), uses saturated salt solution Solution (100ml, x2) is washed, and organic phase is dry with anhydrous sodium sulfate, is dried under reduced pressure recycling, silica gel column chromatography separates white solid Body, i.e. compound 6 (0.51g, yield 50%)；¹H-NMR (400MHz, DMSO-d) δ (ppm): 7.52 (d, J=8Hz, 2H), 7.35~7.26 (m, 7H), 7.13~7.19 (m, 1H), 4.47 (s, 1H), 2.97~2.93 (m, 2H), 2.62 (s, 2H), 2.36 ~2.29 (m, 2H), 1.91~1.86 (m, 2H), 1.43 (s, 9H)

¹³C-NMR(100MHz,DMSO-d):172.7,168.6,156.2,137.3,135.9,128.9,128.5, 128.2,128.1,124.6,120.0,80.8,67.3,54.6,34.2,33.9,31.2,29.7,28.1,24.6,24.5.

HR-MS m/z 472.2032 C₂₅H₃₂N₂O₅S,[M+Na]⁺495.1945

The synthetic route of compound 7:

The preparation method of compound 7: taking compound 6 obtained above in eggplant-shape bottle, and CH is added₂Cl₂(2ml) keeps its molten It solves, TFA 2ml is slowly added under ice bath, react 8h, solvent is then removed under reduced pressure, uses CH repeatedly₂Cl₂Dissolution, is spin-dried for more to remove Remaining TFA, silica gel column chromatography separate white solid to get compound 7, (0.275g, yield 55%)；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.63 (d, J=8Hz, 2H), 7.40~7.32 (m, 7H), 7.11~ 7.07 (m, 2H), 5.06 (s, 2H), 4.38~4.32 (m, 1H), 2.91~2.86 (m, 1H), 2.76~2.71 (m, 1H), 2.62 ~2.58 (m, 2H), 2.34~2.3 (t, 2H), 1.80~1.73 (m, 2H)

¹³C-NMR(100MHz,CDCl₃):174.1,169.4,156.0,138.8,136.9,128.8,128.4,127.9, 127.8,123.5,119.4,65.6,55.4,33.2,32.6,30.8,24.4.

HR-MS m/z 416.1406 C₂₁H₂₄N₂O₅S,[M+Na]⁺439.1304.

The structural formula of the derivative (compound 8- compound 20) of compound 7 are as follows:

Wherein the definition of R is shown in Table 1:

Table 1

7, the preparation of compound 8:

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly Be added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), react in ice bath be added after 4h ammonium hydroxide (9.2 μ l, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, that is, changes Close object 8；(yield 40%)；

¹H-NMR (400MHz, DMSO-d) δ (ppm): 7.60 (d, J=8Hz, 2H), 7.36~7.28 (m, 7H), 7.04 (m,4H),5.03(s,2H),4.30(m,1H),2.56(m,1H),2.54(m,1H),2.52(m,2H),2.11(m,2H),1.70 (m,2H).

¹³C-NMR(100MHz,DMSO-d):174.2,172.7,155.9,137.5,136.1,129.2,128.8, 128.3,124.0,119.9,66.0,57.4,37.5,34.4,31.5,25.4.

HR-MS m/z 415.1566 C₂₁H₂₅N₃O₄S,[M+H]⁺416.1604

8, the preparation of compound 9

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly Be added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), react in ice bath be added after 4h methylamine (11.2 μ l, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, that is, changes Close object 9；(yield 30%)；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.57 (d, J=8Hz, 2H), 7.34~7.27 (m, 7H), 7.09 (m, 1H), 5.12 (s, 2H), 4.49 (s, 1H), 3.04~2.99 (m, 1H), 2.87~2.79 (m, 4H), 2.71~2.43 (m, 2H), 2.34~2.22 (m, 2H), 1.96 (m, 2H)

¹³C-NMR(100MHz,CDCl₃):172.9,168.8,155.4,138.5,128.9,128.2,127.1,119.9, 66.8,57.5,34.5,30.4,29.7,26.5,24.5.

HR-MS m/z 429.1722 C₂₂H₂₇N₃O₄S,[M+H]⁺430.1763.

9, the preparation of compound 10

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly Be added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), react in ice bath be added after 4h ethamine (15.5 μ l, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, that is, changes It closes object 10 (yield 33%)；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.57 (d, J=8Hz, 2H), 7.36~7.24 (m, 7H), 7.23~ 7.11 (m, 1H), 5.11 (s, 2H), 4.52 (s, 1H), 3.28 (m, 2H), 3.01 (m, 1H), 2.82 (m, 1H), 2.75~2.41 (m,2H),2.25(m,2H),1.98(m,2H),1.11(m,3H).

¹³C-NMR(100MHz,CDCl3):172.4,168.8,156.2,137.8,128.9,128.1127.9,119.9, 67.1,54.0,34.6,34.4,30.3,24.5,14.7

HR-MS m/z 443.1879 C₂₃H₂₉N₃O₄S,[M+H]⁺444.1916。

10, compound 11 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly It is added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), n-butylamine amine (10.1 μ is added after reacting 4h in ice bath L, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, i.e., Compound 11 (yield 60%)；

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.57(m,2H),7.33(m,7H),7.08(m,1H),5.10(s, 2H),4.51(s,1H),3.24(m,2H),3.02(m,1H),2.82(m,1H),2.57(m,2H),2.34(m,2H),1.91(m, 2H), 1.45 (m, 2H), 1.29 (m, 2H), 0.96~0.86 (m, 3H)

¹³C-NMR(100MHz,CDCl₃):172.5,168.8,156.2,137.8,136.0,128.9,128.3,124.4, 119.9,67.1,53.9,39.5,34.5,34.4,32.2,31.6,24.5,19.9,13.8

HR-MS m/z 471.2192 C₂₅H₃₃N₃O₄S,[M+H]⁺472.2251.

11, compound 12 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly Be added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), react in ice bath be added after 4h n-hexylamine (31 μ l, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, that is, changes It closes object 12 (yield 16%)；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.59 (d, J=8Hz, 2H), 7.33~7.24 (m, 7H), 7.09 (m, 1H), 5.14 (s, 2H), 4.51 (s, 1H), 3.24 (m, 2H), 3.01 (m, 1H), 2.83 (m, 1H), 2.67~2.58 (m, 2H), 2.36~2.20 (m, 2H), 2.15~1.82 (m, 2H), 1.47 (m, 2H), 1.23 (m, 6H), 0.85 (m, 3H)

¹³C-NMR(100MHz,CDCl₃):172.5,168.8,156.3,137.8,136.1,128.9,128.5,128.2, 119.9,67.2,55.6,39.9,34.4,31.4,30.4,29.5,26.6,24.6,22.6,14.0.

