Compound for specifically labeling Tau protein

Abstract

The invention relates to the field of medicinal chemistry and molecular probes, in particular to a compound for specifically marking Tau protein. The compound is a compound of formula I: Ar1-(C = C) n-Ar2 wherein Ar1 is selected from the group consisting of # imgabs0 # imgabs1 # Ar2 comprises an aromatic ring selected from the group consisting of # imgabs2 # and optionally a counter ion.

Description

Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and molecular probes, and in particular, to a compound for specifically labeling Tau protein. Background Art

[0002] Protein is an important component for maintaining the normal functioning of living organisms and is the basis of life substances. However, when the peptide chain sequence changes or the post-translational modification of amino acids is abnormal, the folding of proteins may be abnormal, which in turn affects the normal physiological function of proteins and ultimately leads to the occurrence of diseases. Among them, Alzheimer's disease (AD), Tau protein-related diseases and Parkinson's disease are all related to the misfolding and abnormal aggregation of related proteins in intracellular or extracellular tissues. Pathological studies have shown that in neurodegenerative diseases including AD and Tau protein-related diseases, the appearance of Tau protein deposits in brain nerve cells is closely related to the onset of the disease and clinical symptoms.

[0003] In recent years, with the development of detection technology, fluorescence imaging has been widely used due to its advantages of simple operation, no radiation damage, effective avoidance of biological tissue autofluorescence, high spatiotemporal resolution, low price and real-time imaging. Therefore, the development of organic small molecule fluorescent probes targeting amyloid protein, especially near-infrared fluorescent probes, with the help of fluorescence imaging technology is of great significance for in vitro diagnosis of diseases and efficacy evaluation.

[0004] At present, there are many fluorescent molecular probes targeting Tau protein that have been reported, but they generally have poor solubility in aqueous solution, which seriously affects their application potential in biological evaluation. Therefore, there is still a lot of room for development in developing new fluorescent small molecule dyes with excellent optical properties and good biocompatibility for in vitro detection of the above two amyloid proteins. Summary of the invention

[0005] The first aspect of the present invention provides a compound of formula I,

[0006] Formula I is Ar1-(C=C) n -Ar2,

[0007] Ar1 is selected from the group consisting of:

[0008] wherein Ar1 is substituted with R1 in the para position relative to -(C=C)2-, and R1 is selected from the group consisting of: halogen, -NC 1-4 Alkyl, -NC 1-4 Halogenated alkyl, -NC 1-4 Alkyl alcohol, -NC 1-4 Alkyl sulfonate, -OC 1-4 Alkyl, -OC1-4 Haloalkyl, -OC 1-4 Alkyl alcohol and -OC 1-4 Alkyl sulfonates;

[0009] Ar2 comprises an aromatic ring selected from the group consisting of: and optionally a counterion,

[0010] Wherein, Y is N and there is no substitution thereon, or Y is N + and R2 is substituted thereon, or Y is O + and thereon is no substitution, R2 at each occurrence is independently selected from the group consisting of: -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkyl alcohol and -C 1-4 Alkyl sulfonates, and

[0011] The aromatic ring is substituted with one or more R3 at positions other than Y, and R3 is independently selected from the group consisting of: -H, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkyl alcohol and -C 1-4 Alkyl sulfonates.

[0012] In the present invention, counterions include, but are not limited to, halogen ions and any suitable anions (e.g., BF4 - "Halogen" refers to fluorine, chlorine, bromine and iodine; "alkyl" refers to a saturated, branched or straight-chain monovalent hydrocarbon group derived by removing a hydrogen atom from a single carbon atom of a parent alkane, and the alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, etc.; -NC 1-4 The alkyl group may be -NH-monoalkyl or -N-dialkyl, for example -NH-CH3 or -N-(CH3)2, -NH-CH2-CH3 or -N-(CH2CH3)2.

[0013] In some embodiments, R1 is selected from the group consisting of: -NC 1-4 Alkyl, -NC 1-4 Alkyl alcohol and -OC 1-4 alkyl.

[0014] In some embodiments, R1 is -N(CH3)2, -OCH3, or -N(CH3)CH2CH2OH.

[0015] In some embodiments, the aromatic ring is wherein Y is N with no substitution thereon, and R3 is -H.

[0016] In some embodiments, the aromatic ring is Where Y is N + and substituted thereon with R2, and R3 at each occurrence is independently -H, methyl, ethyl, halomethyl or haloethyl, wherein R2 at each occurrence is independently selected from the group consisting of: -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkyl alcohol and -C 1-4 Alkyl sulfonates.

[0017] In some embodiments, the aromatic ring is Where Y is O + and there is no substitution thereon, and R3 at each occurrence is independently -H, methyl, ethyl, halomethyl or haloethyl.

[0018] In some embodiments, the aromatic ring is

[0019] Ar2 of the compound of the present invention has an ionized structure. The applicant unexpectedly discovered that Ar2 with a positive charge is connected to -(C=C) n - is connected to Ar1 to obtain the compound of formula I, which exhibits affinity and selectivity for Tau protein and excellent biocompatibility. In the compound of formula I, when Y is N and has no substitution thereon and R3 is -H (i.e., the aromatic ring is ), although Ar2 does not directly carry a positive charge in the compound structure, the compound also exhibits an ionization effect in solutions such as PBS buffer solution (pH = 7.4 ± 0.4), physiological saline (pH = 6.5 ± 0.4) or deionized water (pH = 7.0 ± 0.4), and thus also exhibits the affinity and fluorescence properties of the compound of formula I containing an onium salt provided in the embodiment of the present application for Tau protein or amyloid protein aggregates. The compound of formula I in the embodiment of the present invention can be used to prepare an optical imaging agent or a staining agent for detecting pathological phosphorylated Tau protein or other amyloid protein aggregates.

[0020] In some embodiments, R2 is independently selected at each occurrence from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methanesulfonate (-CH2SO3 - ), ethyl sulfonate (-(CH2)2SO3 - ), n-propyl sulfonate (-(CH2)3SO3 - ), isopropyl sulfonate (-C(CH3)2SO3 - ), n-butyl sulfonate (-(CH2)4SO3 - ) and tert-butyl sulfonate (-C(CH3)2CH2SO3 - ).

[0021] In some embodiments, R2 is methyl or -(CH2)3SO3 - .

[0022] In some embodiments, the compound is selected from the group consisting of:

[0023]

[0024]

[0025] The compound of formula I provided by the present invention has a simple chemical synthesis route and good optical properties and biocompatibility, and at the same time has higher affinity and selectivity for Tau protein.

[0026] The second aspect of the present invention provides an isotope-labeled compound of any of the first aspect of the present invention, wherein the isotope-labeled compound is formed by reacting the compound of formula I with D, 3 H, 11 C, 13 C, 14 C, 123 I, 124 I, 125 I, 131 I or 18 F isotope labeling.

[0027] The third aspect of the present invention provides a pharmaceutical composition, comprising a compound according to any embodiment of the first aspect or an isotope-labeled compound according to any embodiment of the second aspect, and optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0028] A fourth aspect of the present invention provides a kit comprising the compound of any embodiment of the first aspect, the isotope-labeled compound of any embodiment of the second aspect, or the pharmaceutical composition of any embodiment of the third aspect as an active ingredient.

[0029] A fifth aspect of the present invention provides a reagent for diagnosing or detecting a neurological disease characterized by abnormal deposition of amyloid protein aggregates, comprising a compound of any embodiment of the first aspect, an isotope-labeled compound of any embodiment of the second aspect, or a pharmaceutical composition of any embodiment of the third aspect as an active ingredient. Preferably, the amyloid protein is pathologically phosphorylated Tau protein.

