Phenphthalein thiazole amine derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses phthalithiazole amine derivatives as well as a preparation method and application thereof. In particular discloses a phthalithiazole amine derivative, a preparation method thereof and application of the phthalithiazole amine derivative in the aspect of resisting epilepsy accompanied by cognitive impairment. The invention specifically relates to a phthalithiazole amine derivative as shown in a general formula (I). The invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds, and an application of the compounds in preparation of medicines for treating and / or preventing epilepsy accompanied by cognitive impairment.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmaceutical technology. It relates to a class of phthalothiazolamide derivatives represented by general formula (I), pharmaceutically acceptable salts and isomers thereof, methods for preparing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in the preparation of medicaments for the treatment and / or prevention of epilepsy with cognitive impairment. Background Technology

[0002] Cognitive impairment is a common complication of epilepsy. Studies show that 30%–40% of epilepsy patients experience cognitive impairment, especially in chronic epilepsy, where approximately 70%–80% of patients have varying degrees of cognitive impairment. This is even more pronounced in infantile spasms, with data showing that about 80%–95% of affected children experience intellectual disability, language and memory impairments, etc. Compared to epileptic seizures, cognitive impairment has a more severe impact on the lives and work of epilepsy patients, placing a heavy economic burden on their families. Currently, most antiepileptic drugs primarily suppress seizures, neglecting the structural and functional damage to the brain caused by seizures, such as mitochondrial and synaptic dysfunction, neuroinflammation, and neuronal apoptosis, ultimately leading to cognitive impairment and even dementia. Currently, the main treatment for epilepsy with cognitive impairment is combination therapy, such as mannitol sodium combined with levetiracetam. This combination therapy increases the patient's dosage, and drug interactions also bring certain toxic side effects. Studies have shown that donepezil and piracetam are not ideal for improving cognitive function. While memantine is effective for cognitive impairment, clinical trials have shown that its use during labor may worsen epilepsy. To date, no effective drugs have been reported domestically or internationally for treating epilepsy accompanied by cognitive impairment.

[0003] Butylphthalide is a new drug independently developed in my country. It was approved by the China Food and Drug Administration (CFDA) in 2004 for the treatment of mild to moderate ischemic stroke. Butylphthalide can significantly enhance mitochondrial function, reduce the release of cytochrome C and inflammatory factors, inhibit neuroinflammation, reduce oxidative stress, protect neurons, and improve cognitive function. Studies have shown that butylphthalide also has anti-epileptic properties.

[0004]

[0005] Riluzole is a neuroprotective drug approved for the treatment of amyotrophic lateral sclerosis (ALS). It acts on glutamate receptors, inhibiting glutamate release, promoting glutamate uptake, reducing excitotoxicity, and protecting neurons. Furthermore, studies have shown that riluzole and its benzothiophene structure possess antiepileptic activity.

[0006] The occurrence and development of epilepsy and cognitive dysfunction are characterized by multiple mechanisms and factors. Different mechanisms are interconnected and influence each other, forming a complex network regulatory system in the process of epilepsy and cognitive dysfunction.

[0007] Therefore, we adopted a "one drug, multiple targets" design strategy, combining the structures of butylphthalide and riluzole to design and synthesize a series of phthalthiazole amine derivatives for the treatment of epilepsy with cognitive impairment. We expect these phthalthiazole amine derivatives to act on multiple targets in the epilepsy and cognitive impairment disease network, producing synergistic effects such as enhancing mitochondrial function, reducing oxidative stress, and inhibiting neuroinflammation; simultaneously, they can inhibit the release of the excitatory neurotransmitter glutamate, reducing excitotoxicity; protect neurons, and reduce epilepsy-induced cognitive impairment. Summary of the Invention

[0008] The purpose of this invention is to disclose a novel class of phthalthiazole amine derivatives (I).

[0009] Another objective of this invention is to disclose a method for preparing this type of phthalothiazolamine derivative (I).

[0010] Another object of the present invention is to disclose pharmaceutical compositions of such phthalimide thiazolamine derivatives (I).

[0011] Another object of the present invention is to disclose that this class of phthalimide-thiazolamine derivatives (I) has multi-target effects and can be used in the preparation of medicaments for the treatment and / or prevention of epilepsy with cognitive impairment.

[0012] The first aspect of the technical solution of the present invention provides a benzothiazole amine derivative (I) with the following general chemical structural formula:

[0013]

[0014] Wherein, R1 and R2 independently represent hydrogen atoms, methyl or C1-C10 straight-chain or branched alkyl or C3-C10 cycloalkyl or C1-C10 straight-chain or branched alkyl or C3-C10 cycloalkyl or carboxyl or cyano groups containing heteroatoms (oxygen, nitrogen, sulfur), or substituted or unsubstituted C6-C10 aromatic groups, wherein the aromatic group may be substituted by one or more of the following groups: F, Cl, Br, NO2, NH2, OH, CN, CF3, OCF3, SO2CH3, SO2NH2, OCH3 or N(CH3)2; the compound is an R configuration, an S configuration or a racemic mixture;

[0015] R1 and R2 can be the same or different.

[0016] Preferably, the compound is selected from the group consisting of:

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023] The third aspect of the present invention is to provide a method for preparing the compound described in the first aspect. The phthalimide-thiazolamine derivative (I) can be prepared by the following method: using butylphthalide (a) as the starting material, it undergoes a nitration and reduction reaction to obtain 6-amino-3-n-butylphthalide (c); intermediate c undergoes a cyclization reaction to obtain 2-amino-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one (d); intermediate d undergoes a diazo substitution reaction to obtain 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one (e); intermediate e reacts with the corresponding amine to obtain the phthalimide-thiazolamine derivative (I), and the reaction formula is as follows:

[0024]

[0025] In the formula: R1 and R2 are defined in the same way as the general chemical structural formula of phthalthiazole amine derivatives (I).

[0026] The specific steps of the above synthetic route are described below:

[0027] (1) Preparation of intermediate 6-nitro-3-n-butylphthalide (b)

[0028] 3-n-Butylphthalide (a) was added to an appropriate amount of concentrated sulfuric acid, with a volume ratio of a to concentrated sulfuric acid of 1:(1.5-2.0). At 0°C, a mixed solution of concentrated nitric acid and concentrated sulfuric acid was added dropwise, with an equivalent ratio of concentrated nitric acid to a of 1:1.5 and a volume ratio of concentrated nitric acid to concentrated sulfuric acid of 1:1.5. The mixture was stirred at 0°C for 2 hours, and then stirred at room temperature for 6 hours until the reaction was stopped. An appropriate amount of water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried, purified by column chromatography, and concentrated to obtain a pale yellow liquid.

[0029] (2) Preparation of intermediate 6-amino-3-n-butylphthalide (c)

[0030] At room temperature, 6-nitro-3-n-butylphthalide (b) was added to a mixed solvent of ethanol and water (volume ratio of ethanol to water: 4.5:1). Iron powder and ammonium chloride were then added to the mixture, with an equivalent ratio of b to iron powder of 1:10 and b to ammonium chloride of 1:1. The reaction was stopped after reflux for 10 hours under argon protection. The iron powder was removed by hot filtration, and the solvent was removed by cooling and vacuum. The product was separated by silica gel column chromatography [petroleum ether: ethyl acetate (v:v) = (3~5):1] to obtain a pale yellow solid.

[0031] (3) 2-Amino-6-butylisobenzofuran[5,4-d]thiazolyl-8(6H)-one(d)

[0032] Add 6-amino-3-n-butylphthalide (c) to an appropriate amount of acetonitrile, stir, add 1 equivalent of ammonium thiocyanate and 1 equivalent of benzyltrimethylammonium tribromide, stir at room temperature for 5-6 hours, add saturated sodium bicarbonate solution to the reaction solution, precipitate solid, filter, wash with water, dry, and obtain a yellow solid.

[0033] (4) 6-Butyl-2-chloroisobenzofuran[5,4-d]thiazolyl-8(6H)-one(e)

[0034] Dissolve appropriate amounts of copper chloride and nitrosotert-butyl ester in appropriate amounts of acetonitrile. At 0 degrees Celsius, add 2-amino-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one (d) to the reaction flask in 5 portions, with an interval of 15 minutes between each addition. The equivalent ratio of d to copper chloride and nitrosotert-butyl ester is 1:1.5:1.5. After stirring at room temperature for 4 hours, stop the reaction, filter, add 6M hydrochloric acid, remove the organic solvent under reduced pressure, filter, wash the filter cake with water, and obtain a light yellow solid.

[0035] (5) Benphthalthiazoleamine derivatives (f)

[0036] Add an appropriate amount of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one(e) to acetonitrile, and add 1 equivalent of the substituted amine (R1R2NH) and 1.2 equivalents of the substituted triethylamine. Reflux for 8-24 hours, concentrate, dissolve in ethyl acetate, and separate the product by silica gel column chromatography [petroleum ether: ethyl acetate (v:v) = (8-12):1] to obtain a yellow or white solid; or add an appropriate amount of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one(e) to tetrahydrofuran, and add 10 equivalents of the substituted amine (R1R2NH). Stir for 12 hours and stop the reaction. Separate the product by silica gel column chromatography [petroleum ether: ethyl acetate (v:v) = (8-15):1] to obtain a yellow or white solid.

[0037] A third aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more phthalimide-thiazolamine derivatives (I), which may further contain one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of drug or agent that elicits a biological or pharmaceutical response in a tissue, system, or animal targeted by an investigator or physician; the "composition" refers to a product formed by mixing one or more substances or components; the "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance that carries or transports a chemical substance. Ideally, the pharmaceutical composition provided by the present invention comprises, as an active ingredient, 5% to 99.5% by weight of the phthalimide-thiazolamine derivative (I), with the remainder comprising less than 95% by weight.

[0038] The fourth aspect of the present invention is to provide the use of the compound described in the first aspect in the preparation of a drug for treating and / or preventing epilepsy with cognitive impairment. Detailed Implementation

[0039] The present invention will be further described through the following embodiments; however, the scope of the present invention is not limited to the following embodiments. Those skilled in the art will understand that various changes and modifications can be made to the present invention without departing from its spirit and scope.

