A thiadiazole derivative, its preparation method and application

Abstract

The present invention belongs to the technical field of organic compound synthesis and pharmaceutical applications, and specifically relates to a thiadiazole compound, a preparation method thereof, and an application thereof. The thiadiazole compound has a structure represented by General Formula I or II: #imgabs0# wherein, R1 has a structure represented by General Formula (a) or General Formula (b), and Ar or R2 is a substituted phenyl group, a substituted naphthyl group, a substituted or unsubstituted five- or six-membered heteroaryl group, a substituted or unsubstituted C8-C 10 fused ring group; the C8-C 10 fused ring group is a fused ring group formed by a C4-C6 cycloalkyl group and a benzene ring sharing two carbons; Ring A is cyclopentane or cyclohexane; R3 is a substituted or unsubstituted benzyl group, a tetrahydronaphthyl group, and an indanyl group. This compound can play a role by penetrating the blood-brain barrier and can be widely used in the development of drugs for NMDA receptor-related diseases.

Description

Technical Field

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

[0002] The N-methyl-D-aspartate (NMDA) receptor plays 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 on the market targeting the NMDA receptor mainly include: ketamine, dextromethorphan (for treating refractory depression), lacosamide (for treating convulsions), memantine hydrochloride (for treating Alzheimer's disease), dizocilpine (for treating epilepsy). However, these drugs do not have subtype selectivity and have serious neuro-mimicking side effects. Based on this, discovering subtype-selective compounds and using them as pharmacological tools for exploring the function of the NMDA receptor and drugs for treating mental diseases is of great significance for the related research of the NMDA receptor.

[0003] Currently, the representative negative allosteric modulators for the GluN1 / 2A subtype mainly include TCN-201, TCN-213, MPX004, and MPX007, etc. Among them, TCN-201, MPX004, and MPX007 show nanomolar-level inhibitory activity against the NMDA receptor. However, these three compounds cannot penetrate the blood-brain barrier. And the inhibitory activity of TCN-213 against the NMDA receptor is poor. Therefore, further modification of this type of chemical structure is of great significance for discovering novel NMDA receptor modulators with high efficiency and blood-brain barrier permeability.

[0004] Summary of the Invention

[0005] Aiming at the deficiencies of the prior art, the present invention provides a thiadiazole derivative, a preparation method thereof, and an application thereof. This compound has obvious advantages compared with the previously discovered compounds, can penetrate the blood-brain barrier to play a role, solves the problem that the compounds acting on this target cannot penetrate the blood-brain barrier, and can be widely used in the development of drugs for NMDA receptor-related diseases.

[0006] To achieve the above object, the specific technical solutions provided by the present invention are as follows:

[0007] In the first aspect, the present invention provides a thiadiazole derivative or a pharmaceutically acceptable salt thereof, and the thiadiazole derivative has a structure shown in General Formula I or General Formula II:

[0008]

[0009] Among them, R1 has a structure of general formula (a) or general formula (b):

[0010]

[0011] Ar or R2 is a substituted phenyl group, a substituted naphthyl group, a substituted or unsubstituted five - or six - membered heteroaryl group, a substituted and unsubstituted C8 - C 10 fused polycyclic group;

[0012] The C8 - C 10 fused polycyclic group is a fused polycyclic group formed by a C4 - C6 cycloalkyl group and a benzene ring sharing two carbons;

[0013] Ring A is cyclopentane or cyclohexane;

[0014] R3 is a substituted or unsubstituted benzyl group, a tetrahydronaphthyl group and an indanyl group;

[0015] 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.

[0016] In some embodiments, the five - or six - membered heteroaryl group is selected from thienyl or furyl.

[0017] In some embodiments, the C4 - C6 cycloalkyl group is selected from C4 - C6 cycloalkyl or cycloalkenyl and C5 - C6 heteroaryl group.

[0018] In some embodiments, the C8 - C 10 fused polycyclic group is selected from benzocyclobutenyl, indanyl, benzofuryl and tetrahydronaphthyl.

[0019] In some embodiments, the substituents on Ar, R2 and R3 are one or two, and each substituent is independently selected from F, Cl, Br, methyl or methoxy.

[0020] In some embodiments, the position of the substituent is selected from the meta - position and the para - position of the attachment sites of Ar, R2 and R3 in the structure of formula I or formula II.

[0021] In some embodiments, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt of the compound of general formula I or general formula II.

[0022] 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, benzofuryl or 5 - bromo - thien - 2 - yl.

[0023] In some embodiments, R2 is selected from thienyl, 3-fluoro-4-fluorophenyl or 3-fluoro-4-chlorophenyl.

[0024] In some embodiments, R3 is selected from benzyl, tetrahydronaphthyl or indanyl.

[0025] In some embodiments, the thiadiazole derivative has any of the following structures, or a pharmaceutically acceptable salt thereof:

[0026]

[0027] In a second aspect, the present invention provides a method for preparing the thiadiazole derivative or a pharmaceutically acceptable salt thereof described in the first aspect, wherein the thiadiazole derivative has the structure shown in general formula I; wherein, R1 has the structure of general formula (a) , and Ar is as defined in the first aspect;

[0028] The preparation method is carried out according to the following process:

[0029]

[0030] The preparation method includes:

[0031] i: Compound 2 reacts with chloroacetyl chloride to form compound 3;

[0032] ii: Compound 3 reacts with 2-amino-5-mercapto-1,3,4-thiadiazole to form compound 4;

[0033] iii: Compound 4 reacts with or to obtain the compound of formula I;

[0034] 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;

[0035] Alternatively, R4 and the benzene ring form a fused ring structure sharing two carbons, and the fused ring is selected from benzocyclobutenyl, indanyl, benzofuranyl or tetrahydronaphthyl.

[0036] In some embodiments, the thiadiazole derivative has the structure shown in general formula I; wherein, R1 in formula I has the structure of general formula (b) , when ring A is cyclopentane or cyclohexane, as shown in formula I';

[0037] The preparation method is carried out according to the following route:

[0038]

[0039] wherein, the structures of compounds 5p and 5q are shown as follows:

[0040]

[0041] The preparation method includes:

[0042] i: Compound 5p or 5q reacts with carbon disulfide to form compound 6p or 6q;

[0043] ii: Compound 6p or 6q undergoes an oxidation reaction in an alkaline environment to form compound 7p or 7q;

[0044] iii: Compound 7p or 7q undergoes an addition reaction with hydrazine hydrate to form compound 8p or 8q;

[0045] iv: Compound 8p or 8q undergoes a cyclization reaction with carbon disulfide under alkaline conditions to form compound 9p or 9q;

[0046] v: Compound 9p or 9q reacts with 2-chloro-N-(cyclohexylmethyl)acetamide to form the compound of formula I'; wherein, in the compound of formula I', ring A is cyclopentane or cyclohexane.

