CN108586485B - 1- (4-hydroxyiminothieno [2,3-b ] thiopyranoformyl) piperazine compound and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and relates to 1- (4-hydroxyiminothieno [2,3-b ]]Thiopyranoformyl) piperazine compounds and application thereof. The 1- (4-hydroxyiminothieno [2, 3-b)]Thiopyranoformyl) piperazine compounds have the following structure, wherein R is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl and halogenated C1-C4 alkoxy. The 1- (4-hydroxyiminothieno [2,3-b ] of the invention]The thiopyranoformyl) piperazine compound, the stereoisomer, the pharmaceutically acceptable salt, the prodrug or the pharmaceutically active metabolite thereof can be combined with the existing medicaments or used independently for preparing medicaments for treating related diseases with dysregulated epidermal growth factor receptor signaling, wherein the epidermal growth factor receptor is HER-1, HER-2, HER-3 or HER-4, and the related diseases with dysregulated epidermal growth factor receptor signaling are non-small cell lung cancer, gastric cancer, breast cancer, ovarian cancer, renal cell carcinoma, colorectal cancer, bladder cancer and head and neck squamous cell carcinoma.

Description

1- (4-hydroxyiminothieno [2,3-b ] thiopyranoformyl) piperazine compound and application thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a 1- (4-hydroxyiminothieno [2,3-b ] thiopyran formyl) piperazine compound, a preparation method thereof and application thereof as an epidermal growth factor receptor tyrosine kinase inhibitor.

Background

The morbidity and mortality of various tumors in China have a remarkably rising trend in recent years, the tumors with the highest morbidity and mortality in men are lung cancer, and women are breast cancer and lung cancer. Unhealthy habits and habits such as smoking, excessive drinking, insufficient physical activities and the like, haze, and working and living pressure brought to people by rapid development of economic society and social transformation have inconsiderable influence on health, and the rising trend of the death rate of lung Cancer, liver Cancer, colorectal Cancer and breast Cancer related to environment and life style is more obvious, wherein the rising range of the lung Cancer and the breast Cancer is the largest, and the lung Cancer and the breast Cancer respectively rise by 465% and 96% in the last 30 years (StewartBW, Wild CP. WHO: World Cancer Report 2014. Lyon: International Agency for research on Cancer 2014.), so the prevention and the treatment of the lung Cancer and the breast Cancer are the hot spots of the current research.

Based on the differentiation degree and morphological characteristics of cancer cells, a large number of dysregulated epidermal growth factor signaling and overexpression of epidermal growth factor receptor tyrosine kinase are found in many tumor patients. Epidermal Growth Factor Receptor (EGFR), a member of the receptor type tyrosine kinase family, is known as a transmembrane glycoprotein consisting of an extracellular epidermal growth factor binding region (comprising 621 amino acid residues), a hydrophobic transmembrane domain (23 amino acid residues), an intracellular kinase region (542 amino acid residues), and a carboxy-terminal four part. EGFR has 4 types of HER-1, HER-2, HER-3 and HER-4, and when a small molecule ligand binds to EGFR, EGFR is activated, and then a tyrosine kinase region of EGFR is activated, a substrate enzyme for recognizing protein is activated, signals are transmitted into cells, and simultaneously after EGFR is activated, a plurality of downstream signal transduction paths can be activated to stimulate cell growth and proliferation (Zhang H, Berezv A, Wang Q, Zhang G, Drebin J, Murali R, Greene MI ErbB receptors, from genes to target front cancer channels, the Journal of Clinical Investigation, 2007,117(8):2051 and 2058.). The receptor type tyrosine kinase mainly has the difference of an extracellular ligand binding region, and an intracellular tyrosine kinase structural domain has higher homology.

The existing epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, erlotinib, lapatinib and the like, have the skin reactions of diarrhea, rash, pruritus and the like, and possible headache, prolongation of heart QT interval, reduction of bioavailability and the like (Liyingying, Tianchi, Wanglie, Ximengmeng, Chengzeng, research progress of small molecule epidermal growth factor receptor tyrosine kinase inhibitors, tumor pharmacy, 2016,6(2): 81-88.).

The 1- (4-hydroxyiminothieno [2,3-b ] thiopyranoformyl) piperazine compound is used as an epidermal growth factor receptor tyrosine kinase inhibitor with a brand new structure type, has the characteristics of novel structure type and equivalent or superior pharmacodynamic action to the existing medicaments, can be used for treating or preventing related diseases caused by the dysregulation of epidermal growth factor receptor signal conduction, such as non-small cell lung cancer, gastric cancer, breast cancer, ovarian cancer, renal cell carcinoma, colorectal cancer, bladder cancer and head and neck squamous cell carcinoma, and has good application value and development and application prospects.

Disclosure of Invention

The invention aims to provide a compound shown as a formula I, a prodrug, a pharmaceutically active metabolite and a pharmaceutically acceptable salt thereof, and provides application of the compound in preparation of medicines for preventing and treating diseases related to EGFR signaling dysregulation.

The present invention provides compounds of formula (I), prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof:

wherein,

r is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl and halogenated C1-C4 alkoxy.

Further, the air conditioner is provided with a fan,

r is selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy.

In particular, the amount of the solvent to be used,

the group consisting of R together with the phenyl to which it is attached may be independently selected from phenyl, 2-chlorophenyl, 2-ethylphenyl, 4-fluorophenyl, 2-trifluoromethoxyphenyl, 2, 4-dimethylphenyl, 3-bromophenyl, 2-methyl-6-chlorophenyl, 2-methyl-3-chlorophenyl, 4-bromophenyl, 4-chlorophenyl, 3-trifluoromethyl-4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, or 2, 5-dimethylphenyl.