[0040] Example 1: 6-Nitro-3-n-Butylphthalide (b)

[0041] 3-n-Butylphthalide (2.0 g, 10.52 mmol) was added to a reaction flask, followed by 5 mL of concentrated H₂SO₄. A mixture of concentrated H₂NO₃ (0.7 mL, 15.78 mmol) and concentrated H₂SO₄ (2.2 mL) was added dropwise at 0 °C. The mixture was stirred for 2 h, then removed from the ice bath and stirred again at room temperature. The reaction was monitored by TLC. After completion, H₂O was added, and the mixture was extracted with DCM. The organic phases were combined, concentrated with anhydrous Na₂SO₄, and purified by silica gel column chromatography. The resulting organic solution was concentrated to dryness under reduced pressure to give 2.3 g of a yellow oily liquid, with a yield of 92.5%.

[0042] 1H NMR(400MHz, CDCl3)δ / ppm 8.68(dd,J=7.4,2.1Hz,1H),8.53(dt,J=8.4,2.3Hz,1H),7.66(dd,J1=8.3Hz,J2=2.7Hz,1H),5.59(dd,J1=7.9Hz,J2=4.1Hz,1H),2.11(ddq ,J1=14.4Hz,J2=9.8Hz,J3=4.6Hz,1H),1.80(dddd,J1=18.6Hz,J2=10.1Hz,J3=4.7Hz,J4=2.3Hz,1H),1.53-1.28(m,4H),0.96-0.80(m,3H).

[0043] 13 C NMR(100MHz,CDCl3)δ / ppm 168.17,155.48,155.46,149.10,128.94,128.01,127.99,123.37,123.33,121.41,121.37,81.62,81.60,34.17,26.87,22.39,13.85.

[0044] Example 2: 6-Amino-3-n-Butylphthalide (c)

[0045] 6-Nitro-3-n-butylphthalide (2.3 g, 9.78 mmol) was added to a reaction flask, followed by 10 mL of EtOH and 3 mL of H2O. Fe (5.5 g, 97.8 mmol) and NH4Cl (0.5 g, 9.78 mmol) were then added. The mixture was heated to reflux under argon protection, and the reaction was monitored by TLC. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography. The resulting organic solution was concentrated to dryness under reduced pressure to give 1.5 g of a pale yellow solid, with a yield of 72.8%.

[0046] 1 H NMR(400MHz, CDCl3)δ / ppm 7.17(d,J=8.1Hz,1H),7.10(d,J=2.2Hz,1H),6.95(dd,J1=8.1Hz,J2=2.2Hz,1H),5.36(dd,J1=7.7Hz,J2=4.2Hz,1H),1. 96(dddd,J1=14.1Hz,J2=10.0Hz,J3=6.0Hz,J4=4.2Hz,1H),1.76-1.61(m,1H),1.52-1.29(m,4H),0.89(t,J=6.9Hz,3H).

[0047] 13C NMR (100MHz, CDCl3) δ / ppm 171.15,147.60,140.25,127.46,122.43,121.54,109.80,81.53,34.78,26.91,22.54,13.96.

[0048] Example 3 Preparation of 2-amino-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one(d)

[0049] 3-Aminophthalide (1 g, 4.87 mmol) and ammonium thiocyanate (371 mg, 4.87 mmol) were dissolved in 30 mL MeCN, and then benzyltrimethylammonium tribromide (1.899 g, 4.87 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the pH was adjusted to neutral with saturated NaHCO3 solution, the organic phase was removed by concentration under reduced pressure, and the mixture was filtered to obtain 1.1 g of yellow solid, with a yield of 87.6%.

[0050] 1 H NMR(400MHz,DMSO-d6)δ / ppm 7.68(dd,J=8.1,1.5Hz,1H),7.45(dd,J=8.2,1.5Hz,1H),5.65(dd,J=8.1,3.8Hz,1H),2.04(dq,J=14 .8,4.9Hz,1H),1.70(ddt,J=14.1,10.2,3.4Hz,1H),1.41-1.16(m,4H),0.85(dt,J=7.1,3.6Hz,3H).

[0051] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.88,168.41,155.11,144.06,126.63,123.57,119.61,119.28,82.49,34.24,26.90,22.35,14.27.

[0052] Example 4 Preparation of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one(e)

[0053] CuCl2 (0.769 g, 5.72 mmol) and nitrosotert-butyl ester (0.68 mL, 5.72 mmol) were dissolved in 20 mL MeCN. 2-Amino-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one (1 g, 3.81 mmol) was added to the reaction flask in 5 portions at 0 °C. The mixture was stirred at room temperature for 2 h, then heated to reflux. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered, 10 mL of 6 M HCl was added, and the mixture was concentrated under reduced pressure. 800 mg of a yellow solid was obtained by filtration, with a yield of 80.0%.

[0054] 1 H NMR(400MHz, CDCl3)δ / ppm 8.21(d,J=8.2Hz,1H),7.53(d,J=8.3Hz,1H),5.63(dd,J1=7.9Hz,J2=4.1Hz,1H),2.28-2.02(m, 1H),1.82(tdd,J1=12.7Hz,J2=6.7Hz,J3=4.1Hz,1H),1.53-1.35(m,4H),0.90(t,J=7.1Hz,3H).

[0055] 13 C NMR (100MHz, CDCl3) δ / ppm 168.85,156.11,152.63,148.68,132.02,128.23,120.44,119.92,82.59,34.38,26.88,22.41,13.85.

[0056] Example 5 2-Amino-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one (LK16-44)

[0057] 3-Aminophthalide (1 g, 4.87 mmol) and ammonium thiocyanate (371 mg, 4.87 mmol) were dissolved in 30 mL of MeCN, and then benzyltrimethylammonium tribromide (1.899 g, 4.87 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the pH was adjusted to neutral with saturated NaHCO3 solution. The organic phase was removed by concentration under reduced pressure, and the mixture was filtered to obtain 1.1 g of yellow solid, with a yield of 87.6%.

[0058] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.68(dd,J=8.1,1.5Hz,1H),7.45(dd,J=8.2,1.5Hz,1H),5.65(dd,J=8.1,3.8Hz,1H),2.04(dq,J=14 .8,4.9Hz,1H),1.70(ddt,J=14.1,10.2,3.4Hz,1H),1.41-1.16(m,4H),0.85(dt,J=7.1,3.6Hz,3H).

[0059] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.88,168.41,155.11,144.06,126.63,123.57,119.61,119.28,82.49,34.24,26.90,22.35,14.27.

[0060] HRMS(ESI)m / z calcd for C 13 H 15 N2O2S + [M+H] + :263.0849; found:263.0842

[0061] Example 6 6-Butyl-2-(ethylamino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK17-16)

[0062] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then 0.99 mL (17.7 mmol) of 50% ethylamine was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 388 mg of white solid was obtained, with a yield of 75.6%.

[0063] 1 H NMR(500MHz,CDCl3)δ / ppm 7.73(d,J=8.1Hz,1H),7.28(d,J=8.2Hz,1H),5.54(dd,J=7.8,4.1Hz,1H),3.52(q,J=7.2 Hz,2H),2.14-1.96(m,1H),1.85-1.71(m,1H),1.49-1.29(m,7H),0.89(t,J=7.0Hz,3H).

[0064] 13C NMR (100MHz, CDCl3) δ / ppm 170.18,169.51,154.46,144.02,126.50,123.73,119.90,118.86,82.60,40.60,34.78,26.97,22.54,14.85,13.97.

[0065] HRMS(ESI)m / z calcd for C 15 H 19 N2O2S + [M+H] + :291.1162; found:291.1160

[0066] Example 7 6-Butyl-2-(propylamino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-17)

[0067] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then propylamine (1.5 mL, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 423 mg of white solid was obtained, with a yield of 78.6%.

[0068] 1 H NMR(400MHz, CDCl3)δ / ppm 7.75(dd,J=8.1,1.3Hz,1H),7.30(dd,J=8.2,0.8Hz,1H),5.54(dd,J=7.7,4.1Hz,1H),3.44( t,J=7.1Hz,2H),2.26-1.95(m,1H),1.89-1.62(m,3H),1.58-1.34(m,4H),1.08-0.89(m,6H).

[0069] 13 C NMR(100MHz,CDCl3)δ / ppm 170.10,169.76,153.95,144.15,126.22,123.65,120.00,119.01,82.63,47.77,34.80,26.99,22.82,22.57,13.99,11.47.

[0070] HRMS(ESI)m / z calcd for C 16 H 19 N2O2S + [M+H] +:303.1162; found:303.1160

[0071] Example 8 6-Butyl-2-(propylamino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK17-15)

[0072] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then isopropylamine (1.5 mL, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 428 mg of white solid was obtained, with a yield of 79.5%.

[0073] 1 H NMR(400MHz, CDCl3)δ / ppm 7.75(d,J=8.1Hz,1H),7.29(dd,J=8.1,0.8Hz,1H),5.59-5.49(m,1H),3.98(t,J=6.3Hz,1H),2 .16-1.94(m,1H),1.77(tdd,J=9.9,7.8,5.3Hz,1H),1.53-1.29(m,10H),0.89(t,J=7.1Hz,3H).

[0074] 13 C NMR (100MHz, CDCl3) δ / ppm 170.15,168.53,154.40,144.05,126.50,123.77,119.94,118.86,82.58,48.11,34.80,26.97,23.00,22.57,13.99.

[0075] HRMS(ESI)m / z calcd for C 16 H 21 N2O2S + [M+H] + :305.1318; found:305.1314

[0076] Example 9 6-Butyl-2-(dimethylamino)isobenzofuran[5,4-d]thiazol-8(6H)-one (LK18-29)

[0077] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then dimethylamine (789 mg, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 412 mg of white solid was obtained, with a yield of 80.2%.

[0078] 1 H NMR(500MHz,CDCl3)δ / ppm 7.77(d,J=8.2Hz,1H),7.28(d,J=8.2Hz,1H),5.53(dd,J=7.9,4.0Hz,1H),3.25(s,6H),2.10 -1.96(m,1H),1.77(dtd,J=13.8,8.2,3.3Hz,1H),1.53-1.29(m,4H),0.89(t,J=7.1Hz,3H).

