CN103980289B - Thieno-thiopyrano pyrazole compound and pharmaceutical applications thereof - Google Patents

Abstract

The invention belongs to the field of medical technologies, and relates to a thieno-thiopyrano pyrazole compound and pharmaceutical applications thereof. The thieno-thiopyrano pyrazole compound comprises derivatives of the thieno-thiopyrano pyrazole compound and pharmaceutical applicable salts. The thieno-thiopyrano pyrazole compound and salts added by pharmaceutically applicable acids of the compound can be combined with existing drugs or used alone as a lipoxygenase inhibitor, and used for treating related diseases such as chronic dull pains including inflammations, gout, headache, toothache, neuralgia and arthralgia which are relevant to an arachidonic acid metabolizing process.

Description

Thienothiopyranopyrazole compounds and their medical applications

technical field

The invention belongs to the technical field of medicine, and relates to thienothiopyranopyrazole compounds and their application as lipoxygenase inhibitors, and a preparation method thereof.

Background technique

Inflammation is a basic pathological process caused by the body's tissue damage caused by various inflammatory stimuli, and it is also a defense mechanism of the body against infection. Inflammation is mainly manifested as redness, swelling, pain, etc.

For the treatment of inflammation, glucocorticoid anti-inflammatory drugs were widely used in the early days and achieved remarkable results. However, long-term use of glucocorticoids will cause dependence and easily cause side effects such as adrenal cortex decline. Since the emergence of drugs such as Phenylbutazone, Indomethacin and Ibuprofen in the 1950s and 1960s, nonsteroidal anti-inflammatory drugs (NSAIDs) have attracted people's attention , and gradually become the focus of anti-inflammatory drug research and development. In the early 1970s, it was found that the mechanism of action of non-steroidal anti-inflammatory drugs is to inhibit arachidonic acid (Arachidonic Acid, AA) by inhibiting cyclooxygenase (Cycloxygenase, COX) or lipoxygenase (Lipoxygenase, LOX). ) metabolic pathway to achieve the purpose of anti-inflammation.

Inflammation is a complex process, and various factors can generate "inflammatory substances", one of which is related to the metabolic process of arachidonic acid. When the cell membrane is stimulated, phospholipase A ₂ and phospholipase C catalyze the hydrolysis of cell membrane phospholipids to release arachidonic acid, and the metabolism of arachidonic acid in vivo plays an important role in the inflammatory process. The released arachidonic acid can be further biotransformed through two pathways: (1) oxidatively metabolized into prostaglandins (PG) and thromboxanes (Thromboxanes, TX) under the catalysis of cyclooxygenase; Leukotrienes (LT) are generated under the catalysis of oxygenase. There is a certain balance and restriction relationship between the metabolites catalyzed by cyclooxygenase and lipoxygenase. Simply inhibiting one of the metabolic pathways will cause arachidonic acid to enter other metabolic pathways, resulting in the further development of inflammation. Since arachidonic acid can be metabolized to produce inflammatory substances through the two metabolic pathways of cyclooxygenase and lipoxygenase, designing an inhibitor that double blocks cyclooxygenase and lipoxygenase will greatly improve the anti-inflammatory effect. Therefore, the development of inhibitors with dual blocking effects is one of the hot research directions of anti-inflammatory drugs at present.

Contents of the invention

The technical problem solved by the present invention is to provide a compound as shown in formula I or II, its prodrug and pharmaceutically active metabolite and its pharmaceutically acceptable salt, and provide its preparation prevention and treatment lipoxia Drug application for synthase-related diseases.

The present invention is achieved through the following technical solutions:

The compounds involved in the present invention are:

in

n is a natural number such as 1, 2; preferably 1, 2;

R can be H or halogen _;

R can be _hydrogen or halogen;

R ₃ is a benzene ring optionally substituted by 1, 2 or 3 independently selected from H, halogen, -OCH ₃ , -CH ₃ , -CF ₃ , -OCF ₃ , benzhydryl, 4- Chlorobenzhydryl, benzyl;

R ₄ and R ₅ are independently selected from hydrogen, methyl, ethyl, tert-butyl, isopropyl, N,N-diethyl, phenyl, furylmethyl, benzyl, or R ₂ and R ₃ Together with their connected nitrogen atoms, pyrrolidinyl, piperidinyl, N-methylpiperidinyl, morpholinyl, hexamethyleneimino rings are formed.

The present invention also provides the use of the compound described in general formula (I) or (II) in the preparation of medicines for preventing and treating lipoxygenase-related diseases.

The present invention also prefers the following compounds, their prodrugs and pharmaceutically active metabolites, and their pharmaceutically acceptable salts:

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-(4- Methylphenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(diphenyl Methyl)piperazine;

N,N-diethyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-amide;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(3-chloro -4-fluorophenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(4-chloro Phenyl)piperazine;

1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4-(4-tri fluoromethoxyphenyl)piperazine; 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3 -carbonyl)-4-(2-fluorophenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(4-trimethyl Oxyphenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-phenylpiperazine ;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(4-fluoro Phenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4-methylpiperazine ;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-benzylpiperazine ;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4-[(4- Chlorophenyl)(phenyl)methyl]piperazine;

N-tert-butyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c]pyrazole-3-amide;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4-(3-bromo Phenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(4-ethane Oxyphenyl)piperazine;

4-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)morpholine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)pyrrolidine;

N-isopropyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-amide;

N-(2-Diethylamino)ethyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3 - amides;

N,N-Dimethyl-7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiapyrano[4,3-c]pyrazole-3-amide;

N-phenyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-amide; 1-(7- Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)piperidine;

N-benzyl-7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiapyrano[4,3-c]pyrazole-3-amide;

N–(furan-2-ylmethylene)-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3 - amides;

N–(pyridin-2-yl)-7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-amide;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4-(3,5 -ditrifluoromethylphenyl)piperazine;

1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4-(3,4 -difluorophenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(2-methyl phenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(2-chloro Phenyl)piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4-(2,5 - dimethylphenyl) piperazine;

1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4-(3-tri Fluoromethylphenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(benzhydryl Phenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(4-chlorobenzene base) piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-[(4-chloro Phenyl)(phenyl)methyl]piperazine;

N-tert-butyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-methylpiperazine;

N,N-Diethyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(4-methyl Phenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-phenylpiperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(4-trifluoro Methoxyphenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(4-trifluoro Methoxyphenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-benzylpiperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(4-methoxy phenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(3-trifluoro Methylphenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(3-bromobenzene base) piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(3,4- Difluorophenyl)piperazine;

N,N-Dimethyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide;

1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)pyrrolidine;

N-isopropyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide;

N-Benzyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide;

N-phenyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide;

4-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)morpholine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)piperidine;

N-(furan-2-ylmethylene)-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3- amides;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(3-chloro- 4-fluorophenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(2-methyl Phenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(3,5- Ditrifluoromethylphenyl)piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(2-fluorobenzene base) piperazine;

1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-(2-chlorobenzene base) piperazine;

N-tert-butyl-7,8-dibromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-amide;

N,N–Dimethyl-7,8-dibromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-amide .

"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 and II. 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 pharmaceutically acceptable and effective metabolite of the compound of formula I, II.

The present invention also relates to a pharmaceutical composition for inhibiting lipoxygenase, which contains the patented compound or derivative or its pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable carrier.

The term "halogen" as used herein includes chlorine, bromine or fluorine.

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

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.

As a lipoxygenase inhibitor of a new structural type, the compound of the present invention can inhibit cyclooxygenase activity at the same time, and produce a synergistic anti-inflammatory effect by simultaneously blocking the formation of inflammatory mediators prostaglandins and leukotrienes. It is novel in type, and its pharmacodynamic effect is equivalent to or superior to existing drugs. It can be used to treat or prevent chronic dull pain such as inflammation, gout, headache, toothache, neuralgia, and joint pain. It has good application value and development Application prospects.

detailed description

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

The present invention is described in detail with the following examples. However, it should be understood that the present invention is not limited to the specific recited examples below.

Example 1: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-formyl)-4 Preparation of -(4-methylphenyl)piperazine (compound number 01)

Step A: Preparation of 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one

Add 4.64g (0.04mol) of 2-mercaptothiophene into 80mL of tetrahydrofuran, add 11mL of triethylamine and 3.3mL of acrylic acid dropwise under stirring, and heat to reflux for 12h. After cooling slightly, tetrahydrofuran was distilled off. Add 40 mL of ethyl acetate and 20 mL of water, add 6 mol/L hydrochloric acid to adjust the pH to 2, and collect the organic layer. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous magnesium sulfate. Suction filtration and concentration gave a brown oil. Petroleum ether was recrystallized to obtain 6.02 g of white needle-like solid, yield 80.0%, m.p.: 43-45°C.