"pharmaceutically acceptable salts" refers to conventional acid addition salts or base addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfate, perchlorate, thiocyanate, bisulfate, persulfate, borate, formate, acetate, propionate, valerate, pivalate, hexanoate, heptanoate, octanoate, isooctanoate, undecanoate, laurate, palmitate, stearate, oleate, cycloproponate, oxalate, malonate, succinate, maleate, fumarate, adipate, azelate, acrylate, strawberry, crotonate, tiglate, itaconate, sorbate, cinnamate, glycolate, lactate, malate, tartrate, citrate, tartrate, mandelate, prolinate, ascorbyl, gluconate, glucarate, mannitol, caseinate, phenate, cinnamate, phenate, phena.

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

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

"pharmaceutically acceptable" such as pharmaceutically acceptable carriers, excipients, prodrugs, etc., means pharmacologically acceptable and substantially non-toxic to a patient to whom a particular compound is administered.

The term "halogen" as used in the present invention includes fluorine, chlorine or bromine.

"substituted," unless otherwise specified, means that the substituent may be present at one or more positions, the substituents being independently selected from a particular selection.

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

The invention relates to 1- (4-hydroxyiminothieno [2,3-b ] thiopyranoformyl) piperazine compounds, prodrugs and pharmaceutically active metabolites thereof and pharmaceutically acceptable salts thereof, which can be combined with the existing medicines or used independently for preparing medicines for treating related diseases of epidermal growth factor receptor signaling disorder.

The pharmaceutical composition can be combined with the existing medicines or used independently for preparing the medicines for treating related diseases of epidermal growth factor receptor signal transduction disorder.

Wherein the epidermal growth factor receptor is HER-1, HER-2, HER-3 or HER-4, and the related diseases of dysregulation of epidermal growth factor receptor signaling are non-small cell lung cancer, gastric cancer, breast cancer, ovarian cancer, renal cell carcinoma, colorectal cancer, bladder cancer or head and neck squamous cell carcinoma.

Methods of treatment and dosages used

The various diseases and conditions to be treated as described herein are well known and clear to those skilled in the art. It is also understood that one skilled in the art can treat a patient currently afflicted with a disease or condition with a therapeutically effective amount of the compound or affect the disease or condition by prophylactically treating a patient afflicted with a disease or condition.

The term "patient" as used herein refers to a warm-blooded animal, such as a mammal, having a tumor. It is understood that guinea pigs, dogs, cats, rats, mouse horses, cattle, sheep, and humans are examples of animals within the meaning of the term.

The term "therapeutically effective amount" as used herein refers to an amount effective for the control of tumor-associated diseases and conditions. The term "controlling" is intended to refer to all processes by which the progression of the diseases and conditions described herein can be slowed, interrupted, arrested or halted, and not necessarily the complete elimination of all of the symptoms of the disease and condition.

A therapeutically effective amount can be readily determined by the attending diagnostician as one skilled in the art using routine techniques and observing results obtained under analogous circumstances. In determining a therapeutically effective amount of a dosage, the attending diagnostician considers a number of factors, including but not limited to: the species of mammal; its size, age and general health; the specific diseases involved; the degree or complexity or severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; bioavailability characteristics of the administered formulation; a selected dosing regimen; concomitant medication use and other related conditions.

Therapeutically effective amounts of the active compounds are expected to vary from about 0.001 milligrams per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts can be determined by one skilled in the art.

In effectively treating patients suffering from the diseases and conditions described above, such compounds may be administered in any form or manner that makes the compound bioavailable in therapeutically effective amounts, including oral, inhaled, and parenteral routes. For example, the compounds can be administered orally, by inhalation as an aerosol or dry powder, by subcutaneous injection, intramuscular injection, intravenous injection, transdermal administration, intranasal administration, rectal administration, topical administration, and the like. Oral or inhalation administration is generally preferred for the treatment of respiratory diseases such as asthma. One skilled in the art of formulating formulations can readily select the appropriate form and mode of administration depending on the particular characteristics of the compound selected, the condition of the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances.

The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients in the form of pharmaceutical compositions, the proportions and properties of which are determined by the solubility and chemical properties of the compound selected, the route of administration selected, and standard pharmaceutical practice. The compounds of the present invention, while effective per se, may be formulated and administered in the form of their pharmaceutically acceptable salts, such as acid or base addition salts, for the purposes of stability, ease of crystallization, improved solubility, and the like.

The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound admixed or otherwise associated with one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions are prepared according to methods well known in the pharmaceutical art. The carrier or excipient which may serve as a vehicle or medium for the active ingredient may be a solid, semi-solid, or liquid material. Suitable carriers or excipients are well known in the art. The pharmaceutical compositions may be adapted for oral, inhalation, parenteral or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions and the like.

The compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier, which may be enclosed in capsules or compressed into tablets. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These formulations should contain at least 4% of the compound of the invention, i.e. the active ingredient, but may vary depending on the particular form, conveniently between 4% and about 70% by weight of the unit. The amount of the compound present in the composition should be such that a suitable dosage is obtained. Preferred compositions and formulations of the present invention may be determined by one skilled in the art.

The tablets, pills, capsules, lozenges and the like may further contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other, different materials that modify the physical form of the dosage unit, for example as a coating. Syrups, in addition to containing the compound, may contain sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

For parenteral administration, the compounds of the invention may be added to a solution or suspension. These formulations should contain at least 0.1% of the compound of the invention, but may vary between 0.1 and about 50% by weight of the formulation. The amount of compound present in such compositions should be such that a suitable dosage is obtained. Preferred compositions and vitex negundo can be determined by a person skilled in the art.

