1,3,4-substituted 2-sulfide pyridazine derivatives and methods for their preparation

Abstract

The application discloses a 1,3,4-substituted 2-sulfide pyridazine derivative and a preparation method thereof, and has a structural formula as shown in the specification; R1 is various substituted phenyl, heterocyclic aryl or alkyl; R2 is phenyl, heterocyclic aryl or alkyl; R3 is a hydrogen atom, various substituted phenyl or alkyl; and R4 is phenyl or alkyl. The preparation method comprises the following steps: dissolving 1,4-substituted tetrazine and a sulfonium salt in a solvent, adding a base, stirring at a predetermined temperature until the raw material is completely reacted; extracting the obtained reaction system, concentrating the organic layer under reduced pressure to obtain a residue, and performing silica gel column chromatography on the residue to obtain 1,3,4-substituted 2-pyridazine sulfide compounds and derivatives thereof. The preparation method has the advantages of simple operation, easy availability of raw materials, good functional group tolerance of the reaction, fast reaction rate, excellent product yield, easy separation and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of synthesis of compounds, and particularly relates to a 1,3,4-substituted 2-sulfide pyridazine derivative and a preparation method thereof. BACKGROUND

[0002] 2-sulfide pyridazine compounds are a kind of very important small organic molecules. In the fields of medicine and materials, 2-sulfide pyridazine compounds, as an important chemical intermediate, have very high application value and very wide application range. Many bioactive and natural product molecules, such as protein kinase modulators, antibacterial agents, antiviral drugs and the like, have the skeleton of 2-sulfide pyridazine nucleus. The related structures are as follows:

[0003]

[0004] At present, the most common route for the synthesis of 2-sulfide pyridazine derivatives is mainly realized through a two-step process, including halogenation reaction of hydroxyl-substituted pyridazine and substitution reaction of sulfide. In the existing synthesis method of 2-sulfide pyridazine derivatives, the synthesis step of halogen-substituted pyridazine is complex, and needs to use phosphorus oxychloride which has strong toxicity and corrosion, the reaction condition is relatively harsh, and the yield is poor (EP 2042491 A1):

[0005]

[0006] Therefore, a chemical synthesis method which has strong application value for quickly and efficiently constructing 2-sulfide pyridazine compounds with mild reaction conditions, environmental friendliness, strong substrate applicability is needed. SUMMARY

[0007] The purpose of the embodiments of the present application is to provide a 1,3,4-substituted 2-sulfide pyridazine derivative and a preparation method thereof, so as to achieve the purposes of optimizing raw material preparation technology, improving compound yield and improving drug activity.

[0008] According to a first aspect of the embodiments of the present application, a 1,3,4-substituted 2-sulfide pyridazine derivative is provided, and the structure formula of the 1,3,4-substituted 2-sulfide pyridazine derivative is as follows:

[0009]

[0010] wherein R1 is various substituted phenyl, heterocyclic aryl or alkyl; R2 is various substituted phenyl, heterocyclic aryl or alkyl; R3 is a hydrogen atom, various substituted phenyl or alkyl, and R4 is various substituted phenyl or alkyl.

[0011] Further, the 1,3,4-substituted 2-sulfide pyridazine derivative is any one of the following:

[0012] 4-methyl-5-(methylthio)-3,6-di-phenylpyridazine;

[0013] 4-methyl-5-(methylthio)-3,6-p-tolyIpyridazine;

[0014] 3,6-bis(4-fluorophenyl)-4-methyl-5-(methylthio)pyridazine;

[0015] 4-methyl-5-(methylthio)-3,6-bis(naphthalen-2-ylmethyl)pyridazine;

[0016] 3,6-bis(2,6-difluorobenzyl)-4-methyl-5-(methylthio)pyridazine;

[0017] 3,6-bisbenzyl-4-methyl-5-(methylthio)pyridazine;

[0018] 3,6-bis(4-methoxybenzyl)-4-methyl-5-(methylthio)pyridazine;

[0019] 3,6-bis(4-fluorobenzyl)-4-methyl-5-(methylthio)pyridazine;

[0020] 3,5-dimethyl-4-(methylthio)-6-(naphthalen-2-yl)pyridazine;

[0021] (E)-4-(5-(2-(4,6-dimethyl-5-(methylthio)pyridazin-3-yl)vinyl)thiophen-2-yl)-N,N-diphenylaniline;

[0022] 2-(6-benzyl-5-methyl-4-(methylthio)pyridazin-3-yl)ethanol;

[0023] 2-(4-methyl-5-(methylthio)-6-(thiophen-2-yl)pyridazin-3-yl)ethanol;

[0024] 3-(4-bromophenyl)-5,6-dimethyl-4-(methylthio)pyridazine;

[0025] 3-(4-bromophenyl)-4,6-dimethyl-5-(methylthio)pyridazine;

[0026] diethyl (5,6-dimethyl-4-(methylthio)pyridazin-3-yl)methylphosphonate;

[0027] (4-(4,6-dimethyl-5-(methylthio)pyridazin-3-yl)phenyl)boronic acid;

[0028] 3,6-dibenzyl-4-(ethylthio)-5-phenylpyridazine;

[0029] 3,6-dibenzyl-4-((4-bromobutyl)thio)-5-methylpyridazine;

[0030] 3,6-dibenzyl-4-methyl-5-(phenylthio)pyridazine;

[0031] 4-((4-bromobutyl)thio)-6-(4-bromophenyl)-3,5-dimethylpyridazine;

[0032] 2-acetamido-4-((3,6-dibenzyl-5-methylpyridazin-4-yl)thio)-N-phenylacetamide;

[0033] (1 5 ,1 6 - dimethyl-5-oxo-7-(phenylcarbamoyl)-10-thia-6-aza- 1(3,4)- pyridazino-2(1,4)-benzocyclododec-4-yl)carbamate;

[0034] (2-((1 5 ,1 6- dimethyl-5-oxo-7-(phenylcarbamoyl)-10-thia-6-aza- 1(3,4)- pyridazino-2(1,4)-benzocyclododec-4-yl)amino)-2-oxoethyl)carbamate;

[0035] 2-((1 5 ,1 6 dimethyl-5-oxo-7-(phenylcarbamoyl)-10-thia-6-aza- 1(3,4)- pyridazino-2(1,4)-benzocyclododec-4-yl)carbamoyl)pyrrolidine-1- carboxylate;

[0036] (1-((1 5 ,1 6 dimethyl-5-oxo-7-(phenylcarbamoyl)-10-thia-6-aza- 1(3,4)- benzocyclododec-4-yl)amino)-3-hydroxy-1-oxopropyl)carbamate;

[0037] (1-(((1 5 ,1 6 dimethyl-5-oxo-7-(phenylcarbamoyl)-10-thia-6-aza- 1(3,4)- pyridazino-2(1,4)-benzocyclododec-4-yl)amino)-1-oxobutyl)carbamate;

[0038] (1-((1 5 ,1 6tert-Butyl 2-(dimethyl-5-oxo-7-(phenylcarbamoyl)-10-thia-6-aza-1(3,4)- pyridazino-2(1,4)-benzocycloocta-4-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.

