Thiadiazole derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic compound synthesis and medical application, and particularly relates to a thiadiazole compound as well as a preparation method and application thereof. The thiadiazole compound has a structure as shown in a general formula I or II: # imgabs0 #, R1 is a structure as shown in a general formula (a) or a general formula (b), Ar or R2 is substituted phenyl, substituted naphthyl, substituted or unsubstituted five-membered or six-membered heteroaromatic ring group, and substituted or unsubstituted C8-C10 condensed ring group; the C8-C10 condensed ring group is a condensed ring group which is formed by a C4-C6 cyclic hydrocarbon group and a benzene ring and shares two carbons; ring A is cyclopentane or cyclohexane; and R3 is substituted or unsubstituted benzyl, hydrogenated naphthyl and indanyl. The compound has an effect of penetrating through a blood brain barrier, and can be widely applied to development of drugs for NMDA receptor related diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis and pharmaceutical application, and specifically relates to a thiadiazole derivative and a preparation method and application thereof. Background Art

[0002] N-methyl-D-aspartate (NMDA) receptors play an important role in synaptic plasticity and various neurological and psychiatric diseases (such as pain, stroke, epilepsy, schizophrenia, post-traumatic stress disorder, depression and neurodegenerative diseases). Currently, the drugs listed for NMDA receptors are mainly: ketamine, dextromethorphan (treatment of refractory depression), lacosamide (treatment of convulsions), memantine hydrochloride (treatment of Alzheimer's disease), dizocillin (treatment of epilepsy), but these drugs have serious neuromimetic side effects due to their lack of subtype selectivity. Based on this, the discovery of subtype-selective compounds as pharmacological tools to explore the function of NMDA receptors and drugs for the treatment of mental illness is of great significance for the relevant research on NMDA receptors.

[0003] At present, the representative negative allosteric modulators for GluN1 / 2A subtypes mainly include TCN-201, TCN-213, MPX004 and MPX007. Among them, TCN-201, MPX004 and MPX007 show nanomolar inhibitory activity on NMDA receptors, but these three compounds cannot penetrate the blood-brain barrier. TCN-213 has poor inhibitory activity on NMDA receptors. Therefore, further modification of this type of chemical structure is of great significance for the discovery of new NMDA receptor modulators with high efficiency and blood-brain barrier permeability.

[0004] Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a thiadiazole derivative and a preparation method and application thereof. The compound has obvious advantages over previously discovered compounds and can penetrate the blood-brain barrier to exert its effects, thus solving the problem that compounds acting on the target cannot penetrate the blood-brain barrier. The compound can be widely used in the development of drugs for NMDA receptor-related diseases.

[0006] In order to achieve the above object, the specific technical solution provided by the present invention is as follows: In a first aspect, the present invention provides a thiadiazole derivative or a pharmaceutically acceptable salt thereof, wherein the thiadiazole derivative has a structure shown in Formula I or Formula II:

[0007] Wherein, R1 is a structure having the general formula (a) or the general formula (b):

[0008] Ar or R2 is substituted phenyl, substituted naphthyl, substituted or unsubstituted five-membered or six-membered heteroaromatic ring group, substituted or unsubstituted C8-C 10 A fused ring group; The C8-C 10 The fused ring group is a fused ring group formed by a C4-C6 cyclic hydrocarbon group and a benzene ring and sharing two carbon atoms; Ring A is cyclopentane or cyclohexane; R3 is substituted or unsubstituted benzyl, hydronaphthyl and indanyl; The substituents on Ar, R2 and R3 are one or more, and each substituent is independently selected from halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0009] In some embodiments, the five-membered or six-membered heteroaromatic ring group is selected from thienyl or furanyl.

[0010] In some embodiments, the C4-C6 cycloalkyl group is selected from a C4-C6 cycloalkyl or cycloalkenyl group and a C5-C6 aromatic heterocyclic group.

[0011] In some embodiments, the C8-C 10 The fused ring group is selected from benzocyclobutenyl, indanyl, benzofuranyl and hydronaphthyl.

[0012] In some embodiments, the number of substituents on Ar, R2 and R3 is one or two, and each substituent is independently selected from F, Cl, Br, methyl or methoxy.

[0013] In some embodiments, the position of the substituent is selected from the meta position and the para position of the insertion site of Ar, R2 and R3 in the structure of Formula I or Formula II.

[0014] In some embodiments, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt of the compound of Formula I or Formula II.

[0015] In some embodiments, Ar is selected from p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl, p-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-methylphenyl, m-methoxyphenyl, p-bromo-m-methylphenyl, p-chloro-m-chlorophenyl, benzocyclobutenyl, benzofuranyl or 5-bromo-thiophen-2-yl.

[0016] In some embodiments, R2 is selected from thienyl, p-fluoro-m-fluorophenyl, or p-fluoro-m-chlorophenyl.

[0017] In some embodiments, R3 is selected from benzyl, hydronaphthyl, or indanyl.

[0018] In some embodiments, the thiadiazole derivative has any of the following structures, or a pharmaceutically acceptable salt thereof:

[0019] In a second aspect, the present invention provides a method for preparing the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to the first aspect, wherein the thiadiazole derivative has a structure shown in formula I; wherein R1 has a structure of formula (a): , Ar is as defined in the first aspect; The preparation method is carried out according to the following process:

[0020] The preparation method comprises: i: Compound 2 reacts with chloroacetyl chloride to generate compound 3; ii: Compound 3 reacts with 2-amino-5-mercapto-1,3,4-thiadiazole to generate compound 4; iii: Compound 4 and or Reaction to obtain a compound of formula I; Wherein, R4 is a substituent on the benzene ring, R4 is one or more, and R4 is selected from halogen, C1-C3 alkyl and C1-C3 alkoxy; Alternatively, R4 and the benzene ring form a condensed ring structure sharing two carbon atoms, wherein the condensed ring is selected from benzocyclobutenyl, indanyl, benzofuranyl or hydronaphthyl.

[0021] In some embodiments, the thiadiazole derivative has a structure shown in Formula I; wherein R1 in Formula I is a structure having Formula (b): , when ring A is cyclopentane or cyclohexane, as shown in formula I'; The preparation method is carried out according to the following route:

[0022] The structures of compounds 5p and 5q are shown below:

[0023] The preparation method comprises: i: Compound 5p or 5q reacts with carbon disulfide to generate compound 6p or 6q; ii: Compound 6p or 6q undergoes oxidation reaction in an alkaline environment to generate compound 7p or 7q; iii: Compound 7p or 7q undergoes an addition reaction with hydrazine hydrate to generate compound 8p or 8q; iv: Compound 8p or 8q undergoes a cyclization reaction with carbon disulfide under alkaline conditions to generate compound 9p or 9q; v: Compound 9p or 9q is reacted with 2-chloro-N-(cyclohexylmethyl)acetamide to generate a compound of formula I', wherein in the compound of formula I', ring A is cyclopentane or cyclohexane.

[0024] In some embodiments, the thiadiazole derivative has a structure shown in Formula II; wherein R3 is benzyl, R2 is thienyl or phenyl substituted by R5; R5 is one or two substituents on the benzene ring, when there are two R5, they are two identical or different substituents, and R5 is a halogen selected from fluorine, chlorine or bromine; The preparation method is carried out according to the following reaction scheme:

[0025] The preparation method comprises: i: 2-amino-5-mercapto-1,3,4-thiadiazole reacts with benzaldehyde and is reduced by sodium cyanoborocyanide to generate compound 12; ii: Compound 12 reacts with methyl bromoacetate to generate compound 13; iii: Compound 13 is hydrolyzed under the action of lithium hydroxide to generate compound 14; iv: or 2-thiophenesulfonyl chloride reacts with p-aminobenzylamine to generate compound 16a or 16b, wherein R5 is one or two substituents on the benzene ring, and R5 is a halogen selected from fluorine, chlorine or bromine; v: Compound 14 undergoes condensation reaction with compound 16a or compound 16b to generate final product IIa or IIb, wherein in formula IIa, R2 is a phenyl group substituted with one or two halogens, and in formula IIb, R2 is a thienyl group.

[0026] In some embodiments, the thiadiazole derivative has a structure shown in Formula II; wherein R3 is a hydronaphthyl or an indanyl; Formula II has a structure shown in Formula IIc-f; The preparation method is carried out according to the following route:

[0027] Wherein, R2 is: thienyl, p-fluoro-m-fluorophenyl or p-fluoro-m-chlorophenyl; Ring A is cyclopentane or cyclohexane; The preparation method comprises: i: Compound 9p or compound 9q reacts with methyl chloroacetate to generate compounds 17p and 17q; ii: Compounds 17p and 17q are hydrolyzed to generate compounds 18p or 18q; iii: Compound 18p or 18q undergoes a condensation reaction with compound 16a or 16b to generate final product IIc-f; wherein the structure of compound 16a or 16b is .

