Polysubstituted 5-aminoisothiazole derivative as well as preparation method and application thereof

Abstract

The invention discloses a polysubstituted 5-aminoisothiazole derivative, the chemical structural formula of the polysubstituted 5-aminoisothiazole derivative is shown in the specification, a molecule containing a sulfoxide structure is converted into a 5-aminoisothiazole compound containing a specific C-S bond structure through a Pummerer rearrangement reaction, a large number of candidate structures are provided for discovery and development of new drugs, and the polysubstituted 5-aminoisothiazole derivative has a wide application prospect. The polysubstituted 5-aminoisothiazole derivative is applied to prevention and treatment of diabetes mellitus, and experimental results show that the compound has different degrees of activity of promoting 3T3-L1 fat cells to uptake extracellular glucose, so that the compound can be applied to prevention and treatment of diabetes mellitus. The medicine effect of reducing fasting blood-glucose and oral glucose tolerance of a mouse suffering from high-glucose and high-fat induced type 2 diabetes mellitus is achieved; # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a multi-substituted 5-aminoisothiazole derivative and a preparation method thereof, belonging to the field of organic synthesis; the present invention also relates to the use of the multi-substituted 5-aminoisothiazole derivative in the prevention and treatment of diabetes, belonging to the field of pharmaceutical technology. Background Art

[0002] The presence of C-S bonds often endows molecules with special chemical properties, enabling them to play a key role in certain specific biological processes, mainly manifested in the biological activities of natural products and drug molecules. Isothiazole is a five-membered heterocyclic compound containing a C-S bond. In 1956, isothiazole compounds were first discovered and reported by Adams and Slack. In recent decades, in-depth research has been carried out on the synthesis and application transformation of isothiazole and its derivatives. Among them, small molecule compounds containing 5-aminoisothiazole exhibit good biological activities. However, the synthesis methods of 5-aminoisothiazole are still few and single. Therefore, novel synthesis methods are urgently needed to provide more structurally novel 5-aminoisothiazole derivatives for use in drug design and synthesis. The applicant found that the Pummerer rearrangement reaction is an effective way to convert molecules containing a sulfoxide structure into a C-S single bond. Its characteristic is that the raw material must contain a cyano functional group, which is the source of the amino group in the 5-aminoisothiazole structure and the carbon source of the C-S bond. The discovery and application of this reaction provide a new direction for the one-step synthesis of 5-aminoisothiazole compounds containing a specific C-S bond structure.

[0003] Diabetes is a common chronic non-communicable disease. The main symptoms of type 2 diabetes patients are hyperglycemia, hyperlipidemia, insulin resistance, etc., which are also the main causes leading to cataracts, infections, fatty liver, cardiovascular diseases, diabetic foot, and even death. When diabetes is severe, long-term medication is required, resulting in a large amount of medical expenses. In this urgently needed drug market environment, the independent research and development of new drugs for the treatment of diabetes remains a hot topic in pharmaceutical research. Through pharmacological experimental research, the present invention found that novel 5-amino-substituted isothiazole derivatives have a significant hypoglycemic effect. Summary of the Invention

[0004] The present invention provides a multi-substituted 5-aminoisothiazole derivative. At the same time, the present invention found that the Pummerer rearrangement reaction is an effective way to convert molecules containing a sulfoxide structure into a C-S single bond. The discovery and application of this reaction provide new ideas and directions for the synthesis of 5-aminoisothiazole compounds containing a specific C-S bond structure. The substrates of this method are easy to prepare from commercially available raw materials, the reaction conditions are mild, no transition metal catalysis is required, no highly toxic and highly odorous reagents are used, it has the characteristics of wide generality, the synthesized 5-aminoisothiazole compounds contain multiple functional groups and are convenient for derivatization, providing more structurally novel structures for drug research.

[0005] The chemical structural formula of the multi-substituted 5-aminoisothiazole derivative of the present invention is as follows:

[0006]

[0007] R 1 is selected from substituted or unsubstituted C 5 -C 18 alkyl, C 2 -C 24 alkenyl, C 3 -C 6 cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, C 3 -C 8 heterocycloalkyl; when R 1 contains a substituent, R 1-1 is the substituent group on R 1 R 1-1 is selected from nitro, Boc, halogen, C 1 -C 6 alkyl, TBS-protected hydroxyl, hydroxyl, trifluoromethyl, trifluoroethyl, C 1 -C 6 alkoxy, 6-10-membered aryl-substituted C 1 -C 6 alkoxy, 6-10-membered aryl, 5-10-membered heteroaryl;

[0008] R 2 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl; when R 2 contains a substituent, R 1-1 is the substituent group on R 2 R 1-1 is selected from 6-10-membered aryl, C 2 -C 6 alkenyl;

[0009] R 3 is selected from hydrogen, trifluoroacetyl, acetyl, benzoyl, cinnamoyl, C 1 -C 18 alkanoyl, methanesulfonyl, trifluoromethanesulfonyl, benzene and substituted benzene sulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, fluorine-substituted benzene sulfonyl, C 2 -C 18 alkyl acyl, C 2 -C 23 alkenyl acyl, C 3 -C 6Cycloalkyl-substituted formyl, 5- to 10-membered heteroaryl-substituted formyl, C 3 -C 6 Saturated heterocyclic group-substituted formyl;

[0010] R 4 Selected from hydrogen, C 1 -C 18 Alkyl, C 2 -C 24 Alkenyl, C 3 -C 6 Cycloalkyl.

[0011] The preparation method of the multi-substituted 5-aminoisothiazole derivative of the present invention is as follows:

[0012] 1. Add one of trifluoroacetic anhydride, difluoroacetic anhydride, and acyl chloride and a protonic acid or a Lewis acid to a solvent, and react with Compound 1 by stirring at 0 °C for 10 to 20 minutes, then raise the temperature to 25 °C and stir to react to generate a multi-substituted 5-aminoisothiazole derivative 2;

[0013]

[0014] The protonic acid or Lewis acid is selected from p-toluenesulfonic acid, boron trifluoride diethyl etherate, benzenesulfonic acid, methanesulfonic acid, acetic acid, sulfuric acid, benzoic acid, trifluoromethanesulfonic anhydride, phosphorus oxychloride (POCl 3 ); zinc dichloride, ferric trichloride.

[0015] The molar ratio of Compound 1 to the protonic acid or Lewis acid is 1:1 to 5, the molar ratio of Compound 1 to one of trifluoroacetic anhydride, difluoroacetic anhydride, and acyl chloride is 1:1 to 6, the solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, and tetrahydrofuran, and the concentration of the acid anhydride in the solvent is 0.01 mol / L to 10 mol / L;

[0016] 2. In the presence of a solvent, react the multi-substituted 5-aminoisothiazole derivative 2 with one of an alkyl halide, an alkenyl halide, an alkyl aldehyde, and an alkenyl aldehyde with a base or / and a reducing agent to obtain Compound I-1; or react the multi-substituted 5-aminoisothiazole derivative 2 with one of an alkyl acyl chloride, an alkenyl acyl chloride, an alkyl sulfonyl chloride, an alkenyl sulfonyl chloride, an amino acid, an alkyl carboxylic acid, and an alkenyl carboxylic acid with a base or / and a condensing agent to obtain a multi-substituted 5-aminoisothiazole derivative I-1;

[0017]

[0018] The solvent is selected from acetonitrile, methanol, and dichloromethane; the base is selected from K 2 CO 3, triethylamine, N-methylimidazole (NMI); the reducing agent is selected from sodium cyanoborohydride, and the condensing agent is selected from tetramethylchlorourea hexafluorophosphate (TCFH);

[0019] 3. In the presence of a solvent, the polysubstituted 5-aminoisothiazole derivative I-1 reacts with one of an alkyl acyl chloride, an alkenyl acyl chloride, an alkyl sulfonyl chloride, an alkenyl sulfonyl chloride, an amino acid, an alkyl carboxylic acid or an alkenyl carboxylic acid in the presence of a base or / and a condensing agent to obtain a polysubstituted 5-aminoisothiazole derivative I-2;

[0020]

[0021] The solvent is selected from dichloromethane, acetonitrile, 1,2-dichloroethane; the base is selected from triethylamine, N-methylimidazole (NMI); the condensing agent is selected from tetramethylchlorourea hexafluorophosphate (TCFH).

[0022] The compound obtained by the above method has any of the following structures:

[0023]

[0024]

[0025] Another object of the present invention is to apply the above-mentioned polysubstituted 5-aminoisothiazole derivative in the preparation of drugs for preventing and treating diabetes.

[0026] Through pharmacological experimental research, the present invention finds that the polysubstituted 5-aminoisothiazole derivative has a significant hypoglycemic effect, and there is a dose-effect relationship between the drug effects.

