CN105061462B - Tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidines compound containing amide and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to tetrahydrobenzo[4,5]thieno[2,3- d ]pyrimidine compounds containing amides and their application as epidermal growth factor receptor tyrosine kinase inhibitors, and Preparation. Amide-containing tetrahydrobenzo[4,5]thieno[2,3- d ]pyrimidine compounds and pharmaceutically acceptable salts thereof, and pharmaceutically compatible and acceptable carriers or diluents thereof as epidermal growth factor receptor Tyrosine kinase inhibitors. Its general structural formula is as follows: R ₁ and R ₂ are independently selected from hydrogen, C ₁ -C ₄ alkyl, halogen-substituted or unsubstituted phenyl, or R ₁ and R ₂ together with the nitrogen atom they are connected to Composition of pyrrolidinyl, piperidinyl, morpholinyl. The synthesis method of the compound of the present invention is simple and suitable for industrial production. The biological activity test shows that the compound has the function of inhibiting epidermal growth factor, and is an epidermal growth factor receptor tyrosine kinase inhibitor with antitumor effect.

Description

Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines containing amides and their application

technical field

The invention belongs to the technical field of medicine, and relates to tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine compounds containing amides and their application as epidermal growth factor receptor tyrosine kinase inhibitors, and Preparation.

Background technique

According to the degree of differentiation and morphological characteristics of cancer cells, lung cancer can be divided into non-small cell lung cancer and small cell lung cancer. Studies have found that there is a large number of dysregulation of epidermal growth factor signal transduction and overexpression of epidermal growth factor receptor tyrosine kinase in lung cancer patients.

Epidermal growth factor receptor (EGFR) is a transmembrane protein with an extramembrane ligand receptor binding domain and an intracellular tyrosine kinase activity domain. EGFR has four types: HER-1, HER-2, HER-3 and HER-4. When a small molecule ligand binds to EGFR, EGFR is activated, and then the tyrosine kinase domain of EGFR is activated to recognize the substrate enzyme of the protein , the signal will be transmitted into the cell, and at the same time, the activation of EGFR can also activate the phosphorylation of many downstream signaling molecules, start the signal transduction pathway, and ultimately affect cell survival and cell proliferation. Since the main difference of receptor-type tyrosine kinases is the extracellular ligand-binding region, and the intracellular tyrosine kinase domain has higher homology, the present invention aims at synthesizing the extracellular ligand-binding region. Small molecule ligands, thereby inhibiting the active region of intracellular tyrosine kinases, inhibiting the catalytic activity of enzymes and tyrosine autophosphorylation, thereby inhibiting cell cycle progression, angiogenesis and tumor metastasis.

Existing epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, erlotinib, lapatinib, etc., all have skin reactions such as diarrhea, rash, itching, and possible headache, heart attack, etc. Prolonged QT interval and decreased bioavailability, etc.

As an epidermal growth factor receptor tyrosine kinase inhibitor of a new structure type, the compound of the invention has the characteristics of novel structure type and obvious drug effect. It can be used to treat or prevent diseases related to epidermal growth factor receptor signal transduction disorders such as small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, renal cell carcinoma, bronchial asthma , has good application value and development and application prospects.

Contents of the invention

The technical problem solved by the present invention is to provide a kind of compound as shown in formula I, its prodrug and drug active metabolite and its pharmaceutically acceptable salt, and provide its preparation prevention and treatment EGFR signal transduction Drug use in disorders-related diseases.

in

R ₁ and R ₂ are independently selected from hydrogen, C ₁ -C ₄ alkyl, halogen substituted or unsubstituted phenyl, or R ₁ and R ₂ together with their connected nitrogen atoms form pyrrolidinyl, piperidinyl , Morpholinyl.

Preferably,

R ₁ and R ₂ are independently selected from hydrogen, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, or R ₁ and R ₂ together with their connected nitrogen atoms Pyrrolidinyl, piperidinyl, morpholinyl.

"Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases while retaining the biological efficacy and properties of the compounds of formula I. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphoric acid Salt, camphorsulfonate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanate salt, hexanoate, hydrochlorate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate , Nicotinate, Nitrate, Oxalate, Pamoate, Pectinate, Persulfate, 3-Phenylpropionate, Picrate, Pivalate, Propionate, Succinate , Sulfate, Tartrate, Thiocyanate, Tosylate and Undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts of organic bases such as dicyclohexylamine salts, N-methyl-D-glucosamine salts, and salts of amino acids such as arginine, lysine, etc. Also, basic nitrogen-containing groups can be quaternized with such reagents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorine, bromine and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl; long-chain halides such as decyl, lauryl, myristyl and hard Acyl chlorine, bromine and iodide; aralkyl halides, such as benzyl and phenethyl bromide, etc. Preferred acids for the formation of acid addition salts include hydrochloric acid and acetic acid.

"Pharmaceutically acceptable", such as a pharmaceutically acceptable carrier, excipient, prodrug, etc., means pharmacologically acceptable and substantially non-toxic to the patient to whom the particular compound is administered.

"Pharmaceutically active metabolite" refers to a metabolite of a compound of formula I that is pharmaceutically acceptable and effective.

