CN106946761B - Indole carboxamides class compound and its application - Google Patents

Indole carboxamides class compound and its application Download PDF

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Publication number
CN106946761B
CN106946761B CN201710188630.XA CN201710188630A CN106946761B CN 106946761 B CN106946761 B CN 106946761B CN 201710188630 A CN201710188630 A CN 201710188630A CN 106946761 B CN106946761 B CN 106946761B
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oxoethoxy
formamide
ethyl
indoles
methyl
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CN106946761A (en
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胡春
张兰
柯佳
金辄
姚东鸣
郭万欣
刘晓平
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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 indole carboxamides class compound and its application.Indole carboxamides class compound include indole carboxamides class compound derivative and pharmaceutically useful salt, general structure it is as follows: wherein R1、R2、R3As described in claims and specification.Indole carboxamides class compound and the salt of the pharmaceutically useful sour addition of such compound can be used 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

Indole carboxamides class compound and its application
Technical field
The invention belongs to pharmaceutical technology fields, are related to indole carboxamides class compound and its as EGF-R ELISA Tyrosine kinase inhibitor application and preparation method.
Background technique
Malignant tumour is a kind of common disease and frequently-occurring disease for seriously threatening human health, because the death rate caused by it account for it is all The second of mortality, is only second to cardiovascular and cerebrovascular disease.And lung cancer is a kind of current global incidence and case fatality rate is in The pulmonary malignant tumour of situation is risen rapidly, most lung cancer originate from tunica mucosa bronchiorum epithelium.The classification method of lung cancer Very much, according to different classification methods, lung cancer can be divided into different types.It is special according to the differentiation degree of lung carcinoma cell and form Lung cancer is divided into two major classes at present by sign, i.e. non-small cell lung cancer (non-small cell lung cancer, NSCLC) and small Cell lung cancer (small cell lung cancer, SCLC), the former can be further divided into dermoid cancer (abbreviation squamous carcinoma, Squamous-cell carcinoma, SCC), gland cancer (adenopcarcinoma, AC), maxicell undifferentiated carcinoma it is (referred to as big thin Born of the same parents' cancer, large cell carcinoma) and other organization types.In patients with lung cancer, about 85% is NSCLC, wherein gland cancer It is the major tissue types of NSCLC, 5 years survival rates of NSCLC patient are still below 15%.The study found that in patients with lung cancer there is The imbalance of a large amount of epidermal growth factor signal transduction and the overexpression of epidermal growth factor recipient tyrosine kinase.
EGF-R ELISA (epidermal growth factor receptor, EGFR), also known as ErbB receptor, It is that one kind studies to obtain more tyrosine kinase (protein tyrosine kinases, PTKs) so far, it is main Member has EGFR (HER-1/ErbB-1), HER-2 (ErbB-2/neu), HER-3 (ErbB-3), HER-4 (ErbB-4), they are fixed On cell membrane, there is similar structure feature.EGFR is glycosylated single-stranded by the N-terminal that 1186 amino acid residues form Transmembrane glycoprotein, no subunit structure, molecular weight 170kD, comprising: the extracellular area (ECD) of N-terminal, by 621 amino acid residues Composition, site containing ligand binding, including tetra- subprovinces I, II, III, IV；The area cross-film (TM), is made of 23 amino acid residues；C The intracellular region at end is made of 542 amino acid residues, contains a tyrosine kinase domain, including the area nearly film (JM), junket ammonia The area acid kinase (TK), the subprovince of end C- etc. three.The normal growth of cell depends on the adjusting of signal transduction pathway, in recent years, Researchers' discovery, the signal transduction path of EGFR directly affect the apoptosis of cell, proliferation, differentiation, migration and cell cycle and follow Ring link, formation and deterioration with tumour obviously have certain association.It has proven convenient that keeping receptor same after EGFR family and ligand binding Source or Heterodimerization or oligomerization, can activate its tyrosine kinase, make itself tyrosine residue phosphorylation, further cause down The activation of a series of signal access is swum to inspire a series of biological effects, including genetic transcription, protein expression, cell division With increment etc..In conclusion EGFR not only adjusts division, hyperplasia, the differentiation of cell, but also such as viscous with the progression of tumour Attached, erosion, cell survival etc. are related.
Largely studies have shown that the overexpression of any of EGFR and/or one grade ligand or conduct disorder are The molecules feature of many entity tumors of the mankind.In recent years research is even more to find, the lung cancer group of 43%~89% NSCLC patient It knits and detects EGFR expression or high expression in sample, and EGFR expresses high case deterioration and makes fast progress, and treats to chemicotherapy It is insensitive.When EGFR is over-expressed, or even meeting block cell programmed cell death, keep the adjusting and controlling growth of cell out of control, cell is located always In proliferative state, it is eventually developed to as malignant tumour.It is clear that being the molecular targeted therapy of target spot NSCLC's using EGFR Wide prospect is had shown that in treating, and is designed and is obtained efficient, highly selective EGFR inhibitor and grinds as anticancer at this stage Study carefully one of hot spot.The present invention is intended to synthesize the smaller ligand that extracellular ligand binding domain is well combined, to inhibit junket intracellular Histidine kinase active region inhibits the catalytic activity and tyrosine autophosphorylation of enzyme, and then inhibits cell cycle progression, angiogenesis With the transfer of tumour etc..
Existing epidermal growth factor recipient tyrosine kinase inhibitor, such as Gefitinib, Tarceva, Lapatinib Deng, there is the dermoreactions such as diarrhea, fash, itch and it is possible headache, heart QT intervals extend and bioavilability drop It is low.
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
R1It can be independently selected from C1-C4Alkyl；
R2、R3It can be independently selected from H, C1-C4Alkyl, benzyl or substituted benzyl, substituted or unsubstituted C1-C4Alkoxy Phenyl；Or R2、R3Together 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,
R1It can be independently selected from C1-C4Alkyl；
R2、R3H, C can be independently selected from1-C4Alkyl, benzyl or substituted benzyl, substituted or unsubstituted C1-C4Alkoxy benzene Base；Or R2、R36 yuan of aryl or heterocycle are formed together with the nitrogen-atoms that they are connected, the heterocycle is former in addition to the nitrogen connected It is sub outer, 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；
Compound, its pro-drug and pharmaceutical active metabolite that the present invention preferably has the following structure and its pharmaceutically Acceptable salt,
R1It can be independently selected from C1-C4Alkyl；
R2、R3It 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；
Compound, its pro-drug and pharmaceutical active metabolite that the present invention preferably has the following structure and its pharmaceutically Acceptable salt,
R1It can be independently selected from C1-C4Alkyl；
R2、R3It 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 or alpha substituted benzylamine base, anilino- Or substituted anilinic or 2- (2- methoxyphenoxy) ethamine；
Ar can be independently selected 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,
R1It can be independently selected from C1-C4Alkyl；
R2、R3It 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 or alpha substituted benzylamine base, anilino- Or substituted anilinic or 2- (2- methoxyphenoxy) ethylamino-；
Ar can be independently selected from phenyl or substituted-phenyl, furyl, benzyl or substituted benzyl, Phenoxymethyl or substituted benzene Oxygen methyl or substituted-amino alkyl.
Further, the present invention preferably has the compound, its pro-drug and pharmaceutical active metabolite of following structure And its pharmaceutically acceptable salt,
R1It can be independently selected from C1-C4 alkyl；
R2、R3It can independently be selected from H, C1-C4Alkyl；Or 1- piperidyl is formed together with the nitrogen-atoms that they are connected, 1- pyrrolidinyl, 4- morpholinyl, 2- (4- morpholinyl) ethyl, 3- (4- morpholinyl) propyl, benzamido group, 4- fluoroanilino, 4- chlorine Anilino-, 4- toluidine, 4- methoxybenzene amido or 2- (2- methoxyphenoxy) ethylamino-；
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.
The synthesis of embodiment 1:3- substituted amido -2- butenoic acid ethyl
It synthesizes logical method: ethyl acetoacetate (15.01g, 0.12mol) is placed in 100mL eggplant-shape bottle, stir lower slowly drop Adding and replaces amine aqueous solution 0.36mol, the reaction was continued under room temperature after being added dropwise 3h, stratification, organic phase washing is primary, Anhydrous sodium sulfate dries, filters, spare in next step.
(1) synthesis of 3- methylamino -2- butenoic acid ethyl
According to logical method is synthesized, weak yellow liquid 15.08g is obtained, yield: 91.4%.
(2) synthesis of 3- ethylamino- -2- butenoic acid ethyl
According to logical method is synthesized, colourless liquid 16.31g is obtained, yield: 86.5%.
The synthesis of embodiment 2:1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid's ethyl ester
It synthesizes logical method: 1,4-benzoquinone (11.89g, 0.11mol) and acetone 120mL being placed in 250mL eggplant-shape bottle, under stirring It is walked in dropwise addition and intermediate 3- substituted amido -2- butenoic acid ethyl 0.11mol is made, 30 DEG C of rear temperature control is added dropwise, and the reaction was continued Solvent, product crude acetone recrystallization is evaporated off in 2h.
(1) synthesis of 1,2- dimethyl -5- hydroxyl -1H- indole -3-carboxylic acid's ethyl ester
According to logical method is synthesized, white solid 18.92g is obtained, yield: 73.7%, M.p.:208-210 DEG C (lit.: 208-209℃).ESI-MS,m/z:calcd.233.11(M+)；found 234.1([M+H]+),356.1([M+Na]+)。
(2) 2- methyl-1-ethyl-5- hydroxyl-1H- indole -3-carboxylic acid's ethyl ester synthesis
According to logical method is synthesized, yellow solid 20.89g is obtained, yield: 76.8%, M.p.:184-186 DEG C of (lit.:184- 185℃).ESI-MS,m/z:calcd.247.12(M+)；found 248.1([M+H]+),270.1([M+Na]+)。
The synthesis of embodiment 3:1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid
Synthesize logical method: by 1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid's ethyl ester 0.043mol, sodium hydroxide (17.15g, 0.43mol), ethyl alcohol 100mL and water 50mL are placed in 250mL eggplant-shape bottle, heating reflux reaction 12h, and reaction solution is cool A large amount of solids are precipitated with the aqueous hydrochloric acid solution tune pH=2 of 6mol/L to room temperature, filter, product crude product is with ethyl alcohol recrystallization.
(1) synthesis of 1,2- dimethyl -5- hydroxyl -1H- indole -3-carboxylic acid
According to logical method is synthesized, yellow solid 6.79g is obtained, yield 76.98%, M.p.:216-217 DEG C；ESI-MS,m/z: calcd.205.07(M+)；found 204.1([M-H]-)；1H NMR(400MHz,DMSO-d6):δ11.76(s,1H),8.84 (s, 1H), 7.38 (d, J=2.3Hz, 1H), 7.25 (d, J=8.7Hz, 1H), 6.63 (dd, J=8.7,2.4Hz, 1H), 3.63 (s,3H),2.65(s,3H)。
(2) 2- methyl-1-ethyl-5- hydroxyl-1H- indole -3-carboxylic acid synthesis
According to logical method is synthesized, yellow solid 5.11g is obtained, yield: 58.27%, M.p.:221-223 DEG C；ESI-MS,m/ z:calcd.219.09(M+)；found 218.1([M-H]-)；1H NMR(400MHz,DMSO-d6):δ11.76(s,1H), 8.84 (s, 1H), 7.38 (d, J=2.3Hz, 1H), 7.26 (d, J=8.7Hz, 1H), 6.62 (dd, J=8.7,2.4Hz, 1H), 4.13 (q, J=7.1Hz, 2H), 2.66 (s, 3H), 1.21 (t, J=7.1Hz, 3H).
The synthesis of embodiment 4:N- benzyl -1- alkyl -2- methyl -5- hydroxyl -1H- indoles -3- formamide
Synthesize logical method: by 1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid 0.020mol, benzylamine (6.42g, 0.060mol), n,N-Dimethylformamide 10mL and methylene chloride 100mL are placed in 250mL eggplant-shape bottle, successively by HOBt (4.05g, 0.030mol), triethylamine (6.07g, 0.060mol), EDCI (5.75g, 0.030mol) are separately added into wherein, room temperature It is stirred to react 16h, reaction solution is washed with 2mol/L aqueous hydrochloric acid solution and saturated sodium bicarbonate solution, and a large amount of water stirrings, which are added, to be made to analyse Solid out filters, product crude product ethyl alcohol recrystallization.
(1) synthesis of N- benzyl -1,2- dimethyl -5- hydroxyl -1H- indoles -3- formamide
According to logical method is synthesized, white solid 3.41g is obtained, yield 58.0%, M.p.:211-213 DEG C；ESI-MS,m/z: calcd.294.14(M+)；found 295.1([M+H]+),317.1([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 8.81 (s, 1H), 7.94 (d, J=2.3Hz, 1H), 7.37 (d, J=8.6Hz, 1H), 7.36-7.22 (m, 5H), 7.16 (dd, J =8.7,2.3Hz, 1H), 4.47 (d, J=6.0Hz, 2H), 3.61 (s, 3H), 2.56 (s, 3H).
(2) N- benzyl-2- methyl-1-ethyl-5- hydroxyl-1H- indoles-3- formamide synthesis
According to logical method is synthesized, yellow solid 3.62g is obtained, yield 58.8%, M.p.:189-190 DEG C；ESI-MS,m/z: calcd.308.15(M+)；found 309.2([M+H]+)；1H NMR(400MHz,DMSO-d6):δ8.81(s,1H),7.94 (d, J=2.3Hz, 1H), 7.35 (d, J=8.7Hz, 1H), 7.34-7.23 (m, 5H), 7.15 (dd, J=8.7,2.3Hz, 1H), 4.46 (d, J=6.0Hz, 2H), 4.11 (q, J=7.1Hz, 2H), 2.56 (s, 3H), 1.20 (t, J=7.1Hz, 3H).
The synthesis of embodiment 5:N- (4- luorobenzyl) -1- alkyl -2- methyl -5- hydroxyl -1H- indoles -3- formamide
Synthesize logical method: by 1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid 0.020mol, 4- fluorin benzyl amine (7.51g, 0.060mol), n,N-Dimethylformamide 10mL and methylene chloride 100mL are placed in 250mL eggplant-shape bottle, successively will HOBt (4.05g, 0.030mol), triethylamine (6.07g, 0.060mol), EDCI (5.75g, 0.030mol) are separately added into wherein, Reaction 16h is stirred at room temperature, reaction solution is washed with 2mol/L aqueous hydrochloric acid solution and saturated sodium bicarbonate solution, and a large amount of water stirrings are added Make that solid is precipitated, filters, product crude product ethyl alcohol recrystallization.
