CN107021937B - Benzothiazole Carbox amide and its application - Google Patents
Benzothiazole Carbox amide and its application Download PDFInfo
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- CN107021937B CN107021937B CN201710188629.7A CN201710188629A CN107021937B CN 107021937 B CN107021937 B CN 107021937B CN 201710188629 A CN201710188629 A CN 201710188629A CN 107021937 B CN107021937 B CN 107021937B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to pharmaceutical technology fields, are related to benzothiazole Carbox amide and its application.Benzothiazole Carbox amide include benzothiazole Carbox amide derivative and pharmaceutically useful salt, general structure it is as follows: wherein R1、R2, Ar is as described in claims and specification.Benzothiazole Carbox amide and the salt of the pharmaceutically useful sour addition of such compound can merge with existing drug or alone as growth factor tyrosine kinase inhibitor on epidermis, the related disease such as Small Cell Lung Cancer of imbalance is gone to for treating EGF-R ELISA signal, squamous carcinoma, gland cancer, large cell carcinoma, colorectal cancer, breast cancer, oophoroma, clear-cell carcinoma.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to benzothiazole Carbox amide and its as epidermal growth factor
Receptor tyrosine kinase inhibitors application and preparation method.
Background technique
For a long time, the oncotherapy for belonging to global problem is always one of medical research field face and important chooses
War.In recent years, with furtheing elucidate for Tumorigenesis and constantly discovering for antitumor action target spot, protein tyrosine kinase
Enzyme (protein tyrosine kinase, PTK) have become significant effect and the anti-tumor drug target spot that has a extensive future it
One.
EGF-R ELISA (epidermal growth factor receptor, EGFR) is a kind of while having
There is the transmembrane protein in the outer ligand receptor binding domain of film and intracellular tyrosine kinase activity domain.EGFR family mainly include four classes at
Member: EGFR/ErbB-1, HER-2/ErbB-2, HER-3/ErbB-3 and HER-4/ErbB-4.It is dynamic that EGFR is widely distributed in mammality
The epithelial cell membrane of object, the assignment of genes gene mapping are one kind as composed by 1186 amino acid in No. 7 chromosome P12-P14 sections
The transmembrane glycoprotein that relative molecular weight is about 170kD.It includes: the N-terminal extracellular region (ECD) being made of 621 amino acid residues,
With ligand binding site, it is subdivided into tetra- subprovinces I, II, III, IV；There is α spiral knot by what 23 amino acid residues formed
The transmembrane region (TM) of structure is connected by a proline with extracellular region；The C-terminal intracellular region being made of 542 amino acid residues,
It include three subprovinces such as membrane-proximal region (JM), tyrosine kinase area (TK), the end C- with a tyrosine kinase domain.
EGFR signal path includes that ligand induces extracellular region conformation change, transmembrane signal transduction, intracellular region to form kinases and live
Property with downstream signal activation, signal inactivate four parts.Ligand in conjunction with EGFR after form dimer, in combination with 1 ATP point
Son promotes Intracellular domain to interact to form kinase activity, and completes the phosphorylation of Intracellular domain tyrosine residue.EGFR is Dimerized
It after phosphorylation, activates the signal transduction system in downstream and becomes affine site, participate in mitotic signal transduction with a variety of
High affinity interaction occurs for molecule.These systems are intracellular from being extracellularly transmitted to by mitogenic signals, and then effectively adjust thin
Born of the same parents to the reaction of environmental stimuli and cell Proliferation, survive, stick, migrate and break up.
At present largely studies have shown that many entity tumors of the mankind and any one mistake in EGFR and/or one grade ligand
Degree expression or conduct disorder are closely related.Sebastian etc. reports the relationship of EGFR signal transduction and tumour, result of study table
Bright, the human epidermal tumour of at least 33%-50% is related to EGFR, it is the important target spot of Several Epidermal Tumors treatment.EGFR exists
There is high expression phenomenon in kinds of tumor cells, is 90%-95% in head and neck cancer, is 90% in cervix cancer, in breast cancer
It is 76%-89% in kidney for 82%-90%, is 43%-89% in cancer of the esophagus.And oophoroma, prostate cancer, cancer of pancreas,
In the tumour cells such as colon cancer, non-small cell lung cancer, glioma, high level expression phenomenon is equally presented in EGFR.Due to
EGFR and its ligand play an important role in the occurrence and development of kinds of tumors, become in recent years for the antineoplaston of EGFR
Carry out the hot spot of oncotherapy research.
Currently, epidermal growth factor recipient tyrosine kinase inhibitor (epidermal growth factor
Receptor-tyrosine kinase inhibitors, EGFR-TKI) it is broadly divided into two major classes: (1) EGFR monoclonal anti-
Body, representing drug has Cetuximab, Victibix etc.；(2) small molecule EGFR-TKI, representing drug has Gefitinib, A Fa
For Buddhist nun etc..
EGFR-TKI class drug is especially targeted with Gefitinib and Afatinib etc. for the small molecule EGFR-TKI of representative
Therapeutic agent has been achieved for significant achievement in human tumor therapy field application.However, the development of such drug and exploitation
Be faced with lot of challenges: resistance problems caused by as tumor cell gene mutation are got worse；Multiple target point inhibiting effect and
It should seek to balance between highly selective inhibiting effect；Accurate Prediction toxicity of compound, characteristics of pharmacokinetics in preclinical laboratory
Deng.These problems urgently return home solution by science, to improve new drug development efficiency and avoid waste of resource.Therefore, it develops efficient
Less toxic, structure novel small molecule EGFR-TKI has great theory significance and practical significance.
Epidermal growth factor recipient tyrosine kinase inhibitor of the compound of the present invention as brand new type, tool
Have that structure type is novel, drug action and existing drug be quite or the characteristics of be better than existing drug, can be used to treat or prevent with
Related disease such as Small Cell Lung Cancer caused by EGF-R ELISA signal transduction is lacked of proper care, squamous carcinoma, gland cancer, large cell carcinoma, knot
The intestines carcinoma of the rectum, breast cancer, oophoroma, clear-cell carcinoma have good application value and development and application prospect.
Summary of the invention
It is living that technical problem solved by the invention is to provide one kind compound shown in formula I, its pro-drug and drug
Property metabolin and its pharmaceutically acceptable salt, and provide it in preparation to prevent and treat the imbalance of EGFR signal transduction related
Disease drug in application.