[0030] In an embodiment of the present invention, the amyloid protein also includes Aβ protein, which includes but is not limited to Aβ 1-42; Diseases associated with abnormal Tau protein deposition are selected from Alzheimer's disease, but are not limited to Tau protein-related diseases such as Alzheimer's disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, cortical basal ganglia degeneration or Pick's disease.

[0031] In some embodiments, the disease is selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), primary age-related tauopathy (PART), Pick's disease, corticobasal degeneration (CBD), glial globular inclusion tauopathy (GGT), amyotrophic lateral sclerosis (ALS) and dementia with Lewy bodies (DLB).

[0032] The sixth aspect of the present invention provides a use of the compound of any embodiment of the first aspect, the isotope-labeled compound of any embodiment of the second aspect, or the pharmaceutical composition of any embodiment of the third aspect in the preparation of a medicament for treating and / or preventing a disease selected from the group consisting of: Alzheimer's disease (AD), Down syndrome (DS), cognitive deficits in schizophrenia and other neurodegenerative tau pathologies such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE) and Pick's disease.

[0033] By means of the above technical solution, the present invention has at least the following advantages and beneficial effects:

[0034] The molecular fluorescent dye provided by the present invention has good water solubility and optical properties, and can be directly used as a fluorescent probe for detecting pathological Tau protein deposition in biological tissue samples or other biological samples. When using 10nM-1μM compound solution for tissue staining, the staining is fast and effective, with high specificity and good selectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0036] Figure 1Schematic diagram of the synthesis process of the compounds of Example 1-38 of the invention, wherein the reaction reagents and conditions involved are: (a) methanol, piperidine, 80°C, 6h; (b) methanol, room temperature, 12h; (c) N,N-dimethylformamide, potassium tert-butoxide, 80°C, 6h; (d) 1,4-dioxane, tetrakistriphenylphosphine palladium, N2, 110°C, 12h; (e) ethanol, methyl iodide, room temperature, 12h.

[0037] Figure 2 These are the staining results of compounds 1-3, 5, 7-9, 11-12, 16, 22-23, 24-28, 30-32, 37-38 in Example 40 of the present invention on brain sections of AD patients (102 years old, female, temporal lobe).

[0038] Figure 3 These are the staining results of compounds 27-28, 30-32 in Example 40 of the present invention on brain slices of an AD patient (97 years old, female, temporal lobe). DETAILED DESCRIPTION

[0039] In order to facilitate the understanding of the present invention, the implementation process of the present invention is further described below in conjunction with specific implementation examples. These descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0040] Example 1: Synthesis of (E)-4-(4-(dimethylamino)phenylvinyl)-1-methylpyridin-1-ium iodide (Compound 1)

[0041]

[0042] Weigh 1,4-dimethylpyridinium iodide (235 mg, 1 mmol) and 4-dimethylaminobenzaldehyde (149 mg, 1 mmol) in a 100 mL round-bottom flask, add 10 mL of anhydrous methanol to completely dissolve, then add piperidine (200 μL, 0.1 mmol), and reflux at 80°C for 6 h. After the reaction is completed, cool and filter to obtain 170 mg of dark red crystals with a yield of 46.4%. 1 HNMR(400MHz,DMSO-d6)δ8.65(d,J=6.3Hz,2H),8.01(d,J=6.4Hz,2H),7.87(d,J=16.1Hz,1H), 7.56(d,J=8.4Hz,2H),7.14(d,J=16.1Hz,1H),6.75(d,J=8.4Hz,2H),4.14(s,3H),2.98(s,6H). 13C NMR(151MHz,DMSO-d6)δ153.32,151.81,144.26,141.82,130.05,122.41,122.05,117.05,111.87,46.30.HRMS:m / z calcd for[C 16 H 19 N2] + 239.1543, found 239.1542.

[0043] Example 2: Synthesis of 4-((1E,3E)-4-(4-(dimethylamino)phenyl)buta-1,3-dien-1-yl)-1-methylpyridin-1-ium iodide (Compound 2)

[0044]

[0045] According to the method for synthesizing compound 1, compound 2 was prepared from 1,4-dimethylpyridinium iodide and 4-dimethylaminocinnamaldehyde to obtain 123 mg of purple crystals with a yield of 31.4%. 1 H NMR (600MHz, DMSO-d6) δ8.69(d,J=6.5Hz,2H),8.02(d,J=6.6Hz,2H),7.79(dt,J=15.3,5.0Hz, 1H),7.47(d,J=8.7Hz,2H),7.01(d,J=5.3Hz,2H),6.76–6.70(m,3H),4.18(s,3H),2.99(s,6H). 13 C NMR (101MHz, DMSO-d6) δ153.29,151.66,145.03,143.80,142.57,129.63,124.09,123.81,123.62,122.96,112.58,47.05.HRMS:m / z calcd for[C 18 H 21 N2] + 265.1699, found 265.1698.

[0046] Example 3: Synthesis of 4-(1E,3E,5E)-6-(4-(dimethylamino)phenyl)hexa-1,3,5-trien-1-yl)-1-methylpyridin-1-ium iodide (Compound 3)

[0047]

[0048] According to the method for synthesizing compound 1, compound 3 was prepared from 1,4-dimethylpyridinium iodide and (2E,4E)-5-(4-(dimethylamino)phenyl)pentanal to obtain 82.3 mg of a dark red solid with a yield of 39.2%. 1 H NMR (600MHz, DMSO-d6) δ8.71(d,J=6.6Hz,2H),8.03(d,J=6.9Hz,2H),7.74(dd,J=15.4,11.1Hz,1H),7.41(d,J=8.9Hz,2H), 6.94–6.88(d,J=8.9Hz,,2H),6.82(d,J=14.4Hz,1H),6.75–6.69(m,3H),6.60(t,J=12.2Hz,1H),4.18(s,3H),2.96(s,6H). 13 C NMR(151MHz,DMSO-d6)δ153.06,151.16,145.08,143.53,142.89,138.95,129 .85,129.00,124.91,124.76,124.36,123.18,112.63,47.13.HRMS:m / zcalcd for[C 20 H 23 N2] + 291.1856, found 291.1856.

[0049] Example 4: Synthesis of (E)-4-(2-(6-(dimethylamino)pyridin-3-yl)vinyl)-1-methylpyridin-1-ium iodide (Compound 4)

[0050]

[0051] According to the method for synthesizing compound 1, compound 4 was prepared from 1,4-dimethylpyridinium iodide and 6-(dimethylamino)nicotinaldehyde to obtain 80.8 mg of a bright orange solid with a yield of 43.6%. 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=6.9Hz,2H),8.38(d,J=2.4Hz,1H),8.07(d,J=7.0Hz,2H),7.97(dd,J=9.2, 2.5Hz,1H),7.93(d,J=16.2Hz,1H),7.24(d,J=16.2Hz,1H),6.79(d,J=9.1Hz,1H),4.20(s,3H),3.13(s,6H). 13C NMR (101MHz, DMSO-d6) δ159.92,153.67,151.22,145.11,139.52,135.45,122.93,119.53,118.62,106.99,47.08,38.20.HRMS:m / z calcd for[C 15 H 18 N3] + 239.1543, found 239.1542.

[0052] Example 5: Synthesis of 4-((1E,3E)-4-(6-(dimethylamino)pyridin-3-yl)buta-1,3-dien-1-yl)-1-methylpyridin-1-ium iodide (Compound 5)

[0053]

[0054] According to the method for synthesizing compound 1, compound 5 was prepared from 1,4-dimethylpyridinium iodide and (E)-3-(6-(dimethylamino)pyridin-3-yl)acrolein to obtain 73.4 mg of a red solid with a yield of 37.3%. 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=6.9Hz,2H),8.27(d,J=2.3Hz,1H),8.06(d,J=6.9Hz,2H),7.83(ddd,J= 25.3, 12.3, 6.2Hz, 2H), 7.04 (dt, J=23.2, 12.6Hz, 2H), 6.73 (t, J=11.9Hz, 2H), 4.20 (s, 3H), 3.09 (s, 6H). 13 CNMR(101MHz,DMSO-d6)δ159.42,153.17,149.71,145.15,143.38,139.27,135.15,124.47,124.39,123.17,120.39,106.75,47.13,38.18.HRMS:m / z calcdfor[C 17 H 20 N3] + 266.1652, found 266.1652.