[0028] In a third aspect, the present invention provides the use of the thiadiazole derivatives described in the first aspect in the preparation of NMDA receptor modulator drugs or drugs for preventing and / or treating diseases related to abnormal NMDA receptor function, wherein the NMDA receptor modulator drug is an NMDA receptor GluN1 / 2A subtype inhibitor drug.

[0029] In some other embodiments, the diseases associated with abnormal NMDA receptor function include but are not limited to depression, depression, stroke, Huntington's disease, Alzheimer's disease, neuralgia, and schizophrenia.

[0030] In a fourth aspect, the present invention provides a pharmaceutical composition or pharmaceutical preparation, comprising the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to the first aspect; or further comprising an excipient.

[0031] Compared with the prior art, the present invention has the following beneficial effects: (1) The thiadiazole derivatives prepared by the present invention can act on NMDA receptors and can specifically inhibit GluN1 / 2A subtypes, and show certain antidepressant effects in antidepressant experiments at the animal level. Further in vivo distribution experiments in rats confirmed that the compounds have blood-brain barrier permeability.

[0032] (2) The preparation method of the present invention is based on common raw materials and is prepared through simple reactions. The raw materials are cheap and easy to obtain. The synthesis route is scientific, the method steps are simple, the reaction conditions are mild and easy to implement, and the product is easy to separate.

[0033] (3) The thiadiazole derivatives provided by the present invention solve the problem that compounds acting on this target cannot penetrate the blood-brain barrier. The compounds can be widely used in the development of drugs for NMDA receptor-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The activity test results of the three subtypes of GluN1 / 2B, GluN1 / 2C and GluN1 / 2D at 10 μmol / L for compounds Ia, If, In and Ij in Example 2 of the present invention; Figure 2 This is a diagram of the forced swimming test of compound If in Example 2 of the present invention. DETAILED DESCRIPTION

[0035] In order to further illustrate the present invention, the thiadiazole derivatives provided by the present invention and their preparation methods and applications are described in detail below in conjunction with examples. The following examples are only used to help understand the present invention, but cannot limit the content of the present invention.

[0036] Example 1 Preparation of 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-N-(cyclohexylmethyl)acetamide (Compound 4) Synthesis route:

[0037] Cyclohexylmethylamine (compound 2, 10 mmol) and triethylamine (12 mmol) were mixed and added to 50 mL of dichloromethane solution for reaction at 0°C. After 5 minutes, chloroacetyl chloride (12 mmol) was added dropwise to the solution system. The solution changed from clear to earthy yellow. After stirring for 3 hours, TLC monitoring was performed. After the reaction was completed, the solvent was removed by vacuum rotary evaporation. The mixture was extracted three times with dichloromethane and water system (20 mL × 3). After the organic phases were combined, the solvent was removed by vacuum rotary evaporation. The earthy yellow powder, 2-chloro-N-(cyclohexylmethyl)acetamide (compound 3), was obtained by vacuum drying. The yield was 72%, and the melting point was 102~104°C.

[0038] 2-Amino-5-mercapto-1,3,4-thiadiazole (20 mmol), compound 3 (20 mmol) and potassium carbonate (40 mmol) were added to 50 mL DMF, heated at 85°C for 7.5 h, and then monitored by TLC. After the reaction was complete, the reaction solution was added dropwise to a beaker containing 300 mL, stirred for 30 min, and filtered with a Bush funnel after standing. The filter cake was vacuum dried to obtain a white solid, namely compound 4, with a yield of 65.4% and a melting point of 105-107°C. ESI-MS: m / z 287.02 [M+H] + .

[0039] Embodiment 2: Preparation of compounds of formula I (compounds 1a to 1o)

[0040] (1) Preparation of Compound N-(cyclohexylmethyl)-2-((5-((4-fluorobenzyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (Compound Ia)

[0041] Compound Ia Compound 4 (40 mmol), p-toluenesulfonic acid (0.4 mmol) and p-fluorobenzaldehyde (50 mmol) were weighed and added to 20 mL toluene solution. The mixture was heated at 130 °C for 10 h and then monitored by TLC. After the reaction of the raw materials was completed, the reaction system was cooled, and sodium cyanoborocyanide (40 mmol) was added. The mixture was heated at 80 °C for 8 h and then monitored by TLC. After the reaction was complete, the reaction solution was evaporated to dryness, and 50 mL of aqueous solution and 50 mL of ethyl acetate were added. After extraction and separation, the organic phase was washed with saturated NaCl aqueous solution (20 mL × 3), spin-dried, and the product spot was obtained by column chromatography. After drying, the final product, compound Ia, was obtained.

[0042] Yellow solid, yield 30%, melting point: 127-129 ℃.

[0043] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.31 (t, J = 5.8 Hz, 1H), 8.09 (t, J = 5.9 Hz,1H), 7.41-7.35 (m, 2H), 7.20 – 7.14 (m, 2H), 4.44 (d, J = 5.8 Hz, 2H), 3.75 (s,2H), 2.89 (t, J = 6.3 Hz, 2H), 1.61 (qd, J = 7.1, 3.3 Hz, 5H), 1.34 (ddp, J = 11.3,7.2, 3.5 Hz, 1H), 1.18-1.06 (m, 3H), 0.88-0.77 (m, 2H). 13 C NMR (101 MHz, DMSO -d 6) δ 169.55, 166.68, 161.38, 149.88, 134.73, 129.60, 115.15, 47.05, 45.21, 37.82, 37.37, 30.31, 26.02, 25.40.

[0044] ESI-MS: m / z 395.45[M+H] + , C 18 H 23 FN4OS2[394.13].

[0045] Compounds Ia-o were prepared using the above method with different aromatic aldehydes and compound 4. Some of the results are as follows: (2) The preparation method is the same as that of compound Ia, except that p-chlorobenzaldehyde is used to react with compound 4 to obtain compound Ib.

[0046]

[0047] Ib Yellow solid, yield 35%, melting point: 79-81 ℃.

[0048] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.35 (t, J = 5.9 Hz, 1H), 8.09 (t, J = 5.8 Hz,1H), 7.42-7.27 (m, 4H), 4.48 (d, J = 5.9 Hz, 2H), 3.76 (s, 2H), 2.89 (t, J = 6.3Hz, 2H), 1.66-1.54 (m, 5H), 1.33 (dtt, J = 10.8, 6.9, 3.5 Hz, 1H), 1.18-1.05(m, 3H), 0.83 (td, J = 13.4, 6.3 Hz, 2H).

[0049] 13 C NMR (101 MHz, DMSO- d 6) δ 169.53, 166.67, 149.99, 137.65, 131.69, 129.37, 128.34, 47.04, 45.21, 37.80, 37.36, 30.30, 26.02, 25.40.

[0050] ESI-MS: m / z 411.48 [M+H] + , C 18 H 23 ClN4OS2[410.10].

[0051] (3) The preparation method is the same as that of compound Ia, except that p-bromobenzaldehyde is used to react with compound 4 to obtain compound Ic.

[0052]

[0053] Ic Yellow solid, yield 40%, melting point: 112-114 ℃.

[0054] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.36 (t, J = 5.9 Hz, 1H), 8.11 (t, J = 5.8 Hz,1H), 7.54 (d, J = 1.8 Hz, 1H), 7.47 (dt, J = 7.5, 1.8 Hz, 1H), 7.37-7.28 (m, 2H), 4.47 (d, J = 5.9 Hz, 2H), 3.76 (s, 2H), 2.89 (t, J = 6.3 Hz, 2H), 1.62 (qd, J =9.0, 3.7 Hz, 5H), 1.33 (ddp, J = 10.8, 7.1, 3.7 Hz, 1H), 1.20-1.05 (m, J = 9.1Hz, 3H), 0.89-0.75 (m, 2H).

[0055] 13 C NMR (101 MHz, DMSO- d 6) δ 169.46, 166.63, 150.10, 141.49, 130.56, 126.53, 121.66, 47.04, 45.18, 37.78, 37.34, 30.27, 25.99, 25.37.

[0056] ESI-MS: m / z 453.19[MH] - , C 18 H 23 BrN4OS2[454.05].

[0057] (4) The preparation method is the same as that of compound Ia, except that p-methylbenzaldehyde is used to react with compound 4 to obtain compound Id.

[0058]

[0059] Id Yellow solid, yield 34.5%, melting point: 118-120 ℃.

