WO2024001967A1 - Imidazonaphthyridine compound with affinity with tau protein, method for preparing same, and use thereof - Google Patents

Abstract

The present invention relates to the technical field of radiopharmaceutical chemistry and clinical nuclear medicine, and in particular, to an imidazonaphthyridine compound with affinity with a Tau protein, a method for preparing same, and use thereof. The imidazonaphthyridine compound has a structure represented by general formula (I). After being marked by radionuclide, the compound and a derivative thereof can be used for clinical nuclear medicine diagnosis of neurodegenerative diseases, particularly used for diagnosing diseases with Tau protein deposition characteristics including Alzheimer's Disease. The structure of the compound is represented by general formula (I).

Description

Imidazonaphthyridine compounds with affinity to Tau protein and preparation methods and applications thereof

cross reference

This application claims the priority of Chinese patent application No. 202210744927.0, titled "Imidazonaphthyridine compounds with affinity to Tau protein and their preparation methods and applications" submitted on June 27, 2022, and all its disclosures are approved This reference is incorporated into this article in its entirety.

Technical field

The present invention relates to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine. Specifically, it relates to an imidazonaphthyridine compound with high affinity to Tau protein and its preparation method and application.

Background technique

Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by dementia. The condition is progressive and irreversible. There is currently no mechanism for treatment and accurate diagnosis. From the initial diagnosis to the final death, the condition will continue to intensify.

According to the World Alzheimer's Disease Report 2018, there are approximately 50 million people with dementia worldwide, and this number is expected to grow to 152 million by 2050. In China, there are 15.07 million dementia patients aged 60 and above, including 9.83 million Alzheimer's disease. The prevalence rate of mild cognitive impairment is 15.54%, and the number of patients reaches 38.77 million. At present, AD has become a serious threat to human health after tumors, heart disease, stroke, and diabetes. Therefore, early prevention and diagnosis of AD and other neurodegenerative diseases are essential for patients, and research in this area is of extremely important significance.

The pathogenesis of AD is relatively complex. Studies have shown that the two major pathological biomarkers of AD are plaques formed by amyloid beta peptides (Aβ) deposition outside nerve cells and hyperphosphorylated Tau protein within nerve cells. of neurofibrillary tangles.

At present, research on molecular probes targeting Aβ is relatively mature, but using Aβ as the diagnostic standard often leads to false positives because the degree of Aβ deposition is not positively correlated with the development of the disease. On the contrary, Tau protein has a good correlation with the development of the disease. Therefore, for the diagnosis of AD, Tau protein (neurofibrillary tangles in the brain) is regarded as a more ideal target than Aβ.

At present, some molecular probes targeting Tau protein have been released, such as [ ¹⁸ F]T807, [ ¹⁸ F]MK6240, [ ¹¹ C]PBB3 and [ ¹⁸ F]THK5351, etc. However, they all have their own shortcomings. In clinical experiments, [ ¹⁸ F]T807, [ ¹⁸ F]MK6240 and [ ¹⁸ F]THK5351 all off-target MAO-B, while [ ¹¹ C]PBB3 has the ability to target Tau protein. High activity and selectivity, but unstable in vivo. Therefore, the development of Tau protein molecular probes with high activity, high selectivity and high affinity is a current research hotspot.

Contents of the invention

In view of the problems existing in the existing Tau protein molecular probes, the present invention proposes an imidazonaphthyridine compound with high affinity to Tau protein and its preparation method and application. This compound has high affinity and selectivity for Tau protein. After labeling it with a suitable radioactive isotope, it can be used for nuclear medicine imaging, especially for patients with Tau protein deposition characteristics, including Alzheimer's disease. Diagnosis of patients with neurodegenerative diseases.

In the first aspect, the imidazonaphthyridine compound provided by the invention has the following general formula (I) structure:

in:

X ₁ ~ X ₇ independently represent N or CH;

R ₁ is located at positions 1 and 2, R ₂ is located at positions 3 and 4;

R ₁ and R ₂ independently represent H, Where R ₃ represents ^123/125/127 I, ^18/19 F, OH, O ^11/12 CH ₃ , (OCH ₂ CH ₂ ) _m ^18/19 F, m is an integer between 1-6.