The compounds of the invention may also be administered by inhalation, for example as an aerosol or dry powder. May be released by a liquefied or compressed gas or by a suitable pumping system which dispenses the compounds of the invention or their formulations. Formulations for administration by inhalation of the compounds may be delivered in monophasic, biphasic or triphasic systems. For aerosol administration of the compounds, a number of systems are available. Dry powder formulations are prepared by granulating or milling the compound to the appropriate particle size or by mixing the granulated or milled compound with a suitable carrier, such as lactose or the like. Delivery systems by inhalation include the necessary containers, active agents, valves, sub-containers, and the like. Preferred aerosol and dry powder formulations for administration by inhalation can be determined by one skilled in the art.

The compounds of the invention may also be administered topically, in which case the carrier will suitably contain a solution, ointment or gel base. The base may, for example, comprise one or more of the following substances: the concentration of the calcium-containing compound or pharmaceutically acceptable salt thereof in the topical formulation may be from about 0.1 to about 10% w/v (weight per unit volume).

The solution or suspension may also contain one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as vitamin C or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting the osmotic pressure such as sodium chloride or glucose. The parenteral formulations may be presented in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Detailed Description

The following reaction scheme outlines the preparation steps for preparing the compounds of the present invention.

Reaction scheme

The present invention is described in detail by the following examples. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described.

Example 1: preparation of 2- (4-phenylpiperazin-1-ylcarbonyl) -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

Step A: preparation of 3- (thiophene-2-thio) propionic acid

Adding 0.04mol of 2-mercaptothiophene, 0.04mol of acrylic acid and 80mL of tetrahydrofuran into a 250mL round bottom flask, dropwise adding 11mL of triethylamine while stirring, heating and refluxing for reaction for 12h, after the reaction is finished, slightly cooling, and evaporating the tetrahydrofuran. After cooling, 40mL of ethyl acetate and 20mL of water were added, the pH of the solution was adjusted to 2 with 18% hydrochloric acid, the organic layers were collected, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous magnesium sulfate. And (3) carrying out suction filtration, evaporating the solvent from the filtrate, cooling, precipitating a brown solid, and recrystallizing by using petroleum ether to obtain a white solid with the yield of 5.82g and the yield of 77.4%. m.p. 43-45 ℃.

And B: preparation of 5, 6-dihydro-4H-thieno [2,3-b ] thiopyran-4-one

A250 mL three-necked flask was charged with 0.02mol of 3- (thiophene-2-thio) propionic acid, 20mL of dichloromethane, and 2 drops of DMF, and a dichloromethane solution containing oxalyl chloride (2.2 mL of oxalyl chloride, 15mL of dichloromethane) was added dropwise with stirring under nitrogen protection and stirred at room temperature for 2 hours. Cooling the reaction solution with ice salt bath to-10 deg.C or below, and adding dropwise a solution containingA solution of tin tetrachloride in methylene chloride (1.15 mL of tin tetrachloride, 10mL of methylene chloride). After the dripping is finished, stirring is carried out for 2h at the temperature of 0 ℃. To a three-necked flask, 30mL of water was added, the organic layer was extracted, the aqueous layer was extracted with dichloromethane, and the organic layers were combined. The organic layer was washed with a saturated sodium carbonate solution, water and a saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. And (3) carrying out suction filtration, evaporating the solvent from the filtrate, cooling to obtain a brown crude product, and recrystallizing by using petroleum ether to obtain a light yellow solid, wherein the yield is 2.75g and 80.9%. m.p. 59.0-60.5 ℃.¹H-NMR(300MHz,DMSO-d₆):δ2.77(t,2H, J＝6.6Hz),3.47(t,2H,J＝6.6Hz),7.35(d,1H,J＝5.4Hz),7.38(d,1H,J＝5.4Hz)。MS(m/z):171([M+H]⁺)。

And C: preparation of 2-trichloroacetyl-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran-4-one

0.06mol of aluminum trichloride and 20mL of methylene chloride were mixed, and the mixture was charged into a 250mL round-bottom flask and cooled in an ice bath. Dropwise adding dichloromethane solution containing trichloroacetyl chloride (trichloroacetyl chloride 0.026mol, dichloromethane 25mL) under stirring for about 20min, stirring for 30min, and continuously dropwise adding 5, 6-dihydro-4H-thieno [2,3-b ] containing 0.02mol under ice bath]20mL of a solution of thiopyran-4-one in methylene chloride was added dropwise, the mixture was stirred at room temperature for 24 hours, the reaction mixture was poured into 100mL of water, the organic layer was extracted, the aqueous layer was extracted with methylene chloride, and the organic layers were combined and dried over anhydrous magnesium sulfate. Filtering, evaporating the solvent from the filtrate, and recrystallizing with ethanol. Pale yellow crystals were obtained, yield 2.95g, yield 47.0%. m.p. 152.5-154.0 ℃.¹H-NMR(600MHz,CDCl₃)δ:2.92(t,2H,J＝6.6Hz), 3.45(t,2H,J＝6.6Hz),8.45(s,1H)；ESI-MS(m/z):312.9([M-H]^-)。

Step D: preparation of 4-oxo-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran-2-carboxylic acid

0.01mol of 2-trichloroacetyl-5, 6-dihydro-4H-thieno [2,3-b ] was added to a 250mL round-bottom flask]Reacting thiopyran-4-one, 0.013mol of sodium carbonate and 150mL of water at 60 ℃ for 15h, cooling to room temperature after the reaction is finished, performing suction filtration, adjusting the pH value of the filtrate to 2 by using hydrochloric acid, performing suction filtration, and washing the solid by using water to obtain a light yellow powdery solid, wherein the yield is 1.89g, the yield is 88.3%, and the m.p. is 201 and 203 ℃.¹H-NMR(400MHz,DMSO-d₆)δ:2.81(t,2H,J＝6.4),3.45(t,2H, J＝6.4),7.80(s,1H),13.43(s,1H)；ESI-MS(m/z):212.8([M-H]^-)。