[0079] 13 C NMR (100MHz, CDCl3) δ / ppm 170.98,170.51,155.33,143.87,127.27,124.12,120.12,119.23,82.90,40.85,35.14,27.34,22.88,14.31.

[0080] HRMS(ESI)m / z calcd for C 15 H 19 N2O2S + [M+H] + :291.1162; found:291.1167

[0081] Example 10 6-Butyl-2-(diethylamino)isobenzofuran[5,4-d]thiazolyl-8(6H)-one (LK17-25)

[0082] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then diethylamine (1.8 mL, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 448 mg of white solid was obtained, with a yield of 79.6%.

[0083] 1H NMR(400MHz, CDCl3)δ / ppm 7.76(d,J=8.1Hz,1H),7.27(dd,J=8.2,0.8Hz,1H),5.53(ddd,J=7.7,4.1,0.7Hz,1H),3.62(q,J=7.1Hz,4H ), 2.05(dddd,J=14.2,10.2,5.8,4.1Hz,1H),1.85-1.72(m,1H),1.50-1.28(m,10H),0.89(t,J=7.1Hz,3H).

[0084] 13 C NMR (100MHz, CDCl3) δ / ppm 170.26,169.12,143.27,123.49,119.67,118.66,82.49,45.94,34.74,26.85,22.49,13.92,12.81.

[0085] HRMS(ESI)m / z calcd for C 17 H 23 N2O2S + [M+H] + :319.1475; found:319.1472

[0086] Example 11 6-Butyl-2-(dipropylamino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK17-24)

[0087] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then dipropylamine (2.5 mL, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 498 mg of white solid was obtained, with a yield of 81.3%.

[0088] 1 H NMR(400MHz, CDCl3)δ / ppm 7.75(d,J=8.1Hz,1H),7.41-7.20(m,1H),5.53(dd,J=7.7,4.1Hz,1H),3.59-3.42(m,4H),2.11- 1.95(m,1H),1.83-1.66(m,6H),1.51-1.32(m,4H),0.97(t,J=7.4Hz,6H),0.89(t,J=7.1Hz,3H).

[0089] 13C NMR (100MHz, CDCl3) δ / ppm 170.38,169.85,143.35,123.60,119.71,118.71,82.59,53.56,34.85,26.96,22.59,20.81,14.01,11.38.

[0090] HRMS(ESI)m / z calcd for C 19 H 27 N2O2S + [M+H] + :347.1788; found:347.1780

[0091] Example 12 2-(allyl(methyl)amino)-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one (LK18-33)

[0092] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then N-methylallylamine (1.7 mL, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 428 mg of white solid was obtained, with a yield of 76.5%.

[0093] 1 H NMR(500MHz,CDCl3)δ / ppm 7.78(d,J=8.2Hz,1H),7.29(d,J=8.2Hz,1H),5.87(ddt,J=16.3,10.8,5.6Hz,1H),5.54(dd,J=7.8,4.1Hz,1H),5.36-5.11(m,2H),4 .20(d,J=5.6Hz,2H),3.21(s,3H),2.12-1.99(m,1H),1.77(tdd,J=12.7,6.8,4.2Hz,1H),1.55-1.30(m,4H),0.89(t,J=7.0Hz,3H).

[0094] 13 C NMR(100MHz,CDCl3)δ / ppm 170.31,170.19,154.83,143.71,131.47,126.87,123.91,119.86,118.92,118.58,82.59,55.81,38.15,34.82,26.99,22.58,14.00.

[0095] HRMS(ESI)m / z calcd for C 17 H 21 N2O2S + [M+H] + :317.1318; found:317.1323

[0096] Example 13 6-Butyl-2-((2-methoxyethyl)(methyl)amino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK18-37)

[0097] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then N-(2-methoxyethyl)methylamine (1.9 mL, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 464 mg of white solid was obtained, with a yield of 78.4%.

[0098] 1 H NMR(500MHz,CDCl3)δ / ppm 7.77(d,J=8.2Hz,1H),7.28(d,J=8.2Hz,1H),5.54(dd,J=7.9,4.1Hz,1H),3.78(d,J=5.4Hz,2H),3.68(t,J=5.3Hz,2H),3 .36(s,3H),3.28(s,3H),2.09-2.04(m,1H),1.77(dtd,J=14.3,9.8,4.3Hz,1H),1.55-1.31(m,4H),0.89(t,J=7.0Hz,3H).

[0099] 13 C NMR(100MHz,CDCl3)δ / ppm 170.95,169.94,154.83,143.21,126.62,123.55,119.50,118.52,82.25,70.13,58.85,52.81,39.69,34.51,26.66,22.26,13.69.

[0100] HRMS(ESI)m / z calcd for C 17 H 23 N2O3S + [M+H] + :335.1424; found:335.1429

[0101] Example 14 6-Butyl-2-((cyclohexylmethyl)amino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK17-20)

[0102] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then cyclohexylmethylamine (2.3 mL, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 366 mg of white solid was obtained, with a yield of 80.2%.

[0103] 1 H NMR(400MHz, CDCl3)δ / ppm 7.73(d,J=8.1Hz,1H),7.33-7.20(m,1H),5.54(dd,J=7.7,4.1Hz,1H),3.30(d,J=6.8Hz,2H),2.12-1.99(m,1H) ,1.85-1.63(m,7H),1.52-1.33(m,4H),1.30-1.12(m,3H),1.01(qd,J=11.9,3.3Hz,2H),0.90(t,J=7.1Hz,3H).

[0104] 13 C NMR(100MHz,CDCl3)δ / ppm 170.17,170.13,154.54,143.96,126.48,123.72,119.94,118.88,82.59,52.51,38.02,34.82,30.95,26.98,26.42,25.86,22.58,14.00.

[0105] HRMS(ESI)m / z calcd for C 20 H 27 N2O2S + [M+H] + :359.1788; found:359.1783

[0106] Example 15 6-Butyl-2-(pyrrolidone-1-yl)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-7)

[0107] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, and then tetrahydropyrrole (0.15 mL, 1.77 mmol) and Et3N (0.2 mL, 2.12 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 477 mg of white solid was obtained, with a yield of 85.3%.

[0108] 1 H NMR(500MHz,CDCl3)δ / ppm 7.83(d,J=7.8Hz,1H),7.32(d,J=8.3Hz,1H),5.57(dd,J=7.9,4.1Hz,1H),3.65(s,4H),2.16 -2.05(m,5H),1.82(ddt,J=18.4,14.0,6.2Hz,1H),1.59-1.38(m,4H),0.94(d,J=7.1Hz,3H).

[0109] 13 C NMR (100MHz, CDCl3) δ / ppm 170.26,167.09,154.87,143.42,126.55,123.69,119.90,118.96,82.61,49.99,34.86,27.03,25.83,22.59,14.01.

[0110] HRMS(ESI)m / z calcd for C 17 H 21 N2O2S + [M+H] + :317.1318; found:317.1313

[0111] Example 16 6-Butyl-2-(piperidin-1-yl)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-1)

[0112] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, and then piperidine (0.18 mL, 1.77 mmol) and Et3N (0.2 mL, 2.12 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 506 mg of white solid was obtained, with a yield of 86.6%.

[0113] 1H NMR(500MHz,CDCl3)δ / ppm 8.39(d,J=8.3Hz,1H),7.47(d,J=8.3Hz,1H),5.64(dd,J=8.0,4.0Hz,1H),4.66-3.19(m,4H),2.0 7(td,J=9.5,4.7Hz,1H),1.83(dd,J=37.7,5.9Hz,7H),1.45-1.33(m,4H),0.86(d,J=6.7Hz,3H).

[0114] 13 C NMR(100MHz,CDCl3)δ / ppm 168.58,167.23,147.05,141.94,121.89,121.76,120.36,119.14,83.43,53.22,34.37,26.89,25.43,23.05,22.42,13.91.

[0115] HRMS(ESI)m / z calcd for C 18 H 23 N2O2S + [M+H] + :331.1475; found:331.1470

[0116] Example 17 2-(azacyclobutane-1-yl)-6-butylisobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK19-36)

[0117] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 0.12 mL (1.77 mmol) of aziridine and 0.2 mL (2.12 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 445 mg of white solid was obtained, with a yield of 83.2%.

[0118] 1 H NMR(500MHz,CDCl3)δ / ppm 7.79(d,J=8.2Hz,1H),7.29(d,J=8.1Hz,1H),5.53(dd,J=7.8,4.0Hz,1H),4.26(t,J=7.5Hz,4H),2. 56(p,J=7.6Hz,2H),2.04-1.98(m,1H),1.86-1.66(m,1H),1.56-1.30(m,4H),0.89(t,J=7.0Hz,3H).

[0119] 13 C NMR (100MHz, CDCl3) δ / ppm 170.41,170.22,155.24,144.22,127.61,124.37,120.34,119.31,82.86,53.56,35.13,27.32,22.88,17.88,14.31.

[0120] HRMS(ESI)m / z calcd for C 16 H 19 N2O2S + [M+H] + :303.1162; found:303.1167

[0121] Example 18 2-(aza-1-yl)-6-butylisobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK19-37)

[0122] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, and then heptamethylimine (0.3 mL, 1.77 mmol) and Et3N (0.2 mL, 2.12 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 514 mg of white solid was obtained, with a yield of 84.3%.

[0123] 1 H NMR(400MHz, CDCl3)δ / ppm 7.81(d,J=8.1Hz,1H),7.31(d,J=8.2Hz,1H),5.57(dd,J=7.7,4.1Hz,1H),3.73(t,J=5.7Hz,4H),2.08(tt,J=9.9,4.9Hz,1H),1.93(td,J=6.8 ,4.1Hz,4H),1.81(tdd,J=14.2,8.6,4.5Hz,1H),1.65(tt,J=6.7,3.9Hz,4H),1.58(q,J=4.5Hz,2H),1.53-1.35(m,4H),0.93(t,J=6.9Hz,3H).

[0124] 13C NMR(100MHz,CDCl3)δ / ppm 170.38,169.43,155.31,143.20,126.59,123.67,119.71,118.67,82.55,52.29,34.84,26.94,26.58,26.17,26.03,22.58,14.00.