Add 3.76g (0.02mol) of 3-(thiophene-2-thio)propionic acid into 20mL of dichloromethane, drop in 2 drops of DMF, and under nitrogen protection, add dropwise a solution of oxalyl chloride (2.2mL) in dichloromethane ( 16mL), stirred at room temperature for 1h. The reaction solution was cooled to -10°C in an ice-salt bath, and a dichloromethane solution (10 mL) of tin tetrachloride (1.15 mL) was added dropwise with stirring. After the dropwise addition, stir at 0° C. for 0.5 h. Add 20 mL of water, extract the organic phase, wash the aqueous phase with methylene chloride, and combine the organic phases. Wash with saturated sodium carbonate solution, water and saturated sodium chloride solution successively, and dry over anhydrous magnesium sulfate. After suction filtration, concentration and drying, a yellow solid was obtained. Petroleum ether was recrystallized to obtain 2.59 g of white needle-like solid, yield 76.2%, m.p.: 59.0-60.5°C.

Step B: Preparation of methyl 2-oxo-2-(4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-yl)acetate

Sodium metal (0.46 g) was added into 20 mL of anhydrous methanol, stirred until the sodium solid disappeared, and concentrated to remove methanol to obtain white sodium methoxide. Dimethyl oxalate (2.36 g, 0.02 mol), toluene (20 mL), 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one (1.70 g, 0.01mol), after stirring at room temperature for 24 h, the reaction solution was poured into about 100 mL of ice water, and the aqueous phase was extracted. The organic phase was extracted with 20 mL of 10% sodium hydroxide solution. The aqueous phases were combined, washed 3 times with anhydrous ether, adjusted to pH 1 with 6 mol/L hydrochloric acid, a yellow solid was precipitated, filtered with suction, and dried to obtain 2.0 g of a yellow solid with a yield of 79.8%, m.p.: 93.5-95.2°C.

Step C: Preparation of methyl 7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carboxylate

Add 2-oxo-2-(4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-yl)methyl acetate (0.51 g, 2 mmol) to 10 mL In glacial acetic acid, add hydrazine hydrate (2mL, 3.2mmol) while stirring, and heat to reflux for 12h. After cooling, the reaction solution was poured into 200 mL of ice water with stirring, and a white solid was precipitated, which was obtained by suction filtration. Glacial acetic acid-water solution was recrystallized to obtain 0.32 g of white solid, yield 63.2%, m.p.: 94.0-95.7°C.

Add 1,4-dihydrothieno[3',2':5,6]thiopyro[4,3-c]pyrazole-3-carboxylic acid methyl ester (2.52g, 0.01 mol), 50mL glacial acetic acid and 5mL water, add bromine (2.08g, 0.013mol) dropwise under ice-bath cooling and stirring, and react at room temperature for 24h after the dropwise addition. The reaction solution was poured into 200 mL of ice water, and a white solid was precipitated, which was filtered by suction to obtain 2.52 g of a white solid, with a yield of 76.0%.

Step D: Preparation of 7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carboxylic acid

Add 0.62g (2mmol) 1-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carboxylate to a 100mL round bottom flask Acid methyl ester, 20mL water and 0.4g sodium hydroxide, heated to reflux for 2h. The pH of the reaction solution was adjusted to 2 with 18% hydrochloric acid, a white solid was precipitated, and 0.57 g of a white solid was obtained by suction filtration, with a yield of 90.0%.

Step E: Preparation of 4,5,6,7-tetrahydrothieno[2,3-b]thiapin-4-one

Add sodium (3.34g, 0.145mol) into 120mL of absolute ethanol at room temperature, cool down after the sodium completely disappears, add 2-mercaptothiophene (9.8g, 0.1mol), stir at room temperature for about 30min, the reaction solution turns dark red . - Butyrolactone (11.53 mL, 0.15 mol) was added, heated to reflux for about 19 h under nitrogen protection, and the reaction solution became viscous. The product was distilled under reduced pressure to remove ethanol. The remaining solid was washed with about 100 mL of petroleum ether and ethyl acetate (V:V=3:1). The washed solid was added to cooled 1N hydrochloric acid, and a dark red oil was precipitated at the bottom layer. After extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration and concentration afforded a brown oil. Petroleum ether was recrystallized to obtain 8.08 g of white crystals with a yield of 40.0%. m.p.: 40-42°C.

Add 4-(thiophene-2-thio)butyric acid (4.04 g, 0.02 mol) and 25 mL of dichloromethane into a 250 ml three-necked flask. Under the protection of nitrogen, a dichloromethane solution (25 mL) of oxalyl chloride (5.4 mL, 0.06 mol) was added dropwise, and the reaction solution became pale yellow-green, and was stirred for 2 h after the addition. Under the condition of nitrogen protection and ice bath, a dichloromethane solution (20ml) of tin tetrachloride (2.3mL, 0.02mol) was slowly added dropwise, and the reaction solution was dark green. Stir at room temperature for 24h. Add 50ml of hydrochloric acid (V:V=1:1), and stir until no gas is released. The organic layer was washed with water until the pH was near neutral and the organic layer turned orange-yellow. The organic layer was washed with saturated NaCl solution and dried over anhydrous magnesium sulfate. Filter and concentrate to obtain a yellow oil. Petroleum ether was recrystallized to obtain 0.92 g of white crystals, with a yield of 25%. m.p.: 60-62°C.

Step F: Preparation of 4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carboxylic acid

Sodium (0.46 g, 0.02 mol) was added into anhydrous methanol (20 mL), stirred until the sodium solid disappeared, and concentrated to obtain white sodium methoxide. Dimethyl oxalate (2.36 g, 0.02 mol), 4,5,6,7-tetrahydrothieno[2,3-b]thia-5-one (1.84 g, 0.01 mol) and Toluene (20 mL), stirred at room temperature for 40 h. The reaction solution was poured into about 100 mL of ice water, the water layer was taken, the organic layer was extracted with 10% NaOH aqueous solution, and the water layers were combined. The aqueous layer was washed with ether. 18% hydrochloric acid was adjusted to pH=2 to obtain a yellow turbid liquid. After cooling and standing, a red oily substance was precipitated, and 1.62 g of red powder was obtained by recrystallization of petroleum ether, with a yield of 60.0%.

Add methyl (4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thia-5-yl)acetone (0.54 g, 2.0 mmol) into 10 mL of glacial acetic acid , and then added hydrazine hydrate (2mL, 0.032mol), heated to reflux for 3h. The reaction solution was poured into ice water (50 g), and a yellow solid was precipitated, which was filtered and dried to obtain 0.40 g of light yellow powder with a yield of 75.0%. m.p.: 98-100°C.

Add 4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carboxylic acid methyl ester (5.32g , 20mmol), 300mL of water and sodium hydroxide (1g, 25mmol), heated to reflux for 2h. The pH of the reaction solution was adjusted to 2 with 18% hydrochloric acid, and a white solid was precipitated, which was filtered by suction and dried to obtain 4.54 g of a white solid with a yield of 90.0%. Step G: 1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-formyl)-4- Preparation of (4-methylphenyl)piperazine

General method: Add 7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carboxylic acid into a 50mL round bottom flask or 4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carboxylic acid (4mmol), 1-substituted piperazine salt salt (4.2mmol) or other substituted amines (4.2mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1g, 5mmol), 1-hydroxybenzotri Add azole (0.1g, 0.74mmol) into 20mL of dry dichloromethane, add 2mL of triethylamine dropwise, stir at room temperature for 48h, filter, and wash the filtrate with 18% hydrochloric acid, saturated sodium carbonate and saturated sodium chloride successively. The organic phase was extracted and dried over anhydrous magnesium sulfate. Filtration and concentration gave a crude product, which was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target compound.

Synthesized according to the general method to obtain 0.77 g of white solid with a yield of 35%. mp:175-176℃; IR(KBr,cm ^-1 ):3420,2921,2851,1607,1451,1384,1262,1154,1027,997,877,831,705; ¹ H-NMR(600MHz,CDCl ₃ ):2.44(4H ,m),3.79(4H,m),4.16(2H,s),4.25(1H,s),7.19(2H,d,J=8.4Hz),7.28(4H,dd,J=7.2Hz,8.4Hz ), 7.41 (4H, d, J = 7.2 Hz); ESI-MS (m/z): 551.2 [M+H] ⁺ .

Example 2: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (diphenylmethyl)piperazine (compound number 02)

According 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-(diphenylmethyl)piperazine 0.77g, yield 35%. mp:175-176℃; IR(KBr,cm ^-1 ):3420,2921,2851,1607,1451,1384,1262,1154,1027,997,877,831,705; ¹ H-NMR(600MHz,CDCl ₃ ):δ2.44 (4H,m),3.79(4H,m),4.16(2H,s),4.25(1H,s),7.19(2H,d,J＝8.4Hz),7.28(4H,dd,J＝7.2Hz, 8.4 Hz), 7.41 (4H, d, J = 7.2 Hz); ESI-MS (m/z): 551.2 [M+H] ⁺ .