[0027] The polysubstituted 5-aminoisothiazole derivative having a hypoglycemic effect has any of the following structures:

[0028]

[0029] In vitro cell experiments show that: the polysubstituted 5-aminoisothiazole derivatives 386-2-2, IS-4, IS-5, IS-11, IS-12, IS-16, IS-18, IS-22, IS-28, IS-29, IS-18Aa, IS-21B, IS-2A, IS-2J, IS-2K, IS-2L, IS-3B all have the activity of promoting the glucose uptake of 3T3-L1 adipocytes to varying degrees at 20 μM. The drug effects of the compounds IS-2J, IS-2K, IS-2L, IS-19C, IS-4 on the glucose uptake of 3T3-L1 adipocytes cultured in high glucose all have a dose-effect relationship; in vivo animal experiments show that 386-2-2 (20 mg / kg, 80 mg / kg) both have the drug effects of reducing the fasting blood glucose and oral glucose tolerance of type 2 diabetic mice induced by high glucose and high fat to varying degrees.

[0030] The above compounds provided by the present invention have great potential application value in the development of drugs, health products and functional foods for the prevention and treatment of diabetes.

[0031] When the compounds of the present invention are used as drugs, they can be used directly or in the form of pharmaceutical compositions, and the rest are common pharmaceutical carriers and / or excipients that are pharmaceutically acceptable, non-toxic and inert to humans and animals. The pharmaceutical compositions of the present invention are used in the form of the dosage per unit body weight. Different pharmaceutical excipients can be used to prepare solid preparations (tablets, capsules, granules, powders, etc.) or liquid preparations (injections, solutions, suspensions, emulsions, syrups, etc.). The drugs of the present invention can be administered orally and by injection (intravenous injection, intravenous drip, intramuscular injection, subcutaneous injection, intraperitoneal injection, etc.).

[0032] In the present invention, unless otherwise specified, the following terms appearing in the specification and claims of the present invention have the following meanings:

[0033] The term "alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group including a specified number of carbon atoms, and the alkyl can be independently and optionally substituted by one or more substituents described in the present invention. Thus, "C 1 -C 6 alkyl" refers to an alkyl having 1-6 carbon atoms (for example, C 1 -C 3 alkyl, and for another example, methyl); specific examples thereof include but are not limited to: methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 )) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 )) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 ))CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 )) 3 ), n-pentyl (-CH 2 CH 2 CH2 CH 2 CH 3 )、2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 )、3-pentyl (-CH(CH 2 CH 3 ) 2 )、2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 )、3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 )、3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 )、2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 )、n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 )、4-methylpentyl (-CH 2 CH 2 CH 2 CH(CH 3 )CH 3 )、3-methylpentyl (-CH 2 CH 2 CH(CH 3 )CH 2 CH 3 )、2-methylpentyl (-CH 2 CH(CH 3 )CH 2 CH 2 CH 3 )、2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 )、3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3)、3,3 - dimethylbutyl (-CH 2 CH 2 CH 2 (CH 3 ) 2 CH 3 )、2,2 - dimethylbutyl (-CH 2 C(CH 3 ) 2 CH 2 CH 3 )、2 - methyl - 2 - pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 )、3 - methyl - 2 - pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 )、4 - methyl - 2 - pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 )、3 - methyl - 3 - pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 )、2 - methyl - 3 - pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3 - dimethyl - 2 - butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ) or 3,3 - dimethyl - 2 - butyl (-CH(CH 3 )C(CH 3 ) 3 )。

[0034] In the present invention, the term "alkenyl" refers to a straight - chain or branched - chain group containing a specified number of carbon atoms and at least one carbon - carbon double bond. Preferably, there is one carbon - carbon double bond, and up to four non - aromatic carbon - carbon double bonds may be present. Thus, "C 2 -C 6 alkenyl" refers to an alkenyl group having 2 - 6 carbon atoms (for example, C 2 -C 4 alkenyl or C 2 -C 3(alkenyl), including vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight-chain, branched-chain, or cyclic portion of the alkenyl may contain a double bond, and if indicated as a substituted alkenyl, it may be substituted.

[0035] The term "C 3 -C 8 cycloalkyl" means a cyclic hydrocarbon group containing 3 - 8 ring-forming carbon atoms that does not contain heteroatoms; including monocyclic with 3 - 8 carbon atoms or bicyclic or tricyclic (including spiro, bridged, and fused ring systems) with 5 - 8 carbon atoms; wherein one or more hydrogen atoms on the ring are independently optionally substituted by one or more substituents described in the present invention, and the carbon atoms may be oxidized. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like.

[0036] The term "C 2 -C 8 heterocycloalkyl" means a 3 - 12 membered monocyclic or polycyclic group (including spiro, bridged, and fused rings, preferably 5 - 6 membered monocyclic) containing 1, 2, 3, or 4 heteroatoms (selected from one or more of N, S, and O), wherein each ring may contain one or more double bonds, but no ring has a completely conjugated π - electron system; the heteroatoms may or may not be substituted, and the N atom may be quaternized. Suitable heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3 - dioxolanyl, 1,4 - dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiazolyl, etc.

[0037] The term "heteroaryl" refers to a 5- to 10-membered monocyclic or polycyclic aromatic system (preferably a 5- to 6-membered monocyclic aromatic system) containing 1, 2, 3, or 4 heteroatoms (selected from one or more of N, S, and O). The heteroaryl can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. Heteroaryl includes, but is not limited to, a monocyclic ring consisting of 3 to 7 atoms, or a bicyclic ring consisting of 7 to 10 atoms. The bicyclic ring with 7 to 10 atoms can be a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heteroaryl includes, but is not limited to: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl, benzimidazolyl, benzoxazolyl, quinoxalinyl, phthalazinyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolin), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), or tetrahydronaphthyl.

[0038] The term "aryl" refers to a monocyclic or bicyclic carbocyclic system, wherein at least one ring system is aromatic, each ring system contains 3 to 7 carbon atoms, and one or more hydrogen atoms on the ring are independently and optionally substituted by one or more substituents described in the present invention. For example, but not limited to, phenyl, naphthyl, and anthracene.

[0039] In the present invention, Boc refers to tert-butoxycarbonyl; TFAA refers to trifluoroacetic anhydride.

[0040] The advantages and technical effects of the present invention are as follows:

[0041] (1) The present invention utilizes the Pummerer rearrangement reaction, which is an effective way to transform molecules containing sulfoxide structures into C-S single bonds. Its characteristic is that the raw material must contain a cyano functional group, which is the source of the amino group in the 5-aminoisothiazole structure and the carbon source of the C-S bond. The discovery and application of this reaction provide a new direction for the one-step synthesis of 5-aminoisothiazole compounds containing specific C-S bond structures. It can obtain polysubstituted 5-aminoisothiazole compounds that are difficult to prepare by other methods, and such isothiazoles are more easily derivatized, providing a large number of candidate structures for the discovery and development of new drugs and laying a foundation for drug innovation including pesticides;

[0042] (2) The polysubstituted 5-aminoisothiazole derivatives provided by the present invention have the effect of preventing and treating diabetes. Description of the Drawings

[0043] Figure 1 It is the detection result of the activity of polysubstituted 5-aminoisothiazole derivatives in promoting glucose uptake by adipocytes;

[0044] Figure 2 It is the result of the dose-effect relationship of some 5-aminoisothiazole compounds on glucose uptake by 3T3-L1 mature adipocytes;

[0045] In the above figures, *, **, or *** represent the statistical differences from Con, which are p < 0.05, 0.01, or 0.001 respectively;

[0046] Figure 3 It is the result of the effect of compound 386-2-2 on the fasting blood glucose of type 2 diabetic mice induced by high glucose and high fat (the effect of the drug on the fasting blood glucose of mice 1 h after the fifth administration);

[0047] Figure 4 It is the result of the effect of compound 386-2-2 on the oral glucose tolerance of type 2 diabetic mice induced by high glucose and high fat. The left figure shows the blood glucose values of oral glucose tolerance; the right figure is the quantification graph of the area under the curve of the data in the left figure;

[0048] Figure 3-4 In it, **, ***, or **** represent the statistical differences from HFFD, which are p < 0.01, 0.001, or 0.0001 respectively, and # represents the statistical difference between HFFD and the Normal group is p < 0.0001. Detailed Embodiments

[0049] The present invention will be further elaborated in detail below in conjunction with specific embodiments. The embodiments are only used to explain the present invention and are not intended to limit the scope of the present invention. Unless otherwise specified, the test methods used in the following embodiments are all conventional methods; the materials, reagents, etc. used, unless otherwise specified, are reagents and materials that can be obtained from commercial channels.