Wherein
R1、R2It can be independently selected from H, C1-C4Alkyl, benzyl or substituted benzyl, substituted or unsubstituted C1-C4Alkoxy
Phenyl；Or R1、R2Together with the nitrogen-atoms that they are connected form 5-6 member aryl or heterocycle, the heterocycle is in addition to being connected
Outside nitrogen-atoms, the hetero atom of 1-3 N, O or S can also be contained；The substituent group is C1-C4Alkyl, C1-C4Alkoxy, halogen；
Ar can be independently selected from substituted or unsubstituted 5-6 member aryl, substituted or unsubstituted C1-C4Alkoxyl phenyl,
Substituted or unsubstituted benzyl, the substituent group are C1-C4Alkyl, C1-C4Alkoxy, halogen；
Compound, its pro-drug and pharmaceutical active metabolite that the present invention preferably has the following structure and its pharmaceutically
Acceptable salt,
R1、R2It can be independently selected from H, C1-C4Alkyl, benzyl or substituted benzyl, substituted or unsubstituted C1-C4Alkoxy
Phenyl；Or R1、R26 yuan of aryl or heterocycle are formed together with the nitrogen-atoms that they are connected, and the heterocycle is in addition to the nitrogen that is connected
Outside atom, 1 O atom can also be contained；The substituent group is C1-C4Alkyl, C1-C4Alkoxy, halogen；
Ar can be independently selected from substituted or unsubstituted 5-6 member aryl, substituted or unsubstituted C1-C4Alkoxyl phenyl,
Substituted or unsubstituted benzyl；
The compound and its pharmaceutically acceptable salt that the present invention preferably has the following structure,
R1、R2It can be independently selected from H, C1-C4Alkyl；Or 1- piperidyl, 1- are formed together with the nitrogen-atoms that they are connected
Pyrrolidinyl, 4- morpholinyl, 2- (4- morpholinyl) ethyl, 3- (4- morpholinyl) propyl, benzamido group or alpha substituted benzylamine base, anilino-
Or substituted anilinic or 2- (2- methoxyphenoxy) ethamine；
Ar can be independently selected from substituted or unsubstituted 5-6 member aryl, substituted or unsubstituted C1-C4Alkoxyl phenyl,
Substituted or unsubstituted benzyl；
The compound and its pharmaceutically acceptable salt that the present invention preferably has the following structure,
R1、R2It can be independently selected from H, C1-C4Alkyl；Or 1- piperidyl, 1- are formed together with the nitrogen-atoms that they are connected
Pyrrolidinyl, 4- morpholinyl, 2- (4- morpholinyl) ethyl, 3- (4- morpholinyl) propyl, benzamido group or alpha substituted benzylamine base, anilino-
Or substituted anilinic or 2- (2- methoxyphenoxy) ethamine；
Ar can be independently from phenyl or substituted-phenyl, furyl, benzyl or substituted benzyl, Phenoxymethyl or substituted benzene oxygen
Methyl or substituted-amino alkyl.
The compound and its pharmaceutically acceptable salt that the present invention preferably has the following structure,
R1、R2It can be independently selected from H, C1-C4 alkyl；Or 1- piperidyl, 1- are formed together with the nitrogen-atoms that they are connected
Pyrrolidinyl, 4- morpholinyl, 2- (4- morpholinyl) ethyl, 3- (4- morpholinyl) propyl, benzamido group, anilino-, 4- fluoroanilino,
4- chloroanilino, 4- toluidine, 4- methoxybenzene amido or 2- (2- methoxyphenoxy) ethamine；
Ar can be independently selected from phenyl, 4- fluorophenyl, 4- chlorphenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 2- furans
Base, (2- methoxyphenoxy) methyl, 3,4- dimethoxy-benzyls, (4- morpholinyl) methyl or 2- (4- morpholinyl) ethyl.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining compound of formula I, and has with suitable non-toxic
The conventional acid addition salts or base addition salts that machine or inorganic acid or organic or inorganic alkali are formed.The example of acid-addition salts includes acetic acid
Salt, adipate, alginates, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphor
Hydrochlorate, camsilate, cipionate, digluconate, lauryl sulfate, esilate, fumarate, Portugal heptan
Sugar lime, glycerophosphate, Hemisulphate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2- hydroxyl second
Sulfonate, lactate, maleate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oxalates, pamoate, pectin ester
Hydrochlorate, persulfate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate,
Rhodanate, toluene fulfonate and undecylate.Alkali salt includes ammonium salt, alkali metal salt, such as sodium and sylvite, alkali salt,
Such as calcium and magnesium salts, the salt of organic base, such as dicyclohexyl amine salt, the salt of N- methyl-D-glucamine salt and amino acid, such as essence
Propylhomoserin, lysine etc., moreover, Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as first
The chlorine of base, ethyl, propyl and butyl, bromine and iodide；Dialkyl sulfate, such as dimethyl suflfate, diethylester, dibutyl ester and two
Pentyl ester；The chlorine of long chain halide, such as decyl, lauryl, myristyl and stearyl, bromine and iodide；Aralkyl halide,
The bromide of such as benzyl and phenethyl.It is preferred for generating the acid of acid-addition salts including hydrochloric acid and acetic acid.
" pharmaceutically acceptable " such as pharmaceutically acceptable carrier, excipients, pro-drug, referring to can pharmacologically connect
It is receiving and substantially non-toxic to the patient of administration particular compound.
" pharmaceutical active metabolin " refers to the metabolite of pharmaceutically acceptable and effective compound of formula I.
The present invention also relates to the Pharmaceutical composition for inhibiting epidermal growth factor recipient tyrosine kinase, the composition contains formula
Compound I or derivative or its pharmaceutically useful acid-addition salts and pharmaceutically useful carrier.
The compounds of this invention can be taken by different methods to patient, such as oral with capsule or tablet, with nothing
Bacterium solution or suspensions administration, and in some cases, it can be injected intravenously with solution form.It can will be of the invention
Free alkali compound is prepared and is taken with its pharmaceutically useful acid addition salt form thereof.
Specific embodiment
Following reaction process summarises the synthesis step for preparing the compounds of this invention.
The present invention is described in detail with following examples.However, it should be understood that following realities that the present invention is not limited to specifically describe
Example.
1 N- benzyl -6- of embodiment (2- diethylin -2- oxoethoxy) benzo [d] thiazole -2- formamide (compound
ZL01 synthesis)
The synthesis of step A:L- ethylcysteine hydrochloride
L-cysteine (24.20g, 0.20mol) and ethyl alcohol 300mL are placed in 500mL eggplant-shape bottle, under the conditions of ice-water bath
Thionyl chloride (22mL, 0.30mol) is slowly added dropwise, the reaction was continued under room temperature after being added dropwise 3h, heating reflux reaction
12h.Reaction solution is cool to room temperature, and solvent is evaporated off and obtains white powder 36.42g, yield 98.1%.
The synthesis of step B:S- (2,5- dihydroxy phenyl) Ethitanin
L-cysteine carbethoxy hydrochloride (22.28g, 0.12mol) and methanol 60mL are placed in 1000mL eggplant-shape bottle, stirred
It mixes and makes it dissolve.The solution that 1,4-benzoquinone (6.48g, 0.060mol) and methanol 150mL are prepared is added dropwise under the conditions of ice-water bath, drips
The reaction was continued under room temperature 3h after finishing, is evaporated off solvent and obtains product crude product 13.81g, and yield 89.6% is not purified, directly use
It is reacted in next step.
The synthesis of step C:6- hydroxy benzo [d] thiazole -2- Ethyl formate
By S- made from upper step (2,5- dihydroxy phenyl) Ethitanin crude product (13.81g, 0.054mol) and isopropyl
Alcohol 360mL is placed in 1000mL eggplant-shape bottle, and 1M K is successively added dropwise under stirring3Fe(CN)6Aqueous solution 300mL and 4M NaOH aqueous solution
20mL, the reaction was continued under room temperature after being added dropwise 14h.Reaction solution filters, and filtrate is extracted with ethyl acetate, merges organic
Reaction dissolvent is evaporated off in phase, anhydrous sodium sulfate after drying, filtering, resulting brown oil separates (v (petroleum through silica gel column chromatography
Ether): v (ethyl acetate)=3:1) obtain yellow powder 6.41g, yield 53.4%, M.p.:176-177 DEG C of (lit.:178-180
℃)；ESI-MS,m/z:calcd.223.03(M+)；found 224.1([M+H]+),246.1([M+Na]+)；1H NMR
(400MHz,DMSO-d6): δ 7.98 (d, J=9.0Hz, 1H), 7.39 (d, J=2.3Hz, 1H), 7.12 (dd, J=9.0,
2.4Hz, 1H), 4.46 (q, J=7.0Hz, 2H), 1.41 (t, J=7.1Hz, 3H).
The synthesis of step D:6- (2- substituted amido -2- oxoethoxy) benzo [d] thiazole -2- Ethyl formate
Synthesize logical method: by chloracetyl replace amine 0.020mol, 6- hydroxy benzo [d] thiazole -2- Ethyl formate (2.23g,
0.010mol), Anhydrous potassium carbonate (13.81g, 0.10mol), potassium iodide (0.16g, 0.0010mol) and acetone 50mL are placed in
In 100mL eggplant-shape bottle, heating reflux reaction 16h, reaction solution filters out potassium carbonate while hot, and solvent is evaporated off and obtains product crude product, ethyl alcohol weight
Crystallization.