(1) synthesis of N- (4- luorobenzyl) -1,2- dimethyl -5- hydroxyl -1H- indoles -3- formamide
According to logical method is synthesized, white solid 4.56g is obtained, yield 73.0%, M.p.:217-218 DEG C；ESI-MS,m/z: calcd.312.13(M+)；found 313.1([M+H]+),335.1([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 8.82 (s, 1H), 7.95 (d, J=2.4Hz, 1H), 7.39 (dd, J=8.4,5.7Hz, 2H), 7.24 (d, J=8.7Hz, 1H), 7.18-7.11 (m, 3H), 4.44 (d, J=6.0Hz, 2H), 3.62 (s, 3H), 2.56 (s, 3H).
(2) N- (4- luorobenzyl)-2- methyl-1-ethyl-5- hydroxyl-1H- indoles-3- formamide synthesis
According to logical method is synthesized, yellow solid 4.81g is obtained, yield 73.7%, M.p.:167-168 DEG C；ESI-MS,m/z: calcd.326.14(M+)；found 327.1([M+H]+),349.1([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 8.81 (s, 1H), 7.94 (d, J=2.3Hz, 1H), 7.28 (dd, J=8.5,5.6Hz, 2H), 7.16 (d, J=8.7Hz, 1H), 7.11-6.96 (m, 3H), 4.56 (d, J=5.8Hz, 2H), 4.07 (q, J=7.2Hz, 2H), 2.67 (s, 3H), 1.30 (t, J= 7.2Hz,3H)。
Embodiment 6:N- [2- (2- methoxyphenoxy) ethyl] -1- alkyl -2- methyl -5- hydroxyl -1H- indoles -3- first The synthesis of amide
Synthesize logical method: by 1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid 0.020mol, O-methoxy benzene oxygen second Amine (12.16g, 0.060mol), n,N-Dimethylformamide 10mL and methylene chloride 100mL are placed in 250mL eggplant-shape bottle, then according to It is secondary to be separately added into HOBt (4.05g, 0.030mol), triethylamine (6.07g, 0.060mol), EDCI (5.75g, 0.030mol) Wherein, reaction 16h is stirred at room temperature, reaction solution is washed with 2mol/L aqueous hydrochloric acid solution and saturated sodium bicarbonate solution, is added a large amount of Water stirring makes that solid is precipitated, and filters, product crude product ethyl alcohol recrystallization.
(1) conjunction of N- [2- (2- methoxyphenoxy) ethyl] -1,2- dimethyl -5- hydroxyl -1H- indoles -3- formamide At
According to logical method is synthesized, white solid 5.89g is obtained, yield 83.2%, M.p.:193-195 DEG C；ESI-MS,m/z: calcd.354.16(M+)；found 355.2([M+H]+),377.2([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 8.80 (s, 1H), 7.23 (d, J=8.7Hz, 1H), 7.15 (d, J=2.2Hz, 1H), 7.07-6.94 (m, 2H), 6.94-6.84 (m, 2H), 6.64 (dd, J=8.7,2.3Hz, 1H), 4.09 (t, J=6.3Hz, 2H), 3.69 (dd, J=10.5,6.4Hz, 2H) 3.74(s,3H),3.61(s,3H),2.56(s,3H)。
(2) N- [2- (2- methoxyphenoxy) ethyl]-2- methyl-1-ethyl-5- hydroxyl-1H- indoles-3- formamide Synthesis
According to logical method is synthesized, white solid 6.40g is obtained, yield 87.0%, M.p.:153-155 DEG C；ESI-MS,m/z: calcd.368.17(M+)；found 369.2([M+H]+),391.2([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 8.79 (s, 1H), 7.23 (d, J=8.7Hz, 1H), 7.14 (d, J=2.1Hz, 1H), 7.05-6.93 (m, 2H), 6.92-6.84 (m, 2H), 6.63 (dd, J=8.7,2.2Hz, 1H), 4.09 (dd, J=11.6,6.4Hz, 2H), 3.73 (s, 3H), 3.60 (q, J =6.1Hz, 2H), 3.47-3.37 (m, 2H), 2.55 (s, 3H), 1.04 (t, J=7.0Hz, 3H).
Embodiment 7:N- [3- (4- morpholinyl) propyl] -1- alkyl -2- methyl -5- hydroxyl -1H- indoles -3- formamide Synthesis
Synthesize logical method: by 1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid 0.020mol, amine propylmorpholin (8.65g, 0.060mol), n,N-Dimethylformamide 10mL and methylene chloride 100mL are placed in 250mL eggplant-shape bottle, then successively HOBt (4.05g, 0.030mol), triethylamine (6.07g, 0.060mol), EDCI (5.75g, 0.030mol) are separately added into it In, reaction 16h is stirred at room temperature, reaction solution is washed with 2mol/L aqueous hydrochloric acid solution and saturated sodium bicarbonate solution, and a large amount of water are added Stirring makes that solid is precipitated, and filters, product crude product ethyl alcohol recrystallization.
(1) synthesis of N- [3- (4- morpholinyl) propyl] -1,2- dimethyl -5- hydroxyl -1H- indoles -3- formamide
According to logical method is synthesized, white solid 3.20g is obtained, yield 48.3%, M.p.:180-182 DEG C；ESI-MS,m/z: calcd.331.42(M+)；found 332.4([M+H]+),354.4([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 8.81 (s, 1H), 7.22 (d, J=8.7Hz, 1H), 7.10 (d, J=2.0Hz, 1H), 6.64 (dd, J=8.7,2.2Hz, 1H), 3.60 (s, 3H), 3.54 (t, J=4.4Hz, 4H), 3.29 (dd, J=12.6,6.6Hz, 2H), 2.54 (s, 3H), 2.36 (t, J =6.8Hz, 6H), 1.70 (p, J=6.9Hz, 2H).
(2) N- [3- (4- morpholinyl) propyl]-2- methyl-1-ethyl-5- hydroxyl-1H- indoles-3- formamide synthesis
According to logical method is synthesized, white solid 2.89g is obtained, yield 41.9%, M.p.:165-166 DEG C；ESI-MS,m/z: calcd.345.21(M+)；found 346.2([M+H]+),368.2([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 7.23 (d, J=8.7Hz, 1H), 7.11 (d, J=2.1Hz, 1H), 6.64 (dd, J=8.7,2.2Hz, 1H), 4.10 (q, J= 7.0Hz, 2H), 3.54 (t, J=4.4Hz, 4H), 3.29 (dd, J=12.7,6.6Hz, 2H), 2.55 (s, 3H), 2.38 (t, J= 6.6Hz, 6H), 1.70 (p, J=6.9Hz, 2H), 1.20 (t, J=7.1Hz, 3H).
The synthesis of embodiment 8:N- (furans -2- methyl) -1- alkyl -2- methyl -5- hydroxyl -1H- indoles -3- formamide
Synthesize logical method: by 1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid 0.020mol, furylamine (5.83g, 0.060mol), n,N-Dimethylformamide 10mL and methylene chloride 100mL are placed in 250mL eggplant-shape bottle, successively will HOBt (4.05g, 0.030mol), triethylamine (6.07g, 0.060mol), EDCI (5.75g, 0.030mol) are separately added into wherein, Reaction 16h is stirred at room temperature, reaction solution is washed with 2mol/L aqueous hydrochloric acid solution and saturated sodium bicarbonate solution, and a large amount of water stirrings are added Make that solid is precipitated, filters, product crude product is with ethyl alcohol recrystallization.
(1) synthesis of N- (furans -2- methyl) -1,2- dimethyl -5- hydroxyl -1H- indoles -3- formamide
According to logical method is synthesized, yellow solid 4.23g is obtained, yield 74.5%, M.p.:207-208 DEG C；ESI-MS,m/z: calcd.284.12(M+)；found 285.2([M+H]+),307.2([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 8.82 (s, 1H), 7.84 (d, J=5.6Hz, 1H), 7.24 (d, J=8.7Hz, 1H), 7.12 (d, J=2.1Hz, 1H), 6.64 (dd, J=8.7,2.2Hz, 1H), 6.41 (dd, J=5.6,2.8Hz, 1H), 6.26 (d, J=2.8Hz, 1H), 4.45 (d, J= 5.8Hz,2H),3.62(s,3H),2.55(s,3H)。
(2) N- (furans-2- methyl)-2- methyl-1-ethyl-5- hydroxyl-1H- indoles-3- formamide synthesis
According to logical method is synthesized, white solid 4.62g is obtained, yield 77.5%, M.p.:191-192 DEG C；ESI-MS,m/z: calcd.298.13(M+)；found 299.1([M+H]+),321.1([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 8.82 (s, 1H), 7.58 (d, J=5.5Hz, 1H), 7.25 (d, J=8.7Hz, 1H), 7.12 (d, J=2.2Hz, 1H), 6.64 (dd, J=8.7,2.3Hz, 1H), 6.41 (dd, J=5.5,2.9Hz, 1H), 6.27 (d, J=2.9Hz, 1H), 4.45 (d, J= 5.8Hz, 2H), 4.12 (q, J=7.1Hz, 2H), 2.55 (s, 3H), 1.21 (t, J=7.1Hz, 3H).
Embodiment 9:N- [2- (3,4- Dimethoxyphenyl) ethyl] -1- alkyl -2- methyl -5- hydroxyl -1H- indoles -3- The synthesis of formamide
Synthesize logical method: by 1- alkyl -2- methyl -5- hydroxyl -1H- indole -3-carboxylic acid 0.020mol, 3,4- dimethoxy benzene Ethamine (10.87g, 0.060mol), n,N-Dimethylformamide 10mL and methylene chloride 100mL are placed in 250mL eggplant-shape bottle, then Successively HOBt (4.05g, 0.030mol), triethylamine (6.07g, 0.060mol), EDCI (5.75g, 0.030mol) are added respectively Enter wherein, reaction 16h is stirred at room temperature, reaction solution is washed with 2mol/L aqueous hydrochloric acid solution and saturated sodium bicarbonate solution, is added big Amount water stirring makes that solid is precipitated, and filters, product crude product is with ethyl alcohol recrystallization.
(1) N- [2- (3,4- Dimethoxyphenyl) ethyl] -1,2- dimethyl -5- hydroxyl -1H- indoles -3- formamide Synthesis
According to logical method is synthesized, white solid 5.98g is obtained, yield 81.2%, M.p.:216-218 DEG C；ESI-MS,m/z: calcd.368.17(M+)；found 369.2([M+H]+),391.2([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 7.62 (d, J=8.6Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=7.8Hz, 2H), 7.17 (d, J=8.1Hz, 1H), 7.03 (d, J=8.7Hz, 1H), 4.12 (s, 3H), 4.11 (s, 3H), 4.00 (s, 3H), 3.87 (dd, J=13.1,6.5Hz, 2H), (3.19 t, J=7.2Hz, 2H), 2.90 (s, 3H).
(2) N- [2- (3,4- Dimethoxyphenyl) ethyl]-2- methyl-1-ethyl-5- hydroxyl-1H- indoles-3- formamide Synthesis
According to logical method is synthesized, white solid 6.13g is obtained, yield 80.2%, M.p.:195-196 DEG C；ESI-MS,m/z: calcd.382.19(M+)；found 383.2([M+H]+),405.2([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ 9.19 (s, 1H), 7.65 (d, J=8.7Hz, 1H), 7.50 (d, J=2.1Hz, 1H), 7.29 (d, J=8.3Hz, 2H), 7.19 (d, J=8.1Hz, 1H), 7.05 (dd, J=8.7,2.2Hz, 1H), 4.52 (q, J=7.0Hz, 2H), 4.15 (s, 3H), 4.13 (s, 3H), 3.88 (dd, J=13.9,6.5Hz, 2H), 3.21 (t, J=7.4Hz, 2H), 2.92 (s, 3H), 1.61 (t, J= 7.1Hz,3H)。
Embodiment 10:N- benzyl -5- (2- diethylin -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formyl The synthesis of amine (compound Z01)
By chloracetyl diethylamine (2.38g, 0.016mol), N- benzyl -1,2- dimethyl -5- hydroxyl -1H- indoles -3- Formamide (0.89g, 0.0030mol), Anhydrous potassium carbonate (4.28g, 0.031mol), potassium iodide (0.05g, 0.00031mol) and N,N-Dimethylformamide 20mL is placed in 100mL eggplant-shape bottle, 80 DEG C of reaction 16h of temperature control, and reaction solution is cool to room temperature and to be inclined Enter in 250mL water, stir 3h, filter to obtain yellow solid, through silica gel column chromatography separation (v (petroleum ether): v (ethyl acetate)=5: 1) white powder 0.87g is obtained, yield: 71.3%.M.p.:119-120℃；IR:(KBr,cm-1):υ3444.3,2927.6, 1660.6,1620.2,1431.2,1383.6,1257.3,1190.8,1085.3,834.3,776.2,745.1,701.8；ESI- MS,m/z:calcd.407.22(M+)；found 408.3([M+H]+),430.2([M+Na]+),446.2([M+K]+).；1H NMR (400MHz, CDCl3): δ 7.43 (d, J=2.3Hz, 1H), 7.37-7.27 (m, 5H), 7.21 (d, J=8.9Hz, 1H), 6.91 (dd, J=8.9,2.4Hz, 1H), 4.71 (d, J=5.7Hz, 2H), 4.66 (s, 2H), 3.66 (s, 3H), 3.38 (dd, J =7.1,2.9Hz, 2H), 3.35 (dd, J=7.1,2.9Hz, 2H), 2.72 (s, 2H), 1.17 (t, J=7.1Hz, 3H), 1.11 (t, J=7.1Hz, 3H).
Embodiment 11:N- benzyl-5- (2- diethylin-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- The synthesis of formamide (compound Z02)
Referring to the synthetic method of embodiment 10, white solid 0.62g is obtained, yield: 49.2%.M.p.:105-106℃； IR:(KBr,cm-1):υ3434.3,2925.2,1661.7,1617.5,1530.2,1478.3,1347.7,1259.2,1189.2, 1139.2,1082.9,835.4,756.0,704.4；ESI-MS,m/z:calcd.421.24(M+)；found 422.3([M+H]+), 444.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.43 (d, J=2.3Hz, 1H), 7.36-7.27 (m, 5H), 7.21 (d, J=8.9Hz, 1H), 6.90 (dd, J=8.9,2.4Hz, 1H), 4.71 (d, J=5.7Hz, 2H), 4.65 (s, 2H), 4.12 (q, J=7.2Hz, 2H), 3.36 (q, J=7.0Hz, 4H), 2.72 (s, 3H), 1.33 (t, J=7.2Hz, 3H), 1.17 (t, J= 7.1Hz, 3H), 1.11 (t, J=7.1Hz, 3H).