[0060] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.27 (t, J = 5.7 Hz, 1H), 8.09 (t, J = 5.9 Hz,1H), 7.27-7.10 (m, 4H), 4.40 (d, J = 5.8 Hz, 2H), 3.74 (s, 2H), 2.89 (t, J = 6.3Hz, 2H), 2.28 (s, 3H), 1.68-1.53 ​​(m, 5H), 1.33 (ddt, J = 11.1, 7.0, 3.5 Hz,1H), 1.21 – 1.04 (m, 3H), 0.90-0.74 (m, 2H).

[0061] 13 C NMR (101 MHz, DMSO- d 6) δ 169.72, 166.67, 149.56, 136.30, 135.37,128.93, 127.55, 47.68, 45.20, 37.85, 37.36, 30.30, 26.01, 25.40, 20.72.

[0062] ESI-MS: m / z 391.45[M+H] + , C 19 H 26 N4OS2[390.15].

[0063] (5) The preparation method is the same as that of compound Ia, except that p-methoxybenzaldehyde is used to react with compound 4 to obtain compound Ie.

[0064]

[0065] Ie Yellow solid, yield 36.2%, melting point: 122-124 ℃.

[0066] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.30 (t,J = 5.8 Hz, 1H), 8.11 (t, J = 5.9 Hz,1H), 7.25 (t, J = 8.1 Hz, 1H), 6.94-6.87 (m, 2H), 6.83 (ddd, J = 8.2, 2.6, 1.0Hz, 1H), 4.42 (d, J = 5.8 Hz, 2H), 3.74 (d, J = 6.1 Hz, 5H), 2.89 (t, J = 6.3 Hz,2H), 1.68-1.52 (m, 6H), 1.32 (ddt, J = 14.7, 7.0, 4.4 Hz, 1H), 1.26-1.01 (m, 4H), 0.89-0.76 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 169.68, 166.70, 158.51, 149.53, 130.29,129.01, 113.78, 55.10, 47.43, 45.22, 37.87, 37.38, 30.31, 26.03, 25.41. ESI-MS: m / z 407.26[M+H] + , C 19 H 26 N4O2S2[406.15].

[0067] (6) The preparation method is the same as that of compound Ia, except that m-fluorobenzaldehyde is used to react with compound 4 to obtain compound If.

[0068]

[0069] If Yellow solid, yield 34.3%, melting point: 102-104 ℃.

[0070] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.36 (t, J = 5.9 Hz, 1H), 8.10 (t, J = 5.9 Hz,1H), 7.38 (td,J = 7.9, 6.1 Hz, 1H), 7.20-7.02 (m, 3H), 4.48 (d, J = 5.9 Hz, 2H),3.75 (s, 2H), 2.89 (t, J = 6.3 Hz, 2H), 1.69-1.52 (m, 5H), 1.33 (th, J = 10.2,3.2 Hz, 1H), 1.21-1.02 (m, 3H), 0.88-0.75 (m, 2H).

[0071] 13 C NMR (101 MHz, DMSO- d 6) δ 169.55, 166.65, 162.20, 150.06, 141.61,130.34, 123.45, 123.42, 114.19, 113.88, 47.17, 45.18, 37.79, 37.34, 30.27, 25.99, 25.37.

[0072] ESI-MS: m / z 395.59 [M+H] + , C 18 H 23 FN4OS2[394.13].

[0073] (7) The preparation method is the same as that of compound Ia, except that m-chlorobenzaldehyde is used to react with compound 4 to obtain compound Ig.

[0074]

[0075] Ig Yellow solid, yield 31%, melting point: 142-144 ℃.

[0076] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.35 (t, J = 5.9 Hz, 1H), 8.10 (t, J = 5.8 Hz,1H), 7.47-7.30 (m, 4H), 4.45 (d, J = 5.8 Hz, 2H), 3.75 (s, 2H), 2.89 (t, J= 6.3Hz, 2H), 1.67-1.56 (m, 5H), 1.33 (dqd, J = 10.6, 7.3, 3.5 Hz, 1H), 1.20-1.05(m, 3H), 0.82 (qd, J = 12.5, 3.9 Hz, 2H).

[0077] 13 C NMR (101 MHz, DMSO- d 6) δ 169.48, 166.64, 150.11, 141.23, 133.02,130.27, 127.22, 127.07, 126.14, 47.10, 45.18, 37.78, 37.34, 30.27, 25.99,25.37. ESI-MS: m / z 411.43 [M+H] + , C 18 H 23 ClN4OS2[410.10].

[0078] (8) The preparation method is the same as that of compound Ia, except that m-bromobenzaldehyde is used to react with compound 4 to obtain compound Ih.

[0079]

[0080] Ih Yellow solid, yield 36.4%, melting point: 88-90 ℃.

[0081] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.29 (t, J = 5.9 Hz, 1H), 8.04 (t, J = 5.9 Hz,1H), 7.47 (d, J = 1.8 Hz, 1H), 7.40 (dt, J = 7.5, 1.8 Hz, 1H), 7.32-7.20 (m, 2H), 4.40 (d, J = 5.9 Hz, 2H), 3.69 (s, 2H), 2.82 (t, J = 6.3 Hz, 2H), 1.60-1.50 (m,5H), 1.27 (ttd, J= 11.5, 8.5, 4.9 Hz, 1H), 1.19-1.07 (m, 1H), 1.06 (s, 1H),1.03 (s, 1H), 0.73 (dd, J = 13.9, 10.5 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 169.47, 166.66, 150.13, 141.52, 130.60,130.14, 130.00, 126.56, 121.70, 47.05, 45.20, 37.79, 37.37, 30.30, 26.02,25.40.

[0082] ESI-MS: m / z 453.01[MH] - , C 18 H 23 BrN4OS2[454.05].

[0083] (9) The preparation method is the same as that of compound Ia, except that m-methylbenzaldehyde is used to react with compound 4 to obtain compound Ii.

[0084]

[0085] Ii Yellow solid, yield 41.2%, melting point: 112-114 ℃.

[0086] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.29 (t, J = 5.7 Hz, 1H), 8.11 (t, J = 5.9 Hz,1H), 7.22 (t, J = 7.5 Hz, 1H), 7.16-7.10 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 4.41(d, J = 5.7 Hz, 2H), 3.75 (s, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.29 (s, 3H), 1.67-1.56 (m, 6H), 1.34 (ddt, J= 14.7, 7.8, 3.6 Hz, 1H), 1.21-1.03 (m, 4H), 0.82(td, J = 14.4, 7.7 Hz, 3H).

[0087] 13 C NMR (101 MHz, DMSO- d 6) δ 169.71, 166.69, 149.64, 138.36, 137.51,128.33, 128.16, 127.85, 124.67, 47.89, 45.21, 37.85, 37.38, 30.31, 26.03, 25.41, 21.06.

[0088] ESI-MS: m / z 391.84 [M+H] + , C 19 H 26 N4OS2[390.15].

[0089] (10) The preparation method is the same as that of compound Ia, except that m-methoxybenzaldehyde is used to react with compound 4 to obtain compound Ij.

[0090]

[0091] Ij Yellow solid, yield 32.4%, melting point: 118-120 ℃.

[0092] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.24 (t, J = 5.7 Hz, 1H), 8.10 (t, J = 5.9 Hz,1H), 7.29-7.22 (m, 2H), 6.92-6.86 (m, 2H), 4.36 (d, J = 5.6 Hz, 2H), 3.73 (d, J =6.1 Hz, 5H), 2.88 (t, J = 6.3 Hz, 2H), 1.60 (d, J = 9.2 Hz, 6H), 1.33 (dqd, J=10.6, 6.5, 3.2 Hz, 1H), 1.21-1.03 (m, 4H), 0.89-0.75 (m, 3H).

[0093] 13 C NMR (101 MHz, DMSO- d 6) δ 169.72, 166.69, 159.34, 149.74, 140.06,129.51, 119.64, 113.20, 112.49, 55.03, 47.82, 45.21, 37.86, 37.38, 30.31, 26.03, 25.41.

[0094] ESI-MS: m / z 407.90 [M+H] + , C 19 H 26 N4O2S2[406.15].

[0095] (11) The preparation method is the same as that of compound Ia, except that m-bromo-p-methylbenzaldehyde is used to react with compound 4 to obtain compound Ik.

[0096]

[0097] I Yellow solid, yield 34.6%, melting point: 125~127 ℃.

[0098] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.33 (t, J = 5.8 Hz, 1H), 8.10 (t, J = 5.8 Hz,1H), 7.54 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.2, 2.3 Hz,1H), 4.40 (d, J = 5.8 Hz, 2H), 3.75 (s, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.33 (s,3H), 1.67-1.52 (m, 5H), 1.34 (dtd, J= 14.7, 7.3, 3.5 Hz, 1H), 1.20-1.02 (m, 3H), 0.88-0.75 (m, 2H).