The present invention also relates to a pharmaceutical composition for inhibiting epidermal growth factor receptor tyrosine kinase, which contains a compound of formula I or a derivative or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

The compounds of the present invention can be administered to the patient by various methods, for example, orally as capsules or tablets, as sterile solutions or suspensions and, in some cases, as intravenous solutions. The free base compounds of the present invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.

detailed description

Reaction Scheme 1 outlines the synthetic steps for preparing compounds of the present invention.

Reaction scheme 1

The present invention is described in detail with the following examples. It should be understood, however, that the present invention is not limited to the specifically described examples below.

Example 1: 4-[2-(4-morpholinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound number 01)

Step A: Preparation of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

In a 250mL three-necked flask, 10.1g (120mmol) of cyanoacetamide, 3.8g (120mmol) of elemental sulfur, 11.8g (120mmol) of cyclohexanone and 38mL of absolute ethanol were added successively, and 8.8g (120mmol) of diethylamine was slowly dropped Add to the above mixed solution, control the temperature at 40-50°C, stir and react for 5h, cool and crystallize, filter with suction to obtain a brownish-yellow solid, wash it twice with a small amount of absolute ethanol, and dry it naturally to obtain 11.7g of a yellow solid powder, with a yield of 49.6 %, m.p.: 186-188°C.

Step B: Preparation of 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one

Put 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide 11.6g (59.2mmol) and formamide (46.4g, 1031mmol) into a 250mL eggplant-shaped bottle and heat to Stir and reflux at 165°C for 6 hours. After the reaction, add 110 mL of isopropanol, filter with suction after stirring, wash with isopropanol once each, and dry naturally to obtain 9.7 g of brown-yellow solid powder, yield 80.0%, m.p.: 255 -257°C.

Step C: Preparation of 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine

Put 8.7g (42.0mmol) of 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one and 70.9g (467.1mmol) of phosphorus oxychloride into 250mL eggplant Shaped bottle, heated to reflux for 2h, column chromatography (petroleum ether: ethyl acetate = 2:1), 6.7g of yellow solid was obtained, the yield was 70.5%, m.p.: 97-99°C.

Step D: Preparation of 4-(2-methoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine

5.0 g (22.3 mmol) of 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine and 3.4 g (24.5 mmol) into a 250mL eggplant-shaped bottle, add 64mL of n-butanol, add 6.8g (66.9mmol) of triethylamine, heat to reflux for 1h, cool to precipitate crystals, filter with suction, wash once each with 10mL of water and 10mL of ethanol, and dry naturally 6.9 g of yellow crystalline powder was obtained with a yield of 94.5%. mp:160-162℃;IR:(KBr,cm ^-1 ):2936(s),1643(m),1584(s),1496(s),1415(s),1168(s),1129(s ), 832(s); ¹ H-NMR (600MHz, CDCl ₃ ): 1.92-1.96(m, 4H, 2×CH ₂ ), 2.87(s, 2H, CH ₂ ), 3.24(s, 2H, CH ₂ ), 3.79(s,3H,OCH ₃ ),7.01-7.07(m,2H,Ar-H),7.49(t,1H,Ar-H,J＝7.9Hz),7.55(dd,1H,Ar-H , J ₁ =7.5, J ₂ =1.6Hz), δ8.49 (s, 1H, Ar-H); ESI-MS (m/z): 329.3 ([M+H] ⁺ ).

Step E: Preparation of 4-(2-hydroxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine

3.3 g (9.9 mmol) of 4-(2-methoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine and anhydrous 4.0g (29.8mmol) of aluminum trichloride was put into a 250mL eggplant-shaped bottle, 70mL of toluene was added, heated to reflux and stirred, and after 1 hour of reaction, the reaction was stopped, and 100 mL of water was added to the reaction system, stirred at room temperature for 3 hours, suction filtered, and naturally air-dried. The product was subjected to column chromatography (methanol:dichloromethane=1:100) to obtain 1.8 g of off-white crystalline powder with a yield of 58.3%. mp:175-176℃;IR:(KBr,cm ^-1 ):3421(m),2932(m),1632(m),1596(m),1473(s),1409(s),1384(s ), 1142(s), 830(m); ¹ H-NMR (400MHz, CDCl ₃ ): 1.95-1.99(m, 4H, CH ₂ ), 2.90(s, 2H, CH ₂ ), 3.23(s, 2H , CH ₂ ), 6.94(t, J=8.2Hz, 1H), 7.17(dd, J ₁ =8.1, J ₂ =1.0Hz, 1H), 7.42(t, J=7.7Hz, 1H), 7.49(dd , J ₁ =7.8, J ₂ =1.4Hz, 1H), δ8.61 (s, 1H); ESI-MS (m/z): 315.3 ([M+H] ⁺ ).