Step E: preparation of 2- (4-phenylpiperazin-1-ylcarbonyl) -5, 6-dihydro-4H-thieno [2,3-b ] thiopyran-4-one

In a 50mL round-bottom flask, 1.5mmol of 4-oxo-5, 6-dihydro-4H-thieno [2,3-b ] was added]Thiopyran-2-carboxylic acid, 1.5mmol of 1-phenylpiperazine, 1.9mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.3mmol of 1-hydroxybenzotriazole, 1mL of triethylamine and 15mL of dried methylene chloride were stirred at room temperature for 48 hours, filtered, the filtrate was washed with 18% hydrochloric acid, saturated sodium carbonate, water and saturated sodium chloride in this order, and the organic layer was extracted and dried over anhydrous magnesium sulfate. Performing suction filtration, evaporating the solvent from the filtrate to obtain a crude product, and performing silica gel column chromatography separation to obtain 0.28g of white solid yellow solid with the yield of 51.9%; mp is 138-140 ℃; IR (KBr, cm)^-1):3425.0,3303.5, 3084.8,3000.7,2922.0,2850.6,2815.3,1658.2,1600.1,1503.4,1426.7, 1230.3,1178.6,997.7,905.0,758.4；¹H-NMR(600MHz,CDCl₃)δ：7.62(s, 1H),7.30(t,J＝7.8Hz,2H),6.91～6.97(m,3H),3.92(t,J＝5.4Hz,4H),3.40(t, J＝6.0Hz,2H),3.24(t,J＝5.4Hz,4H),2.88(t,J＝6.0Hz,2H)；ESI-MSm/z: 356.9([M-H]^-)。

Step F: preparation of 2- (4-phenylpiperazin-1-ylcarbonyl) -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

0.3mmol of 2- (4-phenylpiperazin-1-ylcarbonyl) -5, 6-dihydro-4H-thieno [2,3-b]Dissolving thiopyran-4-one in 20mL of absolute ethyl alcohol, adding 0.025g (0.3mmol) of sodium acetate and 0.021g (0.3mmol) of hydroxylamine hydrochloride, refluxing for 12h, cooling to separate out a solid, filtering and washing, and recrystallizing by using ethyl alcohol to obtain light yellow powder 0.11g, wherein the yield is 96.2%. m.p. 220-221 ℃; IR (KBr, cm)^-1):3283.3, 3067.3,2922.9,2802.6,1601.8,1533.8,1473.8,1387.8,1280.6,1235.8, 981.9,867.2,764.9,723.5,689.3；¹H-NMR(600MHz,CDCl₃)δ：8.01(s,1H),7.62(s,1H),7.30(t,J＝7.2Hz,2H),6.91～6.98(m,3H),3.91～3.97(m,4H), 3.22～3.25(m,4H),3.07～3.13(m,4H)；ESI-MS m/z:371.9([M-H]^-)。

Example 2: preparation of 2- [4- (2-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis method of example 1, 0.11g of white powder was obtained with a yield of 86.5%. m.p. 224-226 ℃; IR (KBr, cm)^-1):3248.0,3064.1,3020.8,2907.4,2811.8,2749.8, 1604.4,1532.9,1473.2,1428.1,1387.5,1266.6,1232.3,1000.8,980.7,866.9, 773.8,747.5,720.3；¹H-NMR(600MHz,CDCl₃)δ：7.83(s,1H),7.62(s,1H), 7.38(d,J＝7.8Hz,1H),7.23(d,J＝7.8Hz,1H),7.00～7.03(m,2H), 3.92～3.95(m,4H),3.07～3.13(m,8H)；ESI-MS m/z:406.0([M-H]^-)。

Example 3: preparation of 2- [4- (3-ethylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis procedure of example 1, a pale yellow powder was obtained in 86.5% yield. m.p. 201-203 ℃; IR (KBr, cm)^-1):3375.6,3095.5,2918.7,2851.7,2815.6,1581.5, 1526.2,1485.7,1457.7,1436.1,1383.9,1260.4,1148.0,982.4,862.8,768.0；¹H-NMR(600MHz,CDCl₃)δ：7.83(s,1H),7.63(s,1H),7.25(d,J＝7.2Hz, 1H),7.18(t,J＝7.2Hz,1H),7.10(t,J＝7.2Hz,1H),7.05(d,J＝7.2Hz,1H), 3.85～3.94(m,4H),3.06～3.14(m,4H),2.89～2.95(m,4H),2.73(q,J＝6.6Hz, 2H),1.26(t,J＝6.6Hz,3H)；ESI-MS m/z:402.2([M+H]⁺),424.2([M+Na]⁺),440.2([M+K]⁺)。

Example 4: preparation of 2- [4- (4-fluorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis procedure of example 1, white powder was obtained with a yield of 76.9%. 187-189 ℃ in m.p.; IR (KBr, cm)^-1):3273.3,2917.0,2849.5,1601.8,1509.2,1469.6,1447.1, 1387.6,1277.4,1233.2,1159.8,1000.3,984.4,817.4；¹H-NMR(600MHz, CDCl₃)δ：7.73(s,1H),7.60(s,1H),6.97～7.00(m,2H),6.88～6.91(m,2H), 3.90～3.92(m,4H),3.09～3.15(m,8H)；ESI-MSm/z:389.9([M-H]^-)。