HR-MS m/z 499.2505 C₂₇H₃₇N₃O₄S,[M+H]⁺500.2559

12, compound 13 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly Be added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), react in ice bath be added after 4h octylame (40 μ l, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, that is, changes It closes object 13 (yield 90%)；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.58 (d, J=8Hz, 2H), 7.50~7.24 (m, 7H), 7.09 (m, 1H), 5.10 (s, 2H), 4.51 (s, 1H), 3.23 (m, 2H), 3.01 (m, 1H), 2.82 (m, 1H), 2.75~2.42 (m, 2H), 2.34~2.20 (m, 2H), 1.90 (m, 2H), 1.46 (m, 2H), 1.24 (m, 10H), 0.83 (m, 3H)¹³C-NMR(100MHz, CDCl₃):172.5,168.8,156.2,137.8,136.0,128.9,128.5,128.2,119.9,67.1,53.8,39.8, 34.5,31.8,30.2,29.5,29.1,26.9,24.4,22.6,14.1.

HR-MS m/z 527.2818 C₂₉H₄₁N₃O₄S,[M+Na]⁺550.2714

13, compound 14 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly Be added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), react in ice bath be added after 4h decyl amine (48 μ l, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, that is, changes It closes object 14 (yield 76%)；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.57 (d, J=8Hz, 2H), 7.33~7.24 (m, 7H), 7.09 (m, 1H), 5.08 (s, 2H), 4.51 (s, 1H), 3.25~3.20 (m, 2H), 3.02 (m, 1H), 2.83 (m, 1H), 2.79~2.47 (m, 2H), 2.40~2.21 (m, 2H), 2.11~1.89 (m, 2H), 1.45 (s, 2H), 1.22 (s, 14H), 0.87~0.83 (m, 3H).

¹³C-NMR(100MHz,CDCl₃):172.5,168.8,156.4,137.8,136.1,128.9,128.5,128.0, 119.0,67.1,54.7,39.8,34.6,31.9,30.3,29.5,29.3,26.9,24.5,22.7,14.1.

14, compound 15 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly Be added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), react in ice bath be added after 4h tridecyl amine (58 μ l, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, that is, changes It closes object 15 (yield 71%)；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.60 (d, J=8Hz, 2H), 7.37~7.27 (m, 7H), 7.11 (m, 1H), 5.13 (s, 2H), 4.53 (s, 1H), 3.27 (m, 2H), 3.04 (m, 1H), 2.87 (m, 1H), 2.80~2.51 (m, 2H), 2.48~2.12 (m, 2H), 1.94 (m, 2H), 1.45 (m, 2H), 0.93~0.80 (m, 23H)

¹³C-NMR(100MHz,CDCl₃):172.5,168.8,156.2,137.7,136.1,128.8,128.4,128.0, 119.3,67.1,55.7,39.8,34.6,31.7,30.3,29.5,29.3,26.9,26.6,24.5,22.7,14.1.

HR-MS m/z 597.3600 C₃₄H₅₁N₃O₄S,[M+H]⁺598.3495.

15, compound 16 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, THF (2ml) is added and makes it dissolve, three second are then added Amine (33 μ l, 0.24mmol), then tert-butyl glycinate solution (18 μ l, 0.13mmol) is added dropwise, it is finally added dropwise by acetonitrile dissolution Block spy condensing agent BOP (79mg, 0.18mmol), reacts at room temperature 2h, solvent, silicagel column is removed under reduced pressure after TLC monitoring fully reacting Chromatography obtains white crystal, i.e. target compound (yield 92%)；

Compound obtained above is taken, CH is added₂Cl₂(1ml) makes it dissolve, and isometric TFA is then added, reaction Solvent is removed under reduced pressure after 1.5h, TLC monitoring fully reacting, silica gel column chromatography separates to obtain yellow oil, i.e. 16 (yield of compound For 46%)；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.55 (d, J=8Hz, 2H), 7.38~7.23 (m, 7H), 7.09 (m, 1H), 5.08 (m, 2H), 4.44 (m, 1H), 3.90~3.87 (m, 2H), 2.98~2.83 (m, 2H), 2.62 (m, 2H), 2.34 (m,2H),1.88(m,2H).

¹³C-NMR(100MHz,CDCl₃):177.9,174.5,172.7,155.9,138.1,136.5,128.5,128.1, 127.5,120.2,66.5,57.5,42.8,35.3,33.6,30.9,25.2.

HR-MS m/z 473.1621 C₂₃H₂₇N₃O6_S,[M+H]⁺474.1610.

16, compound 17 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, THF (2ml) is added and makes it dissolve, three second are then added Amine (33 μ l, 0.24mmol), adds alanine t-butyl ester hydrochloride (23.6mg, 0.13mmol), is finally added dropwise by acetonitrile Card spy's condensing agent BOP (79mg, 0.18mmol) of dissolution reacts at room temperature 2h, solvent is removed under reduced pressure after TLC monitoring fully reacting, Silica gel column chromatography separates to obtain white crystal, i.e. target compound (yield 64%)；

Compound obtained above is taken, CH is added₂Cl₂(1ml) makes it dissolve, and isometric TFA is then added, reaction Solvent is removed under reduced pressure after 1.5h, TLC monitoring fully reacting, silica gel column chromatography separates to obtain yellow oil, i.e. compound 17 ((is received 66%) rate is；

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.60 (d, J=8Hz, 2H), 7.31~7.23 (m, 7H), 7.09 (m, 1H), 5.10 (s, 2H), 4.47~4.42 (m, 1H), 3.46 (m, 2H), 3.04 (m, 1H), 2.54 (m, 5H), 2.33~2.20 (m, 2H), 1.98~1.85 (m, 2H)

¹³C-NMR(100MHz,CDCl₃):175.5,172.6,156.8,138.5,136.1,128.9,128.6,128.3, 121.5,67.6,54.0,35.6,34.7,34.3,29.7,24.4.HR-MS m/z 487.1777C₂₄H₂₉N₃O₆S,[M+Na]+ 510.1672