Example 3: N,N-diethyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3- Preparation of amides (compound number 03)

According to the method of Example 1, N,N-diethyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c]pyridine was prepared Azole-3-amide (Compound No. 03) 0.75 g, yield 50%. mp: 147-148℃; IR (KBr, cm ^-1 ): 3212, 2958, 2917, 2849, 1735, 1583, 1535, 1508, 1485, 1461, 1375, 1215, 1159, 967, 849; ¹ H-NMR (600MHz ,CDCl ₃ ):δ1.25(6H,m),3.54(4H,m),4.12(2H,s),7.72(1H,s); ESI-MS(m/z):372.0,374.0[M+ H] ⁺ .

Example 4: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (3-chloro-4-fluorophenyl)piperazine

According to the method of Example 1, 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-methan Acyl)-4-(3-chloro-4-fluorophenyl)piperazine (Compound No. 04) 0.72 g, yield 36%. mp: 120℃; IR (KBr, cm ^-1 ): 3233, 2924, 2853, 1745, 1609, 1586, 1502, 1464, 1382, 1223, 1154, 998; ¹ H-NMR (600MHz, CDCl ₃ ): δ3 .16(4H,t,J=6.0Hz),3.95(4H,t,J=6.0Hz),4.26(2H,s),6.79(1H,m),6.95(1H,dd,J=6.3Hz, J=2.4Hz), 7.05 (1H, dd, J=8.7Hz, J=9Hz), 7.25(1H,s); ESI-MS (m/z): 512.8, 514.9, 517.0 [M+H] ⁺ .

Example 5: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (4-chlorophenyl)piperazine

According 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-chlorophenyl)piperazine (Compound No. 05) 0.50 g, yield 25%. mp: 235°C; IR (KBr, cm ^-1 ): 3159.9, 2918.2, 2849.7, 1740.4, 1590.8, 1496.6, 1480.7, 1441.4, 1387.7, 1234.2, 120.6, 1151.0, 998.1, 810.2; ¹ H-NMR (600MHz, -d ₆ ):δ3.10(4H,m),3.51(4H,m),4.26(2H,s),7.21(1H,s),7.56(2H,d,J＝5.4Hz),7.58(2H , d, J = 5.4 Hz), 13.29 (1H, s); ESI-MS (m/z): 497.3, 495.4, 499.2 [M+H] ⁺ .

Example 6: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (4-trifluoromethoxyphenyl)piperazine

According 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-trifluoromethoxyphenyl)piperazine (Compound No. 06) 0.92 g, yield 42%. mp: 228-230℃; IR (KBr, cm ^-1 ): 3240, 2919, 2850, 1730, 1605, 1532, 1510, 1475, 1386, 1368, 1327, 1272, 1153, 1028, 1004; ¹ H-NMR (600MHz,DMSO-d ₆ ):δ3.33(8H,m),4.27(2H,s),7.03(2H,d,J＝8.6Hz),7,20(2H,d,J＝8.6Hz) , 7.56 (1H, s), 13.84 (1H, s); ESI-MS (m/z): 547.0, 545.1 [M+H] ⁺ .

Example 7: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (2-fluorophenyl)piperazine

According 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-(2-fluorophenyl)piperazine (Compound No. 07) 0.75 g, yield 39%. mp: 78-80°C; IR (KBr, cm ^-1 ): 3221, 2921, 2851, 1720, 1641, 1500, 1446, 1394, 1385, 1287, 1240, 1151, 999; ¹ H-NMR (600MHz, CDCl ₃ ): δ3.11(4H,t,J=10.2Hz),4.02(4H,t,J=10.2Hz),4.24(2H,s),7.02(3H,m),7.23(1H,s), 7.38 (1H, d, J = 7.8 Hz); ESI-MS (m/z): 479.1, 481.0 [M+H] ⁺ .

Example 8: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (4-trimethoxyphenyl)piperazine

According 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-trimethoxyphenyl)piperazine (Compound No. 08) 0.87g, yield 44%. mp: 90℃; IR (KBr, cm ^-1 ): 2922, 1730, 1618, 1511, 1446, 1379, 1255, 1224, 1186, 1137, 1096, 1034, 992, 816; ¹ H-NMR (600MHz, CDCl ₃ ) :δ3.13(4H,m),3.99(7H,m),4.28(2H,s),6.85(2H,dd,J＝7.2Hz,2.4Hz),6.91(2H,dd,J＝7.2Hz, 2.4 Hz), 7.24 (1H, s); ESI-MS (m/z): 491.1, 493.2 [M+H] ⁺ .

Example 9: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4- Preparation of phenylpiperazine

According 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-phenylpiperazine (Compound No. 09) 0.85 g, yield 43%. mp: 112°C; IR (KBr, cm ^-1 ): 2923, 2853, 1619, 1517, 1499, 1468, 1377, 1276, 1154, 992, 832; ¹ H-NMR (600MHz, CDCl ₃ ): δ3.26 (4H ,t),4.01(4H,t),4.27(2H,s),6.91(1H,d,J=7.8Hz),6.96(2H,d,J=7.8Hz),7,28(2H,dd, J = 7.8 Hz, 7.8 Hz), 7.25 (1H, s); ESI-MS (m/z): 461.1, 463.1 [M+H] ⁺ .

Example 10: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (4-fluorophenyl)piperazine

According 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-fluorophenyl)piperazine (Compound No. 10) 0.67g, yield 35%. mp:185-186℃; IR(KBr,cm ^-1 ):3443,2922,2852,1605,1507,1443,1384,1225,1116; ¹ H-NMR(600MHz,CDCl ₃ ):δ3.19(4H ,t),4.04(4H,t),4.24(2H,s),7.00(4H,m),7.24(1H,s); ESI-MS(m/z):479.1,481.0[M+H] ⁺ .

Example 11: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4- Preparation of Methylpiperazine

According 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-methylpiperazine (Compound No. 11) 0.95 g, yield 60%. mp: 220-222℃; IR(KBr, cm ^-1 ): 3424.0, 2917.8, 849.5, 1704.1, 1465.5, 1433.1, 1383.9, 1296.8, 1204.9, 940.2; ¹ H-NMR(600MHz, CDCl ₃ ): δ2.36 (3H,s),2.51(4H,t),3.86(4H,t),4.19(2H,s),7.28(1H,s); ESI-MS(m/z):399.2,401.2[M+H ] ⁺ .

Example 12: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carbonyl)-4- Preparation of benzylpiperazine

According 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-benzylpiperazine (Compound No. 12) 0.89 g, yield 47%. mp: 180°C; IR (KBr, cm ^-1 ): 3422, 3206, 2918, 2850, 1730, 1601, 1509, 1446, 1384, 1266, 1126, 1029, 999; ¹ H-NMR (600MHz, CDCl ₃ ) :δ2.50(4H,t),3.54(2H,s),3.77(4H,t),4.28(2H,s),7.24(1H,s),7.31(5H,m); ESI-MS(m /z):474.9,477.1[M+H] ⁺ .

Example 13: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of [(4-chlorophenyl)(phenyl)methyl]piperazine

According 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-chlorophenyl)(phenyl)methyl]piperazine (Compound No. 13) 0.89 g, yield 38%. mp:212-214℃; IR(KBr,cm ^-1 ):3442,2920,2851,1602,1452,1384,1126,998; ¹ H-NMR(600MHz,CDCl ₃ ):δ2.44(4H,m ),3.79(4H,m),4.16(2H,s),4.25(1H,s),7.22(2H,m),7,25(1H,s),7.27(1H,m),7.29(2H, dd, J = 7.8 Hz, 7.8 Hz), 7.37 (4H, m); ESI-MS (m/z): 584.9, 586.8 [M+H] ⁺ .

Example 14: Preparation of N-tert-butyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-amide preparation

According to the method of Example 1, N-tert-butyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole- 3-amide (Compound No. 14) 1.12 g, yield 75%. mp: 205-207℃; IR (KBr, cm ^-1 ): 3364, 3201, 2919, 1638, 1553, 1526, 1492, 1450, 1385, 1296, 1220, 1167, 969, 863; ¹ H-NMR (600MHz, CDCl ₃ ): δ1.49(9H,s),4.49(2H,s),7,21(1H,s),7.40(1H,s); ESI-MS(m/z):372.0,374.2[M+ H] ⁺ .

Example 15: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (3-bromophenyl)piperazine

According 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-(3-bromophenyl)piperazine (Compound No. 15) 0.82 g, yield 38%. mp: 150-151°C; IR (KBr, cm ^-1 ): 3418.7, 3217.5, 2920.0, 2850.7, 1590.4, 1480.6, 1442.9, 1384.6, 1224.6, 1157.9, 999.9, 938.2, 764.3; ¹ H-NMR (600MHz, CDCl ₃ ): δ3.25(4H,m),4.00(4H,m),4.26(2H,s),6.85(1H,m),7.01(1H,m),7.06(1H,m),7.13(1H , m), 7.23 (1H, s); ESI-MS (m/z): 538.9, 540.8, 542.9 [M+H] ⁺ .