[0039] According to a second aspect of the embodiments of the present application, a method for preparing a 1,3,4-substituted 2-sulfide pyridazine derivative is provided, comprising:

[0040] Step (1): dissolving a tetrazine compound and a sulfonium salt derivative in a solvent, adding a base, and stirring at a predetermined temperature until the raw material is completely reacted;

[0041] The structure of the sulfonium salt derivative is:

[0042]

[0043] wherein R3 is a hydrogen atom, various substituted phenyl groups or alkyl groups, R4 is various substituted phenyl groups or alkyl groups, and R5 is various substituted phenyl groups or alkyl groups, and the sulfonium salt anion is a bromide ion, a tetrafluoroborate ion or a triflate ion;

[0044] The structure of the tetrazine compound is:

[0045]

[0046] wherein R1 is a phenyl group, a heterocyclic aromatic group or an alkyl group, and R2 is a phenyl group, a heterocyclic aromatic group or an alkyl group;

[0047] Step (2): extracting the reaction system obtained in step (1), concentrating the obtained organic layer under reduced pressure to obtain a residue, and subjecting the residue to silica gel column chromatography to obtain a 1,3,4-substituted 2-sulfide pyridazine derivative, wherein the structure of the 1,3,4-substituted 2-sulfide pyridazine derivative is:

[0048]

[0049] Further, in step (1), the predetermined temperature is selected from 0°C, 25°C, 40°C and 60°C.

[0050] Further, in step (1), the predetermined temperature is 25°C.

[0051] Further, in step (1), the solvent is selected from one or more of PBS buffer, acetone, tetrahydrofuran, toluene, N,N-dimethylformamide, anhydrous methanol and acetonitrile.

[0052] Further, in step (1), the solvent is acetonitrile.

[0053] Further, the concentration of the solvent is 0.01 mmol / mL-10.00 mmol / ml.

[0054] Further, in step (1), the base is selected from inorganic bases: potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, sodium bicarbonate; organic bases: N,N-diisopropyl ethylamine, triethylamine.

[0055] Further, in step (1), the base is potassium carbonate or triethylamine.

[0056] The technical scheme provided by the embodiment of the present application can include the following beneficial effects:

[0057] From the above examples, the method provided by the present application dissolves the tetrazine and sulfonium salt in the solvent, and adds a base to construct the structure of 1,3,4-substituted sulfide pyridazine derivatives. The reaction temperature of the present application is higher than the yield of the conventional synthesis method, does not need to use heavy / gold metals, the post-processing is convenient, and the compounds may have potential biological activity. The reaction yield is high, easy to purify, and the separation yield of most products is more than 75%; the substrate has wide applicability, and various substrate structures can tolerate the reaction conditions.

[0058] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit the present application. DETAILED DESCRIPTION

[0059] The exemplary embodiments will be described in detail hereinafter with reference to the drawings. The embodiments described in the following exemplary embodiments do not represent all the embodiments consistent with the present application.

[0060] The terms used in the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "an" and "the" used in the present application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise. It should also be understood that the term "and / or" used herein means and includes any or all possible combinations of one or more associated listed items.

[0061] It should be understood that although the terms first, second, third, etc. may be used in the present application to describe various information, these information should not be limited to these terms. These terms are only used to distinguish one type of information from another. For example, without departing from the scope of the present application, the first information can also be referred to as the second information, and similarly, the second information can also be referred to as the first information. Depending on the context, the word "if" as used herein can be interpreted as "when" or "upon determining" or "in response to determining".

[0062] Example 1: 4-methyl-5-(methylthio)-3,6-diphenylpyridazine

[0063]

[0064] Dissolve 3,6-diphenyl-1,2,4,5-tetrazine (1.0 mmol, 1.0 equivalent) and S,S-dimethyl-propargyl sulfonium (1.5 mmol, 1.5 equivalent) in 2 mL of acetonitrile, add potassium carbonate (1.5 mmol, 1.5 equivalent), stir at 25 °C until the raw material is completely reacted. After the reaction is completed, the reaction system is extracted, and the organic layer is concentrated under reduced pressure to obtain a residue. The residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:3) to obtain a colorless oil with a yield of 80%.

[0065] Colorless oil, yield 80%. 1 H NMR (500 MHz, CDC13): δ 7.82 (d, J = 1.5 Hz, 2H), 7.61 (d, J = 1.5 Hz, 2H), 7.55-7.47 (m, 6H), 2.54 (s, 3H), 2.00 (s, 3H); 13 C NMR (126 MHz, CDC13): 160.20, 159.8, 138.6, 137.7, 136.9, 129.5, 129.3, 129.1, 129.1, 128.5, 128.4, 29.7, 18.6, 17.9; HRMS (ESI): m / z calcd for [M+H] + : 293.1107, found: 293.1112.

[0066] Example 2: 4-methyl-5-(methylthio)-3,6-p-tolylyridazine

[0067]

[0068] Synthesis step is the same as example 1, except that 3,6-diphenyl-1,2,4,5-tetrazine is replaced by 3,6-di-p-tolylyridazine, to obtain a colorless oil with a yield of 74%.

[0069] Colorless oil, yield 74%. 1 H NMR (500 MHz, CDC13): δ 7.72 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.0 Hz, 4H), 2.53 (s, 3H), 2.44 (s, 6H), 2.02 (s, 3H); 13C NMR (126 MHz, CDC13) δ 160.1, 160.0, 139.3, 138.9, 138.8, 138.1, 135.2, 134.6, 129.4, 129.2, 129.1, 129.0, 21.5, 21.4, 18.7, 17.9; HRMS (ESI): m / z calcd for [M+H] + : 321.1420, found: 321.1427.

[0070] Example 3: 3,6-Bis(4-fluorophenyl)-4-methyl-5-(methylthio)pyridazine

[0071]

[0072] Synthesis procedure was same as example 1 except 3,6-diphenyl-1,2,4,5-tetrazine was replaced by 3,6-bis(4-fluorophenyl)-1,2,4,5-tetrazine to get colorless oil in 70% yield.