[0047] In some embodiments, the thiadiazole derivative has the structure shown in general 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 R5 is two, they are two identical or different substituents, and R5 is a halogen, selected from fluorine, chlorine or bromine;

[0048] The preparation method proceeds according to the following reaction route:

[0049]

[0050] The preparation method includes:

[0051] i: 2-Amino-5-mercapto-1,3,4-thiadiazole reacts with benzaldehyde and is reduced by sodium cyanoborohydride to form compound 12;

[0052] ii: Compound 12 reacts with methyl bromoacetate to form compound 13;

[0053] iii: Compound 13 is hydrolyzed under the action of lithium hydroxide to form compound 14;

[0054] iv: Or 2-thiophenesulfonyl chloride reacts with 4-aminobenzylamine to form 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;

[0055] v: The condensation reaction of compound 14 with compound 16a or compound 16b yields the end product IIa or IIb. In formula IIa, R2 is a phenyl group substituted with one or two halogens; in formula IIb, R2 is a thiophenyl group.

[0056] In some embodiments, the thiadiazole derivatives have the structure shown in general formula II; wherein, R3 is a tetrahydronaphthyl group or an indanyl group; formula II has the structures shown in formulas IIc-f;

[0057] The preparation method proceeds according to the following route:

[0058]

[0059] wherein, R2 is: a thiophenyl group, a p-fluoro-m-fluorophenyl group or a p-fluoro-m-chlorophenyl group;

[0060] Ring A is a cyclopentane or a cyclohexane;

[0061] The preparation method includes:

[0062] i: The reaction of compound 9p or compound 9q with methyl chloroacetate yields compounds 17p and 17q;

[0063] ii: The hydrolysis reaction of compounds 17p and 17q yields compound 18p or 18q;

[0064] iii: The condensation reaction of compound 18p or 18q with compound 16a or 16b yields the end product IIc-f; wherein, the structure of compound 16a or 16b is .

[0065] In a third aspect, the present invention provides the use of the thiadiazole derivatives described in the first aspect in the preparation of an NMDA receptor modulator drug or a drug 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.

[0066] In some other embodiments, the diseases related to abnormal NMDA receptor function include but are not limited to depression, stroke, Huntington's disease, Alzheimer's disease, neuralgia, schizophrenia.

[0067] In a fourth aspect, the present invention provides a pharmaceutical composition or pharmaceutical preparation, comprising the thiadiazole derivatives described in the first aspect or a pharmaceutically acceptable salt thereof; or further comprising excipients.

[0068] Compared with the prior art, the present invention has the following beneficial effects:

[0069] (1) The thiadiazole derivatives prepared by the present invention can act on NMDA receptors and specifically inhibit the GluN1 / 2A subtype, showing certain antidepressant effects in animal-level antidepressant experiments. Further in vivo distribution experiments in rats confirmed that these compounds have blood-brain barrier permeability.

[0070] (2) The synthetic route of the preparation method of the present invention is based on common raw materials and is prepared through simple reactions. The raw materials are inexpensive and easily available, the synthetic route is scientific, the method steps are simple, the reaction conditions are mild and easy to achieve, and the product separation is convenient.

[0071] (3) The thiadiazole derivatives provided by the present invention solve the problem that compounds acting on this target cannot penetrate the blood-brain barrier, and this compound can be widely used in the development of drugs for NMDA receptor-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 It is the activity test results of compounds Ia, If, In, and Ij in Example 2 of the present invention at 10 μmol / L for three subtypes of GluN1 / 2B, GluN1 / 2C, and GluN1 / 2D;

[0073] Figure 2 It is the forced swimming experiment diagram of compound If in Example 2 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0074] In order to further illustrate the present invention, the thiadiazole derivatives provided by the present invention, their preparation methods and applications will be described in detail below in conjunction with examples. The following examples are only helpful for understanding the present invention, but cannot limit the content of the present invention.

[0075] Example 1

[0076] Preparation of 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-N-(cyclohexylmethyl)acetamide (Compound 4)

[0077] Synthetic route:

[0078]

[0079] Cyclohexanemethylamine (Compound 2, 10 mmol) and triethylamine (12 mmol) were mixed and added to 50 mL of dichloromethane solution, and the reaction was carried out at 0 °C. After 5 min, chloroacetyl chloride (12 mmol) was added dropwise to the solution system. The solution changed from clear to yellowish-brown. After stirring for 3 h, TLC was used for monitoring. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. Extraction was carried out three times with a dichloromethane and water system (20 mL × 3). After combining the organic phases, the solvent was removed by rotary evaporation under reduced pressure, and vacuum drying was carried out to obtain a yellowish-brown powder, namely 2-chloro-N-(cyclohexylmethyl)acetamide (Compound 3), with a yield of 72%, melting point: 102~104 °C.

[0080] 2-Amino-5-mercapto-1,3,4-thiadiazole (20 mmol), Compound 3 (20 mmol) and potassium carbonate (40 mmol) were added to 50 mL of DMF, and the reaction was carried out at 85 °C for 7.5 h. TLC was used for monitoring the reaction. After the reaction was complete, the reaction solution was added dropwise to a beaker containing 300 mL, stirred for 30 min, and then filtered by suction with a Buchner funnel after standing. The filter cake was dried under vacuum to obtain a white solid, namely Compound 4, with a yield of 65.4%, melting point: 105~107 °C. ESI-MS: m / z 287.02 [M+H] + 。

[0081] Example 2:

[0082] Preparation of Compound I (Compound 1a to Compound 1o)

[0083]

[0084] (1) Preparation of N-(cyclohexylmethyl)-2-((5-((4-fluorobenzyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (Compound Ia)

[0085]

[0086] Compound Ia

[0087] Compound 4 (40 mmol), p-toluenesulfonic acid (0.4 mmol) and 4-fluorobenzaldehyde (50 mmol) were weighed and added to 20 mL of toluene solution. The reaction was carried out at 130 °C for 10 h and TLC was used for monitoring the reaction. After the raw materials were reacted completely and the reaction system was cooled, sodium cyanoborohydride (40 mmol) was added, and the reaction was carried out at 80 °C for 8 h and TLC was used for monitoring the reaction. After the reaction was complete, the reaction solution was evaporated to dryness, 50 mL of aqueous solution and 50 mL of ethyl acetate were added, and after extraction and liquid separation, the organic phase was washed with saturated NaCl aqueous solution (20 mL × 3), rotary evaporated to dryness, and the product spot was obtained by column chromatography. After drying, the final product Compound Ia was obtained.