[0125] HRMS(ESI)m / z calcd for C 19 H 25 N2O2S + [M+H] + :345.1631; found:345.1633

[0126] Example 19 6-Butyl-2-(3,5-dimethylpiperidin-1-yl)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK19-38)

[0127] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 0.3 mL (1.77 mmol) of 3,5-dimethylpiperidine and 0.2 mL (2.12 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 522 mg of white solid was obtained, with a yield of 82.3%.

[0128] 1 H NMR(500MHz,CDCl3)δ / ppm 7.79(d,J=8.0Hz,1H),7.32(d,J=8.5Hz,1H),5.57(dd,J=8.0,4.1Hz,1H),4.16(d,J=12.6Hz,2H),2.71(t,J=12.3Hz, 2H), 2.09(tt,J=10.2,5.3Hz,1H),1.92(d,J=13.4Hz,1H),1.86-1.80(m,2H),1.55-1.34(m,4H),1.06-0.88(m,11H).

[0129] 13 C NMR(100MHz,CDCl3)δ / ppm 170.20,170.14,143.56,126.58,123.63,119.71,118.77,82.51,56.03,42.03,34.75,30.98,26.92,22.49,18.94,13.92.

[0130] HRMS(ESI)m / z calcd for C 20 H 27 N2O2S + [M+H] + :359.1788; found:359.1788

[0131] Example 20 6-Butyl-2-(2-azaspiro[3.3]hept-2-yl)isobenzofuran[5,4-d]thiazolyl-8(6H)-one (LK19-40)

[0132] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 172 mg (1.77 mmol) of 2-azaspiro[3.3]heptane and 0.2 mL (2.12 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 496 mg of white solid was obtained, with a yield of 81.9%.

[0133] 1 H NMR(500MHz,CDCl3)δ / ppm 7.87-7.76(m,1H),7.32(d,J=8.3Hz,1H),5.56(dd,J=8.2,4.1Hz,1H),4.30-4.14(m,4H),2.29(d,J=7.7Hz,4H ),2.08(qd,J=9.7,4.4Hz,1H),1.93(p,J=7.7Hz,2H),1.84-1.75(m,1H),1.56-1.32(m,5H),0.99-0.86(m,3H).

[0134] 13 C NMR(100MHz,CDCl3)δ / ppm 170.09,169.92,155.09,143.83,127.44,124.04,119.97,118.92,82.50,65.31,40.10,34.79,33.24,26.98,22.55,16.24,13.98.

[0135] HRMS(ESI)m / z calcd for C 19 H 23 N2O2S + [M+H] + :343.1475; found:343.1477

[0136] Example 21 6-Butyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)isobenzofuran[5,4-d]thiazolyl-8(6H)-one (LK19-48)

[0137] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN. Then, 175 mg (1.77 mmol) of 2-oxa-6-aza-spiro[3,3]heptane and 0.2 mL (2.12 mmol) of Et3N were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 491 mg of white solid was obtained, with a yield of 80.6%.

[0138] 1 H NMR(500MHz,CDCl3)δ / ppm 7.80(d,J=8.1Hz,1H),7.39-7.26(m,1H),5.57(s,1H),4.91(s,4H),4.43(s,4H),2. 07(q,J=11.2Hz,1H),1.80(d,J=12.7Hz,1H),1.50-1.29(m,4H),0.95-0.89(m,3H).

[0139] 13 C NMR(125MHz,CDCl3)δ / ppm 169.94,169.60,154.70,144.26,127.37,124.32,119.99,119.08,82.55,80.76,62.46,40.05,34.72,27.01,22.53,13.98.

[0140] HRMS(ESI)m / z calcd for C 18 H 21 N2O3S + [M+H] + :345.1267; found:345.1267

[0141] Example 22 6-Butyl-2-(piperazin-1-yl)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-12)

[0142] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of piperazine (0.14 mL, 1.77 mmol) and Et3N (0.2 mL, 2.12 mmol). The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 505 mg of white solid was obtained, with a yield of 86.2%.

[0143] 1 H NMR(400MHz, CDCl3)δ / ppm 7.75(d,J=8.2Hz,1H),7.28(dd,J=8.2,0.8Hz,1H),5.53(dd,J=7.8,4.1Hz,1H),3.73-3.57(m,4H),3.02(t,J=5.1Hz,4H ), 2.04(ddt,J=8.6,5.7,4.2Hz,1H),1.77(dddd,J=14.5,9.9,7.8,4.9Hz,1H),1.57-1.30(m,4H),0.89(t,J=7.1Hz,3H).

[0144] 13 C NMR (100MHz, CDCl3) δ / ppm 170.90,170.14,154.82,144.00,126.73,124.17,119.89,118.95,82.59,49.62,45.46,34.81,26.99,22.57,14.00.

[0145] HRMS(ESI)m / z calcd for C 17 H 22 N3O2S + [M+H] + :332.1427; found:332.1422

[0146] Example 23 6-Butyl-2-(4-methylpiperazin-1-yl)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-13)

[0147] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, and then N-methylpiperazine (0.2 mL, 1.77 mmol) and Et3N (0.2 mL, 2.12 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 496 mg of white solid was obtained, with a yield of 84.3%.

[0148] 1 H NMR(500MHz,CDCl3)δ / ppm 7.76(d,J=8.2Hz,1H),7.29(d,J=8.2Hz,1H),5.53(dd,J=7.8,4.1Hz,1H),3.70(t,J=5.1Hz,4H),2.55(t,J=5.1Hz,5H) ,2.35(s,3H),2.10-1.98(m,1H),1.77(dddd,J=14.5,10.3,7.6,4.3Hz,1H),1.53-1.29(m,5H),0.89(t,J=7.0Hz,3H).

[0149] 13 C NMR(100MHz,CDCl3)δ / ppm 170.62,170.12,154.85,144.04,126.87,124.19,119.90,118.96,82.58,54.28,48.51,46.19,34.80,26.99,22.57,14.00.

[0150] HRMS(ESI)m / z calcd for C 18 H 24 N3O2S + [M+H] + :346.1584; found:346.1578

[0151] Example 24 6-Butyl-2-morpholinylisobenzofuran[5,4-d]thiazolyl-8(6H)-one (LK17-14)

[0152] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, and then morpholine (0.15 mL, 1.77 mmol) and Et3N (0.2 mL, 2.12 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 491 mg of white solid was obtained, with a yield of 83.6%.

[0153] 1H NMR(500MHz,CDCl3)δ / ppm 7.84(d,J=8.2Hz,1H),7.34(d,J=8.2Hz,1H),5.56(dd,J=7.9,4.1Hz,1H),3.86(t,J=4.8Hz,4H),3.71(t,J=4. 9Hz, 4H), 2.07 (tt, J = 10.2, 4.7Hz, 1H), 1.83-1.75 (m, 1H), 1.40 (th, J = 15.8, 7.8Hz, 4H), 0.91 (t, J = 7.0Hz, 3H).

[0154] 13 C NMR(100MHz,CDCl3)δ / ppm 170.82,169.99,144.52,126.18,124.31,122.74,120.05,119.30,82.69,66.28,58.59,48.93,34.78,27.01,22.57,18.56,14.00.

[0155] HRMS(ESI)m / z calcd for C 17 H 21 N2O3S + [M+H] + :333.1267; found:333.1261

[0156] Example 25 6-Butyl-2-((1-(methanesulfonyl)piperidin-4-yl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-46)

[0157] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 291 mg (1.77 mmol) of 1-methanesulfonylpiperazine and 0.2 mL (2.12 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 616 mg of white solid was obtained, with a yield of 82.3%.

[0158] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.84(d,J=8.2Hz,1H),7.56(dd,J=8.2,0.7Hz,1H),5.70(dd,J=7.6,3.9Hz,1H),3.77(dd,J=6.3,4.1Hz,4H),3 .40-3.26(m,5H),2.93(s,3H),2.16-2.00(m,1H),1.81-1.62(m,1H),1.44-1.23(m,4H),0.86(t,J=7.1Hz,3H).

[0159] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.83,169.64,154.53,144.74,125.96,124.68,120.39,119.51,82.71,48.35,45.16,34.86,34.14,26.93,22.36,14.28.

[0160] HRMS(ESI)m / z calcd for C 19 H 26 N3O4S2 + [M+H] + :424.1359; found:424.1356

[0161] Example 26 6-Butyl-2-(cyclohexylamino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK17-45)

[0162] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then cyclohexylamine (2 mL, 17.7 mmol) was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 488 mg of white solid was obtained, with a yield of 80.1%.

[0163] 1 H NMR(400MHz,DMSO-d6)δ / ppm 7.73(d,J=8.1Hz,1H),7.44(d,J=8.2Hz,1H),5.65(dd,J=7.6,3.8Hz,1H),3.81-3.66(m,1H),2.12-1. 94(m,3H),1.75-1.68(m,2H),1.58(dd,J=10.7,7.0Hz,1H),1.43-1.12(m,10H),0.86(t,J=7.1Hz,3H).

[0164] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.38,166.53,154.65,143.36,125.54,123.12,119.12,118.74,81.99,53.12,33.79,32.19,26.42,25.21,24.37,21.89,13.80.

[0165] HRMS(ESI)m / z calcd for C 19 H 25 N2O2S + [M+H] + :345.1631; found:345.1632

[0166] Example 27 3-((6-Butyl-8-oxo-6,8-dihydroisobenzofurano[5,4-d]thiazolyl)amino)propionic acid (LK17-30)

[0167] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of β-alanine (158 mg, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol). The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 465 mg of white solid was obtained, with a yield of 76.3%.

[0168] 1 H NMR(400MHz,DMSO-d6)δ / ppm 7.81(d,J=8.2Hz,1H),7.54(d,J=8.2Hz,1H),5.69(dd,J=7.7,3.8Hz,1H),3.67(t,J=6.7Hz,2H),2.65(t,J= 6.6Hz,2H),2.07(ddt,J=14.5,9.1,4.7Hz,1H),1.80-1.63(m,1H),1.38-1.18(m,4H),0.85(t,J=6.9Hz,3H).