(1) synthesis of 6- (2- diethylin -2- oxoethoxy) benzo [d] thiazole -2- Ethyl formate
According to logical method is synthesized, white solid 3.32g is obtained, yield 98.8%, M.p.:139-140 DEG C；ESI-MS,m/z:
calcd.336.11(M+)；found 337.1([M+H]+),359.1([M+Na]+)；1H NMR(400MHz,DMSO-d6):δ
8.10 (d, J=9.1Hz, 1H), 7.72 (d, J=2.5Hz, 1H), 7.25 (dd, J=9.1,2.5Hz, 1H), 4.93 (s, 2H),
4.42 (q, J=7.1Hz, 2H), 3.30 (q, J=7.0Hz, 4H), 1.36 (t, J=7.1Hz, 3H), 1.17 (t, J=7.1Hz,
3H), 1.11 (t, J=7.1Hz, 3H).
(2) synthesis of 6- [2- (1- piperidyl) -2- oxoethoxy] benzo [d] thiazole -2- Ethyl formate
According to logical method is synthesized, yellow solid 3.01g is obtained, yield 86.5%, M.p.:87-89 DEG C；ESI-MS,m/z:
calcd.348.11(M+)；found 349.1([M+H]+),371.1([M+Na]+)；1H NMR(400MHz,DMSO-d6):δ
8.11 (d, J=9.1Hz, 1H), 7.44 (d, J=2.5Hz, 1H), 7.22 (dd, J=9.1,2.5Hz, 1H), 4.79 (s, 2H),
4.53 (q, J=7.1Hz, 2H), 3.56 (t, J=5.1Hz, 2H), 3.54 (t, J=5.1Hz, 2H), 1.65-1.61 (m, 6H),
1.47 (t, J=7.1Hz, 3H).
(3) synthesis of 6- [2- (4- morpholinyl) -2- oxoethoxy] benzo [d] thiazole -2- Ethyl formate
According to logical method is synthesized, yellow solid 2.92g is obtained, yield 83.4%, M.p.:181-183 DEG C；ESI-MS,m/z:
calcd.350.09(M+)；found 351.1([M+H]+),373.1([M+Na]+)；1H NMR(400MHz,DMSO-d6):δ
8.10 (d, J=9.0Hz, 1H), 7.43 (d, J=2.3Hz, 1H), 7.22 (dd, J=9.1,2.3 Hz, 1H), 4.64 (s, 2H),
4.57 (q, J=7.0Hz, 2H), 3.68-3.59 (m, 8H), 1.47 (t, J=7.1Hz, 3H).
(4) synthesis of 6- (2- benzyl -2- oxoethoxy) benzo [d] thiazole -2- Ethyl formate
According to logical method is synthesized, yellow solid 3.64g is obtained, yield 98.4%, M.p.:152-154 DEG C；ESI-MS,m/z:
calcd.370.10(M+)；found 371.1([M+H]+),393.1([M+Na]+)；1H NMR(400MHz,DMSO-d6):δ
8.14 (d, J=9.1Hz, 1H), 7.39 (d, J=2.4Hz, 1H), 7.36-7.33 (m, 5H), 7.19 (dd, J=9.1,2.5Hz,
1H), 4.64 (s, 2H), 4.55-4.54 (m, 4H), 1.48 (t, J=7.1Hz, 3H).
(5) synthesis of 6- [2- (4- luorobenzyl) -2- oxoethoxy] benzo [d] thiazole -2- Ethyl formate
According to logical method is synthesized, yellow solid 2.81g is obtained, yield 72.4%, M.p.:141-143 DEG C；ESI-MS,m/z:
calcd.388.09(M+)；found 389.1([M+H]+)；1H NMR (400MHz, DMSO-d6): δ 8.15 (d, J=9.1Hz,
1H), 7.39 (d, J=2.5Hz, 1H), 7.27-7.24 (m, 2H), 7.20 (dd, J=9.1,2.5Hz, 1H), 7.05-7.02 (m,
2H), 4.65 (s, 2H), 4.56-4.53 (m, 4H), 1.49 (t, J=7.1Hz, 3H).
(6) synthesis of 6- [2- (2- methoxyphenoxy) ethyoxyl] benzo [d] thiazole -2- Ethyl formate
According to logical method is synthesized, yellow solid 3.83g is obtained, yield 89.1%, M.p.:151-152 DEG C；ESI-MS,m/z:
calcd.430.12(M+)；found 431.1([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.34 (d, J=9.0Hz,
1H), 6.96 (d, J=2.7Hz, 1H), 6.91 (dd, J=9.0,2.7Hz, 1H), 6.91-6.82 (m, 4H), 4.43 (s, 2H),
4.12 (t, J=5.0Hz, 2H), 3.83 (s, 3H), 3.75 (t, J=5.4Hz, 2H), 3.48-3.41 (m, 2H), 1.72 (t, J=
7.2Hz,3H)。
Step E:N- benzyl -6- (2- diethylin -2- oxoethoxy) benzo [d] thiazole -2- formamide (compound
ZL01 synthesis)
By 6- (2- substituted amido -2- oxoethoxy) benzo [d] thiazole -2- Ethyl formate 0.030mol, benzylamine
(0.96g, 0.0090mol) and ethyl alcohol 20mL are placed in 100mL eggplant-shape bottle, heating reflux reaction 12h, reaction solution it is cool to room temperature simultaneously
It is poured into 250mL water, stirs 1h, filter to obtain yellow solid, separate (v (petroleum ether): v (acetic acid second through silica gel column chromatography
Ester)=1:1) white powder 0.64g is obtained, yield: 53.8%.M.p.:146-148℃；IR:(KBr,cm-1):υ3422.8,
3347.7,2932.2,1665.3,1632.0,1523.6,1554.6,1259.9,1213.0,1060.2,1030.6,945.7,
827.4,699.0；ESI-MS,m/z:calcd.397.15(M+)；found 398.1([M+H]+),420.1([M+Na]+)；1H
NMR(400MHz,CDCl3): δ 7.90 (d, J=9.0Hz, 1H), 7.39-7.35 (m, 5H), 7.32 (d, J=2.0Hz, 1H),
7.21 (dd, J=9.1,2.1Hz, 1H), 4.77 (s, 2H), 4.68 (d, J=5.8Hz, 2H), 3.41 (q, J=7.1Hz, 4H),
1.24 (t, J=7.0Hz, 3H), 1.15 (t, J=7.1Hz, 3H).
Embodiment 2:N- benzyl -6- [2- (1- piperidyl) -2- oxoethoxy] benzo [d] thiazole -2- formamide (chemical combination
Object ZL02) synthesis
Referring to the synthetic method of embodiment 1, pink solid 0.92g is obtained, yield: 74.8%.M.p.:198-199℃；
IR:(KBr,cm-1):υ3429.8,2921.8,2852.9,1649.8,1521.6,1495.8,1384.4,1249.8,1216.9,
1122.7,1085.8,956.0,829.1,730.0,694.4；ESI-MS,m/z:calcd.409.15(M+)；found 410.1
([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.91 (d, J=9.0Hz, 1H), 7.45 (d, J=2.5Hz, 1H), 7.40-
7.34 (m, 5H), 7.21 (dd, J=9.0,2.5Hz, 1H), 4.78 (s, 2H), 4.68 (d, J=6.0Hz, 2H), 3.59 (t, J=
5.1Hz, 2H), 3.48 (t, J=5.1Hz, 2H), 1.68-1.55 (m, 6H).