[0088] Yellow solid, yield 30%, melting point: 127 - 129 °C.

[0089] The NMR data are as follows:

[0090] 1 H NMR (400 MHz, DMSO- d 6) δ 8.31 (t, J J = 5.8 Hz, 1H), 8.09 (t, J J = 5.9 Hz,1H), 7.41 - 7.35 (m, 2H), 7.20 – 7.14 (m, 2H), 4.44 (d, J J = 5.8 Hz, 2H), 3.75 (s,2H), 2.89 (t, J J = 6.3 Hz, 2H), 1.61 (qd, J J = 7.1, 3.3 Hz, 5H), 1.34 (ddp, J J = 11.3,7.2, 3.5 Hz, 1H), 1.18 - 1.06 (m, 3H), 0.88 - 0.77 (m, 2H).

[0091] 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.

[0092] ESI-MS: m / z 395.45[M+H] + , C 18 H 23 FN4OS2[394.13].

[0093] Compounds Ia - o were respectively prepared from different aromatic aldehydes and compound 4 by the above method, and some results are as follows:

[0094] (2) The preparation method is the same as that of compound Ia, except that p-chlorobenzaldehyde and compound 4 are used for reaction to obtain compound Ib.

[0095]

[0096] Ib

[0097] Yellow solid, yield 35%, melting point: 79 - 81 °C.

[0098] The NMR data are as follows:

[0099] 1 H NMR (400 MHz, DMSO- d 6) δ 8.35 (t, J J = 5.9 Hz, 1H), 8.09 (t, J J = 5.8 Hz,1H), 7.42 - 7.27 (m, 4H), 4.48 (d, J J = 5.9 Hz, 2H), 3.76 (s, 2H), 2.89 (t, J J = 6.3Hz, 2H), 1.66 - 1.54 (m, 5H), 1.33 (dtt, J J = 10.8, 6.9, 3.5 Hz, 1H), 1.18 - 1.05(m, 3H), 0.83 (td, J J = 13.4, 6.3 Hz, 2H).

[0100] 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.

[0101] ESI-MS: m / z 411.48 [M+H] + ,C 18 H 23 ClN4OS2[410.10].

[0102] (3) The preparation method is the same as that of compound Ia, except that p-bromobenzaldehyde and compound 4 are used in the reaction to obtain compound Ic.

[0103]

[0104] Ic

[0105] Yellow solid, yield 40%, melting point: 112 - 114 °C.

[0106] The NMR data are as follows:

[0107] 11H NMR (400 MHz, DMSO- d 6) δ 8.36 (t, J J = 5.9 Hz, 1H), 8.11 (t, J J = 5.8 Hz,1H), 7.54 (d, J J = 1.8 Hz, 1H), 7.47 (dt, J J = 7.5, 1.8 Hz, 1H), 7.37-7.28 (m, 2H),4.47 (d, J J = 5.9 Hz, 2H), 3.76 (s, 2H), 2.89 (t, J J = 6.3 Hz, 2H), 1.62 (qd, J J =9.0, 3.7 Hz, 5H), 1.33 (ddp, J J = 10.8, 7.1, 3.7 Hz, 1H), 1.20-1.05 (m, J J = 9.1Hz, 3H), 0.89-0.75 (m, 2H)。

[0108] 13 13C 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。

[0109] ESI-MS: m / z 453.19[M-H] - ,C 18 H 23 BrN4OS2[454.05]。

[0110] (4)The preparation method is the same as that of compound Ia, except that p-methylbenzaldehyde and compound 4 are used for reaction to obtain compound Id.

[0111]

[0112] Id

[0113] Yellow solid, yield 34.5%, melting point: 118-120 °C.

[0114] The NMR data are as follows:

[0115] 11H NMR (400 MHz, DMSO- d 6) δ 8.27 (t, J J = 5.7 Hz, 1H), 8.09 (t, J J = 5.9 Hz,1H), 7.27-7.10 (m, 4H), 4.40 (d, J J = 5.8 Hz, 2H), 3.74 (s, 2H), 2.89 (t, J J = 6.3Hz, 2H), 2.28 (s, 3H), 1.68-1.53 (m, 5H), 1.33 (ddt, J J = 11.1, 7.0, 3.5 Hz,1H), 1.21 – 1.04 (m, 3H), 0.90-0.74 (m, 2H)。

[0116] 13 13C 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。

[0117] ESI-MS: m / z 391.45[M+H] + ,C 19 H 26 N4OS2[390.15]。

[0118] (5) The preparation method is the same as that of compound Ia, except that p-methoxybenzaldehyde and compound 4 are used for reaction to obtain compound Ie.

[0119]

[0120] Ie

[0121] Yellow solid, yield 36.2%, melting point: 122 - 124 °C.

[0122] The NMR data are as follows:

[0123] 1 1H NMR (400 MHz, DMSO- d 6) δ 8.30 (t, J 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, 1.0 Hz, 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).

[0124] 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.

[0125] ESI - MS: m / z 407.26[M + H] + , C 19 H 26 N4O2S2[406.15].[[]END]]

[0126] (6) The preparation method is the same as that of compound Ia, except that m - fluorobenzaldehyde and compound 4 are used in the reaction to obtain compound If.

[0127]

[0128] If

[0129] Yellow solid, yield 34.3%, melting point: 102 - 104 °C.

[0130] The NMR data are as follows:

[0131] 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).

[0132] 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.