[0073] Colorless oil, yield 70%. 1 H NMR (500 MHz, CDC13): δ 7.76 (dd, J = 8.5, 5.5 Hz, 2H), 7.52 (dd, J = 8.5, 5.5 Hz, 2H), 7.13 (td, J = 8.5, 2.5 Hz, 4H), 2.46 (s, 3H), 1.95 (s, 3H); 13 CNMR (126 MHz, CDC13): δ 164.2 (164.2, 164.2, d, J = 3.7 Hz), 162.2 (162.2, 162.3, d, J = 3.3 Hz), 159.4 (159.5, 159.3, d, J = 15.7 Hz), 139.6, 138.4, 133.9 (133.9, 133.9, d, J = 3.4 Hz), 133.4 (133.3, 133.4, d, J = 3.4 Hz), 131.3 (131.4, 131.4, 131.3, 131.3, dd, J = 18.7, 8.3 Hz), 115.5 (115.6, 115.5, 115.4, 115.4, dd, J = 21.7, 10.4 Hz), 18.6 17.9; HRMS (ESI): m / z calcd for [M+H] + : 329.0919, found: 329.0915.

[0074] Example 4: 4-Methyl-5-(methylthio)-3,6-bis(naphthalen-2-ylmethyl)pyridazine

[0075]

[0076] The synthetic procedure was the same as example 1 except that 3,6-diphenyl- 1,2,4,5-tetrazine was replaced by 3,6-bis(2,6-difluorobenzyl)-1,2,4,5-tetrazine to give colorless oil in 84% yield.

[0077] Colorless oil, yield 84%. 1 H NMR (500 MHz, CDC13): δ 8.29 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.79 (t, J = 9.0 Hz, 2H), 7.67 (dd, J = 10.6, 8.4 Hz, 2H), 7.51 - 7.41 (m, 4H), 7.29 - 7.25 (m, 2H), 7.10 (d, J = 6.5 Hz, 1H), 6.95 - 6.91 (m, 1H), 5.00 (s, 2H), 4.80 (s, 2H), 2.32 (s, 3H), 1.94 (s, 3H). 13 C NMR (126 MHz, CDC13): 162.0, 159.0, 133.7, 132.9, 132.8, 132.2, 131.0, 131.0, 127.8, 127.7, 126.6, 126.3, 125.9, 125.4, 125.2, 125.2, 124.9, 124.7, 124.4, 124.3, 123.0, 122.6, 37.2, 36.7, 17.3, 15.9; HRMS (ESI): m / z calcd for [M+H] + : 421.1733, found: 421.1731.

[0078] Example 5: 3,6-bis(2,6-difluorobenzyl) 4-methyl-5-(methylthio) pyridazine

[0079]

[0080] The synthetic procedure was the same as example 1 except that 3,6-diphenyl- 1,2,4,5-tetrazine was replaced by 3,6-bis(2,6-difluorobenzyl)-1,2,4,5-tetrazine to give colorless oil in 84% yield.

[0081] Colorless oil, yield 74%. 1 H NMR (500 MHz, CDC13): δ 8.29 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.79 (t, J = 9.0 Hz, 2H), 7.67 (dd, J = 10.6, 8.4 Hz, 2H), 7.51 - 7.41 (m, 4H), 7.29 - 7.25 (m, 2H), 7.10 (d, J = 6.5 Hz, 1H), 6.95 - 6.91 (m, 1H), 5.00 (s, 2H), 4.80 (s, 2H), 2.32 (s, 3H), 1.94 (s, 3H). 13C NMR (101 MHz, CDC13) δ 162.9 (162.9, 162.9, 162.8, 162.8, dd, J = 8.4, 5.4 Hz), 160.74, 160.41 (160.5, 160.4, 160.4, 160.3, dd, J = 8.4, 5.5 Hz), 157.9, 140.2, 137.7, 128.2 (128.5, 128.4, 128.3, 128.2, 128.1, 128.0, dt, J = 26.9, 10.3 Hz), 114.6 (114.8, 114.6, 114.4, t, J = 19.8 Hz), 113.6 (113.7, 113.6, 113.4, t, J = 19.8 Hz), 111.4 - 110.8 (111.3, 111.2, 111.2, 111.1, 111.0, 111.0, 110.9, m), 28.2, 27.4, 18.1, 16.4; HRMS (ESI): m / z calcd for [M+H] + : 393.1043, found: 393.1042.

[0082] Example 6: 3,6-Dibenzyl-4-methyl-5-(methylthio)pyridazine

[0083]

[0084] Synthesis procedure as in Example 1, except that 3,6-diphenyl-1,2,4,5-tetrazine was replaced by 3,6-dibenzyl-1,2,4,5-tetrazine, to give colorless oil in 88% yield.

[0085] Colorless oil in 88% yield. 1 H NMR (400 MHz, CDC13): δ 7.35 (d, J = 7.2 Hz, 2H), 7.28 (dd, J = 9.6, 4.4 Hz, 3H), 7.25 - 7.14 (m, 5H), 4.59 (s, 2H), 4.37 (s, 2H), 2.39 (s, 3H), 1.97 (s, 3H); 13 CNMR (101 MHz, CDC13): δ 163.3, 160.3, 141.7, 138.9, 138.9, 137.7, 129.2, 128.8, 128.6, 128.4, 126.6, 126.4, 41.4, 41.0, 18.1, 16.5; HRMS (ESI): m / z calcd for [M+H] + : 321.1420, found: 321.1423.

[0086] Example 7: 3,6-Bis(4-methoxybenzyl)-4-methyl-5-(methylthio)pyridazine

[0087]

[0088] The synthetic procedure was same as Example 1 except that 3,6-diphenyl-1,2,4,5- tetrazine was replaced by 3,6-bis(4-methoxybenzyl)-1,2,4,5-tetrazine to give a white solid in 80% yield.

[0089] A white solid was obtained in 80% yield. 1 H NMR (500 MHz, CDC13) δ 7.28 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 6.84 - 6.78 (m, 4H), 4.54 (s, 2H), 4.32 (s, 2H), 3.76 (d, J = 3.6 Hz, 6H), 2.40 (s, 3H), 2.01 (s, 3H); 13 C NMR (126 MHz, CDC13) δ 163.4, 160.4, 158.4, 158.2, 130.6, 130.3, 129.8, 129.3, 114.1, 113.8, 55.3, 55.2, 40.2, 39.8, 18.2, 16.6; HRMS (ESI): m / z calcd for [M+H] + : 381.1631, found: 381.1637.

[0090] Example 8: 3,6-Bis(4-fluorobenzyl)-4-methyl-5-(methylthio)pyridazine

[0091]

[0092] The synthetic procedure was same as Example 1 except that 3,6-diphenyl-1,2,4,5- tetrazine was replaced by 3,6-bis(4-fluorobenzyl)-1,2,4,5-tetrazine to give a pale yellow oil in 76% yield.