Embodiment 3:N- benzyl -6- [2- (4- morpholinyl) -2- oxoethoxy] benzo [d] thiazole -2- formamide (chemical combination
Object ZL03) synthesis
Referring to the synthetic method of embodiment 1, white solid 0.77g is obtained, yield: 62.6%.M.p.:186-188℃；
IR:(KBr,cm-1):υ3421.4,3277.0,2923.5,2845.7,1666.0,1637.9,1496.5,1436.6,1359.1,
1253.8,1210.2,1114.7,1001.5,838.4,827.6,697.5；ESI-MS,m/z:calcd.411.13(M+)；
found 412.1([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.92 (d, J=9.0Hz, 1H), 7.45 (d, J=2.3Hz,
1H), 7.38-7.34 (m, 5H), 7.19 (dd, J=9.0,2.4Hz, 1H), 4.79 (s, 2H), 4.68 (d, J=6.0Hz, 2H),
3.67–3.65(m,8H)。
Embodiment 4:N- benzyl -6- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } benzo [d] thiophene
The synthesis of azoles -2- formamide (compound ZL04)
Referring to the synthetic method of embodiment 1, white solid 0.81g is obtained, yield: 55.1%.M.p.:139-141℃；
IR:(KBr,cm-1):υ3438.8,2920.5,1651.4,1548.3,1508.0,1384.2,1254.4,1227.3,1124.3,
1071.8,1022.1,824.6,735.9,698.6；ESI-MS,m/z:calcd.491.15(M+)；found492.2([M+H]+),
514.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.92 (d, J=9.0Hz, 1H), 7.40 (d, J=2.5Hz, 1H),
7.39-7.35 (m, 5H), 7.17 (dd, J=9.0,2.6Hz, 1H), 6.89-6.86 (m, 4H), 4.69 (d, J=6.0Hz, 2H),
4.60 (s, 2H), 4.13 (t, J=5.0Hz, 2H), 3.82 (s, 3H), 3.78-3.73 (m, 2H).
Embodiment 5:6- (2- diethylin -2- oxoethoxy)-N- (4- luorobenzyl)-benzo [d] thiazole -2- formamide
The synthesis of (compound ZL05)
Referring to the synthetic method of embodiment 1, yellow solid 0.59g is obtained, yield: 47.2%.M.p.:152-153℃；
IR:(KBr,cm-1):υ3425.9,3349.2,2935.9,1665.7,1630.7,1511.6,1437.9,1384.3,1259.4,
1211.8,1162.2,1059.4,1035.2,947.4,829.1,765.7,645.5；ESI-MS,m/z:calcd.415.14(M+)；found 416.1([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.90 (d, J=9.0Hz, 1H), 7.43 (d, J=
1.7Hz, 1H), 7.35 (dd, J=8.6,5.4Hz, 2H), 7.21 (dd, J=9.1,1.8Hz, 1H), 7.04 (t, J=8.0Hz,
2H), 4.77 (s, 2H), 4.64 (d, J=5.9Hz, 2H), 3.42 (q, J=7.2Hz, 4H), 1.24 (t, J=6.7Hz, 3H),
1.15 (t, J=7.1Hz, 3H).
Embodiment 6:6- [2- (1- piperidyl) -2- oxoethoxy]-N- (4- luorobenzyl)-benzo [d] thiazole -2- formyl
The synthesis of amine (compound ZL06)
Referring to the synthetic method of embodiment 1, white solid 0.84g is obtained, yield: 65.6%.M.p.:151-153℃；
IR:(KBr,cm-1):υ3422.8,3333.9,2919.3,2850.6,1656.0,1508.8,1431.0,1250.9,1215.5,
1085.2,1006.0,847.0,825.1,753.5,673.2；ESI-MS,m/z:calcd.427.14(M+)；found 428.1
([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.91 (d, J=9.0Hz, 1H), 7.45 (d, J=2.5Hz, 1H), 7.36
(dd, J=8.6,5.4Hz, 2H), 7.21 (dd, J=9.1,2.5Hz, 1H), 7.04 (t, J=8.7Hz, 2H), 4.78 (s, 2H),
4.64 (d, J=6.0Hz, 2H), 3.59 (t, J=5.0Hz, 2H), 3.48 (t, J=5.1Hz, 2H), 1.60-1.55 (m, 6H).
Embodiment 7:6- [2- (4- morpholinyl) -2- oxoethoxy]-N- (4- luorobenzyl)-benzo [d] thiazole -2- formyl
The synthesis of amine (compound ZL07)
Referring to the synthetic method of embodiment 1, white solid 0.51g is obtained, yield: 39.5%.M.p.:184-185℃；
IR:(KBr,cm-1):υ3422.6,2928.2,2851.6,1671.2,1635.5,1509.9,1440.0,1384.4,1227.2,
1206.4,1117.5,1001.0,951.5,825.0,767.0,708.8；ESI-MS,m/z:calcd.429.12(M+)；
found 430.1([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.91 (d, J=9.0Hz, 1H), 7.45 (d, J=2.4Hz,
1H), 7.35 (dd, J=8.5,5.4Hz, 2H), 7.18 (dd, J=9.0,2.4Hz, 1H), 7.03 (t, J=8.6Hz, 2H),
4.79 (s, 2H), 4.63 (d, J=6.1Hz, 2H), 3.69-3.60 (m, 8H).
Embodiment 8:6- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy }-N- (4- luorobenzyl)-benzene
And the synthesis of [d] thiazole -2- formamide (compound ZL08)
Referring to the synthetic method of embodiment 1, white solid 0.72g is obtained, yield: 47.1%.M.p.:144-146℃；
IR:(KBr,cm-1):υ3422.7,2921.1,1651.1,1509.7,1384.3,1254.8,1225.5,1124.0,1072.0,
1024.0,825.6,735.7,699.8；ESI-MS,m/z:calcd.509.14(M+)；found510.1([M+H]+),532.1
([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.92 (d, J=9.0Hz, 1H), 7.41 (d, J=2.1Hz, 1H), 7.36
(dd, J=8.6,5.4Hz, 2H), 7.18 (dd, J=9.0,2.2Hz, 1H), 7.05 (t, J=8.6Hz, 2H), 6.91-6.85
(m, 4H), 4.65 (d, J=6.0Hz, 2H), 4.60 (s, 2H), 4.13 (t, J=4.9Hz, 2H), 3.82 (s, 3H), 3.78-
3.71(m,2H)。
Embodiment 9:6- (2- diethylin -2- oxoethoxy)-N- (furans -2- methyl)-benzo [d] thiazole -2- first
The synthesis of amide (compound ZL09)
Referring to the synthetic method of embodiment 1, yellow solid 0.41g is obtained, yield: 35.3%.M.p.:144-146℃；
IR:(KBr,cm-1):υ3381.3,2919.1,1677.9,1660.8,1535.7,1490.4,1223.9,1076.7,1010.9,
967.0,940.8,837.4,816.4,738.8,618.8；ESI-MS,m/z:calcd.387.13(M+)；found 388.1
([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.92 (d, J=8.8Hz, 1H), 7.64 (d, J=2.3Hz, 1H), 7.39 (d,
J=8.7Hz, 1H), 7.21 (dd, J=8.9,2.4Hz, 1H), 6.36-6.30 (m, 2H), 4.77 (s, 2H), 4.67 (d, J=
5.1Hz, 2H), 3.41 (q, J=7.1Hz, 4H), 1.23 (t, J=7.0Hz, 3H), 1.14 (t, J=6.7Hz, 3H).