[0133] ESI - MS: m / z 395.59 [M + H] + ,C 18 H 23 FN4OS2[394.13].[[]]END[]]

[0134] (7) The preparation method is the same as that of compound Ia, except that m - chlorobenzaldehyde and compound 4 are used in the reaction to obtain compound Ig.

[0135]

[0136] Ig

[0137] Yellow solid, yield 31%, melting point: 142 - 144 °C.

[0138] The NMR data are as follows:

[0139] 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).

[0140] 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。

[0141] ESI - MS: m / z 411.43 [M + H] + ,C 18 H 23 ClN4OS2[410.10]。

[0142] (8) The preparation method is the same as that of compound Ia, except that m - bromobenzaldehyde and compound 4 are used in the reaction to obtain compound Ih.

[0143]

[0144] Ih

[0145] Yellow solid, yield 36.4%, melting point: 88 - 90 °C.

[0146] The NMR data are as follows:

[0147] 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).

[0148] 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.

[0149] ESI - MS: m / z 453.01[M - H] - ,C 18 H 23 BrN4OS2[454.05].

[0150] (9) The preparation method is the same as that of compound Ia, except that m - methylbenzaldehyde and compound 4 are used in the reaction to obtain compound Ii.

[0151]

[0152] Ii

[0153] Yellow solid, yield 41.2%, melting point: 112 - 114 °C.

[0154] The NMR data are as follows:

[0155] 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).

[0156] 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。

[0157] ESI - MS: m / z 391.84 [M + H] + , C 19 H 26 N4OS2[390.15]。

[0158] (10) The preparation method is the same as that of compound Ia, except that m - methoxybenzaldehyde and compound 4 are used in the reaction to obtain compound Ij.

[0159]

[0160] Ij

[0161] Yellow solid, yield 32.4%, melting point: 118 - 120 °C.

[0162] The NMR data are as follows:

[0163] 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).

[0164] 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.

[0165] ESI - MS: m / z 407.90 [M + H] + , C 19 H 26 N4O2S2[406.15].

[0166] (11) The preparation method is the same as that of compound Ia, except that m - bromo - p - methylbenzaldehyde and compound 4 are used in the reaction to obtain compound Ik.

[0167]

[0168] Ik

[0169] Yellow solid, yield 34.6%, melting point: 125 - 127 °C.

[0170] The NMR data are as follows:

[0171] 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).

[0172] 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.

[0173] ESI - MS: m / z 469.09 [M + H] + ,C 19 H 25 BrN4OS2[468.07].[[]]END]]

[0174] (12) The preparation method is the same as that of compound Ia, except that 3,4 - dichlorobenzaldehyde and compound 4 are used in the reaction to obtain compound IL.

[0175]

[0176] IL

[0177] Yellow solid, yield 34.5%, melting point: 125 - 127 °C.

[0178] The NMR data are as follows:

[0179] 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).

[0180] 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。

[0181] ESI - MS: m / z 445.28 [M + H] + ,C 18 H 22 Cl2N4OS2[445.28]。

[0182] (13) The preparation method is the same as that of compound Ia, except that 4 - formylbenzocyclobutene and compound 4 are used in the reaction to obtain compound Im.

[0183]

[0184] Im

[0185] Yellow solid, yield 42.2%, melting point: 90 - 92 °C.

[0186] The NMR data are as follows:

[0187] 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).

[0188] 13 C NMR (101 MHz, DMSO - d 6) 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。

[0189] ESI - MS: m / z 401.30 [M + H] + ,C 20 H 26 N4OS2[402.15]。

[0190] (14) The preparation method is the same as that of compound Ia, except that 2,3 - dihydrobenzofuran - 6 - carbaldehyde and compound 4 are used in the reaction to obtain compound In.

[0191]

[0192] In

[0193] Yellow solid, yield 42.4%, melting point: 110 - 112 °C.

[0194] The NMR data are as follows:

[0195] 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).

[0196] 13 C NMR (101 MHz, DMSO- d 6) 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。

[0197] ESI-MS: m / z 419.67 [M+H] + ,C 20 H 26 N4O2S2[418.15]。

[0198] (15) The preparation method is the same as that of compound Ia, except that 5-bromothiophene-2-carbaldehyde and compound 4 are used in the reaction to obtain compound Io.

[0199]

[0200] Io

[0201] Yellow solid, yield 33%, melting point: 100 - 102 °C.

[0202] The NMR data are as follows:

[0203] 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).

[0204] 13 C NMR (101 MHz, DMSO - d 6) 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.

[0205] ESI - MS: m / z 461.02[M + H] + ,C 16 H 21 BrN4OS3[460.01].

[0206] Example 3

[0207] Synthesis route:

[0208]

[0209] (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)

[0210]

[0211] Ip

[0212] Dissolve (( S )-(+)-1 - aminoindanyl hydrochloride (40 mmol), triethylamine (48 mmol), carbon disulfide (80 mmol) and other raw materials in 20 mL of a mixed solution of petroleum ether and ethyl acetate, stir at room temperature overnight for 8 h, monitor by TLC, and after the reaction is complete, evaporate the solvent to dryness to obtain (S)-(2,3 - dihydro - 1H - inden - 1 - yl)aminodithiocarboxylic acid (6p).

[0213] Redissolve 6p in 15 mL of acetonitrile, add 1.04 mL of triethylamine, and slowly add I2 (40 mmol, added dropwise over 30 min) in batches under an ice bath. Elementary sulfur will precipitate from the reaction solution during the reaction. After the precipitation is complete, filter the reaction solution, evaporate the reaction solution to dryness and dissolve it in n - hexane, wash it twice with 1 M HCl and once with water, and evaporate the extract to dryness to obtain ( S)-1-Isothiocyanato-2,3-dihydro-1H-indene (7p).

[0214] 7p was added dropwise as a raw material to an isopropanol solution of 50 mL of hydrazine hydrate. After stirring at room temperature for 30 min, the filter cake was filtered, and after drying, ([[]] S )-N-(2,3-Dihydro-1H-inden-1-yl)hydrazinecarbothioamide (8p) was obtained.

[0215] 8p was dissolved in 30 mL of ethanol, KOH (40 mmol) was added, carbon disulfide (60 mmol) was added dropwise, and after refluxing for 4 h, the solvent was removed by rotary evaporation. H2O was added, and after adjusting the pH = 3 with concentrated hydrochloric acid, extraction was performed three times with dichloromethane (30 mL × 3). 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-thiadiazole-2-thiol (9p).