[0093] A pale yellow oil was obtained in 76% yield. 1 H NMR (400 MHz, CDC13) δ 7.36 (dd, J = 8.4, 5.6 Hz, 2H), 7.23 (dd, J = 8.4, 5.4 Hz, 2H), 6.99 (td, J = 8.4, 6.4 Hz, 4H), 4.58 (s, 2H), 4.36 (s, 2H), 2.43 (s, 3H), 2.05 (s, 3H); 13C NMR (101 MHz, CDC13): δ 163.2, 162.9 (162.9, 162.8, d, J = 13.2 Hz), 160.5, 160., 160.2, 141.6, 138.9, 134.5 (134.5, 134.4, d, J = 3.0 Hz), 133.3 (133.3, 133.2, d, J = 3.0 Hz), 130.7 (130.8, 130.7, d, J = 7.8 Hz), 130.2 (130.3, 130.2, d, J = 7.9 Hz), 115.6, 115.4 (115.4, 115.3, d, J = 11.4 Hz), 115.1, 40.6, 40.1, 18.2, 16.5; HRMS (ESI): m / z calcd for [M+H] + : 357.1232, found: 357.1245.

[0094] Example 9: 3,5-Dimethyl-4-(methylthio)-6-(naphthalen-2-yl)pyridazine

[0095]

[0096] Synthesis procedure was same as example 1 except that 3,6-diphenyl-1,2,4,5-tetrazine was replaced by 3-methyl-6-(naphthalen-2-yl)-1,2,4,5-tetrazine to give a pale yellow oil in 66% yield.

[0097] Pale yellow oil in 66% yield. 1 H NMR (400 MHz, CDC13): δ 8.07 - 7.86 (m, 4H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 - 7.51 (m, 2H), 2.95 (s, 3H), 2.55 (s, 3H), 2.42 (s, 3H); 13 C NMR (101 MHz, CDC13): δ 163.2, 162.9 (162.9, 162.8, d, J = 13.2 Hz), 160.5, 160., 160.2, 141.6, 138.9, 134.5 (134.5, 134.4, d, J = 3.0 Hz), 133.3 (133.3, 133.2, d, J = 3.0 Hz), 130.7 (130.8, 130.7, d, J = 7.8 Hz), 130.2 (130.3, 130.2, d, J = 7.9 Hz), 115.6, 115.4 (115.4, 115.3, d, J = 11.4 Hz), 115.1, 40.6, 40.1, 18.2, 16.5; HRMS (ESI): m / z calcd for [M+H] + : 281.1107, found: 281.1104.

[0098] Example 10: (E)-4-(5-(2-(4,6-dimethyl-5-(methylthio)pyridazin-3-yl)vinyl)thiophen-2-yl)-N,N-diphenylaniline

[0099]

[0100] The synthetic procedure was same as Example 1 except that 3,6-diphenyl-1,2,4,5-tetrazine was replaced by (E)-4-(5-(2-(6-methyl-1,2,4,5-tetrazin-3-yl)vinyl)thiophen-2-yl)-N,N-diphenylaniline to give a bright yellow solid in 54% yield.

[0101] A bright yellow solid was obtained in 54% yield. 1 H NMR (400 MHz, CDC13): δ 8.15 (d, J = 15.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.2 Hz, 3H), 7.11 (ddd, J = 28.4, 20.8, 14.0 Hz, 12H), 2.92 (s, 3H), 2.67 (s, 3H), 2.36 (s, 3H); 13 C NMR (101 MHz, CDC13): δ 159.3, 148.0, 147.6, 147.4, 147.3, 137.59, 133.05, 129.4, 129.3, 126.8, 126.7, 124.8, 124.6, 123.4, 123.3, 123.2, 123.0, 121.8, 29.7, 22.7, 14.2; HRMS (ESI): m / z calcd for [M+K] + : 544.1278, found: 544.1271.

[0102] Example 11: 2-(6-benzyl-5-methyl-4-(methylthio)pyridazin-3-yl)ethanol

[0103]

[0104] The synthetic procedure was same as Example 1 except that 3,6-diphenyl-1,2,4,5-tetrazine was replaced by (E)-4-(5-(2-(6-methyl-1,2,4,5-tetrazin-3-yl)vinyl)thiophen-2-yl)-N,N-diphenylaniline to give a bright yellow solid in 54% yield.

[0105] A bright yellow solid was obtained in 54% yield. 1H NMR (400 MHz, CDC13): δ 7.33 - 7.17 (m, 5H), 4.37 (s, 2H), 4.17 (t, J = 5.2 Hz, 2H), 3.40 (t, J = 5.2 Hz, 2H), 2.44 (s, 3H), 2.26 (s, 3H); 13 CNMR (100 MHz, CDC13): δ 157.8, 146.4, 144.6, 143.4, 129.1, 126.3, 124.6, 121.7, 112.4, 111.6, 110.1, 110.0, 104.9, 53.9, 17.3; HRMS (ESI): m / z calcd for [M+H] + : 275.1213, found: 275.1215.

[0106] Example 12: 2-(4-methyl-5-(methylthio)-6-(thiophen-2-yl)pyridazin-3-yl)ethanol

[0107]

[0108] Synthesis procedure was same as example 1 except 3,6-diphenyl-1,2,4,5-tetrazine was replaced by 2-(6-(thiophen-2-yl)-1,2,4,5-tetrazin-3-yl)ethanol to get pale yellow oil in 21% yield.

[0109] Pale yellow oil in 21% yield. 1 H NMR (500 MHz, CDC13): δ 7.47 - 7.43 (m, 2H), 7.11 (dd, J = 5.2, 4.0 Hz, 1H), 5.23 (s, 1H), 4.13 (t, J = 5.0 Hz, 2H), 3.39 - 3.34 (m, 2H), 2.72 (s, 3H), 2.31 (s, 3H); 13 C NMR (126 MHz, CDC13): δ 161.7, 154.6, 140.2, 140.1, 138.7, 128.9, 128.8, 127.6, 60.6, 36.6, 19.0, 18.1; HRMS (ESI): m / z calcd for [M+H] + : 267.0620, found: 267.0623.

[0110] Example 13: 3-(4-bromophenyl)-5,6-dimethyl-4-(methylthio)pyridazine

[0111]

[0112] The synthetic procedure was the same as Example 1 except that 3,6-diphenyl- 1,2,4,5-tetrazine was replaced by 3-(4-bromophenyl)-6-methyl-1,2,4,5-tetrazine to give a yellowish oil in 45% yield.

