CN105884802B

CN105884802B - Thiazole simultaneously [3,2 b] 1,2,4 triazine derivatives and its application

Info

Publication number: CN105884802B
Application number: CN201610137515.5A
Authority: CN
Inventors: 胡春; 蔡东; 金辄; 黄二芳; 杜月; 刘晓平; 徐威
Original assignee: Shenyang Pharmaceutical University
Current assignee: Shenyang Pharmaceutical University
Priority date: 2016-03-10
Filing date: 2016-03-10
Publication date: 2017-12-15
Anticipated expiration: 2036-03-10
Also published as: CN105884802A

Abstract

The invention belongs to pharmaceutical technology field, it is related to thiazole simultaneously [3,2b] 1,2,4 triazine derivatives and its application in antibacterials are prepared.Its general structure is as follows：Wherein R is selected from H, C1 C6 alkyl, halogen, C1 C6 alkoxies, the C1 C6 alkyl of halogen substitution；Y is selected from C1 C6 alkyl；‑OH；NR ' (OR ' '), the alkyl of wherein R ', R ' ' independently selected from C1 ~ C6；NHR ', NR ' ' R ' ' ', wherein R ' is selected from C1 C6 alkyl, the benzyl of the C1 C6 alkyl of halogen substitution, unsubstituted or C1 C6 alkyl or halogen substitution, 2 furfuryls, 4 (alkoxycarbonylmethyl) 2 thiazolyl, wherein alkoxy are selected from C1 C6 alkoxies；R ' ', R ' ' ' are independently selected from C1 ~ C6 alkyl, or R ' ', R ' ' ' form pyrrolidinyl together with nitrogen-atoms that they are connected, piperidyl, morpholinyl, N methyl piperazine bases, N substitutions（Or do not substitute）Phenylpiperazinyl.Thiazole simultaneously [3,2b] salt of 1,2,4 triazine derivatives and the pharmaceutically useful sour addition of such compound has obvious antibacterial activity, available for the medicine for preparing antibiosis.

Description

Thiazole simultaneously [3,2-b] -1,2,4- triazine derivatives and its application

Technical field:

The invention belongs to pharmaceutical technology field, and more particularly, to a kind of thiazole, simultaneously [3,2-b] -1,2,4- triazines are spread out Biology, preparation method and its application in antibacterials are prepared.

Background technology：

Antibacterials are the medicines that the major class that current clinical application range is extensive, various in style treats pathogenic infection, For many years with popularization and application of the antibacterials in the whole world, serious abuse condition be present, with going out for multiple drug-resistant bacteria strain It is existing.Wherein, the gram-positive bacteria of drug resistance is particularly acute, such as methicillin staphylococcus (methicillin-resistant Staphylococcus, MRS), the staphylococcus aureus (methicillinresistant of methicillin Staphylococcus aureus, MRSA), heterogeneous vancomycin intermediary staphylococcus aureus (heterogeneous Vancomycin-intermediate Staphylococcus aureus, hVISA), drug resistance of vancomycin Staphylococcus aureus Bacterium (vancomycin-resistant Staphylococcus aureus, VRSA) and the streptococcus pneumonia of penicillin (penicillin-resistant Streptococcus pneumoniae, PRSP) etc. is main present on Present clinical Problem.Develop by more than 80 years, the research and development of antibacterials are directed to drug-resistant bacteria from being turned to for various common bacterias.At present Design synthesis has the important side that the antibacterials of brand new type and brand-new mechanism of action have turned into antibacterials research To.

Simultaneously [3,2-b] -1,2,4- triazine derivatives have potential biology living to thiazole as purine formation analog Property, the framework compound was because it receives much concern in terms of the bioactivity such as anticancer, antibacterial, antiviral in recent years.

The content of the invention：

First purpose of the present invention is to provide a kind of new structure thiazole simultaneously [3,2-b] -1,2,4- triazines derivative Thing and its pharmaceutically acceptable salt.

Second object of the present invention is to provide a kind of novel thiazole simultaneously [3,2-b] -1,2,4- triazine derivatives Preparation method.This preparation method synthesis yield is high, and post processing is simple, suitable for a large amount of productions.

Third object of the present invention is to provide a kind of novel thiazole that simultaneously [3,2-b] -1,2,4- triazine derivatives exist Prepare the application in antibacterials.

To reach above-mentioned first purpose, the present invention uses following technical proposals：

The present invention relates to thiazole simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable salt, it has Following general structure：

Wherein

R is selected from H, C1-C6 alkyl, halogen, C1-C6 alkoxies, the C1-C6 alkyl of halogen substitution；

Y is selected from C1-C6 alkoxies；-OH；The alkyl of-NR ' (OR "), wherein R ', R " independently selected from C1~C6；- NHR ' ,-NR " R " ', wherein R ' are selected from C1-C6 alkyl, the C1-C6 alkyl of halogen substitution, unsubstituted or C1-C6 alkyl or halogen Substituted benzyl, 2- furfuryls, wherein 4- (alkoxycarbonylmethyl) -2- thiazolyls, alkoxy are selected from C1-C6 alkoxies； R ", R " ' independently selected from C1~C6 alkyl, or R ", R " ' form pyrrolidinyl, piperidines together with nitrogen-atoms that they are connected Base, morpholinyl, N methyl piperazine base, N- substitution (or not substituting) Phenylpiperazinyls.

The present invention preferably thiazole with following structure simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically may be used The salt of receiving,

Wherein, R is selected from H, C1-C4 alkyl, halogen, C1-C4 alkoxies, the C1-C4 alkyl of halogen substitution.

Y is selected from C1-C4 alkoxies ,-OH ,-NR ' (OR "), the wherein alkyl of R ', R " independently selected from C1~C4；,- NHR ,-NR ' R ", wherein R be selected from C1-C4 alkyl；The C1-C4 alkyl of halogen substitution；Unsubstituted or C1-C4 alkyl or halogen substitution Benzyl, 2- furfuryls, 4- (alkoxycarbonylmethyl) -2- thiazolyls, wherein alkoxy are selected from C1-C4 alkoxies；R’、R” Independently selected from C1~C4 alkyl, or R ', R " pyrrolidinyl, piperidyl, morpholine are formed together with the nitrogen-atoms that they are connected Base, N methyl piperazine base, N- substitution (or not substituting) Phenylpiperazinyls.

Further, thiazole simultaneously [3,2-b] -1 of the present invention preferably with following structure, 2,4- triazine derivatives and its Pharmaceutically acceptable salt,

Wherein, R is selected from H, CH3, F, Cl ,-OCH3 ,-CF3, can exist with optional position.

Y is selected from-OCH2CH3 ,-OH ,-N (CH3) (OCH3) ,-NHR ' ,-NR " R " ', wherein R ' be selected from- CH2CH2CH2CH3；2- chloroethyls；Unsubstituted or methyl or the benzyl of halogen substitution, 2- furfuryls, 4- (ethoxy carbonyl first Base) -2- thiazolyls；R ", R " ' for independently selected from C1~C4 alkyl, or R ", R " ' group together with nitrogen-atoms that they are connected Into pyrrolidinyl, piperidyl, morpholinyl, N methyl piperazine base, N- substitution (or not substituting) Phenylpiperazinyls.

" substituted ", unless otherwise indicated, referring to substituent can exist in one or more positions, and substituent independently selects From specifically option.

To reach above-mentioned second purpose, the present invention uses following technical proposals：

A kind of novel thiazole simultaneously [3,2-b] -1, the preparation method of 2,4- triazine derivatives, comprises the following steps as following Shown in reaction equation：

A) by 1,2,4- compound in triazine class, it is added in the KOH aqueous solution, stirs lower addition 4- chloroacetyl acetacetic esters Organic solution, after room temperature reaction, filter, be washed with water, ethyl acetate washing, dry.

B) thioether analog derivative and polyphosphoric acids (PPA) are mixed, 100-130 DEG C of heating response.Reaction is down to after terminating Room temperature, water on the rocks, after stirring, filter, be washed with water, dry, ethyl acetate weight is brilliant, obtains powder solid.

C) NaOH solution is added in the methanol solution of ester derivative, reaction is stirred at room temperature to terminating, add water, decompression is steamed Distillation methanol, pH=2 is adjusted with HCl after excess cooling, there are a large amount of pale yellow crystals to separate out, ice bath, suction filtration, drying, ethyl acetate Recrystallization, obtains powdery solid.

D) simultaneously [3,2-b] -1,2,4- triazine -2- carboxylic acids and various amine are added in organic solvent the thiazole for obtaining upper step, Then HOBt, EDCHCl and triethylamine are added, reacts room temperature stirring reaction, reaction solution successively uses HCl solution after reaction Washing, saturation NaHCO₃Solution washing, the washing of saturation NaCl solution, organic layer Na₂SO₄Dry, be evaporated under reduced pressure, column chromatography obtains powder Last solid.

Thioether analog derivative and PPA mass ratio described in step b) are 1:1-1:10, PPA content is (with P₂O₅Content Meter) >=80%.

To reach above-mentioned 3rd purpose, the invention provides thiazole, simultaneously [3,2-b] -1,2,4- triazine derivatives are being made Application in standby antibacterials.

Preferably, the bacterium is gram-positive bacteria and Gram-negative bacteria.

The invention further relates to antibacterial Pharmaceutical composition, it is different that said composition contains compound or its solid in said structure formula Structure body or its pharmaceutically useful acid-addition salts and pharmaceutically useful carrier.

Embodiment：

In order to illustrate more clearly of the present invention, with reference to preferred embodiment, the present invention is described further.Ability Field technique personnel should be appreciated that following specifically described content is illustrative and be not restrictive, and this should not be limited with this The protection domain of invention.

Embodiment 1:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N, N- dimethyl The preparation of acetamide (TB01)

Step 1)：4- [(6- benzyl -5- oxo -2,5- dihydro -1,2,4- triazine -3- bases) sulfenyl] -3- ketobutyric acid second The preparation of ester (MA01)

Thio -3,4- dihydros -1,2,4- triazines -5 (2H) -one of 0.01mol (2.19g) 6- benzyls -3- is added to 5mL DMF In, lower addition 10%KOH solution 5.6ml are stirred, it is molten that 0.01mol (1.64g) 4- chloroacetyl acetacetic ester 4ml ethanol is then added dropwise Liquid, after reacting at room temperature 30min, water dilution on the rocks, there are a large amount of crystal to disengage, filter, be washed with water, dry, ethyl acetate is tied again Crystalline substance, obtain white fine sand sprills, yield 54%.

ESI-MS(m/z):347.99(M+H)⁺。

Step 2)：2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases) ethyl acetate (MB11) preparation

By 4.0g 4- [(6- benzyl -5- oxo -2,5- dihydro -1,2,4- triazine -3- bases) sulfenyl] -3- ketobutyric acid second Ester is added in 120 DEG C of 8.0g 85%PPA, stirring reaction 30min.Room temperature is down in reaction after terminating, added 15ml frozen water, stirred After mixing uniformly, filter, be washed with water, dry, re-crystallizing in ethyl acetate, obtain white powder solid, yield 47%.

¹H NMR(400MHz,Chloroform-d)δ7.42–7.34(m,2H),7.39–7.27(m,2H),7.30–7.21 (m, 1H), 6.80 (t, J=1.0Hz, 1H), 4.19 (q, J=7.1Hz, 2H), 4.13 (s, 2H), 3.80 (d, J=1.1Hz, 2H), 1.28 (t, J=7.1Hz, 3H)；ESI-MS(m/z):329.7(M+H)⁺。

Step 3)：2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases) acetic acid (MC11) Prepare

6mL 2mol/L NaOH are added to 0.004mol (1.31g) 2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -3- bases) ethyl acetate 20mL methanol solutions in, react at room temperature 2h, add 40m water, then be evaporated under reduced pressure and remove Alcohol, pH=2 is adjusted with 1mol/L HCl after excess cooling, there are a large amount of pale yellow crystals to separate out, is filtered, is dried, ethyl acetate is tied again Crystalline substance, obtain light yellow solid sprills, yield 65%.