Embodiment 12:N- benzyl -5- (2- di-n-propylamine base -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- first The synthesis of amide (compound Z03)
Referring to the synthetic method of embodiment 10, white solid 1.08g is obtained, yield: 82.4%.M.p.:123-125℃； IR:(KBr,cm-1):υ3349.0,2964.9,2871.1,1656.2,1484.3,1382.6,1270.8,1190.0,1143.3, 1084.6,926.2,839.0,798.2,741.2,697.8；ESI-MS,m/z:calcd.435.25(M+)；found 436.2 ([M+H]+),458.3([M+Na]+)；1H NMR (400MHz, CDCl3): δ 7.43 (d, J=2.3Hz, 1H), 7.38-7.26 (m, 5H), 7.20 (d, J=8.9Hz, 1H), 6.90 (dd, J=8.9,2.4Hz, 1H), 4.71 (d, J=5.7Hz, 2H), 4.67 (s, 2H), 3.66 (s, 3H), 3.26 (q, J=7.0Hz, 4H), 2.72 (s, 2H), 1.56-1.48 (m, 4H), 0.89 (t, J= 7.4Hz, 3H), 0.84 (t, J=7.4Hz, 3H).
Embodiment 13:N- benzyl-5- (2- di-n-propylamine base-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles- The synthesis of 3- formamide (compound Z04)
Referring to the synthetic method of embodiment 10, white solid 1.07g is obtained, yield: 79.3%.M.p.:129-130℃； IR:(KBr,cm-1):υ3444.2,2930.3,1657.5,1618.2,1482.3,1383.6,1272.0,1193.7,1145.4, 1090.3,795.4,698.8；ESI-MS,m/z:calcd.449.27(M+)；found450.2([M+H]+),472.3([M+Na]+) ；1H NMR(400MHz,CDCl3): δ 7.42 (d, J=2.2Hz, 1H), 7.37-7.27 (m, 5H), 7.20 (d, J=8.9Hz, 1H), 6.89 (dd, J=8.9,2.3Hz, 1H), 4.70 (d, J=5.8Hz, 2H), 4.67 (s, 2H), 4.11 (q, J=7.1Hz, 2H), 3.29-3.21 (m, 4H), 2.71 (s, 3H), 1.60-1.52 (m, 4H), 1.34 (t, J=7.3Hz, 3H), 0.89 (t, J= 7.4Hz, 3H), 0.84 (t, J=7.4Hz, 3H).
Embodiment 14:N- benzyl -5- (2- di-iso-butylmanice base -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- first The synthesis of amide (compound Z05)
Referring to the synthetic method of embodiment 10, yellow solid 1.12g is obtained, yield: 80.6%.M.p.:105-106℃； IR:(KBr,cm-1):υ3425.2,2919.0,2850.0,1621.9,1485.5,1384.5,1194.7,1120.5,821.2, 778.6,697.9；ESI-MS,m/z:calcd.463.28(M+)；found 464.3([M+H]+)；1H NMR(400MHz, CDCl3): δ 7.43 (d, J=2.3Hz, 1H), 7.38-7.27 (m, 5H), 7.19 (d, J=8.9Hz, 1H), 6.90 (dd, J= 8.8,2.4Hz, 1H), 4.71 (d, J=5.6Hz, 2H), 4.70 (s, 2H), 3.65 (s, 3H), 3.20-3.11 (m, 2H), 2.72 (s, 3H), 1.29-1.25 (m, 4H), 0.92 (d, J=6.7Hz, 6H), 0.78 (t, J=6.7Hz, 6H).
Embodiment 15:N- benzyl-5- (2- di-iso-butylmanice base-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles- The synthesis of 3- formamide (compound Z06)
Referring to the synthetic method of embodiment 10, white solid 0.75g is obtained, yield: 52.4%.M.p.:101-103℃； IR:(KBr,cm-1):υ3423.1,2959.1,2920.8,1656.7,1621.6,1543.7,1484.8,1422.4,1384.8, 1209.4,1143.3,1091.9,817.5,744.8,698.8；ESI-MS,m/z:calcd.477.30(M+)；found 478.4([M+H]+),500.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.43 (d, J=2.3Hz, 1H), 7.38- 7.25 (m, 5H), 7.20 (d, J=8.9Hz, 1H), 6.89 (dd, J=8.8,2.3Hz, 1H), 4.71 (d, J=5.8Hz, 2H), 4.66 (s, 2H), 4.12 (q, J=7.1Hz, 2H), 3.21-3.14 (m, 4H), 2.72 (s, 3H), 2.02-1.67 (m, 4H), 1.33 (t, J=7.1Hz, 3H), 0.92 (d, J=6.7Hz, 6H), 0.79 (t, J=6.7Hz, 6H).
Embodiment 16:N- benzyl -5- [2- (1- piperidyl) -2- oxoethoxy] -1,2- dimethyl -1H- indoles -3- first The synthesis of amide (compound Z07)
Referring to the synthetic method of embodiment 10, white solid 0.86g is obtained, yield: 68.3%.M.p.:78-80℃；IR: (KBr,cm-1):υ3429.6,2923.2,2853.6,1641.2,1618.1,1488.8,1440.1,1212.0,1163.4, 1082.8,1017.8,874.0,699.6；ESI-MS,m/z:calcd.419.22(M+)；found420.4([M+H]+),442.3 ([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.43 (d, J=2.4Hz, 1H), 7.38-7.26 (m, 5H), 7.20 (d, J= 8.9Hz, 1H), 6.91 (dd, J=8.9,2.4Hz, 1H), 4.71 (d, J=5.8Hz, 1H), 4.66 (s, 2H), 3.66 (s, 3H), 3.52 (t, J=5.3Hz, 2H), 3.45 (t, J=5.0Hz, 2H), 2.72 (s, 3H), 1.61-1.53 (m, 6H).
Embodiment 17:N- benzyl-5- [2- (1- piperidyl)-2- oxoethoxy]-2- methyl-1-ethyl-1H- indoles- The synthesis of 3- formamide (compound Z08)
Referring to the synthetic method of embodiment 10, white solid 0.83g is obtained, yield: 58.0%.M.p.:89-90℃；IR: (KBr,cm-1):υ3551.3,3404.6,3336.9,1646.8,1613.0,1546.0,1488.7,1419.9,1384.5, 1214.2,1164.4,1977.0,984.4,850.0,806.9,727.7,695.2；ESI-MS,m/z:calcd.433.24(M+)；found 434.7([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.43 (d, J=2.3Hz, 1H), 7.38-7.25 (m, 5H), 7.21 (d, J=8.9Hz, 1H), 6.90 (dd, J=8.8,2.4Hz, 1H), 4.71 (d, J=5.7Hz, 2H), 4.66 (s, 2H), 4.12 (q, J=7.2Hz, 2H), 3.52 (t, J=5.3Hz, 2H), 3.44 (t, J=5.0Hz, 2H), 2.71 (s, 3H), 1.66-1.48 (m, 6H), 1.33 (t, J=7.2Hz, 3H).
Embodiment 18:N- benzyl -5- [2- (4- morpholinyl) -2- oxoethoxy] -1,2- dimethyl -1H- indoles -3- first The synthesis of amide (compound Z09)
Referring to the synthetic method of embodiment 10, yellow solid 0.78g is obtained, yield: 61.9%.M.p.:110-112℃； IR:(KBr,cm-1):υ3442.6,2856.0’1653.8,1483.8,1384.1,1274.2,1207.7,1162.8,1031.3, 923.2,850.8,698.4；ESI-MS,m/z:calcd.421.20(M+)；found422.2([M+H]+),444.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.44 (d, J=2.3Hz, 1H), 7.38-7.27 (m, 5H), 7.21 (d, J=8.9Hz, 1H), 6.89 (dd, J=8.9,2.4Hz, 1H), 4.71 (d, J=5.7Hz, 2H), 4.68 (s, 2H), 3.67 (s, 3H), 3.63-3.57 (m,8H),2.72(s,3H)。
Embodiment 19:N- benzyl-5- [2- (4- morpholinyl)-2- oxoethoxy]-2- methyl-1-ethyl-1H- indoles- The synthesis of 3- formamide (compound Z10)
Referring to the synthetic method of embodiment 10, white solid 1.08g is obtained, yield: 82.4%.M.p.:161-162℃； IR:(KBr,cm-1):υ3338.5,2969.3,2931.8,1663.5,1546.4,1481.6,1440.8,1279.5,1196.4, 1161.6,1112.1,1035.4,970.1,851.3,758.6,707.8；ESI-MS,m/z:calcd.435.22(M+)； found 436.7([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.44 (d, J=2.3Hz, 1H), 7.38-7.27 (m, 5H), 7.22 (d, J=8.8Hz, 1H), 6.88 (dd, J=8.8,2.3Hz, 1H), 4.71 (d, J=5.4Hz, 2H), 4.67 (s, 2H), 4.16 (q, J=7.1Hz, 2H), 3.64-3.52 (m, 8H), 2.72 (s, 3H), 1.34 (t, J=7.2Hz, 3H).
Embodiment 20:N- benzyl -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } -1,2- two The synthesis of Methyl-1H-indole -3- formamide (compound Z11)
Referring to the synthetic method of embodiment 10, white solid 0.99g is obtained, yield: 66.0%.M.p.:180-181℃； IR:(KBr,cm-1):υ3426.8,2923.0,2852.3,1628.8,1384.4,1253.4,1124.5,777.8,618.2； ESI-MS,m/z:calcd.501.23(M+)；found 502.4([M+H]+),524.4([M+Na]+)；1H NMR(400MHz, CDCl3): δ 7.40 (d, J=2.3Hz, 1H), 7.38-7.27 (m, 5H), 7.22 (d, J=8.9Hz, 1H), 6.90-6.81 (m, 5H), 4.68 (d, J=5.6Hz, 2H), 4.50 (s, 2H), 4.10 (t, J=5.1Hz, 2H), 3.76 (s, 3H), 3.74-3.71 (m,2H),3.66(s,3H),2.72(s,3H)。
Embodiment 21:N- benzyl -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } -2- methyl - The synthesis of 1- ethyl -1H- indoles -3- formamide (compound Z12)
Referring to the synthetic method of embodiment 10, white solid 1.43g is obtained, yield: 92.3%.M.p.:157-159℃； IR:(KBr,cm-1):υ3455.6,2922.3,1686.6,1619.2,1508.6,1482.9,1384.0,1253.7,1209.9, 1127.8,1027.1,975.5,745.5,698.1；ESI-MS,m/z:calcd.515.24(M+)；found 516.3([M+H]+), 538.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (d, J=2.4Hz, 1H), 7.38-7.27 (m, 5H), 7.23 (d, J=8.8Hz, 1H), 6.89-6.84 (m, 5H), 4.68 (d, J=5.7Hz, 2H), 4.50 (s, 2H), 4.14-4.09 (m, 4H), 3.76 (s, 3H), 3.73 (t, J=5.3Hz, 2H), 2.72 (s, 3H), 1.34 (t, J=7.2Hz, 3H).
Embodiment 22:N- (4- luorobenzyl) -5- (2- diethylin -2- oxoethoxy) -1,2- dimethyl -1H- indoles - The synthesis of 3- formamide (compound Z13)
Referring to the synthetic method of embodiment 10, white solid 0.86g is obtained, yield: 67.2%.M.p.:133-134℃； IR:(KBr,cm-1):υ3442.8,2972.6,2931.4,1658.0,1619.9,1487.1,1383.6,1218.2,1143.2, 1086.9,974.6,822.1,757.6,568.6；ESI-MS,m/z:calcd.425.21(M+)；found 426.3([M+H]+), 448.4([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.41 (dd, J=8.6,5.4Hz, 2H), 7.29 (d, J=2.3Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.03 (t, J=8.7Hz, 2H), 6.91 (dd, J=8.8,2.4Hz, 1H), 4.68 (s, 2H), 4.66 (d, J=5.6Hz, 2H), 3.66 (s, 3H), 3.37 (q, J=6.9Hz, 4H), 2.72 (s, 3H), 1.17 (t, J= 7.1Hz, 3H), 1.10 (t, J=7.1Hz, 3H).
Embodiment 23:N- (4- luorobenzyl)-5- (2- diethylin-2- oxoethoxy)-2- methyl-1-ethyl-1H- Yin The synthesis of diindyl -3- formamide (compound Z14)
Referring to the synthetic method of embodiment 10, white solid 0.85g is obtained, yield: 64.4%.M.p.:135-137℃； IR:(KBr,cm-1):υ3423.8,3278.3,2925.4,1646.1,1625.0,1510.1,1482.6,1383.4,1263.2, 1207.6,1155.5,1070.6,822.5,791.0,706.7；ESI-MS,m/z:calcd.439.23(M+)；found 440.4([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.40 (dd, J=8.5,5.5Hz, 2H), 7.29 (d, J=2.3Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.02 (t, J=8.7Hz, 2H), 6.89 (dd, J=8.8,2.3Hz, 1H), 4.66 (d, J =5.8Hz, 4H), 4.11 (q, J=7.2Hz, 2H), 3.38 (q, J=7.1Hz, 4H), 2.71 (s, 3H), 1.32 (t, J= 7.2Hz, 3H), 1.17 (t, J=7.1Hz, 3H), 1.10 (t, J=7.1Hz, 3H).
Embodiment 24:N- (4- luorobenzyl) -5- (2- di-n-propylamine base -2- oxoethoxy) -1,2- dimethyl -1H- Yin The synthesis of diindyl -3- formamide (compound Z15)
Referring to the synthetic method of embodiment 10, white solid 1.06g is obtained, yield: 77.9%.M.p.:145-147℃； IR:(KBr,cm-1):υ3446.5,2930.0,2360.9,1655.5,1508.8,1484.3,1383.4,1271.9,1190.1, 1095.7,819.2,798.4,777.4；ESI-MS,m/z:calcd.453.24(M+)；found454.4([M+H]+)；1H NMR (400MHz,CDCl3): δ 7.40 (dd, J=8.7,5.4Hz, 2H), 7.28 (d, J=2.3Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.03 (t, J=8.7Hz, 2H), 6.89 (dd, J=8.8,2.4Hz, 1H), 4.70 (s, 2H), 4.67 (d, J=5.6Hz, 2H), 3.66 (s, 3H), 3.29-3.24 (m, 4H), 2.72 (s, 3H), 1.54-1.47 (m, 4H), 0.90 (t, J=7.4Hz, 3H), 0.83 (t, J=7.4Hz, 3H).