[0113] Yellowish oil, 45% yield. 1 H NMR (400 MHz, CDC13): δ 7.62 (d, J = 6.0 Hz, 2H), 7.43 (d, J = 6.0 Hz, 2H), 2.91 (s, 3H), 2.49 (s, 3H), 2.40 (s, 3H); 13 C NMR (101 MHz, CDC13): δ 161.0, 159.7, 139.3, 138.9, 136.5, 131.6, 131.0, 123.3, 22.3, 18.5, 17.7; HRMS (ESI): m / z calcd for [M+H] + : 309.0057, found: 309.0056.

[0114] Example 14: 3-(4-bromophenyl)-4,6-dimethyl-5-(methylthio)pyridazine

[0115]

[0116] The synthetic procedure was the same as Example 1 except that 3,6-diphenyl- 1,2,4,5-tetrazine was replaced by 3-(4-bromophenyl)-6-methyl-1,2,4,5-tetrazine to give a yellowish oil in 45% yield.

[0117] Yellowish oil, 45% yield. 1 H NMR (400 MHz, CDC13): δ 7.62 (d, J = 6.0 Hz, 2H), 7.43 (d, J = 6.0 Hz, 2H), 2.91 (s, 3H), 2.49 (s, 3H), 2.40 (s, 3H); 13 C NMR (101 MHz, CDC13): δ 161.0, 159.7, 139.3, 138.9, 136.5, 131.6, 131.0, 123.3, 22.3, 18.5, 17.7; HRMS (ESI): m / z calcd for [M+H] + : 309.0057, found: 309.0047.

[0118] Example 15: (5,6-dimethyl-4-(methylthio)pyridazin-3-yl)methyl phosphonate diethyl ester

[0119]

[0120] The synthetic procedure was the same as Example 1 except that 3,6-diphenyl-1,2,4,5-tetrazine was replaced by ((6-methyl-1,2,4,5-tetrazin-3-yl)methyl)diethyl phosphonate to give a light yellow oil in 45% yield.

[0121] A light yellow oil was obtained in 45% yield. 1 H NMR (400 MHz, CDC13): δ 4.18 - 4.03 (m, 4H), 3.59 (d, J = 22.0 Hz, 2H), 2.82 (d, J = 1.6 Hz, 3H), 2.62 (s, 3H), 2.30 (s, 3H), 1.28 (t, J = 7.2 Hz, 6H); 13 CNMR (101 MHz, CDC13): δ 161.1 (161.1, 161.1, d, J = 3.2 Hz), 153.9 (153.9, 153.8, d, J = 9.2 Hz), 141.0 (141.0, 140.9, d, J = 4.0 Hz), 138.7 (138.8, 138.7, d, J = 2.4 Hz), 62.5 (62.6, 62.5, d, J = 6.4 Hz), 33.4, 32.0, 22.2, 17.8, 17.2, 16.3 (16.4, 16.3, d, J = 6.4 Hz); HRMS (ESI): m / z calcd for [M+H] + : 305.1083, found: 305.1083.

[0122] Example 16: (4-(4,6-dimethyl-5-(methylthio)pyridazin-3-yl)phenyl)boronic acid

[0123]

[0124] The synthetic procedure was the same as Example 1 except that 3,6-diphenyl-1,2,4,5-tetrazine was replaced by 3-(4-bromophenyl)-6-methyl-1,2,4,5-tetrazine to give a light yellow oil in 31% yield.

[0125] A light yellow oil was obtained in 31% yield. 1 H NMR (400 MHz, CDC13): δ 4.18 - 4.03 (m, 4H), 3.59 (d, J = 22.0 Hz, 2H), 2.82 (d, J = 1.6 Hz, 3H), 2.62 (s, 3H), 2.30 (s, 3H), 1.28 (t, J = 7.2 Hz, 6H); 13C NMR (101 MHz, CDC13): δ 171.0, 159.7, 139.9, 139.0, 136.6, 131.5, 131.0, 123.2, 22.1, 18.5, 17.6; HRMS (ESI): m / z calcd for [M+H] + : 275.1020, found: 275.1026.

[0126] Example 17: 3,6-Dibenzyl-4-(ethylthio)-5-phenylpyridazine

[0127]

[0128] The synthesis procedure was the same as Example 6, except that S,S-dimethyl- propargylsulfonium salt was replaced by S,S-diethyl-propargylsulfonium salt to give a light yellow oil in 72% yield.

[0129] Light yellow oil in 72% yield. 1 H NMR (400 MHz, CDC13): δ 7.41 (d, J = 7.6 Hz, 2H), 7.34 - 7.19 (m, 8H), 4.64 (s, 2H), 4.42 (s, 2H), 2.50 (q, J = 7.6 Hz, 2H), 2.42 (s, 3H), 1.06 (t, J = 7.6 Hz, 3H);13C NMR (101 MHz, DMSO) δ 170.88, 170.00, 169.37, 139.36, 136.92, 131.77, 129.75, 129.44, 129.17, 129.15, 128.56, 128.09, 127.45, 123.86, 119.84, 119.77, 53.29, 40.74, 40.63, 40.42, 40.21, 40.00, 39.79, 39.58, 39.38, 32.31, 30.17, 22.95, 22.85, 15.14.; HRMS (ESI): m / z calcd for [M+H] + : 335.1576, found: 335.1578.

[0130] Example 18: 3,6-Dibenzyl-4-((4-bromobutyl)thio)-5-methylpyridazine

[0131]

[0132] The synthesis procedure was the same as Example 6, except that S,S-dimethyl- propargylsulfonium salt was replaced by S,S-diethyl-propargylsulfonium salt to give a light yellow oil in 72% yield.

[0133] Pale yellow oil, yield 81%. 1 H NMR (400 MHz, CDC13): δ 7.38 (d, J = 7.2 Hz, 2H), 7.34 - 7.19 (m, 8H), 4.62 (s, 2H), 4.41 (s, 2H), 3.26 (t, J = 6.4 Hz, 2H), 2.47 - 2.39 (m, 5H), 1.81 - 1.73 (m, 2H), 1.57 - 1.40 (m, 2H); 13 C NMR (101 MHz, CDC13): δ 163.4, 160.2, 141.9, 138.9, 137.6, 137.5, 129.2, 128.8, 128.7, 128.4, 126.7, 126.4, 41.5, 41.0, 34.6, 32.7, 31.4, 28.0, 16.9; HRMS (ESI): m / z calcd for [M+H] + : 441.0995, found: 441.0992.