Example 16: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (4-ethoxyphenyl)piperazine

According 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) 0.89 g, yield 44%. mp: 178-180℃; IR(KBr, cm ^-1 ): 3443.4, ^2918.4 , 2850.2, 1618.7, 1511.5, 1446.0, 1384.5, 1273.2, 1254.0, 1224.2, 1137.0, 1021.6, 993.6, 834.2, 816.7MR; (600MHz, CDCl ₃ ): δ1.40(3H,t),3.13(4H,t),3.99(6H,m),4.28(2H,s),6.85(2H,dd,J＝7.2Hz,2.4Hz ), 6.91 (2H, dd, J = 7.2Hz, 2.4Hz), 7.24 (1H, s); ESI-MS (m/z): 505.3, 507.3 [M+H] ⁺ .

Example 17: 4-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)morpholine preparation

According to the method of Example 1, 4-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c]pyrazole-3-carbonyl was obtained ) Morpholine (Compound No. 17) 0.76g, yield 49%. mp: 150°C; IR (KBr, cm ^-1 ): 3444.9, 3169.7, 2918.2, 2850.3, 1729.9, 1592.2, 1441.1, 1266.5, 1148.2, 1113.9, 1000.1, 969.6, 844.0; ¹ H-NMR (600MHz, DMSO-d ₆ ): δ3.61(4H,t),3.96(4H,t),4.28(2H,s),7.42(1H,s),13.59(1H,s);ESI-MS(m/z):388.2 [M+H] ⁺ .

Example 18: 1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)pyrrolidine preparation

According 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 ) pyrrolidine (Compound No. 18) 0.77 g, yield 52%. mp: 220°C; IR (KBr, cm ^-1 ): 3442.7, 2920.1, 2851.2, 1606.7, 1575.4, 1508.2, 1454.8, 1384.3, 1156.9, 969.2, 844.5; ¹ H-NMR (600MHz, DMSO-d ₆ ): δ1 .81(2H,t),1.87(2H,t),3.46(2H,t),3.84(2H,t),4.37(2H,s),7.42(1H,s),14.57(1H,s); ESI-MS (m/z): 370.1, 372.3 [M+H] ⁺ .

Example 19: Preparation of N-isopropyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-amide preparation

According to the method of Example 1, N-isopropyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole- 3-amide (Compound No. 19) 0.99g, yield 69%. mp: 189-190°C; IR (KBr, cm ^-1 ): 3400.5, 3207.5, 2974.5, 2921.3, 1637.4, 1556.3, 1528.3, 1452.1, 1384.6, 1175.4, 967.5, 836.5; ¹ H-NMR (600MHz, DMSO-d ₆ ): δ4.50(1H,m),4.39(2H,s),7.50(1H,s),8.08(1H,s); ESI-MS(m/z):357.1,359.1[M+H] ⁺ .

Example 20: N-(2-diethylamino)ethyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c] Preparation of pyrazole-3-amides

According to the method of Example 1, N-(2-diethylamino)ethyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4, 3-c] Pyrazole-3-amide (Compound No. 20) 1.06 g, yield 64%. mp: 165-167℃; IR (KBr, cm ^-1 ): 3420.4, 2968.1, 2921.8, 1635.0, 1556.8, 1528.9, 1456.6, 1384.3, 1124.4, 968.5, 831.9; ¹ H-NMR (600MHz, CDCl ₃ ): δ1 .07(6H,t),2.68(4H,m),2.77(2H,t),3.55(2H,t),4.43(2H,s),7.21(1H,s),8.05(1H,s); ESI-MS (m/z): 415.3 [M+H] ⁺ .

Example 21: N,N-Dimethyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3- Preparation of amides

According to the method of Example 1, N,N-dimethyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c]pyridine was prepared Azole-3-amide (Compound No. 21) 0.94 g, yield 68%. mp: 220°C; IR (KBr, cm ^-1 ): 3443.5, 3205.2, 2920.4, 1612.5, 1536.4, 1485.5, 1420.6, 1384.3, 1259.4, 1160.8, 1101.3, 966.7, 822.5; ¹ H-NMR (600MHz, DMSO-d ₆ ): δ2.97(6H,s),4.26(2H,s),7.43(1H,s),13.54(1H,s); ESI-MS(m/z):344.2,346.3[M+H] ⁺ .

Example 22: Preparation of N-phenyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-amide

According to the method of Example 1, N-phenyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3 was prepared - Amide (Compound No. 22) 0.47g, yield 30%. mp: 190-191°C; IR (KBr, cm ^-1 ): 3443.8, 2919.8, 2850.5, 1730.5, 1612.4, 1555.1, 1441.0, 1384.2, 1296.2, 1114.0, 1038.4, 778.5; ¹ H-NMR (600MHz, DMSO-d ₆ ): δ4.42(2H, s), 7.40(5H, m), 7.42(1H, s), 8.82(1H, s), 13.64(1H, s); ESI-MS(m/z): 415.3 ,417.3[M+Na] ⁺ .

Example 23: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)piperidine preparation

According 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 ) piperidine (Compound No. 23) 0.95 g, yield 62%. mp: 196-198°C; IR (KBr, cm ^-1 ): 3442.6, 2931.0, 2852.9, 1603.1, 1570.1, 1538.8, 1445.3, 1384.3, 274.9, 1112.4, 966.6, 851.8; ¹ H-NMR (600MHz, CDCl ₃ ) :δ1.66(6H,m),3.72(4H,t),4.14(2H,s),7.30(1H,s); ESI-MS(m/z):384.2,386.3[M+H] ⁺ , 406.2, 408.4 [M+Na] ⁺ .

Example 24: Preparation of N-benzyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c]pyrazole-3-amide

According to the method of Example 1, N-benzyl-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3 - Amide (Compound No. 24) 0.91 g, yield 56%. mp: 98-100℃; IR(KBr, cm ^-1 ): 3421.9, 2920.9, 2851.7, 1629.7, 1446.5, 1384.2, 1274.3, 1114.1, 850.9; ¹ H-NMR(600MHz, DMSO-d ₆ ): δ4.40 (2H,d),4.42(2H,s),7.40(5H,m),7.42(1H,s),8.82(1H,s),13.64(1H,s); ESI-MS(m/z): 408.3[M+H] ⁺ , 430.1[M+Na] ⁺ .

Example 25: N–(furan-2-ylmethylene)-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c] Preparation of pyrazole-3-amides

According to the method of Example 1, N-(furan-2-ylmethylene)-7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyro[4, 3-c] Pyrazole-3-amide (Compound No. 25) 0.62 g, yield 39%. mp: 89-90℃; IR(KBr, cm ^-1 ): 3444.2, 2921.3, 2851.3, 16307, 1440.4, 1384.0, 1236.2, 1112.3, 1089.9, 975.6, 737.9; ¹ H-NMR(600MHz, CDCl ₃ ): δ4 .22(2H,s),4.60(2H,d),6.29(1H,d,J=6Hz),6.33(1H,d,J=6Hz),7.20(1H,dd,J=6Hz,6Hz), 7.25 (1H, s); ESI-MS (m/z): 395.3, 397.2 [M+H] ⁺ , 418.3, 420.1 [M + Na] ⁺ .

Example 26: N–(pyridin-2-yl)-7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole- Preparation of 3-amides

According to the method of Example 1, N–(pyridin-2-yl)-7-bromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c ] Pyrazole-3-amide (Compound No. 26) 0.49 g, yield 31%. mp: 83-84℃; IR(KBr, cm ^-1 ): 3421.0, 2921.4, 2851.5, 1630.3, 1445.7, 1384.2, 1274.8, 1126.2; ¹ H-NMR(600MHz, CDCl ₃ ): δ4.31(2H,s ), .6.50(1H,d,J=8.2Hz),6.65(1H,m),7.42(2H,m),8.07(1H,d,J=4.8Hz); ESI-MS(m/z): 395.2[M+H] ⁺ .

Example 27: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (3,5-ditrifluoromethylphenyl)piperazine

According 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-(3,5-bistrifluoromethylphenyl)piperazine (Compound No. 27) 1.08g, yield 45%. mp: 220-221°C; IR (KBr, cm ^-1 ): 3421.2, 2918.2, 1610.2, 1581.2, 1485.5, 1400.4, 1275.0, 1175., 1131.4, 995.3, 963.6, 862.4; ¹ H-NMR (600MHz, DMSO- d ₆ ): δ3.45(4H,t),3.77(2H,t),4.14(2H,t),4.31(2H,s),7.33(1H,s),7.45(1H,s),7.50( 2H, s), 13.64 (1H, s); ESI-MS (m/z): 596.9, 599.1 [M+H] ⁺ , 619.1, 621.0 [M+Na] ⁺ .