¹H NMR(600MHz,DMSO-d₆) δ 12.84 (s, 1H), 7.30-7.24 (m, 5H), 7.21 (tt, J=5.5, 2.5Hz, 1H), 3.89 (d, J=51.1Hz, 4H)；ESI-MS(m/z):302.3(M+H)⁺。

Step 4)：2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N, N- dimethyl The preparation of acetamide (TB01)

2.38mmol (0.19g) dimethylamine hydrochlorides and 2.38mmol (0.72g) 2- (6- benzyl -7- oxo -7H- thiazoles And [3,2-b] -1,2,4- triazine -3- bases) acetic acid is added to 24.0ml CH₂Cl₂In, 2.62mmol is then added into solution again (0.35g) HOBt, 2.62mmol (0.50g) EDC hydrochlorides and triethylamine 10mmol (1.01g).Reaction be stirred at room temperature 10h with On.Reaction solution 5%HCl (3 × 30.0ml), 5%NaHCO₃Solution (40.0ml), H₂O (40.0ml), saturation NaCl (40.0ml), Then Na₂SO₄Dry, column chromatography (CH₂Cl₂/MeOH,50:1) white solid, yield 66% are obtained.

IR(KBr):υ3086,3036,2926,1651,1576,1479,1377,768,718cm^-1；¹H NMR(600MHz, DMSO-d₆)δ7.31–7.19(m,5H),7.16(s,1H),3.94(s,2H),3.84(s,2H),2.95(s,3H),2.79(s, 3H)；ESI-MS(m/z):329.3(M+H)⁺。

Embodiment 2:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N, N- diethyl The preparation of acetamide (TB02)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into diethylamine, yield 76%.

IR(KBr):υ3115,2965,2932,1643,1570,1487,1456,1371,750,698cm^-1；¹H NMR (400MHz,Chloroform-d)δ7.38–7.26(m,4H),7.29–7.20(m,1H),6.78(s,1H),4.13(s,2H), 3.76 (d, J=1.0Hz, 2H), 3.41 (q, J=7.1Hz, 2H), 3.31 (q, J=7.2Hz, 2H), 1.19 (dt, J=25.4, 7.1Hz,6H)；ESI-MS(m/z):357.3(M+H)⁺。

Embodiment 3:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N, N- dibutyl The preparation of acetamide (TB03)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into di-n-butylamine, yield 61%.

IR(KBr):υ3123,2957,2928,2870,1634,1570,1481,1456,1369,747,702cm^-1；¹H NMR(400MHz,Chloroform-d)δ7.39–7.20(m,6H),4.12(s,2H),3.80–3.75(m,2H),3.38–3.30 (m, 2H), 3.28-3.19 (m, 2H), 1.67-1.48 (m, 4H), 1.36 (dq, J=18.2,7.5Hz, 4H), 0.98 (dt, J= 21.1,7.3Hz,6H)；ESI-MS(m/z):413.1(M+H)⁺。

Embodiment 4:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N, N- diisopropyls The preparation of yl acetamide (TB04)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into diisopropylamine, yield 74%.

IR(KBr):υ3111,2969,2947,1639,1603,1566,1479,1449,1373,748,702cm^-1；¹H NMR(400MHz,Chloroform-d)δ7.38–7.31(m,2H),7.35–7.25(m,2H),7.28–7.18(m,1H),6.73 (s, 1H), 4.11 (s, 2H), 3.92 (h, J=6.8Hz, 1H), 3.77 (s, 2H), 1.39 (d, J=6.7Hz, 6H), 1.27 (d, J =6.7Hz, 6H)；ESI-MS(m/z):385.4(M+H)⁺。

Embodiment 5:6- benzyls -3- [2- oxos -2- (piperidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- three The preparation of piperazine -7- ketone (TB05)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into piperidines, yield 55%.

IR(KBr):υ3107,2953,2931,2855,1643,1566,1468,1445,1389,746,706cm^-1；¹H NMR(400MHz,Chloroform-d)δ7.38–7.27(m,4H),7.30–7.20(m,1H),6.76(s,1H),4.14(s, 2H), 3.79-3.74 (m, 2H), 3.57 (t, J=5.6Hz, 2H), 3.38 (t, J=5.5Hz, 2H), 1.70 (q, J=6.4, 5.9Hz, 2H), 1.59 (dh, J=8.2,4.5,4.1Hz, 4H)；ESI-MS(m/z):369.3(M+H)⁺。

Embodiment 6:6- benzyls -3- (2- morpholinyl -2- oxoethyls) -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -7- The preparation of ketone (TB06)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into morpholine, yield 76%.

IR(KBr):υ3076,2967,2920,2845,1649,1576,1491,1441,1375,770,708cm^-1；¹H NMR(400MHz,Chloroform-d)δ7.31(s,3H),7.35–7.24(m,2H),6.78(s,1H),4.14(s,2H), 3.74 (s, 2H), 3.71-3.66 (m, 4H), 3.60 (t, J=4.8Hz, 2H), 3.40 (t, J=4.8Hz, 2H)；ESI-MS(m/ z):371.2(M+H)⁺。

Embodiment 7:6- benzyls -3- [2- (4- methylpiperazine-1-yls) -2- oxoethyls] -7H- thiazoles simultaneously [3,2-b] -1, The preparation of 2,4- triazine -7- ketone (TB07)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into methyl piperazine, yield 52%.

IR(KBr):υ3084,2922,2801,1641,1576,1485,1456,758,696cm^-1；¹H NMR(600MHz, DMSO-d₆) δ 7.27 (d, J=5.9Hz, 4H), 7.21 (ddd, J=8.6,5.6,2.4Hz, 1H), 7.18 (s, 1H), 3.94 (s, 2H), 3.90 (s, 2H), 3.44 (dt, J=24.4,4.9Hz, 4H), 2.33 (d, J=6.4Hz, 2H), 2.26 (s, 2H), 2.19 (s,3H)；ESI-MS(m/z):384.3(M+H)⁺。

Embodiment 8:6- benzyls -3- [2- oxos -2- (pyrrolidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- The preparation of triazine -7- ketone (TB08)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into nafoxidine, yield 45%.

IR(KBr):υ3107,2967,2876,1634,1566,1466,1442,1385,756,704cm^-1；¹H NMR (400MHz, Chloroform-d) δ 7.38-7.21 (m, 5H), 6.84 (d, J=1.2Hz, 1H), 4.15 (s, 2H), 3.69 (s, 2H), 3.48 (t, J=6.9Hz, 2H), 3.37 (t, J=6.8Hz, 2H), 2.01 (p, J=6.7Hz, 2H), 1.92 (p, J= 6.7Hz,2H)；ESI-MS(m/z):355.3(M+H)⁺。

Embodiment 9:6- benzyls -3- [2- oxos -2- (4- phenylpiperazine -1- bases) ethyl] -7H- thiazoles simultaneously [3,2-b] -1, The preparation of 2,4- triazine -7- ketone (TB09)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into phenylpiperazine, yield 59%.

IR(KBr):υ3109,2957,2816,2818,1639,1599,1485,1454,1387,758,702cm^-1；¹H NMR (400MHz, Chloroform-d) δ 7.39-7.17 (m, 7H), 6.98 (dd, J=7.7,3.6Hz, 3H), 6.80 (s, 1H), 4.14 (s, 2H), 3.80 (d, J=8.4Hz, 4H), 3.59 (t, J=5.1Hz, 2H), 3.24-3.16 (m, 4H)；ESI-MS(m/ z):446.3(M+H)⁺。

Embodiment 10:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- isopropyls The preparation of acetamide (TB10)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into isopropylamine, yield 64%.

IR(KBr):υ3076,2875,1659,1585,1499,1454,1385,750,694cm^-1；¹H NMR(600MHz, DMSO-d₆) δ 7.99 (d, J=7.6Hz, 1H), 7.26 (dd, J=13.7,6.5Hz, 4H), 7.23-7.18 (m, 2H), 3.92 (s, 2H), 3.84 (h, J=6.8Hz, 1H), 3.67 (s, 2H), 1.05 (d, J=6.6Hz, 6H)；ESI-MS(m/z):343.3(M +H)⁺。

Embodiment 11:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- cyclopropyl The preparation of acetamide (TB11)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into cyclopropylamine, yield 77%.

IR(KBr):υ3285,3053,2951,2920,1657,1611,1572,1549,1463,1377,739,698cm^-1；¹H NMR (400MHz, Chloroform-d) δ 7.41-7.27 (m, 5H), 6.81 (d, J=6.1Hz, 1H), 5.68 (s, 1H), 4.16 (d, J=2.9Hz, 2H), 3.53 (s, 2H), 2.60 (tq, J=6.9,3.6Hz, 1H), 0.88-0.71 (m, 2H), 0.49- 0.40(m,2H)；ESI-MS(m/z):341.3(M+H)⁺。

Embodiment 12:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (furans - 2- ylmethyls) acetamide (TB12) preparation

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 2- furylamines, yield 65%.

IR(KBr):υ3275,3073,3028,1645,1568,1549,1492,1454,1385,739,698cm^-1；¹H NMR(600MHz,DMSO-d₆) δ 8.53 (t, J=5.7Hz, 1H), 7.56-7.52 (m, 1H), 7.29-7.25 (m, 4H), 7.23- 7.21 (m, 2H), 6.35 (s, 1H), 6.23 (d, J=3.1Hz, 1H), 4.26 (d, J=5.6Hz, 2H), 3.90 (s, 2H), 3.75 (s,2H)；ESI-MS(m/z):381.2(M+H)⁺。

Embodiment 13:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (2- benzyl chlorides Base) acetamide (TB13) preparation

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 2- chlorobenzylamines, yield 66%.

IR(KBr):υ3264,3065,2931,1647,1568,1543,1481,1456,1385,752cm^-1；¹H NMR (400MHz, Chloroform-d) δ 7.40 (dt, J=7.3,1.1Hz, 1H), 7.30-7.18 (m, 8H), 6.83 (s, 1H), 6.00 (s, 1H), 4.43 (d, J=5.9Hz, 2H), 4.07 (s, 2H), 3.62 (s, 2H)；ESI-MS(m/z):425.0(M+H)⁺。

Embodiment 14:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (4- methyl Benzyl) acetamide (TB14) preparation

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 4- methylbenzylamines, yield 72%.

IR(KBr):υ3273,3076,2920,1647,1558,1489,1458,1381,802,748,696cm^-1；¹H NMR(600MHz,DMSO-d₆) δ 8.51 (t, J=6.0Hz, 1H), 7.27-7.23 (m, 5H), 7.22-7.18 (m, 1H), 7.14 (d, J=7.7Hz, 2H), 7.06 (d, J=7.6Hz, 2H), 4.23 (d, J=5.9Hz, 2H), 3.90 (s, 2H), 3.78 (s, 2H),2.23(s,3H)；ESI-MS(m/z):405.0(M+H)⁺。

Embodiment 15:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (4- fluorine benzyls Base) acetamide (TB15) preparation

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 4- fluorin benzyl amines, yield 67%.

IR(KBr):υ3261,3065,2932,2880,1639,1568,1547,1510,1483,1387,833,743, 696cm^-1；¹H NMR(600MHz,DMSO-d₆) δ 8.56 (t, J=6.0Hz, 1H), 7.31-7.17 (m, 8H), 7.08 (t, J= 8.6Hz, 2H), 4.26 (d, J=5.9Hz, 2H), 3.90 (s, 2H), 3.79 (s, 2H)；ESI-MS(m/z):409.4(M+H)⁺。

Embodiment 16:2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (2,4- bis- Chlorobenzyl) acetamide (TB16) preparation

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 2,4- dichloro-benzylamines, yield 57%.