[0134] Example 19: 3,6-Dibenzyl-4-methyl-5-(phenylthio)pyridazine

[0135]

[0136] Synthesis procedure as in Example 6, except S,S-dimethyl-propargyl-sulfonium salt was replaced by S,S-methylphenyl-propargyl-sulfonium salt to give pale yellow oil, yield 80%

[0137] Pale yellow oil, yield 80%. 1 H NMR (500 MHz, CDC13): δ 7.25 (d, J = 7.2 Hz, 2H), 7.21 - 7.01 (m, 11H), 6.75 (dd, J = 7.6, 1.6 Hz, 2H), 4.45 (s, 2H), 4.31 (s, 2H), 2.05 (s, 3H); 13 C NMR (101 MHz, CDC13): δ 163.3, 160.8, 142.2, 138.4, 137.6, 135.8, 134.6, 129.4, 129.3, 128.7, 128.4, 127.7, 126.6, 126.5, 126.4, 41.2, 40.9, 17.0; HRMS (ESI): m / z calcd for [M+H] + : 381.1631, found: 381.1637.

[0138] Example 20: 4-((4-bromobutyl)thio)-6-(4-bromophenyl)-3,5-dimethylpyridazine

[0139]

[0140] The synthetic procedure was same as example 1 except that S,S-dimethyl-propargylsulfonium salt was replaced by S-propargyl-tetrahydrothiophene sulfonium salt and 3,6-dibenzyl-1,2,4,5-tetrazine was replaced by 3-(4-bromophenyl)-6-methyl-1,2,4,5-tetrazine to give a light yellow oil in 68% yield.

[0141] Light yellow oil in 68% yield. 1 H NMR (400 MHz, CDC13): δ 7.89 (t, J = 10.4 Hz, 2H), 7.68 (t, J = 10.4 Hz, 2H), 3.66 (dt, J = 8.4, 5.6 Hz, 2H), 3.23 - 3.16 (m, 3H), 3.13 (dd, J = 16.6, 9.2 Hz, 2H), 2.84 - 2.72 (m, 3H), 2.25 (dd, J = 14.0, 6.8 Hz, 2H), 2.02 (dd, J = 14.0, 6.8 Hz, 2H); 13 C NMR (101 MHz, CDC13): δ 160.9, 131.8, 131.1, 124.2, 34.2, 32.7, 31.4, 28.5, 19.5; HRMS (ESI): m / z calcd for [M+H] + : 381.1631, found: 381.1637.

[0142] Example 21: 2-acetamido-4-((3,6-dibenzyl-5-methylpyridazin-4-yl)thio)-N- phenylacetamide

[0143]

[0144] The synthetic procedure was same as example 6 except that S,S-dimethyl-propargylsulfonium salt was replaced by (3-acetamido-4-oxo-4-(phenylamino)butyl)(methyl)(prop-2-yn-1-yl)sulfonium salt to give a light yellow oil in 50% yield.

[0145] Light yellow oil in 50% yield. 1 H NMR (400 MHz, CDC13): δ 9.05 (s, 1H), 7.50 (m, 1H), 7.27 - 6.98 (m, 15H), 4.51 (s, 2H), 4.27 (s, 2H), 3.86 (m, 2H), 2.95 - 2.87 (m, 2H), 2.55 (d, J = 7.0 Hz, 1H), 2.32 (s, 3H), 1.96 (s, 3H); 13C NMR (101 MHz, DMSO) δ 170.9, 170.0, 169.4, 160.4, 139.4, 136.9, 131.8, 129.8, 129.4, 129.2, 129.2, 129.1, 128.6, 128.1, 127.4, 123.9, 119.8, 119.7, 53.3, 32.3, 30.2, 22.9, 22.8, 15.1; HRMS (ESI): m / z calcd for [M+H] + : 525.6905, found: 525.6910.

[0146] Example 22: (1 5 ,1 6 tert-Butyl 5-oxo-7-(phenylcarbamoyl)-10-thia-6-aza-1 (3,4)- pyridazine-2(1,4)-benzocycloocta-4-yl)carbamate

[0147]

[0148] tert-Butyl (3-(4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl)-1-((4- (methylthio)-1-oxo-1-(phenylamino)butan-2-yl)amino)-1-oxopropan-2- yl)carbamate (1.0 mmol, 1.0 equivalent) and bromoacetylene (5 mmol, 5.0 equivalent), formic acid (1.1 mmol, 1.1 equivalent) were dissolved in 2 mL of a mixed solvent of acetonitrile and water (1:1) and stirred at 25 °C for 24 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and then C18 column chromatography (water: acetonitrile = 3:1) was performed to isolate and purify, to obtain 2,2,1 5 -oxa-15-thia-5,8-11-triazahexadec-17-nit-15-ium salt. The product (1.0 mol, 1.0 equivalent) from the previous step was dissolved in PBS buffer, triethylamine (1% in PBS buffer) was added, and stirred for 1 minute. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and then silica gel column chromatography (cyclohexane: ethyl acetate = 3:1) was performed to isolate and purify, to obtain a white oil with a yield of 55%.

[0149] white oil with a yield of 55%. 1H NMR (400 MHz, CDC13): δ 8.74 (s, 1H), 7.66 - 7.56 (m, 1H), 7.55 (t, J = 7.6 Hz, 3H), 7.41 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 3H), 7.05 (t, J = 7.2 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 5.39 (d, J = 6.4 Hz, 1H), 4.30 (s, 1H), 4.21 - 4.09 (m, 1H), 3.49 (s, 1H), 3.32 (dd, J = 12.0, 5.6 Hz, 1H), 2.92 (d, J = 29.2 Hz, 1H), 2.84 (d, J = 12.0 Hz, 1H), 2.70 (s, 3H), 2.45 (s, 3H), 2.06 (d, J = 12.0 Hz, 1H), 1.59 (s, 1H), 1.40 (s, 9H); 13 C NMR (101 MHz, CDC13): δ 171.81, 168.13, 159.63, 158.27, 155.65, 139.01, 137.55, 136.86, 136.51, 130.21, 129.88, 128.73, 128.52, 124.49, 120.36, 80.73, 58.22, 52.52, 50.86, 38.54, 29.87, 29.70, 28.25, 28.06, 21.22, 16.87; HRMS (ESI): m / z calcd for [M+H] + : 562.2483, found: 562.2481.

[0150] Example 23: (2-((1 5 ,1 6 tert-Butyl (2-((1

[0151]

[0152] The synthetic procedure was the same as Example 22, except that (3-(4-(6-methyl- 1,2,4,5-tetrazin-3-yl)phenyl)-1-((4-(methylthio)-1-oxo-1-(phenylamino)butan-2-yl)amino)- 1-oxopropan-2-yl)carbamic acid tert-butyl ester was replaced by (2-((3-(4-(6-methyl-1,2,4,5- tetrazin-3-yl)phenyl)-1-((4-(methylthio)-1-oxo-1-(phenylamino)butan-2-yl)amino)-1- oxopropan-2-yl)amino)-2-oxoethyl)carbamic acid tert-butyl ester to give a white oil in 51% yield.