Example 5: preparation of 2- [4- (2-trifluoromethoxyphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis procedure of example 1, white powder was obtained with a yield of 77.7%. m.p. 215-216 ℃; IR (KBr, cm)^-1):3293.1,3106.4,2975.6,2913.4,2824.8,1585.0,1530.4, 1494.3,1443.4,1386.5,1289.1,1270.0,1213.0,1171.2,1003.7,985.1,866.5, 774.0,737.4；¹H-NMR(600MHz,CDCl₃)δ：7.63(s,1H),7.20～7.24(m,2H), 7.01～7.06(m,2H),5.05(s,1H),3.89～3.93(m,4H),3.08～3.13(m,8H)； ESI-MS m/z:455.9([M-H]^-)。

Example 6: preparation of 2- [4- (2, 4-dimethylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis method of example 1, white crystals were obtained with a yield of 80.6%. m.p. 193-195 ℃; IR (KBr, cm)^-1):3421.9,2922.2,2853.0,1630.2,1384.4,1117.7,1000.6, 861.7,813.7；¹H-NMR(600MHz,CDCl₃)δ：8.00(s,1H),7.64(s,1H),7.02(s, 1H),6.98(d,J＝7.8Hz,1H),6.90(d,J＝7.8Hz,1H),3.87～3.91(m,4H), 3.07～3.13(m,4H),2.89～2.92(m,4H),2.30(s,3H),2.28(s,3H)；ESI-MS m/z: 400.0([M-H]^-)。

Example 7: preparation of 2- [4- (3-bromophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis procedure of example 1, a pale yellow powder was obtained in 97.1% yield. m.p. 100-102 ℃; IR (KBr, cm)^-1):3255.6,2822.7,1588.9,1479.6,1425.4,1386.3, 1275.5,1232.7,1000.5,983.8,865.7,763.5,682.4；¹H-NMR(600MHz, CDCl₃)δ：8.28(s,1H),7.62(s,1H),7.13(t,J＝7.8Hz,1H),7.04(t,J＝1.8Hz, 1H),7.02(dd,J₁＝7.8Hz,J₂＝1.8Hz,1H),6.83(dd,J₁＝7.8Hz,J₂＝1.8Hz, 1H),3.89(t,J＝5.1Hz,4H),3.23(t,J＝5.1Hz,4H),3.07～3.13(m,4H)； ESI-MS m/z:449.9([M-H]^-)。

Example 8: preparation of 2- [4- (2-methyl-6-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis procedure of example 1, white powder was obtained with a yield of 76.9%. m.p. 245-246 ℃; IR (KBr, cm)^-1):3264.1,2921.3,2851.6,1640.4,1536.3,1454.8,1385.8, 1282.6,1246.7,983.3,797.8,772.3,707.0；¹H-NMR(600MHz,DMSO-d₆)δ： 11.24(s,1H),7.52(s,1H),7.23(d,J＝7.8Hz,1H),7.19(d,J＝7.8Hz,1H), 7.08(t,J＝7.8Hz,1H),3.98～4.02(m,2H),3.94～3.54(m,2H),3.27～3.30(m, 2H),3.20(t,J＝6.0Hz,2H),2.96～2.99(m,2H),2.93(t,J＝6.0Hz,2H), 2.35(s,3H)；ESI-MS m/z:422.1([M+H]⁺),444.1([M+Na]⁺)。

Example 9: preparation of 2- [4- (2-methyl-3-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis procedure of example 1, white powder was obtained with a yield of 95.9%. m.p. 223-225 ℃; IR (KBr, cm)^-1):3285.3,3058.6,3010.9,2915.3,2817.1,1676.7,1641.5, 1580.9,1534.0,1468.1,1442.8,1429.9,,1388.7,1260.7,998.5,982.5,791.6, 728.4,719.7；¹H-NMR(600MHz,DMSO-d₆)δ：11.23(s,1H),7.55(s,1H), 7.16～7.19(m,2H),7.03(dd,J₁＝7.2Hz,J₂＝1.2Hz,1H),3.78～3.84(m,4H), 3.20(t,J＝6.0Hz,2H),2.94(t,J＝6.0Hz,2H),2.87～2.89(m,4H),2.33(s,3H)；ESI-MS m/z:422.2([M+H]⁺),444.1([M+Na]⁺),460.0([M+K]⁺)。

Example 10: preparation of 2- [4- (4-bromophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis method of example 1, white crystals were obtained with a yield of 97.1%. m.p. 214-215 ℃; IR (KBr, cm)^-1):3438.9,2957.4,2891.5,2846.4,1581.1,1529.0,1495.1, 1448.0,1386.0,1237.9,976.0,799.3,734.7,644.1；¹H-NMR(600MHz, DMSO-d₆)δ：11.24(s,1H),7.55(s,1H),7.37(d,J＝9.0Hz,2H),6.90(d,J＝ 9.0Hz,2H),3.75～3.80(m,4H),3.18～3.22(m,6H),2.94(t,J＝6.0Hz,2H)； ESI-MS m/z:449.9([M-H]^-)。

Example 11: preparation of 2- [4- (4-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis method of example 1, white crystals were obtained with a yield of 96.2%. m.p. 203-205 ℃; IR (KBr, cm)^-1):3336.5,3081.8,2981.4,2891.1,2860.9,1605.5,1522.7, 1494.6,1447.7,1386.1,1233.3,1155.3,1009.9,981.9,817.0,737.6,702.6；¹H-NMR(600MHz,CDCl₃)δ：7.59(s,1H),7.55(s,1H),7.24(d,J＝9.0Hz, 2H),6.84(d,J＝9.0Hz,2H),3.90(t,J＝5.1Hz,4H),3.19(t,J＝5.1Hz,4H), 3.08～3.13(m,4H)；ESI-MS m/z:406.0([M-H]^-)。