[0055] Example 6: Synthesis of (E)-4-(2-(6-(dimethylamino)naphthalen-2-yl)vinyl)-1-methylpyridin-1-ium iodide (Compound 6)

[0056]

[0057] According to the method for synthesizing compound 1, compound 6 was prepared from 1,4-dimethylpyridinium iodide and 6-(dimethylamino)-2-naphthaldehyde to obtain 38.7 mg of a dark red solid with a yield of 37.2%. 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=6.9Hz,2H),8.18(d,J=7.0Hz,2H),8.09(d,J=16.2Hz,1H),8.00(s,1H),7.84–7.76(m,2H) ,7.73(d,J=8.7Hz,1H),7.48(d,J=16.1Hz,1H),7.26(dd,J=9.1,2.6Hz,1H),6.97(d,J=2.5Hz,1H),4.23(s,3H),3.07(s,6H). 13 C NMR(101MHz,DMSO-d6)δ153.40,150.10,145.31,142.07,136.46,130.75,130.20, 128.94,127.32,126.02,124.49,123.46,121.27,117.05,105.96,47.25.HRMS:m / z calcd for[C 20 H 21 N2] + 289.1699, found 289.1700.

[0058] Example 7: Synthesis of 4-((1E,3E)-4-(6-(dimethylamino)naphthalen-2-yl)buta-1,3-dien-1-yl)-1-methylpyridin-1-ium iodide (Compound 7)

[0059]

[0060] According to the method for synthesizing compound 1, compound 7 was prepared from 1,4-dimethylpyridinium iodide and (E)-3-(6-(dimethylamino)naphthalen-2-yl)acrolein to obtain 53.7 mg of a black solid with a yield of 24.3%. 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=6.4Hz,2H),8.11(d,J=6.4Hz,2H),7.87(s,2H),7.77(d,J=9.1Hz,1H),7.69 (d,J=4.3Hz,2H),7.23(dd,J=16.3,8.6Hz,3H),6.95(s,1H),6.85(d,J=15.3Hz,1H),4.23(s,3H),3.07(s,6H). 13C NMR(101MHz,DMSO-d6)δ153.02,149.71,145.26,143.05,142.05,135.86,129.85,129.13 ,127.18,126.63,126.30,125.68,124.37,123.42,117.00,106.05,47.21.HRMS:m / zcalcd for[C 22 H 23 N2] + 315.1856, found 315.1855.

[0061] Example 8: Synthesis of (E)-4-(2-(2-(dimethylamino)pyrimidin-5-yl)vinyl)-1-methylpyridin-1-ium iodide (Compound 8)

[0062]

[0063] According to the method for synthesizing compound 1, compound 8 was prepared from 1,4-dimethylpyridinium iodide and 2-(dimethylamino)pyrimidine-5-carbaldehyde to obtain 226 mg of an orange-yellow solid with a yield of 61.4%. 1 H NMR(400MHz, DMSO-d6)δ8.79(d,J=6.9Hz,2H),8.74(s,2H),8.09(d,J=7.0Hz, 2H),7.87(d,J=16.4Hz,1H),7.37(d,J=16.4Hz,1H),4.23(s,3H),3.21(s,6H). 13 C NMR (151MHz, DMSO-d6) δ161.90,158.30,153.32,145.38,136.50,123.26,119.57,117.53,47.28,37.39.HRMS:m / z calcd for[C 14 H 17 N4] + 241.1448, found 241.1448.

[0064] Example 9: Synthesis of 4-((1E,3E)-4-(2-(dimethylamino)pyrimidin-5-yl)buta-1,3-dien-1-yl)-1-methylpyridin-1-ium iodide (Compound 9)

[0065]

[0066] According to the method for synthesizing compound 1, compound 9 was prepared from 1,4-dimethylpyridinium iodide and (E)-3-(2-(dimethylamino)pyrimidin-5-yl)acrolein to obtain 34.1 mg of an orange-red solid with a yield of 34.5%. 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=6.9Hz,2H),8.66(s,2H),8.10(d,J=6.9Hz,2H),7.78(dd,J=15.4,10.7Hz, 1H),7.15(dd,J=15.5,10.7Hz,1H),6.92(d,J=15.6Hz,1H),6.78(d,J=15.4Hz,1H),4.21(s,3H),3.18(s,6H). 13 C NMR (101MHz, DMSO-d6) δ161.00,156.78,152.33,144.65,142.17,135.23,124.81,124.57,122.79,117.70,46.59,36.68.HRMS:m / z calcd for[C 16 H 19 N4] + 267.1604, found 267.1604.

[0067] Example 10: Synthesis of 4-((1E,3E,5E)-6-(2-(dimethylamino)pyrimidin-5-yl)hexa-1,3,5-trien-1-yl)-1-methylpyridin-1-ium iodide (Compound 10)

[0068]

[0069] According to the method for synthesizing compound 1, compound 10 was prepared from 1,4-dimethylpyridinium iodide and (2E,4E)-5-(2-(dimethylamino)pyrimidin-5-yl)pentanal to obtain 27.8 mg of a black solid with a yield of 53.1%. 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=6.8Hz,2H),8.59(s,2H),8.07(d,J=6.9Hz,2H),7.75(dd,J=15.4,11.0Hz,1H),7.05(dd,J=15.6, 10.9Hz, 1H), 6.88 (dd, J=14.6, 11.0Hz, 1H), 6.78 (dd, J=20.4, 15.5Hz, 2H), 6.63 (dd, J=14.6, 11.0Hz, 1H), 4.20 (s, 3H), 3.16 (s, 6H). 13C NMR (101MHz, DMSO-d6) δ160.80,156.23,152.25,144.61,141.81,141.72,131.67,130.52,125.42,125.29,122.80,118.21,46.59,36.66.HRMS: m / z calcd for[C 18 H 21 N4] + 293.1761, found 293.1761.

[0070] Example 11: Synthesis of (E)-2-(4-(dimethylamino)phenylvinyl)-1-methylpyridin-1-ium iodide (Compound 11)

[0071]

[0072] According to the method for synthesizing compound 1, compound 11 was prepared from 1,2-dimethylpyridinium iodide and 4-(dimethylamino)benzaldehyde to obtain 89.8 mg of a red solid with a yield of 49.2%. 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=6.2Hz,1H),8.45(d,J=8.4Hz,1H),8.34(t,J=7.9Hz,1H),7.92(d,J=15 .7Hz,1H),7.72(d,J=8.6Hz,3H),7.24(d,J=15.7Hz,1H),6.79(d,J=8.9Hz,2H),4.29(s,3H),3.04(s,6H). 13 CNMR(101MHz,DMSO-d6)δ153.79,152.67,145.84,144.71,143.63,131.29,124.13,123.58,122.84,112.32,111.14,46.26.HRMS:m / z calcd for[C 16 H 19 N2] + 239.1543, found 239.1542.