Example 28: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (3,4-difluorophenyl)piperazine

According 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-(3,4-difluorophenyl)piperazine (Compound No. 28) 0.88g, yield 44%. mp: 190-192℃; IR(KBr, cm ^-1 ): 3444.2, 2919.8, 1656.7, 1560.4, 1417.7, 1384.3, 1276.6, 1116.2; ¹ H-NMR(600MHz, DMSO-d ₆ ): δ3.15(4H ,t),3.72(4H,t),4.27(2H,s),6.75(1H,m),7.03(1H,m),7.25(1H,d,J=9.6Hz),7.45(1H,s) ; ESI-MS (m/z): 518.9, 521.0 [M+Na] ⁺ .

Example 29: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (2-methylphenyl)piperazine

According 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-(2-methylphenyl)piperazine (Compound No. 29) 0.91 g, yield 48%. mp: 167-170℃; IR(KBr, cm ^-1 ): 3442.6, ^2920.4 , 2851.6, 1621.6, 1491.9, 1443.3, 1384.0, 1327.3, 1274.9, 1224.2, 1126.5, 1021.8, 1000.2, 762.3; 61 H-NMR ( , CDCl ₃ ): δ2.35(3H,s),2.98(4H,t),3.97(4H,t),4.23(2H,s),7.01(2H,m),7.20(2H,m),7.25 (1H,s); ESI-MS (m/z): 475.1, 476.4 [M+H] ⁺ .

Example 30: 1-(7-bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (2-chlorophenyl)piperazine

According 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-(2-Chlorophenyl)piperazine (Compound No. 30) 0.73g, yield 37%. mp: 185-186℃; IR(KBr, cm ^-1 ): 3444.2, 2920.3, 2851.4, 1610.1, 1478.0, 1384.4, 1265.9, 1227.6, 1124.4, 1022.3; ¹ H-NMR(600MHz, CDCl ₃ ): δ3.11 (4H,t),4.02(4H,t), 4.24(2H,s),7.02(3H,m),7.23(1H,s),7.38(1H,d,J＝7.8Hz); ESI-MS( m/z): 495.1, 497.1 [M+H] ⁺ .

Example 31: 1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (2,5-Dimethylphenyl)piperazine

According 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-(2,5-dimethylphenyl)piperazine (Compound No. 31) 0.92 g, yield 47%. mp:150-152℃; IR(KBr,cm ^-1 ):3443.5,2919.6,2850.9,1606.7,1457.4,1384.1,1125.3; ¹ H-NMR(600MHz,CDCl ₃ ):δ2.29(3H,s), 2.30(3H,s),2.95(4H,t),3.96(4H,t),4.27(2H,s),6.82(1H,s),6.84(1H,d,J＝7.2Hz),7.08(1H , d, J = 7.2 Hz), 7.25 (1H, s); ESI-MS (m/z): 489.1, 491.1 [M+H] ⁺ .

Example 32: 1-(7-Bromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-carbonyl)-4- Preparation of (3-trifluoromethylphenyl)piperazine

According 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-(3-trifluoromethylphenyl)piperazine (Compound No. 32) 0.95 g, yield 45%. mp: 185-186℃; IR(KBr, cm ^-1 ): 3444.9, 3219.1, 2918.2, 2849.8, 1591.1, 1444.4, 1384.4, 1349.9, 1319.6, 1269.0, 1222.1, 1163.5, 1112.2, 1075.2, 9499.4, 949.6, 785.5; ¹ H-NMR (600MHz, DMSO-d ₆ ): δ3.31(8H, t), 4.27(2H, s), 7.09(d, J=7.7Hz, 1H), 7.24(d, J=8.4 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.50 (1H, s); MS (m/z): 427.2, 429.0 [MH] ⁺ .

Example 33: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of benzhydryl phenyl) piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(Benzhydrylphenyl)piperazine (Compound No. 33) 0.74 g, yield 38%. mp: 138-139℃; IR(KBr, cm ^-1 ): 3422.1, 3207.1, 2919.3, 2851.1, 1617.2, 1491.3, 1448.8, 1384.3, 1285.9, 1242.7, 1142.9, 995.3, 859.8, 747.1, 706-NMR; ¹ H (600MHz, CDCl ₃ ): δ2.44(4H,t),3.08(2H,t),3.47(2H,t),3.76(4H,t),5.25(1H,s),7.19(2H,d, J=7.2Hz),7.22(1H,d,J=5.4Hz),7.26(1H,d,J=5.4Hz),7.28(4H,t,J=7.2Hz),7.41(4H,d,J= 7.2 Hz); MS (m/z): 487.2 [M+H] ⁺ .

Example 34: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 4-chlorophenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(4-Chlorophenyl)piperazine (Compound No. 34) 0.60 g, yield 35%. mp: 140-141℃; IR(KBr, cm ^-1 ): 3381.8, 2920.9, 2850.4, ^1613.8 , 1493.2, 1440.8, 1383.9, 1342.3, 1270.7, 1230.9, 1155.5, 1021.5, 998.6, 883.5, 860.0, 81 H -NMR (600MHz, CDCl ₃ ): δ3.10(2H,t), 3.21(4H,t), 3.47(2H,t), 3.94(4H,t), 6.90(2H,d,J=9.0Hz) ,7.12(2H,d,J=9.0Hz),7.23(1H,d,J=5.4Hz),7.26(1H,d,J=5.4Hz); MS(m/z):431.1[M+H] ⁺ .

Example 35: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-[ Preparation of (4-chlorophenyl)(phenyl)methyl]piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-[(4-Chlorophenyl)(phenyl)methyl]piperazine (Compound No. 35) 0.87g, yield 42%. mp: 142-143°C; IR (KBr, cm ^-1 ): 3432.2, 2919.3, 2851.4, 1618.6, 1488.1, 1445.5, 1384.4, 1286.8, 1241.9, 1142.8, 995.7, 860.1, 757.4, 719.2; ¹ H-NMR (600 MHz , CDCl ₃ ): δ2.32(4H,t), 3.02(2H,t), 3.38(2H,t), 3.68(4H,t), 4.16(1H,s), 7.12(d,J＝5.4Hz ,1H),7.19(d,J=5.4Hz,1H),7.24(3H,m),7.28(2H,d,J=5.4Hz),7.33(4H,m); MS(m/z):521.2 [M+H] ⁺ .

Example 36: Preparation of N-tert-butyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide

According to the method of Example 1, N-tert-butyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3 - Amide (Compound No. 36) 0.64 g, yield 52%. mp: 170-171℃; IR(KBr, cm ^-1 ): 3393.2, 3253.5, ^2962.0 , 2921.2, 2851.0, 1644.8, 1521.4, 1484.0, 1384.6, 1363.0, 1258.8, 1217.8, 1124.6, 1053.3, 875 H.2, -NMR (600MHz, CDCl ₃ ): δ1.47 (9H, s), 3.10 (2H, t), 3.69 (2H, t), 7.21 (1H, d, J=5.4Hz), 7.24 (1H, d, J = 5.4 Hz); MS (m/z): 308.2 [M+H] ⁺ .

Example 37: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-methanol Preparation of base piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-Methylpiperazine (Compound No. 37) 0.60 g, yield 45%. mp: 107-108℃; IR(KBr, cm ^-1 ): 3429.0, 3228.4, 2915.6, 2792.8, 1608.8, 1504.8, 1439.5, 1352.5, 1290.1, 1253.7, 1225.3, 1142.0, 997.9, 861.7, ¹ H-NMR; (600MHz, CDCl ₃ ): δ2.33(3H,s),2.46(4H,t),3.10(2H,t),3.46(2H,t),3.91(4H,t),7.23(1H,d, J=5.4Hz,), 7.26 (1H,d, J=5.4Hz); MS (m/z): 335.2[M+H] ⁺ .

Example 38: N,N-Diethyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide preparation of

According to the method of Example 1, N,N-diethyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole was prepared -3-amide (Compound No. 38) 0.69 g, yield 56%. mp:183-185℃; IR(KBr,cm ^-1 ):3443.6, ^3200.5 , 2929.8, 1601.5, 1509.2, 1479.3, 1374.1, 1284.1, 1262.2, 1195.5, 1127.7, 1092.8, 1073.0, 1015.8, 881.0, -NMR (600MHz, CDCl ₃ ): δ1.24(6H,t), 3.10(2H,t), 3.42(2H,t), 3.54(4H,m), 7.22(1H,d,J=5.4Hz) , 7.25 (1H, d, J = 5.4 Hz); MS (m/z): 308.2 [M+H] ⁺ .