Step F: 4-[2-(4-Morpholinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d ] Preparation of pyrimidine (compound number 01)

0.5g (1.6mmol) of 4-(2-hydroxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine, anhydrous potassium carbonate 2.2g (15.9mmol), 0.1g (0.8mmol) of potassium iodide, 50mL of acetone and 0.3g (1.8mmol) of 4-chloroacetylmorpholine were successively put into a 100mL eggplant-shaped bottle, heated to reflux and stirred for 12h, and evaporated under reduced pressure after the reaction was completed. Remove the solvent, then add 50 mL of dichloromethane and 50 mL of water to the residue for extraction, wash the organic phase once with 100 mL of saturated NaCl aqueous solution, collect the organic phase and dry it with anhydrous magnesium sulfate for 30 min, filter, and perform column chromatography (methanol:dichloro methane=1:50) to obtain 0.6 g of yellow solid with a yield of 78.6%. mp: 164-165℃; IR: (KBr, cm ^-1 ) 3441(m), 2943(s), 1643(s), 1626(s), 1557(s), 1504(s), 1471(s) ,1436(s),1305(s),1198(s),1115(s),1070(s),977(s),777(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.94 -1.95(m,4H,2×CH ₂ ),2.90(m,2H,CH ₂ ),3.13(m,2H,CH ₂ ),3.32(t,2H,CH ₂ -N),3.50(t,2H ,CH ₂ -N),3.54-3.57(m,2H,CH ₂ -O),3.60-3.62(m,2H,CH ₂ -O),3.65(s,2H,CH ₂ -O),7.20(dd ,1H,Ar-H,J ₁ =8.0Hz,J ₂ =1.2Hz),7.28-7.32(m,1H,Ar-H),7.35-7.40(m,1H,Ar-H),(dd,1H , Ar-H, J ₁ =8.0 Hz, J ₂ =1.2 Hz), 8.45 (s, 1H, Ar-H); ESI-MS (m/z): 442.4 ([M+H] ⁺ ).

Example 2: 4-[2-(1-piperidinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound number 02)

Referring to the method of Example 1, 4-[2-(1-piperidinyl)formylmethoxyphenylsulfanyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d]pyrimidine 0.5g, yield 85.7%. mp: 127-129℃; IR: (KBr, cm ^-1 ) 3426(m), 2939(s), 2856(s), 1642(s), 1624(s), 1556(s), 1506(s) , 1471(s), 1390(s), 1309(s), 1193(s), 1138(s), 1070(s), 978(s), 774(s); ¹ H-NMR (400MHz, CDCl ₃ ):δ1.40-1.52(m,4H,2×CH ₂ ),1.55-1.60(m,2H,CH ₂ ),1.92-1.97(m,4H,2×CH ₂ ),2.89(m,2H, CH ₂ ),3.14(m,2H,CH ₂ ),3.25(t,2H,CH ₂ -N),3.49(t,2H,CH ₂ -N),3.68(s,2H,CH ₂ -O), 7.19 (dd, 1H, Ar-H, J ₁ =7.6Hz, J ₂ =1.6Hz), 7.27-7.37 (m, 2H, Ar-H), 7.64 (dd, 1H, Ar-H, J ₁ =7.6 Hz, J ₂ =1.6 Hz), 8.45 (s, 1H, Ar-H); ESI-MS (m/z): 440.2 ([M+H] ⁺ ).

Example 3: 4-(2-Diethylcarbamoylmethoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (Compound No. 03) Preparation

Referring to the method of Example 1, 4-(2-diethylcarbamoylmethoxyphenylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3 -d] Pyrimidine (Compound No. 03) 0.4 g, yield 72.2%. mp: 117-119℃; IR: (KBr, cm ^-1 ) 3428(m), 2936(s), 1649(s), 1559(s), 1503(s), 1466(s), 1390(s) ,1309(s),1193(s),1136(s),1069(s),974(s),781(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.06-1.10(m, 6H,2×CH ₃ ),1.91-1.96(m,4H,2×CH ₂ ),2.88-2.91(m,2H,CH ₂ ),3.12-3.15(m,2H,CH ₂ ),3.18-3.24( m, 2H, CH ₂ -N), 3.31-3.36 (m, 2H, CH ₂ -N), 3.66 (s, 2H, CH ₂ -O), 7.19 (dd, 1H, Ar-H, J ₁ =8.0 Hz, J2 = 1.6Hz), 7.26-7.30 (m, 1H, Ar _- H), 7.33-7.37 (m, 1H, Ar-H), 7.62 (dd, 1H, Ar-H, J1 ₌ 8.0Hz , J ₂ =1.6 Hz), 8.45 (s, 1H, Ar—H); ESI-MS (m/z): 428.2 ([M+H] ⁺ ).

Example 4: 4-[2-(1-pyrrolidinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 04)

Referring to the method of Example 1, 4-[2-(1-pyrrolidinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d]pyrimidine (Compound No. 04) 0.6g, yield 80.9%. mp: 146-147℃; IR: (KBr, cm ^-1 ) 3432(m), 2937(s), 2878(m), 1646(s), 1628(s), 1557(s), 1506(s) , 1471(s), 1435(s), 1391(s), 1307(s), 1194(s), 1070(s), 977(s), 776(s); ¹ H-NMR (400MHz, CDCl ₃ ):δ1.77-1.88(m,4H,2×CH ₂ ),1.91-1.99(m,4H,2×CH ₂ ),2.89(m,2H,CH ₂ ),3.13(m,2H,CH ₂ ),3.32(t,2H,CH ₂ -N),3.43(t,2H,CH ₂ -N),3.60(s,2H,CH ₂ -O),7.19(dd,1H,Ar-H,J ₁ =7.6Hz, J ₂ =1.6Hz), 7.27-7.36(m, 2H, Ar-H), 7.66(dd, 1H, Ar-H, J ₁ =7.6Hz, J ₂ =1.6Hz), 8.45(s , 1H, Ar-H); ESI-MS (m/z): 426.0 ([M+H] ⁺ ).