[0216] 9p (40 mmol), intermediate 3 (40 mmol), and potassium carbonate (60 mmol) were added to 10 mL of DMF, and the reaction was carried out at 80 °C for 7.5 h. Then TLC monitoring was performed. After the reaction was complete, the reaction solution was dried by rotary evaporation with an oil pump. 50 mL of an aqueous solution and 50 mL of ethyl acetate were added to the reaction solution. After extraction and liquid separation, the organic phase was washed with a saturated NaCl aqueous solution (20 mL), and after rotary evaporation, column chromatography was performed to obtain the final product Ip.

[0217] Yellow solid, yield 34.3%, melting point: 166 - 168 °C.

[0218] The NMR data are as follows:

[0219] 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (t, J J = 5.9 Hz, 1H), 8.07 (t, J J = 5.7 Hz,1H), 7.06 (d, J J = 3.7 Hz, 1H), 6.90 (d, J J = 3.7 Hz, 1H), 4.58 (d, J J = 5.8 Hz, 2H),3.77 (s, 2H), 2.90 (td, J 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).

[0220] 13 C NMR (101 MHz, DMSO- d 6) 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.

[0221] ESI-MS: m / z 403.15 [M+H] + , C 20 H 26 N4OS2[402.15].

[0222] (2)The preparation method is the same as that of compound Ip, except that the raw material used is ([[]] S )-1,2,3,4-tetrahydronaphthalen-1-amine, and compound Iq is obtained.

[0223]

[0224] Iq

[0225] Yellow solid, yield 33.5%, melting point: 202 - 204 °C.

[0226] The NMR data are as follows:

[0227] 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).

[0228] 1313C NMR (101 MHz, DMSO- d 6) 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。

[0229] ESI-MS: m / z 417.54 [M+H] + ,C 21 H 28 N4OS2[416.17]。

[0230] Example 4:

[0231] Synthesis route:

[0232]

[0233]

[0234] (1) Preparation of 2-((5-(benzylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(4-(((3,4-difluorophenyl)sulfamoyl)methyl)phenyl)acetamide (IIa)

[0235]

[0236] IIa

[0237] 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 of toluene solution. After heating at 130 °C for 10 h, TLC monitoring was carried out. After the raw materials reacted completely, it was cooled to room temperature. Sodium cyanoborohydride (40 mmol) was added and heated to 80 °C for 8 h, followed by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness. 50 mL of aqueous solution and 50 mL of ethyl acetate were added to the reaction solution. After extraction and liquid separation, the organic phase was washed with saturated NaCl aqueous solution (20 mL), dried by rotary evaporation, and purified by column chromatography to obtain the product 5-(benzoylamino)-1,3,4-thiadiazole-2-thiol.

[0238] The product 5-(benzoylamino)-1,3,4-thiadiazole-2-thiol, methyl bromoacetate, and potassium carbonate were added to 50 mL of DMF. After reacting at room temperature for 7.5 h, the reaction was monitored by TLC. After the reaction was complete, the reaction solution was rotary evaporated with an oil pump. 50 mL of aqueous solution and 50 mL of ethyl acetate were added to the reaction solution. After extraction and liquid separation, the organic phase was washed with saturated NaCl aqueous solution (20 mL). After rotary evaporation, the following was obtained ( S )-Methyl 2-((5-((2,3-dihydro-1H-inden-1-yl)amino)-1,3,4-thiadiazol-2-yl)thio)acetate.

[0239] ( S )-Methyl 2-((5-((2,3-dihydro-1H-inden-1-yl)amino)-1,3,4-thiadiazol-2-yl)thio)acetate was dissolved in 20 mL of methanol. Lithium hydroxide was dissolved in 10 mL of aqueous solution and added dropwise to the methanol system. After reacting at room temperature for 3 h, 50 mL of water and 50 mL of ethyl acetate were added to the reaction solution. After extraction and liquid separation, the organic phase was washed with saturated NaCl aqueous solution (20 mL). After rotary evaporation, the following was obtained ( S )-2-((5-((2,3-dihydro-1H-inden-1-yl)amino)-1,3,4-thiadiazol-2-yl)thio)acetic acid.

[0240] 3,4-Difluorobenzenesulfonyl chloride (20 mmol) and 4-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 liquid separation, the organic phase was washed with saturated NaCl aqueous solution (20 mL). After rotary evaporation, N-(4-aminophenyl)-3,4-difluorobenzenesulfonamide was obtained.

[0241] ( 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-difluorobenzenesulfonamide (40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (40 mmol), 1-hydroxybenzotriazole (40 mmol), and triethylamine (60 mmol) were dissolved in anhydrous dichloromethane. After reacting at room temperature for 8 h, the reaction was monitored by TLC. After the reaction was complete, the reaction solution was rotary evaporated with an oil pump. 50 mL of aqueous solution and 50 mL of dichloromethane were added to the reaction solution. After extraction and liquid separation, the organic phase was washed with saturated NaCl aqueous solution (20 mL). After rotary evaporation, the final product IIa was obtained by column chromatography.

[0242] ESI-MS: m / z 562.54 [M+H] + ,C 24 H 21 F2N5O3S3[561.08].

[0243] (2) The preparation method is the same as that of Compound IIa, except that 2-thiophenesulfonyl chloride is used as the raw material to obtain Compound IIb.

[0244]

[0245] IIb

[0246] ESI-MS: m / z 532.24 [M+H] + ,C 22 H 21 N5O3S4[531.05].

[0247] Example 5

[0248] Synthesis route:

[0249]

[0250] (1) Preparation of (S)-2-N-(4-(((3,4-difluorophenyl)sulfonamido)methyl)phenyl)-2-((5-((2,3-dihydro-1H-inden-1-yl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (IIc)

[0251]

[0252] IIc

[0253] Methyl bromoacetate (40 mmol) and potassium carbonate were added to 50 mL of DMF, and the reaction was carried out at room temperature for 7.5 h. Then, the reaction solution was concentrated to dryness by 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 saturated NaCl aqueous solution (20 mL), and then concentrated to dryness to obtain Intermediate 17p.