[0073] Example 12: Synthesis of 2-((1E,3E)-4-(4-(dimethylamino)phenyl)buta-1,3-dien-1-yl)-1-methylpyridin-1ium iodide (Compound 12)

[0074]

[0075] According to the method for synthesizing compound 1, compound 12 was prepared from 1,2-dimethylpyridinium iodide and (E)-3-(4-dimethylaminophenyl)acrolein to obtain 86.3 mg of a brown-red solid with a yield of 44%. 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=6.3Hz,1H),8.35(s,1H),8.32(d,J=7.3Hz,2H),7.78(dd,J=14.4,9.9Hz,1H),7.69 (s,1H),7.43(d,J=8.4Hz,2H),7.05(s,1H),6.93(d,J=14.9Hz,1H),6.71(d,J=8.5Hz,2H),4.18(s,3H),2.95(s,6H). 13 C NMR (101MHz, DMSO-d6) δ153.05,151.78,146.03,145.63,143.81,143.31,129.70,124.22,124.03,123.86,123.58,117.32,112.62,46.13.HRMS: m / z calcd for[C 18 H 21 N2] + 265.1699, found 265.1698.

[0076] Example 13: Synthesis of 2-((1E,3E,5E)-6-(4-(dimethylamino)phenyl)hexa-1,3,5-trien-1-yl)-1-methylpyridin-1-ium iodide (Compound 13)

[0077]

[0078] According to the method for synthesizing compound 1, compound 13 was prepared from 1,2-dimethylpyridinium iodide and (2E,4E)-5-(4-(dimethylamino)phenyl)pentanal to obtain 77.6 mg of black solid powder with a yield of 74.2%. 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=5.9Hz,1H),8.38(dt,J=15.5,8.3Hz,2H),7.77(dd,J=16.9,9.2Hz,2H),7.43(d ,J=8.5Hz,2H),6.95(dd,J=13.9,7.8Hz,2H),6.92–6.81(m,1H),6.71(d,J=9.0Hz,4H),4.23(s,3H),2.97(s,6H). 13C NMR(101MHz,DMSO-d6)δ152.99,151.71,146.16,144.80,144.44,143.89,139.67, 129.64,129.16,124.68,124.55,124.32,124.09,118.35,112.58,46.17.HRMS:m / z calcd for[C 20 H 23 N2] + 291.1856, found 291.1855.

[0079] Example 14: Synthesis of (E)-2-(2-(6-(dimethylamino)pyridin-3-yl)vinyl)-1-methylpyridin-1-ium iodide (Compound 14)

[0080]

[0081] According to the method for synthesizing compound 1, compound 14 was prepared from 1,2-dimethylpyridinium iodide and 6-(dimethylamino)nicotinaldehyde to obtain 103.7 mg of a red solid with a yield of 56.2%. 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=6.1Hz,1H),8.47(d,J=7.7Hz,2H),8.39(t,J=7.6Hz,1H),8.15(dd,J=9.1,2.5Hz,1H),7.93 (d,J=15.8Hz,1H),7.76(ddd,J=7.6,6.2,1.5Hz,1H),7.32(d,J=15.8Hz,1H),6.80(d,J=9.1Hz,1H),4.31(s,3H),3.14(s,6H). 13 C NMR (101MHz, DMSO-d6) δ160.06,153.55,151.79,146.03,143.94,141.86,136.02,124.21,119.44,112.26,106.82,46.38,38.21.HRMS:m / z calcd for[C 15 H 18 N3] + 240.1495, found 240.1495.

[0082] Example 15: Synthesis of 2-((1E,3E)-4-(6-(dimethylamino)pyridin-3-yl)buta-1,3-dien-1-yl)-1-methylpyridin-1-ium iodide (Compound 15)

[0083]

[0084] According to the method for synthesizing compound 1, compound 15 was prepared from 1,2-dimethylpyridinium iodide and (E)-3-(6-(dimethylamino)pyridin-3-yl)acrolein to obtain 49 mg of a dark red solid with a yield of 48.8%. 1 H NMR (600MHz, DMSO-d6) δ8.77(d,J=6.0Hz,1H),8.36(dt,J=15.4,7.9Hz,3H),8.24(s,1H),7.81(d,J=9.0Hz,1H),7.77(d,J=4.1Hz,1H),7.73(d d,J=11.7,4.6Hz,2H),7.12(d,J=10.7Hz,1H),7.03(d,J=15.4Hz,1H),6.95(d,J=15.0Hz,1H),6.71(d,J=9.0Hz,1H),4.20(s,3H),3.06(s,6H). 13 C NMR (101MHz, DMSO-d6) δ159.40,152.92,149.73,146.17,145.16,144.03,139.93,135.11,124.40,118.16,106.97,46.19,44.27,38.22.HRMS: m / z calcd for[C 17 H 20 N3] + 266.1652, found 266.1653.

[0085] Example 16: Synthesis of (E)-2-(2-(6-(dimethylamino)naphthalen-2-yl)vinyl)-1-methylpyridin-1-ium iodide (Compound 16)

[0086]

[0087] According to the method for synthesizing compound 1, compound 16 was prepared from 1,2-dimethylpyridinium iodide and 6-(dimethylamino)-2-naphthaldehyde to obtain 32.7 mg of a dark red solid with a yield of 31.4%. 1H NMR (400MHz, DMSO-d6) δ8.86(d,J=6.0Hz,1H),8.55(d,J=7.6Hz,1H),8.46(t,J=7.8Hz,1H),8.12–8.02(m,2H),7.94(dd,J=8.7,1.8Hz,1H),7.8 3(d,J=9.3Hz,2H),7.75(d,J=8.8Hz,1H),7.55(d,J=15.8Hz,1H),7.27(dd,J=9.1,2.6Hz,1H),6.99(d,J=2.5Hz,1H),4.38(s,3H),3.08(s,6H). 13 C NMR (101MHz, DMSO-d6) δ152.66,149.56,145.67,143.68,135.99,130.70,129.64,126.56,124.25,116.42,114.43,105.26,45.84.HRMS:m / z calcd for[C 20 H 21 N2] + 289.1700, found 289.1700.

[0088] Example 17: Synthesis of 2-((1E,3E)-4-(6-(dimethylamino)naphthalen-2-yl)buta-1,3-dien-1-yl)-1-methylpyridin-1-ium iodide (Compound 17)

[0089]

[0090] According to the method for synthesizing compound 1, compound 17 was prepared from 1,2-dimethylpyridinium iodide and (E)-3-(6-(dimethylamino)naphthalen-2-yl)acrolein to obtain 98.2 mg of a black solid with a yield of 44.5%. 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=6.3Hz,1H),8.44(dt,J=15.4,7.6Hz,3H),7.92–7.83(m,2H),7.78(d,J=9.2Hz,1H),7.69(s, 2H),7.38(dd,J=15.4,10.5Hz,1H),7.31–7.20(m,2H),7.10(d,J=15.0Hz,1H),6.95(d,J=2.5Hz,1H),4.27(s,3H),3.05(s,6H). 13C NMR (101MHz, DMSO-d6) δ152.76,149.76,146.27,144.80,144.17,142.67,129.90,129.65,129. 36,127.27,126.61,126.26,124.71,124.61,124.19,119.44,117.03,106.00,46.25.HRMS:m / z calcd for[C 22 H 23 N2] + 315.1856, found 315.1856.

[0091] Example 18: Synthesis of (E)-2-(2-(2-(dimethylamino)pyrimidin-5-yl)vinyl)-1-methylpyridin-1-ium iodide (Compound 18)

[0092]

[0093] According to the method for synthesizing compound 1, compound 18 was prepared from 1,2-dimethylpyridinium iodide and 2-(dimethylamino)pyrimidine-5-carbaldehyde to obtain 89.2 mg of a yellow solid with a yield of 48.5%. 1 H NMR(400MHz,DMSO-d6)δ8.86(s,2H),8.83(d,J=6.2Hz,1H),8.44(d,J=3.9H z,2H),7.88–7.79(m,2H),7.46(d,J=16.1Hz,1H),4.32(s,3H),3.22(s,6H). 13 C NMR (101MHz, DMSO-d6) δ161.96,158.82,153.17,146.30,144.33,138.78,124.66(d,J=16.9Hz),113.47,46.53,37.37.HRMS:m / z calcd for[C 14 H 17 N4] + 241.1448, found 241.1448.