Embodiment 10:6- [2- (1- piperidyl) -2- oxoethoxy]-N- (furans -2- methyl)-benzo [d] thiazole -2-
The synthesis of formamide (compound ZL10)
Referring to the synthetic method of embodiment 1, white solid 0.81g is obtained, yield: 67.5%.M.p.:196-198℃；
IR:(KBr,cm-1):υ3426.6,2927.1,2853.3,1653.1,1529.7,1498.4,1384.4,1251.5,1221.3,
1127.3,1084.8,1008.4,962.8,829.1,753.0；ESI-MS,m/z:calcd.399.13(M+)；found
400.1([M+H]+),422.1([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.93 (d, J=9.0Hz, 1H), 7.44 (d,
J=2.5Hz, 1H), 7.39 (d, J=8.7Hz, 1H), 7.21 (dd, J=9.0,2.6Hz, 1H), 6.35-6.33 (m, 2H),
4.78 (s, 2H), 4.67 (d, J=5.9Hz, 2H), 3.58 (t, J=5.1Hz, 2H), 3.43 (t, J=5.1Hz, 2H), 1.68-
1.63(m,6H)。
Embodiment 11:6- [2- (4- morpholinyl) -2- oxoethoxy]-N- (furans -2- methyl)-benzo [d] thiazole -2-
The synthesis of formamide (compound ZL11)
Referring to the synthetic method of embodiment 1, white solid 0.72g is obtained, yield: 60.0%.M.p.:188-190℃；
IR:(KBr,cm-1):υ3422.6,2919.0,2850.2,1640.8,1497.3,1384.1,1255.3,1208.7,1112.1,
1000.6,828.3,745.0；ESI-MS,m/z:calcd.401.10(M+)；found 402.1([M+H]+),424.1([M+
Na]+)；1H NMR(400MHz,CDCl3): δ 7.94 (d, J=9.0Hz, 1H), 7.45 (d, J=2.5Hz, 1H), 7.39 (d, J=
8.5Hz, 1H), 7.19 (dd, J=9.1,2.6Hz, 1H), 6.35-6.33 (m, 2H), 4.79 (s, 2H), 4.67 (d, J=
5.9Hz,2H),3.69–3.65(m,8H)。
Embodiment 12:6- (2- benzamido group -2- oxoethoxy)-N- (furans -2- methyl)-benzo [d] thiazole -2- formyl
The synthesis of amine (compound ZL12)
Referring to the synthetic method of embodiment 1, white solid 0.79g is obtained, yield: 62.7%.M.p.:166-168℃；
IR:(KBr,cm-1):υ3413.3,2921.4,1659.0,1530.7,1442.6,1384.2,1226.0,1069.5,1006.6,
969.4,917.1,834.0,731.7,698.0；ESI-MS,m/z:calcd.421.11(M+)；found422.1([M+H]+),
444.1([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.95 (d, J=9.0Hz, 1H), 7.40 (d, 1H), 7.34 (d, J=
7.9Hz, 1H), 7.31-7.27 (m, 5H), 7.16 (dd, J=9.0,2.5Hz, 1H), 6.36-6.33 (m, 2H), 4.68 (d, J=
5.9Hz, 2H), 4.64 (s, 2H), 4.56 (d, J=5.9Hz, 2H).
Embodiment 13:6- [2- (4- luorobenzyl) -2- oxoethoxy]-N- (furans -2- methyl)-benzo [d] thiazole -2-
The synthesis of formamide (compound ZL13)
Referring to the synthetic method of embodiment 1, white solid 0.76g is obtained, yield: 57.6%.M.p.:185-186℃；
IR:(KBr,cm-1):υ3421.8,2919.1,1656.9,1640.5,1533.2,1509.5,1384.2,1222.2,1065.6,
1014.3,870.6,844.2,827.4,744.0；ESI-MS,m/z:calcd.439.10(M+)；found440.1([M+H]+),
462.1([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.95 (d, J=9.0Hz, 1H), 7.40 (dd, J=1.7Hz, 1H),
7.26-7.24 (m, 3H), 7.16 (dd, J=9.0,2.6Hz, 1H), 7.01 (t, J=8.7Hz, 2H), 6.36-6.33 (m, 2H),
4.68 (d, J=5.9Hz, 2H), 4.63 (s, 2H), 4.53 (d, J=6.0Hz, 2H).
Embodiment 14:6- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy }-N- (furans -2- first
Base)-benzo [d] thiazole -2- formamide (compound ZL14) synthesis
Referring to the synthetic method of embodiment 1, white solid 0.81g is obtained, yield: 56.3%.M.p.:144-146℃；
IR:(KBr,cm-1):υ3444.9,2921.7,1664.9,1646.6,1527.5,1509.1,1384.4,1257.4,1225.5,
1122.7,1070.7,1018.2,847.2,821.9,742.5；ESI-MS,m/z:calcd.481.13(M+)；found
482.2([M+H]+),504.1([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.93 (d, J=9.0Hz, 1H), 7.40 (d,
J=2.7Hz, 1H), 7.39 (d, J=8.7Hz, 1H), 7.18 (dd, J=9.0,2.6Hz, 1H), 6.89-6.85 (m, 4H),
6.36-6.34 (m, 2H), 4.68 (d, J=5.9Hz, 2H), 4.60 (s, 2H), 4.12 (t, J=5.0Hz, 2H), 3.82 (s,
2H),3.77–3.68(m,2H)。
Embodiment 15:6- (2- diethylin -2- oxoethoxy)-N- [2- (2- methoxyphenoxy) ethyl]-benzo
The synthesis of [d] thiazole -2- formamide (compound ZL15)
Referring to the synthetic method of embodiment 1, white solid 0.86g is obtained, yield: 62.8%.M.p.:141-143℃；
IR:(KBr,cm-1):υ3435.5,2965.8,1688.8,1651.5,1533.8,1454.8,1257.7,1218.4,1124.3,
1077.6,1026.7,826.2,799.0,730.4；ESI-MS,m/z:calcd.457.17(M+)；found458.2([M+H]+)；1H
NMR(400MHz,CDCl3): δ 7.95 (d, J=9.0Hz, 1H), 7.43 (d, J=2.4Hz, 1H), 7.22 (dd, J=9.0,
2.4Hz, 1H), 6.99-6.93 (m, 4H), 4.77 (s, 2H), 4.23 (t, J=5.1Hz, 2H), 3.93 (s, 3H), 3.88 (dd, J
=10.7,5.4Hz, 2H), 3.44-3.40 (m, 4H), 1.24 (t, J=7.0Hz, 3H), 1.15 (t, J=7.1Hz, 3H).
Embodiment 16:6- [2- (1- piperidyl) -2- oxoethoxy]-N- [2- (2- methoxyphenoxy) ethyl]-benzene
And the synthesis of [d] thiazole -2- formamide (compound ZL16)
Referring to the synthetic method of embodiment 1, white solid 0.68g is obtained, yield: 48.2%.M.p.:136-137℃；
IR:(KBr,cm-1):υ3460.5,2936.4,2856.6,1651.0,1529.1,1507.8,1439.8,1252.5,1218.1,
1123.7,1086.8,865.5,752.5；ESI-MS,m/z:calcd.469.17(M+)；found470.2([M+H]+),492.2
([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.95 (d, J=9.0Hz, 1H), 7.44 (d, J=2.5Hz, 1H), 7.21
(dd, J=9.0,2.3Hz, 1H), 7.00-6.93 (m, 4H), 4.78 (s, 2H), 4.23 (t, J=5.2Hz, 2H), 3.93 (s,
3H), 3.88 (dd, J=10.8,5.4Hz, 2H), 3.58-3.49 (m, 6H), 1.67-1.61 (m, 6H).