[0254] 17p was dissolved in 20 mL of methanol, and lithium hydroxide dissolved in 10 mL of water was added dropwise to the reaction system. The reaction was carried out at room temperature for 3 h. 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 saturated NaCl aqueous solution (20 mL), and then concentrated to dryness to obtain 18p. Melting point: 100~102 °C, yield: 70%.

[0255] Dissolve intermediate 18 p (40 mmol), intermediate N-(4-aminophenyl)-3,4-difluorobenzenesulfonamide (40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (40 mmol), 1-hydroxybenzotriazole (40 mmol), and triethylamine (60 mmol) in anhydrous dichloromethane. React at room temperature for 8 h and monitor the reaction by TLC. After the reaction is complete, rotary evaporate the reaction solution with an oil pump. Add 50 mL of aqueous solution and 50 mL of dichloromethane to the reaction solution. After extraction and separation, wash the organic phase with saturated NaCl aqueous solution (20 mL). Rotary evaporate and then perform column chromatography to obtain the product spot. After drying, the final product IIc is obtained.

[0256] Grayish-red solid, yield 18%, melting point: 160 - 162 °C.

[0257] The NMR data are as follows:

[0258] 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).

[0259] 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.

[0260] ESI-MS: m / z 602.07 [M+H] + ,C 27 H 25 F2N5O3S3[601.11].

[0261] Compounds IId-f were separately prepared from different sulfonyl chlorides and amines by the above method, and some results are as follows:

[0262] (2) The preparation method was the same as that of compound IIc, except that 3-chloro-4-fluorobenzenesulfonyl chloride was used to obtain compound IId.

[0263]

[0264] IId

[0265] Greyish-red solid, yield 16%, melting point: 100 - 102 °C.

[0266] The NMR data are as follows:

[0267] 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).

[0268] 13 C NMR (101 MHz, DMSO- d6) 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。

[0269] ESI-MS: m / z 617.92 [M+H] + ,C 27 H 25 ClFN5O3S3[617.08]。

[0270] (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 obtain Compound IIe.

[0271]

[0272] IIe

[0273] The operation is the same as above, except that 3,4-difluorobenzenesulfonyl chloride and (S)-(+)-1-aminoindanyl hydrochloride are used.

[0274] Greyish-red solid, yield 20%, melting point: 190 - 192 °C.

[0275] The NMR data are as follows:

[0276] 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).

[0277] 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。

[0278] ESI - MS: m / z 588.08 [M + H] + ,C 26 H 23 F2N5O3S3[587.09]。

[0279] (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 obtain compound IIe.

[0280]

[0281] IIf

[0282] Grey - red solid, yield 20.5%, melting point: 180 - 182 °C.

[0283] The NMR data are as follows:

[0284] 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 = 7.3 Hz, 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).

[0285] 13 C NMR (101 MHz, DMSO - d 6) 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。

[0286] ESI - MS: m / z 603.90 [M + H] + ,C 26 H 23 ClFN5O3S3[603.06]。

[0287] Example 6

[0288] Activity of Thiadiazole Derivatives against NMDA Receptors

[0289] Testing Principle

[0290] The in vitro activity screening of compounds against NMDA receptors was carried out using the two - electrode voltage - clamp method (TEVC).

[0291] Ion channel properties: Ion channels allow specific ions to pass through, forming transmembrane ionic current (I). The resistance (R) of the membrane is inversely proportional to its permeability, i.e., membrane conductance (G). This means that when the membrane permeability to a certain ion increases, in fact, the membrane resistance decreases, that is, the conductance of the membrane to this ion increases. According to Ohm's law V = IR, i.e., I = V / R = VG. Therefore, by fixing the potential difference (V) across the membrane and measuring the change in transmembrane current (I), it can be used as a measure of the change in membrane conductance, thereby understanding the change in membrane permeability.

[0292] Voltage clamp technique: The voltage clamp technique places two electrodes on the cell membrane. One is called the clamping electrode, which is used to control the membrane potential, and the other is called the reference electrode, which is used to measure the change in membrane potential. The clamping electrode is connected to the reference electrode through a negative feedback circuit, so that the potential of the clamping electrode remains a constant difference from the reference electrode. In this way, when the membrane potential changes, the clamping electrode will adjust the current to keep the potential difference unchanged, thereby allowing the measurement of the change in membrane potential.

[0293] The NMDA receptor GluN1 / 2A subtype is specifically expressed on the membrane of Xenopus oocytes. 10 μmol / L glycine and 300 μmol / L glutamate are used to activate the receptor, and the electrical signals inside and outside the cell membrane are measured at this time and calibrated as 100%. Subsequently, a 10 μmol / L test compound is passed through the receptor, and the electrical signal of the test compound at a concentration of 10 μmol / L. The ratio of this signal to the calibrated signal is the inhibition rate of the compound on the GluN1 / 2A subtype at a concentration of 10 μmol / L. Subsequently, compounds with higher inhibition rates are measured at different concentration gradients to obtain the inhibition IC 50 of the compound on the GluN1 / 2A subtype, that is, the compound concentration when the inhibitory activity of the compound on the GluN1 / 2A subtype reaches 50%.

[0294] For compounds with good activity, the inhibition rates on the GluN1 / 2B, GluN1 / 2C, and GluN1 / 2D subtypes are measured at a concentration of 10 μmol / L respectively.

[0295] Test materials

[0296] The plasmid miniprep kit QIAprep Spin Miniprep Kit (250) was purchased from Guangzhou Yuwei Biotechnology Co., Ltd. The plasmid midiprep kit HiSpeed Plasmid Midi Kit (25) was purchased from Guangzhou Yuwei Biotechnology Co., Ltd. The DNA purification kit QIAquick PCR Purification kit (50) was purchased from Guangzhou Yuwei Biotechnology Co., Ltd. The Ambion mMessage mMachine T7 Ultra kit was purchased from Invitrogen (Shanghai) Trading Co., Ltd. Mature female African clawed frogs used in the experiment were provided by Zenop Experimental Equipment Business Office in Changshu City, Jiangsu Province. Feeding of clawed frogs: Place mature and larger female clawed frogs in a clean glass water tank with a water depth of about 15 - 25 cm. Clawed frogs need to be fed twice a week, and the breeding water is changed after each feeding. Chopped hearts or livers of cows or other animals are used as breeding materials. HEPES, sodium chloride, potassium chloride, calcium chloride, absolute ethanol, manganese chloride, L-glutamic acid, magnesium chloride, penicillin-streptomycin; all are products of SIGMA Reagent Company. Collagenase, Type 1 (42D22410, Worthington Biochemical Corporation, USA). Experimental instruments:

[0297] Clawed frog incubator CND-260A Yanghui, China.