Example 12: preparation of 2- [4- (3-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis method of example 1, pale yellow crystals were obtained with a yield of 36.1%. m.p. 86-88 ℃; IR (KBr, cm)^-1):3260.3,2967.6,2915.4,2826.1,1592.8,1532.5,1476.7, 1430.0,1387.4,1235.2,1000.9,986.6,938.4,866.2,836.8,773.4,681.8；¹H-NMR(600MHz,CDCl₃)δ：8.49(s,1H),7.64(s,1H),7.19(t,J＝7.8Hz,1H), 6.85～6.88(m,2H),6.78(dd,J₁＝7.8Hz,J₂＝1.8Hz,1H),3.90(t,J＝5.1Hz, 4H),3.23(t,J＝5.1Hz,4H),3.08～3.12(m,4H)；ESI-MS m/z:406.2([M-H]^-)。

Example 13: preparation of 2- [4- (3-trifluoromethyl-4-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

Following the synthesis procedure of example 1, a pale yellow powder was obtained in 38.8% yield. m.p. 175-178 ℃; IR (KBr, cm)^-1):3245.9,2996.0,2918.5,2832.4,1605.3,1527.4, 1489.9,1427.3,1389.6,1309.7,1235.3,1132.5,986.5,947.4,866.5,828.7, 736.0,705.4；¹H-NMR(600MHz,CDCl₃)δ：8.99(s,1H),7.68(s,1H),7.36(d,J ＝7.8Hz,1H),7.16(s,1H),6.96(d,J＝7.8Hz,1H),3.89～3.94(m,4H), 3.22～3.26(m,4H),3.05～3.14(m,4H)；ESI-MS m/z:474.0([M-H]^-)。

Example 14: preparation of 2- [4- (4-methoxyphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis procedure of example 1, a pale yellow powder was obtained in 86.5% yield. m.p. 144-146 ℃; IR (KBr, cm)^-1):3250.2,2983.8,2916.0,2827.3,1612.3,1587.0, 1510.5,1437.5,1384.5,1280.2,1242.8,1225.0,1209.6,1178.5,1149.8, 1030.2,984.8,826.7,795.5；¹H-NMR(600MHz,CDCl₃)δ：8.41(s,1H),7.62(s, 1H),6.92(d,J＝9.0Hz,2H),6.85(d,J＝9.0Hz,2H),3.91～3.94(m,4H), 3.78(s,3H),3.08～3.12(m,8H)；ESI-MS m/z:402.0([M-H]^-)。

Example 15: preparation of 2- [4- (4-methylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis method of example 1, pale yellow crystals were obtained with a yield of 80.6%. 188-190 ℃ in m.p.; IR (KBr, cm)^-1):3301.8,3013.1,2965.4,2906.1,2848.4,2806.0, 1597.3,1517.0,1468.0,1385.8,1277.8,1234.8,1154.2,982.7,806.0；¹H-NMR(600MHz,CDCl₃)δ：7.79(s,1H),7.60(s,1H),7.10(d,J＝8.4Hz, 2H),6.85(d,J＝8.4Hz,2H),3.91(t,J＝4.8Hz,4H),3.17(t,J＝4.8Hz,4H), 3.08～3.13(m,4H),2.28(s,3H)；ESI-MS m/z:388.2([M+H]⁺), 410.2([M+Na]⁺),426.2([M+K]⁺)。

Example 16: preparation of 2- [4- (3-trifluoromethylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

According to the synthesis procedure of example 1, a pale yellow powder was obtained in a yield of 96.2%. m.p. 167-169 ℃; IR (KBr, cm)^-1):3263.6,2918.3,2850.8,1608.3,1495.3,1447.8, 1387.0,1234.5,1117.8,992.0,940.9,865.1,785.7,696.0；¹H-NMR(600MHz, CDCl₃)δ：7.88(s,1H),7.62(s,1H),7.38(t,J＝7.8Hz,1H),7.14(d,J＝7.8Hz, 1H),7.12(s,1H),7.07(d,J＝7.8Hz,1H),3.93(t,J＝4.8Hz,4H),3.29(t,J＝ 4.8Hz,4H),3.08～3.14(m,4H)；ESI-MS m/z:440.0([M-H]^-)。

Example 17: preparation of 2- [4- (2, 5-dimethylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran

Procedure according to example 1The obtained product was obtained as a white powder with a yield of 86.5%. 196 to 198 ℃ in m.p.; IR (KBr, cm)^-1):3313.2,3011.5,2912.5,2820.5,1580.8,1468.9,1431.6, 1387.5,1266.9,1243.9,981.4,877.0,820.0,726.9；¹H-NMR(600MHz, CDCl₃)δ：7.60(s,1H),7.56(s,1H),7.08(d,J＝7.8Hz,1H),6.83(d,J＝7.8Hz, 1H),6.74(s,1H),3.87～3.91(m,4H),2.92～2.95(m,4H),3.08～3.14(m,4H), 2.30(s,3H),2.28(s,3H)；ESI-MS m/z:400.0([M-H]^-)。

Pharmacological examples

Example 18: inhibition effect on human lung adenocarcinoma cells A549 and human large cell lung cancer cells NCI-H460

Positive drug: gefitinib, available from Dalian Meiren Biotechnology Ltd.

Cell lines: human lung adenocarcinoma cells a 549; human large cell lung carcinoma cell NCI-H460 (Shanghai cell Bank of Chinese academy).