[0169] 13 C NMR(100MHz,DMSO-d6)δ / ppm 173.08,169.58,167.70,151.25,144.88,124.65,122.93,120.33,119.52,82.76,40.99,34.12,33.63,26.90,22.34,14.27.

[0170] HRMS(ESI)m / z calcd for C 16 H 19 N2O4S + [M+H] + :335.1060; found:335.1055

[0171] Example 28 4-((6-Butyl-8-oxo-6,8-dihydroisobenzofurano[5,4-d]thiazolyl)amino)butyric acid (LK17-27)

[0172] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of γ-aminobutyric acid (183 mg, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol). The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 482 mg of white solid was obtained, with a yield of 78.2%.

[0173] 1 H NMR(400MHz,DMSO-d6)δ / ppm 7.84(d,J=8.2Hz,1H),7.58(d,J=8.2Hz,1H),5.71(dd,J=7.7,3.8Hz,1H),3.52(t,J=7.0Hz,2H),2.37(t,J=7.4Hz,2H),2.07 (td,J=9.5,4.5Hz,1H),1.87(p,J=7.3Hz,2H),1.72(dtd,J=10.2,5.9,2.8Hz,1H),1.47-1.13(m,4H),0.85(t,J=7.0Hz,3H).

[0174] 13 C NMR(100MHz,DMSO-d6)δ / ppm 173.99,168.98,167.32,144.89,126.63,123.12,121.76,120.30,120 .22,119.23,82.47,44.38,33.61,30.90,26.48,23.82,21.90,13.83.

[0175] HRMS(ESI)m / z calcd for C 17 H 21 N2O4S + [M+H] + :349.1217; found:349.1218

[0176] Example 29 5-((6-Butyl-8-oxo-6,8-dihydroisobenzofurano[5,4-d]thiazolyl)amino)valerate (LK17-29)

[0177] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 207 mg (1.77 mmol) of 5-aminovaleric acid and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 492 mg of white solid was obtained, with a yield of 76.8%.

[0178] 1 H NMR(400MHz,DMSO-d6)δ / ppm 7.85(d,J=8.2Hz,1H),7.59(d,J=8.2Hz,1H),5.71(dd,J=7.7,3.8Hz,1H),3.52(t,J=6.5Hz,2H),2. 27(t,J=6.9Hz,2H),2.15-1.99(m,1H),1.80-1.53(m,5H),1.46-1.13(m,5H),0.85(t,J=7.0Hz,3H).

[0179] 13 C NMR(100MHz,DMSO-d6)δ / ppm 174.33,168.96,167.24,148.00,144.95,122.92,121.62,120.37,119.26,82.50,44.86,33.61,33.26,27.77,26.49,21.90,13.83.

[0180] HRMS(ESI)m / z calcd for C 18 H 23 N2O4S + [M+H] + :363.1373; found:363.1372

[0181] Example 30 (6-Butyl-8-oxo-6,8-dihydroisobenzofuran[5,4-d]thiazo-2-yl)proline (LK17-31)

[0182] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of proline (204 mg, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol). The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 484 mg of white solid was obtained, with a yield of 75.9%.

[0183] 1 H NMR(400MHz,DMSO-d6)δ / ppm 7.83(d,J=8.2Hz,1H),7.53(d,J=8.3Hz,1H),5.70(dd,J=7.6,3.8Hz,1H),4.52(s,1H),3.67-3.59(m,1H),3.34(s,1H),2.47-2. 30(m,1H),2.09(ddtd,J=16.1,10.9,7.0,2.8Hz,4H),1.72(ddt,J=13.9,9.8,6.4Hz,1H),1.38-1.22(m,4H),0.90-0.78(m,4H).

[0184] 13 C NMR(100MHz,DMSO-d6)δ / ppm 173.18,169.50,165.87,154.73,143.87,125.64,124.16,119.99,119.26,82.42,62.05,50.36,33.94,30.52,26.68,23.95,22.11,14.03.

[0185] HRMS(ESI)m / z calcd for C 18 H 21 N2O4S + [M+H] + :361.1217; found:361.1219

[0186] Example 31 2-(1-(((6-Butyl-8-oxo-6,8-dihydroisobenzofuran[5,4-d]thiazo-2-yl)amino)methyl)cyclohexyl)acetic acid (LK17-33)

[0187] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 303 mg (1.77 mmol) of 1-(aminomethyl)cyclohexaneacetic acid and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 539 mg of white solid was obtained, with a yield of 73.2%.

[0188] 1 H NMR(400MHz,DMSO-d6)δ / ppm 7.68(d,J=8.1Hz,1H),7.43(d,J=8.1Hz,1H),5.63(dd,J=7.6,3.9Hz,1H),3.54(d,J=4.5Hz,2H),2.46(q,J=1.9Hz,2H),2.29(s,2 H),2.02(tt,J=8.9,5.0Hz,1H),1.72-1.60(m,1H),1.55-1.33(m,10H),1.28(dtd,J=8.9,6.8,2.9Hz,4H),0.82(t,J=6.9Hz,3H).

[0189] 13 C NMR(100MHz,DMSO-d6)δ / ppm 174.52,169.55,158.46,150.46,147.58,127.43,127.03,120.66,119.99,82.92,5 9.04,45.90,44.12,36.79,36.14,34.01,27.03,25.60,22.76,22.35,14.27,8.94.

[0190] HRMS(ESI)m / z calcd for C 22 H 29 N2O4S + [M+H] + :417.1843; found:417.1837

[0191] Example 32 6-Butyl-2-(prop-2-yn-1-ylamino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-21)

[0192] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of THF, and then 1.2 mL (17.7 mmol) of propargylamine was added. The mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 436 mg of white solid was obtained, with a yield of 82.1%.

[0193] 1 H NMR(400MHz, CDCl3)δ / ppm 7.83(d,J=8.2Hz,1H),7.32(dd,J=8.1,0.8Hz,1H),5.56(dd,J=7.7,4.1Hz,1H),4.33(d,J=2.6Hz,2H),2.34(t, J=2.5Hz,1H),2.06(ddt,J=14.2,5.8,4.1Hz,1H),1.90-1.72(m,1H),1.62-1.31(m,4H),0.90(t,J=7.1Hz,3H).

[0194] 13 C NMR(100MHz,CDCl3)δ / ppm 169.72,167.87,153.78,144.45,126.67,124.25,119.72,118.68,82.32,78.60,72.53,34.44,34.34,26.66,22.25,13.68.

[0195] HRMS(ESI)m / z calcd for C 16 H 17 N2O2S + [M+H] + :301.1005; found:301.1009

[0196] Example 33 2-(benzylamino)-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one (LK17-18)

[0197] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, and then benzylamine (0.19 mL, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 500 mg of white solid was obtained, with a yield of 80.2%.

[0198] 1H NMR(400MHz, CDCl3)δ / ppm 7.65(d,J=8.2Hz,1H),7.44-7.23(m,6H),5.60-5.47(m,1H),4.68(s,2H),2.06(dddd,J=14.2,10.1, 5.8,4.1Hz,1H),1.78(dddd,J=14.4,10.0,7.8,5.0Hz,1H),1.58-1.32(m,4H),0.90(t,J=7.1Hz,3H).

[0199] 13 C NMR(100MHz,CDCl3)δ / ppm 170.06,169.54,154.28,144.30,137.07,129.04,128.15,127.86,126. 59,124.00,120.00,118.94,82.57,49.64,34.79,26.98,22.57,14.00.

[0200] HRMS(ESI)m / z calcd for C 20 H 21 N2O2S + [M+H] + :353.1318; found:353.1316

[0201] Example 34 6-Butyl-2-((4-methylbenzyl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-43)

[0202] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 0.23 mL (1.77 mmol) of 4-methylbenzylamine and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 528 mg of white solid was obtained, with a yield of 81.5%.

[0203] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.74(d,J=8.1Hz,1H),7.46(dd,J=8.1,0.8Hz,1H),7.35-7.25(m,2H),7.20-7.10(m,2H),5.66(dd,J=7.6,3.8Hz,1H),4.58(d ,J=5.7Hz,2H),2.27(s,3H),2.13-1.97(m,1H),1.70(ddd,J=14.6,7.2,2.8Hz,1H),1.42-1.17(m,4H),0.85(t,J=7.0Hz,3H).

[0204] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.82,168.10,154.81,144.14,136.77,135.88,129.45,127.94,126.21, 123.89,119.74,119.33,82.53,47.76,34.23,26.90,22.36,21.15,14.27.

[0205] HRMS(ESI)m / z calcd for C 21 H 23 N2O2S + [M+H] + :367.1475; found:367.1475

[0206] Example 35 6-Butyl-2-((4-hydroxybenzyl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-22)

[0207] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 218 mg (1.77 mmol) of 4-hydroxybenzylamine and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 532 mg of white solid was obtained, with a yield of 81.6%.

[0208] 1H NMR(400MHz,MeOD)δ / ppm 7.69(d,J=8.2Hz,1H),7.37(dd,J=8.2,0.8Hz,1H),7.23-7.14(m,2H),6.79-6.68(m,2H),5.57(dd,J=7.8,3.9Hz,1H), 3.27(p,J=1.7Hz,2H),2.07(ddt,J=15.2,9.2,4.5Hz,1H),1.84-1.65(m,1H),1.47-1.29(m,5H),0.88(t,J=7.1Hz,4H).

[0209] 13 C NMR(100MHz,MeOD)δ / ppm 171.82,170.42,158.11,155.51,145.74,130.21,129.88,127.29,124.44,120.54,120.22,116.38,84.22,35.60,28.05,23.49,14.24.

[0210] HRMS(ESI)m / z calcd for C 20 H 21 N2O3S + [M+H] + :369.1267; found:369.1267

[0211] Example 36 2-((4-aminobenzyl)amino)-6-butylisobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-23)

[0212] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 0.2 mL (1.77 mmol) of 4-aminobenzylamine and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 522 mg of white solid was obtained, with a yield of 80.3%.

[0213] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.74(d,J=8.1Hz,1H),7.46(dd,J=8.2,0.7Hz,1H),7.13-7.01(m,2H),6.62-6.45(m,2H),5.66(dd,J=7.6,3.8Hz, 1H),4.43(dd,J=5.3,1.5Hz,2H),2.16-2.01(m,1H),1.80-1.62(m,1H),1.42-1.21(m,4H),0.86(t,J=7.0Hz,3H).