Example 39: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 4-methylphenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained - 0.71 g of 4-(4-methylphenyl)piperazine (Compound No. 39), yield 43%. mp: 186-187℃; IR(KBr, cm ^-1 ): 3124.2, 2916.4, 1631.5, 1579.3, 1513.5, 1443.3, 1384.4, 1340.9, 1264.6, 1236.5, 1203.3, 1154.1, 1016.6, 999.2, 1116.3, ⁸ ; -NMR (600MHz, CDCl ₃ ): δ2.28(3H,s), 3.10(2H,t), 3.18(4H,t), 3.47(2H,t), 3.93(4H,t), 6.85(2H, d, J = 8.4Hz), 7.10 (2H, d, J = 8.4Hz), 7.23 (1H, d, J = 5.4Hz), 7.27 (1H, d, J = 5.4Hz); MS (m/z) :411.2[M+H] ⁺ .

Example 40: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-benzene Preparation of base piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-Phenylpiperazine (Compound No. 40) 0.75 g, yield 47%. mp: 74-75℃; IR(KBr, cm ^-1 ): 3441.7, 3209.2, 2920.5, 2851.6, 1599.6, 1495.6, 1444.2, 1384.1, 1260.4, 1230.6, 1153.3, 1016.0, 998.3, 875.4, 759-NMR; ¹ H (600MHz, CDCl ₃ ): δ3.10(2H,t),3.20(1H,t),3.27(4H,t),3.47(1H,t),4.02(4H,t),6.90(1H,m) ,6.95(2H,m),7.23(1H,d,J=5.4Hz),7.28(1H,d,J=5.4Hz),7.29(2H,m); MS(m/z):397.2[M+ H] ⁺ .

Example 41: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 4-trifluoromethoxyphenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(4-trifluoromethoxyphenyl)piperazine (Compound No. 41) 0.85 g, yield 44%. mp: 85-86℃; IR(KBr, cm ^-1 ): 3441.7, 3209.2, 2920.5, 2851.6, 1599.6, 1495.6, 1444.2, 1384.1, 1260.4, 1230.6, 1153.3, 1016.0, 998.3, 875.4, 759-NMR; ¹ H (600MHz, CDCl ₃ ): δ3.10(2H,t),3.21(4H,t),3.47(2H,t),3.94(4H,t),6.90(2H,d,J＝9.0Hz),7.12 (2H, d, J = 9.0 Hz), 7.23 (1 H, d, J = 5.4 Hz), 7.26 (1 H, d, J = 5.4 Hz); MS (m/z): 481.1 [M+H] ⁺ .

Example 42: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 4-trifluoromethoxyphenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(4-trifluoromethoxyphenyl)piperazine (Compound No. 42) 0.75 g, yield 45%. mp: 195-197℃; IR(KBr, cm ^-1 ): 3441.9, 2919.7, 2851.3, 1603.7, 1509.0, 1444.9, 1384.5, 1341.8, 1263.2, 1229.1, 1157.7, 1017.4, 999.5, ^877.7 , 817 H-NMR; (600MHz, CDCl ₃ ): δ3.11(2H,t),3.30(4H,t),3.50(2H,t),3.98(4H,t),6.91(2H,dd,J＝9.1Hz,4.2Hz ),6.99(2H,dd,J=9.1Hz,4.2Hz),7.24(1H,d,J=5.4Hz),7.25(1H,d,J=5.4Hz); MS(m/z):415.1[ M+H] ⁺ .

Example 43: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-benzyl Preparation of base piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained - 0.80 g of 4-benzylpiperazine (Compound No. 43), yield 49%. mp: 72-73℃; IR(KBr, cm ^-1 ): 3427.6, ^3210.5 , 2918.4, 2851.1, 2809.1, 1613.9, 1446.0, 1384.2, 1347.7, 1287.2, 1229.1, 1143.5, 997.1, 860.2, 740.7, 69 H9. -NMR (600MHz, CDCl ₃ ): δ2.50(4H,t), 3.10(2H,t), 3.44(2H,t), 3.54(2H,s), 3.77(4H,t), 7.24(d, J = 4.8Hz, 1H), 7.26 (d, J = 4.8Hz, 1H), 7.31 (5H, m); MS (m/z): 411.2 [M+H] ⁺ , 433.1 [M + Na] ⁺ .

Example 44: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 4-methoxyphenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(4-Methoxyphenyl)piperazine (Compound No. 44) 0.84g, yield 49%. mp: 156-158℃; IR(KBr, cm ^-1 ): 3443.8, ^3196.6 , 2920.6, 2851.1, 1611.7, 1510.5, 1445.2, 1384.2, 1279.1, 1246.5, 1225.8, 1154.6, 1034.6, 995.2, 159 H-N.4; (600MHz, CDCl ₃ ): δ3.11(10H,m),3.47(2H,t),3.78(3H,s),6.85(2H,J＝9Hz),6.92(2H,d,J＝9Hz), 7.24 (d, J=4.8Hz, 1H), 7.32 (d, J=4.8Hz, 1H); MS (m/z): 427.2[M+H] ⁺ , 449.2[M+Na] ⁺ .

Example 45: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 3-trifluoromethylphenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained - 0.80 g of 4-(3-trifluoromethylphenyl)piperazine (Compound No. 45), yield 43%. mp: 85-87°C; IR (KBr, cm ^-1 ): 3444.3, 3212.2, 2919.3, 2851.0, 1610.1, 1495.4, 1445.9, 1384.5, 1348.8, 1232.6, 1162.9, 1120.8, 995.3, 860.3; ¹ H-NMR (600 MHz , CDCl ₃ ): δ3.11(2H, t), 3.30(4H, t), 3.50(2H, t), 3.98(4H, t), 7.08(1H, d, J=8.4Hz), 7.13(2H , m), 7.25 (2H), 7.38 (1H, dd, J=8.4Hz, 8.4Hz), 10.26 (1H, s); MS (m/z): 465.1 [M+H] ⁺ .

Example 46: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 3-bromophenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(3-Bromophenyl)piperazine (Compound No. 46) 0.76g, yield 40%. mp: 195-197℃; IR(KBr, cm ^-1 ): 3443.9, 2920.9, 2851.1, 1589.7, 1444.0, 1384.1, 1236.2, 1124.2, 994.4, 860.0; ¹ H-NMR(600MHz, CDCl ₃ ): δ3.06 (2H,t),3.24(8H,t),3.78(2H,t),6.94(2H,m),7.10(1H,d),7.15(1H,t),7.54(d,J=5.4Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H), 13.15 (1H, s); MS (m/z): 474.4, 476.3 [M+H] ⁺ .

Example 47: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 3,4-difluorophenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(3,4-difluorophenyl)piperazine (Compound No. 47) 0.80 g, yield 46%. mp: 230-232℃; IR (KBr, cm ^-1 ): 3369.6, 3258.9, 2920.5, 2850.8, 1662.4, 1629.5, 1555.5, 1515.3, 1434.9, 1384.1, 1280.9, 1222.0, 1189.0, 1116.2, 18504.1; ¹ H-NMR (600MHz, CDCl ₃ ): δ2.95(4H,t),3.15(2H,t),3.74(2H,t),3.91(4H,t),7.13(1H),7.22(1H, d, J = 5.4 Hz), 7.24 (1H, m), 7.28 (1 H, d, J = 5.4 Hz), 7.80 (1 H, m); MS (m/z): 433.2 [M+H] ⁺ .

Example 48: N,N-Dimethyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide preparation of

According to the method of Example 1, N,N-dimethyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole was prepared -3-amide (Compound No. 48) 0.59 g, yield 53%. mp: 232-233℃; IR(KBr, cm ^-1 ): 3199.3, 3153.2, 3055.3, 2924.6, 1616.9, 1524.1, 1425.8, 1385.1, 1144.7, 1088.7, 1007.5, 914.6, 861.8, 769.0, 696.6-NMR; ¹ H (600MHz, CDCl ₃ ): δ3.10(2H,t),3.16(6H,m),3.45(2H,t),7.24(1H,d,J＝5.5Hz,),7.27(1H,d,J = 5.5 Hz,); MS (m/z): 280.0 [M+H] ⁺ .

Example 49: Preparation of 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)pyrrolidine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained Pyrrolidine (Compound No. 49) 0.60 g, yield 49%. mp: 170℃; IR(KBr, cm ^-1 ): 3263.2, ^2920.4 , 2875.7, 1595.8, 1526.9, 1492.2, 1470.4, 1432.4, 1382.8, 1339.4, 1224.1, 1007.6, 898.7, 861.2, 760.5, 618 H8.5; (600MHz, CDCl ₃ ): δ1.82(2H,m),1.93(2H,m),3.11(2H,t),3.37(4H,t),3.59(2H,t),7.23(1H,d, J=5.5 Hz), 7.25 (1H,d, J=5.5 Hz); MS (m/z): 306.2 [M+H] ⁺ , 328.1 [M+Na] ⁺ .