Example 5: 4-(2-anicarboylmethoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (compound Preparation of number 05)

Referring to the method of Example 1, 4-(2-anilinoylmethoxyphenylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d ] Pyrimidine (Compound No. 05) 0.3 g, yield 57.9%. mp: 187-189℃; IR: (KBr, cm ^-1 ) 3440(m), 3256(d), 2936(d), 1659(s), 1604(s), 1552(s), 1502(s) , 1470(s), 1390(s), 1334(s), 1306(s), 1194(s), 1067(s), 974(s), 767(m); ¹ H-NMR (400MHz, CDCl ₃ ):δ1.92-1.96(m,4H,2×CH ₂ ),2.88-2.90(m,2H,CH ₂ ),3.12-3.14(m,2H,CH ₂ ),3.69(s,2H,CH ₂ -O), 7.08-7.12(m, 1H, Ar-H), 7.20(dd, 1H, Ar-H, J ₁ ＝8.0Hz, J ₂ ＝1.2Hz), 7.25-7.38(m, 6H, Ar- H), 7.46 (dd, 1H, Ar-H, J ₁ =8.0Hz, J ₂ =1.2Hz), 8.37 (s, 1H, Ar-H), 8.53 (s, 1H, NH); ESI-MS ( m/z): 448.1 ([M+H] ⁺ ).

Example 6: 4-[2-(4-fluoroanilino)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 06)

Referring to the method of Example 1, 4-[2-(4-fluoroanilino)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidine (Compound No. 06) 0.2 g, yield 39.0%. mp:122-124℃;IR:(KBr,cm ^-1 )3275(m),2934(s),1670(s),1556(s),1508(s),1469(s),1436(s) ,1390(s),1305(s),1197(s),1067(s),974(s),835(s),777(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.92 -1.96(m,4H,2×CH ₂ ),2.89(m,2H,CH ₂ ),3.12(m,2H,CH ₂ ),3.69(s,2H,CH ₂ -O),6.96(t,2H ,Ar-H),7.19-7.29(m,4H,Ar-H),7.34-7.39(m,1H,Ar-H),7.45(dd,1H,Ar-H,J ₁ ＝8.0Hz,J ₂ = 1.6 Hz), 8.32 (s, 1H, Ar-H), 8.56 (s, 1H, NH); ESI-MS (m/z): 488.1 ([M+H] ⁺ ).

Example 7: 4-[3-(4-morpholinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 07)

Referring to the method of Example 1, 4-[3-(4-morpholinyl)formylmethoxyphenylsulfanyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidine (Compound No. 07) 0.5 g, yield 87.5%. mp: 117-119℃; IR: (KBr, cm ^-1 ) 3444(m), 2929(s), 2857(s), 1679(s), 1659(s), 1591(s), 1496(s) , 1468(s), 1416(s), 1382(s), 1219(s), 1112(s), 1031(s), 831(s), 773(s), 684(s); ¹ H-NMR (400MHz, CDCl ₃ ): δ1.92-1.96(m,4H,2×CH ₂ ),2.87-2.89(m,2H,CH ₂ ),3.17-3.19(m,2H,CH ₂ ),3.60-3.68 (m,8H,2×CH ₂ -N,2×CH ₂ -O),4.72(s,2H,CH ₂ -O),7.06(dd,1H,Ar-H,J ₁ =7.6Hz,J ₂ =2.8Hz), 7.18(t,1H,Ar-H),7.23(d,1H,Ar-H,J=8.0Hz),7.39(t,1H,Ar-H),8.53(s,1H,Ar -H); ESI-MS (m/z): 441.9 ([M+H] ⁺ ).

Example 8: 4-[3-(1-pyrrolidinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 08)

Referring to the method of Example 1, 4-[3-(1-pyrrolidinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidine (Compound No. 08) 0.2 g, yield 30.9%. mp: 103-105℃; IR: (KBr, cm ^-1 ) 3422(m), 2932(m), 2867(s), 1678(s), 1574(s), 1493(s), 1407(s) ,1352(s),1281(s),1227(s),1092(s),829(s),789(s),689(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.83 -2.00(m,8H,4×CH ₂ ),2.88(m,2H,CH ₂ ),3.18(m,2H,CH ₂ ),3.53(t,4H,CH ₂ -N),4.64(s,2H ,CH ₂ -O), 7.06(dd,1H,Ar-H,J ₁ =8.4Hz,J ₂ =2.0Hz),7.20(t,2H,Ar-H),7.38(t,1H,Ar-H ), 8.54 (s, 1H, Ar-H); ESI-MS (m/z): 426.1 ([M+H] ⁺ ).