[0298] Stereomicroscope SZ650 CNOPTEC, China.

[0299] Electrode puller NARISHIGE PC-100 Warner Istruments, USA.

[0300] Microinjector NANO J ECT III Drummond Scientific, USA.

[0301] SRLAB Startle Response system 0610-SRLAB San Diego Instruments, San Diego.

[0302] SV-04 Hide channel switching valve QHF-SY04-X-S-T10-K1.2-Se RUNZE FLUID, China.

[0303] Oocyte two-electrode amplifier Oocytes Voltage Clamp OC-725D Warner, USA.

[0304] Manual micromanipulator CA94949, Sutter, USA.

[0305] Experimental methods

[0306] (1) Isolation of Xenopus oocytes

[0307] Prepare surgical instruments: ordinary scissors (one for skin and one for tissue), fine forceps, straight forceps, needle holder, absorbable suture (4-0); prepare items: alcohol cotton balls, pads, cotton swabs, gauze.

[0308] Surgery: Prepare 2 L of anesthetic solution at 0.8 g / L, place one African clawed frog in it for about 15 - 30 min until the frog is completely anesthetized. Place it on ice with its abdomen facing up, disinfect with iodophor, use scissors to avoid major blood vessels in the midline, make an incision about 1 cm long on the skin and tissue on one side of the abdomen. The ovarian lobe will be clearly visible. Use forceps and scissors to remove a small amount of ovarian tissue, and check the quality of the oocytes under a dissecting microscope. There should be an obvious boundary difference between the animal hemisphere and the vegetal hemisphere, with one half black and the other half yellow, covered by a layer of vitelline layer, a layer of follicular cells, and connective tissue containing blood vessels. If the oocytes are healthy, take out enough oocytes for use according to the experimental plan, place them in OR2 solution, suture the wound with absorbable suture (4-0), disinfect with iodophor, then isolate and raise the frog separately, 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. Soak the breeding tank in a 0.008 g / L potassium permanganate solution for 24 h once a week, and then rinse it with clean water and set it aside for use.

[0309] Digestion: Use fine forceps to tear the ovarian tissue sample in OR2 solution into small pieces and transfer it to a 50 mL centrifuge tube. Add OR2 solution containing 1 mg / mL collagenase (Collagenase, Type1), incubate at room temperature on a shaker for 1 - 2 h until about 1 / 3 of the follicles of the oocytes fall off. During this process, it should be frequently observed under a stereomicroscope to prevent over-digestion and damage to the oocytes. Wash the oocytes with fresh OR2 solution until the collagenase is completely removed, then transfer them to a 50 mL centrifuge tube containing OR2, shake at room temperature on a shaker for about 1 h to make as many follicles as possible fall off. Then transfer the oocytes to a culture dish containing MBS culture medium and place it in a 17°C incubator.

[0310] Selection: Select oocytes with good quality, appropriate size, and no follicular wrapping under a stereomicroscope.

[0311] (2) Injection and expression of RNA in Xenopus oocytes

[0312] RNA preparation: After measuring the concentration of cRNA, it is uniformly diluted to 1.5 μg / μL with Nuclease-free H2O. For the hG1uN1 / hG1uN2A type NMDA receptor, it is then further diluted with Nuclease-free H2O according to the following table. The diluted cRNA of hG1uN1 and hG1uN2A is injected in a ratio of 1:2 and a total volume of 50 μL. The excess RNA after dilution can be stored in a -80°C refrigerator. Microinjection of RNA: Fill the injection dish with Barth's culture solution, and use a Pasteur pipette to neatly arrange the oocytes in the grooves. Use a Nano J ectIII microinjector to inject RNA. First, seal the glass electrode with mineral oil to increase airtightness, then aspirate a certain volume of RNA and inject it into the oocytes. The injection volume is 50 μL, and the tip should be thin enough for the oocytes to penetrate with minimal denaturation. After pulling out the needle, there should be no leakage at the injection site, and the injection wound is almost invisible.

[0313] Expression: Place the injected Xenopus laevis oocytes in a culture dish containing Barth's culture solution and incubate at 17°C for 1 - 2 days to express the hGluN1 / hG1uN2A type NMDA receptor.

[0314] (3) Electrical signal testing of Xenopus laevis oocytes

[0315] The current of Xenopus laevis oocytes is recorded using EasyOocyte software for electrophysiological recording of HEK293T cells. The oocytes are placed in a recording chamber with a volume of approximately 1 mL. A small piece of mesh is glued to the bottom center of the recording chamber to prevent the oocytes from sliding at the bottom during clamping and perfusion. Different extracellular solutions are continuously perfused. Two pulled glass microelectrodes are inserted into the probes of the amplifier respectively. Use a micromanipulator to place the two electrodes into the recording chamber respectively. When the electrode tips enter the liquid surface, adjust the mV and V on the amplifier panel to 0 potential. Subsequently, use 10 μmol / L glycine and 300 μmol / L glutamate to activate the receptor, measure the electrical signals inside and outside the cell membrane at this time, and calibrate it as 100%. Then use 10 μmol / L of the test compound to flow through the receptor, measure the electrical signal of the test compound at a concentration of 10 μmol / L, and the ratio of its electrical signal to the calibrated electrical signal is the inhibition rate of the compound on the GluN1 / 2A subtype at a concentration of 10 μmol / L. Subsequently, measure the compounds with higher inhibition rates at different concentration gradients to obtain the inhibition IC 50 50 of the compound on the GluN1 / 2A subtype, that is, the compound concentration when the inhibition activity of the compound on the GluN1 / 2A subtype reaches 50%. All experiments are carried out at room temperature (21 - 23°C).

[0316] The activity tests of the compound against three subtypes, GluN1 / 2B, GluN1 / 2C, and GluN1 / 2D, were similar to the experimental procedures for the GluN1 / 2A activity test. The difference was that the hG1uN1 / hG1uN2A type RNA was replaced with the corresponding RNA subtype.

[0317] The NMDA receptor activity tests of the synthesized thiadiazole derivatives at the cellular level were carried out according to the above experimental method, and the activity results are shown in Table 1 and Table 2.