IR(KBr):υ3271,3076,2928,1647,1558,1489,1419,1386,831,748,696cm^-1；¹H NMR(600MHz,DMSO-d₆) δ 8.61 (t, J=5.9Hz, 1H), 7.58 (d, J=2.1Hz, 1H), 7.37-7.29 (m, 2H), 7.27-7.17 (m, 6H), 4.31 (d, J=5.8Hz, 2H), 3.91 (s, 2H), 3.84 (s, 2H)；ESI-MS(m/z):459.1(M +H)⁺。

Embodiment 17:2- { 2- [2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases) acetyl Amino] thiazole-4-yl ethyl acetate (TB17) preparation

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 2- (thiazolamine -4- Base) ethyl acetate, yield 56%.

IR(KBr):υ3179,3107,2976,2926,1734,1692,1638,1553,1481,1452,1387,1255, 754,700cm^-1；¹H NMR(400MHz,Chloroform-d)δ9.67(s,1H),7.32–7.24(m,2H),7.20–7.12 (m, 3H), 6.87 (d, J=6.8Hz, 2H), 4.19 (q, J=7.1Hz, 2H), 4.12 (s, 2H), 3.90 (s, 2H), 3.76- 3.70 (m, 2H), 1.28 (t, J=7.1Hz, 3H)；ESI-MS(m/z):470.3(M+H)⁺。

Embodiment 18:6- benzyls -3- { 2- [4- (2,4 dichloro benzene base) piperazine -1- bases] -2- oxoethyls } -7H- thiazoles And the preparation of [3,2-b] -1,2,4- triazine -7- ketone (TB18)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 1- (2,4- dichlorophenyl) piperazine Piperazine, yield 64%.

IR(KBr):υ3109,2955,2824,1649,1593,1570,1490,1450,1387,851,806,750, 704cm^-1；¹H-NMR(300MHz,CDCl₃):δ 7.21 (2H, d, J=8.6Hz), 7.20 (1H, d), 6.85 (1H, s), 6.82 (2H, dd), 6.76 (2H, d, J=8.6Hz), 6.64 (1H, s), 4.19 (2H, t), 3.94 (2H, s), 3.76 (7H, s), 2.86 (2H,t),2.63(4H,s),2.10(3H,s)；ESI-MS(m/z):514.1(M+H)⁺。

Embodiment 19:6- benzyls -3- { 2- [4- (2,6- 3,5-dimethylphenyls) piperazine -1- bases] -2- oxoethyls } -7H- thiophenes The preparation of azoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TB19)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 1- (2,6- 3,5-dimethylphenyl) Piperazine, yield 68%.

IR(KBr):υ3073,3003,2918,2816,1655,1606,1576,1487,1454,1441,1377,779, 762,710cm^-1；¹H NMR(400MHz,Chloroform-d)δ7.40–7.21(m,5H),7.09–7.00(m,3H),6.82 (s, 1H), 4.16 (s, 2H), 3.83 (s, 2H), 3.74 (t, J=5.0Hz, 2H), 3.54 (t, J=4.8Hz, 2H), 3.14 (dt, J=10.1,5.0Hz, 4H), 2.36 (s, 6H)；ESI-MS(m/z):475.5(M+H)⁺

Embodiment 20:6- benzyls -3- { 2- [4- (2,4- 3,5-dimethylphenyls) piperazine -1- bases] -2- oxoethyls } -7H- thiophenes The preparation of azoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TB20)

According to the method for embodiment 1, difference is, changes dimethylamine hydrochloride in step 4) into 1- (2,4- 3,5-dimethylphenyl) Piperazine, yield 70%.

IR(KBr):υ3115,2957,2918,2806,1649,1572,1476,1447,1373,814,752,696cm^-1 ；¹H NMR(400MHz,Chloroform-d)δ7.35(s,2H),7.39–7.30(m,2H),7.34-7.22(m,2H),7.10– 6.98 (m, 2H), 6.91 (d, J=8.1Hz, 1H), 4.16 (s, 2H), 3.79 (dd, J=19.4,3.0Hz, 4H), 3.57 (t, J =4.9Hz, 2H), 2.90 (q, J=5.0Hz, 4H), 2.34 (d, J=13.7Hz, 6H)；ESI-MS(m/z):474.3(M+H)⁺。

Embodiment 21:2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N, The preparation of N- diethyl acetamides (TB21)

Step 1)：3- oxos -4- [(5- oxos -6- (2- chloros benzyl) -2,5- dihydro -1,2,4- triazine -3- bases) sulphur Base] ethyl butyrate (MA02) preparation

Thio -3,4- dihydros -1,2,4- triazines -5 (2H) -one of 0.01mol (2.54g) 6- (2- chlorobenzyls) -3- is added to In 5mL DMF, lower addition 10%KOH solution 5.6ml are stirred, 0.01mol (1.64g) 4- chloroacetyl acetacetic esters are then added dropwise 4ml ethanol solutions, after reacting at room temperature 30min, water dilution on the rocks, there are a large amount of crystal to disengage, filter, be washed with water, dry, acetic acid Ethyl ester recrystallizes, and obtains white fine sand sprills, yield 38%.

ESI-MS(m/z):381.96(M+H)⁺。

Step 2)：2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid second The preparation of ester (MB12)

By 4.0g 3- oxos -4- { [5- oxos -6- (2- chloros benzyl) -2,5- dihydro -1,2,4- triazine -3- bases] sulphur Base } ethyl butyrate is added in 120 DEG C of 8.0g 85%PPA, stirring reaction 30min.Reaction is down to room temperature after terminating, and adds 15ml frozen water, after stirring, filter, be washed with water, dry, re-crystallizing in ethyl acetate, obtain white powder solid, yield 46%.

¹H NMR(600MHz,DMSO-d₆) δ 7.43 (d, J=7.6Hz, 1H), 7.35 (dd, J=7.1,2.1Hz, 1H), 7.28 (dt, J=8.5,5.8Hz, 3H), 4.10 (s, 2H), 3.91 (q, J=7.1Hz, 2H), 3.74 (s, 2H), 1.09 (t, J= 7.1Hz,3H)；ESI-MS(m/z):364.1(M+H)⁺。

Step 3)：2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid (MC12) preparation

6mL 2mol/L NaOH are added into 0.004mol (1.45g) 2-, and (6- (2- chlorobenzyls) -7- oxo -7H- thiazoles are simultaneously [3,2-b] -1,2,4- triazine -3- bases) ethyl acetate 20mL methanol solutions in, react at room temperature 2h, add 40m water, then depressurize Distillation removes alcohol, adjusts pH=2 with 1mol/L HCl after excess cooling, has a large amount of pale yellow crystals to separate out, filter, dries, acetic acid second Ester recrystallizes, and obtains light yellow solid sprills, yield 45%.

¹H NMR(600MHz,DMSO-d₆) δ 12.66 (s, 1H), 7.42 (dd, J=7.4,1.8Hz, 1H), 7.33 (dd, J =7.1,2.2Hz, 1H), 7.30-7.22 (m, 3H), 4.09 (s, 2H), 3.69 (s, 2H)；ESI-MS(m/z):336.7(M+H )⁺。

Step 4)：2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N, N- The preparation of diethyl acetamide (TB21)

2.38mmol (0.18g) diethylamine and 2.38mmol (0.80g) 2- (6- (2- methoxybenzyls) -7- oxo -7H- thiophenes Azoles simultaneously [3,2-b] -1,2,4- triazine -3- bases) acetic acid is added to 24.0ml CH₂Cl₂In, 2.62mmol is then added into solution again (0.35g) HOBt, 2.62mmol (0.50g) EDC hydrochlorides and triethylamine 10mmol (1.01g).Reaction be stirred at room temperature 10h with On.Reaction solution 5%HCl (3 × 30.0ml), 5%NaHCO₃Solution (40.0ml), H₂O (40.0ml), saturation NaCl (40.0ml), Then Na₂SO₄Dry, column chromatography (CH₂Cl₂/MeOH,50:1) white solid, yield 65% are obtained.

IR(KBr):υ3327,1702,1645,1564,1502,1489,1474,1354,819cm^-1；¹H NMR (400MHz, Chloroform-d) δ 7.38 (dt, J=5.9,4.2Hz, 2H), 7.31-7.19 (m, 3H), 6.82 (d, J= 1.2Hz, 1H), 4.31 (s, 2H), 3.65 (d, J=0.9Hz, 2H), 3.34 (q, J=7.1Hz, 2H), 3.17 (q, J=7.2Hz, 2H), 1.11 (td, J=7.2,2.5Hz, 6H)；ESI-MS(m/z):391.1(M+H)⁺。

Embodiment 22:2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of butyl acetamide (TB22)

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into n-butylamine, yield 68%.

IR(KBr):υ3293,3069,2928,1652,1567,1486,1383,754cm^-1；¹H NMR(600MHz, DMSO-d₆) δ 7.84 (t, J=5.6Hz, 1H), 7.45-7.40 (m, 1H), 7.32-7.24 (m, 2H), 7.27-7.18 (m, 2H), 4.07 (s, 2H), 3.57 (s, 2H), 2.96 (q, J=6.6Hz, 2H), 1.31 (p, J=7.1Hz, 2H), 1.22 (h, J= 7.3Hz, 2H), 0.81 (t, J=7.3Hz, 3H)；ESI-MS(m/z):391.2(M+H)⁺。

Embodiment 23:6- (2- chlorobenzyls) -3- (2- morpholinyl -2- oxoethyls) -7H- thiazoles simultaneously [3,2-b] -1,2,4- The preparation of triazine -7- ketone (TB23)

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into morpholine, yield 71%.

IR(KBr):υ 3100,1639,1578,1512,1483,1417,1238,1213,1038,770cm^-1；¹H NMR (400MHz,Chloroform-d)δ7.45–7.33(m,2H),7.33–7.21(m,2H),6.78(s,1H),4.31(s,2H), 3.71-3.59 (m, 6H), 3.54 (t, J=4.9Hz, 2H), 3.27 (t, J=4.8Hz, 2H)；ESI-MS(m/z):405.0(M+ H)⁺。

Embodiment 24:6- (2- chlorobenzyls) -3- [2- oxos -2- (pyrrolidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -7- ketone (TB24) preparation

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into nafoxidine, yield 55%.

¹H NMR(400MHz,DMSO-d₆) δ 7.45 (dd, J=7.6,1.7Hz, 1H), 7.38 (dd, J=7.1,2.2Hz, 1H), 7.35-7.26 (m, 2H), 7.19 (s, 1H), 4.12 (s, 2H), 3.34 (s, 2H), 3.16 (t, J=6.8Hz, 4H), 1.92–1.71(m,4H)；ESI-MS(m/z):389.1(M+H)⁺。

Embodiment 25:2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of cyclopropyl-acetamide (TB25)

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into cyclopropylamine, yield 43%.

¹H NMR (400MHz, Chloroform-d) δ 7.43 (ddd, J=21.3,5.7,3.6Hz, 2H), 7.34-7.21 (m, 2H), 6.82 (s, 1H), 5.52 (s, 1H), 4.33 (d, J=5.5Hz, 2H), 3.42 (s, 2H), 2.53 (dq, J=7.1, 3.5Hz, 1H), 0.77 (td, J=7.0,5.3Hz, 2H), 0.48-0.39 (m, 2H)；ESI-MS(m/z):375.0(M+H)⁺。

Embodiment 26:6- (2- chlorobenzyls) -3- [2- (4- (2- chlorphenyls) piperazine -1- bases) -2- oxoethyls] -7H- thiophenes The preparation of azoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TB26)

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into 1- (2- chlorphenyls) piperazine, yield 54%.