[0050] Example 1: Synthesis of Multi-Substituted 5-Aminoisothiazole Derivatives

[0051] Add the tert-butanesulfinamide compound 1 (1.0 mmol) and dichloromethane (10 mL) into a round-bottom flask. After dissolution, add p-toluenesulfonic acid (1.0 mmol) and trifluoroacetic anhydride (TFAA, 1.5 mmol) successively at 0 °C. After reacting for 10 min, raise the temperature to 25 °C and stir the reaction. After the reaction is completed, add Na 2 CO 3 saturated aqueous solution (5 mL) and stir well for 1 h. Then, distill under reduced pressure at 40 °C to remove the dichloromethane solvent. Add water (10 mL) for dilution, extract with EA (3 × 50 mL), collect and combine the extraction liquid, dry it with anhydrous sodium sulfate, filter, and then remove the solvent from the filtrate under reduced pressure. Separate the product by silica gel column chromatography, and the eluent is petroleum ether:ethyl acetate = 6:1 - 1:1 to obtain compound 2;

[0052]

[0053] Referring to the above method, only change the raw materials accordingly to obtain the compounds in 1 - 46 as follows:

[0054] 1. 3-phenylisothiazol-5-amine, yield 71%;

[0055]

[0056] 1 H NMR(600MHz,DMSO-d 6 )δ7.83(dt,J=7.38Hz,J=1.38Hz,2H),7.41(td,J=6.72Hz,J=1.38Hz,2H),7.36(dt,J=7.9,3.7Hz,1H),6.74(s,2H),6.63(s,1H). 13 C NMR(150MHz,DMSO-d 6 )δ174.63,165.48,135.33,128.67,128.64,126.26,99.85.

[0057] 2. 3-(naphthalen-1-yl)isothiazol-5-amine, yield 50%;

[0058]

[0059] 1 H NMR(600MHz, DMSO-d 6 ) δ8.45(dd, J = 6.4, 3.5Hz, 1H), 7.95(t, J = 6.7Hz, 2H), 7.63(dd, J = 7.1, 1.3Hz, 1H), 7.58 - 7.47(m, 3H), 6.82(s, 2H), 6.47(s, 1H). 13 C NMR(150MHz, DMSO-d 6 ) δ173.97, 166.41, 133.96, 133.50, 130.57, 128.72, 128.28, 126.85, 126.44, 125.99, 125.90, 125.40, 103.98.

[0060] 3. 3-(anthracen-9-yl)isothiazol-5-amine, yield 65%,;

[0061]

[0062] 1 H NMR(400MHz, DMSO-d 6 ) δ8.66(s, 1H), 8.12(d, J = 7.9Hz, 2H), 7.74(d, J = 8.6Hz, 2H), 7.56 - 7.43(m, 4H), 6.94(s, 2H), 6.34(s, 1H). 13 C NMR(100MHz, DMSO-d 6 ) δ174.24, 164.89, 131.85, 130.79, 129.55, 128.33, 127.19, 125.98(d, J = 9.4Hz), 125.45, 105.79.

[0063] 4. 3-(quinolin-6-yl)isothiazol-5-amine, yield 43%;

[0064]

[0065] 1 H NMR(600MHz, DMSO-d 6) δ 8.96 (s, 1H), 8.61 (s, 1H), 8.54 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.61 (dd, J = 8.3, 4.2 Hz, 1H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 174.78, 162.80, 151.11, 147.67, 136.81, 131.83, 129.39, 127.81, 127.58, 126.01, 121.98, 108.89.

[0066] 5, 3-(dec-9-en-1-yl)isothiazol-5-amine, yield 70%;

[0067]

[0068] 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.49 (s, 2H), 5.96 (s, 1H), 5.77 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 4.97 (d, J = 17.2 Hz, 1H), 4.92 (d, J = 10.2 Hz, 1H), 2.47 - 2.37 (m, 2H), 1.98 (q, J = 6.8 Hz, 2H), 1.56 - 1.48 (m, 2H), 1.36 - 1.16 (m, 10H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 173.38, 170.17, 138.84, 114.66, 101.89, 33.16, 32.91, 28.75, 28.46, 28.32, 28.22.

[0069] 6, (E)-3-(prop-1-en-1-yl)isothiazol-5-amine, yield 43%;

[0070]

[0071] 1 H NMR (600 MHz, DMSO-d 6 ) δ 6.55 (s, 1H), 6.24 (s, 1H), 1.80 (s, 1H). 13 C NMR (150 MHz, DMSO-d 6) δ 173.32, 165.70, 130.03, 127.25, 99.25, 18.13.

[0072] 7, 3-(tert-butyl)isothiazol-5-amine, yield 78%;

[0073]

[0074] 1 H NMR (600 MHz, DMSO-d 6 ) δ 6.43 (s, 2H), 6.09 (s, 1H), 1.19 (s, 9H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 177.82, 173.39, 99.83, 35.95, 29.89.

[0075] 8, 3-neopentylisothiazol-5-amine, yield 64%;

[0076]

[0077] 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.48 (s, 2H), 5.93 (s, 1H), 2.36 (s, 2H), 0.89 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 172.84, 167.88, 104.02, 46.74, 31.26, 29.64.

[0078] 9, 3-cyclopropylisothiazol-5-amine, yield 61%;

[0079]

[0080] 1 H NMR (600 MHz, DMSO-d 6 ) δ 6.48 (s, 2H), 5.90 (s, 1H), 1.87 (s, 1H), 0.89 - 0.65 (m, 4H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 173.40, 171.20, 100.08, 13.92, 8.42.

[0081] 10、3-cyclobutylisothiazol-5-amine, yield 50%;

[0082]

[0083] 1 H NMR(400MHz, DMSO-d 6 ) δ6.51(s, 2H), 6.01(s, 1H), 3.35(p, J = 8.6Hz, 1H), 2.23 - 2.04(m, 4H), 1.97 - 1.71(m, 2H). 13 C NMR(100MHz, DMSO-d 6 ) δ173.88, 173.58, 100.86, 38.09, 28.17, 18.26.

[0084] 11、3-cyclohexylisothiazol-5-amine, yield 85%;

[0085]

[0086] 1 H NMR(400MHz, DMSO-d 6 ) δ6.47(s, 2H), 5.99(s, 1H), 2.45(s, 1H), 1.83 - 1.14(m, 10H). 13 C NMR(100MHz, DMSO-d 6 ) δ174.85, 173.46, 100.78, 42.19, 32.29, 26.01, 25.86.

[0087] 12、(E)-3-styrylisothiazol-5-amine, yield 64%;

[0088]

[0089] 1 H NMR(600MHz, DMSO-d 6 ) δ7.59(s, 2H), 7.37(s, 2H), 7.29(s, 1H), 7.19(d, J = 16.5Hz, 1H), 7.02(d, J = 16.3Hz, 1H), 6.66(s, 2H), 6.45(s, 1H). 13 C NMR(150MHz, DMSO-d 6)δ 173.63, 165.30, 136.43, 132.07, 128.79, 128.21, 126.79, 123.87, 99.96.

[0090] 13. 3-(4-Fluorophenyl)isothiazol-5-amine, yield 54%;

[0091]

[0092] 1 H NMR(400 MHz, DMSO-d 6 )δ 7.88 (dd, J = 8.6, 5.7 Hz, 2H), 7.31 - 7.19 (m, 2H), 6.77 (s, 2H), 6.62 (s, 1H). 13 C NMR(100 MHz, DMSO-d 6 )δ 175.20, 164.80, 161.55, 132.35, 128.76, 115.79, 100.14.

[0093] 14. 3-(4-Chlorophenyl)isothiazol-5-amine, yield 82%;

[0094]

[0095] 1 H NMR(600 MHz, DMSO-d 6 )δ 7.84 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 6.78 (s, 2H), 6.63 (s, 1H). 13 C NMR(150 MHz, DMSO-d 6 )δ 174.93, 164.12, 134.05, 133.24, 128.64, 127.99, 99.73.

[0096] 15. 3-(4-Bromophenyl)isothiazol-5-amine, yield 43%;

[0097]

[0098] 1 H NMR(400 MHz, DMSO-d 6 )δ 7.91 (s, 2H), 7.69 (s, 2H), 7.60 (s, 1H). 13 C NMR(101 MHz, DMSO-d6 ) δ 162.97, 160.24, 133.67, 132.38, 129.01, 123.34, 109.17.

[0099] 16. 3-(4-nitrophenyl)isothiazol-5-amine, yield 56%;

[0100]

[0101] 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.33 (d, J = 8.2 Hz, 2H), 8.24 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 161.46, 160.38, 147.71, 139.54, 127.75, 124.25, 109.43.

[0102] 17. 3-(2,5-dimethoxyphenyl)isothiazol-5-amine, yield 60%;

[0103]

[0104] 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.39 (s, 1H), 7.02 (d, J = 5.1 Hz, 1H), 6.92 (d, J = 5.5 Hz, 1H), 6.73 (s, 1H), 6.62 (s, 2H), 3.77 (s, 3H), 3.72 (s, 3H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 173.66, 162.71, 153.07, 150.47, 125.27, 115.24, 114.07, 113.58, 104.10, 56.20, 55.40.