Embodiment 17:6- [2- (4- morpholinyl) -2- oxoethoxy]-N- [2- (2- methoxyphenoxy) ethyl]-benzene
And the synthesis of [d] thiazole -2- formamide (compound ZL17)
Referring to the synthetic method of embodiment 1, white solid 0.87g is obtained, yield: 61.7%.M.p.:193-194℃；
IR:(KBr,cm-1):υ3423.4,2920.1,1677.1,1657.8,1527.9,1507.4,1433.1,1254.5,1217.8,
1121.8,1030.8,864.2,797.9,748.4,702.9；ESI-MS,m/z:calcd.471.15(M+)；found 472.1
([M+H]+),494.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.96 (d, J=9.0Hz, 1H), 7.45 (d, J=
2.5Hz, 1H), 7.20 (dd, J=9.0,2.5Hz, 1H), 6.99-6.92 (m, 4H), 4.79 (s, 2H), 4.23 (q, J=
5.0Hz,2H),3.92(s,3H),3.90–3.86(m,2H),3.69–3.61(m,8H)。
Embodiment 18:6- (2- benzamido group -2- oxoethoxy)-N- [2- (2- methoxyphenoxy) ethyl]-benzo [d]
The synthesis of thiazole -2- formamide (compound ZL18)
Referring to the synthetic method of embodiment 1, white solid 0.94g is obtained, yield: 63.9%.M.p.:176-178℃；
IR:(KBr,cm-1):υ3428.6,3306.5,2923.9,1692.5,1651.7,1536.2,1500.3,1435.4,1384.4,
1253.1,1226.2,1117.3,1028.3,856.4,836.7,753.4,701.3；ESI-MS,m/z:calcd.491.15(M+)；found 492.2([M+H]+),514.1([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.97 (d, J=9.0Hz,
1H), 7.41 (d, J=2.5Hz, 1H), 7.35-7.27 (m, 5H), 7.16 (dd, J=9.0,2.6Hz, 1H), 7.01-6.93 (m,
4H), 4.64 (s, 2H), 4.57 (d, J=5.9Hz, 2H), 4.24 (t, J=5.1Hz, 2H), 3.93 (s, 3H), 3.88 (dd, J=
10.7,5.5Hz,2H)。
Embodiment 19:6- [2- (4- luorobenzyl) -2- oxoethoxy]-N- [2- (2- methoxyphenoxy) ethyl]-benzene
And the synthesis of [d] thiazole -2- formamide (compound ZL19)
Referring to the synthetic method of embodiment 1, white solid 0.56g is obtained, yield: 36.6%.M.p.:147-149℃；
IR:(KBr,cm-1):υ3420.4,2919.9,1656.1,1535.0,1508.3,1384.0,1254.9,1219.2,1123.2,
1079.8,1021.8,843.1,743.9；ESI-MS,m/z:calcd.509.14(M+)；found510.1([M+H]+),532.1
([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.96 (d, J=9.0Hz, 1H), 7.39 (d, J=2.5Hz, 1H), 7.26-
7.23 (m, 2H), 7.15 (dd, J=9.0,2.5Hz, 1H), 7.03-7.00 (m, 2H), 6.98-6.91 (m, 4H), 4.63 (s,
2H), 4.52 (d, J=6.0Hz, 2H), 4.23 (t, J=5.1Hz, 2H), 3.92 (s, 3H), 3.88 (dd, J=10.4,5.2Hz,
2H)。
Embodiment 20:6- (2- diethylin -2- oxoethoxy)-N- (3,4- Dimethoxyphenethyl)-benzo [d] thiophene
The synthesis of azoles -2- formamide (compound ZL20)
Referring to the synthetic method of embodiment 1, pink solid 0.61g is obtained, yield: 43.3%.M.p.:169-170℃；
IR:(KBr,cm-1):υ3323.3,2927.1,1657.7,1543.7,1515.5,1430.7,1262.7,1236.2,1137.7,
1076.7,1025.2,861.7,819.6,767.1,700.3；ESI-MS,m/z:calcd.471.18(M+)；found 472.2
([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.91 (d, J=9.0Hz, 1H), 7.43 (d, J=2.4Hz, 1H), 7.21
(dd, J=9.0,2.5Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 6.80 (d, J=1.8Hz, 1H), 6.78 (t, J=1.7Hz,
1H), 4.77 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.72 (dd, J=13.4,6.9Hz, 2H), 3.46-3.38 (m,
4H), 2.91 (t, J=7.1Hz, 2H), 1.24 (t, J=7.0Hz, 3H), 1.15 (t, J=7.1Hz, 3H).
Embodiment 21:6- (2- diethylin -2- oxoethoxy)-N- [3- (4- morpholinyl) propyl]-benzo [d] thiophene
The synthesis of azoles -2- formamide (compound ZL21)
Referring to the synthetic method of embodiment 1, yellow solid 0.81g is obtained, yield: 62.3%.M.p.:70-72℃；IR:
(KBr,cm-1):υ3423.5,2923.4,2853.0,1666.2,1526.9,1460.9,1383.8,1256.9,1221.6,
1113.1,1075.8,856.5,810.4,738.5；ESI-MS,m/z:calcd.434.20(M+)；found435.2([M+H]+),
457.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.95 (d, J=9.0Hz, 1H), 7.44 (d, J=2.5Hz, 1H),
7.21 (dd, J=9.0,2.6Hz, 1H), 4.77 (s, 2H), 3.92 (t, J=4.3Hz, 4H), 3.62 (dd, J=11.8,
5.7Hz, 2H), 3.46-3.37 (m, 4H), 2.64-2.55 (m, 6H), 1.88-1.81 (m, 2H), 1.24 (t, J=7.1Hz,
3H), 1.15 (t, J=7.1Hz, 3H).
Embodiment 22:6- (2- benzamido group -2- oxoethoxy)-N- [3- (4- morpholinyl) propyl]-benzo [d] thiazole -
The synthesis of 2- formamide (compound ZL22)
Referring to the synthetic method of embodiment 1, white solid 0.73g is obtained, yield: 52.1%.M.p.:172-174℃；
IR:(KBr,cm-1):υ3422.3,2920.8,2806.2,1664.5,1528.0,1441.2,1384.4,1253.2,1225.8,
1115.3,1071.8,987.7,930.0,833.0,742.2；ESI-MS,m/z:calcd.468.18(M+)；found 469.2
([M+H]+),491.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.97 (d, J=9.0Hz, 1H), 7.40 (d, J=
2.5Hz, 1H), 7.34-7.28 (m, 5H), 7.16 (dd, J=9.0,2.6Hz, 1H), 4.64 (s, 2H), 4.57 (d, J=
6.0Hz, 2H), 3.92 (t, J=4.0Hz, 4H), 3.62 (dd, J=11.6,5.6Hz, 2H), 2.68-2.53 (m, 6H), 1.89-
1.83(m,2H)。
Embodiment 23:6- [2- (4- luorobenzyl) -2- oxoethoxy]-N- [3- (4- morpholinyl) propyl]-benzo [d] thiophene
The synthesis of azoles -2- formamide (compound ZL23)
Referring to the synthetic method of embodiment 1, white solid 0.82g is obtained, yield: 56.2%.M.p.:160-161℃；
IR:(KBr,cm-1):υ3330.3,2924.7,2855.1,1699.6,1653.9,1545.0,1510.2,1435.5,1254.6,
1223.4,1115.4,1068.1,986.4,849.5,814.2,770.3；ESI-MS,m/z:calcd.486.17(M+)；
found 487.3([M+H]+),509.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.96 (d, J=9.0Hz, 1H),
7.40 (d, J=2.5Hz, 1H), 7.25-7.23 (m, 2H), 7.15 (dd, J=9.0,2.6Hz, 1H), 7.02-6.99 (m, 2H),
4.63 (s, 2H), 4.53 (d, J=6.0Hz, 2H), 3.91 (t, J=4.6Hz, 4H), 3.62 (dd, J=11.6,5.6Hz, 2H),
2.63–2.52(m,6H),1.86–1.79(m,2H)。
Embodiment 24:6- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy }-N- [3- (4- morpholine
Base) propyl]-benzo [d] thiazole -2- formamide (compound ZL24) synthesis
Referring to the synthetic method of embodiment 1, white solid 0.57g is obtained, yield: 36.1%.M.p.:156-158℃；
IR:(KBr,cm-1):υ3424.6,2923.0,1656.7,1506.6,1384.7,1256.7,1225.3,1122.6,1076.2,
1050.6,1018.1,827.5,733.2；ESI-MS,m/z:calcd.528.20(M+)；found529.2([M+H]+),551.2
([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.95 (d, J=9.0Hz, 1H), 7.39 (d, J=2.5Hz, 1H), 7.26-
7.24 (m, 2H), 7.17 (dd, J=9.0,2.6Hz, 1H), 7.03-6.98 (m, 2H), 4.62 (s, 2H), 4.51 (d, J=
6.0Hz, 2H), 3.94 (t, J=4.6Hz, 4H), 3.64-3.58 (m, 2H), 2.63-2.52 (m, 6H), 1.86-1.79 (m,
2H)。
The above described is only a preferred embodiment of the present invention, being not that the invention has other forms of limitations, appoint
What those skilled in the art changed or be modified as possibly also with the technology contents of the disclosure above equivalent variations etc.