17, compound 18 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, THF (2ml) is added and makes it dissolve, three second are then added Amine (33 μ l, 0.24mmol), adds aminobutyric acid t-butyl ester hydrochloride (25.4mg, 0.13mmol), is finally added dropwise by acetonitrile Card spy's condensing agent BOP (79mg, 0.18mmol) of dissolution reacts at room temperature 2h, solvent is removed under reduced pressure after TLC monitoring fully reacting, Silica gel column chromatography separates to obtain white crystal, i.e. target compound (yield 68%)；

Compound obtained above is taken, CH is added₂Cl₂(1ml) makes it dissolve, and isometric TFA is then added, reaction Solvent is removed under reduced pressure after 1.5h, TLC monitoring fully reacting, silica gel column chromatography separates to obtain yellow oil, i.e. 18 (yield of compound For 55%).

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.56~7.50 (d, J=8Hz, 2H), 7.25 (m, 7H), 7.11 (m, 1H), 5.10 (s, 2H), 4.53 (m, 1H), 3.24 (m, 2H), 3.01~2.84 (m, 2H), 2.55 (m, 2H), 2.34 (m, 4H), 1.86~1.80 (m, 4H)

¹³C-NMR(100MHz,CDCl₃):182.2,172.6,168.5,155.9,139.4,129.8,129.4,129.0, 121.5,67.8,57.4,39.7,35.7,34.6,32.5,26.6,25.7.

HR-MS m/z 501.1034 C₂₅H₃₁N₃O₆S,[M+Na]⁺524.1815.

18, compound 19 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly Be added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), react in ice bath be added after 4h aniline (21.8 μ l, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates to obtain white solid, that is, changes It closes object 19 (yield 33%).

¹H-NMR(400MHz,CDCl₃) δ (ppm): 7.48 (d, J=8Hz, 2H), 7.32~7.24 (m, 9H), 7.08 (m, 2H), 5.13 (s, 2H), 4.52 (m, 1H), 3.01~291 (m, 2H), 2.63 (m, 2H), 2.45 (m, 2H), 2.01 (m, 2H)

¹³C-NMR(100MHz,CDCl₃):179.7,171.0,168.6,156.3,136.0,129.0,128.6,128.2, 120.0,67.3,54.4,35.5,34.4,30.9,24.5.

HR-MS m/z 491.1879 C₂₇H₂₉N₃O₄S,[M+H]⁺492.1934

19, compound 20 synthesizes

It takes compound 7 (50mg, 0.12mmol) in eggplant type bottle, 2ml THF is added and makes it dissolve completely, under ice bath slowly It is added dropwise IBCF (45 μ l, 0.36mmol), NMM (40 μ l, 0.36mmol), paranitroanilinum is added after reacting 4h in ice bath (30.7mg, 0.24mmol), reaction is stayed overnight at room temperature.Then solvent is removed under reduced pressure, silica gel column chromatography separates white Solid, i.e. compound 20 (yield 86%).

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.14 (d, J=8Hz, 2H), 7.70 (d, J=8Hz, 2H), 7.47 (d, J=8Hz, 2H), 7.35~7.27 (m, 7H), 7.13 (m, 1H), 5.16 (s, 2H), 4.54 (m, 1H), 3.02~2.99 (m, 2H),2.97(m,2H),2.69(m,2H),2.48(m,2H),2.06(m,2H).

¹³C NMR(100MHz,CDCl₃):178.9,172.6,168.6,156.7,143.9,143.2,136.8,135.6, 129.1,128.7,128.5,124.9,120.4,118.9,67.6,54.9,35.9,33.9,31.6,24.6.

HR-MS m/z 536.1730 C₂₇H₂₈N₄O₆S,[M+H]⁺537.1794

Experimental example 2.

The specific synthetic route of general formula III class compound

Wherein, the definition of R is shown in Table 2.

1, the synthetic route of compound 21:

The preparation of compound 21: compound 4 (2g, 7.6mmol) is taken to use 10%Na₂CO₃THF is used in solution 15ml dissolution, addition The Fmoc-Cl (2.94g, 11.4mmol) of dissolution, room temperature reaction adjust PH4~5 overnight, with 10% citric acid, are removed under reduced pressure CH is added in THF₂Cl₂Extraction, organic phase are washed with saturation NaCl solution, are dried under reduced pressure, obtain product pale tan oil 21 (200mg, yield 10%)；

¹H NMR (400MHz, DMSO-d) δ 7.85 (d, J=7.5Hz, 2H), 7.77~7.61 (m, 3H), 7.37 (t, J= 7.5Hz, 2H), 7.28 (t, J=7.4Hz, 2H), 4.32~4.14 (m, 3H), 4.08 (qd, J=8.8,4.6Hz, 1H), 2.86 (dt, J=24.4,10.2Hz, 1H), 2.70 (ddd, J=15.2,9.6,5.6Hz, 1H), 2.55~2.41 (m, 2H), 2.23 (t, J=7.3Hz, 2H), 1.68 (dd, J=8.4,6.1Hz, 2H), 1.33 (s, 9H)

¹³C-NMR(100MHz,DMSO-d):175.9,173.1,155.9,143.6,142.6,126.7,126.2, 125.2,120.5,82.1,67.3,58.1,47.2,33.4,33.1,32.328.7,24.4.

HR-MS m/z 485.1872 C₂₆H₃₁NO₆S,[M+H]⁺486.1866

2, the synthesis of compound 22:

It takes compound 21 (1.2g, 2.47mml) in 100ml eggplant type bottle, methanol 20ml is added,

10min is stirred in ice bath, oxalyl chloride (653 μ l, 7.41mmol) is slowly added dropwise, and is dripped off and is continued ice bath reaction 5min, Ice bath is removed, 2h is reacted at room temperature, is removed under reduced pressure after excess of solvent successively with saturation Na₂CO₃, NaCl is washed, and it is dry to be concentrated, it obtains white Color floccule, i.e. compound 22 (780mg, yield 65%)；

¹H NMR (400MHz, DMSO-d) δ 7.85 (d, J=7.5Hz, 2H), 7.77~7.61 (m, 3H), 7.37 (t, J= 7.5Hz, 2H), 7.28 (t, J=7.4Hz, 2H), 4.32~4.14 (m, 3H), 4.08 (qd, J=8.8,4.6Hz, 1H), 3.68 (s, 3H), 2.86 (dt, J=24.4,10.2Hz, 1H), 2.70 (ddd, J=15.2,9.6,5.6Hz, 1H), 2.55~2.41 (m, 2H), 2.23 (t, J=7.3Hz, 2H), 1.68 (dd, J=8.4,6.1Hz, 2H), 1.33 (s, 9H)

¹³C-NMR(100MHz,DMSO-d):173.1,171.5,155.9,143.6,142.6,126.7,126.2, 125.2,120.5,82.1,67.3,58.2,51.9,47.1,33.4,32.3,28.7,24.4.