[0105] 18. 3-(2,3,4-trimethoxyphenyl)isothiazol-5-amine, yield 78%;

[0106]

[0107] 1 H NMR (600 MHz, DMSO-d 6)δ 7.53 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.64 (s, 1H), 6.62 (s, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.73 (s, 3H). 13 C NMR (150 MHz, DMSO-d 6 )δ 173.79, 162.65, 153.79, 151.09, 141.94, 123.90, 122.68, 108.13, 102.92, 60.95, 60.47, 55.88.

[0108] 19. 3-(3-((tert-butyldimethylsilyl)oxy)-4-methoxyphenyl)isothiazol-5-amine, yield 77%;

[0109]

[0110] 1 H NMR (400 MHz, DMSO-d 6 )δ 7.98 (d, J = 1.2 Hz, 1H), 7.97 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.47 (s, 1H), 4.32 (s, 3H), 1.47 (s, 9H), 0.63 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 )δ 216.00, 174.28, 169.20, 162.70, 155.55, 138.37, 131.05, 129.37, 122.51, 118.81, 65.49, 35.76, 28.71, 5.24.

[0111] 20. 3-(benzo[b]thiophen-3-yl)isothiazol-5-amine, yield 50%;

[0112]

[0113] 1 H NMR (400 MHz, DMSO-d 6 )δ 8.80 (d, J = 7.4 Hz, 1H), 8.17 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.50 - 7.34 (m, 2H), 6.78 (s, 2H), 6.67 (s, 1H). 13 C NMR (100 MHz, DMSO-d 6)δ173.36,162.25,139.84,136.86,131.51,127.45,125.06,124.67,122.79,101.31.

[0114] 21. 3-(benzofuran-3-yl)isothiazol-5-amine, yield 52%;

[0115]

[0116] 1 H NMR(600MHz, DMSO-d 6 )δ8.52(s, 1H), 8.29(d, J = 7.6Hz, 1H), 7.62(d, J = 7.9Hz, 1H), 7.41 - 7.26(m, 2H), 6.79(s, 2H), 6.63(s, 1H). 13 C NMR(150MHz, DMSO-d 6 )δ173.69, 159.35, 154.94, 144.94, 125.26, 124.90, 123.43, 122.52, 117.79, 111.45, 100.18.

[0117] 22. 3-(thiophen-3-yl)isothiazol-5-amine, yield 49%;

[0118]

[0119] 1 H NMR(400MHz, DMSO-d 6 )δ7.50(s, 1H), 7.44(s, 1H), 7.07(s, 1H), 6.79(s, 2H), 6.55(s, 1H). 13 C NMR(100MHz, DMSO-d 6 )δ174.40, 160.36, 139.83, 127.77, 126.92, 125.45, 99.25.

[0120] 23. tert-butyl 4-(5-aminoisothiazol-3-yl)piperidine-1-carboxylate, yield 17%;

[0121]

[0122] 1 H NMR(600MHz, DMSO-d6 ) δ 6.53 (s, 2H), 6.00 (s, 1H), 3.97 - 3.93 (m, 2H), 2.78 (s, 2H), 2.66 (tt, J = 11.6, 3.7 Hz, 1H), 1.80 (d, J = 12.4 Hz, 2H), 1.43 (d, J = 3.9 Hz, 2H), 1.39 (s, 9H). 13 C NMR (150 MHz, DMSO - d 6 ) δ 173.66, 172.78, 153.98, 100.52, 78.58, 39.94, 39.10, 30.96, 28.13.

[0123] 24. 3-(pyridin - 3 - yl)isothiazol - 5 - amine, yield 49%;

[0124]

[0125] 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.22 (s, 1H), 8.70 (d, J = 4.5 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.64 (dd, J = 7.9, 4.9 Hz, 1H). 13 C NMR (100 MHz, DMSO - d 6 ) δ 160.67, 160.17, 148.93, 146.40, 135.48, 130.28, 124.69, 109.01.

[0126] 25. 3 - cyclopentylisothiazol - 5 - amine, yield 63%;

[0127]

[0128] 1 H NMR (400 MHz, DMSO - d 6 ) δ 6.06 (s, 2H), 5.58 (s, 1H), 2.09 (d, J = 1.8 Hz, 1H), 1.51 - 1.09 (m, 8H). 13 C NMR (100 MHz, DMSO - d 6 ) δ 174.11, 173.56, 101.18, 43.57, 32.34, 25.24.

[0129] 26. 3-(4-morpholinophenyl)isothiazol-5-amine, yield 30%;

[0130]

[0131] 1 H NMR(400MHz, DMSO-d 6 ) δ 7.83(s, 2H), 7.51(s, 1H), 7.02(s, 2H), 3.74(s, 4H), 3.18(s, 4H). 13 C NMR(100MHz, DMSO-d 6 ) δ 163.77, 151.77, 127.54, 124.91, 117.05, 114.63, 108.19, 66.08, 47.74.

[0132] 27. 3-(4-(tert-butyl)phenyl)isothiazol-5-amine, yield 55%;

[0133]

[0134] 1 H NMR(400MHz, DMSO-d 6 ) δ 7.75(d, J = 8.4Hz, 2H), 7.42(d, J = 8.4Hz, 2H), 6.72(s, 2H), 6.59(s, 1H), 1.29(s, 9H). 13 C NMR(100MHz, DMSO-d 6 ) δ 174.85, 165.89, 151.56, 133.17, 126.46, 125.79, 100.15, 34.85, 31.51.

[0135] 28. 3-(1-methyl-1H-pyrrol-2-yl)isothiazol-5-amine, yield 49%;

[0136]

[0137] 1 H NMR(400MHz, DMSO-d 6 ) δ 6.78(t, J = 2.2Hz, 1H), 6.60(s, 2H), 6.38(dd, J = 3.7, 1.8Hz, 1H), 6.35(s, 1H), 5.99(dd, J = 3.7, 2.6Hz, 1H), 3.89(s, 3H). 1313C NMR (100 MHz, DMSO-d 6 ) δ 172.76, 160.38, 128.82, 125.85, 110.62, 107.23, 101.04, 36.85.

[0138] 29. 3-(o-tolyl)isothiazol-5-amine, yield 72%;

[0139]

[0140] 1 1H NMR (600 MHz, DMSO-d 6 ) δ 7.40 (d, J = 7.5 Hz, 1H), 7.28 - 7.19 (m, 3H), 6.69 (s, 2H), 6.32 (s, 1H), 2.38 (s, 3H). 13 13C NMR (151 MHz, DMSO-d 6 ) δ 173.72, 167.17, 136.08, 135.47, 130.77, 128.99, 128.15, 125.73, 103.26, 20.72.

[0141] 30. 3-(4-methoxyphenyl)isothiazol-5-amine;

[0142] Referring to the above synthesis method, different acids were used according to the following table, and the yields are shown in the following table;

[0143]

[0144] Serial number Reagent Yield of IS-31 % Serial number Reagent Yield of IS-31 % 1 TsOH 89 2 TfOH / 3 <![CDATA[H 2 SO 4 > 70 4 TFA 80 5 <![CDATA[BF 3 ·OEt 2 > 32 6 MsOH 65 7 AcOH 41

[0145] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.77 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.69 (s, 2H), 6.56 (s, 1H), 3.77 (s, 3H). 13 13C NMR (100 MHz, DMSO-d 6 ) δ 174.31, 165.23, 159.62, 128.27, 127.66, 113.91, 99.44, 55.17.

[0146] 31、3-((2R,3R)-2-(benzo[d][1,3]dioxol-5-yl)-7-methoxy-3-methyl-2,3-dihydrobenzofuran-5-yl)isothiazol-5-amine, yield 43%;

[0147]

[0148] 1 H NMR(400MHz,Chloroform-d)δ7.23(s,1H),7.07(s,1H),6.78(s,1H),6.73(d,J = 8.0Hz,1H),6.64(d,J = 7.8Hz,1H),6.47(d,J = 2.2Hz,1H),5.79(s,2H),4.99(d,J = 8.9Hz,1H),3.78(s,3H),3.30(p,J = 7.2Hz,1H),1.25(d,J = 6.8Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ172.21,167.01,148.16,147.95,147.71,144.19,134.02,133.12,129.70,120.29,114.67,110.22,108.14,106.79,103.02,101.17,93.72,56.08,45.67,17.93.

[0149] 32、4-allyl-3-(anthracen-9-yl)isothiazol-5-amine, yield 38%;

[0150]

[0151] 1 H NMR(400MHz,DMSO-d 6 )δ8.67(s,1H),8.12(d,J = 8.3Hz,2H),7.55 - 7.39(m,6H),6.61(s,1H),5.27(d,J = 6.6Hz,1H),4.53 - 4.41(m,2H),2.72(d,J = 5.8Hz,2H). 13 C NMR(100MHz,DMSO-d 6)δ170.13,165.52,135.30,132.05,131.22,130.25,128.83,127.70,126.45,126.27,125.88,115.07,114.12,28.99.