Embodiment 25:N- (4- luorobenzyl)-5- (2- di-n-propylamine base-2- oxoethoxy)-2- methyl-1-ethyl-1H- The synthesis of indoles -3- formamide (compound Z16)
Referring to the synthetic method of embodiment 10, white solid 0.68g is obtained, yield: 46.9%.M.p.:120-122℃； IR:(KBr,cm-1):υ3304.4,2963.1,2931.9,1658.7,1619.4,1510.7,1483.0,1423.2,1272.9, 1207.6,1158.4,1091.3,835.3,794.0,706.7；ESI-MS,m/z:calcd.467.26(M+)；found 468.4([M+H]+),490.4([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (dd, J=8.5,5.4Hz, 2H), 7.29 (d, J=2.3Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.02 (t, J=8.7Hz, 2H), 6.88 (dd, J=8.8, 2.4Hz, 1H), 4.69 (s, 2H), 4.67 (d, J=5.8Hz, 2H), 4.12 (q, J=7.2Hz, 2H), 3.32-3.21 (m, 4H), 2.72 (s, 3H), 1.59-1.49 (m, 4H), 1.33 (t, J=7.2Hz, 3H), 0.90 (t, J=7.4Hz, 3H), 0.83 (t, J= 7.4Hz,3H)。
Embodiment 26:N- (4- luorobenzyl) -5- (2- di-iso-butylmanice base -2- oxoethoxy) -1,2- dimethyl -1H- Yin The synthesis of diindyl -3- formamide (compound Z17)
Referring to the synthetic method of embodiment 10, white solid 0.88g is obtained, yield: 61.1%.M.p.:137-139℃； IR:(KBr,cm-1):υ3355.2,2961.8,1656.6,1540.3,1485.8,1385.1,1215.7,1145.0,1082.5, 821.1,795.3,758.4,712.4,589.9；ESI-MS,m/z:calcd.481.27(M+)；found 482.4([M+H]+), 504.4([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.41 (dd, J=8.7,5.4Hz, 2H), 7.30 (d, J=2.3Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 7.02 (t, J=8.7Hz, 2H), 6.89 (dd, J=8.8,2.4Hz, 1H), 4.73 (s, 2H), 4.67 (d, J=5.6Hz, 2H), 3.66 (s, 3H), 3.20-3.13 (m, 2H), 2.72 (s, 3H), 2.01-1.87 (m, 4H), 0.93 (d, J=6.7Hz, 6H), 0.77 (t, J=6.7Hz, 6H).
Embodiment 27:N- (4- luorobenzyl)-5- (2- di-iso-butylmanice base-2- oxoethoxy)-2- methyl-1-ethyl-1H- The synthesis of indoles -3- formamide (compound Z18)
Referring to the synthetic method of embodiment 10, white solid 0.78g is obtained, yield: 50.7%.M.p.:112-114℃； IR:(KBr,cm-1):υ3444.7,3295.3,2960.1,2921.4,1665.1,1631.3,1509.6,1483.6,1384.2, 1213.4,1151.4,1090.2,842.8,821.8,796.1,749.7,691.1；ESI-MS,m/z:calcd.495.29(M+)；found 496.3([M+H]+),518.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (dd, J=8.6, 5.4Hz, 2H), 7.30 (d, J=2.3Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 7.02 (t, J=8.7Hz, 2H), 6.88 (dd, J=8.8,2.4Hz, 1H), 4.73 (s, 2H), 4.66 (d, J=5.9Hz, 2H), 4.12 (q, J=7.2Hz, 2H), 3.20- 3.15 (m, 2H), 2.71 (s, 3H), 2.08-1.99 (m, 4H), 0.93 (d, J=6.8Hz, 6H), 0.76 (t, J=6.7Hz, 6H)。
Embodiment 28:N- (4- luorobenzyl) -5- [2- (1- piperidyl) -2- oxoethoxy] -1,2- dimethyl -1H- Yin The synthesis of diindyl -3- formamide (compound Z19)
Referring to the synthetic method of embodiment 10, white solid 0.56g is obtained, yield: 42.7%.M.p.:92-94℃；IR: (KBr,cm-1):υ3423.8,2920.5,2851.1,1626.7,1509.2,1445.4,1220.0,1156.9,1014.3, 874.3,803.4,714.5；ESI-MS,m/z:calcd.437.21(M+)；found 438.4([M+H]+),560.4([M+Na]+) ；1H NMR(400MHz,CDCl3): δ 7.41 (dd, J=8.6,5.4Hz, 2H), 7.29 (d, J=2.4Hz, 1H), 7.21 (d, J= 8.9Hz, 1H), 7.03 (t, J=8.7Hz, 2H), 6.90 (dd, J=8.8,2.4Hz, 1H), 4.69 (s, 2H), 4.67 (d, J= 5.8Hz, 2H), 3.66 (s, 3H), 3.51 (t, J=5.2Hz, 2H), 3.45 (t, J=5.1Hz, 2H), 2.72 (s, 3H), 1.55- 1.47(m,6H)。
Embodiment 29:N- (4- luorobenzyl)-5- [2- (1- piperidyl)-2- oxoethoxy]-2- methyl-1-ethyl-1H- The synthesis of indoles -3- formamide (compound Z20)
Referring to the synthetic method of embodiment 10, yellow solid 0.60g is obtained, yield: 42.9%.M.p.:126-127℃； IR:(KBr,cm-1):υ3513.3,3308.9,2918.1,2849.7,1655.9,1608.0,1544.5,1510.5,1439.8, 1231.5,1210.6,1160.6,1087.6,837.8,809.2,771.2,689.3；ESI-MS,m/z:calcd.451.23(M+)；found 452.2([M+H]+),474.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.41 (dd, J=8.4, 5.5Hz, 2H), 7.28 (d, J=2.3Hz, 1H), 7.21 (d, J=8.8Hz, 1H), 7.02 (t, J=8.7Hz, 2H), 6.89 (dd, J=8.8,2.3Hz, 1H), 4.68 (s, 2H), 4.66 (d, J=5.9Hz, 2H), 4.12 (q, J=7.2Hz, 2H), 3.52 (t, J=5.1Hz, 2H), 3.44 (t, J=5.0Hz, 2H), 2.71 (s, 3H), 1.67-1.52 (m, 6H), 1.33 (t, J= 7.2Hz,3H)。
Embodiment 30:N- (4- luorobenzyl) -5- [2- (4- morpholinyl) -2- oxoethoxy] -1,2- dimethyl -1H- Yin The synthesis of diindyl -3- formamide (compound Z21)
Referring to the synthetic method of embodiment 10, yellow solid 1.07g is obtained, yield: 81.1%.M.p.:181-182℃； IR:(KBr,cm-1):υ3422.9,2919.7,2860.2,1677.1,1627.6,1506.2,1444.1,1214.8,1162.4, 1117.0,1032.2,845.3,808.7,720.8；ESI-MS,m/z:calcd.439.19(M+)；found 440.3([M+H]+), 462.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.41 (dd, J=8.5,5.4Hz, 2H), 7.28 (d, J=2.4Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.03 (t, J=8.7Hz, 2H), 6.88 (dd, J=8.8,2.4Hz, 1H), 4.70 (s, 2H), 4.67 (d, J=5.8Hz, 2H), 3.66 (s, 3H), 3.63-3.58 (m, 8H), 2.71 (s, 3H).
Embodiment 31:N- (4- luorobenzyl)-5- [2- (4- morpholinyl)-2- oxoethoxy]-2- methyl-1-ethyl-1H- The synthesis of indoles -3- formamide (compound Z22)
Referring to the synthetic method of embodiment 10, white solid 1.11g is obtained, yield: 79.3%.M.p.:151-153℃； IR:(KBr,cm-1):υ3369.5,2966.9,2851.8,1669.9,1620.5,1510.2,1481.1,1352.4,1188.6, 1112.9,1028.0,841.8,777.3,707.4；ESI-MS,m/z:calcd.453.21(M+)；found 454.2([M+H]+), 476.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.42 (dd, J=8.7,5.4Hz, 2H), 7.29 (d, J=2.4Hz, 1H), 7.23 (d, J=8.9Hz, 1H), 7.04 (t, J=8.7Hz, 2H), 6.88 (dd, J=8.8,2.4Hz, 1H), 4.70 (s, 2H), 4.67 (d, J=5.7Hz, 2H), 4.13 (q, J=7.2Hz, 2H), 3.63-3.59 (m, 8H), 2.72 (s, 3H), 1.34 (t, J=7.2Hz, 3H).
Embodiment 32:N- (4- luorobenzyl) -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } - The synthesis of 1,2- dimethyl -1H- indoles -3- formamide (compound Z23)
Referring to the synthetic method of embodiment 10, white solid 0.72g is obtained, yield: 46.2%.M.p.:187-189℃； IR:(KBr,cm-1):υ3453.5,3238.6,2912.8,1681.0,1627.1,1506.3,1485.9,1384.4,1252.9, 1222.8,1126.3,1026.5,829,.6,790.9,736.4；ESI-MS,m/z:calcd.519.22(M+)；found 520.3([M+H]+),542.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.35 (dd, J=8.6,5.4Hz, 2H), 7.23 (d, J=2.3Hz, 1H), 7.19 (d, J=8.9Hz, 1H), 7.03 (t, J=8.7Hz, 2H), 6.95 (dd, J=3.8, 1.2Hz, 1H), 6.89-6.83 (m, 4H), 4.64 (d, J=5.8Hz, 2H), 4.53 (s, 2H), 4.10 (t, J=5.1Hz, 2H), 3.75(s,3H),3.74–3.70(m,2H),3.66(s,3H),2.71(s,3H)。
Embodiment 33:N- (4- luorobenzyl) -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } - The synthesis of 2- methyl-1-ethyl-1H- indoles-3- formamide (compound Z24)
Referring to the synthetic method of embodiment 10, white solid 1.07g is obtained, yield: 64.9%.M.p.:166-168℃； IR:(KBr,cm-1):υ3268.1,1673.3,1622.3,1507.4,1482.0,1254.0,1220.4,1125.7,1026.3, 831.0,739,8,720.1；ESI-MS,m/z:calcd.533.23(M+)；found534.2([M+H]+),556.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.35 (dd, J=8.6,5.4Hz, 2H), 7.23 (d, J=2.3Hz, 1H), 7.21 (d, J= 8.9Hz, 1H), 7.03 (t, J=8.7Hz, 2H), 6.94 (dd, J=8.9,2.3Hz, 1H), 6.89-6.82 (m, 5H), 4.64 (d, J=5.8Hz, 2H), 4.53 (s, 2H), 4.14-4.10 (m, 4H), 3.76 (s, 3H), 3.74-3.70 (m, 2H), 2.71 (s, 3H), 1.34 (t, J=7.2Hz, 3H).
Embodiment 34:N- [2- (2- methoxyphenoxy) ethyl] -5- (2- diethylin -2- oxoethoxy) -1,2- The synthesis of dimethyl -1H- indoles -3- formamide (compound Z25)
Referring to the synthetic method of embodiment 10, white solid 0.70g is obtained, yield: 53.4%.M.p.:164-165℃； IR:(KBr,cm-1):υ3441.3,3274.6,2932,3,1648.8,1551.8,1482.8,1383.1,1256.1,1203.5, 1162.1,1119.4,1048.3,1048.3,872.5,794.0,754.4；ESI-MS,m/z:calcd.467.24(M+)； found 468.2([M+H]+),490.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.39 (d, J=2.3Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 7.00 (dd, J=7.7,1.8Hz, 1H), 6.97-6.86 (m, 4H), 4.62 (s, 2H), 4.26 (t, J=5.1Hz, 2H), 3.89 (dd, J=10.5,5.4Hz, 2H), 3.73 (s, 3H), 3.66 (s, 3H), 3.36 (q, J= 7.1Hz, 2H), 3.25 (q, J=7.1Hz, 2H), 2.70 (s, 3H), 1.13-1.08 (m, 6H).
Embodiment 35:N- [2- (2- methoxyphenoxy) ethyl] -5- (2- diethylin -2- oxoethoxy) -2- first The synthesis of base -1- ethyl -1H- indoles -3- formamide (compound Z26)
Referring to the synthetic method of embodiment 10, white solid 0.64g is obtained, yield: 49.2%.M.p.:138-139℃； IR:(KBr,cm-1):υ3440.6,2931.5,1647.3,1547.0,1504.4,1465.7,1383.4,1224.3,1120.2, 871.4,751.4,619.7；ESI-MS,m/z:calcd.481.26(M+)；found482.3([M+H]+),504.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.39 (d, J=2.3Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.00 (dd, J=7.7, 1.7Hz, 1H), 6.96-6.86 (m, 4H), 4.61 (s, 2H), 4.26 (t, J=5.1Hz, 2H), 4.13 (q, J=7.2Hz, 2H), 3.89 (dd, J=10.5,5.4Hz, 2H), 3.73 (s, 3H), 3.37 (q, J=7.1Hz, 2H), 3.25 (q, J=7.1Hz, 2H), 2.70 (s, 3H), 1.34 (t, J=7.2Hz, 3H), 1.11-1.07 (m, 6H).
Embodiment 36:N- [2- (2- methoxyphenoxy) ethyl] -5- (2- di-n-propylamine base -2- oxoethoxy) -1, The synthesis of 2- dimethyl -1H- indoles -3- formamide (compound Z27)
Referring to the synthetic method of embodiment 10, white solid 1.10g is obtained, yield: 73.8%.M.p.:101-103℃； IR:(KBr,cm-1):υ3328.1,2921.1,1650.6,1626.7,1547.4,1458.7,1250.8,1210.7,1124.3, 1025.5,931.6,835.9,746.3；ESI-MS,m/z:calcd.495.27(M+)；found496.3([M+H]+)；1H NMR (400MHz,CDCl3): δ 7.38 (d, J=2.2Hz, 1H), 7.20 (d, J=8.8Hz, 1H), 7.00 (dd, J=7.7,1.6Hz, 1H), 6.96-6.85 (m, 4H), 4.64 (s, 2H), 4.26 (t, J=5.1Hz, 2H), 3.91-3.87 (m, 2H), 3.72 (s, 3H), 3.66 (s, 3H), 3.30-3.25 (m, 2H), 3.16-3.11 (m, 2H), 1.54 (dd, J=15.0,7.5Hz, 4H), 0.88–0.82(m,6H)。
Embodiment 37:N- [2- (2- methoxyphenoxy) ethyl] -5- (2- di-n-propylamine base -2- oxoethoxy) -2- The synthesis of methyl-1-ethyl-1H- indoles-3- formamide (compound Z28)
Referring to the synthetic method of embodiment 10, yellow solid 0.82g is obtained, yield: 53.6%.M.p.:91-92℃；IR: (KBr,cm-1):υ3288.5,2918.3,1644.0,1533.6,1504.4,1464.0,1419.4,1279.0,1250.9, 1122.6,1025.2,848.8,802.4,748.8；ESI-MS,m/z:calcd.509.29(M+)；found510.3([M+H]+), 532.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.38 (d, J=2.3Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.00 (dd, J=7.7,1.8Hz, 1H), 6.95-6.86 (m, 4H), 4.63 (s, 2H), 4.25 (t, J=5.1Hz, 2H), 4.12 (q, J=7.2Hz, 2H), 3.89 (q, J=5.2Hz, 2H), 3.29-3.25 (m, 2H), 3.16-3.12 (m, 2H), 2.70 (s, 3H), 1.58-1.50 (m, 4H), 1.33 (t, J=7.2Hz, 3H), 0.87-0.82 (m, 6H).