[0094] Example 19: Synthesis of (E)-4-(4-methoxyphenylvinyl)-1-methylpyridin-1-ium iodide (Compound 19)

[0095]

[0096] According to the method for synthesizing compound 1, compound 19 was prepared from 1,4-dimethylpyridinium iodide and 4-methoxybenzaldehyde to obtain 107 mg of a yellow solid with a yield of 83%. 1 H NMR (400MHz, DMSO-d6) δ8.81(d,J=6.9Hz,2H),8.16(d,J=6.9Hz,2H),7.98(d,J=16.3Hz,1H),7 .72(d,J=8.8Hz,2H),7.37(d,J=16.3Hz,1H),7.07(d,J=8.8Hz,2H),4.23(s,3H),3.83(s,3H). 13 C NMR (101MHz, DMSO-d6) δ161.71,153.39,145.39,141.09,130.55,128.34,123.56,121.23,115.19,56.01,47.32.HRMS:m / z calcd for[C 15 H 16 NO] + 226.1226, found 226.1226.

[0097] Example 20: Synthesis of 4-(1E,3E,5E)-6-(4-methoxyphenyl)hexa-1,3,5-trien-1-yl)-1-methylpyridin-1-ium iodide (Compound 20)

[0098]

[0099] According to the method for synthesizing compound 1, compound 20 was prepared from 1,4-dimethylpyridinium iodide and (2E,4E)-5-(4-methoxyphenyl)pentanal to obtain 117 mg of a dark red solid with a yield of 57.7%. 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=6.8Hz,2H),8.08(d,J=7.0Hz,2H),7.76(dd,J=15.4,11.0Hz,1H),7.53(d,J=8.8Hz,2H),7.04(dd,J=15 .4,10.7Hz,1H),6.96(d,J=8.8Hz,2H),6.89(t,J=5.4Hz,1H),6.86–6.78(m,2H),6.68(dd,J=14.4,11.0Hz,1H),4.21(s,3H),3.79(s,3H). 13C NMR(101MHz,DMSO-d6)δ160.27,152.87,145.26,142.48,142.35,137.50,131 .48,129.74,129.07,126.98,126.11,123.46,114.91,55.83,47.26.HRMS:m / z calcd.for[C 19 H 20 NO] + 278.1539, found 278.1539.

[0100] Example 21: Synthesis of (E)-2-(4-(dimethylamino)phenylvinyl)-4,6-dimethylpyran tetrafluoroborate (Compound 21)

[0101]

[0102] According to the method for synthesizing compound 1, compound 21 was prepared from 2,4,6-trimethylpyran tetrafluoroborate and 4-(dimethylamino)benzaldehyde to obtain 245.3 mg of a dark blue solid with a yield of 71.9%. 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=15.3Hz,1H),7.75(d,J=8.8Hz,2H),7.68(s ,2H),7.12(d,J=15.2Hz,1H),6.90(d,J=9.0Hz,2H),3.15(s,6H),2.62(s,6H). 13 C NMR(151MHz,DMSO-d6)δ171.12,160.76,154.28,151.87,133.58,122.37,116.35,115.05,112.61,20.29.HRMS:m / z calcd.for[C 17 H 20 NO] + 341.1545, found 254.1538.

[0103] Example 22: Synthesis of 2-((1E,3E)-4-(4-(dimethylamino)phenyl)buta-1,3-dien-1-yl)-4,6-dimethylpyran tetrafluoroborate (Compound 22)

[0104]

[0105] According to the method for synthesizing compound 1, compound 22 was prepared from 2,4,6-trimethylpyran tetrafluoroborate and (E)-3-(4-dimethylaminophenyl)acrolein to obtain 127 mg of a dark green solid with a yield of 34.6%.1 H NMR (400MHz, DMSO-d6) δ8.24(dd,J=14.6,11.1Hz,1H),7.73(s,2H),7.64(d,J=8.9Hz,2H),7.38(d,J=14.8Hz, 1H),7.26(dd,J=14.8,11.1Hz,1H),6.81(d,J=9.1Hz,2H),6.61(d,J=14.6Hz,1H),3.09(s,6H),2.63(s,6H).. 13 C NMR (151MHz, DMSO-d6) δ171.92,161.64,153.70,153.21,150.95,131.69,123.48,123.22,121.22,114.40,112.23,20.35..HRMS:m / z calcd.for[C 19 H 22 NO] + 280.1696, found 280.1696.

[0106] Example 23: Synthesis of 2-(1E,3E,5E)-6-(4-(dimethylamino)phenyl)hexa-1,3,5-trien-1-yl)-4,6-dimethylpyran tetrafluoroborate (Compound 23)

[0107]

[0108] According to the method for synthesizing compound 1, compound 23 was prepared from 2,4,6-trimethylpyran tetrafluoroborate and (2E,4E)-5-(4-(dimethylamino)phenyl)pentanal to obtain 98.2 mg of a dark blue solid with a yield of 50%. 1 H NMR (400MHz, DMSO-d6) δ8.17(dd,J=14.7,11.6Hz,1H),7.78(s,2H),7.52(d,J=8.5Hz,2H),7.24(dd,J=25.6,14.9 HRMS: m / z calcd for[C 21 H 24 NO] + 306.1852, found 306.1851.

[0109] Example 24: Synthesis of (E)-4-(4-(dimethylamino)phenylvinyl)-1-(3-sulfopropyl)pyridin-1-ium salt (Compound 24)

[0110]

[0111] According to the method for synthesizing compound 1, compound 24 was prepared from 4-methyl-1-(3-sulfopropyl)pyridin-1-ium and 4-dimethylaminobenzaldehyde to obtain 224 mg of a red solid with a yield of 64.5%. 1 H NMR (600MHz, DMSO-d6) δ8.78(d,J=6.6Hz,2H),8.06(d,J=6.6Hz,2H),7.92(d,J=16.1Hz,1H),7.60(d,J=8.9Hz,2H),7.18(d,J= 16.1Hz,1H),6.79(d,J=8.8Hz,2H),4.55(t,J=7.0Hz,2H),3.02(s,6H),2.43(t,J=7.1Hz,2H),2.19(p,J=7.1Hz,2H).HRMS:m / z calcd for[C 18 H 23 O3N2S] + 347.14239, found 347.14206.

[0112] Example 25: Synthesis of 4-((1E,3E)-4-(4-(dimethylamino)phenyl)buta-1,3-dien-1-yl)-1-(3-sulfopropyl)pyridin-1-ium salt (Compound 25)

[0113]

[0114] According to the method for synthesizing compound 1, compound 25 was prepared from 4-methyl-1-(3-sulfopropyl)pyridin-1-ium and 4-dimethylaminocinnamaldehyde to obtain 59 mg of a purple solid with a yield of 30.2%. 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=6.4Hz,2H),8.04(d,J=6.5Hz,2H),7.80(dt,J=15.6,4.9Hz,1H),7.47(d,J=8.4Hz,2H),7.01(d ,J=5.0Hz,2H),6.73(d,J=9.2Hz,3H),4.56(t,J=6.8Hz,2H),2.99(s,6H),2.42(t,J=7.0Hz,2H),2.19(p,J=6.9Hz,2H).HRMS:m / z calcd for[C 20 H 25O3N2S] + 373.15804, found 373.15759.