[0152] 33. 4-allyl-3-(quinolin-6-yl)isothiazol-5-amine, yield 23%;

[0153]

[0154] 1 H NMR(600MHz, DMSO-d 6 )δ9.00(d, J = 4.0Hz, 1H), 8.50(d, J = 8.2Hz, 1H), 8.25(s, 1H), 8.13(d, J = 8.7Hz, 1H), 8.01(d, J = 8.7Hz, 1H), 7.64(ddt, J = 8.5, 4.4, 2.6Hz, 1H), 6.00 - 5.80(m, 1H), 4.99(d, J = 10.1Hz, 1H), 4.79(d, J = 18.7Hz, 1H), 3.75(d, J = 5.1Hz, 2H). 13 C NMR(151MHz, DMSO-d 6 )δ170.64, 163.63, 151.05, 146.89, 137.19, 135.74, 133.41, 129.76, 128.62, 127.80, 127.60, 122.11, 120.65, 115.61, 28.77.

[0155] 34. 4-allyl-3-(tert-butyl)isothiazol-5-amine, yield 16%;

[0156]

[0157] 1 H NLJM-7RB(600MHz, DMSO-d 6 )δ5.98(s, 2H), 5.83 - 5.75(m, 1H), 5.00 - 4.90(m, 2H), 3.30(d, J = 5.4Hz, 2H), 1.24(s, 9H). 13 C NMR(150MHz, DMSO-d 6 )δ174.52, 170.21, 136.19, 115.15, 110.31, 37.40, 29.92, 29.67.

[0158] 35. 4-allyl-3-(benzofuran-3-yl)isothiazol-5-amine, yield 45%;

[0159]

[0160] 1 H NMR(600MHz, DMSO-d 6 )δ8.20(s, 1H), 8.17(d, J = 7.7Hz, 1H), 7.62(d, J = 8.2Hz, 1H), 7.36(t, J = 7.7Hz, 1H), 7.31(t, J = 7.5Hz, 1H), 6.47(s, 2H), 5.88(ddt, J = 15.9, 10.5, 5.5Hz, 1H), 5.02 - 4.90(m, 2H), 3.37(s, 2H). 13 C NMR(151MHz, DMSO-d 6 )δ170.25, 158.94, 154.69, 143.56, 136.23, 126.82, 125.35, 123.68, 123.19, 117.60, 115.38, 111.69, 111.09, 28.61.

[0161] 36. 4-allyl-3-(pyrimidin-5-yl)isothiazol-5-amine, yield 8%;

[0162]

[0163] 1 H NMR(600MHz, DMSO-d 6 )δ9.21(s, 1H), 8.93(s, 2H), 6.62(s, 2H), 5.89 - 5.76(m, 1H), 4.97(d, J = 11.3Hz, 1H), 4.84(d, J = 18.5Hz, 1H), 3.26(d, J = 5.4Hz, 2H). 13 C NMR(150MHz, DMSO-d 6 )δ171.23, 160.42, 157.88, 155.29, 135.94, 130.52, 115.15, 110.60, 28.14.

[0164] 37. 4-allyl-3-(4-methoxyphenyl)isothiazol-5-amine, yield 89%;

[0165]

[0166] 1 1H NMR (600 MHz, Chloroform-d) δ 7.37 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 5.77 (ddt, J = 17.2, 10.2, 5.2 Hz, 1H), 5.14 - 4.74 (m, 2H), 4.59 (s, 2H), 3.67 (s, 3H), 3.25 - 2.88 (m, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 168.62, 167.38, 159.68, 134.75, 129.30, 129.19, 115.76, 113.61, 112.56, 55.16, 29.65.

[0167] 38. 4 - allyl - 3 - (2 - methoxyphenyl)isothiazol - 5 - amine, yield 75%;

[0168]

[0169] 1 1H NMR (400 MHz, Chloroform-d) δ 7.49 - 7.14 (m, 2H), 7.14 - 6.75 (m, 2H), 5.75 (ddt, J = 16.4, 10.2, 6.0 Hz, 1H), 5.15 - 4.87 (m, 2H), 4.61 (s, 2H), 3.73 (s, 3H), 3.04 (d, J = 6.0 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 167.64, 165.82, 156.73, 135.21, 130.89, 129.98, 125.89, 120.49, 115.50, 114.52, 110.74, 55.29, 30.04.

[0170] 39. 4 - allyl - 3 - (3,4 - dimethoxyphenyl)isothiazol - 5 - amine, yield 75%

[0171]

[0172] 11H NMR (400 MHz, Chloroform-d) δ 6.97 - 6.87 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 5.72 (ddt, J = 17.1, 10.3, 5.3 Hz, 1H), 4.95 - 4.68 (m, 2H), 3.56 (d, J = 7.2 Hz, 6H), 3.05 (d, J = 4.9 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 170.25, 166.42, 149.06, 148.45, 136.34, 129.79, 120.27, 114.96, 111.62, 111.36, 110.28, 55.55, 55.53, 29.07.

[0173] 40. 4-allyl-3-(4-(trifluoromethyl)phenyl)isothiazol-5-amine, yield 57%;

[0174]

[0175] 1 1H NMR (600 MHz, DMSO-d 6 ) δ 7.79 - 7.56 (m, 4H), 6.45 (s, 2H), 5.79 (ddt, J = 17.3, 10.4, 5.4 Hz, 1H), 5.06 - 4.71 (m, 2H), 3.18 (d, J = 5.5 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d 6 ) δ 170.99, 164.90, 140.80, 135.88, 128.73 (J 2 = 32.1), 128.59, 125.21 (J 3 = 3.75), 124.31 (J 1 = 260.25), 115.05, 110.51.

[0176] 41. 4-allyl-3-(2,3,4-trifluorophenyl)isothiazol-5-amine, yield 89%;

[0177]

[0178] 11H NMR (600 MHz, Chloroform-d) δ 7.69 (dd, J = 8.8, 6.7 Hz, 2H), 6.85 (s, 2H), 6.17 (ddt, J = 17.3, 10.4, 5.4 Hz, 1H), 5.33 (dd, J = 10.2, 2.0 Hz, 1H), 5.20 (dd, J = 17.2, 2.0 Hz, 1H), 3.62 - 3.45 (m, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 171.60, 163.10, 151.36, 151.33, 151.29, 151.27, 149.72, 149.69, 149.65, 149.63, 140.10, 138.44, 136.36, 133.69, 133.66, 115.44, 112.72, 112.69, 112.60, 112.57, 110.40, 28.79.

[0179] 42. 4-benzyl-3-cyclohexylisothiazol-5-amine, yield 67%;

[0180]

[0181] 1 1H NMR (600 MHz, DMSO-d 6 ) δ 7.18 (t, J = 7.5 Hz, 2H), 7.10 - 7.04 (m, 3H), 6.23 (s, 2H), 3.69 (s, 2H), 2.44 (s, 1H), 1.57 - 1.06 (m, 10H). 13 13C NMR (150 MHz, DMSO-d 6 ) δ 173.47, 141.32, 128.63, 126.19, 112.24, 32.06, 29.76, 26.47, 26.15.

[0182] 43. 4-benzyl-3-(4-nitrophenyl)isothiazol-5-amine, yield 28%;

[0183]

[0184] 1 1H NMR (600 MHz, DMSO-d 6) δ 8.19 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.13 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 7.6 Hz, 2H), 6.71 (s, 2H), 3.92 (s, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) δ 172.04, 164.64, 147.48, 143.42, 140.40, 129.40, 128.84, 128.18, 123.92, 30.06.

[0185] 44. 4-benzyl-3-(2,3,4-trimethoxyphenyl)isothiazol-5-amine, yield 77%;

[0186]

[0187] 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.13 (t, J = 7.5 Hz, 2H), 6.88 (d, J = 7.4 Hz, 2H), 6.75 (s, 2H), 6.39 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.66 (s, 2H), 3.48 (s, 3H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 169.28, 165.42, 153.94, 151.65, 140.82, 128.38, 125.97, 125.20, 114.18, 107.80, 61.39, 60.96, 56.29, 30.21.

[0188] 45. 4-benzyl-3-(3-((tert-butyldimethylsilyl)oxy)-4-methoxyphenyl)isothiazol-5-amine, yield 87%;

[0189]

[0190] 1 H NMR (400 MHz, DMSO-d 6) δ 7.31 - 7.10 (m, 4H), 7.09 - 6.90 (m, 4H), 6.80 (s, 1H), 6.51 (s, 1H), 3.86 (s, 2H), 3.76 (s, 3H), 0.86 (s, 9H), -0.00 (s, 6H). 13 C NMR (101 MHz, DMSO - d 6 ) δ 171.09, 151.11, 144.02, 140.64, 130.10, 128.83, 128.11, 126.26, 122.09, 120.32, 112.40, 111.33, 55.81, 30.45, 25.96, 18.52, -4.41.