Example 9: 4-(3-anicarboylmethoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (compound Preparation of number 09)

Referring to the method of Example 1, 4-(3-anilinoylmethoxyphenylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d ] Pyrimidine (Compound No. 09) 0.1 g, yield 18.3%. mp: 123-125℃; IR: (KBr, cm ^-1 ) 3375(s), 2929(s), 2855(s), 1685(s), 1603(s), 1544(s), 1493(s) , 1444(s), 1407(s), 1319(s), 1226(s), 1129(s), 832(s), 764(s), 689(s); ¹ H-NMR (400MHz, CDCl ₃ ):δ1.94-1.96(m,4H,2×CH ₂ ),2.88-2.90(m,2H,CH ₂ ),3.17-3.19(m,2H,CH ₂ ),4.65(s,2H,CH ₂ -O), 7.10(dd, 1H, Ar-H, J ₁ =8.4Hz, J ₂ =2.0Hz), 7.16(t, 1H, Ar-H), 7.28(t, 1H, Ar-H), 7.36 (t,3H,Ar-H),7.44(t,1H,Ar-H),7.58(d,2H,J=7.6Hz),8.25(s,1H,NH),8.49(s,1H,Ar- H); ESI-MS (m/z): 448.3 ([M+H] ⁺ ).

Example 10: 4-[3-(4-fluoroanilino)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 10)

With reference to the method of Example 1, 4-[3-(4-fluoroanilino)formylmethoxyphenylsulfanyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d]pyrimidine (Compound No. 10) 0.6g, yield 85.1%. mp: 151-152℃; IR: (KBr, cm ^-1 ) 3406(s), 2944(m), 1689(s), 1589(s), 1509(m), 1408(s), 1223(s) ,1058(s),829(s),793(s),687(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.92-1.99(m,4H,2×CH ₂ ),2.88- 2.90(m,2H, _CH2 ),3.17-3.19(m,2H, _CH2 ),4.65(s,2H, _CH2 -O),7.03-7.10(m,3H,Ar-H),7.25-7.30 (m,2H,Ar-H),7.44(t,1H,Ar-H,),7.52-7.57(m,2H,Ar-H),8.23(s,1H,NH),8.51(s,1H, Ar-H); ESI-MS (m/z): 466.1 ([M+H] ⁺ ).

Example 11: 4-[4-(4-morpholinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 11)

Referring to the method of Example 1, 4-[4-(4-morpholinyl)formylmethoxyphenylsulfanyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d]pyrimidine (Compound No. 11) 0.6g, yield 78.6%. mp: 141-144℃; IR: (KBr, cm ^-1 ) 3442(m), 2932(s), 2857(s), 1650(s), 1591(s), 1492(s), 1440(s) ,1409(s),1380(s),1236(s),1110(s),1031(s),829(s),731(s); ¹ H-NMR(600MHz,CDCl ₃ ):δ1.92 -1.96(m,4H,2×CH ₂ ),2.87-2.88(m,2H,CH ₂ ),3.18-3.19(m,2H,CH ₂ ),3.61-3.63(m,2H,CH ₂ -N) ,3.65-3.66(m,2H,CH ₂ -N),3.68-3.70(m,4H,CH ₂ -O),4.75(s,2H,CH ₂ -O),7.04(d,2H,Ar-H ,J=8.4Hz), 7.50(d,2H,Ar-H,J=8.4Hz),8.52(s,1H,Ar-H); ESI-MS(m/z):442.0([M+H] ⁺ ).

Example 12: 4-[4-(1-piperidinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] preparation of pyrimidine (compound No. 12)

Referring to the method of Example 1, 4-[4-(1-piperidinyl)formylmethoxyphenylsulfanyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d]pyrimidine (Compound No. 12) 0.6g, yield 91.4%. mp: 84-86℃; IR: (KBr, cm ^-1 ) 3443(m), 2935(s), 2855(s), 1639(s), 1592(s), 1493(s), 1383(s) ,1241(s),1178(s),1128(s),1036(m),826(s),727(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.58-1.66(m, 6H,3×CH ₂ ),1.91-1.97(m,4H,2×CH ₂ ),2.86-2.88(m,2H,CH ₂ ),3.19(brs,2H,CH ₂ ),3.50(t,2H, CH ₂ -N), 3.58(t, 2H, CH ₂ -N), 4.73(s, 2H, CH ₂ -O), 7.04(d, 2H, Ar-H, J=8.4Hz), 7.49(d, 2H, Ar-H, J = 8.4 Hz), 8.51 (s, 1H, Ar-H); ESI-MS (m/z): 440.5 ([M+H] ⁺ ).

Example 13: 4-(4-Diethylcarbamoylmethoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (compound number 13) preparation

Referring to the method of Example 1, 4-(4-diethylcarbamoylmethoxyphenylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3 -d] Pyrimidine (Compound No. 13) 0.6 g, yield 90.8%. mp: 88-91℃; IR: (KBr, cm ^-1 ) 3577(s), 3489(s), 2971(s), 2934(s), 1647(s), 1614(s), 1594(s) ,1494(s),1410(s),1250(s),1078(s),835(s),728(s),616(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.16 (t,3H,CH ₃ ),1.24(t,3H,CH ₃ ),1.94(t,4H,CH ₂ ),2.87(t,2H,CH ₂ ),3.18(t,2H,CH ₂ ),3.41 (m,4H,2×CH ₂ -N),4.72(s,2H,CH ₂ -O),7.04(d,2H,Ar-H,J=8.8Hz),7.49(d,2H,Ar-H , J=8.8 Hz), 8.52 (s, 1H, Ar-H); ESI-MS (m/z): 428.2 ([M+H] ⁺ ).