[0214] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.39,167.50,154.46,148.00,143.51,128.72,125.74,124.98,123. 28,119.20,118.81,113.75,82.05,47.60,33.79,26.44,21.90,13.82.

[0215] HRMS(ESI)m / z calcd for C 20 H 22 N3O2S + [M+H] + :368.1427; found:368.1418

[0216] Example 37 6-Butyl-2-((4-methoxybenzyl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-34)

[0217] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 0.23 mL (1.77 mmol) of 4-methoxybenzylamine and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 552 mg of white solid was obtained, with a yield of 81.6%.

[0218] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.74(d,J=8.2Hz,1H),7.49-7.43(m,1H),7.36-7.26(m,2H),6.96-6.86(m,2H),5.66(dd,J=7.6,3.8Hz,1H),4.55(d,J=5.8Hz,2H ),3.72(s,3H),2.06(ddt,J=14.5,8.9,4.5Hz,1H),1.70(dtd,J=14.1,8.8,5.5Hz,1H),1.42-1.15(m,4H),0.85(t,J=7.0Hz,3H).

[0219] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.77,167.98,158.94,154.77,144.08,130.74,129.33,126.14,123.82, 119.69,119.27,114.26,82.48,55.49,47.46,34.18,26.84,22.31,14.22.

[0220] HRMS(ESI)m / z calcd for C 21 H 23 N2O3S + [M+H] + :383.1424; found:383.1421

[0221] Example 38 6-Butyl-2-((4-fluorobenzyl)amino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK17-36)

[0222] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of p-fluorobenzylamine (222 mg, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol). The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 528 mg of white solid was obtained, with a yield of 80.6%.

[0223] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.75(d,J=8.1Hz,1H),7.58-7.39(m,3H),7.30-7.11(m,2H),5.67(dd,J=7.6,3.8Hz,1H),4.63(d,J=5.7H z,2H),2.16-2.01(m,1H),1.71(dtt,J=14.2,10.1,4.6Hz,1H),1.44-1.16(m,4H),0.85(t,J=7.0Hz,3H).

[0224] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.53,167.76,162.80,160.39,154.46,143.98,134.94,134.91,129.74,129.66,125. 95,123.70,119.51,119.09,115.50,115.29,82.27,46.93,33.95,26.63,22.09,14.00.

[0225] HRMS(ESI)m / z calcd for C 20 H 20 FN2O2S + [M+H] + :371.1224; found:371.1223

[0226] Example 39 6-Butyl-2-((4-(trifluoromethyl)benzyl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-19)

[0227] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, and then 0.25 mL (1.77 mmol) of 4-(trifluoromethyl)benzylamine and 0.7 mL (5.31 mmol) of Et3N were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 592 mg of white solid was obtained, with a yield of 79.6%.

[0228] 1H NMR(400MHz, CDCl3)δ / ppm 7.67(d,J=8.2Hz,1H),7.61(d,J=8.2Hz,2H),7.53(d,J=8.1Hz,2H),7.33-7.23(m,1H),5.54(dd,J=7.7,4.1Hz,1 H),4.78(s,2H),2.12-1.99(m,1H),1.77(tdd,J=10.0,7.8,5.2Hz,1H),1.55-1.33(m,4H),0.90(t,J=7.1Hz,3H).

[0229] 13 C NMR(100MHz,CDCl3)δ / ppm 170.06,169.14,154.26,144.60,141.41,127.98,126.72,125.98,125.94, 125.48,124.26,120.07,119.04,82.66,48.83,34.78,26.99,22.57,13.99.

[0230] HRMS(ESI)m / z calcd for C 21 H 20 F3N2O2S + [M+H] + :421.1192; found:421.1189

[0231] Example 40 4-(((6-Butyl-8-oxo-6,8-dihydroisobenzofuran[5,4-d]thiazolyl-2-yl)amino)methyl)benzonitrile (LK17-39)

[0232] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 0.21 mL (1.77 mmol) of 4-cyanoanisole and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 549 mg of white solid was obtained, with a yield of 82.3%.

[0233] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.83-7.75(m,2H),7.69(d,J=8.2Hz,1H),7.59-7.50(m,2H),7.43(d,J=8.2Hz,1H),5.62(dd,J=7.6,3.8Hz,1H),4.7 0(d,J=6.2Hz,2H),2.02(ddt,J=14.6,9.1,4.7Hz,1H),1.74-1.58(m,1H),1.35-1.18(m,4H),0.81(t,J=7.0Hz,3H).

[0234] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.76,168.05,154.57,145.11,144.41,132.89,128.56,126.25,124.10, 119.85,119.39,119.30,110.33,82.56,47.41,34.19,26.89,22.35,14.27.

[0235] HRMS(ESI)m / z calcd for C 21 H 20 N3O2S + [M+H] + :378.1271; found:378.1271

[0236] Example 41 6-Butyl-2-((4-(trifluoromethoxy)benzyl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-40)

[0237] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 0.27 mL (1.77 mmol) of 4-(trifluoromethoxy)benzylamine and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 616 mg of white solid was obtained, with a yield of 79.8%.

[0238] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.76(d,J=8.1Hz,1H),7.58-7.45(m,3H),7.39-7.32(m,2H),5.68(dd,J=7.6,3.8Hz,1H),4.68(dd, J=5.6,1.6Hz,2H),2.15-2.00(m,1H),1.84-1.59(m,1H),1.44-1.15(m,4H),0.86(t,J=7.0Hz,3H).

[0239] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.78,168.04,154.68,147.91,144.32,138.60,129.77,126.23,124.02, 121.83,121.58,119.81,119.37,82.55,47.12,34.21,26.89,22.35,14.26.

[0240] HRMS(ESI)m / z calcd for C 21 H 20 F3N2O3S + [M+H] + :437.1141; found:437.1139

[0241] Example 42 6-Butyl-2-((4-(methanesulfonyl)benzyl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-26)

[0242] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of 328 mg (1.77 mmol) of 4-methylsulfonylbenzylamine and 0.7 mL (5.31 mmol) of Et3N. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 582 mg of white solid was obtained, with a yield of 76.5%.

[0243] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.95-7.88(m,2H),7.74(d,J=8.2Hz,1H),7.67-7.62(m,2H),7.48(dd,J=8.2,0.7Hz,1H),5.67(dd,J=7.5,3.8Hz,1H),4.82-4.7 0(m,2H),3.19(s,3H),2.06(tt,J=9.0,5.2Hz,1H),1.70(dtd,J=14.3,8.8,5.7Hz,1H),1.44-1.18(m,4H),0.85(t,J=7.1Hz,3H).

[0244] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.31,167.58,154.12,144.83,143.94,139.58,128.00,127.23,125.77, 123.64,119.39,118.92,82.10,46.86,43.57,33.71,26.41,21.89,13.81.

[0245] HRMS(ESI)m / z calcd for C 21 H 23 N2O4S2 + [M+H] + :431.1094; found:431.1092

[0246] Example 43 4-(((6-Butyl-8-oxo-6,8-dihydroisobenzofuran[5,4-d]thiazo-2-yl)amino)methyl)benzenesulfonamide (LK17-38)

[0247] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, followed by the addition of sulfabenzylamine (394 mg, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol). The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 574 mg of white solid was obtained, with a yield of 75.3%.

[0248] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.86-7.79(m,2H),7.75(d,J=8.1Hz,1H),7.61-7.53(m,2H),7.48(dd,J=8.2,0.7Hz,1H),5.67(dd,J=7.6,3.8Hz,1H),4.73 (d,J=5.8Hz,2H),2.06(dt,J=9.5,4.1Hz,1H),1.71(ddq,J=17.8,9.9,4.5Hz,1H),1.44-1.20(m,4H),0.86(t,J=7.0Hz,3H).

[0249] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.11,167.38,153.97,143.68,142.72,142.49,127.45,125.66,125. 56,123.40,119.16,118.70,81.89,46.73,33.53,26.22,21.69,13.60.

[0250] HRMS(ESI)m / z calcd for C 20 H 22 N3O4S2 + [M+H] + :432.1046; found:432.1070

[0251] Example 44 2-(benzyl(methyl)amino)-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one (LK17-48)

[0252] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN, and then N-methylbenzylamine (0.23 mL, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 561 mg of white solid was obtained, with a yield of 86.5%.

[0253] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.81(d,J=8.2Hz,1H),7.52(dd,J=8.2,0.7Hz,1H),7.42-7.23(m,5H),5.68(dd,J=7.6,3.8Hz,1H),4.95-4.74(m, 2H),3.20(s,3H),2.19-1.96(m,1H),1.72(ddd,J=14.6,7.2,2.8Hz,1H),1.43-1.19(m,4H),0.85(t,J=7.0Hz,3H).

[0254] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.92,169.72,155.06,144.09,136.94,129.17,127.99,127.78,126.02, 124.24,120.21,119.46,82.64,56.12,38.89,34.19,26.91,22.37,14.27.

[0255] HRMS(ESI)m / z calcd for C 21 H 23 N2O2S + [M+H] + :367.1475; found:367.1470

[0256] Example 45 6-Butyl-2-(methyl(4-methylbenzyl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-49)

[0257] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN. Then, N-methyl-N-(4-methylbenzyl)amine (0.26 mL, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 573 mg of white solid was obtained, with a yield of 85.3%.

[0258] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.81(d,J=8.2Hz,1H),7.52(dd,J=8.2,0.7Hz,1H),7.26-7.10(m,4H),5.68(dd,J=7.6,3.8Hz,1H),4.78(d,J=4.4Hz,2H), 3.17(s,3H),2.27(s,3H),2.13-2.02(m,1H),1.71(ddd,J=14.5,7.2,2.9Hz,1H),1.45-1.14(m,4H),0.85(t,J=7.0Hz,3H).

[0259] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.88,169.72,155.07,144.05,137.21,133.82,129.71,127.85,126.00,124 .21,120.19,119.44,82.63,55.93,38.74,34.20,26.91,22.37,21.15,14.27.