HR-MS m/z 499.2025 C₂₇H₃₃NO₆S,[M+H]⁺500.2122.

3, the synthesis of compound 23

It takes compound 22 in eggplant type bottle, CH is added₂Cl₂, 10min is stirred in ice bath, and TFA (CH is slowly added dropwise₂Cl₂:TFA =1:1), it drips off and continues ice bath reaction 5min, remove ice bath, react at room temperature 2h, CH is removed under reduced pressure₂Cl₂And TFA, it obtains light yellow Grease (yield 90%).

¹H NMR (400MHz, DMSO-d) δ 12.07 (s, 1H), 7.86 (t, J=6.6Hz, 3H), 7.68 (d, J= 7.4Hz, 2H), 7.38 (t, J=7.4Hz, 1H), 7.29 (t, J=7.4Hz, 2H), 4.31~4.24 (m, 2H), 4.22~4.12 (m, 2H), 3.60 (s, 3H), 2.84 (dd, J=13.7,5.1Hz, 1H), 2.71 (dd, J=13.7,9.3Hz, 1H), 2.50 (d, J=7.3Hz, 2H), 2.25 (t, J=7.3Hz, 2H), 1.73~1.63 (m, 2H)

¹³C-NMR(100MHz,DMSO-d):178.4,171.5,155.9,143.6,142.6,126.7,126.2, 125.2,120.5,67.3,58.2,51.9,47.1,35.2,33.4,32.3,24.1.

HR-MS m/z 443.1403 C₂₃H₂₅NO₆S,[M+H]⁺444.1508.

The structural formula of 23 derivative of compound (i.e. compound 24- compound 36) are as follows:

Wherein the definition of R is shown in Table 2:

Table 2

3, the synthesis of compound 24

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, after stirring 10min It is added ammonium hydroxide (17.7 μ l, 0.451mmol), reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, with 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates to obtain white solid after dry concentration (yield 86%)；

It takes above compound (50mg, 0.113mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (8.1mg, 0.339mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 24 (yield 80%) afterwards.

¹H NMR(400MHz,CDCl₃) δ 12.01 (s, 1H), 7.86 (t, J=6.6Hz, 3H), 7.55 (d, J=7.4Hz, 2H), 7.38 (t, J=7.4Hz, 2H), 7.29 (t, J=7.4Hz, 2H), 7.16 (s, 2H), 4.28~4.20 (m, 3H), 4.15 ~4.10 (m, 1H), 2.74 (dd, J=13.7,5.1Hz, 1H), 2.68 (dd, J=13.7,9.3Hz, 1H), 2.48 (d, J= 7.3Hz, 2H), 2.20 (t, J=7.3Hz, 2H), 1.63~1.53 (m, 2H)

¹³C-NMR(100MHz,CDCl₃):176.4,173.5,155.9,143.7,143.6,126.7,126.2,125.2, 120.5,67.3,58.2,47.1,37.2,33.1,31.9,24.7.

HR-MS m/z 428.1406 C₂₂H₂₄N₂O₅S,[M+H]⁺429.1514.

4, the synthesis of compound 25

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Methylamine (17.8 μ l, 0.451mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, with 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates to obtain white solid after dry concentration (yield 78%)；

It takes above compound (50mg, 0.109mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (7.8mg, 0.327mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 25 (yield 81%) afterwards.

¹H NMR(400MHz,CDCl₃) δ 12.15 (s, 1H), 8.13 (s, 2H), 7.86 (t, J=6.6Hz, 2H), 7.65 (d, J=7.4Hz, 2H), 7.38 (t, J=7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 4.29~4.21 (m, 3H), 4.21 ~4.11 (m, 1H), 3.11 (s, 3H), 2.74 (dd, J=13.7,5.1Hz, 1H), 2.60 (dd, J=13.7,9.3Hz, 1H), 2.51 (d, J=7.3Hz, 2H), 2.25 (t, J=7.3Hz, 2H), 1.71~1.53 (m, 2H)

¹³C-NMR(100MHz,CDCl₃):175.5,173.4,155.8,143.5,142.7,126.5,126.4,125.3, 120.6,67.3,58.2,47.3,36.5,34.2,33.1,26.2,15.1.

HR-MS m/z 442.1562 C₂₃H₂₆N₂O₅S,[M+H]⁺443.1566.

5, the synthesis of compound 26

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Ethamine (25.1 μ l, 0.451mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, with 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates to obtain white solid after dry concentration (yield 85%)；

It takes above compound (50mg, 0.106mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (7.6mg, 0.319mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 26 (yield 90%) afterwards；

¹H NMR(400MHz,CDCl₃) δ 12.05 (s, 1H), 8.03 (s, 2H), 7.87 (t, J=6.6Hz, 2H), 7.55 (d, J=7.4Hz, 2H), 7.38 (t, J=7.4Hz, 2H), 7.28 (t, J=7.4Hz, 2H), 4.28~4.20 (m, 3H), 4.15 ~4.10 (m, 1H), 3.05 (s, 3H), 2.72 (dd, J=13.7,5.1Hz, 1H), 2.51 (d, J=7.3Hz, 2H), 2.25 (t, J=7.3Hz, 2H), 1.70~1.55 (m, 2H), 1.04 (t, J=7.2Hz, 3H)

¹³C-NMR(100MHz,CDCl₃):175.4,173.3,155.9,143.6,142.6,126.7,126.2,125.2, 120.5,67.1,58.1,47.1,36.2,35.6,33.1,31.9,15.1.

HR-MS m/z 456.1719 C₂₄H₂₈N₂O₅S,[M+H]⁺456.1721.