Cell culture conditions: RMPI1640 medium: fetal bovine serum 1:9, penicillin: 100 units/ml; streptomycin: 100 units/ml. At 37 ℃ with 5% CO₂Cultivation in constant temperature incubatorAnd (5) breeding and subculturing.

Main reagents for the test: RMPI1640 medium (GIBCO, usa); fetal bovine serum (Hyclone, USA); pancreatin (Sigma, usa); thiazole blue (MTT, Sigma, usa);

main instruments for the test: autoclave SN510C (YAMATO, japan); CO2 incubator (SANYO, Japan), inverted microscope (CKX31, OLYMPUS, Japan), enzyme labeling photometer (MULTISKAN MC, England).

The test method comprises the following steps: the test drug (stock solution concentration: 4mM) was first prepared into a solution of 80. mu.M using RM 1640. After the cells are cultured to a logarithmic growth phase, digesting adherent cells for about 5min by using 0.25% pancreatin digestive juice, adding 10% fetal calf serum RMPI1640 culture medium to stop digestion, blowing and beating the cells into a cell suspension, transferring the cell suspension into a 15ml centrifuge tube, performing 1000-turn centrifugation for 5min (the suspended growing cells do not need to be digested, directly transferring the cell suspension into the 15ml centrifuge tube, performing 1000-turn centrifugation for 5min), discarding the supernatant, adding 10% fetal calf serum RMPI1640 culture medium, blowing and beating the cell suspension uniformly to prepare a single cell suspension, and adjusting the concentration of the cell suspension to be 3.0 multiplied by 10 by uniformly⁴Spreading the cell suspension in a 96-well plate with each well being 200 μ l, each group having 3 wells; 3 wells were left separately and 200. mu.l of 10% fetal bovine serum RMPI1640 medium was added to each well as a blank control. After further culturing for 24h, adding 2 mul of the tested medicine with the concentration of 80 mul into each group of the experimental group; RMPI 16402 μ l was added to the control group; and (3) continuing culturing for 24h, taking out the culture plate 4h before finishing culturing, adding 20 mu l of MTT (methanol to toluene) of 5mg/ml into each hole (keeping out of the sun), continuing culturing, after finishing culturing, absorbing and removing the culture medium, adding 150 mu l of DMSO into each hole, shaking up uniformly, and measuring the absorbance value on a microplate reader at the wavelength of 562 nm. Repeat 3 times.

The cell growth inhibition rate calculation formula is as follows: the growth inhibition rate was ═ 1- (experimental absorbance average-blank absorbance average)/(control absorbance average-blank absorbance average) ] × 100%.

The experiment performed on the compound of the invention shows that the compound has an inhibitory effect on the cell proliferation of human lung adenocarcinoma cells A549 with high EGFR expression and human large cell lung cancer cells NCI-H460, and the inhibition rate is listed as follows:

example 19: inhibition of human breast cancer cells MCF-7

The experimental method comprises the following steps: human breast cancer cell MCF-7 is used as a test cell line and cultured in RPM I-1640 culture solution containing 10% (w) fetal calf serum for 24 hours at 37 ℃ in a CO2 culture box with the volume fraction of 5%. Cells in logarithmic growth phase (1.5X 10) were taken⁴one/mL) was inoculated into a 96-well plate at a concentration of 100. mu. mol. multidot.L per well^-1And measuring the light absorption value of the target compound and the positive control drug tamoxifen at 490nm by using an enzyme-labeling instrument. According to the formula: the cell growth inhibition rate was 1- (number of cells in addition well/number of cells in control well) × 100%, and the cell growth inhibition rate at a concentration of 100 μ M was calculated. The inhibition rates for some samples were as follows:

the experimental result shows that the screened partial compounds have the inhibiting effect on the growth of human breast cancer cells MCF-7 at the concentration of 100 mu M.

In examples 20-40, "active compound" refers to a compound of formula I, or a salt or solvate thereof. The following non-limiting examples illustrate formulations for different topical administration modes. In formulations for transdermal administration, the active compound is generally used in an amount of 0.001 to 0.2% w/w), preferably 0.01 to 0.1% w/w).

Example 20: tablet formulation

25-1000mg of active compound, 45mg of starch, 35mg of microcrystalline cellulose, 4mL of polyvinylpyrrolidone (as a 10% aqueous solution), 4.5mg of sodium carboxymethylcellulose, 0.5mg of magnesium stearate, and 1mg of talc.

Example 21: suspending agent formula

0.1-1000mg of active compound, 50mg of sodium carboxymethylcellulose, 1.25mg of syrup, 0.1mg of sodium benzoate, a proper amount of flavoring agent and a proper amount of coloring agent, and adding pure water to 5 mL.

Example 22: aerosol formulations

0.25mg of active compound, 25-75mL of ethanol and 70mg of propellant 22 (chlorodifluoromethane).

Example 23: suppository formula

250mg of active compound, 2000mL of saturated fatty acid glycerides.

Example 24: injectable formulation

50mg of active compound, 1000mL of isotonic saline solution.

Example 25: ointment formulation

0.025g of micronized active compound, 10g of liquid paraffin, and 100g of soft white wax.

Example 26: ointment formulation

0.025g of active compound, 5g of propylene glycol, 5g of sorbitan sesquioleate, 10g of liquid paraffin and 100g of soft white wax.

Example 27: oil-in-water cream formulation

0.025g of active compound, 5g of cetyl alcohol, 5g of glycerol monostearate, 10g of liquid paraffin, 10002 g g of Ce tomacriol, 0.1g of citric acid, 0.2g of sodium citrate, 35g of propylene glycol and water to 100 g.