Embodiment 38:N- [2- (2- methoxyphenoxy) ethyl] -5- (2- di-iso-butylmanice base -2- oxoethoxy) -1, The synthesis of 2- dimethyl -1H- indoles -3- formamide (compound Z29)
Referring to the synthetic method of embodiment 10, white solid 0.87g is obtained, yield: 55.4%.M.p.:85-87℃；IR: (KBr,cm-1):υ3424.4,2920.5,1649.2,1626.5,1505.2,1484.7,1384.1,1250.8,1212.0, 1122.0,1024.7,837.8,797.8,745.8；ESI-MS,m/z:calcd.523.3(M+)；found524.3([M+H]+), 546.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.38 (d, J=2.3Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 7.00 (dd, J=7.6,1.4Hz, 1H), 6.97-6.86 (m, 4H), 4.68 (s, 2H), 4.25 (t, J=5.1Hz, 2H), 3.88 (q, J=5.1Hz, 2H), 3.72 (s, 3H), 3.65 (s, 3H), 3.19 (d, J=7.6Hz, 2H), 3.06 (d, J=7.6Hz, 2H),2.70(s,3H),1.97–1.70(m,4H),0.87–0.81(m,12H)。
Embodiment 39:N- [2- (2- methoxyphenoxy) ethyl] -5- (2- di-iso-butylmanice base -2- oxoethoxy) -2- The synthesis of methyl-1-ethyl-1H- indoles-3- formamide (compound Z30)
Referring to the synthetic method of embodiment 10, yellow solid 0.84g is obtained, yield: 52.2%.M.p.:95-97℃；IR: (KBr,cm-1):υ3447.0,2920.2,1655.7,1543.8,1482.9,1384.3,1256.8,1204.8,1123.6, 1026.5,777.7,741.8；ESI-MS,m/z:calcd.537.32(M+)；found 538.3([M+H]+)；1H NMR (400MHz,CDCl3): δ 7.38 (d, J=2.3Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.00 (dd, J=7.7,1.7Hz, 1H), 6.96-6.86 (m, 4H), 4.69 (s, 2H), 4.26 (t, J=5.1Hz, 2H), 4.12 (q, J=7.2Hz, 2H), 3.72 (s, 3H), 3.19 (d, J=7.6Hz, 2H), 3.06 (d, J=7.6Hz, 2H), 2.70 (s, 3H), 2.02-1.86 (m, 4H), 1.33 (t, J=7.2Hz, 3H), 0.87-0.80 (m, 12H).
Embodiment 40:N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (1- piperidyl) -2- oxoethoxy] -1, The synthesis of 2- dimethyl -1H- indoles -3- formamide (compound Z31)
Referring to the synthetic method of embodiment 10, white solid 0.78g is obtained, yield: 54.2%.M.p.:152-153℃； IR:(KBr,cm-1):υ3465.3,2931.0,2854.9,1644.2,1549.1,1504.7,1406.3,1252.2,1219.9, 1124.7,1020.5,934.8,851.7,745.3；ESI-MS,m/z:calcd.479.24(M+)；found 480.2.2([M+ H]+),502.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (d, J=2.4Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 7.00 (dd, J=7.6,1.7Hz, 1H), 6.96-6.86 (m, 4H), 4.63 (s, 2H), 4.26 (t, J=5.1Hz, 2H), 3.89 (dd, J=10.4,5.4Hz, 2H), 3.73 (s, 3H), 3.66 (s, 3H), 3.53-3.50 (m, 2H), 3.36-3.32 (m, 2H),2.70(s,3H),1.60–1.45(m,6H)。
Embodiment 41:N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (1- piperidyl) -2- oxoethoxy] -2- The synthesis of methyl-1-ethyl-1H- indoles-3- formamide (compound Z32)
Referring to the synthetic method of embodiment 10, yellow solid 0.84g is obtained, yield: 56.8%.M.p.:78-79℃；IR: (KBr,cm-1):υ3427.9,2930.7,1638.2,1538.3,1503.7,1467.9,1254.7,1202.3,1163.3, 1124.3,1027.0,877.8,852.6,745.9；ESI-MS,m/z:calcd.493.26(M+)；found494.3([M+H]+), 516.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (d, J=2.4Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.00 (dd, J=7.7,1.7Hz, 1H), 6.95-6.87 (m, 4H), 4.63 (s, 2H), 4.26 (t, J=5.1Hz, 2H), 4.13 (q, J=7.2Hz, 2H), 3.89 (dd, J=10.4,5.4Hz, 2H), 3.74 (s, 3H), 3.54-3.50 (m, 2H), 3.36- 3.33 (m, 2H), 2.70 (s, 3H), 1.64-1.56 (m, 6H), 1.34 (t, J=7.2Hz, 3H).
Embodiment 42:N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (4- morpholinyl) -2- oxoethoxy] -1, The synthesis of 2- dimethyl -1H- indoles -3- formamide (compound Z33)
Referring to the synthetic method of embodiment 10, white solid 0.93g is obtained, yield: 64.6%.M.p.:111-113℃； IR:(KBr,cm-1):υ3455.0,1653.7,1547.2,1486.1,1384.1,1252.0,1217.3,1125.5,1111.0, 1032.6,849.6,743.5；ESI-MS,m/z:calcd.481.22(M+)；found482.2([M+H]+),504.2([M+Na]+) ；1H NMR(400MHz,CDCl3): δ 7.40 (d, J=2.4Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 7.01 (dd, J=7.7, 1.7Hz, 1H), 6.98-6.89 (m, 4H), 4.64 (s, 2H), 4.27 (t, J=5.0Hz, 2H), 3.89 (dd, J=10.3, 5.4Hz,2H),3.73(s,3H),3.67(s,3H),3.61–3.43(m,8H),2.71(s,3H)。
Embodiment 43:N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (4- morpholinyl) -2- oxoethoxy] -2- The synthesis of methyl-1-ethyl-1H- indoles-3- formamide (compound Z34)
Referring to the synthetic method of embodiment 10, white solid 1.04g is obtained, yield: 69.8%.M.p.:84-85℃；IR: (KBr,cm-1):υ3431.3,2925.5,1633.6,1482.6,1384.1,1251.3,1201.6,1122.6,1028.7, 876.8,754.8；ESI-MS,m/z:calcd.495.24(M+)；found 496.2([M+H]+),518.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (d, J=2.4Hz, 1H), 7.22 (d, J=8.9Hz, 1H), 7.01 (dd, J=7.7, 1.7Hz, 1H), 6.97-6.86 (m, 4H), 4.64 (s, 2H), 4.26 (t, J=5.0Hz, 2H), 4.13 (q, J=7.2Hz, 2H), 3.89 (dd, J=10.4,5.4Hz, 2H), 3.73 (s, 3H), 3.61-3.42 (m, 8H), 2.70 (s, 3H), 1.34 (t, J= 7.2Hz,3H)。
Embodiment 44:N- [2- (2- methoxyphenoxy) ethyl] -5- (2- benzamido group -2- oxoethoxy) -1,2- two The synthesis of Methyl-1H-indole -3- formamide (compound Z35)
Referring to the synthetic method of embodiment 10, yellow solid 0.70g is obtained, yield: 46.7%.M.p.:172-174℃； IR:(KBr,cm-1):υ3395.2,2933.0,1676.4,1646.3,1544.7,1503.1,1384.7,1252.5,1206.5, 1164.2,1125.1,1050.9,927.1,839.3,749.6；ESI-MS,m/z:calcd.501.23(M+)；found 502.2([M+H]+),524.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.38 (d, J=2.3Hz, 1H), 7.33- 7.27 (m, 5H), 7.21 (d, J=8.9Hz, 1H), 6.97 (dd, J=7.4,1.8Hz, 1H), 6.93-6.84 (m, 4H), 4.55 (s, 2H), 4.52 (d, J=6.0Hz, 2H), 4.22 (t, J=5.0Hz, 2H), 3.89 (dd, J=10.3,5.3Hz, 2H), 3.72 (s,3H),3.67(s,3H),2.70(s,3H)。
Embodiment 45:N- [2- (2- methoxyphenoxy) ethyl] -5- (2- benzamido group -2- oxoethoxy) -2- methyl - The synthesis of 1- ethyl -1H- indoles -3- formamide (compound Z36)
Referring to the synthetic method of embodiment 10, white solid 0.84g is obtained, yield: 54.2%.M.p.:128-129℃； IR:(KBr,cm-1):υ3434.2,3297.7,2927.7,1626.2,1540.0,1481.4,1384.5,1259.3,1230.7, 1122.0,1089.5,1037.0,841.7,736.2,703.2；ESI-MS,m/z:calcd.515.24(M+)；found 516.2([M+H]+),538.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.39 (d, J=2.3Hz, 1H), 7.33- 7.27 (m, 5H), 7.22 (d, J=8.8Hz, 1H), 6.97 (dd, J=7.5,2.0Hz, 1H), 6.94-6.84 (m, 4H), 4.55 (s, 2H), 4.52 (d, J=6.0Hz, 2H), 4.22 (t, J=4.9Hz, 2H), 4.13 (q, J=7.2Hz, 2H), 3.89 (dd, J =10.1,5.2Hz, 2H), 3.71 (s, 3H), 2.70 (s, 3H), 1.34 (t, J=7.2Hz, 3H).
Embodiment 46:N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (4- fluorin benzyl amine base) -2- oxoethoxy] - The synthesis of 1,2- dimethyl -1H- indoles -3- formamide (compound Z37)
Referring to the synthetic method of embodiment 10, white solid 0.86g is obtained, yield: 55.1%.M.p.:169-171℃； IR:(KBr,cm-1):υ3414.8,2928.3,1675.1,1642.7,1542.5,1503.5,1252.7,1221.7,1166.2, 1124.2,1048.9,1025.8,843.0,823.5,748.9；ESI-MS,m/z:calcd.519.22(M+)；found 520.2([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.39 (d, J=2.4Hz, 1H), 7.22 (d, J=3.1Hz, 2H), 7.20 (d, J=3.0Hz, 1H), 7.00-6.90 (m, 5H), 6.84 (d, J=7.8Hz, 2H), 4.54 (s, 2H), 4.47 (d, J= 6.1Hz, 2H), 4.23 (t, J=5.0Hz, 2H), 3.89 (dd, J=10.3,5.5Hz, 2H), 3.72 (s, 3H), 3.66 (s, 3H),2.70(s,3H)。
Embodiment 47:N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (4- fluorin benzyl amine base) -2- oxoethoxy] - The synthesis of 2- methyl-1-ethyl-1H- indoles-3- formamide (compound Z38)
Referring to the synthetic method of embodiment 10, white solid 1.08g is obtained, yield: 67.5%.M.p.:131-132℃； IR:(KBr,cm-1):υ3436.0,2929.7,1629.8,1543.9,1509.2,1482.1,1384.3,1259.9,1230.9, 1211.0,1122.9,1037.5,841.1,735.8；ESI-MS,m/z:calcd.533.23(M+)；found 534.2([M+ H]+),556.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (d, J=2.3Hz, 1H), 7.24-7.20 (m, 4H), 6.99-6.86 (m, 6H), 4.55 (s, 2H), 4.47 (d, J=6.1Hz, 2H), 4.23 (t, J=5.0Hz, 2H), 4.14 (q, J= 7.2Hz, 2H), 3.90 (dd, J=10.3,5.3Hz, 2H), 3.72 (s, 3H), 2.70 (s, 3H), 1.34 (t, J=7.2Hz, 3H)。
Embodiment 48:N- [3- (4- morpholinyl) propyl] -5- (2- benzamido group -2- oxoethoxy) -1,2- dimethyl - The synthesis of 1H- indoles -3- formamide (compound Z39)
Referring to the synthetic method of embodiment 10, white solid 0.53g is obtained, yield: 37.1%.M.p.:135-137℃； IR:(KBr,cm-1):υ3425.9,2921.4,2852.3,1665.3,1623.0,1539.2,1484.2,1273.8,1202.5, 1161.7,917.6,862.4,799.3,700.3；ESI-MS,m/z:calcd.478.26(M+)；found 479.3([M+H]+), 501.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.33 (d, J=1.5Hz, 1H), 7.31-7.27 (m, 5H), 7.22 (d, J=8.8Hz, 1H), 6.85 (dd, J=8.8,2.4Hz, 1H), 4.61 (s, 2H), 4.56 (d, J=6.0Hz, 2H), 3.67 (s,3H),3.61–3.58(m,2H),3.56–3.53(m,4H),2.70(s,3H),2.53–2.41(m,6H),1.86–1.78 (m,2H)。
Embodiment 49:N- [3- (4- morpholinyl) propyl]-5- (2- benzamido group-2- oxoethoxy)-2- methyl-1-second The synthesis of base -1H- indoles -3- formamide (compound Z40)
Referring to the synthetic method of embodiment 10, white solid 0.54g is obtained, yield: 37.8%.M.p.:156-157℃； IR:(KBr,cm-1):υ3453.3,2931.3,1628.9,1545.7,1484.2,1437.8,1383.8,1271.3,1207.6, 1164.4,1114.9,872.1,697.4；ESI-MS,m/z:calcd.492.27(M+)；found493.3([M+H]+),515.3 ([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.32 (d, J=1.6Hz, 1H), 7.31-7.27 (m, 5H), 7.23 (d, J= 8.8Hz, 1H), 6.84 (dd, J=8.8,2.3Hz, 1H), 4.61 (s, 2H), 4.56 (d, J=6.0Hz, 2H), 4.13 (q, J= 7.2Hz,2H),3.62–3.57(m,4H),3.57–3.54(m,2H),2.70(s,3H),2.56–2.40(m,6H),1.86– 1.79 (m, 2H), 1.34 (t, J=7.2Hz, 3H).
Embodiment 50:N- [3- (4- morpholinyl) propyl] -5- [2- (4- fluorin benzyl amine base) -2- oxoethoxy] -1,2- two The synthesis of Methyl-1H-indole -3- formamide (compound Z41)
Referring to the synthetic method of embodiment 10, white solid 0.53g is obtained, yield: 35.6%.M.p.:208-209℃； IR:(KBr,cm-1):υ3336.6,3303.7,2859.7,1633.3,1532.3,1509.5,1485.7,1384.3,1210.3, 1168.3,1119.4,1059.0,873.4,770.8；ESI-MS,m/z:calcd.496.25(M+)；found 497.3([M+ H]+)；1H NMR(400MHz,CDCl3): δ 7.28 (d, J=1.6Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 6.99 (t, J= 8.6Hz, 4H), 6.84 (dd, J=8.9,2.4Hz, 1H), 4.62 (s, 2H), 4.51 (d, J=6.1Hz, 2H), 3.67 (s, 3H), 3.64–3.57(m,6H),2.71(s,3H),2.62–2.42(m,6H),1.31–1.19(m,2H)。
Embodiment 51:N- [3- (4- morpholinyl) propyl] -5- [2- (4- fluorin benzyl amine base) -2- oxoethoxy] -2- methyl - The synthesis of 1- ethyl -1H- indoles -3- formamide (compound Z42)
Referring to the synthetic method of embodiment 10, white solid 1.08g is obtained, yield: 73.0%.M.p.:182-184℃； IR:(KBr,cm-1):υ3429.1,2926.6,2856.3,1651.3,1511.7,1482.2,1383.6,1338.7,1270.6, 1228.6,1210.1,1164.3,1117.8,859.6,768.4；ESI-MS,m/z:calcd.510.26(M+)；found 511.3([M+H]+),533.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.29 (d, J=2.2Hz, 1H), 7.22 (d, J=9.7Hz, 1H), 7.03-6.99 (m, 4H), 6.83 (dd, J=8.8,1.7Hz, 1H), 4.60 (s, 2H), 4.51 (d, J= 6.0Hz, 2H), 4.13 (q, J=7.1Hz, 2H), 3.58 (d, J=6.1Hz, 2H), 3.56-3.53 (m, 4H), 2.69 (s, 3H), 2.51-2.41 (m, 6H), 1.86-1.78 (m, 2H), 1.33 (t, J=7.1Hz, 3H).