[0099] 13 C NMR (101 MHz, DMSO- d 6) δ 169.54, 166.65, 149.91, 138.25, 137.10,132.03, 130.24, 126.99, 122.62, 47.12, 45.18, 30.27, 25.99, 25.37, 22.42.

[0100] ESI-MS: m / z 469.09 [M+H] + , C 19 H 25 BrN4OS2[468.07].

[0101] (12) The preparation method is the same as that of compound Ia, except that 3,4-dichlorobenzaldehyde is used to react with compound 4 to obtain compound IL.

[0102]

[0103] IL Yellow solid, yield 34.5%, melting point: 125~127 ℃.

[0104] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.37 (t, J = 5.9 Hz, 1H), 8.10 (t, J = 5.9 Hz,1H), 7.65-7.57 (m, 2H), 7.33 (dd, J = 8.3, 2.1 Hz, 1H), 4.47 (d, J = 5.9 Hz, 2H),3.76 (s, 2H), 2.89 (t, J = 6.3 Hz, 2H), 1.60 (qd, J = 9.1, 4.5 Hz, 6H), 1.33(dqd, J = 10.7, 7.2, 3.5 Hz, 1H), 1.19-1.04 (m, 3H), 0.88-0.74 (m, 2H).

[0105] 13 C NMR (101 MHz, DMSO- d 6) δ 169.34, 166.62, 150.32, 140.00, 130.93,130.55, 129.60, 129.41, 127.80, 46.49, 45.17, 37.74, 37.34, 30.27, 26.00,25.36.

[0106] ESI-MS: m / z 445.28 [M+H] + , C 18 H 22 Cl2N4OS2[445.28].

[0107] (13) The preparation method is the same as that of compound Ia, except that 4-formylbenzocyclobutene is used to react with compound 4 to obtain compound Im.

[0108]

[0109] Im Yellow solid, yield 42.2%, melting point: 90-92 ℃.

[0110] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.27 (t, J = 5.8 Hz, 1H), 8.09 (t, J = 5.9 Hz,1H), 7.15 (d, J = 7.5 Hz, 1H), 7.07-7.01 (m, 2H), 4.39 (d, J = 5.7 Hz, 2H), 3.74(s, 2H), 3.10 (s, 4H), 2.89 (t, J = 6.3 Hz, 2H), 1.61 (d, J = 12.0 Hz, 6H), 1.40-1.26 (m, 2H), 1.12 (q, J = 13.0 Hz, 4H), 0.88-0.76 (m, 3H).

[0111] 13 C NMR (101 MHz, DMSO- d6) δ 169.68, 166.66, 149.50, 145.27, 144.12,136.96, 126.34, 122.34, 121.93, 48.55, 45.18, 37.84, 37.34, 30.28, 28.92, 28.86, 26.00, 25.38.

[0112] ESI-MS: m / z 401.30 [M+H] + , C 20 H 26 N4OS2[402.15].

[0113] (14) The preparation method is the same as that of compound Ia, except that 2,3-dihydrobenzofuran-6-carboxaldehyde is reacted with compound 4 to obtain compound In.

[0114]

[0115] In Yellow solid, yield 42.4%, melting point: 110-112 ℃.

[0116] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.22 (s, 1H), 8.09 (s, 1H), 7.22 (d, J =11.1 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.76-6.64 (m, 1H), 4.49 (tt, J = 10.8,5.5 Hz, 2H), 4.40-4.29 (m, 2H), 3.82-3.69 (m, 2H), 3.20-3.10 (m, 2H), 2.94-2.84 (m, 2H), 1.63 (t, J = 12.3 Hz, 5H), 1.35 (s, 1H), 1.13 (s, 3H), 0.82 (d, J =11.1 Hz, 2H).

[0117] 13 C NMR (101 MHz, DMSO- d6) δ 169.66, 166.67, 158.98, 149.44, 130.17,127.46, 127.41, 124.64, 108.54, 70.93, 47.74, 45.19, 37.85, 37.35, 30.29, 29.03, 26.00, 25.38.

[0118] ESI-MS: m / z 419.67 [M+H] + , C 20 H 26 N4O2S2[418.15].

[0119] (15) The preparation method is the same as that of compound Ia, except that 5-bromothiophene-2-carboxaldehyde is reacted with compound 4 to obtain compound Io.

[0120]

[0121] Io Yellow solid, yield 33%, melting point: 100-102 ℃.

[0122] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (t, J = 5.9 Hz, 1H), 8.07 (t, J = 5.7 Hz,1H), 7.06 (d, J = 3.7 Hz, 1H), 6.90 (d, J = 3.7 Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 3.77 (s, 2H), 2.90 (td, J = 6.3, 2.0 Hz, 2H), 1.73-1.54 (m, 5H), 1.41-1.28 (m,1H), 1.22-1.01 (m, 3H), 0.90-0.77 (m, 2H).

[0123] 13 C NMR (101 MHz, DMSO- d6) δ 169.00, 166.70, 166.62, 150.62, 143.58,129.74, 127.03, 45.19, 42.69, 37.74, 37.34, 30.29, 26.00, 25.38.

[0124] ESI-MS: m / z 461.02[M+H] + , C 16 H 21 BrN4OS3[460.01].

[0125] Example 3 Synthesis route:

[0126] (1) Preparation of (S)-N-(cyclohexylmethyl)-2-((5-((2,3-dihydro-1H-inden-1-yl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (Ip)

[0127] Ip Will( S )-(+)-1-Aminoindanyl hydrochloride (40 mmol), triethylamine (48 mmol), carbon disulfide (80 mmol) and other raw materials were dissolved in 20 mL of a mixed solution of petroleum ether and ethyl acetate, stirred at room temperature overnight for 8 h, monitored by TLC, and after the reaction was complete, the solvent was dried and (S)-(2,3-dihydro-1H-inden-1-yl)aminodithioic acid (6p) was obtained.

[0128] 6p was redissolved in 15 mL acetonitrile, 1.04 mL triethylamine was added, and I2 (40 mmol, 30 min) was slowly added in batches under ice bath. During the reaction, elemental sulfur would precipitate from the reaction solution. After precipitation was completed, the reaction solution was filtered, the reaction solution was spin-dried and dissolved in n-hexane, washed twice with 1 M HCl and once with water, and the extract was spin-dried to obtain ( S )-1-isothiocyanato-2,3-dihydro-1H-indene (7p).

[0129] 7p was added dropwise to 50 mL of hydrazine hydrate isopropanol solution as a raw material, stirred at room temperature for 30 min, and then the filter cake was filtered and dried to obtain ( S )-N-(2,3-dihydro-1H-inden-1-yl)hydrazinecarbothioamide (8p).

[0130] 8p was dissolved in 30 mL of ethanol, KOH (40 mmol) was added, carbon disulfide (60 mmol) was added dropwise, and the reaction was refluxed for 4 h, and the solvent was removed by rotary evaporation, H2O was added, and the pH was adjusted to 3 with concentrated hydrochloric acid, and then extracted with dichloromethane three times (30 mL × 3), and the organic phases were combined, concentrated under reduced pressure, and then column chromatography was performed to obtain ( S )-5-((2,3-dihydro-1H-inden-1-yl)amino)-1,3,4-thiazole-2-thiol (9p).

[0131] 9p (40 mmol), intermediate 3 (40 mmol), and potassium carbonate (60 mmol) were added to 10 mL of DMF. The mixture was reacted at 80 °C for 7.5 h and then monitored by TLC. When the reaction was complete, the reaction solution was spin-dried with an oil pump. 50 mL of aqueous solution and 50 mL of ethyl acetate were added to the reaction solution. After extraction and separation, the organic phase was washed with saturated aqueous NaCl solution (20 mL), spin-dried, and then column chromatography was performed to obtain the final product Ip.

[0132] Yellow solid, yield 34.3%, melting point: 166-168 ℃.

[0133] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (t, J = 5.9 Hz, 1H), 8.07 (t, J = 5.7 Hz,1H), 7.06 (d, J = 3.7 Hz, 1H), 6.90 (d, J = 3.7 Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 3.77 (s, 2H), 2.90 (td, J = 6.3, 2.0 Hz, 3H), 1.73-1.54 (m, 5H), 1.41-1.28 (m,1H), 1.22-1.01 (m, 3H), 0.83 (td, J = 12.5, 8.8 Hz, 2H).

[0134] 13 C NMR (101 MHz, DMSO- d6) δ 169.37, 166.70, 149.57, 143.15, 143.06,127.85, 126.39, 124.70, 124.21, 59.47, 45.20, 37.86, 37.36, 33.03, 30.29, 29.66, 25.99, 25.39. ESI-MS: m / z 403.15 [M+H] + , C 20 H 26 N4OS2[402.15].