6, the synthesis of compound 27

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min After be added a n-butylamine (18.9 μ l, 0.451mmol), react at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, use 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates after dry concentration White solid (yield 85%)；

It takes above compound (50mg, 0.10mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, in ice bath About 10min is reacted, THF:H is added₂The LiOH (7.2mg, 0.301mmol) of O (3:1) solution dissolution, after about 10min fully reacting 10% citric acid is added and terminates reaction, uses CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄After dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 27 (yield is respectively 80%, 88%)；

¹H NMR(400MHz,CDCl₃) δ 12.10 (s, 1H), 8.03 (s, 2H), 7.86 (t, J=6.6Hz, 2H), 7.65 (d, J=7.4Hz, 2H), 7.38 (t, J=7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 4.29~4.21 (m, 3H), 4.21 ~4.11 (m, 1H), 3.02~2.85 (m, 3H), 2.60 (dd, J=13.7,9.3Hz, 1H), 2.51 (t, J=7.4Hz, 2H), 2.25 (t, J=7.3Hz, 2H), 1.71~1.53 (m, 2H) .1.52 (m, 2H), 1.31 (m, 2H), 1.11 (t, J=7.4Hz, 3H)

¹³C-NMR(100MHz,CDCl₃):175.9,172.6,155.8,143.6,142.7,126.7,126.4,125.3, 120.5,67.3,58.1,47.1,38.9,,35.4,33.1,32.2,31.8,25.2,19.8,13.5.

HR-MS m/z 484.2032 C₂₆H₃₂N₂O₅S,[M+H]⁺484.2114.

7, the synthesis of compound 28

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min N-hexylamine (60 μ l, 0.451mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, with 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates to obtain white solid after dry concentration (yield 84%)；

It takes above compound (50mg, 0.095mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (6.8mg, 0.285mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 28 (yield 92%) afterwards；

¹H NMR(400MHz,CDCl₃) δ 12.10 (s, 1H), 8.03 (s, 2H), 7.86 (t, J=6.6Hz, 2H), 7.65 (d, J=7.4Hz, 2H), 7.38 (t, J=7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 4.29~4.21 (m, 3H), 4.21 ~4.11 (m, 1H), 3.02~2.85 (m, 3H), 2.60 (dd, J=13.7,9.3Hz, 1H), 2.51 (t, J=7.4Hz, 2H), 2.34 (t, J=7.3Hz, 2H), 1.81~1.53 (m, 2H) .1.52 (m, 2H), 1.29~1.31 (m, 6H), 0.99 (t, J= 7.4Hz,3H)

¹³C-NMR(100MHz,CDCl₃):175.9,172.6,155.8,143.6,142.7,126.7,126.4,125.3, 120.5,67.3,58.1,47.1,38.9,35.4,33.1,31.9,31.5,30.1,26.4,25.1,22.7,14.1.

HR-MS m/z 512.2345 C₂₈H₃₆N₂O₅S,[M+H]⁺513.2651.

8, the synthesis of compound 29

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Octylame (74.6 μ l, 0.451mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, with 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates to obtain white solid after dry concentration (yield 79%)；

It takes above compound (50mg, 0.090mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (6.5mg, 0.27mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 29 (yield 89%) afterwards；

¹H NMR(400MHz,CDCl₃) δ 12.10 (s, 1H), 8.03 (s, 2H), 7.86 (t, J=6.6Hz, 2H), 7.65 (d, J=7.4Hz, 2H), 7.38 (t, J=7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 4.29~4.21 (m, 3H), 4.21 ~4.11 (m, 1H), 3.02~2.85 (m, 3H), 2.60 (dd, J=13.7,9.3Hz, 1H), 2.51 (t, J=7.4Hz, 2H), 2.34 (t, J=7.3Hz, 2H), 1.81~1.53 (m, 2H) .1.52 (m, 2H), 1.29~1.31 (m, 10H), 0.99 (t, J= 7.4Hz,3H)

¹³C-NMR(100MHz,CDCl₃):175.9,172.6,155.8,143.6,142.7,126.7,126.4,125.3, 120.5,67.3,58.1,47.1,39.1,35.4,33.1,31.9,30.1,29.3,26.4,25.1,22.7,14.1.

HR-MS m/z 540.2658 C₃₀H₄₀N₂O₅S,[M+H]⁺541.3546.

9, the synthesis of compound 30

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Decyl amine (90 μ l, 0.451mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, with 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates to obtain white solid after dry concentration (yield 80%)；

It takes above compound (50mg, 0.085mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (6.18mg, 0.257mmol) of O (3:1) solution dissolution, about 10min has reacted 10% citric acid is added after complete and terminates reaction, uses CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Drying is dense Silica gel column chromatography separates to obtain white solid, i.e. compound 30 (yield 91%) after contracting；

¹H NMR(400MHz,CDCl₃) δ 12.10 (s, 1H), 8.03 (s, 2H), 7.86 (t, J=6.6Hz, 2H), 7.65 (d, J=7.4Hz, 2H), 7.38 (t, J=7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 4.29~4.21 (m, 3H), 4.21 ~4.11 (m, 1H), 3.02~2.85 (m, 3H), 2.60 (dd, J=13.7,9.3Hz, 1H), 2.51 (t, J=7.4Hz, 2H), 2.34 (t, J=7.3Hz, 2H), 1.81~1.53 (m, 2H) .1.52 (m, 2H), 1.29~1.31 (m, 14H), 0.99 (t, J= 7.4Hz,3H)

¹³C-NMR(100MHz,CDCl₃):175.9,172.6,155.8,143.6,142.7,126.7,126.4,125.3, 120.5,67.3,58.1,47.1,39.1,35.4,33.1,31.9,30.1,29.3,29.6,26.4,25.1,22.7,14.1.

HR-MS m/z 568.2971 C₃₂H₄₄N₂O₅S,[M+H]⁺569.4788.

10, the synthesis of compound 31

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Tridecyl amine (109 μ l, 0.451mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, use 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates white solid after dry concentration Body (yield 87%)；

It takes above compound (50mg, 0.080mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (5.7mg, 0.240mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 31 (yield 90%) afterwards.