As a preferred solution, in the structure of general formula (I), X ₁ , X ₃ and X ₆ all represent N, that is, the imidazonaphthyridine compounds provided by the present invention have the following structure of general formula (II):

Among them, X ₂ , X ₄ , X ₅ , X ₇ , R ₁ and R ₂ are defined as above.

As a preferred solution, in the structure of general formula (I) and the structure of general formula (II), R ₁ is located at position 1.

As a preferred solution, in the structure of general formula (I) and the structure of general formula (II), R ₂ is located at the 3-position.

As a preferred solution, in the structure of general formula (I) and the structure of general formula (II), R ₁ represents

As a preferred solution, in the structure of general formula (I) and the structure of general formula (II), R ₂ represents H.

As a preferred solution, in the structure of general formula (I) and the structure of general formula (II), R ₃ represents ^123/125/127 I, ^18/19 F, O ^11/12 CH ₃ , (OCH ₂ CH ₂ ) _m ^18/ 19F.

As a preferred solution, in the structure of general formula (I) and the structure of general formula (II), m is an integer between 1 and 3.

As a preferred solution, in the structure of general formula (I), X ₁ , X ₃ and X ₆ all represent N, X ₂ represents C, and X ₄ , X ₅ and X ₇ all represent CH.

As a preferred solution, in the structure of general formula (II), X ₂ represents C, and X ₄ , X ₅ and X ₇ all represent CH.

The compound of general formula (I) with a naphthyridimidazole structure as the main body provided by the invention can be used as a radioactive drug with high affinity for neurofibrillary tangles (Tau protein deposition) ( ¹⁸ F, ¹¹ C or ^123/125 I, Used for PET or SPECT imaging) to achieve early diagnosis of Tau protein-related diseases, especially Alzheimer's disease.

Preferably, the compound of general formula (I) is selected from the following compounds:

Among them, I in compound 1-4, compound 14-17, and compound 19 is ¹²³ I, ¹²⁵ I or ¹²⁷ I;

F in compound 5-13 and compound 18 is ¹⁸ F or ¹⁹ F.

The above preferred compounds have higher activity, higher affinity and selectivity for Tau protein.

In a second aspect, the present invention provides a method for preparing preferred imidazonaphthyridine compounds, including:

When I is ¹²³ I or ¹²⁵ I, compounds 1-4, 14-17, and 19 are prepared from trialkyl tin, trialkyl silicon, boric acid or borate ester precursor compounds and [ ^123/125 I]NaI solution in Obtained by reaction in the presence of oxidizing agent;

When F is ¹⁸ F, compounds 5-13 and 18 are reacted by OTs, trimethyl quaternary ammonium salt, boric acid, borate ester or hypervalent iodine prosthetic group precursor compound and [ ¹⁸ F]F anion in the presence of a phase transfer catalyst get.

In a third aspect, the present invention also provides derivatives of the above-mentioned imidazonaphthyridine compounds, which are pharmaceutically acceptable salts, esters or amide compounds or prodrugs of the compounds represented by the general formula (I).

In a fourth aspect, the present invention also provides a diagnostic or detection reagent for neurofibrillary tangle diseases caused by Tau protein deposition, the active ingredient of which is a compound represented by formula (I), and/or a derivative thereof.

These diseases include, but are not limited to, Alzheimer's disease, frontotemporal degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, or Pick's disease.

In a fifth aspect, the present invention further provides the use of the compound represented by formula (I) and/or its derivatives in the preparation of nuclear medicine imaging agents.

Specifically, the nuclear medicine imaging agent is PET or SPECT imaging agent.

Compared with the prior art, the present invention has the following advantages:

The compound shown in (I) provided by the present invention has high affinity and selectivity for Tau protein. After labeling it with a suitable radioactive isotope, it can be used for nuclear medicine imaging, especially suitable for patients including Alzheimer's disease. Diagnosis of patients with neurodegenerative diseases characterized by tau protein deposition, including tau protein deposition.