[0153] White oil, yield 51%. 1 H NMR (400 MHz, CDC13): δ 9.03 (s, 1H), 8.05 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.59 - 7.51 (m, 3H), 7.26 (t, J = 8.0 Hz, 3H), 7.07 (t, J = 7.2 Hz, 1H), 6.75 (s, 1H), 5.68 (s, 1H), 4.69 (s, 1H), 4.54 (s, 1H), 4.07 (d, J = 13.6 Hz, 1H), 3.95 (d, J = 15.6 Hz, 1H), 3.47 (s, 1H), 2.96 (dd, J = 21.2, 9.4 Hz, 1H), 2.73 (s, 3H), 2.48 (s, 3H), 2.07 (d, J = 12.8 Hz, 2H), 1.76 (s, 2H), 1.47 (s, 9H); HRMS (ESI): m / z calcd for [M+H] + : 619.2697, found: 619.2694.

[0154] Example 24: 2-((1 5 ,1 6 -((3-(4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl)-1-((4-(methylthio)-1-oxo-1- (phenylamino)butan-2-yl)amino)-1-oxopropan-2-yl)amino)-2-oxoethyl)carbamic acid tert-butyl ester

[0155]

[0156] The synthetic procedure was the same as Example 22, except that tert-butyl (3-(4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl)-1-((4-(methylthio)-1-oxo-1-(phenylamino)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate was replaced by tert-butyl 2-((3-(4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl)-1-((4-(methylthio)-1-oxo-1-(phenylamino)butan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate to give a white oil in 41% yield.

[0157] White oil in 41% yield. 1 H NMR (400 MHz, CDC13): δ 7.64 (t, J = 12.8 Hz, 4H), 7.48 (d, J = 21.9 Hz, 1H), 7.31 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 7.2 Hz, 1H), 6.09 (s, 1H), 4.36 (s, 2H), 4.24 (t, J = 7.6 Hz, 1H), 3.45 (d, J = 32.4 Hz, 2H), 3.34 (dd, J = 11.8, 5.2 Hz, 1H), 3.00 (s, 1H), 2.75 (s, 3H), 2.50 (s, 3H), 2.24 (d, J = 7.2 Hz, 2H), 2.15 - 2.02 (m, 2H), 1.86 (s, 9H); HRMS (ESI): m / z calcd for [M+H] + : 659.3010, found: 659.3011.

[0158] Example 25: tert-butyl (1-((1 5 ,1 6- dimethyl-5-oxo-7-(phenylcarbamoyl)-10-thia-6-aza-1(3,4)-benzocyclododec-4-yl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate

[0159]

[0160] The synthetic procedure was the same as in Example 22, except that (3-(4-(6- methyl- 1,2,4,5-tetrazin-3-yl)phenyl)- 1 -((4-(methylthio)- 1 -oxo- 1 -(phenylamino)butan-2- yl)amino)- 1 -oxopropan-2-yl)carbamic acid tert-butyl ester was replaced by (3- hydroxy- 1 -((3-(4-(6-methyl- 1,2,4,5-tetrazin-3-yl)phenyl)- 1 -((4-(methylthio)- 1 -oxo- 1 -(phenylamino)butan-2-yl)amino)- 1 -oxopropan-2-yl)carbamic acid tert-butyl ester to give a white oil in 38% yield.

[0161] White oil, 38% yield. 1 H NMR (400 MHz, CDC13): δ 8.71 (s, 1H), 7.85 - 7.40 (m, 7H), 7.10 (m, 1H), 6.14 (s, 1H), 5.38 (s, 1H), 4.52 (d, J = 13.6 Hz, 1H), 4.45 (d, J = 15.6 Hz, 1H), 3.97 (dd, 12.0, 5.6 Hz, 2H), 3.44 (dd, 11.6, 5.2 Hz, 1H), 2.98 (t, J = 11.6 Hz, 1H), 2.75 (s, 3H), 2.50 (s, 3H), 2.05 (m, 2H), 1.50 (s, 9H); HRMS (ESI): m / z calcd for [M+H] + : 649.2803, found: 649.2804.

[0162] Example 26: (1-(((1 5 ,1 6 -oxo-7-(phenylcarbamoyl)-10-thia-6-aza- 1 (3,4)-pyridazine-2( 1,4)-benzene dicarboxylate

[0163]

[0164] The synthetic procedure was the same as in Example 22, except that (3-(4-(6- methyl- 1,2,4,5-tetrazin-3-yl)phenyl)- 1 -((4-(methylthio)- 1 -oxo- 1 -(phenylamino)butan-2- yl)amino)- 1 -oxopropan-2-yl)carbamic acid tert-butyl ester was replaced by (1-((3-(4-(6-methyl- 1,2,4,5-tetrazinyl)phenyl)- 1 -((4-(methylthio)- 1 -oxo- 1 -(phenylamino)butan-2- yl)amino)- 1 -oxopropan-2-yl)amino)- 1 -oxobutan-2-ylcarbamic acid tert-butyl ester to give a white oil in 40% yield.

[0165] White oil, yield 40%. 1 H NMR (400 MHz, CDC13): δ 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.27 (t, J = 7.6 Hz, 4H), 6.97 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.41 - 5.20 (m, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.74 (t, J = 11.2 Hz, 1H), 4.65 (t, J = 17.6 Hz, 1H), 3.97 (s, 1H), 3.69 (d, J = 9.2 Hz, 2H), 3.25 (d, J = 13.2 Hz, 1H), 3.11 (s, 1H), 2.83 (s, 1H), 2.61 (s, 3H), 2.55 (s, 1H), 2.42 (s, 3H), 1.92 (m, 2H), 1.83 (s, 3H), 1.36 (s, 2H), 1.28 (s, 9H); HRMS (ESI): m / z calcd for [M+H] + : 647.3010, found: 647.3004.

[0166] Example 27: (1-((1 5 ,1 6 tert-Butyl (1-((1

[0167]

[0168] The synthesis procedure was the same as Example 22, except that tert-butyl (3- methyl-1-((3-(4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl)-1-((4-(methylthio)-1- oxido-1-(phenylamino)butan-2-yl)amino)-1-oxopropan-2-yl)amino)tert-butyl) carbonate was replaced by tert-butyl (3-methyl-1-((3-(4-(6-methyl-1,2,4,5-tetrazin-3- yl)phenyl)-1-((4-(methylthio)-1-oxido-1-(phenylamino)butan-2-yl)amino)-1- oxopropan-2-yl)amino)tert-butyl) carbonate to give white oil, yield 37%.