¹H NMR (400MHz, Chloroform-d) δ 7.47-7.41 (m, 2H), 7.38 (dd, J=5.7,3.6Hz, 1H), 7.34-7.23 (m, 3H), 7.09 (t, J=7.5Hz, 2H), 6.80 (s, 1H), 4.32 (s, 2H), 3.72 (d, J=19.7Hz, 4H), 3.47 (d, J=5.2Hz, 2H), 3.04 (s, 4H)；ESI-MS(m/z):514.0(M+H)⁺。

Embodiment 27:2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of (furans -2- ylmethyls) acetamide (TB27)

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into 2- furylamines, yield 48%.

¹H NMR(600MHz,DMSO-d₆) δ 8.36 (t, J=5.7Hz, 1H), 7.53 (s, 1H), 7.43 (d, J=7.7Hz, 1H), 7.32-7.19 (m, 4H), 6.36-6.32 (m, 1H), 6.19 (d, J=3.1Hz, 1H), 4.16 (d, J=5.6Hz, 2H), 4.06(s,2H),3.62(s,2H)；ESI-MS(m/z):414.9(M+H)⁺

Embodiment 28:N- (2- chlorobenzyls) -2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- Triazine -3- bases] acetamide (TB28) preparation

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into 2- chlorobenzylamines, yield 47%.

IR(KBr):υ3275,3069,1647,1560,1487,1441,1379,1242,750cm^-1；¹H NMR (400MHz, Chloroform-d) δ 7.38 (ddd, J=21.4,6.6,2.6Hz, 2H), 7.35-7.12 (m, 6H), 6.82 (d, J =0.8Hz, 1H), 5.85 (s, 1H), 4.39 (d, J=6.0Hz, 2H), 4.26 (s, 2H), 3.53 (d, J=0.9Hz, 2H)； ESI-MS(m/z):459.0(M+H)⁺。

Embodiment 29:2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of (4- luorobenzyls) acetamide (TB29)

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into 4- fluorin benzyl amines, yield 42%.

¹H NMR (400MHz, Chloroform-d) δ 7.36-7.25 (m, 2H), 7.17 (qd, J=6.5,5.6,3.6Hz, 4H), 7.08-6.99 (m, 2H), 6.84 (s, 1H), 5.75 (d, J=7.0Hz, 1H), 4.32-4.23 (m, 4H), 3.52 (s, 2H)；ESI-MS(m/z):442.1(M+H)⁺。

Embodiment 30:2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of (4- methyl-benzyls) acetamide (TB30)

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into 4- methylbenzylamines, yield 58%.

¹H NMR(400MHz,Chloroform-d)δ7.37–7.28(m,1H),7.25–7.12(m,5H),7.06(d,J =7.8Hz, 2H), 6.84 (s, 1H), 5.67 (s, 1H), 4.30-4.23 (m, 4H), 3.50 (s, 2H), 2.37 (s, 3H)；ESI- MS(m/z):439.0(M+H)⁺

Embodiment 31:6- (2- chlorobenzyls) -3- { 2- [4- (2,6- 3,5-dimethylphenyls) piperazine -1- bases] -2- oxoethyls } - The preparation of 7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TB31)

According to the method for embodiment 21, difference is, changes diethylamine in step 4) into 1- (2,6- 3,5-dimethylphenyl) piperazine, Yield 69%.

¹H NMR (400MHz, Chloroform-d) δ 7.41 (ddd, J=9.4,4.8,2.5Hz, 2H), 7.28-7.23 (m, 2H), 7.04 (d, J=2.2Hz, 3H), 6.82 (s, 1H), 4.32 (s, 2H), 3.71 (s, 2H), 3.67 (s, 2H), 3.39 (t, J=4.9Hz, 2H), 3.09 (t, J=4.7Hz, 4H), 2.36 (s, 6H)；ESI-MS(m/z):508.2(M+H)⁺

Embodiment 32:3- (2- morpholinyl -2- oxoethyls) -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -7- ketone (TB32) preparation

Step 1)：3- oxos -4- { [5- oxos -6- (4- (trifluoromethyl) benzyl) -2,5- dihydro -1,2,4- triazines -3- Base] sulfenyl ethyl butyrate (MA03) preparation

By 0.01mol (2.87g) 6- [4- (trifluoromethyl) benzyl] thio -3,4- dihydros -1,2,4- triazines -5 of -3- (2H) -one is added in 5mL DMF, stirs lower addition 10%KOH solution 5.6ml, 0.01mol (1.64g) 4- chloroethenes are then added dropwise Ethyl acetoacetic acid ethyl ester 4ml ethanol solutions, after reacting at room temperature 30min, water dilution on the rocks, there are a large amount of crystal to disengage, filter, be washed with water Wash, dry, re-crystallizing in ethyl acetate, obtain white fine sand sprills, yield 44%.

ESI-MS(m/z):416.1(M+H)⁺。

Step 2)：2- { 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -3- Base } ethyl acetate (MB13) preparation

By 4.0g 3- oxos -4- { [5- oxos -6- (4- (trifluoromethyl) benzyl) -2,5- dihydro -1,2,4- triazines -3- Base] sulfenyl } ethyl butyrate is added in 120 DEG C of 8.0g 85%PPA, stirring reaction 30min.Reaction is down to room temperature after terminating, and adds Enter 15ml frozen water, after stirring, filter, be washed with water, dry, re-crystallizing in ethyl acetate, obtain white powder solid, yield 60%.

¹H NMR(400MHz,Chloroform-d)δ7.45–7.37(m,2H),7.20–7.13(m,2H),6.82(d,J =1.0Hz, 1H), 4.24-4.10 (m, 4H), 3.81 (d, J=1.0Hz, 2H), 1.27 (t, J=7.1Hz, 3H)；ESI-MS(m/ z):398.1(M+H)⁺。

Step 3)：2- { 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -3- Base } acetic acid (MC13) preparation

By 6mL 2mol/L NaOH be added to 0.004mol (1.59g) 2- 7- oxos -6- [4- (trifluoromethyl) benzyl] - 7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases } ethyl acetate 20mL methanol solutions in, react at room temperature 2h, add 40m Water, then be evaporated under reduced pressure except alcohol, pH=2 is adjusted with 1mol/L HCl after excess cooling, there are a large amount of pale yellow crystals to separate out, is filtered, is done It is dry, re-crystallizing in ethyl acetate, obtain light yellow solid sprills, yield 65%.

¹H NMR (400MHz, Chloroform-d) δ 7.44-7.36 (m, 2H), 7.16 (d, J=8.2Hz, 2H), 6.86 (s,1H),4.13(s,2H),3.86(s,2H)；ESI-MS(m/z):370.3(M+H)⁺。

Step 4)：3- (2- morpholinyl -2- oxoethyls) -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] - The preparation of 1,2,4- triazine -7- ketone (TB32)

2.38mmol (0.21g) morpholines and 2.38mmol (0.89g) 2- 7- oxos -6- [4- (trifluoromethyl) benzyl] - 7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases } acetic acid is added to 24.0ml CH₂Cl₂In, then added again into solution 2.62mmol (0.35g) HOBt, 2.62mmol (0.50g) EDC hydrochlorides and triethylamine 10mmol (1.01g).Reaction room temperature is stirred Mix more than 10h.Reaction solution 5%HCl (3 × 30.0ml), 5%NaHCO₃Solution (40.0ml), H₂O (40.0ml), saturation NaCl (40.0ml), then Na₂SO₄Dry, column chromatography (CH₂Cl₂/MeOH,50:1) white solid, yield 51% are obtained.

IR(KBr):υ3107,2957,2853,1643,1574,1510,1484,1443,1391,826cm^-1；¹H NMR (400MHz, Chloroform-d) δ 7.41-7.34 (m, 2H), 7.18 (d, J=8.1Hz, 2H), 6.82 (s, 1H), 4.14 (s, 2H), 3.80-3.69 (m, 6H), 3.64 (t, J=4.7Hz, 2H), 3.47 (t, J=4.9Hz, 2H)；ESI-MS(m/z):439.5 (M+H)⁺。

Embodiment 33:N- cyclopropyl -2- 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] -1, 2,4- triazine -3- bases } acetamide (TB33) preparation

According to the method for embodiment 32, difference is, changes morpholine in step 4) into cyclopropylamine, yield 45%.

¹H NMR(600MHz,DMSO-d₆) δ 8.13-8.09 (m, 1H), 7.42 (d, J=8.3Hz, 2H), 7.26 (d, J= 8.2Hz, 2H), 7.20 (s, 1H), 3.97 (s, 2H), 3.63 (s, 2H), 2.58 (dt, J=7.4,3.6Hz, 1H), 0.60 (td, J =6.9,4.8Hz, 2H), 0.36 (p, J=4.5Hz, 2H)；ESI-MS(m/z):409.2(M+H)⁺。

Embodiment 34:N- (2- chlorobenzyls) -2- { 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -3- bases acetamide (TB34) preparation

According to the method for embodiment 32, difference is, changes morpholine in step 4) into 2- chlorobenzylamines, yield 49%.

¹H NMR (400MHz, Chloroform-d) δ 7.41 (dd, J=7.4,1.7Hz, 1H), 7.36 (dd, J=7.0, 2.3Hz, 1H), 7.33-7.22 (m, 4H), 7.12 (d, J=8.2Hz, 2H), 6.84 (s, 1H), 6.12 (s, 1H), 4.52 (d, J =5.9Hz, 2H), 4.02 (s, 2H), 3.67 (s, 2H)；ESI-MS(m/z):493.1(M+H)⁺。

Embodiment 35:N- (4- methyl-benzyls) -2- { 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -3- bases acetamide (TB35) preparation

According to the method for embodiment 32, difference is, changes morpholine in step 4) into 4- methylbenzylamines, yield 61%.

¹H NMR (400MHz, Chloroform-d) δ 7.26 (s, 1H), 7.14 (tt, J=15.2,7.7Hz, 7H), 6.86 (s, 1H), 5.88 (s, 1H), 4.38 (d, J=5.7Hz, 2H), 4.06 (s, 2H), 3.65 (d, J=0.9Hz, 2H), 2.36 (s, 3H)；ESI-MS(m/z):473.1(M+H)⁺。

Embodiment 36:N- (2,4- dichloro benzyls) -2- 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3, 2-b] -1,2,4- triazine -3- bases acetamide (TB36) preparation

According to the method for embodiment 32, difference is, changes morpholine in step 4) into 2,4- dichloro-benzylamines, yield 55%.

¹H NMR(600MHz,DMSO-d₆) δ 8.60 (t, J=6.0Hz, 1H), 7.56 (d, J=1.8Hz, 1H), 7.38- 7.31 (m, 4H), 7.26 (s, 1H), 7.22 (d, J=8.2Hz, 2H), 4.30 (d, J=5.8Hz, 2H), 3.95 (s, 2H), 3.83 (s,2H)；ESI-MS(m/z):527.2(M+H)⁺。

Embodiment 37:N, N- diethyl -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2, 4- triazine -3- bases] acetamide (TC01) preparation

Step 1)：3- oxos -4- { [5- oxos -6- (4- methoxy-benzyls) -2,5- dihydro -1,2,4- triazine -3- bases] sulphur Base } ethyl butyrate (MA04) preparation

By 0.01mol (2.49g) 6- [4- (methoxy-benzyl) -3- is thio] -3,4- dihydro -1,2,4- triazines -5 (2H) - Ketone is added in 5mL DMF, stirs lower addition 10%KOH solution 5.6ml, 0.01mol (1.64g) 4- chloroethene ethyl acetoacetic acids are then added dropwise Ethyl ester 4ml ethanol solutions, after reacting at room temperature 30min, water dilution on the rocks, there are a large amount of crystal to disengage, filter, be washed with water, dry, Re-crystallizing in ethyl acetate, obtain white fine sand sprills, yield 39%.