[0115] Example 26: Synthesis of 4-(1E,3E,5E)-6-(4-(dimethylamino)phenyl)hexa-1,3,5-trien-1-yl)-1-(3-sulfopropyl)pyridin-1-ium salt (Compound 26)

[0116]

[0117] According to the method for synthesizing compound 1, compound 26 was prepared from 4-methyl-1-(3-sulfopropyl)pyridin-1-ium and (2E,4E)-5-(4-(dimethylamino)phenyl)pentanal to obtain 77.5 mg of a dark purple solid with a yield of 38.8%. 1 H NMR(600MHz,DMSO-d6)δ8.81(d,J=6.5Hz,2H),8.05(d,J=6.7Hz,2H),7.75(d d,J=15.4,11.1Hz,1H),7.41(d,J=8.4Hz,2H),6.94–6.89(m,2H),6.82(d,J= 14.1Hz,1H),6.76–6.67(m,3H),6.60(t,J=12.1Hz,1H),4.57(t,J=7.0Hz,2H ),2.96(s,6H),2.42(t,J=7.1Hz,2H),2.19(p,J=7.1Hz,2H).HRMS:m / zcalcd for[C 22 H 27 O3N2S] + 399.17369, found 399.17340.

[0118] Example 27: Synthesis of (E)-N,N-dimethylamino-4-(2-(pyridin-4-yl)vinyl)aniline (Compound 27)

[0119]

[0120] 4-Dimethylaminobenzaldehyde (150 mg, 1 mmol), 4-methylpyridine (111.6 mg, 1.2 mmol), potassium tert-butoxide (134 mg, 1.2 mmol) were weighed and dissolved in 10 mL of anhydrous N,N-dimethylaminoformamide solution, and refluxed at 80°C for 6 h. The mixture was cooled to room temperature, the precipitate was filtered, and washed with ethanol to obtain 72.3 mg of purified light yellow solid compound 27 with a yield of 32.3%. 1H NMR (400MHz, CDCl3) δ8.51(d,J=5.5Hz,2H),7.44(d,J=8.8Hz,2H),7.33(d,J=5.9Hz,2 H),7.25(d,J=16.1Hz,1H),6.80(d,J=16.2Hz,1H),6.71(d,J=8.8Hz,2H),3.01(s,6H). 13 CNMR(151MHz, CDCl3)δ150.91,149.92,145.82,133.58,128.42,124.35,121.21,120.50,112.29,40.37.HRMS:m / z calcd for[C 15 H 17 N2] + 225.1385, found 225.1385.

[0121] Example 28: Synthesis of N,N-dimethylamino-4-((1E,3E)-4-(pyridin-4-yl)buta-1,3-dien-1-yl)aniline (Compound 28)

[0122]

[0123] According to the method for synthesizing compound 27, compound 28 was prepared from 4-dimethylaminocinnamaldehyde (175 mg, 1 mmol) and 4-methylpyridine (111.6 mg, 1.2 mmol) to obtain 96 mg of a yellow solid with a yield of 38.4%. 1 H NMR (600MHz, CDCl3) δ8.50(d,J=5.2Hz,2H),7.36(d,J=8.9Hz,2H),7.28(d,J=5.3Hz,2H),7.14(dd,J=15.5,10.0Hz,1 H), 6.79 (dd, J = 15.4, 10.0Hz, 1H), 6.73 (d, J = 15.5Hz, 1H), 6.69 (d, J = 8.8Hz, 2H), 6.47 (d, J = 15.5Hz, 1H), 3.00 (s, 6H). 13 C NMR (151MHz, CDCl3) δ150.60,149.41,145.80,136.84,135.05,128.09,126.77,124.97,123.85,120.48,112.28,40.33.HRMS:m / zcalcd for[C 17 H 19 N2] + 251.1542, found 251.1543.

[0124] Example 29: Synthesis of N,N-dimethylamino-4-((1E,3E,5E)-6-(pyridin-4-yl)hexa-1,3,5-trien-1-yl)aniline (Compound 29)

[0125]

[0126] According to the method for synthesizing compound 27, compound 29 was prepared from (2E,4E)-5-(4-(dimethylamino)phenyl)penta-2,4-dienal (201 mg, 1 mmol) and 4-methylpyridine (111.6 mg, 1.2 mmol) to obtain 46.6 mg of an orange solid with a yield of 36.7%. 1 H NMR (400MHz, CDCl3) δ8.51(d,J=6.2Hz,2H),7.33(d,J=8.8Hz,2H),7.24(d,J=6.3Hz,2H),7.06(dd,J=15.5,10.8Hz,1H) ,6.74(d,J=10.6Hz,1H),6.68(d,J=8.8Hz,2H),6.65–6.55(m,2H),6.43(dt,J=14.8,5.0Hz,2H),2.99(s,6H).HRMS:m / z calcd for[C 19 H 21 N2] + 277.1699, found 277.1699.

[0127] Example 30: Synthesis of (E)-N,N-dimethylamino-4-(2-(pyridin-2-yl)vinyl)aniline (Compound 30)

[0128]

[0129] According to the method for synthesizing compound 27, compound 30 was prepared from 4-dimethylaminobenzaldehyde (150 mg, 1 mmol) and 2-methylpyridine (111.6 mg, 1.2 mmol) to obtain 44.7 mg of a light yellow solid with a yield of 20.4%. 1 H NMR (600MHz, CDCl3) δ8.56(ddd,J=4.9,1.9,0.9Hz,1H),7.62(td,J=7.7,1.9Hz,1H),7.56(d,J=16.0Hz,1H),7.48(d,J=8.6H z,2H),7.34(d,J=7.9Hz,1H),7.07(ddd,J=7.5,4.8,1.1Hz,1H),6.99(d,J=16.0Hz,1H),6.72(d,J=8.9Hz,2H),3.00(s,6H).13 C NMR (151MHz, DMSO-d6) δ155.74,150.32,149.20,136.50,132.38,128.13,123.98,122.95,121.41,121.24,112.04.HRMS:m / z calcd.for[C 15 H 17 N2] + 225.1386, found 225.1386.

[0130] Example 31: Synthesis of (E)-N,N-dimethylamino-5-(2-(pyridin-4-yl)vinyl)pyridin-2-amine (Compound 31)

[0131]

[0132] According to the method for synthesizing compound 27, compound 31 was prepared from 6-(dimethylamino)nicotinaldehyde (73 mg, 0.5 mmol) and 4-methylpyridine (56 mg, 0.6 mmol) to obtain 67 mg of an orange solid with a yield of 55%. 1 H NMR (600MHz, CDCl3) δ8.53(d,J=6.0Hz,2H),8.27(d,J=2.4Hz,1H),7.72(dd,J=9.0,2.4Hz,1H),7.33(d,J=6.2Hz ,2H),7.21(d,J=16.3Hz,1H),6.79(d,J=16.3Hz,1H),6.56(d,J=8.9Hz,1H),3.15(s,6H).HRMS:m / zcalcd.for[C 14 H 16 N3] + 226.1335, found 226.1338.

[0133] Example 32: Synthesis of (E)-4-(4-methoxyphenylvinyl)pyridine (Compound 32)

[0134]

[0135] According to the method for synthesizing compound 27, compound 32 was prepared from p-methoxybenzaldehyde (136 mg, 1 mmol) and 4-methylpyridine (111.6 mg, 1.2 mmol) to obtain 70 mg of a light yellow solid with a yield of 33.2%. 1H NMR (400MHz, CDCl3) δ8.54(d,J=5.4Hz,2H),7.48(d,J=8.6Hz,2H),7.34(d,J=5 .3Hz,2H),7.26(d,J=13.0Hz,2H),6.91(d,J=8.5Hz,2H),3.84(s,3H).HRMS:m / z calcd.for[C 14 H 14 NO] + 212.0677, found 212.0699.