[0169] White oil, yield 37%. 1H NMR (400 MHz, CDC13): δ 8.83-8.62 (m, 1H), 7.60 (d, J = 17.2 Hz, 6H), 7.09 (d, J = 30.4 Hz, 2H), 6.23-5.77 (m, 1H), 5.27-5.12 (m, 1H), 4.51 (d, J = 16.8 Hz, 1H)), 4.08 (d, J = 15.6 Hz, 1H)), 3.61-3.56 (m, 1H), 3.51-3.46 (m, 1H), 3.02 (s, 1H), 2.84 (s, 1H), 2.56 (s, 3H), 2.06 (d, J = 24.7 Hz, 5H), 1.92-1.85 (m, 2H), 1.52 (s, 9H), 1.31 (m, 6H); HRMS (ESI): m / z calcd for [M+H] + : 661.3167, found: 661.3164.

[0170] It should be noted that in the above various embodiments, the solvent acetonitrile is a preferred scheme, and the solvent can be selected from one or more of PBS buffer, acetone, tetrahydrofuran, toluene, N,N-dimethylformamide (DMF), anhydrous methanol, acetonitrile, dichloromethane, preferably acetonitrile or PBS buffer.

[0171] The concentration of the solvent is 0.01 mmol / mL to 10.00 mmol / mL.

[0172] The base is preferably selected from potassium carbonate and triethylamine, and the base can be selected from potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, N,N-diisopropylethylamine (DIPEA), triethylamine, preferably potassium carbonate or triethylamine.

[0173] Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. It is intended that the application be limited only by the scope of the claims, including any amendments thereof, and other equivalents to the claims. It is intended that the application not be limited to the examples and embodiments described above but cover each and every variation included within the scope of the application along with full use of equivalents using obvious modifications by those skilled in the art reading the foregoing description.

[0174] It should be understood that the application is not limited to the precise construction and compositions described above and as illustrated in the accompanying drawings which serve the purpose of illustration only. Various modifications and changes can be made to the application without departing from its scope.

Claims

1. A process for the preparation of 1,3,4-substituted 2-sulfide pyridazine derivatives, characterized in that, The 1,3,4-substituted 2-sulfide pyridazine derivative has the structural formula of: ， The 1,3,4-substituted 2-sulfide pyridazine derivative is any one of the following: 4-methyl-5-(methylthio)-3,6-diphenylpyridazine; 4-methyl-5-(methylthio)-3,6-p-xylylpyridazine; 3,6-bis(4-fluorophenyl)-4-methyl-5-(methylthio)pyridazine; 4-methyl-5-(methylthio)-3,6-bis(naphthalen-2-ylmethyl)pyridazine; 3,6-bis(2,6-difluorobenzyl)-4-methyl-5-(methylthio)pyridazine; 3,6-bis(benzyl)-4-methyl-5-(methylthio)pyridazine; 3,6-bis(4-methoxybenzyl)-4-methyl-5-(methylthio)pyridazine; 3,6-bis(4-fluorobenzyl)-4-methyl-5-(methylthio)pyridazine; 3,5-dimethyl-4-(methylthio)-6-(naphthalen-2-yl)pyridazine; (E)-4-(5-(2-(4,6-dimethyl-5-(methylthio)pyridazin-3-yl)vinyl)thiophen-2-yl)-N,N-diphenylaniline; 2-(6-benzyl-5-methyl-4-(methylthio)pyridazin-3-yl)ethanol; 2-(4-methyl-5-(methylthio)-6-(thiophen-2-yl)pyridazin-3-yl)ethanol; 3-(4-bromophenyl)-5,6-dimethyl-4-(methylthio)pyridazine; 3-(4-bromophenyl)-4,6-dimethyl-5-(methylthio)pyridazine; diethyl (5,6-dimethyl-4-(methylthio)pyridazin-3-yl)methylphosphonate; (4-(4,6-dimethyl-5-(methylthio)pyridazin-3-yl)phenyl)boronic acid; 3,6-dibenzyl-4-(ethylthio)-5-phenylpyridazine; 3,6-dibenzyl-4-((4-bromobutyl)thio)-5-methylpyridazine; 3,6-dibenzyl-4-methyl-5-(phenylthio)pyridazine; 4-((4-bromobutyl)thio)-6-(4-bromophenyl)-3,5-dimethylpyridazine; 2-acetamido-4-((3,6-dibenzyl-5-methylpyridazin-4-yl)thio)-N-phenylacetamide; wherein R1, R2 are as defined in the product; The method comprises the following steps: Step (1): dissolving the tetrazine compound and the sulfonium salt derivative in a solvent, adding a base, stirring at a predetermined temperature until the raw material is completely reacted, wherein the predetermined temperature is selected from 0°C, 25°C, 40°C, 60°C, and the base is selected from inorganic bases: potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, sodium bicarbonate; organic bases: N,N-diisopropylethylamine, triethylamine; The sulfonium salt derivative has the structural formula of: ， wherein R3, R4 are as defined in the product, and R5 is various substituted alkyl groups, wherein the sulfonium salt anion is bromide ion, tetrafluoroborate ion or triflate ion; The tetrazine compound has the structural formula of: ， Step (2): the reaction system obtained in step (1) is extracted, and the obtained organic layer is concentrated under reduced pressure to obtain a residue; the residue is subjected to silica gel column chromatography to obtain a 1,3,4-substituted 2-sulfide pyridazine derivative, and the structural formula of the 1,3,4-substituted 2-sulfide pyridazine derivative is: 。 2. The process for the preparation of 1,3,4-substituted 2-sulfide pyridazine derivatives according to claim 1, characterized in that, In step (1), the predetermined temperature is 25°C.

3. The process for preparing 1,3,4-substituted 2-sulfide pyridazine derivatives according to claim 1, characterized in that, In step (1), the solvent is selected from one or more of PBS buffer, acetone, tetrahydrofuran, toluene, N,N-dimethylformamide, anhydrous methanol and acetonitrile.

4. The process for preparing 1, 3, 4-substituted 2-sulfide pyridazine derivatives according to claim 1, characterized in that, In step (1), the solvent is acetonitrile.

5. The process for preparing 1, 3, 4-substituted 2-sulfide pyridazine derivatives according to claim 1, characterized in that, The concentration of the solvent is 0.01 mmol / mL to 10.00 mmol / mL.

6. The method of producing a 1, 3, 4-substituted 2-sulfide pyridazine derivative according to claim 1, characterized by, In step (1), the base is potassium carbonate or triethylamine.

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