Embodiment 52:N- [3- (4- morpholinyl) propyl] -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxo Ethyoxyl } -1,2- dimethyl -1H- indoles -3- formamide (compound Z43) synthesis
Referring to the synthetic method of embodiment 10, white solid 0.94g is obtained, yield: 58.4%.M.p.:91-92℃；IR: (KBr,cm-1):υ3448.0,2919.7,1653.0,1595.9,1485.2,1384.7,1256.5,1202.8,1117.8, 1023.6,872.5,741.6；ESI-MS,m/z:calcd.538.28(M+)；found 539.3([M+H]+),561.3([M+ Na]+)；1H NMR(400MHz,CDCl3): δ 7.18 (d, J=8.8Hz, 1H), 6.98-6.88 (m, 5H), 6.87-6.85 (m, 1H), 4.59 (s, 3H), 4.13 (t, J=5.2Hz, 2H), 3.80 (s, 3H), 3.76 (dd, J=10.8,5.5Hz, 2H), 3.65 (s,3H),3.63–3.55(m,6H),2.70(s,3H),2.58–2.35(m,6H),1.93–1.78(m,2H)。
Embodiment 53:N- [3- (4- morpholinyl) propyl] -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxo Ethyoxyl } synthesis of-2- methyl-1-ethyl-1H- indoles-3- formamide (compound Z44)
Referring to the synthetic method of embodiment 10, white solid 1.10g is obtained, yield: 68.8%.M.p.:97-98℃；IR: (KBr,cm-1):υ3424.3,2921.2,1668.9,1628.6,1541.7,1505.7,1481.8,1418.9,1254.5, 1161.9,1124.5,1026.4,863.9,799.7,746.4；ESI-MS,m/z:calcd.552.29(M+)；found 553.3([M+H]+),575.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.30 (d, J=2.3Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 6.96-6.87 (m, 1H), 4.56 (s, 2H), 4.15-4.10 (m, 4H), 3.80 (s, 3H), 3.76 (dd, J =10.6,5.5Hz, 2H), 3.59-3.53 (m, 6H), 2.69 (s, 3H), 2.49-2.41 (m, 6H), 1.85-1.77 (m, 2H), 1.33 (t, J=7.2Hz, 3H).
Embodiment 54:N- (furans -2- methyl) -5- (2- diethylin -2- oxoethoxy) -1,2- dimethyl -1H- Yin The synthesis of diindyl -3- formamide (compound Z45)
Referring to the synthetic method of embodiment 10, white solid 0.74g is obtained, yield: 62.2%.M.p.:145-147℃； IR:(KBr,cm-1):υ3425.1,2921.9,2851.8,1657.1,1631.4,1483.8,1465.4,1384.3,1162.0, 838.0,700.6,666.4；ESI-MS,m/z:calcd.397.20(M+)；found398.2([M+H]+),420.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.38 (d, J=5.6Hz, 1H), 7.29 (d, J=2.3Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 6.92 (dd, J=8.9,2.4Hz, 1H), 6.34 (dd, J=5.6,3.0Hz, 1H), 6.32 (d, J=3.0Hz, 1H), 4.72 (d, J=5.7Hz, 2H), 4.65 (s, 2H), 3.65 (s, 3H), 3.40 (q, J=7.0Hz, 4H), 2.70 (s, 3H), 1.21 (t, J=7.1Hz, 3H), 1.13 (t, J=7.1Hz, 3H).
Embodiment 55:N- (furans-2- methyl)-5- (2- diethylin-2- oxoethoxy)-2- methyl-1-ethyl- The synthesis of 1H- indoles -3- formamide (compound Z46)
Referring to the synthetic method of embodiment 10, white solid 0.62g is obtained, yield: 50.4%.M.p.:120-121℃； IR:(KBr,cm-1):υ3426.7,2922.1,1636.2,1536.4,1481.4,1419.4,1383.7,1263.8,1191.2, 1162.4,1146.0,1084.7,1015.0,921.8,801.0,744.3；ESI-MS,m/z:calcd.411.22(M+)； found 412.2([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.37 (d, J=5.5Hz, 1H), 7.29 (d, J=2.3Hz, 1H), 7.20 (d, J=8.7Hz, 1H), 6.90 (dd, J=8.7,2.3Hz, 1H), 6.32 (dd, J=5.5,3.1Hz, 1H), 6.21 (d, J=3.0Hz, 1H), 4.71 (d, J=5.7Hz, 2H), 4.69 (s, 2H), 4.11 (d, J=7.1Hz, 2H), 3.39 (q, J=6.9Hz, 4H), 2.69 (s, 3H), 1.32 (t, J=6.9Hz, 3H), 1.21 (t, J=6.8Hz, 3H), 1.13 (t, J= 6.8Hz,3H)。
Embodiment 56:N- (furans -2- methyl) -5- (2- di-n-propylamine base -2- oxoethoxy) -1,2- dimethyl -1H- The synthesis of indoles -3- formamide (compound Z47)
Referring to the synthetic method of embodiment 10, white solid 0.92g is obtained, yield: 71.9%.M.p.:123-124℃； IR:(KBr,cm-1):υ3439.7,3346.9,2921.0,1659.8,1622.1,1519.3,1484.4,1383.6,1281.7, 1198.5,1146.2,1085.1,1017.9,927.0,832.2,752.2；ESI-MS,m/z:calcd.397.20(M+)； found 398.2([M+H]+),420.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.37 (d, J=5.7Hz, 1H), 7.28 (d, J=2.2Hz, 1H), 7.19 (d, J=8.9Hz, 1H), 6.90 (dd, J=8.8,2.2Hz, 1H), 6.33 (dd, J= 5.7,3.0Hz, 1H), 6.31 (d, J=3.0Hz, 1H), 4.71 (d, J=5.6Hz, 2H), 4.69 (s, 2H), 3.64 (s, 3H), 3.29-3.21 (m, 4H), 2.70 (s, 3H), 1.68-1.52 (m, 4H), 0.92 (t, J=7.4Hz, 3H), 0.86 (t, J= 7.4Hz,3H)。
Embodiment 57:N- (furans-2- methyl)-5- (2- di-n-propylamine base-2- oxoethoxy)-2- methyl-1-ethyl- The synthesis of 1H- indoles -3- formamide (compound Z48)
Referring to the synthetic method of embodiment 10, white solid 0.72g is obtained, yield: 54.5%.M.p.:96-97℃；IR: (KBr,cm-1):υ3424.3,3279.9,2924.6,1656.8,1619.3,1482.4,1424.1,1383.1,1273.3, 1200.9,1162.4,1089.5,1009.7,917.9,832.5,794.6,726.2；ESI-MS,m/z:calcd.439.25(M+)；found 440.2([M+H]+),462.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.37 (d, J=5.6Hz, 1H), 7.29 (d, J=2.4Hz, 1H), 7.20 (d, J=8.8Hz, 1H), 6.90 (dd, J=8.8,2.3Hz, 1H), 6.33 (dd, J=5.7,3.1Hz, 1H), 6.31 (d, J=3.2Hz, 1H), 4.71 (s, 2H), 4.69 (d, J=5.5Hz, 2H), 4.11 (q, J =7.1Hz, 2H), 3.29-3.22 (m, 4H), 2.70 (s, 3H), 1.64-1.53 (m, 4H), 1.32 (t, J=7.2Hz, 3H), 0.92 (t, J=7.4Hz, 3H), 0.86 (t, J=7.4Hz, 3H).
Embodiment 58:N- (furans -2- methyl) -5- (2- di-iso-butylmanice base -2- oxoethoxy) -1,2- dimethyl -1H- The synthesis of indoles -3- formamide (compound Z49)
Referring to the synthetic method of embodiment 10, white solid 0.72g is obtained, yield: 52.9%.M.p.:102-104℃； IR:(KBr,cm-1):υ3424.8,2921.9,1662.7,1624.9,1482.6,1384.4,1281.8,1158.6,1141.8, 1076.2,1015.3,917.3,883.2,839.9,795.6,752.7；ESI-MS,m/z:calcd.453.26(M+)；found 454.2([M+H]+),476.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.37 (d, J=5.9Hz, 1H), 7.29 (d, J=2.3Hz, 1H), 7.18 (d, J=8.9Hz, 1H), 6.90 (dd, J=8.8,2.3Hz, 1H), 6.33 (dd, J=5.9, 3.1Hz, 1H), 6.31 (d, J=3.1Hz, 1H), 4.74 (d, J=5.7Hz, 2H), 4.68 (s, 2H), 3.63 (s, 3H), 3.23- 3.20 (m, 2H), 2.69 (s, 3H), 2.05-1.70 (m, 4H), 0.93 (d, J=6.7Hz, 6H), 0.81 (d, J=6.7Hz, 6H)。
Embodiment 59:N- (furans-2- methyl)-5- (2- di-iso-butylmanice base-2- oxoethoxy)-2- methyl-1-ethyl- The synthesis of 1H- indoles -3- formamide (compound Z50)
Referring to the synthetic method of embodiment 10, yellow solid 0.69g is obtained, yield: 49.3%.M.p.:68-70℃；IR: (KBr,cm-1):υ3417.0,2955.8,2922.0,1661.0,1625.5,1529.4,1480.5,1421.1,1385.1, 1347.0,1283.1,1271.2,1190.8,1159.4,1142.4,1077.2,1016.8,919.0,840.7,791.8, 758.9；ESI-MS,m/z:calcd.467.28(M+)；found 468.2([M+H]+),490.2([M+Na]+)；1H NMR (400MHz,CDCl3): δ 7.37 (d, J=5.6Hz, 1H), 7.29 (d, J=2.3Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 6.90 (dd, J=8.8,2.3Hz, 1H), 6.33 (dd, J=5.8,3.2Hz, 1H), 6.31 (d, J=3.1Hz, 1H), 4.75 (s, 2H), 4.68 (d, J=5.6Hz, 2H), 4.11 (q, J=6.9Hz, 2H), 3.21-3.19 (m, 2H), 2.70 (s, 3H), 1.99- 1.79 (m, 4H), 1.32 (t, J=7.2Hz, 3H), 0.94 (d, J=6.6Hz, 6H), 0.81 (d, J=6.7Hz, 6H).
Embodiment 60:N- (furans -2- methyl) -5- [2- (1- piperidyl) -2- oxoethoxy] -1,2- dimethyl -1H- The synthesis of indoles -3- formamide (compound Z51)
Referring to the synthetic method of embodiment 10, white solid 0.71g is obtained, yield: 57.7%.M.p.:79-80℃；IR: (KBr,cm-1):υ3424.1,2929.9,2854.9,1639.4,1487.0,1443.2,1384.1,1208.2,1140.5, 1079.9,1010.0,839.7,803.8,758.4,602.8；ESI-MS,m/z:calcd.409.20(M+)；found 410.2 ([M+H]+),432.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.38 (d, J=5.9Hz, 1H), 7.29 (d, J= 2.3Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 6.92 (dd, J=8.9,2.4Hz, 1H), 6.34 (dd, J=5.8,3.1Hz, 1H), 6.32 (d, J=3.1Hz, 1H), 4.73 (d, J=5.8Hz, 2H), 4.64 (s, 2H), 3.65 (s, 3H), 3.54 (t, J= 5.3Hz, 2H), 3.46 (t, J=5.0Hz, 2H), 2.70 (s, 3H), 1.61-1.53 (m, 6H).
Embodiment 61:N- (furans-2- methyl)-5- [2- (1- piperidyl)-2- oxoethoxy]-2- methyl-1-ethyl- The synthesis of 1H- indoles -3- formamide (compound Z52)
Referring to the synthetic method of embodiment 10, white solid 0.84g is obtained, yield: 66.1%.M.p.:81-82℃；IR: (KBr,cm-1):υ3527.8,3414.4,3936.2,2855.6,1647.5,1618.6,1545.0,1487.3,1441.5, 1383.9,1207.6,1165.7,1140.5,1074.8,1006.4,878.0,852.9,812.7,745.8；ESI-MS,m/z: calcd.423.22(M+)；found 424.2([M+H]+),446.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.38 (d, J=5.7Hz, 1H), 7.30 (d, J=2.4Hz, 1H), 7.21 (d, J=8.9Hz, 1H), 6.91 (dd, J=8.9,2.4Hz, 1H), 6.34 (dd, J=5.7,3.1Hz, 1H), 6.32 (d, J=3.1Hz, 1H), 4.70 (d, J=5.7Hz, 2H), 4.69 (s, 2H), 4.12 (q, J=7.2Hz, 2H), 3.56 (t, J=5.2Hz, 2H), 3.50 (t, J=5.2Hz, 2H), 2.70 (s, 3H), 1.64-1.61 (m, 6H), 1.33 (t, J=7.2Hz, 3H).
Embodiment 62:N- (furans -2- methyl) -5- [2- (4- morpholinyl) -2- oxoethoxy] -1,2- dimethyl -1H- The synthesis of indoles -3- formamide (compound Z53)
Referring to the synthetic method of embodiment 10, white solid 0.98g is obtained, yield: 79.7%.M.p.:181-183℃； IR:(KBr,cm-1):υ3423.2,2923.5,2853.5,1654.1,1616.3,1483.7,1412.5,1356.8,1269.4, 1191.1,1158.7,1029.9,1002.5,841.6,799.0,741.7；ESI-MS,m/z:calcd.411.18(M+)； found 412.1([M+H]+),434.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.38 (d, J=5.9Hz, 1H), 7.28 (d, J=2.4Hz, 1H), 7.19 (d, J=8.9Hz, 1H), 6.88 (dd, J=8.8,2.4Hz, 1H), 6.34 (dd, J= 5.8,3.1Hz, 1H), 6.32 (d, J=3.1Hz, 1H), 4.71 (s, 2H), 4.68 (d, J=5.5Hz, 2H), 3.64 (s, 3H), 3.62–3.59(m,8H),2.68(s,3H).Embodiment 63:N- (furans -2- methyl) -5- [2- (4- morpholinyl) -2- oxo second Oxygroup] synthesis of-2- methyl-1-ethyl-1H- indoles-3- formamide (compound Z54)
Referring to the synthetic method of embodiment 10, white solid 0.83g is obtained, yield: 64.8%.M.p.:128-129℃； IR:(KBr,cm-1):υ3322.6,2973.1,1666.4,1639.9,1544.6,1440.6,1357.3,1308.3,1278.5, 1202.0,1161.5,1113.3,1037.7,966.3,879.1,851.8,801.8,757.0；ESI-MS,m/z: calcd.425.20(M+)；found 426.1([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.37 (d, J=5.8Hz, 1H), 7.29 (d, J=2.4Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 6.87 (dd, J=8.8,2.4Hz, 1H), 6.33 (dd, J=5.8,3.2Hz, 1H), 6.31 (d, J=3.2Hz, 1H), 4.70 (s, 2H), 4.68 (d, J=5.6Hz, 2H), 4.10 (q, J =7.2Hz, 2H), 3.66-3.58 (m, 8H), 2.68 (s, 3H), 1.31 (t, J=7.2Hz, 3H).