[0260] HRMS(ESI)m / z calcd for C 22 H 25 N2O2S + [M+H] + :381.1631; found:381.1626

[0261] Example 46 6-Butyl-2-((4-methoxybenzyl)(methyl)amino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK17-47)

[0262] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one was dissolved in 20 mL of MeCN. Then, N-(4-methoxybenzyl)-N-methylamine (0.27 mL, 1.77 mmol) and Et3N (0.7 mL, 5.31 mmol) were added. The mixture was stirred at 70 °C. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography. 606 mg of white solid was obtained, with a yield of 86.4%.

[0263] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.81(d,J=8.2Hz,1H),7.52(dd,J=8.2,0.7Hz,1H),7.35-7.21(m,2H),6.96-6.86(m,2H),5.68(dd,J=7.6,3.8Hz,1 H),4.81-4.68(m,2H),3.72(s,3H),2.15-2.00(m,1H),1.81-1.63(m,1H),1.41-1.21(m,4H),0.85(t,J=7.1Hz,3H).

[0264] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.83,169.73,159.23,155.07,144.04,129.35,128.70,125.99,124.19,120 .19,119.44,114.55,82.63,55.62,55.52,38.60,34.20,26.91,22.37,14.27.

[0265] HRMS(ESI)m / z calcd for C 22 H 25 N2O3S + [M+H] + :397.1580; found:397.1574

[0266] Example 47 6-Butyl-2-(phenylamino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK17-50)

[0267] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one, 170 mg (1.77 mmol) of sodium tert-butoxide, 10 mg (10 mg) of palladium acetate (Pd(OAc)2) and 10 mg (10 mg) of Xantphos were placed in a double-necked flask. Under argon protection, 20 mL of PhMe and 0.03 mL (1.77 mmol) were added by injection. The mixture was heated to reflux at 125 °C. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and 20 mL of H2O was added. The organic phase was separated, concentrated, and separated by silica gel column chromatography to obtain 297 mg of white solid, with a yield of 49.6%.

[0268] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.97(d,J=8.2Hz,1H),7.85-7.76(m,2H),7.59(dd,J=8.2,0.7Hz,1H),7.44-7.33(m,2H),7.07(tt,J=7.3,1.1Hz,1H),5.73( dd,J=7.7,3.8Hz,1H),2.11(dddd,J=14.0,9.2,6.4,3.9Hz,1H),1.81-1.67(m,1H),1.50-1.24(m,4H),0.88(t,J=7.0Hz,3H).

[0269] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.26,162.94,153.99,145.07,140.23,129.10,125.36,124.58,122.57,119.70,118.95,118.03,82.22,33.68,26.50,21.89,13.81.

[0270] HRMS(ESI)m / z calcd for C 19 H 19 N2O2S + [M+H] + :339.1162; found:339.1174

[0271] Example 48 6-Butyl-2-(p-Tolueneamino)isobenzofurano[5,4-d]thiazolyl-8(6H)-one (LK18-25)

[0272] 6-Butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one (500 mg, 1.77 mmol), sodium tert-butoxide (170 mg, 1.77 mmol), palladium acetate (Pd(OAc)2) (10 mg), and Xantphos (10 mg) were placed in a double-necked flask. Under argon protection, 20 mL of toluene and 4-methylaniline (190 mg, 1.77 mmol) were added by injection. The mixture was heated to reflux at 125 °C. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and 20 mL of H2O was added. The organic phase was separated, concentrated, and separated by silica gel column chromatography to obtain 300 mg of white solid, with a yield of 48.2%.

[0273] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.92(d,J=8.2Hz,1H),7.75-7.61(m,2H),7.55(dd,J=8.1,0.8Hz,1H),7.26-7.13(m,2H),5.69(dd,J=7.7 ,3.8Hz,1H),2.28(s,3H),2.14-2.02(m,1H),1.79-1.63(m,1H),1.42-1.22(m,4H),0.86(t,J=7.0Hz,3H).

[0274] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.27,163.09,154.10,144.87,137.82,131.60,129.47,125.34,124. 40,119.62,118.92,118.18,82.19,33.71,26.51,21.90,20.44,13.81.

[0275] HRMS(ESI)m / z calcd for C 20 H 21 N2O2S + [M+H] + :353.1318; found:353.1315

[0276] Example 49 6-Butyl-2-((4-fluorophenyl)amino)isobenzofurano[5,4-d]thiazol-8(6H)-one (LK18-24)

[0277] 500 mg (1.77 mmol) of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one, 170 mg (1.77 mmol) of sodium tert-butoxide, 10 mg (10 mg) of palladium acetate (Pd(OAc)2) and 10 mg (10 mg) of Xantphos were placed in a double-necked flask. Under argon protection, 20 mL of toluene and 0.17 mL (1.77 mmol) of 4-fluoroaniline were added by injection. The mixture was heated to reflux at 125 °C. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and 20 mL of H2O was added. The organic phase was separated, concentrated, and separated by silica gel column chromatography to obtain 286 mg of white solid, with a yield of 45.3%.

[0278] 1H NMR(400MHz,DMSO-d6)δ / ppm 7.92(d,J=8.1Hz,1H),7.85-7.77(m,2H),7.55(d,J=8.2Hz,1H),7.32-7.14(m,2H),5.69(dd,J=7.8,3.8 Hz,1H),2.08(ddt,J=14.2,9.1,5.0Hz,1H),1.79-1.64(m,1H),1.47-1.25(m,4H),0.85(t,J=6.9Hz,3H).

[0279] 13 C NMR(100MHz,DMSO-d6)δ / ppm 169.22,163.00,158.79,156.42,153.89,145.05,136.71,136.69,125.33,124.52,1 19.74,119.68,119.66,118.94,115.75,115.53,82.21,33.68,26.52,21.88,13.79.

[0280] HRMS(ESI)m / z calcd for C 19 H 18 FN2O2S + [M+H] + :357.1068; found:357.1090 Pharmacological experiments

[0281] The phthalimide-thiazolamine derivatives (I) disclosed in this invention were screened for bioactivity as follows.

[0282] Experimental Example 1. Inhibitory activity of phthalimide-thiazolamine derivatives (I) on electric shock convulsions in mice.

[0283] Using a mouse model of maximal electroshock seizures, we explored the effects of phthalimide-thiazolidinylamine derivatives (I) on electroconvulsive seizures in mice.

[0284] Experimental materials:

[0285] Animals: Male ICR mice, Beijing Huafukang Experimental Animal Technology Co., Ltd.

[0286] Experimental reagents and instruments:

[0287] Carbamazepine (Cas No: 298-46-4), store sealed and protected from light at -20℃. Prepare with pure water. Oral administration volume: 10 ml / kg.

[0288] Test samples: LK16-44, LK17-01, LK17-16, LK17-21, LK17-27, LK17-31, LK17-33, LK17-34; stored at 4℃ in a sealed container protected from light. Grind 1‰ Tween 80 and prepare with physiological saline. Intraperitoneal injection volume: 10 ml / kg.

[0289] Instrument: LYS-9A Physiological and Pharmacological Electronic Stimulator, Jinan Yiyan Technology Development Co., Ltd.

[0290] Experimental Groups:

[0291] The experiment was divided into 10 groups: Model, Carbamazepine - 2 mg / kg, LK16-44 - 10 mg / kg, LK16-44 - 50 mg / kg, LK17-01 - 10 mg / kg, LK17-01 - 50 mg / kg, LK17-16 - 10 mg / kg, LK17-16 - 50 mg / kg, LK17-21 - 10 mg / kg, LK17 -21-50mg / kg, LK17-27-10mg / kg, LK17-27-50mg / kg, LK17-31-10mg / kg, LK17-31-50mg / kg, LK17-33-10mg / kg, LK17-33-50mg / kg, LK17-34-10mg / kg, LK17-34-50mg / kg, N=8.

[0292] Experimental methods:

[0293] Model preparation and drug administration:

[0294] The procedure was performed according to Chapter 25, "Experimental Methods for Anticonvulsant Drugs - Electroconvulsion Method," page 862 of *Pharmacological Experimental Methodology* (3rd Edition, Xu Shuyun). The test drug was injected intraperitoneally one day before and 30 minutes before electrical stimulation (the model group received an equal volume of physiological saline). Positive control drugs were administered via gavage only once 30 minutes before stimulation. Parameter settings included: continuous wave output; waveform: square wave + gap + negative square wave; voltage 80V; wave width 2ms; gap 1ms; wave number 40; current 4mA. During the experiment, a suitable amount of physiological saline was applied to both ears of the animal, and the ear electrodes were clamped to the tips of both ears to apply the current. The electroconvulsive events in the mice were observed and recorded (the occurrence of hind limb rigidity was used as the criterion for convulsion): the number of convulsions and deaths, and the duration of convulsions.

[0295] Data processing:

[0296] The number of mice experiencing seizures and deaths in each group was statistically analyzed using the chi-square test. A p-value < 0.05 was considered statistically significant when comparing the treatment group and the model group. The duration of seizures was assessed using the TTest test, again comparing the treatment group and the model group; a p-value < 0.05 was considered statistically significant.

[0297] Experimental results:

[0298] Table 1. Statistics on the number of cases and duration of seizures in the maximal electroshock seizure (MES) experiment (mean ± SEM) of phthalthiazole derivatives (I).

[0299]

[0300]

[0301] Compared with the model group: *P<0.05, **P<0.01.

[0302] 2. Inhibitory activity of phthalimide-thiazolamine derivatives (I) against pentylenetetrazol (PTZ)-induced epilepsy in mice.

[0303] Using a pentylenetetrazol-induced mouse epilepsy model, we investigated the effect of benzothiazolamine derivatives (I) on epileptic seizures in mice.

[0304] Experimental materials:

[0305] Animals: Male ICR mice, Beijing Huafukang Experimental Animal Technology Co., Ltd.

[0306] Experimental reagents and instruments:

[0307] Pentylenetetrazole (PTZ): Purchased from Sigma, catalog number P6500, prepared with normal saline, freshly prepared for use. Intraperitoneal injection volume: 10 ml / kg. Dosage: 65 mg / kg.