ESI-MS(m/z):416.1(M+H)⁺。

Step 2)：2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] second The preparation of acetoacetic ester (MB14)

By 4.0g 3- oxos -4- { [5- oxos -6- (4- methoxy-benzyls) -2,5- dihydro -1,2,4- triazine -3- bases] sulphur Base } ethyl butyrate is added in 120 DEG C of 8.0g 85%PPA, stirring reaction 30min.Reaction is down to room temperature after terminating, and adds 15ml frozen water, after stirring, filter, be washed with water, dry, re-crystallizing in ethyl acetate, obtain white powder solid, yield 43%.

¹H NMR(400MHz,Chloroform-d)δ7.34-7.26(m,2H),6.90–6.77(m,3H),4.21(q,J =7.1Hz, 2H), 4.06 (s, 2H), 3.81 (d, J=1.0Hz, 2H), 3.80 (s, 3H), 1.29 (t, J=7.2Hz, 3H)； ESI-MS(m/z):359.7(M+H)⁺。

Step 3)：2- [6- (4- methoxybenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid (MC14) preparation

6mL 2mol/L NaOH are added to 0.004mol (1.44g) 2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiophenes Azoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] ethyl acetate 20mL methanol solutions in, react at room temperature 2h, add 40m water, then Vacuum distillation removes alcohol, adjusts pH=2 with 1mol/L HCl after excess cooling, has a large amount of pale yellow crystals to separate out, filter, dries, second Acetoacetic ester recrystallizes, and obtains light yellow solid sprills, yield 47%.

¹H NMR(600MHz,DMSO-d₆) δ 12.84 (s, 1H), 7.26 (s, 1H), 7.19 (d, J=8.3Hz, 2H), 6.82 (d, J=8.4Hz, 2H), 3.86 (d, J=8.0Hz, 4H), 3.70 (s, 3H)；ESI-MS(m/z):332.4(M+H)⁺。

Step 4)：N, N- diethyl -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- Triazine -3- bases] acetamide (TC01) preparation

2.38mmol (0.18g) diethylamine and 2.38mmol (0.79g) 2- [6- (4- methoxybenzyls) -7- oxo -7H- thiophenes Azoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid is added to 24.0ml CH₂Cl₂In, 2.62mmol is then added into solution again (0.35g) HOBt, 2.62mmol (0.50g) EDC hydrochlorides and triethylamine 10mmol (1.01g).Reaction be stirred at room temperature 10h with On.Reaction solution 5%HCl (3 × 30.0ml), 5%NaHCO₃Solution (40.0ml), H₂O (40.0ml), saturation NaCl (40.0ml), Then Na₂SO₄Dry, column chromatography (CH₂Cl₂/MeOH,50:1) white solid, yield 57% are obtained.

¹H NMR (400MHz, Chloroform-d) δ 7.26 (d, J=8.5Hz, 2H), 6.88-6.81 (m, 2H), 6.79 (s, 1H), 4.07 (s, 2H), 3.80 (s, 3H), 3.78 (s, 2H), 3.38 (dq, J=30.6,7.2Hz, 4H), 1.20 (dt, J= 29.4,7.1Hz,6H)；ESI-MS(m/z):386.8(M+H)⁺。

Embodiment 38:N- cyclopropyl -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- Triazine -3- bases] acetamide (TC03) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into cyclopropylamine, yield 44%.

¹H NMR(400MHz,DMSO-d₆) δ 8.17 (d, J=4.0Hz, 1H), 7.23 (d, J=2.2Hz, 1H), 7.22 (t, J=2.2Hz, 2H), 6.88-6.81 (m, 2H), 3.87 (s, 2H), 3.72 (s, 3H), 3.66 (s, 2H), 2.63 (tq, J=7.7, 4.0Hz, 1H), 0.64 (td, J=7.0,4.7Hz, 2H), 0.45-0.36 (m, 2H)；ESI-MS(m/z):371.1(M+H)⁺。

Embodiment 39:N- butyl -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- three Piperazine -3- bases] acetamide (TC04) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into n-butylamine, yield 48%.

¹H NMR(400MHz,Chloroform-d)δ7.26(s,1H),6.90–6.84(m,2H),6.81(s,1H), 5.79(s,1H),4.09(s,2H),3.81(s,3H),3.61(s,2H),3.20–3.10(m,2H),1.46–1.36(m,2H), 1.36-1.26 (m, 2H), 0.93 (t, J=7.2Hz, 3H)；ESI-MS(m/z):387.0(M+H)⁺。

Embodiment 40:6- (4- methoxy-benzyls) -3- [2- oxos -2- (pyrrolidin-1-yl) ethyl] -7H- thiazoles simultaneously [3, 2-b] -1,2,4- triazine -7- ketone (TC05) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into nafoxidine, yield 65%.

¹H NMR (400MHz, Chloroform-d) δ 7.26 (d, J=8.4Hz, 2H), 6.85 (d, J=7.7Hz, 3H), 4.08 (s, 2H), 3.81 (s, 3H), 3.71 (s, 2H), 3.49 (t, J=6.9Hz, 2H), 3.42 (t, J=6.7Hz, 2H), 2.02 (q, J=6.7Hz, 2H), 1.94 (q, J=6.8Hz, 2H)；ESI-MS(m/z):385.1.0(M+H)⁺。

Embodiment 41:6- (4- methoxy-benzyls) -3- (2- morpholinyl -2- oxoethyls) -7H- thiazoles simultaneously [3,2-b] -1, The preparation of 2,4- triazine -7- ketone (TC06)

According to the method for embodiment 4, difference is, changes diethylamine in step 4) into morpholine, yield 72%.

¹H NMR (400MHz, Chloroform-d) δ 7.25 (d, J=7.9Hz, 2H), 6.86 (d, J=7.6Hz, 2H), 6.79 (s, 1H), 4.09 (s, 2H), 3.82 (s, 3H), 3.79-3.68 (m, 6H), 3.63 (d, J=4.3Hz, 2H), 3.43 (s, 2H)；ESI-MS(m/z):401.5(M+H)⁺。

Embodiment 42:N- (furans -2- ylmethyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -3- bases] acetamide (TC08) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into 2- furylamines, yield 51%.

¹H NMR (400MHz, Chloroform-d) δ 7.37 (dd, J=1.8,0.8Hz, 1H), 7.23 (d, J=8.6Hz, 2H), 6.90-6.80 (m, 3H), 6.35 (dd, J=3.3,1.9Hz, 1H), 6.22 (d, J=3.2Hz, 1H), 5.94 (s, 1H), 4.36 (d, J=5.6Hz, 2H), 4.07 (s, 2H), 3.79 (s, 3H), 3.60 (s, 2H)；ESI-MS(m/z):411.0(M+H)⁺。

Embodiment 43:N- (2- chlorobenzyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1, 2,4- triazine -3- bases] acetamide (TC09) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into 2- chlorobenzylamines, yield 60%.

¹H NMR(400MHz,DMSO-d₆) δ 8.61 (t, J=5.9Hz, 1H), 7.41 (ddd, J=24.4,5.8,3.7Hz, 2H), 7.33-7.24 (m, 3H), 7.24-7.16 (m, 2H), 6.86-6.78 (m, 2H), 4.37 (d, J=5.8Hz, 2H), 3.87 (s,4H),3.71(s,3H)；ESI-MS(m/z):456.0(M+H)⁺。

Embodiment 44:N- (2,4- dichloro benzyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -3- bases] acetamide (TC10) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into 2,4- dichloro-benzylamines, yield 55%.

¹H NMR(400MHz,DMSO-d₆) δ 8.63 (t, J=5.9Hz, 1H), 7.60 (d, J=1.9Hz, 1H), 7.41- 7.30 (m, 2H), 7.26 (s, 1H), 7.18 (d, J=8.7Hz, 2H), 6.81 (d, J=8.6Hz, 2H), 4.33 (d, J= 5.8Hz,2H),3.86(s,4H),3.71(s,3H)；ESI-MS(m/z):490.4(M+H)⁺。

Embodiment 45:N- (4- luorobenzyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1, 2,4- triazine -3- bases] acetamide (TC11) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into 4- fluorin benzyl amines, yield 46%.

¹H NMR(400MHz,DMSO-d₆) δ 8.58 (t, J=6.0Hz, 1H), 7.34-7.28 (m, 2H), 7.25 (s, 1H), 7.20-7.15 (m, 2H), 7.14-7.07 (m, 2H), 6.85-6.78 (m, 2H), 4.28 (d, J=5.9Hz, 2H), 3.83 (d, J =15.0Hz, 4H), 3.71 (s, 3H)；ESI-MS(m/z):439.1(M+H)⁺。

Embodiment 46:N- (4- methyl-benzyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] - 1,2,4- triazine -3- bases] acetamide (TC12) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into 4- methylbenzylamines, yield 60%.

¹H NMR (400MHz, Chloroform-d) δ 7.14 (dd, J=16.9,7.6Hz, 6H), 6.84-6.75 (m, 3H), 6.15 (s, 1H), 4.32 (d, J=5.6Hz, 2H), 4.00 (s, 2H), 3.73 (s, 3H), 3.64 (s, 2H), 2.35 (s, 3H)；ESI-MS(m/z):435.1(M+H)⁺。

Embodiment 47:N- methoxyl groups -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- Triazine -3- bases]-N- methylacetamides (TC14) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into N, O- dimethyl hydroxylamine hydrochlorides, receives Rate 32%.

¹H NMR(400MHz,Chloroform-d)δ7.28–7.24(m,2H),6.88–6.80(m,2H),6.78(s, 1H),4.08(s,2H),3.90(s,2H),3.80(s,3H),3.67(s,3H),3.23(s,3H)；ESI-MS(m/z):375.1 (M+H)⁺。

Embodiment 48:3- { 2- [4- (2,4 3,5-dimethylphenyl) piperazine -1- bases] -2- oxoethyls } -6- (4- methoxybenzyls Base) -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TC16) preparation

According to the method for embodiment 37, difference is, changes diethylamine in step 4) into 1- (2,4 3,5-dimethylphenyl) piperazine, Yield 45%.

IR(KBr):υ 3109,2941,1643,1572,1512,1481,1373,1302,1031,814cm^-1；¹H NMR (400MHz, Chloroform-d) δ 7.26 (d, J=2.2Hz, 1H), 7.07 (d, J=2.0Hz, 1H), 7.04-6.98 (m, 2H), 6.91 (d, J=8.0Hz, 4H), 6.90-6.82 (m, 2H), 6.80 (s, 1H), 4.09 (s, 2H), 3.83 (s, 2H), 3.77 (s, 4H), 3.60 (s, 1H), 2.90 (q, J=5.7,4.8Hz, 3H), 2.33 (d, J=12.1Hz, 6H)；ESI-MS(m/z): 504.3(M+H)⁺。

Embodiment 49:2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N, The preparation of N- dimethyl acetamides (TC49)

Step 1)：3- oxos -4- { [5- oxos -6- (4- chloros benzyl) -2,5- dihydro -1,2,4- triazine -3- bases] sulphur Base } ethyl butyrate (MA05) preparation

0.01mol (2.54g) 6- [thio -3,4- dihydros -1,2,4- triazines -5 (2H) -one of 4- (chlorobenzyl) -3-] is added Into 5mL DMF, lower addition 10%KOH solution 5.6ml are stirred, 0.01mol (1.64g) 4- chloroacetyl acetacetic esters are then added dropwise 4ml ethanol solutions, after reacting at room temperature 30min, water dilution on the rocks, there are a large amount of crystal to disengage, filter, be washed with water, dry, acetic acid Ethyl ester recrystallizes, and obtains white fine sand sprills, yield 46%.