[0135] (2) The preparation method is the same as that of compound Ip, except that the raw materials used are ( S )-1,2,3,4-tetrahydronaphthalene-1-amine to obtain compound Iq.

[0136]

[0137] Iq Yellow solid, yield 33.5%, melting point: 202-204 ℃.

[0138] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.22-8.06 (m, 2H), 7.28 (dd, J = 6.9, 1.3Hz, 1H), 7.24-7.05 (m, 3H), 4.95 (q, J = 5.8 Hz, 1H), 3.76 (s, 2H), 2.91 (t, J =6.3 Hz, 2H), 2.84-2.63 (m, 2H), 2.06-1.70 (m, 4H), 1.69-1.54 (m, 5H), 1.41-1.29 (m, 1H), 1.24-1.04 (m, 3H), 0.83 (q, J = 12.0 Hz, 2H).

[0139] 13 C NMR (101 MHz, DMSO- d6) δ 168.99, 166.73, 149.28, 137.11, 136.61,128.89, 128.74, 127.20, 125.89, 52.21, 45.20, 37.85, 37.36, 30.29, 28.77, 28.63, 26.00, 25.40, 19.22.

[0140] ESI-MS: m / z 417.54 [M+H] + , C 21 H 28 N4OS2[416.17].

[0141] Embodiment 4: Synthesis route:

[0142]

[0143] (1) Preparation of 2-((5-(Benzylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(4-(((3,4-difluorophenyl)sulfonamido)methyl)phenyl)acetamide (IIa)

[0144] IIa 2-Amino-5-mercapto-1,3,4-thiadiazole (40 mmol), p-toluenesulfonic acid (0.4 mmol) and benzaldehyde (50 mmol) were added to 20 mL toluene solution, heated at 130 °C for 10 h and monitored by TLC. After the reaction of the raw materials was completed, the mixture was cooled to room temperature, sodium cyanoborocyanide (40 mmol) was added and heated to 80 °C for 8 h and monitored by TLC. After the reaction was completed, the reaction solution was evaporated to dryness, 50 mL of aqueous solution and 50 mL of ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated NaCl aqueous solution (20 mL) after extraction and separation, and then spin-dried, column chromatographed, and dried to obtain the product 5-(benzamido)-1,3,4-thiadiazole-2-thiol.

[0145] The product 5-(benzamido)-1,3,4-thiadiazole-2-thiol, methyl bromoacetate and potassium carbonate were added to 50 mL of DMF, and the reaction was carried out at room temperature for 7.5 h. The reaction was monitored by TLC. When the reaction was complete, the reaction solution was spin-dried with an oil pump. 50 mL of aqueous solution and 50 mL of ethyl acetate were added to the reaction solution. After extraction and separation, the organic phase was washed with a saturated NaCl aqueous solution (20 mL) and spin-dried to obtain ( S)-methyl 2-((5-((2,3-dihydro-1H-inden-1-yl)amino)1,3,4-thiadiazol-2-yl)thio)acetate.

[0146] Will( S )-2-((5-((2,3-dihydro-1H-inden-1-yl)amino)1,3,4-thiadiazol-2-yl)thio)acetic acid methyl ester was dissolved in 20 mL of methanol, lithium hydroxide was dissolved in 10 mL of aqueous solution and added dropwise to the methanol system, reacted at room temperature for 3 hours, 50 mL of water and 50 mL of ethyl acetate were added to the reaction solution, the organic phase was washed with saturated NaCl aqueous solution (20 mL) after extraction and separation, and then spin-dried to obtain ( S )-2-((5-((2,3-dihydro-1H-inden-1-yl)amino)-1,3,4-thiadiazol-2-yl)thio)acetic acid.

[0147] 3,4-Difluorobenzenesulfonyl chloride (20 mmol) and p-aminobenzylamine (20 mmol) were added to 30 mL of dichloromethane solution, and triethylamine (30 mmol) was added dropwise thereto. After reacting at room temperature for 4 h, 50 mL of water and 50 mL of dichloromethane were added to the reaction solution. After extraction and separation, the organic phase was washed with saturated NaCl aqueous solution (20 mL) and dried by spin drying to obtain N-(4-aminophenyl)-3,4-difluorobenzene toluenesulfonamide.

[0148] Will( S )-2-((5-((2,3-dihydro-1H-inden-1-yl)amino)-1,3,4-thiadiazol-2-yl)thio)acetic acid (40 mmol), N-(4-aminophenyl)-3,4-difluorobenzene toluenesulfonamide (40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (40 mmol), 1-hydroxybenzotriazole (40 mmol), and triethylamine (60 mmol) were dissolved in anhydrous dichloromethane. The reaction was reacted at room temperature for 8 h and then monitored by TLC. After the reaction was complete, the reaction solution was spin-dried with an oil pump, and 50 mL of aqueous solution and 50 mL of dichloromethane were added to the reaction solution. After extraction and separation, the organic phase was washed with a saturated NaCl aqueous solution (20 mL), spin-dried, and then column chromatography was performed to obtain the final product IIa.

[0149] ESI-MS: m / z 562.54 [M+H] + , C 24 H 21 F2N5O3S3[561.08].

[0150] (2) The preparation method is the same as that of compound IIa, except that 2-thiophenesulfonyl chloride is used as the starting material to obtain compound IIb.

[0151]

[0152] IIb ESI-MS: m / z 532.24 [M+H] + , C 22 H 21 N5O3S4[531.05].

[0153] Example 5 Synthesis route:

[0154] (1) Preparation of (S)-2-N-(4-(((3,4-difluorophenyl)sulfonamido)methyl)phenyl)-2-((5-((2,3-dihydro-1H-indan-1-yl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (IIc)

[0155] IIc The intermediate 9p (40 mmol), methyl bromoacetate and potassium carbonate were added to 50 mL of DMF. After the reaction at room temperature for 7.5 h, the reaction solution was spin-dried with an oil pump. 50 mL of water and 50 mL of ethyl acetate were added to the reaction solution. After extraction and separation, the organic phase was washed with a saturated NaCl aqueous solution (20 mL) and spin-dried to obtain the intermediate 17p.

[0156] Dissolve 17 p in 20 mL methanol, dissolve lithium hydroxide in 10 mL water and add dropwise to the reaction system, react at room temperature for 3 h, add 50 mL water and 50 mL ethyl acetate to the reaction solution, extract and separate, wash the organic phase with saturated NaCl aqueous solution (20 mL), and spin dry to obtain 18 p. Melting point: 100~102 ℃, yield 70%.

[0157] Intermediate 18p (40 mmol), intermediate N-(4-aminophenyl)-3,4-difluorobenzene toluenesulfonamide (40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (40 mmol), 1-hydroxybenzotriazole (40 mmol), and triethylamine (60 mmol) were dissolved in anhydrous dichloromethane. The reaction was allowed to react at room temperature for 8 h and then monitored by TLC. When the reaction was complete, the reaction solution was spin-dried with an oil pump, and 50 mL of aqueous solution and 50 mL of dichloromethane were added to the reaction solution. After extraction and separation, the organic phase was washed with a saturated NaCl aqueous solution (20 mL), spin-dried, and then column chromatography was performed to obtain the product spot, which was then dried to obtain the final product IIc.

[0158] Gray-red solid, yield 18%, melting point: 160-162 ℃.

[0159] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 10.20 (s, 1H), 8.21 (t, J = 6.3 Hz, 1H),8.10 (d, J = 8.1 Hz, 1H), 7.77-7.70 (m, 1H), 7.63-7.55 (m, 2H), 7.44-7.36 (m,2H), 7.21 (dd, J = 7.4, 1.8 Hz, 1H), 7.13-7.02 (m, 5H), 4.89 (q, J = 5.7 Hz, 1H), 3.98-3.87 (m, 4H), 2.66 (ddt, J = 23.3, 16.5, 8.6 Hz, 2H), 1.95-1.61 (m, 5H).

[0160] 13 C NMR (101 MHz, DMSO- d 6) δ 168.99, 165.77, 149.11, 138.05, 137.93,137.11, 136.60, 132.32, 128.92, 128.80, 128.26, 127.24, 125.95, 124.41,118.95, 118.71, 118.52, 116.51, 116.32, 52.18, 45.81, 38.76, 28.76, 28.64,19.22.

[0161] ESI-MS: m / z 602.07 [M+H] + , C 27 H 25 F2N5O3S3[601.11].

[0162] Compounds IId-f were prepared using the above method with different sulfonyl chlorides and amines. Some of the results are as follows: (2) The preparation method is the same as that of compound IIc, except that 3-chloro-4-fluorobenzenesulfonyl chloride is used to prepare compound IId.