Embodiment 64:N- (furans -2- methyl) -5- (2- benzamido group -2- oxoethoxy) -1,2- dimethyl -1H- Yin The synthesis of diindyl -3- formamide (compound Z55)
Referring to the synthetic method of embodiment 10, yellow solid 0.69g is obtained, yield: 53.5%.M.p.:169-170℃； IR:(KBr,cm-1):υ3402.6,2918.1,2849.8,1681.3,1616.2,1545.0,1485.0,1383.9,1213.9, 1164.4,1054.6,917.8,827.2,795.7,729.6,696.2；ESI-MS,m/z:calcd.431.18(M+)；found 432.2([M+H]+),454.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (d, J=5.6Hz, 1H), 7.33- 7.29 (m, 5H), 7.23 (d, J=2.2Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 6.83 (dd, J=8.8,2.3Hz, 1H), 6.34 (dd, J=5.6,3.0Hz, 1H), 6.30 (d, J=3.1Hz, 1H), 4.67 (d, J=5.5Hz, 2H), 4.57 (s, 2H), 4.55 (d, J=6.1Hz, 2H), 3.65 (s, 3H), 2.68 (s, 3H).
Embodiment 65:N- (furans-2- methyl)-5- (2- benzamido group-2- oxoethoxy)-2- methyl-1-ethyl-1H- The synthesis of indoles -3- formamide (compound Z56)
Referring to the synthetic method of embodiment 10, white solid 1.29g is obtained, yield: 96.3%.M.p.:170-172℃； IR:(KBr,cm-1):υ3397.5,2920.7,2851.2,1672.1,1625.6,1543.2,1482.7,1384.2,1264.4, 1199.8,1163.7,1028.1,920.8,804.3,738.8,699.3；ESI-MS,m/z:calcd.445.20(M+)； found 446.2([M+H]+),468.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.40 (d, J=5.8Hz, 1H), 7.34-7.29 (m, 5H), 7.24 (d, J=2.4Hz, 1H), 7.22 (d, J=8.9Hz, 1H), 6.84 (dd, J=8.8,2.4Hz, 1H), 6.34 (dd, J=5.8,3.0Hz, 1H), 6.30 (d, J=3.1Hz, 1H), 4.68 (d, J=5.5Hz, 2H), 4.58 (s, 2H), 4.56 (d, J=6.0Hz, 2H), 4.12 (q, J=7.2Hz, 2H), 2.69 (s, 3H), 1.33 (t, J=7.2Hz, 3H).
Embodiment 66:N- (furans -2- methyl) -5- [2- (4- fluorin benzyl amine base) -2- oxoethoxy] -1,2- dimethyl - The synthesis of 1H- indoles -3- formamide (compound Z57)
Referring to the synthetic method of embodiment 10, white solid 1.12g is obtained, yield: 83.0%.M.p.:198-200℃； IR:(KBr,cm-1):υ3426.1,2923.2,2852.7,1740.5,1630.7,1465.3,1384.0,1259.7,1166.0, 1117.4,618.3；ESI-MS,m/z:calcd.449.18(M+)；found450.2([M+H]+),472.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.41 (d, J=5.7Hz, 1H), 7.24 (d, J=2.4Hz, 2H), 7.21 (d, J=8.8Hz, 1H), 7.01 (d, J=8.7Hz, 2H), 6.98 (d, J=2.3Hz, 1H), 6.84 (dd, J=8.8,2.4Hz, 1H), 6.35 (dd, J=5.7,3.1Hz, 1H), 6.31 (d, J=3.2Hz, 1H), 4.68 (d, J=5.4Hz, 2H), 4.58 (s, 2H), 4.52 (d, J =6.0Hz, 2H), 3.66 (s, 3H), 2.70 (s, 3H).
Embodiment 67:N- (furans-2- methyl)-5- [2- (4- fluorin benzyl amine base)-2- oxoethoxy]-2- methyl-1-second The synthesis of base -1H- indoles -3- formamide (compound Z58)
Referring to the synthetic method of embodiment 10, white solid 1.22g is obtained, yield: 87.8%.M.p.:154-156℃； IR:(KBr,cm-1):υ3403.0,2920.5,2850.9,1650.6,1625.0,1510.3,1483.0,1384.1,1339.2, 1266.6,1223.2,1159.0,1015.3,796.6,772.3,730.9；ESI-MS,m/z:calcd.463.19(M+)； found 464.2([M+H]+),486.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.41 (d, J=5.7Hz, 1H), 7.25 (d, J=2.5Hz, 2H), 7.22 (d, J=8.9Hz, 1H), 7.03 (d, J=2.2Hz, 1H), 6.99 (d, J=5.6Hz, 2H), 6.83 (dd, J=8.8,2.3Hz, 1H), 6.34 (dd, J=5.7,3.1Hz, 1H), 6.30 (d, J=3.1Hz, 1H), 4.68 (d, J=5.3Hz, 2H), 4.58 (s, 2H), 4.51 (d, J=5.9Hz, 2H), 4.13 (q, J=7.1Hz, 2H), 2.69 (s, 3H), 1.33 (t, J=7.2Hz, 3H).
Embodiment 68:N- (furans -2- methyl) -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxo ethoxy Base } -1,2- dimethyl -1H- indoles -3- formamide (compound Z59) synthesis
Referring to the synthetic method of embodiment 10, white solid 1.24g is obtained, yield: 84.4%.M.p.:178-180℃； IR:(KBr,cm-1):υ3456.2,3258.1,2920.9,1680.7,1627.5,1507.2,1486.7,1384.2,1254.0, 1230.0,1165.0,1126.2,1024.9,923.0,841.9,788.5,739.0；ESI-MS,m/z:calcd.491.21(M+)；found 492.2([M+H]+),514.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.43 (d, J=5.7Hz, 1H), 7.24 (d, J=8.7Hz, 1H), 6.97 (dd, J=8.7,2.3Hz, 1H), 6.93-6.84 (m, 4H), 6.66 (d, J= 2.3Hz, 1H), 6.41 (dd, J=5.7,3.1Hz, 1H), 6.27 (d, J=3.0Hz, 1H), 4.70 (d, J=5.7Hz, 2H), 4.47 (s, 2H), 4.11 (t, J=5.4Hz, 2H), 3.77 (s, 3H), 3.76-3.72 (m, 2H), 3.62 (s, 3H), 2.50 (s, 3H)。
Embodiment 69:N- (furans -2- methyl) -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxo ethoxy Base } synthesis of-2- methyl-1-ethyl-1H- indoles-3- formamide (compound Z60)
Referring to the synthetic method of embodiment 10, white solid 1.12g is obtained, yield: 73.7%.M.p.:164-166℃； IR:(KBr,cm-1):υ3443.7,3269.6,2969.7,1679.6,1619.0,1556.4,1508.4,1482.6,1386.5, 1254.1,1222.1,1126.2,1076.0,1011.2,924.3,860.7,786.8,738.3,698.6；ESI-MS,m/z: calcd.505.22(M+)；found 506.2([M+H]+),528.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.42 (d, J=5.7Hz, 1H), 7.20 (d, J=8.9Hz, 1H), 6.95 (dd, J=8.9,2.2Hz, 1H), 6.90-6.87 (m, 4H), 6.86 (d, J=2.2Hz, 1H), 6.33 (dd, J=5.7,3.1Hz, 1H), 6.29 (d, J=3.2Hz, 1H), 4.66 (d, J= 5.5Hz, 2H), 4.55 (s, 2H), 4.14 (q, J=7.1Hz, 2H), 4.12 (t, J=5.5Hz, 2H), 3.78 (s, 3H), 3.77- 3.74 (m, 2H), 2.70 (s, 3H), 1.33 (t, J=7.2Hz, 3H).
Embodiment 70:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- (2- diethylin -2- oxoethoxy) -1, The synthesis of 2- dimethyl -1H- indoles -3- formamide (compound Z61)
Referring to the synthetic method of embodiment 10, yellow solid 0.62g is obtained, yield: 43.1%.M.p.:112-114℃； IR:(KBr,cm-1):υ3429.8,3324.1,2923.7,1657.9,1613.5,1515.6,1481.3,1383.6,1260.1, 1236.4,1187.5,1160.4,1139.3,1028.0,835.7,801.0,763.0；ESI-MS,m/z:calcd.481.26 (M+)；found 482.3([M+H]+),504.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.18 (d, J=3.3Hz, 1H), 7.16 (d, J=3.2Hz, 1H), 6.89 (dd, J=8.9,2.1Hz, 1H), 6.82 (d, J=4.8Hz, 3H), 4.64 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.74 (dd, J=12.8,6.8Hz, 2H), 3.62 (s, 3H), 3.39 (q, J= 7.1Hz, 4H), 2.94 (t, J=7.0Hz, 2H), 2.64 (s, 3H), 1.19 (t, J=7.0Hz, 3H), 1.12 (t, J=7.1Hz, 3H)。
Embodiment 71:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- (2- diethylin -2- oxoethoxy) -2- The synthesis of methyl-1-ethyl-1H- indoles-3- formamide (compound Z62)
Referring to the synthetic method of embodiment 10, white solid 0.62g is obtained, yield: 41.6%.M.p.:116-117℃； IR:(KBr,cm-1):υ3441.5,2924.5,1641.9,1626.4,1517.0,1483.1,1383.8,1263.0,1235.0, 1209.8,1139.8,1030.5,789.3,720.6,704.0；ESI-MS,m/z:calcd.495.27(M+)；found 496.2([M+H]+),518.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.20 (d, J=3.3Hz, 1H), 7.18 (d, J=2.2Hz, 1H), 6.89 (dd, J=8.8,2.1Hz, 1H), 6.82 (d, J=6.2Hz, 3H), 4.65 (s, 2H), 4.10 (q, J =7.2Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.75 (dd, J=12.5,6.5Hz, 2H), 3.40 (q, J=7.1Hz, 4H), 2.95 (t, J=7.0Hz, 2H), 2.66 (s, 3H), 1.32 (t, J=7.2Hz, 3H), 1.20 (t, J=7.0Hz, 3H), 1.13 (t, J=7.1Hz, 3H).
Embodiment 72:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- [2- (1- piperidyl) -2- oxoethoxy] - The synthesis of 1,2- dimethyl -1H- indoles -3- formamide (compound Z63)
Referring to the synthetic method of embodiment 10, yellow solid 0.64g is obtained, yield: 43.2%.M.p.:62-64℃；IR: (KBr,cm-1):υ3429.7,2930.2,2853.7,1631.9,1514.8,1483.1,1383.9,1259.8,1234.5, 1157.0,1138.9,1025.8,798.5,763.9；ESI-MS,m/z:calcd.493.26(M+)；found494.3([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.17 (d, J=8.9Hz, 1H), 7.15 (d, J=2.3Hz, 1H), 6.88 (dd, J=8.8, 2.4Hz, 1H), 6.82 (t, J=2.5Hz, 3H), 4.64 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.75 (dd, J= 12.8,6.9Hz, 2H), 3.63 (s, 3H), 3.56-3.52 (m, 2H), 3.50-3.47 (m, 2H), 2.95 (t, J=7.0Hz, 2H),2.65(s,3H),1.63–1.51(m,6H)。
Embodiment 73:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- [2- (1- piperidyl) -2- oxoethoxy] - The synthesis of 2- methyl-1-ethyl-1H- indoles-3- formamide (compound Z64)
Referring to the synthetic method of embodiment 10, yellow solid 0.48g is obtained, yield: 31.6%.M.p.:96-98℃；IR: (KBr,cm-1):υ3344.3,2930.9,1659.8,1616.8,1513.9,1480.3,1260.6,1235.2,1187.2, 1157.8,1087.1,1027.3,845.5,784.1,763.6；ESI-MS,m/z:calcd.507.27(M+)；found 508.3([M+H]+),530.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.20 (d, J=8.8Hz, 1H), 7.15 (s, 1H), 6.89 (dd, J=8.8,2.0Hz, 1H), 6.83 (d, J=4.5Hz, 3H), 4.65 (s, 2H), 4.11 (dd, J=7.2Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.76 (d, J=3.5Hz, 2H), 3.57-3.48 (m, 4H), 2.96 (t, J= 6.9Hz, 2H), 2.67 (s, 3H), 1.73-1.61 (m, 6H), 1.32 (t, J=7.2Hz, 3H).
Embodiment 74:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- [2- (4- morpholinyl) -2- oxoethoxy] - The synthesis of 1,2- dimethyl -1H- indoles -3- formamide (compound Z65)
Referring to the synthetic method of embodiment 10, yellow solid 0.63g is obtained, yield: 42.3%.M.p.:79-80℃；IR: (KBr,cm-1):υ3438.0,2921.8,2852.3,1631.8,1515.4,1484.3,1384.2,1261.6,1235.8, 1158.3,1113.9,1028.8,850.2,801.6；ESI-MS,m/z:calcd.495.24(M+)；found496.2([M+H]+), 518.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.19 (d, J=8.8Hz, 1H), 7.11 (d, J=1.8Hz, 1H), 6.87 (dd, J=8.8,2.3Hz, 1H), 6.82 (d, J=4.6Hz, 3H), 4.65 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.78-3.74 (m, 2H), 3.65 (s, 3H), 3.64-3.59 (m, 8H), 2.96 (t, J=6.9Hz, 2H), 2.66 (s, 3H)。
Embodiment 75:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- [2- (4- morpholinyl) -2- oxoethoxy] - The synthesis of 2- methyl-1-ethyl-1H- indoles-3- formamide (compound Z66)
Referring to the synthetic method of embodiment 10, yellow solid 0.64g is obtained, yield: 41.8%.M.p.:67-68℃；IR: (KBr,cm-1):υ3439.1,2922.0,2852.1,1631.4,1514.6,1464.5,1384.1,1261.7,1235.1, 1156.9,1113.3,1027.6,849.2,798.8,619.1；ESI-MS,m/z:calcd.509.25(M+)；found 510.2([M+H]+),532.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.20 (d, J=8.8Hz, 1H), 7.11 (d, J=1.8Hz, 1H), 6.86 (dd, J=8.7,2.0Hz, 1H), 6.82 (d, J=5.6Hz, 3H), 4.65 (s, 2H), 4.11 (q, J =7.1Hz, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.76 (d, J=5.0Hz, 2H), 3.66-3.61 (m, 8H), 2.96 (t, J=6.6Hz, 2H), 2.66 (s, 3H), 1.32 (t, J=7.1Hz, 3H).