ESI-MS(m/z):381.96(M+H)⁺。

Step 2)：2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid second The preparation of ester (MB15)

By 4.0g 3- oxos -4-- { [5- oxos -6- (4- chloros benzyl) -2,5- dihydro -1,2,4- triazine -3- bases] sulphur Base } ethyl butyrate is added in 120 DEG C of 8.0g 85%PPA, stirring reaction 30min.Reaction is down to room temperature after terminating, and adds 15ml frozen water, after stirring, filter, be washed with water, dry, re-crystallizing in ethyl acetate, obtain white powder solid, yield 49%.

¹H NMR (400MHz, Chloroform-d) δ 7.35-7.25 (m, 4H), 6.81 (s, 1H), 4.19 (q, J= 7.1Hz, 2H), 4.09 (s, 2H), 3.80 (d, J=1.0Hz, 2H), 1.29 (t, J=7.1Hz, 3H)；ESI-MS(m/z): 364.0(M+H)⁺。

Step 3)：2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid (MC15) preparation

6mL 2mol/L NaOH are added into 0.004mol (1.45g) 2-, and [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles are simultaneously [3,2-b] -1,2,4- triazine -3- bases] ethyl acetate 20mL methanol solutions in, react at room temperature 2h, add 40m water, then depressurize Distillation removes alcohol, adjusts pH=2 with 1mol/L HCl after excess cooling, has a large amount of pale yellow crystals to separate out, filter, dries, acetic acid second Ester recrystallizes, and obtains light yellow solid sprills, yield 68%.

¹H NMR(600MHz,DMSO-d₆) δ 12.78 (s, 1H), 7.31 (q, J=8.3Hz, 4H), 7.27 (s, 1H), 3.82 (s,2H),3.30(s,2H)；ESI-MS(m/z):336.7(M+H)⁺。

Step 4)：N, N- diethyl -2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines - 3- yls] acetamide (TC49) preparation

2.38mmol (0.20g) dimethylamine hydrochloride hydrochlorides and 2.38mmol (0.79g) 2- [6- (4- methoxybenzyls]- 7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases) acetic acid is added to 24.0ml CH₂Cl₂In, then again into solution Add 2.62mmol (0.35g) HOBt, 2.62mmol (0.50g) EDC hydrochlorides and triethylamine 10mmol (1.01g).Reative cell Temperature stirring more than 10h.Reaction solution 5%HCl (3 × 30.0ml), 5%NaHCO₃Solution (40.0ml), H₂O (40.0ml), saturation NaCl (40.0ml), then Na₂SO₄Dry, column chromatography (CH₂Cl₂/MeOH,50:1) white solid, yield 55% are obtained.

¹H NMR(400MHz,Chloroform-d)δ7.34-7.21(m,4H),6.76(s,1H),4.11(s,2H), 3.70 (s, 2H), 2.98 (d, J=9.1Hz, 6H)；ESI-MS(m/z):363.1(M+H)⁺。

Embodiment 50:6- (4- chlorobenzyls) -3- [2- oxos -2- (piperidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] - The preparation of 1,2,4- triazine -7- ketone (TC52)

According to the method for embodiment 49, difference is, changes dimethylamine hydrochloride in step 4) into piperidines, yield 40%.

¹H NMR(400MHz,DMSO-d₆)δ7.39–7.26(m,4H),7.18(s,1H),3.97(s,2H),3.84(s, 2H), 3.37 (t, J=5.5Hz, 4H), 1.64-1.34 (m, 6H)；ESI-MS(m/z):402.7(M+H)⁺。

Embodiment 51:6- (4- chlorobenzyls) -3- (2- morpholinyl -2- oxoethyls) -7H- thiazoles simultaneously [3,2-b] -1,2,4- The preparation of triazine -7- ketone (TC53)

According to the method for embodiment 49, difference is, changes dimethylamine hydrochloride in step 4) into morpholine, yield 52%.

¹H NMR(400MHz,Chloroform-d)δ7.34-7.22(m,4H),6.80(s,1H),4.11(s,2H), 3.76-3.68 (m, 6H), 3.62 (t, J=4.8Hz, 2H), 3.43 (t, J=4.8Hz, 2H)；ESI-MS(m/z):405.1(M+ H)⁺。

Embodiment 52:2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of (furans -3- ylmethyls) acetamide (TC54)

According to the method for embodiment 49, difference is, changes dimethylamine hydrochloride in step 4) into 2- furylamines, yield 46%.

¹H NMR(400MHz,DMSO-d₆) δ 8.53 (t, J=5.6Hz, 1H), 7.57 (t, J=1.3Hz, 1H), 7.32 (q, J=8.6Hz, 4H), 7.24 (s, 1H), 6.38 (dd, J=3.2,1.8Hz, 1H), 6.25 (d, J=3.2Hz, 1H), 4.27 (d, J =5.6Hz, 2H), 3.93 (s, 2H), 3.75 (s, 2H)；ESI-MS(m/z):405.0(M+H).

Embodiment 53:2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of (4- methyl-benzyls) acetamide (TC56)

According to the method for embodiment 49, difference is, changes dimethylamine hydrochloride in step 4) into 4- methylbenzylamines, yield 48%.

¹H NMR (400MHz, Chloroform-d) δ 7.39 (dd, J=8.5,5.5Hz, 4H), 7.01 (t, J=8.7Hz, 4H),4.12(s,2H),3.61(s,4H),2.53(s,2H),2.06–1.96(m,3H)；ESI-MS(m/z):439.0(M+H)⁺。

Embodiment 54:6- (4- chlorobenzyls) -3- [2- oxos -2- (4- phenylpiperazine -1- bases) ethyl] -7H- thiazoles simultaneously [3, 2-b] -1,2,4- triazine -7- ketone (TC57) preparation

According to the method for embodiment 49, difference is, changes dimethylamine hydrochloride in step 4) into phenylpiperazine, yield 49%.

¹H NMR(400MHz,Chloroform-d)δ7.37–7.31(m,2H),7.31–7.24(m,4H),6.99(d,J =7.9Hz, 3H), 6.82 (d, J=1.0Hz, 1H), 4.11 (s, 2H), 3.84-3.78 (m, 4H), 3.62 (t, J=5.0Hz, 2H),3.26–3.19(m,4H)；ESI-MS(m/z):480.1(M+H)⁺。

Embodiment 55:6- (4- chlorobenzyls) -3- [2- (4- (3,4- dichlorophenyls) piperazine -1- bases] -2- oxoethyls) - The preparation of 7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TC58)

According to the method for embodiment 49, difference is, changes dimethylamine hydrochloride in step 4) into 1- (3,4- dichlorophenyl) Piperazine, yield 60%.

¹H NMR(600MHz,DMSO-d₆) δ 7.41 (d, J=8.9Hz, 1H), 7.27 (q, J=8.4Hz, 4H), 7.19 (s, 1H), 7.16 (d, J=2.9Hz, 1H), 6.95 (dd, J=9.0,2.9Hz, 1H), 3.93 (d, J=13.3Hz, 4H), 3.60- 3.51 (m, 4H), 3.23 (d, J=5.6Hz, 2H), 3.16 (t, J=5.3Hz, 2H)；ESI-MS(m/z):548.2(M+H)⁺。

Embodiment 56:6- (4- chlorobenzyls) -3- [2- (4- (2,4- 3,5-dimethylphenyls) piperazine -1- bases] -2- oxoethyls) - The preparation of 7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TC59)

According to the method for embodiment 49, difference is, changes dimethylamine hydrochloride in step 4) into 1- (2,4- dimethyl benzenes Base) piperazine, yield 56%.

¹H NMR(400MHz,DMSO-d₆)δ7.40–7.26(m,4H),7.22(s,1H),7.05–6.84(m,3H),3.99 (s, 2H), 3.92 (s, 2H), 3.61-3.53 (m, 4H), 2.85-2.71 (m, 4H), 2.25 (d, J=19.8Hz, 6H)；ESI-MS (m/z):508.1(M+H)⁺¹。

Embodiment 57:N, N- diethyl -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- Triazine -3- bases] acetamide (TC60) preparation

Step 1)：3- oxos -4- { [5- oxos -6- (4- methyl-benzyls) -2,5- dihydro -1,2,4- triazine -3- bases] sulphur Base } ethyl butyrate (MA06) preparation

By 0.01mol (1.43g) 6- [thio -3,4- dihydros -1,2,4- triazines -5 (2H) -one of 4- (methyl-benzyl) -3-] It is added in 5mL DMF, stirs lower addition 10%KOH solution 5.6ml, 0.01mol (1.64g) 4- chloroethene ethyl acetoacetic acid second is then added dropwise Ester 4ml ethanol solutions, after reacting at room temperature 30min, water dilution on the rocks, there are a large amount of crystal to disengage, filter, be washed with water, dry, second Acetoacetic ester recrystallizes, and obtains white fine sand sprills, yield 44%.

ESI-MS(m/z):361.95(M+H)⁺。

Step 2)：2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid The preparation of ethyl ester (MB16)

By 4.0g 3- oxos -4- { [5- oxos -6- (4- methyl-benzyls) -2,5- dihydro -1,2,4- triazine -3- bases] sulphur Base } ethyl butyrate is added in 120 DEG C of 8.0g 85%PPA, stirring reaction 30min.Reaction is down to room temperature after terminating, and adds 15ml frozen water, after stirring, filter, be washed with water, dry, re-crystallizing in ethyl acetate, obtain white powder solid, yield 49%.

¹H NMR (400MHz, Chloroform-d) δ 7.30-7.23 (m, 2H), 7.12 (d, J=7.8Hz, 2H), 6.79 (s, 1H), 4.20 (q, J=7.2Hz, 2H), 4.08 (s, 2H), 3.81 (d, J=1.1Hz, 2H), 2.33 (s, 3H), 1.28 (t, J =7.1Hz, 3H)；ESI-MS(m/z):343.7(M+H)⁺。

Step 3)：2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid (MC16) preparation

6mL 2mol/L NaOH are added to 0.004mol (1.37g) 2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles And [3,2-b] -1,2,4- triazine -3- bases] ethyl acetate 20mL methanol solutions in, react at room temperature 2h, add 40m water, then subtract Pressure distillation removes alcohol, adjusts pH=2 with 1mol/L HCl after excess cooling, has a large amount of pale yellow crystals to separate out, filter, dries, acetic acid Ethyl ester recrystallizes, and obtains light yellow solid sprills, yield 64%.

¹H NMR(400MHz,DMSO-d₆) δ 12.82 (s, 1H), 7.28 (s, 1H), 7.18 (d, J=7.8Hz, 2H), 7.09 (d, J=7.8Hz, 2H), 3.89 (d, J=9.4Hz, 4H), 2.26 (s, 3H)；ESI-MS(m/z):316.4(M+H)⁺。

Step 4)：N, N- diethyl -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- Triazine -3- bases] acetamide (TC60) preparation

2.38mmol (0.18g) diethylamine and 2.38mmol (0.75g) 2- (6- (4- methyl-benzyls) -7- oxo -7H- thiophenes Azoles simultaneously [3,2-b] -1,2,4- triazine -3- bases) acetic acid is added to 24.0ml CH₂Cl₂In, 2.62mmol is then added into solution again (0.35g) HOBt, 2.62mmol (0.50g) EDC hydrochlorides and triethylamine 10mmol (1.01g).Reaction be stirred at room temperature 10h with On.Reaction solution 5%HCl (3 × 30.0ml), 5%NaHCO₃Solution (40.0ml), H₂O (40.0ml), saturation NaCl (40.0ml), Then Na₂SO₄Dry, column chromatography (CH₂Cl₂/MeOH,50:1) white solid, yield 68% are obtained.