Imitate embodiment.But without departing from the technical solutions of the present invention, according to the technical essence of the invention to above embodiments institute
Any simple modification, equivalent variations and the remodeling made, still fall within the protection scope of technical solution of the present invention.
Pharmacological Examples
Embodiment 25: inhibitory activity of the test-compound to A549, HeLa, SW480, HepG2 and HL7702 cell Proliferation
Primary dcreening operation experimental method.
1. experimental material
Cell line: A549, HeLa, SW480, HepG2 and HL7702 cell are laid on 96 orifice plates with the density in 6000/ hole, often
Hole 100ul, uses afterwards for 24 hours.
Number ZL01-ZL24 target compound: being dissolved with DMSO, is formulated as 50 μM, 20 μM, 10 μM, 5 with culture solution dilution
μM, 2 μM of five various concentrations be stored in -20 DEG C it is stand-by, final concentration of the DMSO in culture solution is lower than 0.1%.
Positive control drug: 5 FU 5 fluorouracil (5-Fu).
MTT: 5mg/mL is dissolved as with PBS, is stored in -20 DEG C.
2. experimental method
Using MTT method, A549, HeLa, SW480, HepG2 and HL7702 cell are chosen to evaluate the anti-swollen of test sample
Tumor increment activity.Cell strain is cultivated on the improved Eagle culture medium (DMEM) of DulbeccoShi, which includes
10% calf serum (FBS).It is set to merge the secondary culture then carried out no more than 20 generations when cell Proliferation is to 80-90%,
Then make them adapt to environment before next step is disposed to reach for 24 hours.These cells are placed on 96 orifice plates (8 × 104/mL), so
Afterwards in the moist environment containing 5%CO2 overnight incubation and temperature control at 37 DEG C.The invention that various concentration is added later for 24 hours represents
Property compound.Using culture for 24 hours, MTT (5mg/mL) is added thereto and continues to cultivate 4h.Culture substrate is removed, it will be brilliant
Body is dissolved in DMSO, measures extinction under 490nm wavelength using microplate reader (TECAN SPECTRA, Wetzlar, Germany)
Degree.According to formula: inhibitory rate of cell growth=(1- medicine group OD value/control group OD value) × 100% calculates under respective concentration
Inhibitory rate of cell growth makees logarithmic curve with the various concentration of test-compound and to the inhibiting rate of cell, calculates tested chemical combination
The corresponding IC of object50Value.Representative compound of the present invention is measured according to the method described above, as a result shown in table 1:
Table 1
Embodiment 26: extracorporeal extracorporeal suppression experimental method of the test-compound to EGFR kinase activity.
(1) experimental material
Wild type and various saltant types (T790M, L858/T70M) EGFR, untested compound are that cell inhibitory effect is living
The preferable compound of property.
(2) experimental method
By a series of test-compound of gradient concentrations, it is incubated for jointly with the enzyme solutions of certain concentration at room temperature
5min, is added suitable enzyme reaction substrate, ATP later, starts enzyme reaction process, after 30min, is added into enzyme reaction system suitable
The reaction terminating liquid and detection liquid of amount, it is multi-functional in the Flexstation III of Molecular Device company after being incubated for 1h
In microplate reader, the enzyme activity under specific compound concentration is measured, and the inhibition for calculating the compounds on enzyme activities of various concentration is living
Property, later according to quadruplex parameters, the inhibitory activity of enzyme activity under various concentration compound is fitted, calculates IC50Value.
Representative compound of the present invention is measured according to the method described above, is as a result shown in table 2:
Table 2
Example of formulations
The protection scope that following example of formulations only illustrates the present invention, but do not constitute and limit in any way.
Embodiment 27: gelatine capsule
The preparation of hard gelatin capsule uses:
Above-mentioned preparation can be improved according to provided reasonable change.
Embodiment 28: tablet
The preparation of tablet uses
By said components mix and it is tabletted.
Embodiment 29: tablet
Tablet preparation in every containing 2.5-1000mg active component is as follows:
So that active constituent, starch and cellulose is passed through the mesh of the U.S. 45 and is thoroughly mixed.Polyvinylpyrrolidone is molten
Liquid is mixed with gained powder, through the mesh of the U.S. 14 after.The particle of generation is dried at 50-60 DEG C and through the mesh of the U.S. 18
Sieve.The sodium carboxymethylcellulose, magnesium stearate and talcum powder that first pass through No. 60 meshes in the U.S. in advance are added in above-mentioned particle, with
After mix, on tablet press machine compacting obtain tablet.
Embodiment 30: suspension
The suspension preparation that every 5ml contains 0.1-1000mg drug is as follows:
Drug is enabled to be mixed to form smooth paste through the mesh of the U.S. 45 and with sodium carboxymethylcellulose and syrup.By benzene first
Acid solution, corrigent and colorant are diluted with some water and aforesaid paste are added under stiring.Enough water is added then to reach
To required volume.
Embodiment 31: combined tablet-preparation
So that active constituent, starch and cellulose is passed through the mesh of the U.S. 45 and is thoroughly mixed.Polyvinylpyrrolidone is molten
Liquid is mixed with gained powder, through the mesh of the U.S. 14 after.The particle of generation is dried at 50-60 DEG C and through the mesh of the U.S. 18
Sieve.The sodium carboxymethylcellulose, magnesium stearate and talcum powder that first pass through No. 60 meshes in the U.S. in advance are added in above-mentioned particle, with
After mix, on tablet press machine compacting obtain tablet.
For above description, essential feature of the invention is readily understood in those skilled in the art, without departing substantially from the present invention
Spirit and scope, the present invention can carry out various changes and improve to adapt to different application and condition.
Claims (12)
1. Formulas I compound represented and its pharmaceutically acceptable salt,
Wherein
R1、R2It can be independently selected from H, C1-C4Alkyl, benzyl or substituted benzyl；Or R1、R2Together with the nitrogen-atoms that they are connected
5-6 circle heterocyclic ring base, 2- (2- methoxyphenoxy) ethylamino- are formed, the heterocycle may be used also other than the nitrogen-atoms connected
With the hetero atom containing 1-3 N, O or S；The substituent group is C1-C4Alkyl, C1-C4Alkoxy, halogen；
Ar can be independently selected from phenyl or substituted-phenyl, furyl, (4- morpholinyl) methyl, 2- (4- morpholinyl) ethyl, benzene
Oxygen methyl or substituted benzene oxygen methyl, substituted or unsubstituted benzyl, the substituent group are C1-C4Alkyl, C1-C4Alkoxy, halogen
Element.
2. Formulas I compound represented as described in claim 1 and its pharmaceutically acceptable salt, wherein
R1、R2It can be independently selected from H, C1-C4Alkyl, benzyl or substituted benzyl；Or R1、R2Together with the nitrogen-atoms that they are connected
6 circle heterocyclic ring bases are formed, the heterocycle can also contain 1 O atom other than the nitrogen-atoms connected；The substituent group is
C1-C4Alkyl, C1-C4Alkoxy, halogen.