[0136] Example 33: Synthesis of N,N-dimethylamino-4-(pyridin-4-yl)aniline (Compound 33)

[0137]

[0138] Weigh 4-bromo-N,N-dimethylaniline (600 mg, 3 mmol), 4-pyridine boronic acid (490 mg, 4 mmol) and tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol) in a 100 mL round-bottom flask, add 15 mL of 1,4-dioxane to completely dissolve it, then add potassium carbonate solution (1260 mg, 9 mmol) drop by drop, and reflux at 110 ° C for 12 hours under nitrogen protection. After the reaction is completed, the organic solvent is removed by rotary evaporation, and the organic phase is combined and dried after extraction with dichloromethane. 179 mg of beige solid is obtained by column separation, with a yield of 30.1%. 1 H NMR (600MHz, CDCl3) δ8.55(d,J=5.0Hz,2H),7.57(d,J=8.9Hz,2H),7.47(d,J=6.3Hz,2H),6.78(d,J=8.9Hz,2H),3.02(s,6H).HRMS:m / z calcd.for[C 13 H 15 N2] + 199.12298, found 199.12317.

[0139] Example 34: Synthesis of N,N-dimethylamino-[3,4'-bipyridine]-6-amine (Compound 34)

[0140]

[0141] According to the method for synthesizing compound 33, compound 34 was prepared from 5-bromo-2-(N,N-dimethyl-1-)pyridine (600 mg, 3 mmol) and 4-pyridineboronic acid (490 mg, 4 mmol) as an off-white solid (324 mg), with a yield of 54.3%. 1H NMR (600MHz, CDCl3) δ8.58 (d, J = 5.7Hz, 2H), 8.52 (d, J = 2.5Hz, 1H), 7.74 (dd, J = 8. 9,1.9Hz,1H),7.44(d,J=5.6Hz,2H),6.59(d,J=8.9Hz,1H),3.15(s,6H).HRMS:m / z calcd.for[C 12 H 14 N3] + 200.11822, found 200.11853.

[0142] Example 35: Synthesis of 4-(4-(dimethylamino)phenyl)-1-methylpyridinium-1-iodonium salt (Compound 35)

[0143]

[0144] Weigh compound 33 (100 mg, 0.5 mmol) into a 100 mL round-bottom flask, add 60 μL of iodomethane solution, and stir at room temperature for 12 h. After cooling to room temperature, solid precipitates, which is filtered and washed with petroleum ether to obtain 79 mg of orange-yellow solid, with a yield of 46.5%. 1 H NMR (600MHz, CDCl3) δ8.85(m,2H),7.99(d,J=5.7Hz,2H),7.74(d,J=8.2Hz,2H),6.76(d,J=8.2Hz,2H),4.46(s,3H),3.11(s,6H).HRMS:m / z calcd.for[C 13 H 17 N2] + 213.13863, found 213.13882.

[0145] Example 36: Synthesis of 6-(dimethylamino)-1'-methyl-[3,4'-bipyridine]-1'-iodonium salt (Compound 36)

[0146]

[0147] According to the method for synthesizing compound 35, compound 36 was prepared from compound 34 (80 mg, 0.4 mmol) and iodomethane (50 μL, 0.8 mmol) as a brown-yellow solid (53.1 mg) with a yield of 38.9%. 1H NMR (600MHz, CDCl3) δ8.91(d,J=6.6Hz,2H),8.68(d,J=2.7Hz,1H),8.04(d,J=6.4Hz, 2H),7.94(d,J=9.2Hz,1H),6.65(d,J=9.2Hz,1H),4.51(s,3H),3.22(s,6H).HRMS:m / z calcd.for[C 13 H 16 N3] + 214.13387, found 214.13417.

[0148] Example 37: Synthesis of 4-((1E,3E)-4-(4-(2-hydroxyethyl)(methyl)amino)phenyl)buta-1,3-dien-1-yl)-1-methylpyridin-1-ium iodide (Compound 37)

[0149]

[0150] According to the method for synthesizing compound 1, compound 37 was prepared from 1,4-dimethylpyridinium iodide and (E)-3-(4-(2-hydroxyethyl)(methyl)aminophenyl)acrolein to obtain 19.7 mg of dark purple crystals with a yield of 26.7%. 1 H NMR (600MHz, DMSO-d6) δ8.69(d,J=7.0Hz,2H),8.02(d,J=7.1Hz,2H),7.45(d,J=8.6Hz,2H),6.99(d,J=4.0Hz,1H),6.79(d,J=8.6Hz,2H ),6.75–6.71(m,3H),4.77–4.69(s,1H),4.17(s,3H),3.56(dt,J=11.4,5.6Hz,2H),3.48(dt,J=20.2,6.1Hz,2H),3.00(s,3H).HRMS:m / z calcd for[C 19 H 23 N2O] + 295.1905, found 295.30.

[0151] Example 38: Synthesis of 2-(methyl(4-((1E,3E)-4-(pyridin-4-yl)buta-1,3-dien-1-yl)phenyl)amino)ethanol (Compound 38)

[0152]

[0153] According to the method for synthesizing compound 27, compound 38 was prepared from 4-methylpyridine and (E)-3-(4-(2-hydroxyethyl)(methyl)aminophenyl)acrolein to obtain 24.6 mg of a yellow solid with a yield of 43.9%. 1 H NMR (600MHz, CDCl3) δ8.48(d,J=5.2Hz,2H),7.31(d,J=8.9Hz,2H),7.24(d,J=5. 4Hz,2H),7.06(dd,J=15.5,10.0Hz,1H),6.79(dd,J=15.4,10.0Hz,1H),6.73(d,J =15.5Hz,1H),6.69(d,J=8.8Hz,2H),6.47(d,J=15.5Hz,1H),3.00(s,6H)3.41(d t,J=11.4,5.6Hz,2H),3.29(dt,J=20.2,6.1Hz,2H),2.99(s,3H).HRMS:m / zcalcd for[C 18 H 20 N2O] + 280.1576, found 280.20

[0154] Example 39: Determination of Optical Properties of Compounds

[0155] 1. Experimental steps:

[0156] (1) UV absorption spectroscopy: accurately prepare DMSO solutions of compound with gradient concentrations (5-40 μM) and measure the maximum absorption wavelength (λ abs ,nm) and molar extinction coefficient (ε,L·mol -1 cm -1 ).

[0157] (2) Fluorescence spectroscopy: 10 μM solutions of the compounds were prepared in solvents of different polarities (dichloromethane, tetrahydrofuran, methanol, dimethyl sulfoxide and PBS buffer solution). The optimal excitation (λ ex ,nm) and emission spectra (λ em ,nm).

[0158] 2. Experimental results:

[0159] The UV-visible absorption spectrum of compound 1-32 in DMSO solution is single-peaked, and the maximum absorption wavelength is at 330-654nm. As the polyene bond of the compound is extended, its maximum absorption wavelength increases. Among them, the maximum absorption wavelength obtained when N,N-dimethylamino is the electron donor is greater than that of the compound with methoxy as the electron donor, and the maximum absorption wavelength of the compound containing naphthalene ring is greater than that of compounds 1-3, 11-13 containing benzene ring. And the maximum absorption wavelength of the compound containing neutral pyridine ring electron acceptor is the shortest, at 330-418nm. The molar extinction coefficient of the probe is 3930-50327L·mol -1 cm -1 Among them, compound 3 has the largest molar extinction coefficient.

[0160] The results of fluorescence spectrum measurement show that although compound 1-32 has a D-π-A structure, the maximum excitation and emission wavelengths do not change significantly in solvents of different polarities (Table 1), and the maximum excitation and emission wavelengths are the largest in dichloromethane. When the substituents are the same, the fluorescence wavelength is significantly red-shifted as the polyene bond is extended; the maximum emission wavelength of the compound containing N,N-dimethylamino is greater than that of the compound containing methoxy. Compounds 1-26 all have large Stokes shifts (63-286nm).