[0163]

[0164] IId Gray-red solid, yield 16%, melting point: 100-102 ℃.

[0165] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 10.23 (s, 1H), 8.27 (t, J = 6.2 Hz, 1H),8.14 (d, J = 8.1 Hz, 1H), 7.87 (dd, J = 6.9, 2.3 Hz, 1H), 7.77 (ddd, J = 8.7, 4.5,2.3 Hz, 1H), 7.60 (t, J = 8.9 Hz, 1H), 7.53-7.37 (m, 2H), 7.34-7.24 (m, 1H), 7.23-7.06 (m, 6H), 4.96 (q, J = 6.1 Hz, 1H), 3.99 (s, 2H), 3.98 (d, J = 5.7 Hz, 2H), 2.78-2.69 (m, 2H), 1.97-1.86 (m, 2H).

[0166] 13 C NMR (101 MHz, DMSO- d 6) δ 169.01, 165.73, 149.09, 138.38, 137.93,137.09, 136.59, 132.21, 129.09, 128.89, 128.75, 128.25, 127.92, 127.83,127.20, 125.92, 118.90, 117.97, 117.74, 52.20, 45.81, 38.76, 28.76, 28.61,19.21.

[0167] ESI-MS: m / z 617.92 [M+H] + , C 27 H 25 ClFN5O3S3[617.08].

[0168] (3) The preparation method is the same as that of compound IIc, except that 3,4-difluorobenzenesulfonyl chloride and (S)-(+)-1-aminoindanyl hydrochloride are used to prepare compound IIe.

[0169]

[0170] IIe The procedure is the same as above, except that 3,4-difluorobenzenesulfonyl chloride and (S)-(+)-1-aminoindanyl hydrochloride are used.

[0171] Gray-red solid, yield 20%, melting point: 190-192 ℃.

[0172] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 10.23 (s, 1H), 8.25 (t, J = 6.3 Hz, 1H),8.17 (d, J = 7.7 Hz, 1H), 7.83-7.75 (m, 1H), 7.70-7.59 (m, 2H), 7.51-7.44 (m,2H), 7.32 (d, J = 7.3 Hz, 1H), 7.29-7.19 (m, 2H), 7.18-7.13 (m, 3H), 5.24 (q, J =7.3 Hz, 1H), 4.00 (s, 2H), 3.98 (d, J = 6.3 Hz, 2H), 2.95 (ddd, J = 15.9, 8.6,4.2 Hz, 1H), 2.82 (dt, J = 15.8, 7.9 Hz, 1H), 2.57-2.52 (m, 1H), 1.93-1.76 (m, 1H).

[0173] 13 C NMR (101 MHz, DMSO- d 6) δ 169.39, 165.72, 149.38, 143.12, 143.05,138.05, 137.89, 132.31, 128.22, 127.85, 126.41, 124.69, 124.37, 124.22,118.94, 118.66, 118.48, 116.46, 116.28, 59.45, 45.78, 38.76, 33.02, 29.66.

[0174] ESI-MS: m / z 588.08 [M+H]+ , C 26 H 23 F2N5O3S3[587.09].

[0175] (4) The preparation method is the same as that of compound IIc, except that 3-chloro-4-fluorobenzenesulfonyl chloride and (S)-(+)-1-aminoindanyl hydrochloride are used to prepare compound IIe.

[0176]

[0177] IIf Gray-red solid, yield 20.5%, melting point: 180-182 ℃.

[0178] The NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 10.27 (s, 1H), 8.29 (t, J = 6.3 Hz, 1H),8.20 (d, J = 7.7 Hz, 1H), 7.87 (dd, J = 6.9, 2.3 Hz, 1H), 7.77 (ddd, J = 8.7, 4.5,2.3 Hz, 1H), 7.61 (t, J = 8.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 7.3Hz, 1H), 7.29-7.19 (m, 3H), 7.16 (dd, J = 8.3, 6.3 Hz, 3H), 5.24 (q, J = 7.3 Hz,1H), 4.01 (s, 2H), 3.98 (d, J = 6.3 Hz, 2H), 2.95 (ddd, J = 16.0, 8.6, 4.2 Hz,1H), 2.82 (dt, J = 15.8, 7.9 Hz, 1H), 1.85 (dq, J = 12.8, 7.9 Hz, 1H).

[0179] 13 C NMR (101 MHz, DMSO- d6) δ 169.40, 165.75, 160.54, 158.02, 149.43,143.12, 138.39, 137.97, 132.22, 129.12, 128.30, 127.96, 127.89, 126.45,124.74, 124.27, 120.57, 118.90, 117.91, 59.45, 45.83, 38.78, 33.08, 29.70.

[0180] ESI-MS: m / z 603.90 [M+H] + , C 26 H 23 ClFN5O3S3[603.06].

[0181] Example 6 Activity of thiadiazole derivatives on NMDA receptors Test Principle The two-electrode voltage clamp method (TEVC) was used to screen the in vitro activity of compounds against NMDA receptors.

[0182] Ion channel characteristics: Ion channels allow specific ions to pass through, forming transmembrane ion current (I). The resistance (R) of the membrane is inversely proportional to its permeability, that is, the membrane conductance (G), which means that when the membrane permeability to a certain ion increases, the membrane resistance actually decreases, that is, the membrane conductance to the ion increases. According to Ohm's law V = IR, that is, I = V / R = VG, the potential difference (V) on both sides of the membrane can be fixed and the change in transmembrane current (I) can be measured as a measure of the change in membrane conductance, thereby understanding the change in membrane permeability.

[0183] Voltage clamp technique: Voltage clamp technique places two electrodes on the cell membrane, one is called the clamp electrode, which is used to control the membrane potential, and the other is called the reference electrode, which is used to measure changes in membrane potential. The clamp electrode is connected to the reference electrode through a negative feedback circuit, so that the potential difference between the clamp electrode and the reference electrode remains constant. In this way, when the membrane potential changes, the clamp electrode will adjust the current to keep the potential difference unchanged, so that changes in membrane potential can be measured.

[0184] The NMDA receptor GluN1 / 2A subtype was specifically expressed on the Xenopus oocyte membrane, and the receptor was activated with 10 μmol / L glycine and 300 μmol / L glutamate. The electrical signals inside and outside the cell membrane were measured and calibrated to 100%. Then, 10 μmol / L of the test compound flowed through the receptor. The ratio of the electrical signal of the test compound at a concentration of 10 μmol / L to the calibrated electrical signal was the inhibition rate of the compound on the GluN1 / 2A subtype at a concentration of 10 μmol / L. Subsequently, the compounds with higher inhibition rates were measured using different concentration gradients to obtain the inhibitory IC of the compound on the GluN1 / 2A subtype. 50 , that is, the concentration of the compound at which the inhibitory activity of the compound on GluN1 / 2A subtype reaches 50%.

[0185] For compounds with better activity, the inhibition rates of the three subtypes of GluN1 / 2B, GluN1 / 2C, and GluN1 / 2D were measured at a concentration of 10 μmol / L.

[0186] Test Materials Plasmid extraction kit QIAprep Spin Miniprep Kit (250) was purchased from Guangzhou Yuwei Biotechnology Instrument Co., Ltd. Plasmid extraction kit HiSpeed ​​Plasmid Midi Kit (25) was purchased from Guangzhou Yuwei Biotechnology Instrument Co., Ltd. DNA purification kit QIAquick PCR Purification kit (50) was purchased from Guangzhou Yuwei Biotechnology Instrument Co., Ltd. Ambion mMessage mMachine T7 Ultra kit was purchased from Yingwei Jieji (Shanghai) Trading Co., Ltd. Mature female African clawed frogs used in the experiment were provided by Zenop Laboratory Equipment Business Office, Changshu City, Jiangsu Province. Clawed frog breeding: Take mature and larger female clawed frogs and place them in a clean glass tank with a water depth of about 15-25 cm. Clawed frogs need to be fed twice a week, and the breeding water should be changed after each feeding. Chopped hearts and livers of cows or other animals are used as feeding materials. HEPES, sodium chloride, potassium chloride, calcium chloride, anhydrous ethanol, manganese chloride, L-glutamine, magnesium chloride, and penicillin-streptomycin are all products of SIGMA Reagent Company. Collagenase, Type 1 (42D22410, Worthington Biochemical Corporation, USA). Experimental instruments: Xenopus incubator CND-260A Yanghui, China.

[0187] Stereo microscope SZ650 CNOPTEC, China.

[0188] Electrode drawing instrument NARISHIGE PC-100 Warner Instruments, USA.

[0189] Microinjection Instrument NANO J ECT III Drummond Scientific, USA.

[0190] SRLAB Startle Response System 0610 - SRLAB San Diego Instruments, San Diego.