¹H NMR(400MHz,CDCl₃) δ 12.10 (s, 1H), 8.03 (s, 2H), 7.86 (t, J=6.6Hz, 2H), 7.65 (d, J=7.4Hz, 2H), 7.38 (t, J=7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 4.29~4.21 (m, 3H), 4.21 ~4.11 (m, 1H), 3.02~2.85 (m, 3H), 2.60 (dd, J=13.7,9.3Hz, 1H), 2.51 (t, J=7.4Hz, 2H), 2.34 (t, J=7.3Hz, 2H), 1.81~1.53 (m, 2H) .1.52 (m, 2H), 1.29~1.31 (m, 20H), 0.99 (t, J= 7.4Hz,3H).

¹³C-NMR(100MHz,CDCl₃):175.9,172.6,155.8,143.6,142.7,126.7,126.4,125.3, 120.5,67.3,58.1,47.1,39.1,35.4,33.1,31.9,30.1,29.3,29.6,26.4,25.1,22.7,14.1.

HR-MS m/z 610.3440 C₃₅H₅₀N₂O₅S,[M+H]⁺610.3514.

11, the synthesis of compound 32

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Tert-butyl glycinate (61 μ l, 0.451mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, use 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates after dry concentration White solid (yield 75%)；

It takes above compound (50mg, 0.089mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (6.4mg, 0.269mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 32 (yield 86%) afterwards.

¹H NMR(400MHz,CDCl₃) δ 7.74 (d, J=7.2Hz, 2H), 7.65 (t, J=7.4Hz, 2H), 7.38 (t, J =7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 6.48 (s, 1H), 5.90 (d, J=7.2Hz, 1H), 4.64 (s, 1H), 4.35 (d, J=7.2Hz, 2H), 4.21 (t, J=7.4Hz, 1H), 4.07 (s, 2H), 3.16~3.13 (m, 1H), 3.01~ 2.97 (m, 1H), 2.61~2.52 (m, 2H), 2.46~2.39 (m, 2H), 2.02~1.84 (m, 2H), 1.43 (s, 9H),

¹³C-NMR(100MHz,CDCl₃):177.9,175.6,169.7,143.6,142.7,126.7,126.4,125.3, 120.5,82.1,67.5,54.0,47.4,35.6,35.2,34.8,32.3,30.1,29.6,25.6.

HR-MS m/z 542.2087 C₂₈H₃₄N₂O₇S,[M+H]⁺543.4528。

12, the synthesis of compound 33

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Alanine tert-butyl ester hydrochloride (81.9mg, 0.451mmol) is added afterwards, reacts at room temperature 3h.It is added about 40ml's after fully reacting CH₂Cl₂, washed twice with 10ml 1N HCl, then washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column layer after dry concentration Analysis separates to obtain white solid (yield 78%)；

It takes above compound (50mg, 0.087mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (6.3mg, 0.263mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 33 (yield 82%) afterwards；

¹H NMR(400MHz,CDCl₃) δ 7.74 (d, J=7.2Hz, 2H), 7.65 (t, J=7.4Hz, 2H), 7.38 (t, J =7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 6.48 (s, 1H), 5.90 (d, J=7.2Hz, 1H), 4.64 (s, 1H), 4.35 (d, J=7.2Hz, 2H), 4.21 (t, J=7.4Hz, 1H), 3.53~3.40 (m, 2H), 3.16~3.13 (m, 1H), 3.01~2.97 (m, 1H), 2.61~2.52 (m, 2H), 2.46~2.39 (m, 2H), 2.21~2.15 (m, 2H), 2.02~ 1.84(m,2H),1.43(s,9H),

¹³C-NMR(100MHz,CDCl₃):177.9,175.6,169.7,143.6,142.7,126.7,126.4,125.3, 120.5,82.1,67.5,54.0,47.4,35.6,35.2,34.8,32.3,30.1,29.6,25.6.

HR-MS m/z 556.2243 C₂₉H₃₆N₂O₇S,[M+H]⁺557.5641

13, the synthesis of compound 34

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Aminobutyric acid t-butyl ester hydrochloride (88.2mg, 0.451mmol) is added afterwards, reacts at room temperature 3h.About 40ml is added after fully reacting CH₂Cl₂, washed twice with 10ml 1N HCl, then washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silicagel column after dry concentration Chromatography obtains white solid (yield 77%)；

It takes above compound (50mg, 0.085mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (6.1mg, 0.256mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 34 (yield 79%) afterwards；

¹H NMR(400MHz,CDCl₃) δ 7.74 (d, J=7.2Hz, 2H), 7.65 (t, J=7.4Hz, 2H), 7.38 (t, J =7.4Hz, 2H), 7.30 (t, J=7.4Hz, 2H), 6.48 (s, 1H), 5.90 (d, J=7.2Hz, 1H), 4.64 (s, 1H), 4.35 (d, J=7.2Hz, 2H), 4.21 (t, J=7.4Hz, 1H), 3.53~3.40 (m, 2H), 3.16~3.13 (m, 1H), 3.01~2.97 (m, 1H), 2.61~2.52 (m, 2H), 2.46~2.39 (m, 2H), 2.34~2.25 (m, 2H), 2.15~ 2.04 (m, 2H), 2.02~1.84 (m, 2H), 1.43 (s, 9H),

¹³C-NMR(100MHz,CDCl₃):177.9,175.6,169.7,143.6,142.7,126.7,126.4,125.3, 120.5,82.1,67.5,54.0,47.4,39.7,35.6,35.2,34.8,32.3,30.1,29.6,25.6,23.7.

HR-MS m/z 570.2400 C₃₀H₃₈N₂O₇S,[M+H]⁺570.3541.

14, the synthesis of compound 35

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), HBTU (128.5mg, 0.339mmol) is added after stirring 10min, stirs 10min Aniline (41.1 μ l, 0.451mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, with 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates to obtain white solid after dry concentration (yield 65%)；

It takes above compound (50mg, 0.096mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (7mg, 0.29mmol) of O (3:1) solution dissolution, after about 10min fully reacting 10% citric acid is added and terminates reaction, uses CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄After dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 35 (yield 81%)

¹H NMR(400MHz,CDCl₃) δ 12.01 (s, 1H), 7.86 (t, J=6.6Hz, 3H), 7.61~7.55 (m, 4H), 7.43~7.38 (m, 4H), 7.29~7.19 (m, 3H), 4.28~4.20 (m, 3H), 4.15~4.10 (m, 1H), 2.81 (dd, J =13.7,5.1Hz, 1H) 2.74 (dd, J=13.7,5.1Hz, 1H), 2.68 (t, J=7.4Hz, 2H), 2.48 (t, J= 7.4Hz,2H),2.20(m,2H).