3. Formulas I compound represented as claimed in claim 1 or 2 and its pharmaceutically acceptable salt, wherein
R1、R2It can be independently selected from H, C1-C4Alkyl；Or 1- piperidyl, 1- pyrroles are formed together with the nitrogen-atoms that they are connected
Alkyl, 4- morpholinyl, benzamido group or 2- (2- methoxyphenoxy) ethylamino-.
4. Formulas I compound represented and its pharmaceutically acceptable salt as described in claim 1-2 any one, wherein
Ar can be C independently selected from benzyl or substituted benzyl, the substituent group1-C4Alkyl, C1-C4Alkoxy, halogen.
5. Formulas I compound represented as claimed in claim 3 and its pharmaceutically acceptable salt, wherein
Ar can be independently selected from phenyl or substituted-phenyl, and furyl, benzyl or substituted benzyl, the substituent group are C1-C4Alkane
Base, C1-C4Alkoxy, halogen.
6. Formulas I compound represented and its pharmaceutically acceptable salt as described in 1,2,5 any one of claim, wherein
Ar is phenyl, 4- fluorophenyl, 4- chlorphenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 2- furyl, (2- methoxyphenoxy)
Methyl, 3,4- dimethoxy-benzyls.
7. Formulas I compound represented and its pharmaceutically acceptable salt as described in claim 1-3 any one, are selected from:
N- benzyl -6- (2- diethylin -2- oxoethoxy) benzo [d] thiazole -2- formamide；
N- benzyl -6- [2- (1- piperidyl) -2- oxoethoxy] benzo [d] thiazole -2- formamide；
N- benzyl -6- [2- (4- morpholinyl) -2- oxoethoxy] benzo [d] thiazole -2- formamide；
N- benzyl -6- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } benzo [d] thiazole -2- formamide；
6- (2- diethylin -2- oxoethoxy)-N- (4- luorobenzyl)-benzo [d] thiazole -2- formamide；
6- [2- (1- piperidyl) -2- oxoethoxy]-N- (4- luorobenzyl)-benzo [d] thiazole -2- formamide；
6- [2- (4- morpholinyl) -2- oxoethoxy]-N- (4- luorobenzyl)-benzo [d] thiazole -2- formamide；
6- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy }-N- (4- luorobenzyl)-benzo [d] thiazole -2-
Formamide；
6- (2- diethylin -2- oxoethoxy)-N- (furans -2- methyl)-benzo [d] thiazole -2- formamide；
6- [2- (1- piperidyl) -2- oxoethoxy]-N- (furans -2- methyl)-benzo [d] thiazole -2- formamide；
6- [2- (4- morpholinyl) -2- oxoethoxy]-N- (furans -2- methyl)-benzo [d] thiazole -2- formamide；
6- (2- benzamido group -2- oxoethoxy)-N- (furans -2- methyl)-benzo [d] thiazole -2- formamide；
6- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy }-N- (furans -2- methyl)-benzo [d] thiophene
Azoles -2- formamide；
6- (2- diethylin -2- oxoethoxy)-N- [2- (2- methoxyphenoxy) ethyl]-benzo [d] thiazole -2- formyl
Amine；
6- [2- (1- piperidyl) -2- oxoethoxy]-N- [2- (2- methoxyphenoxy) ethyl]-benzo [d] thiazole -2- first
Amide；
6- [2- (4- morpholinyl) -2- oxoethoxy]-N- [2- (2- methoxyphenoxy) ethyl]-benzo [d] thiazole -2- first
Amide；
6- (2- benzamido group -2- oxoethoxy)-N- [2- (2- methoxyphenoxy) ethyl]-benzo [d] thiazole -2- formyl
Amine；
6- (2- diethylin -2- oxoethoxy)-N- (3,4- Dimethoxyphenethyl)-benzo [d] thiazole -2- formamide；
6- (2- diethylin -2- oxoethoxy)-N- [3- (4- morpholinyl) propyl]-benzo [d] thiazole -2- formamide；
6- (2- benzamido group -2- oxoethoxy)-N- [3- (4- morpholinyl) propyl]-benzo [d] thiazole -2- formamide；
6- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy }-N- [3- (4- morpholinyl) propyl]-benzo
[d] thiazole -2- formamide.
8. a kind of pharmaceutical composition, which is characterized in that include Formulas I compound represented described in claim 1-7 any one
And its pharmaceutically acceptable salt.
9. Formulas I compound represented and its pharmaceutically acceptable salt or claim described in claim 1--7 any one
Pharmaceutical composition application in preparation of anti-tumor drugs described in 8.
10. Formulas I compound represented and its pharmaceutically acceptable salt or claim described in claim 1-7 any one
The answering in the related disease drug of preparation treatment EGF-R ELISA signal transduction imbalance of pharmaceutical composition described in 8
With.
11. the application as described in claim 9 or 10, which is characterized in that the tumour and EGF-R ELISA letter
The related disease of number conduction disorder is Small Cell Lung Cancer, squamous carcinoma, gland cancer, large cell carcinoma, colorectal cancer, breast cancer, oophoroma,
Clear-cell carcinoma.
12. application as claimed in claim 10, which is characterized in that the EGF-R ELISA is EGFR kinases.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1290165A (en) * | 1997-11-10 | 2001-04-04 | 布里斯托尔-迈尔斯斯奎布公司 | Benzothiazole Protein tyrosine kinase inhibitors |
| JP2008524282A (en) * | 2004-12-22 | 2008-07-10 | ４エスツェー アクチェンゲゼルシャフト | 2,5- and 2,6-disubstituted benzazole derivatives useful as protein kinase inhibitors |
| CN101891704A (en) * | 2009-05-22 | 2010-11-24 | 四川大学 | N-(2-(2-amine)oxyethylthiobenzothiazole-6-)-2-formamide derivative as well as preparation method and applciaiton thereof |
| CN103102314A (en) * | 2012-01-12 | 2013-05-15 | 四川大学 | Benzothiazole, benzimidazole, benzoxazole derivatives and preparation method and application thereof |
| CN106008394A (en) * | 2016-05-23 | 2016-10-12 | 中国人民解放军第二军医大学 | Mercaptobenzothiazole amide compound, preparation method thereof, application of mercaptobenzothiazole amide compound serving as medicament |
| CN106478606A (en) * | 2016-09-21 | 2017-03-08 | 沈阳药科大学 | N substituted indole analog derivative and its application |
-
2017
- 2017-03-27 CN CN201710188629.7A patent/CN107021937B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1290165A (en) * | 1997-11-10 | 2001-04-04 | 布里斯托尔-迈尔斯斯奎布公司 | Benzothiazole Protein tyrosine kinase inhibitors |
| JP2008524282A (en) * | 2004-12-22 | 2008-07-10 | ４エスツェー アクチェンゲゼルシャフト | 2,5- and 2,6-disubstituted benzazole derivatives useful as protein kinase inhibitors |
| CN101891704A (en) * | 2009-05-22 | 2010-11-24 | 四川大学 | N-(2-(2-amine)oxyethylthiobenzothiazole-6-)-2-formamide derivative as well as preparation method and applciaiton thereof |
| CN103102314A (en) * | 2012-01-12 | 2013-05-15 | 四川大学 | Benzothiazole, benzimidazole, benzoxazole derivatives and preparation method and application thereof |
| CN106008394A (en) * | 2016-05-23 | 2016-10-12 | 中国人民解放军第二军医大学 | Mercaptobenzothiazole amide compound, preparation method thereof, application of mercaptobenzothiazole amide compound serving as medicament |
| CN106478606A (en) * | 2016-09-21 | 2017-03-08 | 沈阳药科大学 | N substituted indole analog derivative and its application |
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