Example 14: 4-[4-(1-pyrrolidinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] preparation of pyrimidine (compound No. 14)

Referring to the method of Example 1, 4-[4-(1-pyrrolidinyl)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d]pyrimidine (Compound No. 14) 0.6g, yield 83.8%. mp: 125-127℃; IR: (KBr, cm ^-1 ) 3556(s), 3476(s), 2936(s), 2882(s), 1649(s), 1595(s), 1494(s) ,1410(s),1251(s),1175(s),833(s),720(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.84-2.02(m,8H,4×CH ₂ ),2.87(t,2H,CH ₂ ),3.19(t,2H,CH ₂ ),3.55(t,4H,2×CH ₂ -N),4.67(s,2H,CH ₂ -O),7.04 (d, 2H, Ar-H, J=8.8Hz), 7.49(d, 2H, Ar-H, J=8.8Hz), 8.52(s, 1H, Ar-H); ESI-MS(m/z) :426.1([M+H] ⁺ ).

Example 15: 4-(4-anicarboylmethoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (compound No. 15) Preparation

With reference to the method of Example 1, 4-(4-anilinoylmethoxyphenylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d ] Pyrimidine (Compound No. 15) 0.6 g, yield 77.5%. mp: 196-198℃; IR: (KBr, cm ^-1 ) 3374(s), 2929(s), 1684(s), 1599(s), 1534(s), 1492(s), 1438(s) ,1408(s),1244(d),1180(s),820(s),761(s),695(s); ¹ H-NMR(400MHz,CDCl ₃ ):δ1.94-1.95(m, 4H,2×CH ₂ ),2.88(s,2H,CH ₂ ),3.19(s,2H,CH ₂ ),4.68(s,2H,CH ₂ -O),7.10(d,2H,Ar-H, J=8.8Hz),7.18(t,1H,Ar-H),7.38(t,2H,Ar-H),7.56-7.61(m,4H,Ar-H),8.24(s,1H,NH), 8.52 (s, 1H, Ar-H); ESI-MS (m/z): 448.1 ([M+H] ⁺ ).

Example 16: 4-[4-(4-fluoroanilino)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 16)

Referring to the method of Example 1, 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c]pyrazole-3-carbonyl was obtained )-4-(4-ethoxyphenyl)piperazine (Compound No. 16) 0.6 g, yield 85.1%. mp: 195-197℃; IR: (KBr, cm ^-1 ) 3270(s), 2929(s), 1680(s), 1537(s), 1510(d), 1412(s), 1257(s) , 1216(s), 827(s); ¹ H-NMR (400MHz, CDCl ₃ ): δ1.95(t, 4H, 2×CH ₂ ), 2.88(s, 2H, CH ₂ ), 3.19(s, 2H,CH ₂ ),4.67(s,2H,CH ₂ -O),7.05-7.10(m,4H,Ar-H),7.55-7.58(m,4H,Ar-H),8.22(s,1H, NH), 8.52 (s, 1H, Ar-H); ESI-MS (m/z): 466.2 ([M+H] ⁺ ).

Example 17: 4-[4-(4-Chloroanilino)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 17)

Referring to the method of Example 1, 4-[4-(4-chloroanilino)formylmethoxyphenylsulfanyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidine (Compound No. 17) 0.3 g, yield 41.0%. mp: 208-210℃; IR: (KBr, cm ^-1 ) 3262(s), 2926(s), 1682(s), 1593(s), 1532(s), 1492(s), 1413(s) ,1258(s),1090(s),827(s); ¹ H-NMR(600MHz,CDCl ₃ ):δ1.92-1.95(m,4H,2×CH ₂ ),2.86-2.88(m,2H , CH ₂ ), 3.17-3.19 (m, 2H, CH ₂ ), 4.66 (s, 2H, CH ₂ -O), 7.08 (d, 2H, Ar-H, J=8.4Hz), 7.33 (d, 2H ESI-MS (m/z): 482.1 ([M+H] ⁺ ).

Example 18: 4-[4-(4-bromoanilino)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d] Preparation of pyrimidine (compound No. 18)

Referring to the method of Example 1, 4-[4-(4-bromoanilino)formylmethoxyphenylthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidine (Compound No. 18) 0.1 g, yield 10.0%. mp: 198-199℃; IR: (KBr, cm ^-1 ) 3261(s), 2925(s), 1682(s), 1654(s), 1531(s), 1492(s), 1412(s) , 1255(s), 1071(s), 813(d); ¹ H-NMR (400MHz, CDCl ₃ ): δ1.95(s, 4H, 2×CH ₂ ), 2.88(s, 2H, CH ₂ ) ,3.19(s,2H,CH ₂ ),4.66(s,2H,CH ₂ -O),7.08(d,2H,Ar-H,J=8.4Hz),7.47-7.59(m,6H,Ar-H ), 8.24 (s, 1H, NH), 8.52 (s, 1H, Ar-H); ESI-MS (m/z): 426.4 ([M+H] ⁺ ).

The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention to other forms. Any skilled person who is familiar with this profession may use the technical content disclosed above to change or remodel it into an equivalent change. Example. However, any simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still belong to the protection scope of the technical solution of the present invention.

Pharmacological Example

Example 19:

In vitro activity assay of epidermal growth factor (EGFR)

This determination was carried out according to the method introduced by Mowafy et al. (Eur.J.Med.Chem, 2013, 61, 132-145).