Example 50: Preparation of N-isopropyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide

According to the method of Example 1, N-isopropyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3 was prepared - Amide (Compound No. 50) 0.66g, yield 56%. mp: 214-215°C; IR (KBr, cm ^-1 ): 3408.8, 3256.4, 2922.4, 1644.1, 1543.5, 1523.7, 1485.7, 1446.4, 1384.0, 1125.5, 1007.9, 859.5, 760.8, 692.2; ¹ H-NMR (600 MHz , CDCl ₃ ): δ1.26(6H,d),3.12(2H,t),3.71(2H,t),4.25(1H,m),7.20(1H,d,J＝5.5Hz),7.24(1H , d, J = 5.5 Hz); MS (m/z): 294.1 [M+H] ⁺ .

Example 51: Preparation of N-benzyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide

According to the method of Example 1, N-benzyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3- Amide (Compound No. 51) 0.63 g, yield 46%. mp: 136-138°C; IR (KBr, cm ^-1 ): 33401.9, 3217.8, 2921.8, 2851.3, 1648.5, 1546.9, 1452.8, 1384.2, 1241.6, 1128.0, 861.8, 752.2, 698.0, 615.7; ¹ H-NMR (600 MHz , CDCl ₃ ): δ3.12(2H,t), 3.73(2H,t), 4.62(2H,d), 7.20(1H,m), 7.23(1H,d,J=5.5Hz), 7.28(1H , d, J = 5.5 Hz), 7.34 (4H, m); MS (m/z): 342.1 [M+H] ⁺ .

Example 52: Preparation of N-phenyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-amide

According to the method of Example 1, N-phenyl-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3- Amide (Compound No. 52) 0.50 g, yield 38%. mp: 240°C; IR (KBr, cm ^-1 ): 3422.8, 2921.0, 2850.9, 1663.2, 1596.1, 1542.8, 1440.4, 1384.1, 1121.3, 861.5, 753.4, 694.0, 618.0; ¹ H-NMR (600MHz, CDCl ₃ ) :δ3.15(2H,t),3.76(2H,t),7.13(1H,m),7.22(1H,d,J＝5.5Hz),7.28(1H,d,J＝5.5Hz),7.37 (2H, dd, J = 7.9 Hz, 7.9 Hz), 7.68 (2H, d, J = 7.9 Hz); MS (m/z): 328.1 [M+H] ⁺ .

Example 53: Preparation of 4-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)morpholine

According to the method of Example 1, 4-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained Morpholine (Compound No. 53) 0.67g, yield 52%. mp: 176-178°C; IR (KBr, cm ^-1 ): 3439.5, 2920.5, 2851.6, 1611.7, 1434.2, 1271.5, 1242.1, 1194.6, 1115.5, 1024.6, 995.5, 861.4, 619.7; ¹ H-NMR (600MHz, CDCl ₃ ): δ3.11(2H,t),3.48(2H,t),3.75(4H,t),3.81(4H,t),7.22(1H,d,J＝5.4Hz),7.25(1H,d , J=5.4 Hz); MS (m/z): 322.0 [M+H] ⁺ .

Example 54: Preparation of 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)piperidine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained Piperidine (Compound No. 54) 0.55 g, yield 43%. mp: 76-78℃; IR(KBr, cm ^-1 ): 3435.9, 3229.1, 2920.1, 2851.2, 1607.8, 1514.6, 1445.3, 1384.1, 1254.9, 1138.8, 1027.8, 989.4, 859.0, 774.5, 617.9; ¹ H-N (600MHz, CDCl ₃ ): δ1.27(2H,m),1.64(4H,m),3.11(2H,t),3.42(2H,t),3.66(4H,t),7.23(1H,d, J = 5.4 Hz), 7.24 (1H,d, J = 5.4 Hz); MS (m/z): 320.1 [M+H] ⁺ .

Example 55: N-(furan-2-ylmethylene)-4,5-dihydro-3aH-thieno[2',3':2,3]thialo[4,5-c]pyridine Preparation of azole-3-amides

According to the method of Example 1, N-(furan-2-ylmethylene)-4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5 -c] Pyrazole-3-amide (Compound No. 55) 0.46 g, yield 35%. mp: 155-156℃; IR(KBr, cm ^-1 ): 3408.3, 3227.4, 2921.6, 2850.7, 1650.4, 1542.9, 1523.7, 1484.0, 1417.8, 1384.2, 1190.0, 1147.0, 1003.1, 964.7, 8961.9, 6; ¹ H-NMR (600MHz, CDCl ₃ ): δ3.12(2H,t),3.71(2H,t),4.60(2H,d),6.29(1H,m),6.33(1H,m),7.20( 1H, d, J = 5.4 Hz), 7.25 (1 H, d, J = 5.4 Hz), 7.37 (1 H, m); MS (m/z): 331.6 [M+H] ⁺ .

Example 56: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 3-chloro-4-fluorophenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(3-Chloro-4-fluorophenyl)piperazine (Compound No. 56) 0.88g, yield 49%. mp: 205-206℃; IR(KBr, cm ^-1 ): 33434.2, ^3288.2 , 2919.2, 2850.7, 1603.4, 1503.1, 1462.9, 1444.8, 1384.2, 1223.5, 1156.2, 994.4, 945.2, 865.3, 783.5, 61 H -NMR (600MHz, CDCl ₃ ): δ3.12(2H, t), 3.16(4H, t), 3.49(2H, t), 3.95(4H, t), 6.79(1H, m), 6.95(1H, dd, J = 6.3Hz, 2.4Hz), 7.05 (1H, dd, J = 9.0Hz, 8.7Hz), 7.23 (1H, d, J = 5.4Hz), 7.25 (1H, d, J = 5.4Hz); MS (m/z): 449.0, 450.8 [M+H] ⁺ .

Example 57: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 2-methylphenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(2-Methylphenyl)piperazine (Compound No. 57) 0.72 g, yield 44%. mp: 192-194℃; IR(KBr, cm ^-1 ): 3442.6, ^3264.4 , 2919.3, 2851.2, 1601.8, 1492.0, 1474.7, 1442.8, 1383.7, 1223.1, 1152.0, 1026.2, 995.5, 861.7, 761.01, 69 H -NMR (600MHz, CDCl ₃ ): δ2.33(3H, s), 2.95(4H, t), 3.12(2H, t), 3.48(2H, t), 3.91(4H, t), 7.02(2H, m), 7.18 (2H, m), 7.23 (1H, d, J = 5.5 Hz), 7.27 (1 H, d, J = 5.5 Hz); MS (m/z): 409.0 [MH] ⁺ .

Example 58: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 3,5-ditrifluoromethylphenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(3,5-Ditrifluoromethylphenyl)piperazine (Compound No. 58) 0.92g, yield 43%. mp: 89-91℃; IR (KBr, cm ^-1 ): 3444.6, 2920.4, 1618.5, 1476.8, 1384.9, 1277.4, 1240.0, 1177.9, 1130.4, 995.0, 963.9, 861.1, 720.5, 682.3; ¹ H-NMR (600MHz , CDCl ₃ ): δ3.12(2H,t),3.38(4H,t),3.51(2H,t),4.01(4H,t),7.23(2H,m),7.27(1H,s),7.24 (1H,s), 7.34 (1H,s); MS (m/z): 533.4 [M+H] ⁺ .

Example 59: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 2-fluorophenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(2-Fluorophenyl)piperazine (Compound No. 59) 0.66 g, yield 40%. mp: 79-81℃; IR(KBr, cm ^-1 ): 3439.4, 2918.7, 1611.8, 1500.0, 1440.3, 1384.7, 1342.1, 1286.6, 1236.6, 1201.2, 1147.9, 998.6, 884.5, 860.5, 747.8; ¹ H-NMR (600MHz, CDCl ₃ ): δ2.23(2H,t),3.12(4H,t),3.48(4H,t),3.66(2H,t),7.01(1H,m),7.03(1H,m) , 7.25(2H,m), 7.38(1H,m), 7.39(1H,m); MS(m/z): 415.3[M+H] ⁺ , 437.1[M+Na] ⁺ .

Example 60: 1-(4,5-Dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl)-4-( Preparation of 2-chlorophenyl)piperazine

According to the method of Example 1, 1-(4,5-dihydro-3aH-thieno[2',3':2,3]thia[4,5-c]pyrazole-3-carbonyl) was obtained -4-(2-Chlorophenyl)piperazine (Compound No. 60) 0.66g, yield 38%. mp: 203-205℃; IR(KBr, cm ^-1 ): 3441.5, 3214.1, 2920.0, 2851.1, 1601.9, 1500.3, 1477.4, 1443.6, 1384.1, 1336.5, 1286.9, 1237.1, 1202.8, 1146.5, 1991.1, 1991.1 759.2,689.2; ¹ H-NMR (600MHz, CDCl ₃ ): δ2.23(2H,t),3.12(4H,t),3.48(4H,t),3.66(2H,t),7.02(2H,m ), 7.25 (2H, m), 7.38 (2H, m); MS (m/z): 431.0, 432.9 [M+H] ⁺ .