¹H NMR (400MHz, Chloroform-d) δ 7.23 (d, J=7.8Hz, 2H), 7.11 (d, J=7.8Hz, 2H), 6.78 (s, 1H), 4.09 (s, 2H), 3.77 (s, 2H), 3.41 (q, J=7.1Hz, 2H), 3.33 (q, J=7.2Hz, 2H), 2.33 (s, 3H), 1.20 (dt, J=25.5,7.1Hz, 6H)；ESI-MS(m/z):371.0(M+H)⁺。

Embodiment 58:N- isopropyls -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- three Piperazine -3- bases] acetamide (TC61) preparation

According to the method for embodiment 57, difference is, changes diethylamine in step 4) into isopropylamine, yield 70%.

¹H NMR (400MHz, Chloroform-d) δ 7.27 (d, J=7.8Hz, 2H), 7.15 (d, J=7.8Hz, 2H), 6.83 (s, 1H), 5.46 (s, 1H), 4.12 (s, 2H), 4.04 (dq, J=13.5,6.7Hz, 1H), 3.60 (s, 2H), 2.35 (s, 3H), 1.12 (d, J=6.6Hz, 6H)；ESI-MS(m/z):356.9(M+H)⁺。

Embodiment 59:N- butyl -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines - 3- yls] acetamide (TC62) preparation

According to the method for embodiment 57, difference is, changes diethylamine in step 4 into n-butylamine, yield 65%.

¹H NMR (400MHz, Chloroform-d) δ 7.25 (d, J=8.0Hz, 2H), 7.17 (d, J=7.8Hz, 2H), 6.82(s,1H),5.52(s,1H),4.14(s,2H),3.59–3.54(m,2H),3.16–3.06(m,2H),2.37(s,3H), 1.45-1.23 (m, 4H), 0.93 (t, J=7.2Hz, 3H)；ESI-MS(m/z):371.0(M+H)⁺。

Embodiment 60:6- (4- methyl-benzyls) -3- [2- oxos -2- (pyrrolidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -7- ketone (TC63) preparation

According to the method for embodiment 57, difference is, changes diethylamine in step 4) into nafoxidine, yield 74%.

¹H NMR (400MHz, Chloroform-d) δ 7.22 (d, J=7.8Hz, 2H), 7.12 (d, J=7.8Hz, 2H), 6.84 (s, 1H), 4.10 (s, 2H), 3.70 (s, 2H), 3.49 (t, J=6.9Hz, 2H), 3.40 (t, J=6.8Hz, 2H), 2.34 (s, 3H), 2.02 (p, J=6.7Hz, 2H), 1.93 (q, J=6.7Hz, 2H)；ESI-MS(m/z):368.7(M+H)⁺。

Embodiment 61:N- (furans -3- ylmethyls) -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] - 1,2,4- triazine -3- bases] acetamide (TC65) preparation

According to the method for embodiment 57, difference is, changes diethylamine in step 4) into 2- furylamines, yield 54%.

¹H NMR (400MHz, Chloroform-d) δ 7.37 (dd, J=1.8,0.8Hz, 1H), 7.23-7.10 (m, 4H), 6.82 (s, 1H), 6.35 (dd, J=3.2,1.9Hz, 1H), 6.20 (d, J=3.2Hz, 1H), 5.91 (s, 1H), 4.33 (d, J= 5.4Hz,2H),4.09(s,2H),3.59(s,2H),2.33(s,3H)；ESI-MS(m/z):395.3(M+H)⁺。

Embodiment 62:3- [2- (4- (2,4- 3,5-dimethylphenyls) piperazine -1- bases) -2- oxoethyls } -6- (4- benzyl chlorides Base) -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TC68) preparation

According to the method for embodiment 57, difference is, changes diethylamine in step 4) into 1- (2,4- 3,5-dimethylphenyl) piperazine, Yield 60%.

¹H NMR (400MHz, Chloroform-d) δ 7.24 (d, J=7.8Hz, 2H), 7.13 (d, J=7.8Hz, 2H), 7.08 (s, 1H), 7.05-6.99 (m, 1H), 6.92 (d, J=8.0Hz, 1H), 6.80 (s, 1H), 4.11 (s, 2H), 3.85- 3.81 (m, 2H), 3.79 (s, 2H), 3.60 (t, J=4.8Hz, 2H), 2.92 (q, J=4.8Hz, 4H), 2.36 (s, 3H), 2.32 (d, J=2.9Hz, 6H)；ESI-MS(m/z):488.3(M+H)⁺。

Embodiment 63:6- (4- chlorobenzyls) -3- [2- (4- (3,4- dichlorophenyls) piperazine -1- bases] -2- oxoethyls } - The preparation of 7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone (TC69)

According to the method for embodiment 57, difference is, changes diethylamine in step 4) into 1- (3,4- dichlorophenyl) piperazine, receives Rate 58%.

¹H NMR (400MHz, Chloroform-d) δ 7.37 (d, J=8.8Hz, 1H), 7.21 (d, J=8.0Hz, 2H), 7.11 (d, J=7.8Hz, 2H), 7.03 (d, J=2.7Hz, 1H), 6.82 (dd, J=8.8,2.8Hz, 1H), 6.80 (s, 1H), 4.10 (s, 2H), 3.82 (s, 2H), 3.79 (d, J=5.5Hz, 2H), 3.60 (s, 2H), 3.18 (d, J=5.3Hz, 4H), 2.30 (s,3H)；ESI-MS(m/z):528.3(M+H)⁺。

Embodiment 64:N- methoxy-. N-methyls -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1, 2,4- triazine -3- bases] acetamide (TC70) preparation

According to the method for embodiment 57, difference is, changes diethylamine in step 4) into N, O- dimethyl hydroxylamine hydrochlorides, receives Rate 43%.

¹H NMR (400MHz, Chloroform-d) δ 7.23 (d, J=7.9Hz, 2H), 7.12 (d, J=7.8Hz, 2H), 6.77(s,1H),4.10(s,2H),3.89(s,2H),3.66(s,3H),3.22(s,3H),2.33(s,3H)；ESI-MS(m/ z):359.0(M+H)⁺。

Embodiment 65:2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of (furans -3- ylmethyls) acetamide (TC75)

Step 1)：4- [6- (4- Fluoro-benz rLls) -5- oxo -2,5- dihydro -1,2,4- triazine -3- bases) sulfenyl] -3- oxygen Generation } ethyl butyrate (MA07) preparation

By thio -3,4- dihydros -1,2,4- triazines -5 (2H) -one of 0.01mol (2.37g) 6- [4- (methyl-benzyl)] -3- It is added in 5mL DMF, stirs lower addition 10%KOH solution 5.6ml, 0.01mol (1.64g) 4- chloroethene ethyl acetoacetic acid second is then added dropwise Ester 4ml ethanol solutions, after reacting at room temperature 30min, water dilution on the rocks, there are a large amount of crystal to disengage, filter, be washed with water, dry, second Acetoacetic ester recrystallizes, and obtains white fine sand sprills, yield 45%.

ESI-MS(m/z):365.94(M+H)⁺。

Step 2)：2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid second The preparation of ester (MB17)

By 4.0g 4- { [6- (4- Fluoro-benz rLls) -5- oxo -2,5- dihydro -1,2,4- triazine -3- bases] sulfenyl } -3- oxygen It is added to for ethyl butyrate in 120 DEG C of 8.0g 85%PPA, stirring reaction 30min.Room temperature is down in reaction after terminating, add 15ml Frozen water, after stirring, filter, be washed with water, dry, re-crystallizing in ethyl acetate, obtain white powder solid, yield 56%.

¹H NMR (400MHz, Chloroform-d) δ 7.38-7.30 (m, 2H), 7.00 (t, J=8.7Hz, 2H), 6.81 (d, J=1.0Hz, 1H), 4.19 (q, J=7.1Hz, 2H), 4.10 (s, 2H), 3.82-3.70 (m, 2H), 1.33-1.23 (m, 3H)；ESI-MS(m/z):347.9(M+H)⁺。

Step 3)：2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetic acid (MC17) preparation

6mL 2mol/L NaOH are added into 0.004mol (1.39g) 2-, and (6- (4- luorobenzyls) -7- oxo -7H- thiazoles are simultaneously [3,2-b] -1,2,4- triazine -3- bases) ethyl acetate 20mL methanol solutions in, react at room temperature 2h, add 40m water, then depressurize Distillation removes alcohol, adjusts pH=2 with 1mol/L HCl after excess cooling, has a large amount of pale yellow crystals to separate out, filter, dries, acetic acid second Ester recrystallizes, and obtains light yellow solid sprills, yield 66%.

¹H NMR(600MHz,DMSO-d₆)δ12.82(s,1H),7.33–7.28(m,2H),7.26(s,1H),7.12– 7.05(m,2H),3.94(s,2H),3.82(s,2H)；ESI-MS(m/z):320.9(M+H)⁺。

Step 4)：2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- (furans Mutter -3- ylmethyls) preparation of acetamide (TC75)

2.38mmol (0.23g) 2- furylamines and 2.38mmol (0.76g) 2- (6- (4- luorobenzyls) -7- oxos -7H- Thiazole simultaneously [3,2-b] -1,2,4- triazine -3- bases) acetic acid is added to 24.0ml CH₂Cl₂In, then added again into solution 2.62mmol (0.35g) HOBt, 2.62mmol (0.50g) EDC hydrochlorides and triethylamine 10mmol (1.01g).Reaction room temperature is stirred Mix more than 10h.Reaction solution 5%HCl (3 × 30.0ml), 5%NaHCO₃Solution (40.0ml), H₂O (40.0ml), saturation NaCl (40.0ml), then Na₂SO₄Dry, column chromatography (CH₂Cl₂/MeOH,50:1) white solid, yield 59% are obtained.

¹H NMR(400MHz,DMSO-d₆) δ 8.53 (t, J=5.6Hz, 1H), 7.60-7.54 (m, 1H), 7.36-7.27 (m, 2H), 7.24 (s, 1H), 7.15-7.06 (m, 2H), 6.38 (dd, J=3.2,1.8Hz, 1H), 6.25 (d, J=3.3Hz, 1H), 4.27 (d, J=5.6Hz, 2H), 3.92 (s, 2H), 3.75 (s, 2H)；ESI-MS(m/z):399.0(M+H)⁺。

Embodiment 66:2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of methoxy N-methylacetamide (TC79)

According to the method for embodiment 65, difference is, changes 2- furylamines in step 4) into N, O- dimethyl hydroxylamine hydrochloric acid Salt, yield 48%.

¹H NMR (400MHz, Chloroform-d) δ 7.34-7.27 (m, 2H), 7.00 (t, J=8.6Hz, 2H), 6.79 (s,1H),4.12(s,2H),3.88(s,2H),3.68(s,3H),3.22(s,3H)；ESI-MS(m/z):362.7(M+H)⁺。

Embodiment 67:2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of methoxy N-methylacetamide (TC79)

According to the method for embodiment 65, difference is, the amount of the PPA in step 2) is changed into 4g, yield 44%.

Embodiment 68:2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of methoxy N-methylacetamide (TC79)

According to the method for embodiment 65, difference is, the amount of the PPA in step 2) is changed into 40g, yield 58%.

Embodiment 69:2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of methoxy N-methylacetamide (TC79)

According to the method for embodiment 65, difference is, the reaction condition of step 2) is changed to and " 100 DEG C of stirring reaction 1h ", received Rate 55%.