[0191] SV-04 channel switching valve QHF-SY04-XS-T10-K1.2-Se RUNZE FLUID,China.

[0192] Oocytes Voltage Clamp OC-725D Warner, USA.

[0193] Manual micromanipulator CA94949 Sutter, USA.

[0194] Experimental methods (1) Isolation of Xenopus oocytes Prepare surgical instruments: ordinary scissors (one pair for skin and one pair for tissue), fine forceps, straight forceps, needle holder, absorbable suture (4-0); prepare items: alcohol cotton balls, pads, cotton swabs, and gauze.

[0195] Surgery: Prepare 2 L of 0.8 g / L anesthetic and place an African clawed frog in it for about 15-30 min until the clawed frog is completely anesthetized. Place it on ice with the abdomen facing up and disinfect it with iodine. Use scissors to avoid the main blood vessels in the midline and make an incision of about 1 cm on the skin and tissue on one side of the abdomen. The ovarian lobe is clearly visible. Use forceps and scissors to remove a small amount of ovarian tissue. Check the quality of the oocyte under a dissecting microscope. There should be a clear boundary difference between the animal hemisphere and the vegetal hemisphere. Half is black and the other half is yellow. It is covered by a layer of yolk layer, a layer of follicle cells and connective tissue containing blood vessels. If the oocyte is healthy, remove enough oocytes for use according to the experimental plan, place it in OR2 solution, suture the wound with absorbable sutures (4-0), disinfect it with iodine, and then isolate the clawed frog and place it in water to regain consciousness for about 30 min. Add 100 mM sodium chloride and 100 μg / mL oxytetracycline to prevent infection. Change the water every day for at least one week. The breeding tank is soaked in 0.008 g / L potassium permanganate solution for 24 hours once a week, then rinsed with clean water for later use.

[0196] Digestion: Use fine forceps to tear the ovarian tissue sample in the OR2 solution into small pieces and transfer them to a 50 mL centrifuge tube. Add OR2 solution containing 1 mg / mL collagenase (Type 1) and incubate on a shaker at room temperature for 1-2 h until about 1 / 3 of the follicles of the oocytes fall off. During this process, the oocytes should be frequently observed under a stereomicroscope to prevent over-digestion and damage to the oocytes. Use fresh OR2 solution to wash the oocytes until the collagenase is completely removed, and then transfer them to a 50 mL centrifuge tube containing OR2. Shake on a shaker at room temperature for about 1 h to allow the oocytes to collide with each other to fall off as many follicles as possible. Then transfer the oocytes to a culture dish containing MBS culture medium and place it in a 17°C incubator.

[0197] Selection: Select oocytes of good quality, moderate size and without follicle encapsulation under a stereomicroscope.

[0198] (2) Xenopus oocyte injection and RNA expression RNA preparation: After the concentration of cRNA is measured, it is uniformly diluted to 1.5 μg / uL with Nuclease-free H2O. For hG1uN1 / hG1uN2A NMDA receptors, it is then diluted with Nuclease-free H2O according to the table below. The diluted hG1uN1 and hG1uN2A cRNAs are injected at a ratio of 1:2 and a total volume of 50 mL. The excess RNA after dilution can be stored in a -80℃ refrigerator. Microinjection of RNA: Fill the injection dish with Barth culture medium, and use a Pasteur pipette to neatly arrange the oocytes in the grooves. Use Nano J To inject RNA using the ectIII microinjector, the glass electrode is first sealed with mineral oil to increase airtightness, then a certain volume of RNA is sucked in and injected into the oocyte. The injection volume is 50 mL. The tip should be thin enough to allow the oocyte to penetrate with minimal degeneration. After the needle is pulled out, there should be no penetration at the injection site and the injection wound should be almost invisible.

[0199] Expression: The injected Xenopus oocytes were placed in a culture dish containing Barth's medium and incubated at 17°C for 1-2 days to express hGluN1 / hG1uN2A type NMDA receptors.

[0200] (3) Electrical signal testing of Xenopus oocytes EasyOocyte software was used for recording the current of Xenopus oocytes and electrophysiological recording of HEK293T cells. The oocyte was placed in a recording tank with a volume of about 1 mL. A small piece of mesh sheet was glued to the bottom of the recording tank in the middle to prevent the oocyte from sliding at the bottom during clamping and perfusion. Various extracellular fluids were continuously perfused. The two drawn glass microelectrodes were inserted into the probe of the amplifier respectively. The two electrodes were placed in the recording tank respectively using a micromanipulator. When the tip of the electrode entered the liquid surface, the mV and V: on the amplifier panel were adjusted to 0 potential. Then 10 μmol / L glycine and 300 μmol / L glutamate were used to activate the receptors, and the electrical signals inside and outside the cell membrane were measured at this time and calibrated to 100%. Then 10 μmol / L of the test compound was used to flow through the receptor. The electrical signal of the test compound at a concentration of 10 μmol / L, and its ratio to the calibrated electrical signal was the inhibition rate of the compound on the GluN1 / 2A subtype at a concentration of 10 μmol / L. Then, the compounds with higher inhibition rates were measured using different concentration gradients to obtain the inhibitory IC of the compounds on GluN1 / 2A subtypes. 50 , which is the concentration of the compound at which the inhibitory activity of the compound on GluN1 / 2A subtype reaches 50%. All experiments were performed at room temperature (21-23°C).

[0201] The activity test of the compound on the three subtypes of GluN1 / 2B, GluN1 / 2C, and GluN1 / 2D is similar to the experimental steps of the GluN1 / 2A activity test, except that the hG1uN1 / hG1uN2A type RNA is replaced by the corresponding RNA subtype.

[0202] According to the above experimental method, the NMDA receptor activity of the synthesized thiadiazole derivatives was tested at the cellular level. The activity results are shown in Tables 1 and 2. Table 1 Test results of NMDA receptor inhibition rate at the cellular level of thiadiazole derivatives and reference drugs

[0203] Note: a Inhibition rate: The inhibition rate of the compound on GluN1 / 2A subtype at 10 μmol / L. Table 2 Test results of NMDA receptor inhibitory activity of thiadiazole derivatives and reference drugs at the cellular level

[0204] b IC 50 : The concentration of the compound at which the inhibitory activity on GluN1 / 2A subtype reaches 50%. Glycine concentration during testing: 10 μmol / L, glutamate concentration: 300 μmol / L.

[0205] The activity test results of some compounds on the three subtypes of GluN1 / 2B, GluN1 / 2C, and GluN1 / 2D at 10 μmol / L are shown in Figure 1 The glycine concentration during the test was 10 μmol / L and the glutamate concentration was 300 μmol / L.

[0206] Embodiment 7: Taking compound If as an example, study the metabolism of this type of compound in rats Objective: This study aimed to observe the time course of the plasma concentration of If (for example) in rats after intravenous injection and oral gavage, and to estimate the corresponding pharmacokinetic parameters and absolute bioavailability.

[0207] Methods: Six rats were divided into two groups and given 1f by intravenous injection and oral gavage, respectively. Blood samples of about 0.25 mL were collected from the jugular vein at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration in the intravenous injection group and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration in the oral gavage group. The concentration of 1f in rat plasma samples was determined by LC-MS / MS, and the pharmacokinetic parameters were calculated using WinNolin software.

[0208] Results: After a single intravenous injection of 3 mg / kg 1f and oral administration of 10 mg / kg 1f in rats, the main pharmacokinetic parameters of intravenous administration were: C max 2997 ng / mL, T max is 0.0833 h, T 1 / 2 For 0.200 h, AUC 0-T is 1014 hr*ng / mL, AUC 0-∞ is 1015 hr*ng / mL, Vz is 852 mL / kg, Cl is 2959 mL / hr / kg, MRT 0-t 0.210 h, MRT 0-∞ The main pharmacokinetic parameters of oral administration are: C max 105 ng / mL, T max is 0.333 h, T 1 / 2 2.05 h, AUC 0-t 123 hr*ng / mL, AUC 0-∞ 151 hr*ng / mL, MRT 0-t 1.21 h, MRT 0-∞ The oral bioavailability is 4.45%.

[0209] Example 8 Taking compound If as an example, the permeability of this compound in the rat blood-brain barrier was studied. Objective: This study aimed to observe the time course of plasma drug concentration of test substance 1f after intravenous injection in rats and to estimate the corresponding pharmacokinetic parameters and absolute bioavailability.

[0210] Methods: Twelve rats were given 1f intravenously, and about 0.25 mL of blood and brain tissue were collected from the jugular vein at 5 min, 15 min, 30 min, and 1 h after administration. The concentration of 1f in rat plasma samples was determined by LC-MS / MS, and the pharmacokinetic parameters were calculated using WinNolin software.