[0318] Table 1 Test results of the NMDA receptor inhibition rate of thiadiazole derivatives and reference drugs at the cellular level

[0319]

[0320] Note: a Inhibition rate: The inhibition rate of the compound against the GluN1 / 2A subtype at 10 μmol / L.

[0321] Table 2 Test results of the NMDA receptor inhibitory activity of thiadiazole derivatives and reference drugs at the cellular level

[0322]

[0323] b IC 50 : The compound concentration when the inhibitory activity of the compound against the GluN1 / 2A subtype reaches 50%. Glycine concentration during the test: 10 μmol / L, glutamate concentration: 300 μmol / L.

[0324] The activity test results of some compounds against the three subtypes, GluN1 / 2B, GluN1 / 2C, and GluN1 / 2D, at 10 μmol / L are shown in Figure 1 . Glycine concentration during the test: 10 μmol / L, glutamate concentration: 300 μmol / L.

[0325] Example 7:

[0326] Taking compound If as an example, the metabolism of such compounds in rats was studied

[0327] Objective: This study aimed to observe the time-course of the blood drug concentration of If (as an example) after the test article If was intravenously injected and gavaged to rats respectively, and to estimate the corresponding pharmacokinetic parameters and absolute bioavailability.

[0328] Methods: Six rats were divided into two groups and given 1f by intravenous injection and intragastric administration respectively. For the intravenous injection group, about 0.25 mL of blood samples 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. For the intragastric administration group, blood samples were collected at the same time points. The concentration of 1f in rat plasma samples was determined by LC-MS / MS method, and the pharmacokinetic parameters were calculated using WinNolin software.

[0329] Results: After a single intravenous injection of 3 mg / kg 1f and intragastric administration of 10 mg / kg 1f to rats, the main pharmacokinetic parameters of intravenous injection were: C max was 2997 ng / mL, T max was 0.0833 h, T 1 / 2 was 0.200 h, AUC 0-T was 1014 hr*ng / mL, AUC 0-∞ was 1015 hr*ng / mL, Vz was 852 mL / kg, Cl was 2959 mL / hr / kg, MRT 0-t was 0.210 h, MRT 0-∞ was 0.211 h. The main pharmacokinetic parameters of intragastric administration were: C max was 105 ng / mL, T max was 0.333 h, T 1 / 2 was 2.05 h, AUC 0-t was 123 hr*ng / mL, AUC 0-∞ was 151 hr*ng / mL, MRT 0-t was 1.21 h, MRT 0-∞ was 2.30 h, and the oral bioavailability was 4.45%.

[0330] Example 8

[0331] Taking compound If as an example, the permeability of this compound across the blood-brain barrier in rats was studied

[0332] Objective: This study aimed to observe the time course of blood drug concentration of 1f after intravenous injection of the test article 1f to rats, and estimate the corresponding pharmacokinetic parameters and absolute bioavailability.

[0333] Method: Twelve rats were grouped together. 1f was administered by intravenous injection. Blood samples (about 0.25 mL) and brain tissues 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 method, and pharmacokinetic parameters were calculated using WinNolin software.

[0334] Results: After a single intravenous injection of 10 mg / kg 1f to rats, the main pharmacokinetic parameters of intravenous injection in plasma were as follows: C max was 10577 ng / mL, T max was 0.0833 h, T 1 / 2 was 0.152 h, AUC 0-T was 3361 hr*ng / mL, AUC 0-∞ was 3388 hr*ng / mL, Vz was 646 mL / kg, Cl was 2952 mL / hr / kg, MRT 0-t was 0.172 h, MRT 0-∞ was 0.181 h. The main pharmacokinetic parameters of intravenous injection in brain tissues were as follows: C max was 6850 ng / mL, T max was 0.0833 h, T 1 / 2 was 0.145 h, AUC 0-T was 2093 hr*ng / mL, AUC 0-∞ was 2106 hr*ng / mL, Vz was 992 mL / kg, Cl was 4748 mL / hr / kg, MRT 0-t was 0.158 h, MRT 0-∞ was 0.165 h. The brain-blood exposure ratio was: 0.622.

[0335] Example 9

[0336] Taking compound If as an example, the pharmacodynamics of this compound in animal experiments

[0337] was evaluated by the forced swimming test in mice. The experimental animals were ICR mice, male, weighing 20 - 24 g. They needed to be fasted for 12 h before the forced swimming test. Compound 1f was dissolved in DMSO and diluted to 1 mmol / L with normal saline. A blank control group (DMSO), a dosing group, and a positive control (imipramine, 1 mmol / L) were set up. There were 8 - 10 rats in each group.

[0338] One 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 pre-swimming for 15 min at a water temperature of 28°C. After the pre-swimming, the rats were taken out, dried with a dry cloth, and then put back into the breeding cage. The formal forced swimming experiment was carried out the next day. 30 min before the start of the experiment, the corresponding samples (blank control group, drug administration group, positive control drug group) were intraperitoneally injected (the injection volume was 10 mL / kg). Half an hour later, the forced swimming experiment was carried out for a total of 6 min, and the cumulative immobility time within 2 - 6 min was recorded.

[0339] The criterion for determining immobility was that the animal stopped struggling in the water, floated, and only had slight limb movements to keep the head above the water surface. The results are shown in Figure 2 , and the experimental data were statistically analyzed using GraphPad Prism software.

Claims

1. A thiadiazole derivative or a pharmaceutically acceptable salt thereof, characterized in that: A substance selected from the following structures:

2. A method for preparing the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The preparation method of If, Ij and In is carried out according to the following process: The preparation method is: 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 Reaction to obtain formula If, Ij and In.

3. A method for preparing the thiadiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The preparation method of IIa and IIb is carried out according to the following reaction scheme: The preparation method is: 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; v: Compound 14 undergoes condensation reaction with compound 16a or compound 16b to generate final product IIa or IIb.

4. A use of the thiadiazole derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 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.

5. The use according to claim 4, characterized in that: The disease associated with abnormal NMDA receptor function is depression, depression, stroke, Huntington's disease, Alzheimer's disease, neuralgia or schizophrenia.

6. A pharmaceutical composition or pharmaceutical preparation, characterized in that: The invention comprises the thiadiazole derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1.

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