Example 61: N-tert-butyl-7,8-dibromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3 - Preparation of amides

According to the method of Example 1, N-tert-butyl-7,8-dibromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3-c] was obtained Pyrazole-3-amide (Compound No. 61) 0.58g, yield 32%. mp: 224-226℃; IR(KBr, cm ^-1 ): 3391.7, 3075.6, 2935.1, 1653.5, 1544.7, 1520.1, 1439.2, 1366.5, 1265.9, 1217.1, 1018.8, 987.3, 966.9, 858.4, 822.7-NMR; ¹ H (600MHz, CDCl ₃ ): δ1.49(9H,s), 4.49(2H,s), 7.40(1H,s); ESI-MS(m/z): 450.2,452.2,454.2[M+H] ⁺ .

Example 62: N,N-Dimethyl-7,8-dibromo-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole - Preparation of 3-amides

According to the method of Example 1, N,N-dimethyl-7,8-dibromo-1,4-dihydrothieno[3',2':5,6]thiopyrano[4,3- c] Pyrazole-3-amide (Compound No. 62) 0.76 g, yield 42%. mp: 159-160°C; IR (KBr, cm ^-1 ): 3422.3, 2977.2, 2933.9, 2603.8, 1602.2, 1476.5, 1397.8, 1383.3, 1271.0, 1172.0, 1036.7, 850.8, 807.0; ¹ H-NMR (600MHz, CDCl ₃ ): δ1.25 (6H, m), 3.54 (4H, m), 4.12 (2H, s); ESI-MS (m/z): 450.2, 452.2, 454.2 [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 modify the equivalent of equivalent changes. 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 embodiment Embodiment 63:

Inhibition of 5-lipoxygenase by representative compounds of the present invention is shown in the table below. The 5-lipoxygenase inhibitory activity was determined by measuring the inhibition of 5-HETE and LYB ₄ formation using a method isolated from peripheral blood of rabbits. The calcium ionophore (A ₂₃₁₈₇ ) stimulated neutrophils, and the ability of the compounds of the present invention to inhibit the formation of 5-HETE and LYB ₄ was studied. Neutrophils were isolated using standard methods, briefly, by heart puncture, heparinized/calcium-chelated blood from New Zealand Albino (NZA) rabbits, and red blood cells removed by dextran sedimentation at 4°C. . The leukocytes contained in the supernatant fraction are sedimented by centrifugation, and by hypotonic lysis, the fraction mixed with erythrocytes is removed. After lysing and centrifuging the erythrocytes, white blood cell sheets were obtained, which were resuspended in Dulbecco's PBS (Ca ²⁺ /Mg ²⁺ free) and placed on a 60% Histopaque-1083/40% Histopaque-1119 pad (Sigma Chemical. St. Louis , Missouri, USA.) into layers. The Histopaque was then centrifuged and the resulting neutrophil pellet washed and resuspended in 1/25 original volume of blood. Aliquots of this cell suspension were taken and pretreated at 37°C with vehicle (DMSO) or test compounds dissolved in DMSO, _CaCl2 was immediately added to the cell suspension, and by adding 5 microliters (μL) containing ( Cells were stimulated by a DMSO mixture of 1- ¹⁴ C)-arachidonic acid and A ₂₃₁₈₇ . The final concentrations of CaCl ₂ , (1- ¹⁴ C)-arachidonic acid and A ₂₃₁₈₇ were 5.0 millimolar (mM), 52 μL and 5.0 μL, respectively. After incubation at 37°C for 3 minutes, the reaction was terminated by adding 2 volumes of acetone. ( _1-14C ) ^-labeled arachidonic acid metabolites were extracted and analyzed by reverse phase (C18-5[mu]) HPLC as described by Graff and Anderson.

Table 1

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 64: Gelatin Capsules

Hard gelatin capsules are prepared using:

The above formulations can be modified with reasonable variation provided.

Example 65: Tablets

Tablets are prepared using

The above ingredients are mixed and compressed into tablets.

Example 66: Tablets

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

The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder, which was then passed through a No. 14 mesh U.S. sieve. The resulting granulation was dried at 50-60°C and passed through a No. 18 mesh US sieve. The sodium carboxymethylcellulose, magnesium stearate and talc, previously passed through a No. 60 U.S. sieve, are added to the above granules, which are then mixed and compressed on a tablet machine to obtain tablets.

Example 67: 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 U.S. sieve 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 68: Combination Tablets

The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder, which was then passed through a No. 14 mesh U.S. sieve. The resulting granulation was dried at 50-60°C and passed through a No. 18 mesh US sieve. The sodium carboxymethylcellulose, magnesium stearate and talc, previously passed through a No. 60 U.S. sieve, are added to the above granules, which are then mixed and compressed 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 (1)

1. following thieno thiapyran and pyrazole compound, and its pharmaceutically acceptable salt preparing treatment 5- lipoxygenase The formation of blocking inflammatory mediator leukotriene and the application in the neuralgia and arthralgia medicine that produce：

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- formoxyls) -4- (4- methylbenzene Base) piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (diphenyl methyl) Piperazine；

N,NThe bromo- 1,4- dihydro-thiophenes of-diethyl -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (the chloro- 4- fluorobenzene of 3- Base) piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (4- chlorphenyls) piperazine Piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (4- trifluoro methoxies Base phenyl) piperazine；1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (2- Fluorophenyl) piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (4- trimethoxies Phenyl) piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- phenylpiperazines；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (4- fluorophenyls) piperazine Piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- methyl piperazines；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- benzyl diethylenediamines；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- [(4- chlorphenyls) (phenyl) methyl] piperazine；

NThe bromo- 1,4- dihydro-thiophenes of-tert-butyl group -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (3- bromophenyls) piperazine Piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (4- ethoxybenzenes Base) piperazine；

4- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) morpholine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) pyrrolidine；

NThe bromo- 1,4- dihydro-thiophenes of-isopropyl -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide；

NThe bromo- 1,4- dihydro-thiophenes of-(2- diethylin) ethyl -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- acyls Amine；

N,NThe bromo- 1,4- dihydro-thiophenes of-dimethyl -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide；

NThe bromo- 1,4- dihydro-thiophenes of-phenyl -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) piperidines；

NThe bromo- 1,4- dihydro-thiophenes of-benzyl -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide；

NThe bromo- 1,4- dihydro-thiophenes of-(furan -2- methylenes) -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- acyls Amine；

NThe bromo- 1,4- dihydro-thiophenes of-(pyridine -2- bases) -7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (trifluoros of 3,5- bis- Aminomethyl phenyl) piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (3,4- difluorobenzenes Base) piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (2- aminomethyl phenyls) Piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (2- chlorphenyls) piperazine Piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (2,5- dimethyl Phenyl) piperazine；

1- (the bromo- 1,4- dihydro-thiophenes of 7- simultaneously [3 ', 2 ':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- carbonyls) -4- (3- trifluoromethyls Phenyl) piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (benzhydryl benzene Base) piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (4- chlorphenyls) piperazine Piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- [(4- chlorphenyls) (phenyl) methyl] piperazine；

N- the tert-butyl group -4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- amide；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- methyl piperazines；

N,N- diethyl -4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- amide；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (4- aminomethyl phenyls) Piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- phenylpiperazines；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (4- trifluoro methoxies Base phenyl) piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (4- trifluoro methoxies Base phenyl) piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- benzyl diethylenediamines；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (4- methoxybenzenes Base) piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (3- trifluoromethyls Phenyl) piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (3- bromophenyls) piperazine Piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (3,4- difluorobenzenes Base) piperazine；

N,N- dimethyl -4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- amide；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) pyrrolidine；

N- isopropyl -4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- amide；

N- benzyl -4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- amide；

N- phenyl -4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- amide；

4- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) morpholine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) piperidines；

N- (furan -2- methylenes) -4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- acyls Amine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (the chloro- 4- fluorobenzene of 3- Base) piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (2- aminomethyl phenyls) Piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (trifluoros of 3,5- bis- Aminomethyl phenyl) piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (2- fluorophenyls) piperazine Piperazine；

1- (4,5- dihydro -3aH- thieno [2', 3':2,3] thia simultaneously [4,5-c] pyrazoles -3- carbonyls) -4- (2- chlorphenyls) piperazine Piperazine；

NThe bromo- 1,4- dihydro-thiophenes of-tert-butyl group -7,8- two simultaneously [3', 2':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide；

N,NThe bromo- 1,4- dihydro-thiophenes of-dimethyl -7,8- two simultaneously [3', 2':5,6] thiapyran simultaneously [4,3-c] pyrazoles -3- amide.