[0191] 46. 4 - benzyl - 3 - cyclopentylisothiazol - 5 - amine, yield 67%;

[0192]

[0193] 1 H NMR (600 MHz, DMSO - d 6 ) δ 7.26 (t, J = 7.5 Hz, 2H), 7.14 (dd, J = 20.1, 7.4 Hz, 3H), 6.30 (s, 2H), 3.79 (s, 2H), 2.91 (s, 1H), 1.54 (d, J = 100.6 Hz, 8H). 13 C NMR (151 MHz, DMSO - d 6 ) δ 172.55, 169.51, 141.20, 128.65, 126.17, 112.58, 41.60, 31.93, 29.74, 25.70.

[0194] Example 2: Synthesis of polysubstituted 5 - aminoisothiazole derivatives

[0195] 1. Add compound 2 (1.0 mmol), K 2 CO 3 (2.0 mmol), alkyl halide or alkenyl halide (1.5 mmol), and acetonitrile (10 mL) into a pressure - resistant sealed tube. After reacting at 60 °C for 6 h, distill under reduced pressure at 40 °C, and separate the product by silica gel column chromatography. The eluent is petroleum ether:ethyl acetate = 20:1 to obtain compound I - 1;

[0196]

[0197] Refer to the above method to obtain compound 47, as follows:

[0198] 47. N-allyl-3-(4-methoxyphenyl)isothiazol-5-amine, yield 45%;

[0199]

[0200] 1 H NMR(500MHz,Chloroform-d)δ7.64 - 7.58(m,2H),7.31(s,1H),6.90 - 6.85(m,2H),5.91(tt,J=13.7,6.2Hz,1H),5.52(t,J=4.4Hz,1H),5.20(dt,J=13.4,1.0Hz,2H),4.23(ddt,J=6.3,4.3,1.0Hz,2H),3.84(s,2H). 13 C NMR(125MHz,Common NMR Solvents)δ167.93,161.53,158.95,133.76,129.17,128.40,115.99,113.74,102.68,55.32,48.73.

[0201] 2. Add compound 2 (1.0 mmol), aldehyde (1.0 mmol), sodium cyanoborohydride (2 mmol), acetic acid (2 mmol), and methanol (10 mL) into a round-bottom flask, react at 25 °C, after monitoring the reaction by TLC until it is completed, add water (5 mL) in batches and stir for 0.1 h, then distill under reduced pressure at 50 °C to remove methanol, add water (10 mL) for dilution, extract with EA (3 × 50 mL), collect and combine the extraction solutions, dry with anhydrous sodium sulfate, filter, then remove the solvent from the filtrate under reduced pressure, and separate the product by silica gel column chromatography with the eluent of petroleum ether:ethyl acetate = 15:1 - 10:1 to obtain compound I-1;

[0202] Refer to the above method to obtain compound 48, specifically as follows:

[0203] 48. N-benzyl-3-(4-methoxyphenyl)isothiazol-5-amine, yield 52%;

[0204]

[0205] 11H NMR (500 MHz, Chloroform-d) δ 7.69 - 7.64 (m, 2H), 7.37 (ddt, J = 7.3, 1.6, 0.9 Hz, 2H), 7.36 - 7.28 (m, 2H), 7.28 - 7.21 (m, 1H), 7.14 (s, 1H), 6.91 - 6.85 (m, 2H), 6.54 (t, J = 8.7 Hz, 1H), 4.78 (dt, J = 8.6, 1.0 Hz, 2H), 3.83 (s, 2H). 13 13C NMR (125 MHz, Common NMR Solvents) δ 168.95, 161.26, 159.28, 139.07, 129.90, 128.60, 128.36, 127.93, 127.49, 114.03, 102.10, 55.35, 48.77.

[0206] 3. Add compound 2 (1.0 mmol), triethylamine (2.0 mmol), acyl chloride or acid anhydride (1.5 mmol), and dichloromethane (10 mL) to a round-bottom flask. React at 25 °C. After monitoring the reaction by TLC until it is complete, perform distillation under reduced pressure at 40 °C. Separate the product by silica gel column chromatography with an eluent of petroleum ether:ethyl acetate = 15:1 - 10:1 to obtain compound I-1;

[0207] Refer to the above method and only change the raw materials accordingly to obtain the compounds in items 49 - 57 as follows:

[0208] 49. N-(3-(4-methoxyphenyl)isothiazol-5-yl)cyclohexanecarboxamide, yield 45%;

[0209]

[0210] 1 1H NMR (500 MHz, Chloroform-d) δ 7.69 - 7.63 (m, 1H), 6.91 - 6.85 (m, 1H), 3.82 (s, 1H), 2.56 - 2.47 (m, 0H), 1.96 - 1.84 (m, 1H), 1.73 - 1.59 (m, 2H), 1.57 - 1.40 (m, 2H). 13 13C NMR (125 MHz, Common NMR Solvents) δ 173.29, 167.04, 160.65, 159.26, 128.64, 128.29, 114.03, 107.27, 55.35, 42.65, 29.43, 25.65, 25.29.

[0211] 50. N-(3-cyclohexylisothiazol-5-yl)pivalamide, yield 57%;

[0212]

[0213] 1 H NMR (500 MHz, Chloroform-d) δ 2.89 - 2.80 (m, 0H), 1.86 - 1.56 (m, 4H), 1.59 - 1.38 (m, 1H), 1.12 (s, 3H). 13 C NMR (125 MHz, Common NMR Solvents) δ 176.11, 175.97, 168.51, 108.49, 40.70, 39.55, 32.18, 27.57, 26.33, 26.10.

[0214] 51. 4-methoxy-N-(3-(4-methoxyphenyl)isothiazol-5-yl)benzamide, yield 32%;

[0215]

[0216] 1 H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 8.9 Hz, 4H), 6.98 (d, J = 8.9 Hz, 4H), 3.89 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 175.04, 165.62, 160.06, 138.87, 129.28, 129.17, 128.83, 128.58, 128.44, 128.09, 127.92, 127.59, 127.02, 126.82, 126.80, 114.25, 97.96, 63.32, 62.20, 55.53, 50.43.

[0217] 52. 2,2,2-trifluoro-N-(3-(4-nitrophenyl)isothiazol-5-yl)acetamide, yield 70%;

[0218]

[0219] 1 H NMR (400 MHz, DMSO-d 6) δ 8.31 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 8.9 Hz, 2H), 7.70 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 161.83, 160.80, 155.321 (J 2 =39.0), 148.09, 139.95, 128.13, 124.64, 115.926 (J 1 =284.6), 109.82.

[0220] 53. 2,2,2 - trifluoro - N-(3-(2,3,4 - trimethoxyphenyl)isothiazol - 5 - yl)acetamide, yield 90%;

[0221]

[0222] 1 H NMR (600 MHz, Chloroform - d) δ 7.81 - 7.62 (m, 2H), 6.97 (t, J = 7.7 Hz, 1H), 3.94 - 3.77 (m, 9H). 13 C NMR (151 MHz, Chloroform - d) δ 161.16, 159.70, 115.92 (J 2 =36.1), 154.91, 151.60, 142.36, 124.40, 121.47, 115.931 (J 1 =289.0), 112.14, 108.79, 61.39, 60.85, 56.31.

[0223] 54. 2,2,2 - trifluoro - N-(3 - phenylisothiazol - 5 - yl)acetamide, yield 76%;

[0224]

[0225] 1 H NMR (400 MHz, Chloroform - d) δ 7.82 - 7.76 (m, 2H), 7.49 - 7.43 (m, 3H), 7.42 - 7.35 (m, 1H). 13 C NMR (101 MHz, Chloroform - d) δ 164.08, 159.74, 155.05 (J 2= 38.9), 134.49, 129.84, 129.34, 126.92, 115.90 (J 1 = 284.5), 109.16.

[0226] 55. (E)-2,2,2-trifluoro-N-(3-styrylisothiazol-5-yl)acetamide, yield 51%;

[0227]

[0228] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 - 7.61 (m, 2H), 7.56 - 7.31 (m, 6H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 163.60, 155.10 (J 2 = 38.7), 136.44, 134.07, 129.25, 129.07, 127.52, 123.04, 115.96 (J 1 = 284.4), 110.04.

[0229] 56. 2,2,2-trifluoro-N-(3-(4-fluorophenyl)isothiazol-5-yl)acetamide, yield 54%;

[0230]

[0231] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 - 7.98 (m, 2H), 7.60 (s, 1H), 7.38 - 7.28 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 164.47, 163.04, 162.02, 159.98, 131.18, 131.15, 129.26, 129.17, 117.35, 116.39, 116.18.