This assay uses the Kinase-Glo Plus Luminescent Kinase Assay Kit. It assesses kinase activity by measuring the amount of ATP in the solvent after the kinase reaction. The strength of the luminescent signal is directly proportional to the amount of ATP and inversely proportional to the kinase activity. Test compounds were diluted to 100 [mu]M in 10% DMSO, and 5 [mu]l of the dilution was added to 50 [mu]l reactions to ensure a final concentration of 1% DMSO in all reactions. All enzymatic reactions were performed at 30°C for 40 min. A reaction mixture containing 40 mM Tris (Tris), 10 mM MgCl ₂ , 0.1 mg/mL bovine serum albumin (BSA), 0.2 mg/mL complex matrix (Glu, Tyr) in 50 μl of reaction mixture, 10 μM ATP and EGFR, and keep the pH at 7.4. After the enzymatic reaction, 50 μl of Kinase-Glo Plus Luminescent Kinase Assay Solvent was added to each reaction and incubated at room temperature for 5 minutes. The luminescent signal was determined by Tecan's Infinity M1000 microplate reader.

Determination of _IC50 values was done by using ADP-GloTM detection kit. It measures the production of ADP by protein kinases, and in the above kits ADP produced concomitantly with the kinase reaction results in an enhanced luminescent signal. First, the reaction mixture was placed in a 96-well plate and incubated at 30° C. for 30 min, and then 25 μl of ADP-GloTM reagent was added thereto. Shake the 96-well plate, and then continue to incubate at room temperature for 40 min. Finally, 50 μl of kinase detection reagent was added, and then the results of the 96-well plate were read by a GloMax microplate reader. The test method of the blank group is completely parallel to that of the sample group. Finally, protein kinase activity values were corrected by subtracting the value of the blank group.

According to the above method, the binding of representative compounds of the present invention to EGFR was tested, and the results of IC ₅₀ values are shown in Table 1.

Table 1

Example 20: A-549 Cell Proliferation Assay

This determination was carried out according to the method introduced by Stockert et al. (Acta Histochemicala, 2012, 114(8), 785-796).

This assay uses MTT method and human lung cancer cell line A549 to evaluate the anti-tumor proliferation activity of representative compounds of the invention. The A549 cell line was cultured on Dulbecco's modified Eagle medium (DMEM), which contained 10% fetal bovine serum (FBS), 100 U/mL penicillin and 100 g/mL streptomycin. When the cells proliferated to 80-90%, they were merged and subcultured for no more than 20 passages, and then they were allowed to adapt to the environment for 24 hours before the next treatment. These cells were placed on a 96-well plate (8×10 ⁴ /mL), and then cultured overnight at 37° C. in a humidified environment containing 5% CO ₂ . After 24 h, 20 μM/50 μM of inventive representative compounds were added. After another 24h of cultivation, MTT (5mg/mL) was added to it and the cultivation was continued for 4h. The culture substrate was removed, the crystals were dissolved in DMSO, and the absorbance was measured at a wavelength of 490 nm using a microplate reader (TECAN SPECTRA, Wetzlar, Germany). Inhibition was expressed by inhibition rate and IC ₅₀ value.

Representative compounds of the present invention were determined according to the above method, and the results are shown in Table 2.

Table 2

Example 21: Effect on proliferation of ovarian cancer cell SKOV3

Digest the cells in the logarithmic growth phase with trypsin, add 6×10 ³ cells/well to a 96-well culture plate, and culture in a 37°C, 5% CO ₂ incubator, and wait for most of the cells to adhere to the wall on the second day Afterwards, it was placed in a 4°C incubator for 1 hour to promote the synchronized growth of cells. Aspirate the supernatant, add RPMI 1640 culture solution containing 10% newborn calf serum (FCS), 200 μL/well, and divide into groups according to the experimental design. The compound injection prepared by sterile normal saline was added to 96 wells, and 200 μL was added to each well, so that the drug concentrations in each well were 1 mg/mL, 2 mg/mL and 5 mg/mL, and 0 mg/mL was used as the negative control group. After continuing to culture for 24, 48, and 72 hours, add 20 μL of MTT solution (concentration: 5 mg/mL) to each well, gently shake the culture plate, put it back into the incubator and incubate for another 4 hours, then suck up the supernatant, and put it in each well. Add 200 μL of dimethyl sulfoxide to medium, shake on a shaker for 5-10 minutes, measure the absorbance value (A=580) at a wavelength of 580 nm in each well with an enzyme-labeled photometer, and the value of A=580 is proportional to the number of viable cells.

Representative compounds of the present invention were determined according to the above method, and the results are shown in Table 3.

table 3

Example 22: Effect on proliferation of osteosarcoma cell U2OS-EGFP-4A12G

The cells in the logarithmic growth phase were digested with trypsin, counted with trypan blue, prepared into a cell suspension with a cell density of 1× ¹⁰ cells/mL, and inoculated in a 96-well plate, 200 μL per well, about 2×10 ³ cells were pre-cultured for 24 hours, and the compound injection prepared by sterile normal saline was added to 96 wells, and 200 μL was added to each well, so that the drug concentration in each well was 1 mg/mL, 2 mg/mL and 5 mg/mL, respectively. 0mg/mL was the negative control group. After culturing for 0 h, 12 h, 24 h and 48 h, 20 μL of MTT solution (5 mg/mL) was added to each well, and the incubation was continued for 4 h, and the culture was terminated. Carefully discard the supernatant in the culture wells, add 150 μL of dimethyl sulfoxide (DMSO) to each well, shake for 10 minutes to fully dissolve the formazan, select a wavelength of 490 nm, and measure the light absorption of each well on an enzyme-linked immunosorbent detector value (A value), repeated detection 5 times.