[0211] Results: After a single intravenous injection of 10 mg / kg 1f in rats, the main pharmacokinetic parameters of intravenous administration in plasma were: C max 10577 ng / mL, T max is 0.0833 h, T 1 / 2 0.152 h, AUC 0-T 3361 hr*ng / mL, AUC 0-∞ is 3388 hr*ng / mL, Vz is 646 mL / kg, Cl is 2952 mL / hr / kg, MRT 0-t 0.172 h, MRT 0-∞ The main pharmacokinetic parameters of brain tissue after intravenous injection are: C max 6850 ng / mL, T max is 0.0833 h, T 1 / 2 0.145 h, AUC 0-T 2093 hr*ng / mL, AUC 0-∞ is 2106 hr*ng / mL, Vz is 992 mL / kg, Cl is 4748 mL / hr / kg, MRT 0-t 0.158 h, MRT 0-∞ The brain-blood exposure ratio is 0.622.

[0212] Example 9 Taking compound If as an example, the pharmacodynamics of this compound in animal experiments was studied. The pharmacodynamics was evaluated by the forced swimming test in mice. The experimental animals were ICR mice, male, weighing 20-24g, and fasted for 12h before the forced swimming test. Compound 1f was dissolved in DMSO and diluted to 1 mmol / L with saline. A blank control group (DMSO), a drug-treated group, and a positive control (imipramine, 1 mmol / L) were set up. There were 8-10 rats in each group.

[0213] The day before the experiment, the rats were placed in a glass tank with a height of 40 cm, an inner diameter of 18 cm, and a water depth of 23 cm for a pre-swim of 15 min, and the water temperature was 28°C. After the pre-swim, the rats were taken out, wiped dry with a dry cloth, and returned to the breeding cage. The formal forced swimming experiment was carried out the next day, and the corresponding samples were injected intraperitoneally 30 min before the start of the experiment (blank control group, drug group, positive control drug group, injection volume was 10mL / kg). Half an hour later, the forced usefulness experiment was carried out for a total of 6 min, and the cumulative immobility time within 2-6 min was recorded.

[0214] The criterion for judging immobility is that the animal stops struggling in the water and is floating, with only slight limb movements to keep the head above the water. Figure 2 The experimental data were statistically analyzed using GraphPad Prism software.

Claims

1. A thiadiazole derivative or a pharmaceutically acceptable salt thereof, wherein the thiadiazole derivative has a structure shown in Formula I or Formula II: in, R1 is a structure having the general formula (a) or the general formula (b): Ar or R2 is substituted phenyl, substituted naphthyl, substituted or unsubstituted five-membered or six-membered heteroaromatic ring group, substituted or unsubstituted C8-C 10 A fused ring group; The C8-C 10 The fused ring group is a fused ring group formed by a C4-C6 cyclic hydrocarbon group and a benzene ring and sharing two carbon atoms; Ring A is cyclopentane or cyclohexane; R3 is substituted or unsubstituted benzyl, hydronaphthyl and indanyl; The substituents on Ar, R2 and R3 are one or more, and each substituent is independently selected from halogen, C1-C3 alkyl or C1-C3 alkoxy.

2. The thiadiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The five-membered or six-membered heteroaromatic ring group is selected from thienyl or furyl; The C4-C6 cycloalkyl group is selected from a C4-C6 cycloalkyl or cycloalkenyl group and a C5-C6 aromatic heterocyclic group; The C8-C 10 The fused ring group is selected from benzocyclobutenyl, indanyl, benzofuranyl and hydronaphthyl; The substituents on Ar, R2 and R3 are one or two, each of which is independently selected from F, Cl, Br, methyl or methoxy; The position of the substituent is selected from the meta position and the para position of the insertion site of Ar, R2 and R3 in the structure of Formula I or Formula II; The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt of the compound of formula I or formula II; Ar is selected from p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl, p-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-methylphenyl, m-methoxyphenyl, p-bromo-m-methylphenyl, p-chloro-m-chlorophenyl, benzocyclobutenyl, benzofuranyl or 5-bromo-thiophen-2-yl; R2 is selected from thienyl, p-fluoro-m-fluorophenyl or p-fluoro-m-chlorophenyl; R3 is selected from benzyl, hydronaphthyl or indanyl.

3. The thiadiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Having any of the following structures, or a pharmaceutically acceptable salt thereof: 。 4. A method for preparing the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The thiadiazole derivative has a structure shown in the general formula I; wherein R1 has a structure of the general formula (a): , Ar is as defined in claim 1 or 2; The preparation method is carried out according to the following process: The preparation method comprises: i: Compound 2 reacts with chloroacetyl chloride to generate compound 3; ii: Compound 3 reacts with 2-amino-5-mercapto-1,3,4-thiadiazole to generate compound 4; iii: Compound 4 and or Reaction to obtain a compound of formula I; Wherein, R4 is a substituent on the benzene ring, R4 is one or more, and R4 is selected from halogen, C1-C3 alkyl and C1-C3 alkoxy; Alternatively, R4 and the benzene ring form a condensed ring structure sharing two carbon atoms, wherein the condensed ring is selected from benzocyclobutenyl, indanyl, benzofuranyl or hydronaphthyl.

5. A method for preparing the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The thiadiazole derivative has a structure shown in the general formula I; wherein R1 in the formula I is a structure having the general formula (b): , when ring A is cyclopentane or cyclohexane, as shown in formula I'; The preparation method is carried out according to the following route: The structures of compounds 5p and 5q are shown below: The preparation method comprises: i: Compound 5p or 5q reacts with carbon disulfide to generate compound 6p or 6q; ii: Compound 6p or 6q undergoes oxidation reaction in an alkaline environment to generate compound 7p or 7q; iii: Compound 7p or 7q undergoes an addition reaction with hydrazine hydrate to generate compound 8p or 8q; iv: Compound 8p or 8q undergoes a cyclization reaction with carbon disulfide under alkaline conditions to generate compound 9p or 9q; v: Compound 9p or 9q is reacted with 2-chloro-N-(cyclohexylmethyl)acetamide to generate a compound of formula I', wherein in the compound of formula I', ring A is cyclopentane or cyclohexane.

6. A method for preparing the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The thiadiazole derivative has a structure shown in the general formula II; wherein R3 is a benzyl group, R2 is a thienyl group or a phenyl group substituted by R5, and the formula II has the structures shown in IIa and IIb respectively; wherein R5 is one or two substituents on the benzene ring, and when there are two R5s, they are two identical or different substituents, and R5 is a halogen selected from fluorine, chlorine or bromine; The preparation method is carried out according to the following reaction scheme: The preparation method comprises: i: 2-amino-5-mercapto-1,3,4-thiadiazole reacts with benzaldehyde and is reduced by sodium cyanoborocyanide to generate compound 12; ii: Compound 12 reacts with methyl bromoacetate to generate compound 13; iii: Compound 13 is hydrolyzed under the action of lithium hydroxide to generate compound 14; iv: or 2-thiophenesulfonyl chloride reacts with p-aminobenzylamine to generate compound 16a or 16b, wherein R5 is one or two substituents on the benzene ring, and R5 is a halogen selected from fluorine, chlorine or bromine; v: Compound 14 undergoes condensation reaction with compound 16a or compound 16b to generate final product IIa or IIb, wherein in formula IIa, R2 is a phenyl group substituted with one or two halogens, and in formula IIb, R2 is a thienyl group.

7. A method for preparing the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The thiadiazole derivative has a structure shown in general formula II; wherein, when R3 is a hydronaphthyl group or an indanyl group, formula II has a structure shown in formula IIc-f; The preparation method is carried out according to the following route: Wherein, R2 is thienyl, p-fluoro-m-fluorophenyl or p-fluoro-m-chlorophenyl; Ring A is cyclopentane or cyclohexane; The preparation method comprises: i: Compound 9p or compound 9q reacts with methyl chloroacetate to generate compounds 17p and 17q; ii: Compounds 17p and 17q are hydrolyzed to generate compounds 18p or 18q; iii: Compound 18p or 18q undergoes a condensation reaction with compound 16a or 16b to generate final product IIc-f; wherein the structure of compound 16a or 16b is .

8. Use of a thiadiazole derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the preparation of an NMDA receptor modulator drug or a drug for preventing and / or treating diseases associated with abnormal NMDA receptor function, wherein: The NMDA receptor modulator drug is an NMDA receptor GluN1 / 2A subtype inhibitor drug.

9. The use according to claim 8, characterized in that: The diseases associated with abnormal NMDA receptor function include depression, depression, stroke, Huntington's disease, Alzheimer's disease, neuralgia or schizophrenia.

10. A pharmaceutical composition or pharmaceutical preparation, characterized in that: The invention comprises the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

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