Embodiment 70:2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- The preparation of methoxy N-methylacetamide (TC79)

According to the method for embodiment 65, difference is, the reaction condition of step 2) is changed to " 130 DEG C of stirring reaction 20min ", Yield 58%.

Embodiment 71:Thiazole simultaneously [3,2-b] -1,2,4- triazine derivative Determination of Antibacterial Activity

The compounds of this invention as antibacterial and treating tuberculosis inhibitor activity can by many standards biological test or Pharmacology test determines.

Using MIC (μ g/ml) value of agar dilution determination experiment compound.

The preparation of antibacterials stoste：2mg/mL solution is configured to after methanol dissolving, it is degerming with filtration method.

The preparation of drug containing agar stoste：Stoste is diluted to multiple gradient concentrations with dilution method.1ml is taken to be added to respectively Perform in the internal diameter 90mm plate well of mark.Take sterilized 50 DEG C of M-H agar 19ml cold after bacterium in plate well, mixing again But.

Inoculation：Be inoculated with one by one in plate well with inoculator, each inoculum concentration be 1~2 μ L (bacteria containing amount is about 5 × 10⁵CFU/ml).The growth control plate of not drug containing is finally inoculated with, to check the survival shape that strain is tested in whole experiment process State.

It is incubated：Flat board is placed in 37 DEG C of incubation 24h.

As a result judge：It is the compound to detection strain that bacterium colony grows the lowest concentration of drug that is totally constrained completely MIC.Single colony growth can be neglected.

Thiazole simultaneously [3,2-b] -1,2,4- triazine derivative Determination of Antibacterial Activity results

As a result show, simultaneously [3,2-b] -1,2,4- triazine derivatives are false single to Escherichia coli (E.coli), verdigris for thiazole Born of the same parents bacterium (P.aeruginosa), staphylococcus aureus (S.aureus) and bacillus subtilis (B.subtilis) have difference The inhibitory action of degree.

Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not pair The restriction of embodiments of the present invention, for those of ordinary skill in the field, may be used also on the basis of the above description To make other changes in different forms, all embodiments can not be exhaustive here, it is every to belong to this hair Row of the obvious changes or variations that bright technical scheme is extended out still in protection scope of the present invention.

Claims

1. the thiazole of logical formula (I) simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable salt,

Wherein

Y is selected from C1-C6 alkoxies；-OH；The alkyl of-NR ' (OR "), wherein R ', R " independently selected from C1~C6；- NHR ' ,-NR " R " ', wherein R ' are selected from C1-C6 alkyl, the C1-C6 alkyl of halogen substitution, the benzyl that unsubstituted or C1-C6 alkyl or halogen substitute Base, 2- furfuryls, R ", R " ' independently selected from C1~C6 alkyl, or R ", R " ' formed together with the nitrogen-atoms that they are connected Pyrrolidinyl, piperidyl, morpholinyl, N methyl piperazine base, N- Phenylpiperazinyls.

2. thiazole as claimed in claim 1 simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable salt,

3. thiazole as claimed in claim 1 or 2 simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable Salt,

Wherein, R is selected from H, CH₃, F, Cl ,-OCH₃,-CF₃。

4. thiazole as described in claim 1-2 any one simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically may be used The salt of receiving,

Wherein, Y is selected from C1-C4 alkoxies；-OH；The alkyl of-NR ' (OR "), wherein R ', R " independently selected from C1~C6；- NHR ' ,-NR " R " ', wherein R are selected from C1-C4 alkyl, and the C1-C4 alkyl of halogen substitution, unsubstituted or C1-C4 alkyl or halogen take The nitrogen-atoms one that the benzyl in generation, 2- furfuryls, R ", R " ' independently selected from C1~C4 alkyl, or R ", R " ' are connected with them Play composition pyrrolidinyl, piperidyl, morpholinyl, N methyl piperazine base, N- Phenylpiperazinyls.

5. thiazole as claimed in claim 3 simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable salt,

6. thiazole as described in claim 1 or 2 or 5 simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable Salt,

Wherein, Y is selected from-OCH₂CH₃；-OH；-N(CH₃)(OCH₃)；- NHR ' ,-NR " R " ', wherein R ' are selected from-CH₂CH₂CH₂CH₃, The benzyl of 2- chloroethyls, unsubstituted or methyl or halogen substitution, 2- furfuryls, R ", R " ' for independently selected from C1~C4 alkane Base, or R ", R " ' with they be connected nitrogen-atoms together with form pyrrolidinyl, piperidyl, morpholinyl, N methyl piperazine base, N- benzene Base piperazinyl.

7. thiazole as claimed in claim 3 simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable salt,

8. thiazole as claimed in claim 4 simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable salt,

9. thiazole simultaneously [3,2-b] -1,2,4- triazine derivatives and its pharmaceutically acceptable salt, are selected from：

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-DMAC N,N' dimethyl acetamide；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N, N- diethyl acetamides；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N, N- dibutyl acetamides；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N, N- diisopropyl acetamides；

6- benzyls -3- [2- oxos -2- (piperidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone；

6- benzyls -3- (2- morpholinyl -2- oxoethyls) -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone；

6- benzyls -3- [2- (4- methylpiperazine-1-yls) -2- oxoethyls] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -7- Ketone；

6- benzyls -3- [2- oxos -2- (pyrrolidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone；

6- benzyls -3- [2- oxos -2- (4- phenylpiperazine -1- bases) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -7- Ketone；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- isopropyl yl acetamides；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- cyclopropyl-acetamides；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (furans -2- ylmethyls) acetyl Amine；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (2- chlorobenzyls) acetamide；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (4- methyl-benzyls) acetamide；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (4- luorobenzyls) acetamide；

2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases)-N- (2,4- dichloro benzyls) acetyl Amine；

2- { 2- [2- (6- benzyl -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases) acetylamino] thiazole -4- Base } ethyl acetate；

6- benzyls -3- { 2- [4- (2,4 dichloro benzene base) piperazine -1- bases] -2- oxoethyls } -7H- thiazoles simultaneously [3,2-b] -1,2, 4- triazine -7- ketone；

6- benzyls -3- { 2- [4- (2,6- 3,5-dimethylphenyls) piperazine -1- bases] -2- oxoethyls } -7H- thiazoles simultaneously [3,2-b] -1, 2,4- triazine -7- ketone；

6- benzyls -3- { 2- [4- (2,4- 3,5-dimethylphenyls) piperazine -1- bases] -2- oxoethyls } -7H- thiazoles simultaneously [3,2-b] -1, 2,4- triazine -7- ketone；

2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N, N- diethyl acetyl Amine；

2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- butyl acetamides；

6- (2- chlorobenzyls) -3- (2- morpholinyl -2- oxoethyls) -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone；

6- (2- chlorobenzyls) -3- [2- oxos -2- (pyrrolidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines - 7- ketone；

2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- cyclopropyl-acetamides；

6- (2- chlorobenzyls) -3- [2- (4- (2- chlorphenyls) piperazine -1- bases) -2- oxoethyls] -7H- thiazoles simultaneously [3,2-b] -1, 2,4- triazine -7- ketone；

2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- (furans -2- Ji Jia Base) acetamide；

N- (2- chlorobenzyls) -2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetyl Amine；

2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- (4- luorobenzyls) acetyl Amine；

2- [6- (2- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- (4- methyl-benzyls) second Acid amides；

6- (2- chlorobenzyls) -3- { 2- [4- (2,6- 3,5-dimethylphenyls) piperazine -1- bases] -2- oxoethyls } -7H- thiazoles simultaneously [3, 2-b] -1,2,4- triazine -7- ketone；

3- (2- morpholinyl -2- oxoethyls) -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines - 7- ketone；

N- cyclopropyl -2- { 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases } Acetamide；

N- (2- chlorobenzyls) -2- 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines - 3- yls } acetamide；

N- (4- methyl-benzyls) -2- { 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- three Piperazine -3- bases } acetamide；

N- (2,4- dichloro benzyls) -2- { 7- oxos -6- [4- (trifluoromethyl) benzyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- three Piperazine -3- bases } acetamide；

N, N- diethyl -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] second Acid amides；

N- cyclopropyl -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetyl Amine；

N- butyl -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetyl Amine；

6- (4- methoxy-benzyls) -3- [2- oxos -2- (pyrrolidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- three Piperazine -7- ketone；

6- (4- methoxy-benzyls) -3- (2- morpholinyl -2- oxoethyls) -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -7- Ketone；

N- (furans -2- ylmethyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines - 3- yls] acetamide；

N- (2- chlorobenzyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] Acetamide；

N- (2,4- dichloro benzyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines - 3- yls] acetamide；

N- (4- luorobenzyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] Acetamide；

N- (4- methyl-benzyls) -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -3- Base] acetamide；

N- methoxyl groups -2- [6- (4- methoxy-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- Methyl vinyl；

- 7H- thiazoles are simultaneously by -6- (4- methoxy-benzyls) by 3- { 2- [4- (2,4 3,5-dimethylphenyl) piperazine -1- bases] -2- oxoethyls } [3,2-b] -1,2,4- triazine -7- ketone；

2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N, N- dimethylacetamides Amine；

6- (4- chlorobenzyls) -3- [2- oxos -2- (piperidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -7- Ketone；

6- (4- chlorobenzyls) -3- (2- morpholinyl -2- oxoethyls) -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketone；

2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- (furans -3- Ji Jia Base) acetamide；

2- [6- (4- chlorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- (4- methyl-benzyls) second Acid amides；

6- (4- chlorobenzyls) -3- [2- oxos -2- (4- phenylpiperazine -1- bases) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- three Piperazine -7- ketone；

6- (4- chlorobenzyls) -3- [2- (4- (3,4- dichlorophenyls) piperazine -1- bases] -2- oxoethyls) -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -7- ketone；

6- (4- chlorobenzyls) -3- [2- (4- (2,4- 3,5-dimethylphenyls) piperazine -1- bases] -2- oxoethyls) -7H- thiazoles simultaneously [3, 2-b] -1,2,4- triazine -7- ketone；

N, N- diethyl -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetyl Amine；

N- isopropyls -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetyl Amine；

N- butyl -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases] acetamide；

6- (4- methyl-benzyls) -3- [2- oxos -2- (pyrrolidin-1-yl) ethyl] -7H- thiazoles simultaneously [3,2-b] -1,2,4- three Piperazine -7- ketone；

N- (furans -3- ylmethyls) -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -3- Base] acetamide；

3- { [2- (4- (2,4- 3,5-dimethylphenyls) piperazine -1- bases) -2- oxoethyls } -6- (4- chlorobenzyls) -7H- thiazoles simultaneously [3, 2-b] -1,2,4- triazine -7- ketone；

6- (4- chlorobenzyls) -3- { [2- (4- (3,4- dichlorophenyls) piperazine -1- bases] -2- oxoethyls } -7H- thiazoles simultaneously [3,2- B] -1,2,4- triazine -7- ketone；

N- methoxy-. N-methyls -2- [6- (4- methyl-benzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazines -3- Base] acetamide；

2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- (furans -3- Ji Jia Base) acetamide；

2- [6- (4- luorobenzyls) -7- oxo -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -3- bases]-N- methoxy-. N-methyls Acetamide.

10. a kind of Pharmaceutical composition, said composition contains derivative described in claim 1-9 any one or it pharmaceutically may be used The salt of receiving, and its pharmaceutically acceptable carrier.

11. the derivative or its pharmaceutically acceptable salt described in claim 1-9 any one are in antibacterials are prepared Using.

12. application of the Pharmaceutical composition in antibacterials are prepared described in claim 10.

13. the application as described in claim 11 or 12, it is characterised in that：The bacterium is gram-positive bacteria or Gram-negative Bacterium.