Embodiment 76:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- (2- benzamido group -2- oxoethoxy) -1,2- The synthesis of dimethyl -1H- indoles -3- formamide (compound Z67)
Referring to the synthetic method of embodiment 10, white solid 0.71g is obtained, yield: 45.8%.M.p.:175-176℃； IR:(KBr,cm-1):υ3420.4,2923.7,1647.6,1616.5,1514.9,1481.2,1383.9,1262.4,1232.1, 1157.9,1029.3,859.7,799.9,743.5,699.5；ESI-MS,m/z:calcd.515.24(M+)；found 516.2 ([M+H]+),538.2([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.34-7.28 (m, 5H), 7.19 (d, J=8.8Hz, 1H), 6.92 (d, J=2.3Hz, 1H), 6.85 (d, J=8.2Hz, 3H), 6.80 (d, J=8.6Hz, 1H), 4.58 (d, J= 6.1Hz, 2H), 4.53 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.73 (d, J=6.7Hz, 2H), 3.65 (s, 3H), 2.93 (t, J=6.8Hz, 2H), 2.67 (s, 3H).
Embodiment 77:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- (2- benzamido group -2- oxoethoxy) -2- first The synthesis of base -1- ethyl -1H- indoles -3- formamide (compound Z68)
Referring to the synthetic method of embodiment 10, yellow solid 0.81g is obtained, yield: 50.9%.M.p.:158-159℃； IR:(KBr,cm-1):υ3425.7,2919.6,1678.9,1625.7,1515.1,1481.5,1384.1,1259.7,1236.3, 1157.5,1140.3,1027.7,796.0,751.7；ESI-MS,m/z:calcd.529.26(M+)；found 530.2([M+ H]+),5552.3([M+Na]+)；1H NMR(400MHz,CDCl3): δ 7.34-7.29 (m, 5H), 7.20 (d, J=8.9Hz, 1H), 6.93 (d, J=2.7Hz, 1H), 6.85-6.80 (m, 3H), 6.79 (d, J=1.4Hz, 1H), 4.58 (d, J=6.3Hz, 2H), 4.53 (s, 2H), 4.11 (dd, J=15.1,7.6Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.73 (d, J= 6.7Hz, 2H), 2.93 (t, J=7.2Hz, 2H), 2.67 (s, 3H), 1.32 (t, J=7.5Hz, 3H).
Embodiment 78:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- [2- (4- fluorin benzyl amine base) -2- oxo ethoxy Base] -1,2- dimethyl -1H- indoles -3- formamide (compound Z69) synthesis
Referring to the synthetic method of embodiment 10, white solid 0.89g is obtained, yield: 55.6%.M.p.:164-166℃； IR:(KBr,cm-1):υ3411.4,2925.8,1678.4,1629.2,1511.5,1485.6,1260.4,1234.3,1157.0, 1023.8,874.9,808.1,774.3,706.6；ESI-MS,m/z:calcd.533.23(M+)；found 534.2([M+H]+)；1H NMR(400MHz,CDCl3): δ 7.30-7.27 (m, 2H), 7.18 (d, J=8.1Hz, 1H), 6.99 (t, J=8.3Hz, 2H), 6.89 (d, J=2.3Hz, 1H), 6.84-6.78 (m, 4H), 4.54 (d, J=6.1Hz, 2H), 4.51 (s, 2H), 3.80 (s, 3H), 3.76 (d, J=6.2Hz, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 2.93 (t, J=6.7Hz, 2H), 2.66 (s, 3H).
Embodiment 79:N- [2- (3,4- Dimethoxyphenyl) ethyl] -5- [2- (4- fluorin benzyl amine base) -2- oxo ethoxy Base] synthesis of-2- methyl-1-ethyl-1H- indoles-3- formamide (compound Z70)
Referring to the synthetic method of embodiment 10, white solid 0.92g is obtained, yield: 56.1%.M.p.:131-133℃； IR:(KBr,cm-1):υ3420.6,2921.1,2851.5,1631.6,1546.7,1509.9,1468.2,1384.4,1161.5, 1136.7,1026.3,617.9；ESI-MS,m/z:calcd.547.25(M+)；found548.3([M+H]+),570.2([M+ Na]+)；1H NMR(400MHz,CDCl3): δ 7.30-7.27 (m, 2H), 7.20 (d, J=8.9Hz, 1H), 7.01-6.97 (m, 2H), 6.91 (d, J=2.3Hz, 1H), 6.85-6.79 (m, 4H), 4.54 (d, J=6.1Hz, 2H), 4.52 (s, 2H), 4.11 (q, J=7.2Hz, 2H), 3.81 (s, 3H), 3.76 (d, J=6.5Hz, 2H), 3.75 (s, 3H), 2.93 (t, J=6.7Hz, 2H), 2.67 (s, 3H), 1.32 (t, J=7.2Hz, 3H).
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 80: 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.
Compound number Z01-Z70 target compound: being dissolved with DMSO, is formulated as 50 μM, 20 μM, 10 with culture solution dilution μM, 5 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 absorbance under 490nm wavelength using microplate reader (TECAN SPECTRA, Wetzlar, Germany). According to formula: inhibitory rate of cell growth=(1- medicine group OD value/control group OD value) × 100% calculates thin under respective concentration Intracellular growth inhibiting rate makees logarithmic curve with the various concentration of test-compound and to the inhibiting rate of cell, calculates test-compound Corresponding IC50Value.Representative compound of the present invention is measured according to the method described above, as a result shown in table 1:
Table 1
Embodiment 81: 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 82: gelatine capsule
The preparation of hard gelatin capsule uses:
Above-mentioned preparation can be improved according to provided reasonable change.
Embodiment 83: tablet
The preparation of tablet uses
By said components mix and it is tabletted.
Embodiment 84: 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 85: 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 86: 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 (8)

1. Formulas I compound represented and its pharmaceutically acceptable salt,
Wherein,
R1It can be independently selected from C1-C4 alkyl；
R2、R3It can be independently selected from H, C1-C4 alkyl；Or 1- piperidyl, 1- pyrroles are formed together with the nitrogen-atoms that they are connected Alkyl, 4- morpholinyl, benzamido group or alpha substituted benzylamine base, anilino- or substituted anilinic or 2- (2- methoxyphenoxy) ethamine Base；The substituent group is C1-C4 alkyl, C1-C4 alkoxy, halogen；
Ar can be independently selected from phenyl or substituted-phenyl, furyl, benzyl or substituted benzyl, Phenoxymethyl or substituted benzene oxygen first Base, (4- morpholinyl) methyl, 2- (4- morpholinyl) ethyl；The substituent group is C1-C4 alkyl, C1-C4 alkoxy, halogen.
2. Formulas I compound represented as described in claim 1 and its pharmaceutically acceptable salt,
Wherein,
Ar is phenyl, 4- fluorophenyl, 4- chlorphenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 2- furyl, (2- methoxybenzene oxygen Base) methyl, 3,4- dimethoxy-benzyls.
3. compound and its pharmaceutically acceptable salt as follows, are selected from:
N- benzyl -5- (2- diethylin -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formamide；
N- benzyl-5- (2- diethylin-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- formamide；
N- benzyl -5- (2- di-n-propylamine base -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formamide；
N- benzyl-5- (2- di-n-propylamine base-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- formamide；
N- benzyl -5- (2- di-iso-butylmanice base -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formamide；
N- benzyl-5- (2- di-iso-butylmanice base-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- formamide；
N- benzyl -5- [2- (1- piperidyl) -2- oxoethoxy] -1,2- dimethyl -1H- indoles -3- formamide；
N- benzyl-5- [2- (1- piperidyl)-2- oxoethoxy]-2- methyl-1-ethyl-1H- indoles-3- formamide；
N- benzyl -5- [2- (4- morpholinyl) -2- oxoethoxy] -1,2- dimethyl -1H- indoles -3- formamide；
N- benzyl-5- [2- (4- morpholinyl)-2- oxoethoxy]-2- methyl-1-ethyl-1H- indoles-3- formamide；
N- benzyl -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } -1,2- dimethyl -1H- indoles - 3- formamide；
N- benzyl-5- { 2- [2- (2- methoxyphenoxy) ethylamino-]-2- oxoethoxy }-2- methyl-1-ethyl-1H- Yin Diindyl -3- formamide；
N- (4- luorobenzyl) -5- (2- diethylin -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formamide；
N- (4- luorobenzyl)-5- (2- diethylin-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- formamide；
N- (4- luorobenzyl) -5- (2- di-n-propylamine base -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formamide；
N- (4- luorobenzyl)-5- (2- di-n-propylamine base-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- formyl Amine；
N- (4- luorobenzyl) -5- (2- di-iso-butylmanice base -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formamide；
N- (4- luorobenzyl)-5- (2- di-iso-butylmanice base-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- formyl Amine；
N- (4- luorobenzyl) -5- [2- (1- piperidyl) -2- oxoethoxy] -1,2- dimethyl -1H- indoles -3- formamide；
N- (4- luorobenzyl)-5- [2- (1- piperidyl)-2- oxoethoxy]-2- methyl-1-ethyl-1H- indoles-3- formyl Amine；
N- (4- luorobenzyl) -5- [2- (4- morpholinyl) -2- oxoethoxy] -1,2- dimethyl -1H- indoles -3- formamide；
N- (4- luorobenzyl)-5- [2- (4- morpholinyl)-2- oxoethoxy]-2- methyl-1-ethyl-1H- indoles-3- formyl Amine；
N- (4- luorobenzyl) -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } -1,2- dimethyl -1H- Indoles -3- formamide；
N- (4- luorobenzyl)-5- { 2- [2- (2- methoxyphenoxy) ethylamino-]-2- oxoethoxy }-2- methyl-1-ethyl- 1H- indoles -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl] -5- (2- diethylin -2- oxoethoxy) -1,2- dimethyl -1H- Yin Diindyl -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl]-5- (2- diethylin-2- oxoethoxy)-2- methyl-1-ethyl-1H- Indoles -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl] -5- (2- di-n-propylamine base -2- oxoethoxy) -1,2- dimethyl -1H- Yin Diindyl -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl]-5- (2- di-n-propylamine base-2- oxoethoxy)-2- methyl-1-ethyl- 1H- indoles -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl] -5- (2- di-iso-butylmanice base -2- oxoethoxy) -1,2- dimethyl -1H- Yin Diindyl -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl]-5- (2- di-iso-butylmanice base-2- oxoethoxy)-2- methyl-1-ethyl- 1H- indoles -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (1- piperidyl) -2- oxoethoxy] -1,2- dimethyl -1H- Yin Diindyl -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl]-5- [2- (1- piperidyl)-2- oxoethoxy]-2- methyl-1-ethyl- 1H- indoles -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (4- morpholinyl) -2- oxoethoxy] -1,2- dimethyl -1H- Yin Diindyl -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl]-5- [2- (4- morpholinyl)-2- oxoethoxy]-2- methyl-1-ethyl- 1H- indoles -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl] -5- (2- benzamido group -2- oxoethoxy) -1,2- dimethyl -1H- indoles - 3- formamide；
N- [2- (2- methoxyphenoxy) ethyl]-5- (2- benzamido group-2- oxoethoxy)-2- methyl-1-ethyl-1H- Yin Diindyl -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl] -5- [2- (4- fluorin benzyl amine base) -2- oxoethoxy] -1,2- dimethyl -1H- Indoles -3- formamide；
N- [2- (2- methoxyphenoxy) ethyl]-5- [2- (4- fluorin benzyl amine base)-2- oxoethoxy]-2- methyl-1-ethyl- 1H- indoles -3- formamide；
N- [3- (4- morpholinyl) propyl] -5- (2- benzamido group -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formyl Amine；
N- [3- (4- morpholinyl) propyl]-5- (2- benzamido group-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- first Amide；
N- [3- (4- morpholinyl) propyl] -5- [2- (4- fluorin benzyl amine base) -2- oxoethoxy] -1,2- dimethyl -1H- indoles - 3- formamide；
N- [3- (4- morpholinyl) propyl]-5- [2- (4- fluorin benzyl amine base)-2- oxoethoxy]-2- methyl-1-ethyl-1H- Yin Diindyl -3- formamide；
N- [3- (4- morpholinyl) propyl] -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } -1,2- two Methyl-1H-indole -3- formamide；
N- [3- (4- morpholinyl) propyl] -5- { 2- [2- (2- methoxyphenoxy) ethylamino-] -2- oxoethoxy } -2- first Base -1- ethyl -1H- indoles -3- formamide；
N- (furans -2- methyl) -5- (2- diethylin -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formamide；
N- (furans-2- methyl)-5- (2- diethylin-2- oxoethoxy)-2- methyl-1-ethyl-1H- indoles-3- formyl Amine；
N- (furans -2- methyl) -5- (2- di-n-propylamine base -2- oxoethoxy) -1,2- dimethyl -1H- indoles -3- formyl Amine.
4. a kind of pharmaceutical composition, which is characterized in that include Formulas I compound represented described in claim 1-3 any one And its pharmaceutically acceptable salt.
5. Formulas I compound represented and its pharmaceutically acceptable salt or claim 4 described in claim 1-3 any one The pharmaceutical composition application in preparation of anti-tumor drugs.
6. its pharmaceutically acceptable salt of Formulas I compound represented or claim 4 institute described in claim 1-3 any one Application of the pharmaceutical composition stated in the related disease drug of preparation treatment EGF-R ELISA signal transduction imbalance.
7. such as application described in claim 5 or 6, which is characterized in that the tumour and EGF-R ELISA signal The related disease of conduction disorder is Small Cell Lung Cancer, squamous carcinoma, gland cancer, large cell carcinoma, colorectal cancer, breast cancer, oophoroma, kidney Cell cancer.
8. application as claimed in claim 6, which is characterized in that the EGF-R ELISA be HER-1, HER-2, HER-3 or HER-4.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105658625A (en) * 2013-08-22 2016-06-08 株式会社Lg生命科学 Indole amide compound as inhibitor of necrosis

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Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105658625A (en) * 2013-08-22 2016-06-08 株式会社Lg生命科学 Indole amide compound as inhibitor of necrosis

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors;Kamal Sweidan et al.;《Bioorganic & Medicinal Chemistry Letters》;20160406;第26卷;第2686页Scheme 1，第2689页倒数第3段
EGFR and Src are involved in indole-3-carbinol-induced death and cell cycle arrest of human breast cancer cells;Elena P.Moiseeva et al.;《Carcinogenesis》;20060906;第28卷(第2期);第435-445页
EGFR酪氨酸激酶抑制剂5H-嘧啶并[5,4-b]吲哚类化合物的设计与合成;王久亮.;《中国优秀硕士学位论文全文数据库·医药科技辑》;20150815(第08期);E079-100

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