[0308] Diazepam tablets: Purchased from the hospital, batch number: 20180402, approval number: H11020898. Dissolved in pure water, oral administration volume: 10 ml / kg. Test samples: LK16-44, LK17-01, LK17-16, LK17-21, LK17-27, LK17-31, LK17-33, LK17-34; stored at 4℃, sealed and protected from light. Grind 1‰ Tween 80 and dissolve in physiological saline. Intraperitoneal injection volume: 10 ml / kg.

[0309] Instrument: LYS-9A Physiological and Pharmacological Electronic Stimulator, Jinan Yiyan Technology Development Co., Ltd.

[0310] Experimental Groups:

[0311] The experiment was divided into 10 groups: Model, Diazepam - 2 mg / kg, LK16-44-10 mg / kg, LK16-44-50 mg / kg, LK17-01-10 mg / kg, LK17-01-50 mg / kg, LK17-16-10 mg / kg, LK17-16-50 mg / kg, LK17-21-10 mg / kg, LK17- 21-50mg / kg, LK17-27-10mg / kg, LK17-27-50mg / kg, LK17-31-10mg / kg, LK17-31-50mg / kg, LK17-33-10mg / kg, LK17-33-50mg / kg, LK17-34-10mg / kg, LK17-34-50mg / kg, N=8.

[0312] Experimental methods:

[0313] Model preparation and drug administration:

[0314] The test drug was administered once the afternoon before modeling. The model group received an equal volume of physiological saline. On the day of modeling, 30 minutes after the intraperitoneal injection of the test drug, PTZ-65 mg / kg (the modeling agent) was injected into the contralateral intraperitoneal cavity. The positive control drug was administered once 20 minutes before modeling. Observation continued for 15 minutes after PTZ injection.

[0315] Observation indicators: ① Seizure frequency: duration of seizures ranging from grade III to VI; ② Mortality.

[0316] Seizure severity: Refer to the Racine classification: Grade 0: No response; Grade I: Twitching of facial muscles or corner of the mouth; Grade II: Head nodding; Grade III: Twitching of one limb; Grade IV: Tonic or generalized limb twitching; Grade V: Generalized tonic seizure (generalized tonic-clonic seizure).

[0317] Data processing:

[0318] The number of mice experiencing seizures and deaths in each group was recorded in the statistical experiment; the latency periods for grade III and IV seizures were also recorded, along with the seizure grade. The latency period for mice that did not experience a seizure up to grade IV was recorded as the maximum value of 900 seconds, and the seizure grade for deceased mice was recorded as grade V. The chi-square test was used to statistically analyze the number of cases. The mean and standard error of the latency were calculated using TTEST. The model group was compared with other groups, and a p-value < 0.05 was considered statistically significant.

[0319] Experimental results:

[0320] Table 2. Statistics of the number of cases in the experiment of phthalimide thiazolamide derivatives (I) on PTZ-induced epilepsy in mice.

[0321]

[0322]

[0323] Compared with the model group: *P<0.05, **P<0.01.

[0324] Table 3. Latency (mean ± SEM) of phthalthiazole derivatives (I) in PTZ-induced seizures in mice - grade III and IV epileptic seizures.

[0325]

[0326] Compared with the model group: *P<0.05, **P<0.01

[0327] Discussion of experimental results:

[0328] In an experiment evaluating the anticonvulsant activity of phthalimide derivatives using a mouse maximal electroconvulsive disorder (EMS) model, compound LK17-01, at a dose of 50 mg / kg, exhibited significantly better inhibitory activity against EMS compared to other compounds, reducing the seizure rate in mice to 43% and shortening the seizure duration to 4.4 s, showing a significant difference from other groups. Furthermore, at a dose of 50 mg / kg, compound LK17-27 reduced the seizure duration in mice to 7.3 s, also showing a significant difference from other groups. The results of different dose groups of the same compound indicate that the anticonvulsant activity of some compounds does not exhibit dose-dependent characteristics.

[0329] In evaluating the antiepileptic activity using a PTZ-induced mouse epilepsy model, unlike the results of the antielectroconvulsant activity test, compounds LK17-01 and LK17-27 did not show good antiepileptic activity even at a dose of 50 mg / kg. However, at a dose of 50 mg / kg, compound LK17-31 reduced the rate of grade IV seizures in mice to 38%, increased the latency of grade IV seizures to 621.3 s, and controlled the seizure grade to 3.4, showing significant differences from other groups. Compound LK17-16, at a dose of 10 mg / kg, significantly increased the latency of grade IV seizures to 604.1 s; however, at a dose of 50 mg / kg, the latency of grade IV seizures actually decreased.

[0330] In summary, compounds LK17-01 and LK17-31 exhibited different inhibitory activities in different animal models of epilepsy, i.e., different types of epilepsy. LK17-01 showed good inhibitory activity in the electrical stimulation model, i.e., it could inhibit tonic-clonic seizures; while LK17-31 showed good inhibitory activity in the pentylenetetrazole (PTZ)-induced mouse epilepsy model, i.e., it could inhibit myoclonic seizures.

Claims

1. A class of phthalimide-thiazolamine derivatives and their pharmaceutically acceptable salts, characterized in that, The general chemical structural formula of this type of compound is shown in (I): Wherein, R1 and R2 independently represent hydrogen atoms, methyl or C1-C10 straight-chain, branched alkyl or C3-C10 cycloalkyl or C1-C10 straight-chain, branched alkyl or C3-C10 cycloalkyl or carboxyl or cyano, or substituted or unsubstituted C6-C10 aromatic groups, wherein the aromatic group may be substituted by one or more of the following groups: F, Cl, Br, NO2, NH2, OH, CN, CF3, OCF3, SO2CH3, SO2NH2, OCH3 or N(CH3)2; the compound is an R configuration, an S configuration or a racemic mixture; the heteroatom is selected from oxygen, nitrogen, and sulfur; R1 and R2 can be the same or different.

2. The phthalylthiazolamide derivatives according to claim 1 and their pharmaceutically acceptable salts, characterized in that, The compound is:

3. A method for preparing any phthalimide-thiazolamine derivative and its pharmaceutically acceptable salt as described in any one of claims 1 to 2, characterized in that, The preparation steps are as follows: (1) Preparation of intermediates (b) 3-n-Butylphthalide (a) was added to an appropriate amount of concentrated sulfuric acid, with a volume ratio of a to concentrated sulfuric acid of 1:(1.5-2.0). At 0 degrees Celsius, a mixed solution of concentrated nitric acid and concentrated sulfuric acid was added dropwise, with an equivalent ratio of concentrated nitric acid to a of 1:1.5 and a volume ratio of concentrated nitric acid to concentrated sulfuric acid of 1:1.

5. The mixture was stirred at 0 degrees Celsius for 1 hour, and then stirred at room temperature for 3 hours before the reaction was stopped. An appropriate amount of water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried, and concentrated by column chromatography to obtain a pale yellow liquid. (2) Preparation of intermediate 6-amino-3-n-butylphthalide (c) At room temperature, 6-nitro-3-n-butylphthalide (b) was added to a mixed solvent of ethanol and water (volume ratio of ethanol to water: 4.5:1). Iron powder and ammonium chloride were then added to the mixture, with the equivalent ratio of b to iron powder being 1:10 and the equivalent ratio of b to ammonium chloride being 1:

1. The reaction was stopped after reflux for 10 hours under argon protection. The iron powder was removed by hot filtration, and the solvent was removed by cooling and vacuum. The product was separated by silica gel column chromatography [petroleum ether: ethyl acetate (v:v) = (3~5):1] to obtain a pale yellow solid. (3) 2-Amino-6-butylisobenzofuran[5,4-d]thiazolyl-8(6H)-one(d) Add 6-amino-3-n-butylphthalide (c) to an appropriate amount of acetonitrile, stir, add 1 equivalent of ammonium thiocyanate and 1 equivalent of benzyltrimethylammonium tribromide, stir at room temperature for 5-6 hours, add saturated sodium bicarbonate solution to the reaction solution, precipitate solid, filter, wash with water, dry, and obtain a yellow solid; (4) 6-Butyl-2-chloroisobenzofuran[5,4-d]thiazolyl-8(6H)-one(e) Dissolve appropriate amounts of copper chloride and nitrosotert-butyl ester in appropriate amounts of acetonitrile. At 0 degrees Celsius, add 2-amino-6-butylisobenzofuran[5,4-d]thiazol-8(6H)-one (d) to the reaction flask in 5 portions, with an interval of 15 minutes between each addition. The equivalent ratio of d to copper chloride and nitrosotert-butyl ester is 1:1.5:1.

5. Stop the reaction after stirring or refluxing at room temperature for 4-6 hours. Filter, add 6M hydrochloric acid, remove the organic solvent under reduced pressure, filter, wash the filter cake with water, and obtain a light yellow solid. (5) Benphthalthiazoleamine derivatives (f) Add an appropriate amount of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one(e) to acetonitrile, and add 1 equivalent of the substituted amine (R1R2NH) and 1.2 equivalents of the substituted triethylamine. Reflux for 8-10 hours, concentrate, dissolve in ethyl acetate, and separate the product by silica gel column chromatography [petroleum ether: ethyl acetate (v:v) = (8-12):1] to obtain a yellow or white solid; or add an appropriate amount of 6-butyl-2-chloroisobenzofuran[5,4-d]thiazol-8(6H)-one(e) to tetrahydrofuran, and add 10 equivalents of the substituted amine (R1R2NH). Stir for 12 hours and stop the reaction. Separate the product by silica gel column chromatography [petroleum ether: ethyl acetate (v:v) = (8-15):1] to obtain a yellow or white solid.

4. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the benzothiazolamide derivatives of any one of claims 1 to 2 and their pharmaceutically acceptable salts or pharmaceutically acceptable carriers or excipients.

5. The pharmaceutical composition according to claim 4, characterized in that, The pharmaceutical composition comprises an oral dosage form, an injection, a respiratory dosage form, or a combination of various pharmaceutical carriers and / or diluents, whichever is a pharmaceutically acceptable dosage form.

6. The use of the phthalimide-thiazolamine derivatives and their pharmaceutically acceptable salts as described in any one of claims 1 to 2 in the preparation of medicaments for the treatment and / or prevention of epilepsy with cognitive impairment.

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