¹³C-NMR(100MHz,CDCl₃):176.4,173.5,155.9,143.7,142.6,138.7,128.9,128.1, 126.7,126.2,125.2,121.6,120.6,67.5,58.1,47.2,35.1,33.1,31.9,25.2.

HR-MS m/z 504.1719 C₂₈H₂₈N₂O₅S,[M+H]⁺504.2151。

15, the synthesis of compound 36

It takes compound 23 (100mg, 0.226mmol) in eggplant type bottle, dry CH is added₂Cl₂About 4ml, after dissolution completely It is added DIEA (78.60 μ l, 0.451mmol), POCl is added after stirring 10min₃(41.4 μ l, 0.451mmol) stirs 10min Paranitroanilinum (32.8 μ l, 0.339mmol) is added afterwards, reacts at room temperature 3h.The CH of about 40ml is added after fully reacting₂Cl₂, use 10ml 1N HCl is washed twice, then is washed twice with saturation NaCl solution, anhydrous Na₂SO₄Silica gel column chromatography separates after dry concentration White solid (yield 30%)；

It takes above compound (50mg, 0.088mmol) in eggplant type bottle, THF:H is added₂O (3:1) solution 10ml, ice bath THF:H is added in middle reaction about 10min₂The LiOH (6.4mg, 0.26mmol) of O (3:1) solution dissolution, about 10min fully reacting After be added 10% citric acid terminate reaction, use CH₂Cl₂Extraction, is washed once, anhydrous Na with saturation NaCl solution₂SO₄Dry concentration Silica gel column chromatography separates to obtain white solid, i.e. compound 36 (yield 78%) afterwards

¹H NMR(400MHz,CDCl₃) δ 12.01 (s, 1H), 8.24 (m, 3H), 7.87~7.82 (m, 4H), 7.55 (m, 2H), 7.38~7.28 (m, 5H), 4.28~4.20 (m, 3H), 4.15~4.10 (m, 1H), 2.85 (dd, J=13.7,5.1Hz, 1H) 2.71 (dd, J=13.7,5.1Hz, 1H), 2.68 (t, J=7.4Hz, 2H), 2.48 (t, J=7.4Hz, 2H), 2.14 (m, 2H).

¹³C-NMR(100MHz,CDCl₃):176.4,173.5,155.9,144.7,143.6,143.5,142.6,126.7, 126.2,125.2,120.6,119.8,67.5,58.1,47.2,35.1,33.1,31.9,25.2.

HR-MS m/z 549.1570 C₂₈H₂₇N₃O₇S,[M+H]⁺540.2344.

Solid phase peptide synthssis, each chemical combination are carried out to compound 24 to compound 36 by Shanghai Mu Jin Biotechnology Co., Ltd The corresponding polypeptide of object, which is numbered, is

24-1,25-1,26-1,27-1,28-1,29-1,30-1,31-1,32-1,33-1,34-1,35-1,36-1.Synthesis Polypeptide be KQTARCSTGGK, K indicate lysine (lysine), Q indicate glutamine (glutamine), T indicate threonine (threonine), A indicates that alanine (alanine), R indicate that arginine (arginie), C indicate cysteine (cysteine), S indicates that serine (serine), G indicate glycine (glycine).

Basic framework after synthesis polypeptide is as follows:

Wherein, polypeptide and in basic structure the definition of R it is identical with table 2, number be shown in Table 3:

Mass spectrometric data:

24-1 theoretical value: 1220.67 measured values: [M+2H]²⁺611.65

25-1 theoretical value: 1234.68 measured values: [M+2H]²⁺618.70

26-1 theoretical value: 1248.70 measured values: [M+2H]²⁺625.70

27-1 theoretical value: 1276.73 measured values: [M+2H]²⁺639.70

28-1 theoretical value: 1304.76 measured values: [M+2H]²⁺653.60

29-1 theoretical value: 1332.79 measured values: [M+2H]²⁺667.75

30-1 theoretical value: 1360.82 measured values: [M+2H]²⁺681.80

31-1 theoretical value: 1402.87 measured values: [M+2H]²⁺702.90

32-1 theoretical value: 1278.67 measured values: [M+2H]²⁺640.65

33-1 theoretical value: 1292.69 measured values: [M+2H]²⁺647.65

34-1 theoretical value: 1306.70 measured values: [M+2H]²⁺654.45

35-1 theoretical value: 1296.70 measured values: [M+2H]²⁺649.75

36-1 theoretical value: 1341.68 measured values: [M+2H]²⁺671.84.

Experimental example 3:

Screening active ingredients

Existing Sirtuins hypotype is 1,2,3,5,6, corresponding 1,2, the substrate polypeptide H3K9AcWW (200 of 3 hypotypes μM) and its coenzyme NAD (1mM)；5 substrate polypeptide H3K9SuWW (200 μM) and its coenzyme NAD (1mM)；6 substrate polypeptide H3K9MyWW (200 μM) and its coenzyme NAD (1mM).

The enzyme reaction of 6.1SIRT1,2,3

Substrate polypeptide H3K9AcWW (200 μM) and its coenzyme NAD (1mM) contain DTT (1mM) for (1 μM) with SIRT1,2,3 TrispH7.4 (20mM) solution in 37 DEG C reaction be respectively 45min, 10min, 30min.Positive group is added during the reaction Drug component to be measured, preliminary screening drug concentration is with 100 μM.If two negative control groups, one group is not added screening drug, one group The albumen of SIRT1,2,3 is not added.All components are quenched with hydrochloric acid/acetum after reaction 45min, 10min, 30min Reaction.12000 × g of high speed centrifugation send HPLC to be measured.

6.2SIRT5 enzyme reaction

Substrate polypeptide H3K9SuWW (200 μM) and its coenzyme NAD (1mM) are containing DTT (1mM) with SIRT5 (1 μM) 37 DEG C of reaction 15min in Tris pH 7.4 (20mM) solution.Drug component to be measured is added in positive group during the reaction, tentatively It screens drug concentration and selects 100 μM.If two negative control groups, one group screening drug is not added, and one group SIRT5 egg is not added It is white.All groupings carry out quenching reaction with hydrochloric acid/acetum after reaction 15min.12000 × g of high speed centrifugation send HPLC to wait for It surveys.