[0232] 57. 2,2,2-trifluoro-N-(3-(4-methoxyphenyl)isothiazol-5-yl)acetamide, yield 79%

[0233]

[0234] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 - 7.57 (m, 2H), 6.90 - 6.79 (m, 2H), 6.56 (s, 1H), 6.46 (s, 1H), 3.66 (s, 3H). 13 C NMR (101 MHz, MeOD-d 4 ) δ 165.85, 162.32, 160.37, 156.66 (q, 2 J C-F =39.0 Hz) 129.27, 128.55, 117.24 (q, 1 J C-F =284.0 Hz), 109.21 (q, 3 J C-F =1.0 Hz), 115.26, 55.91.

[0235] 4. Add compound 2 (0.1 mmol) and amino acid (0.1 mmol) into a 25 mL round-bottom flask, add anhydrous acetonitrile (5 mL) as the solvent, then successively add NMI (2.1 mmol) and TCFH (0.11 mmol), react for 12 h, monitor the reaction by TLC. After the reaction is completed, quench it with saturated NaHCO 3 solution (2 mL), extract the product with ethyl acetate (3 × 10 mL), collect the combined extract, dry it over anhydrous sodium sulfate, filter, distill it under reduced pressure at 40 °C, and separate it by silica gel column chromatography. The eluent is petroleum ether:ethyl acetate = 5:1 - 1:1 to obtain compound I-1;

[0236] Refer to the above synthesis method, only change the raw materials accordingly, and obtain the compounds in 58 - 62 as follows:

[0237] 58. (9H-fluoren-9-yl)methyl (R)-(1-((3-(tert-butyl)isothiazol-5-yl)amino)-1-oxo-3-phenylpropane-2-yl)carbamate, yield 90%;

[0238]

[0239] 1 H NMR (600 MHz, DMSO-d 6)δ 11.98 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.69 - 7.61 (m, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.36 - 7.24 (m, 6H), 7.21 (t, J = 7.2 Hz, 1H), 6.86 (s, 1H), 4.47 (s, 1H), 4.26 - 4.12 (m, 3H), 3.09 (dd, J = 13.7, 4.7 Hz, 1H), 2.98 - 2.87 (m, 1H), 1.27 (s, 9H). 13 C NMR (150 MHz, DMSO - d 6 )δ 175.52, 156.42, 144.17, 141.13, 137.98, 129.64, 128.68, 128.11, 127.53, 126.99, 125.78, 120.58, 105.91, 66.23, 56.50, 47.02, 37.33, 36.25, 30.30.

[0240] 59. (9H - fluoren - 9 - yl)methyl (R)-(1 - ((3 - neopentylisothiazol - 5 - yl)amino)-1 - oxo - 3 - phenylpropane - 2 - yl)carbamate, yield 86%;

[0241]

[0242] 1 H NMR (600 MHz, DMSO - d 6 )δ 12.04 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.73 - 7.64 (m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.38 - 7.28 (m, 6H), 7.23 (t, J = 7.3 Hz, 1H), 6.77 (s, 1H), 4.51 (ddd, J = 10.3, 8.2, 4.8 Hz, 1H), 4.29 - 4.17 (m, 1H), 3.20 - 2.85 (m, 1H), 2.59 (s, 2H), 0.94 (s, 9H). 13 C NMR (151 MHz, DMSO - d 6)δ 170.83, 165.54, 159.37, 156.45, 144.18, 141.14, 137.98, 129.66, 128.66, 128.11, 127.53, 126.98, 125.70, 120.57, 110.09, 66.25, 56.53, 47.04, 46.75, 37.40, 31.85, 29.92.

[0243] 60. (9H - fluoren - 9 - yl)methyl (R)-(1 - ((3 - cyclobutylisothiazol - 5 - yl)amino)-1 - oxo - 3 - phenylpropan - 2 - yl)carbamate, yield 77%;

[0244]

[0245] 1 H NMR (400 MHz, Chloroform - d) δ 10.36 (s, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.20 - 7.06 (m, 6H), 7.03 (dd, J = 9.5, 7.0 Hz, 3H), 4.71 - 4.60 (m, 1H), 4.16 (dd, J = 20.9, 7.0 Hz, 3H), 3.39 (q, J = 8.1 Hz, 1H), 3.16 - 2.96 (m, 2H), 2.09 (dt, J = 19.2, 9.6 Hz, 6H). 13 C NMR (101 MHz, Chloroform - d) δ 171.12, 169.69, 158.86, 156.67, 143.41, 141.25, 135.56, 129.20, 128.86, 127.92, 127.39, 127.18, 124.96, 120.10, 106.90, 67.76, 60.50, 56.20, 46.82, 37.90, 28.44, 18.53, 14.23.

[0246] 61. (9H - fluoren - 9 - yl)methyl (R)-(1 - oxo - 3 - phenyl - 1 - ((3 - (2,3,4 - trimethoxyphenyl)

[0247] isothiazol - 5 - yl)amino)propan - 2 - yl)carbamate, yield 87%;

[0248]

[0249] 1 H NMR (400 MHz, Chloroform-d) δ 10.25 (s, 1H), 7.64 - 6.96 (m, 19H), 6.61 (d, J = 8.7 Hz, 1H), 4.68 (s, 1H), 4.19 (dt, J = 30.1, 9.4 Hz, 2H), 3.75 (s, 1H), 3.70 (s, 3H), 3.52 (s, 3H), 3.13 - 2.92 (m, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 171.47, 160.95, 158.76, 156.61, 154.44, 151.62, 143.29, 142.23, 141.25, 135.68, 129.22, 128.81, 127.87, 127.15, 124.99, 124.59, 122.27, 120.04, 109.54, 107.80, 61.09, 60.96, 60.56, 56.03, 46.87, 38.42.

[0250] 62. tert-butyl (2 - ((3-(2,5 - dimethoxyphenyl)isothiazol - 5 - yl)amino)-2 - oxoethyl)carbamate, yield 74%;

[0251]

[0252] 1 H NMR (600 MHz, Chloroform-d) δ 7.56 (s, 1H), 7.42 (s, 1H), 6.89 (s, 2H), 4.06 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 1.48 (s, 9H). 13 C NMR (151 MHz, Chloroform-d) δ 167.81, 161.16, 158.72, 153.95, 151.01, 124.87, 116.61, 114.42, 113.29, 110.34, 56.40, 55.96, 28.42.

[0253] Example 3: Synthesis of Multi-Substituted 5-Amino Isothiazole Derivatives

[0254] Compound I-1 (1.0 mmol), triethylamine (2.0 mmol), acyl chloride or acid anhydride (1.5 mmol), and dichloromethane (10 mL) were added to a round-bottom flask and reacted at 25 °C. After the reaction was monitored by TLC and completed, it was distilled under reduced pressure at 40 °C, and the product was separated by silica gel column chromatography with an eluent of petroleum ether:ethyl acetate = 25:1 - 10:1 to obtain Compound I-2;

[0255]

[0256] 63. N-benzyl-N-(3-(4-methoxyphenyl)isothiazol-5-yl)pivalamide, yield 28%;

[0257]

[0258] 1 H NMR (500 MHz, Chloroform-d) δ 7.72 - 7.66 (m, 1H), 7.34 - 7.27 (m, 1H), 7.30 (s, 1H), 7.31 - 7.19 (m, 1H), 6.91 - 6.85 (m, 1H), 5.29 (d, J = 0.9 Hz, 1H), 3.82 (s, 1H), 1.23 (s, 3H). 13 C NMR (125 MHz, Common NMR Solvents) δ 179.08, 162.82, 160.69, 137.94, 128.58, 128.18, 128.14, 127.76, 126.67, 114.01, 108.59, 55.32, 50.61, 44.29, 26.48.

[0259] Example 4: Detection of the activity of multi-substituted 5-aminoisothiazole derivatives in promoting glucose uptake by adipocytes

[0260] 1. Conventional culture of 3T3-L1 preadipocytes

[0261] 3T3-L1 preadipocytes were cultured in vitro with high-glucose DMEM medium containing 10% FBS and 1% penicillin-streptomycin, and routine cell culture and passage were carried out in an incubator at 37 °C and 5% CO 2 26. Incubator;

[0262] 2. Differentiation of 3T3-L1 preadipocytes into mature adipocytes

[0263] 3T3-L1 cells before passage 8 were seeded in a 10-cm culture dish and the medium was changed every 2 days. After the dish was confluent, the medium was not changed anymore (starvation). After 2 days of starvation, when clear nuclear outlines appeared in the cells, differentiation could begin: First, the medium was replaced with high-glucose DMEM containing the differentiation-inducing reagents IBMX (500 μM), insulin (1 μg / mL), rosiglitazone (1 μM), and dexamethasone (1 μM) and cultured for 3 days. Then, it was replaced with DMEM containing insulin (1 μg / mL) and cultured for 2 days to promote the formation of adipocytes. One day later, it was changed to high-glucose DMEM medium without insulin for subsequent experiments.