Example 28: oil-in-water cream formulation

0.025g of micronized active compound, 15g of soft white wax, 5g of liquid paraffin, 5g of cetyl alcohol, 2g of Sorbimcarol stearate, 0.5g of sorbitan monostearate, 0.2g of sorbic acid, 0.1g of citric acid, 0.2g of sodium citrate, and water to 100 g.

Example 29: water-in-oil cream formulation

0.025g of active compound, 35g of soft white wax, 5g of liquid paraffin, 5g of sorbitan sesquioleate, 0.2g of sorbic acid, 0.1g of citric acid and 0.2g of sodium citrate, and water is added until the weight is 100 g.

Example 30: lotion formulation

0.25g of active compound, 0.5mL of isopropanol, 3mg of carboxyvinyl polymer, a suitable amount of NaOH and water to 1 g.

Example 31: suspension formulation for injection

0.05-10mg of active compound, 7mg of sodium carboxymethylcellulose, 7mg of NaCl, 0.5mg of polyoxyethylene (20) sorbitan monooleate, 8mg of benzyl alcohol, and sterile water to 1 ml.

Example 32: aerosol formulation for oral and nasal inhalation

0.1% w/w active compound, 0.7% w/w sorbitan trioleate, 24.8% w/w trichlorofluoromethane, 24.8% w/w dichlorotetrafluoroethane and 49.6% w/w dichlorodifluoromethane.

Example 33: atomized solution formulation

7mg of active compound, 5mg of propylene glycol, water to 10 g.

Example 34: powder formulations for inhalation

Gelatine capsules were filled with a mixture of the following ingredients, micronised active compound 0.1mg, lactose 20mg and the powder was inhaled with the aid of an inhalation device.

Example 35: powder formulations for inhalation

The spheronized powder was loaded into a multi-dose powder inhaler containing 0.1mg of micronized active compound per dose.

Example 36: powder formulations for inhalation

The spheronized powder was loaded into a multi-dose powder inhaler containing 0.1mg of micronized active compound and 1mg of micronized lactose per dose.

Example 37: capsule formulation

1.0 part of active compound, 321mg of small sugar spheres, 306.6 mg of Aquacoat ECD, 0.5mg of acetyl tributyl citrate, 800.1 mg of Tween-800, 100-5517.5 mg of Eudragit L, 1.8mg of triethyl citrate, 8.8mg of talcum powder and 0.lmg of defoamer MMS.

Example 38: capsule seedling formula

2.0mg of active compound, 305mg of small sugar spheres, Aquocoat ECD 305.0 mg, acetyl tributyl citrate 0.4mg, Tween-800.14 mg, Eudragit NE30D 12.6.6 mg, Eudragit S10012.6 mg, talc 0.l6 mg.

Example 39: enema formula

0.2mg of active compound, 25mg of sodium carboxymethylcellulose, 0.5mg of disodium ethylenediaminetetraacetate, 0.8mg of methylparaben, 0.2mg of propylparaben, 7mg of sodium chloride, 1.8mg of citric acid, 800.01 mg of tween-800, and 1mL of pure water.

Example 40: formulation containing liposome

A. Preparation of the instillation formulation

The synthesized dipalmitoyl lecithin (45mg), dimyristoyl lecithin (7mg), dipalmitoyl phosphatidylglycerol (1mg) and (active compound (5mg) were mixed in a glass tube, and all components were dissolved in chloroform with N₂Adding an aqueous solution (0.9% NaCl) to the lipids, forming liposomes at a temperature above the phase inversion temperature of the lipids, the resulting suspension containing liposomes ranging in size from very small vesicles to 2 μm.

B. Preparation of formulations for inhalation

Liposomes were prepared as in example A, with an aqueous solution containing 10% lactose at a 7:3 lactose to lipid ratio. The liposome suspension was frozen with dry ice and freeze-dried, and the dried product was micronized, and the Mass Mean Aerodynamic Diameter (MMAD) of the resulting particles was about 2 μm.

The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.

Claims (8)

1. A compound of formula (I) and pharmaceutically acceptable salts thereof:

r is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl and halogenated C1-C4 alkoxy.

2. The compound of claim 1, and pharmaceutically acceptable salts thereof:

wherein R is selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy.

3. The compound of claim 1 and pharmaceutically acceptable salts thereof:

wherein, the groups that R together with the phenyl to which it is attached may be independently selected from phenyl, 2-chlorophenyl, 2-ethylphenyl, 4-fluorophenyl, 2-trifluoromethoxyphenyl, 3-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 3-trifluoromethylphenyl.

4. A compound selected from the group consisting of:

2- (4-phenylpiperazin-1-ylcarbonyl) -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (2-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (3-ethylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (4-fluorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (2-trifluoromethoxyphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (2, 4-dimethylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (3-bromophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (2-methyl-6-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (2-methyl-3-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (4-bromophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (4-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (3-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (3-trifluoromethyl-4-chlorophenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (4-methoxyphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (4-methylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (3-trifluoromethylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran;

2- [4- (2, 5-dimethylphenyl) piperazin-1-ylcarbonyl ] -4-hydroxyimino-5, 6-dihydro-4H-thieno [2,3-b ] thiopyran.

5. A process for the preparation of the compounds of claim 1 and pharmaceutically acceptable salts thereof, according to the reaction scheme:

wherein R is as defined in claim 1.

6. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 4 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

7. The use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 6, for the manufacture of a medicament for the treatment of a disease associated with dysregulation of epidermal growth factor receptor signalling, said disease associated with dysregulation of growth factor receptor signalling being cancer.

8. Use according to claim 7, characterized in that: the cancer is non-small cell lung cancer, gastric cancer, breast cancer, ovarian cancer, renal cell carcinoma, colorectal cancer, bladder cancer or head and neck squamous cell carcinoma.