Representative compounds of the present invention were determined according to the above method, and the results are shown in Table 4.

Table 4

Formulation example

The following formulation examples only illustrate the scope of protection of the present invention, but are not intended to be limiting in any way.

Example 23: Gelatin Capsules

Hard gelatin capsules are prepared using:

The above formulations can be modified with reasonable variation provided.

Example 77: Tablets

Tablets are prepared using

The above ingredients are mixed and compressed into tablets.

Example 24: Tablets

Tablets containing 2.5-1000 mg of active ingredient in each tablet are prepared as follows:

Pass the active ingredient, starch and cellulose through a No. 45 mesh screen and mix thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder, which was then passed through a No. 14 mesh sieve. The resulting granules were dried at 50-60°C and passed through a No. 18 mesh screen. The sodium carboxymethyl cellulose, magnesium stearate and talc powder that have passed through a No. 60 mesh sieve in advance are added to the above granules, followed by mixing and compressing on a tablet machine to obtain tablets.

Example 25: Suspension

A suspension containing 0.1-1000 mg of the drug per 5 ml is prepared as follows:

The drug was passed through a No. 45 mesh screen and mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some water and added to the above paste with stirring. Sufficient water is then added to achieve the desired volume.

Example 26: Combination Tablets

Pass the active ingredient, starch and cellulose through a No. 45 mesh screen and mix thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder, which was then passed through a No. 14 mesh sieve. The resulting granules were dried at 50-60°C and passed through a No. 18 mesh screen. The sodium carboxymethyl cellulose, magnesium stearate and talc powder that have passed through a No. 60 mesh sieve in advance are added to the above granules, followed by mixing and compressing on a tablet machine to obtain tablets.

From the above description, those skilled in the art can easily understand the essential features of the present invention. Without departing from the spirit and scope of the present invention, various changes and improvements can be made to the present invention to adapt to different applications and conditions.

Claims (9)

1. a kind of compound of formula I or its pharmaceutically acceptable salt：

Wherein

R₁、R₂Separately it is selected from hydrogen, C₁-C₄The substituted or unsubstituted phenyl of alkyl, halogen or R₁、R₂It is connected with them Nitrogen-atoms constitutes pyrrolidinyl, piperidyl, morpholinyl together.

2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein：

R₁、R₂Separately it is selected from hydrogen, ethyl, phenyl, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, or R₁、R₂With their phases With nitrogen-atoms together with constitute pyrrolidinyl, piperidyl, morpholinyl.

3. the compound of formula as claimed in claim 1 or 2 I or its pharmaceutically acceptable salt, are selected from：

4- [2- (4- morpholinyls) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- [2- (1- piperidyls) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- (2- diethylin formoxyls Methoxv-phenylsulfanvl) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；

4- [2- (1- pyrrolidinyls) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- (2- anilino- formoxyls Methoxv-phenylsulfanvl) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；

4- [2- (4- fluoroanilinos) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- [3- (4- morpholinyls) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- [3- (1- pyrrolidinyls) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- (3- anilino- formoxyls Methoxv-phenylsulfanvl) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；

4- [3- (4- fluoroanilinos) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- [4- (4- morpholinyls) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- [4- (1- piperidyls) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- (4- diethylin formoxyls Methoxv-phenylsulfanvl) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；

4- [4- (1- pyrrolidinyls) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- (4- anilino- formoxyls Methoxv-phenylsulfanvl) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；

4- [4- (4- fluoroanilinos) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- [4- (4- chloroanilinos) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine；

4- [4- (4- bromobenzenes amido) formoxyl Methoxv-phenylsulfanvl] -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic Pyridine.

4. a kind of pharmaceutical composition, the compound comprising the formula I described in claim 1-3 any one or its is pharmaceutically acceptable Salt as active component and pharmaceutically acceptable carrier.

5. the pharmaceutical composition described in the type I compound or claim 4 described in claim 1-3 any one is preparing anti-swelling Application in tumor medicine.

6. the pharmaceutical composition described in the type I compound or claim 4 described in claim 1-3 any one is preparing treatment Application in non-small cell lung cancer drug.

7. the pharmaceutical composition described in the type I compound or claim 4 described in claim 1-3 any one is preparing prevention Application in the disease medicament related to the imbalance of EGF-R ELISA signal transduction to treating.

8. application according to claim 7, it is characterised in that：The EGF-R ELISA be HER-1, HER-2, HER-3 or HER-4.

9. application according to claim 7, it is characterised in that：Wherein described EGF-R ELISA signal transduction loses The relevant disease of tune is squamous carcinoma, and gland cancer, large cell carcinoma, colorectal cancer, breast cancer, oophoroma, clear-cell carcinoma or bronchus are roared Breathe heavily.