[0264] 3. Detection of extracellular glucose uptake by 3T3-L1 adipocytes

[0265] To differentiated and mature adipocytes, the multi-substituted 5-aminoisothiazole derivatives (20 μM) or the positive control insulin (INS, 0.1 μM) were added respectively. After incubation for 24 hours, 10 μL of the medium was taken and added to the working solution of a 100-μL glucose detection kit, and incubated at 37 °C for 10 minutes. Subsequently, the absorbance was read at 492 nm using an enzyme-linked immunosorbent assay (ELISA) reader (EnVision-PerkinElmer). Then, the absolute value of the glucose uptake by the cells and the percentage ratio relative to the blank well were calculated according to the following formulas respectively, and the glucose uptake was corrected based on the total protein amount in each well;

[0266] Glucose uptake (mmol / L) = Absorbance of glucose content in the blank well - Absorbance of glucose content in the drug-treated well;

[0267] Corrected glucose uptake value (mmol / L / mg) = Glucose uptake (mmol / L) / Protein amount (mg);

[0268] Increase ratio of glucose uptake (%) = (Corrected glucose uptake value / Corrected glucose uptake value of the blank well) × 100%

[0269] The results are shown in Figure 1 , and compounds 386-2-2, IS-4, IS-5, IS-11, IS-12, IS-16, IS-18, IS-22, IS-28, IS-29, IS-18Aa, IS-21B, IS-2A, IS-2J, IS-2K, IS-2L, IS-3B all had varying degrees of activity in promoting extracellular glucose uptake by 3T3-L1 adipocytes at 20 μM.

[0270] Example 5: Dose-effect relationship of some multi-substituted 5-aminoisothiazole derivatives in promoting glucose uptake by 3T3-L1 mature adipocytes

[0271] 1. Conventional culture of 3T3-L1 preadipocytes

[0272] 3T3-L1 preadipocytes were cultured in vitro in high-glucose DMEM medium containing 10% FBS and 1% penicillin-streptomycin at 37°C and 5% CO. 2 Routine cell culture and subculturing were performed in an incubator.

[0273] 2. Differentiation of 3T3-L1 preadipocytes into mature adipocytes

[0274] 3T3-L1 cells before the 8th generation were inoculated in a 10 cm culture dish, and the medium was changed every 2 days; the culture medium was no longer changed after the culture dish was full (starvation); after 2 days of starvation, the cell nucleus was observed to have a clear nuclear outline and differentiation could begin: first, the culture medium was replaced with high-glucose DMEM containing differentiation induction reagent IBMX (500 μM), insulin (1 μg / mL), rosiglitazone (1 μM), and dexamethasone (1 μM) for 3 days; then, it was replaced with DMEM containing insulin (1 μg / mL) for 2 days to promote the formation of adipocytes; after 1 day, it was replaced with high-glucose DMEM medium without insulin for subsequent experiments.

[0275] 3. Detection of extracellular glucose uptake by 3T3-L1 adipocytes

[0276] Differentiated mature adipocytes were added with 5, 10, 20, 40 μM of compound 386-2-2; 2.5, 5, 10, 20, 40 μM of compound IS-4, IS-2J, IS-2L; 1.25, 2.5, 5, 10, 20 μM of compound IS-2K; 0.625, 1.25, 2.5, 5, 10 μM of compound IS-19C; positive control insulin (INS, 0.1 μM). After incubation for 24 hours, 10 μL of the culture medium was added to 100 μL of the working solution of the glucose detection kit, incubated at 37°C for 10 minutes, and then the absorbance was read at 492 nm with an enzyme reader (EnVision-PerkinElmer). The experiment was repeated three times, and the increase ratio of glucose uptake was calculated according to the method in Example 4;

[0277] Results Figure 2 The activities of compounds IS-4, IS-19C, IS-2J, IS-2K, and IS-2L in promoting glucose uptake by adipocytes all have a dose-effect relationship.

[0278] Example 6: Effect of 386-2-2 on blood glucose in mice induced by high sugar and high fat intake

[0279] 1. C57BL / 6J mice at 6 - 8 weeks of age were purchased from the Experimental Animal Center of Yunnan University (Production License Number: CXK(Dian)K2021 - 0001). The animals were housed in a sterile animal room at a room temperature of 22 - 25°C and a relative humidity of 60 - 70%.

[0280] 2. After inducing diabetes in mice by a high - sugar and high - fat diet (fed with 45% high - fat feed + 15% fructose) for 16 weeks, the diabetic mice were equally divided into a model group (HFFD group), a 20mg / kg 386 - 2 - 2 experimental group, an 80mg / kg 386 - 2 - 2 experimental group, a 200mg / kg metformin (Met) group, and a normal mouse group (Normol), with 10 animals in each group. Among them, the compounds in the Met group and the 386 - 2 - 2 experimental groups were dissolved in normal saline containing 10% PEG300, 1% Tween80, and 6% DMSO for intragastric administration, and the other groups were given normal saline containing 10% PEG300, 1% Tween80, and 6% DMSO for intragastric administration; the intragastric volume was 50μL / 10g body weight, once in the morning and once in the evening, and administered continuously for 4 times; then the mice were starved for 12 hours and given the drug for the 5th time; 0 - minute blood glucose was taken as the fasting blood glucose of the mice 1 hour after administration, then 2g / kg glucose was intragastrically administered, and blood was collected at 30, 60, 90, and 120 minutes after intragastric administration of glucose to detect the oral glucose tolerance of the mice after drug administration. Finally, a glucose detection kit was used to detect the blood glucose value.

[0281] The results are shown in Figure 3 , Figure 4 . The results showed that both 20mg / kg 386 - 2 - 2 and 80mg / kg 386 - 2 - 2 had the efficacy of reducing the fasting blood glucose and oral glucose tolerance of type 2 diabetic mice induced by high - sugar and high - fat diet to varying degrees.

Claims

1. A polysubstituted 5-aminoisothiazole derivative, whose chemical structure is as follows: R 1 Selected from substituted or unsubstituted C5-C 18 Alkyl, C2-C 24 alkenyl, C3-C6 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C3-C8 heterocycloalkyl; when R 1 When there is a substituent, R 1-1 For R 1 The substituent group on 1-1 Selected from nitro, Boc, halogen, C1-C6 alkyl, TBS-protected hydroxy, hydroxy, trifluoromethyl, trifluoroethyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with 6-10 membered aryl, 6-10 membered aryl, 5-10 membered heteroaryl; R 2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl; when R 2 When there is a substituent, R 1-1 For R 2 The substituent group on 1-1 Selected from 6-10 membered aryl, C2-C6 alkenyl; R 3 is selected from hydrogen, trifluoroacetyl, Acetyl, benzoyl, cinnamoyl, C1-C 18 Alkanoyl, methanesulfonyl, trifluorosulfonyl, benzene and substituted benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, fluorine-substituted benzenesulfonyl, C2-C 18 Alkyl acyl, C2-C 23 Alkenyl acyl, C3-C6 cycloalkyl substituted formyl, 5-10 membered heteroaromatic ring substituted formyl, C3-C6 saturated heterocyclic substituted formyl; R 4 Selected from hydrogen, C1-C 18 Alkyl, C2-C 24 Alkenyl, C3-C6 cycloalkyl.

2. The method for preparing a polysubstituted 5-aminoisothiazole derivative according to claim 1, characterized in that: (1) adding one of trifluoroacetic anhydride, difluoroacetic anhydride, and acyl chloride and a protonic acid or a Lewis acid to a solvent, reacting with compound 1 at 0° C. with stirring for 10 to 20 minutes, and then heating to 25° C. with stirring to react to generate a polysubstituted 5-aminoisothiazole derivative 2; (2) reacting a polysubstituted 5-aminoisothiazole derivative 2 with one of alkyl halide, alkenyl halide, alkyl aldehyde, alkenyl aldehyde and base or / and a reducing agent in the presence of a solvent to obtain compound I-1; or reacting a polysubstituted 5-aminoisothiazole derivative 2 with one of alkyl acid chloride, alkenyl acid chloride, alkyl sulfonyl chloride, alkenyl sulfonyl chloride, amino acid, alkyl carboxylic acid or alkenyl carboxylic acid and base or / and a condensing agent to obtain a polysubstituted 5-aminoisothiazole derivative I-1; (3) reacting the polysubstituted 5-aminoisothiazole derivative I-1 with one of alkyl acid chloride, alkenyl acid chloride, alkyl sulfonyl chloride, alkenyl sulfonyl chloride, amino acid, alkyl carboxylic acid or alkenyl carboxylic acid and a base and / or a condensing agent in the presence of a solvent to obtain the polysubstituted 5-aminoisothiazole derivative I-2; 3. Use of the polysubstituted 5-aminoisothiazole derivatives according to claim 1 in the preparation of drugs for preventing and treating diabetes.

4. The use according to claim 3, characterized in that: The polysubstituted 5-aminoisothiazole derivative is any of the following structures:

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