[0161] Table 1 Optical properties of compounds

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] Example 40: Determination of the affinity of compounds for Tau protein deposition

[0169] 1. Experimental steps:

[0170] (1) Brain paraffin sections were dewaxed by immersion in xylene for 5 min, rinsed with ethanol for 3 min, and finally rinsed with deionized water.

[0171] (2) An inhibition group and a blank control group were set up respectively. The inhibition group contained 10 nM of the test compound. 125I] PND-1 (SPECT imaging agent with high affinity and selectivity for Tau protein reported in the literature) solution (0.2MBq / mL, 10% ethanol), and the blank control group contained only [ 125 I] PND-1 solution (0.2 MBq / mL, 10% ethanol).

[0172] (3) The two solutions were dripped onto the surface of the sliced ​​brain tissue and incubated at room temperature for 60 min. Then, the solution on the tissue surface was discarded and the slices were incubated with 50% ethanol for another 30 min at room temperature. The solution on the tissue surface was discarded again and the slices were rinsed with 40% ethanol solution.

[0173] (4) After drying, place the sections under a phosphor screen and expose them overnight.

[0174] (5) Scan and read the image using a phosphor screen imaging system.

[0175] (6) Calculate the inhibition rate (% Inhib.) based on the semi-quantitative results of the images.

[0176] 2. Experimental results:

[0177] As an example, some of the synthesized compounds were extracted and tested. The experimental results are shown in Table 2. The compounds 1-3, 5, 7, 20-23 of the present invention all showed an effect on [ 125 I] PND-1 had a certain inhibitory effect (11-47%), indicating that compounds 1-3, 5, 7, 20-23 all have a certain affinity with Tau protein. This result is also consistent with Figure 2 The results of fluorescent staining shown in are consistent. In addition, the inhibition rate of compound 20 (35%) is comparable to that of compound 1 (34%), indicating that within the scope of the compound of formula I defined in the present invention, the change of the electron-donating group (i.e., R1 in the compound of formula I) does not significantly affect the affinity of the compound to the Tau protein. Similarly, compounds 12 and 15 have similar inhibition rates, and compounds 2 and 12 also have comparable inhibition rates, indicating that within the scope of the compound of formula I defined in the present invention, the change of Ar1 and Ar2 does not significantly affect the affinity of the compound to the Tau protein.

[0178] Table 2 Affinity data of compounds to Tau protein fibrils.

[0179]

[0180]

[0181] Example 41: In vitro fluorescence staining experiment

[0182] 1. Experimental steps:

[0183] (1) Prepare a 10% ethanol solution of the test compound to a final concentration of 1 μmol / L;

[0184] (2) The brain paraffin sections were dewaxed by immersion in xylene for 5 min, rinsed with ethanol for 3 min, and finally rinsed with deionized water.

[0185] (3) Add the prepared solution dropwise onto the slices, ensuring that the solution completely covers the brain tissue, and incubate at room temperature for 5 min.

[0186] (4) The surface of the brain slices was rinsed with 100% ethanol and then with deionized water, and then observed and photographed under a fluorescence microscope.

[0187] 2. Experimental results:

[0188] The staining results are as follows Figure 2-Figure 3 As shown, the compounds 1-3, 5, 7-9, 11-12, 16, 22-23, 24-28, 30-32, 37-38 provided by the present invention (corresponding to Figure 2-Figure 3 Probes 1-3, 5, 7-9, 11-12, 16, 22-23, 24-28, 30-32, 37-38) can clearly and selectively mark pathological Tau protein deposits in brain tissues of AD patients (female, 102 years old), including neurofibrillary tangles (NFTs), neuritic plaques (NPs) and neuropil filaments (NTs). It is worth noting that as the number of double bonds increases, the wavelength gradually becomes longer, covering the 350-670nm band, which can be adapted to a variety of fluorescence microscopes. In addition, Figure 3 As shown, compounds 27-28, 30-32 can mark Aβ plaques in brain tissues of AD patients in DAPI and GFP bands.

Claims

1. A compound of formula I, characterized in that Formula I is Ar1-(C=C) n -Ar2, Ar1 is selected from the group consisting of: Where Ar1 is relative to -(C=C) n - is substituted at the para position with R1, R1 is selected from the group consisting of: halogen, -NC 1-4 Alkyl, -NC 1-4 Halogenated alkyl, -NC 1-4 Alkyl alcohol, -NC 1-4 Alkyl sulfonate, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -OC 1-4 Alkyl alcohol and -OC 1-4 Alkyl sulfonates; Ar2 comprises an aromatic ring selected from the group consisting of: and optionally a counterion, wherein Y is N and has no substitution thereon, or Y is N + and R2 is substituted thereon, or Y is O + and thereon without substitution, wherein each occurrence of R2 is independently selected from the group consisting of: -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkyl alcohol and -C 1-4 Alkyl sulfonates, and The aromatic ring is substituted with one or more R3 at positions other than Y, and R3 is independently selected from the group consisting of: -H, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkyl alcohol and -C 1-4 Alkyl sulfonates.

2. The compound according to claim 1, characterized in that R1 is selected from the group consisting of: -NC 1-4 Alkyl, -NC 1-4 Alkyl alcohol and -OC 1-4 Alkyl, preferably, R1 is -N(CH3)2, -OCH3 or -N(CH3)CH2CH2OH.

3. The compound according to claim 1 or 2, characterized in that The aromatic ring is wherein Y is N with no substitution thereon, and R3 is -H; or Where Y is N + and substituted thereon with R2, and R3 at each occurrence is independently -H, methyl, ethyl, halomethyl or haloethyl, wherein R2 at each occurrence is independently selected from the group consisting of: -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkyl alcohol and -C 1-4 Alkyl sulfonates; or Where Y is O + and thereon is no substitution, and R3 at each occurrence is independently -H, methyl, ethyl, halomethyl or haloethyl, Preferably, the aromatic ring is 4. The compound according to claim 3, characterized in that R2 is independently selected at each occurrence from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methanesulfonate (-CH2SO3 - ), ethyl sulfonate (-(CH2)2SO3 - ), n-propyl sulfonate (-(CH2)3SO3 - ), isopropyl sulfonate (-C(CH3)2SO3 - ), n-butyl sulfonate (-(CH2)4SO3 - ) and tert-butyl sulfonate (-C(CH3)2CH2SO3 - ), preferably, R2 is methyl or -(CH2)3SO3 - .

5. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

6. The isotope-labeled compound of any one of claims 1 to 5, characterized in that The isotope-labeled compound is formed by reacting the compound of formula I with D, 3 H, 11 C, 13 C, 14 C, 123 I, 124 I, 125 I, 131 I or 18 F isotope labeling.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 5 or the isotope-labeled compound according to claim 6, and optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

8. A kit, characterized in that: The kit comprises the compound according to any one of claims 1 to 5, the isotope-labeled compound according to claim 6, or the composition according to claim 7 as an active ingredient.

9. A reagent for diagnosing or detecting a nervous system disease caused by abnormal deposition of amyloid aggregates, characterized in that: The reagent comprises the compound according to any one of claims 1 to 5, the isotope-labeled compound according to claim 6, or the composition according to claim 7 as an active ingredient. Preferably, the amyloid protein is pathological phosphorylated Tau protein.

10. The reagent according to claim 9, characterized in that The disease is selected from the group consisting of: Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), primary age-related tauopathy (PART), Pick's disease, corticobasal degeneration (CBD), glial globular inclusion tauopathy (GGT), amyotrophic lateral sclerosis (ALS) and dementia with Lewy bodies (DLB).

11. Use of the compound according to any one of claims 1 to 5, the isotope-labeled compound according to claim 6, or the composition according to claim 7 in the preparation of a medicament for treating and / or preventing a disease selected from the group consisting of: Alzheimer's disease (AD), Down syndrome (DS), cognitive deficits in schizophrenia and other neurodegenerative tauopathies such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE) and Pick's disease.

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