6.3SIRT6 enzyme reaction

Substrate polypeptide H3K9MyWW (200 μM) and its coenzyme NAD (1mM) contain DTT (1mM) with (1 μM) of SIRT6 37 DEG C of reactions are respectively 45min in TrispH7.4 (20mM) solution.Drug component to be measured is added in positive group during the reaction, Preliminary screening drug concentration is with 100 μM.If two negative control groups, one group screening drug is not added, and one group SIRT6 egg is not added It is white.All components carry out quenching reaction with hydrochloric acid/acetum after reaction 45min.12000 × g of high speed centrifugation send HPLC to wait for It surveys.

Activity determination is carried out after Sirtuin carries out enzyme activity reaction as substrate using H3K9AcWW, then with HPLC, removes acetyl The product H3K9WW of change is prior to substrate H3K9AcWW appearance, then compares the calculated by peak area yield of the two, and assessment Sirtuin is changing Close the enzymatic activity under object effect, the inhibitory activity of more each compound.

6.4 the selection result

It chooses small molecule class inhibitor and carries out screening active ingredients, primary dcreening operation concentration is 100 μM, and results of preliminary screening is as shown in table 4:

Inhibiting rate of the table 4 to each hypotype of Sirtuin

It follows that, for SIRT1 albumen, compound 9,10,11 and 12 has obvious inhibition to make under 100 μM of concentration With wherein the inhibiting rate of compound 10 and 11 is lower than 50%；For SIRT2, compound 9~13 has inhibiting effect, wherein compound 10 inhibiting effect is best；38% is reached for 10 inhibiting rate of SIRT3 compound；There is inhibition for SIRT5 compound 16~20 Effect, wherein 16,17 inhibitory effects are most obvious；For SIRT6, the compound 13~15 with long-chain is inhibited.Change Close that object 10,11 more confirms the strong deacetylation effect of SIRT1~SIRT3 and the faint of SIRT5 and SIRT6 removes acetyl Change effect；Compound 16~18 with carboxyl structure obviously has more inhibiting effect, long-chain fat chain amide pair to SIRT5 For the selectivity of SIRT6 also above other Sirtuin hypotypes, this illustrates that such compound is more selective.And have to each albumen Inhibiting effect can be used for strong to Sirtuin selectivity, high-efficiency low-toxicity Sirtuin inhibitors antitumor drugs object.

When concentration is 100 μM, the inhibiting rate of polypeptide compounds is considerably beyond small molecule class, so gradually reducing screening Concentration finally chooses 5 μM of minimum inhibitory concentration, and inhibiting rate is shown in Table 5:

Inhibitory activity of 5 24-1 of the table~36-1 compound to each hypotype of Sirtuin

As shown in Table 4, under 100 μM of concentration, for SIRT1~SIRT3 albumen, compound 10,11 has obvious inhibition to make With, inhibiting rate is higher than 50%, but compared with table 5, under 5 μM of concentration, 25-1,26-1,27-1 can reach nearly 50 inhibiting rate, The inhibitory effect of polypeptide compounds is apparent；For SIRT5 albumen, it has faint deacetylation activity, opposite to have Have it is very strong go succinyl and malonylization activity, so, corresponding compound 16~18 has inhibiting effect to it, wherein 16,17 inhibitory effects are more obvious, in table 5, under 5 μM of concentration, compound 32-1~34-1 nearly to its inhibitory activity 60%；It is right In SIRT6 albumen, the compound 13~15 with long-chain is inhibited, and 29-1,30-1,31-1 inhibit under 5 μM of concentration Effect becomes apparent.Compound 10,11,25-1,26-1,27-1 more confirm that the strong deacetylation of SIRT1~SIRT3 is made With and the faint deacetylation effect of SIRT5 and SIRT6；Compound 16~18,32-1~34-1 with carboxyl structure are bright Aobvious to have more inhibiting effect to SIRT5, to the selectivity of SIRT6 also above other Sirtuin hypotypes, this says long-chain fat chain amide The bright designed compound synthesized is more selective and inhibited to each albumen, can be used for Sirtuin selectivity By force, the Sirtuin inhibitors antitumor drugs object of high-efficiency low-toxicity.

Claims (4)

1. a kind of lysine derivative histone deacetylases inhibitor, it is characterised in that: the structural formula of the inhibitor Are as follows:

The R₁: it is benzyloxycarbonyl group, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, first (second) oxygen carbonyl, phthalyl, p-toluenesulfonyl, replaces benzenesulfonyl, trifluoroacetyl group, spy at trichloro-ethoxycarbonyl Valeryl, benzoyl, trityl, 2,4- dimethoxy-benzyl, to methoxy-benzyl, benzyl；

The R₂: it is alkoxy, unsaturated alkoxy, aralkoxy, benzyloxy, substituted benzyloxy, two benzyloxies, 4- pyrrole Pyridine methoxyl group, tri-chloroethoxy base, methyl thio ethyoxyl, tolysulfonyl ethyoxyl, p-nitrophenyl thio ethoxy, front three (second) base siloxy, tert-butoxy, anilino-, benzamido group, alpha substituted benzylamine base；

The R₃: alkylamino radical, anilino-, substituted anilinic, benzamido group, alpha substituted benzylamine base, the 2- amino of amino, 1-13 carbon Ethanesulfonic acid base or 2- nitro ethylamino-；

The X: being S, O or NH；

The Y: being CH₂Or NH；

The Z: being S or O.

2. a kind of synthetic method of lysine derivative histone deacetylases inhibitor as described in claim 1, It is characterized in that: being synthesized by following routes:

The R₁, R₂,R₃, the X and R in claim 1₁, R₂,R₃, X is identical.

3. a kind of synthetic method of lysine derivative histone deacetylases inhibitor as described in claim 1, It is characterized in that: being synthesized by following routes:

The R₁, R₂,R₃, the X and R in claim 1₁, R₂,R₃, X is identical.

4. a kind of lysine derivative histone deacetylases inhibitor as claimed in any one of claims 1-3 is answered With, it is characterised in that: as Sirtuin inhibitor application in preparation of anti-tumor drugs.