Description of drawings

Figure 1 is a schematic diagram of the synthesis process of compounds in Examples 1-20 of the present invention, in which the reaction reagents and conditions involved are:

(a) Sodium bicarbonate, ethanol, reflux, overnight; (b) n-hexabutyldistin, tetrakistriphenylphosphine palladium, toluene, 110°C, nitrogen protection, 10 hours; (c) Na ¹²⁵ I, 3% hydrogenated Hydrogen oxide, 1M hydrochloric acid, room temperature, 15 minutes; (d) ¹⁸ F ^- , tetraethylammonium bicarbonate, Cu(OTf) ₂ (Py) ₄ , n-butanol, dimethylacetamide, 110°C, 20 minutes ; (e) 1-bromo-2 fluoroethane, cesium carbonate, DMF, 80°C, overnight; (f) bromoethanol or 2-(2-chloroethoxy)ethanol or chloro-dipolyethylene glycol, Cesium carbonate, DMF, 80℃, overnight; (g) p-toluenesulfonyl chloride, triethylamine, methylene chloride, room temperature, 7 hours; (h) Tetrabutylammonium fluoride, tetrahydrofuran, 60℃, 2 hours ; (i) ¹⁸ F ^- , K ₂₂₂ /K ₂ CO ₃ , acetonitrile, 100°C, 10 minutes.

Figure 2 is a schematic diagram of the synthesis process of the compounds of Examples 21-30 of the present invention. The reaction reagents and conditions involved are:

(a) Sodium bicarbonate, ethanol, reflux, overnight; (b) Trimethylamine, trifluoroacetic anhydride, methylene chloride, room temperature, half an hour; (c) Tetrabutylammonium fluoride, acetonitrile, 60°C, 2 hours ; (d) ¹⁸ F ^- , tetrabutylammonium bicarbonate, DMSO, 100°C, 6 minutes; (e) mCPBA, methylene chloride, room temperature, 2 hours; (f) (1) NaH, anhydrous tetrahydrofuran, ice Bath, 1 hour; (2) Diethylene glycol, 140°C, 4 hours; (g) p-Toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature, 5 hours (h) ¹⁸ F ^- , K ₂₂₂ /K ₂ CO ₃ , acetonitrile, 100°C, 5 minutes.

Figure 3 is a schematic diagram of the synthesis process of compounds in Examples 31-39 of the present invention, in which the reaction reagents and conditions involved are:

(a) Sodium bicarbonate, ethanol, reflux, overnight; (b) Trifluoroacetic acid, methylene chloride, room temperature, 3 hours; (c) 1-bromo-3-fluoropropane or 3-bromo-1-propanol, Cesium carbonate, acetonitrile, 80°C, 10 hours; (d) p-toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature, 7 hours; (e) ¹⁸ F ^- , K ₂₂₂ /K ₂ CO ₃ , acetonitrile , 100°C, 10 minutes; (f) mCPBA, dichloromethane, room temperature, 2 hours; (g) Trimethylamine, trifluoroacetic anhydride, dichloromethane, room temperature, half an hour; (h) Tetrabutylammonium fluoride , acetonitrile, 60°C, 2 hours; (i) ¹⁸ F ^- , tetrabutylammonium bicarbonate, DMSO, 100°C, 6 minutes.

Figure 4 is a schematic diagram of the synthesis process of compounds in Examples 40-51 of the present invention, in which the reaction reagents and conditions involved are:

(a) Ethanol, reflux, 3 hours; (b) DMF, 130°C, 2 hours; (c) Sodium periodate, THF/H ₂ O (1:1), room temperature, 24 hours; (d) Iron powder , ethanol/water (10:1), concentrated hydrochloric acid; (e) potassium hydroxide, ethanol; (f) n-hexabutyl distin, tetrakis triphenylphosphine palladium, toluene, 110°C, nitrogen protection, 10 hours; ( g) Na ¹²⁵ I, 3% hydrogen peroxide, 1M hydrochloric acid, room temperature, 15 minutes. Figure 5 is a schematic diagram of the synthesis process of compounds of Examples 52-58 of the present invention. The reaction reagents and conditions involved are:

(a) Sodium bicarbonate, ethanol, reflux, overnight; (b) n-hexabutyldistin, tetrakistriphenylphosphine palladium, toluene, 110°C, nitrogen protection, 10 hours; (c) TFA, peroxymonosulfonic acid Potassium, chloroform, ethanol, room temperature, 4 hours; (d) Na ¹²⁵ I, 3% hydrogen peroxide, 1M hydrochloric acid, room temperature, 15 minutes; (e) ¹⁸ F ^- , TEAB, DMSO, 110°C, 10 minutes.

Figure 6 is a schematic diagram of the synthesis process of compounds in Examples 59-61 of the present invention. The reaction reagents and conditions involved are:

(a) NBS, TMS-OTf, acetonitrile, 40°C, half an hour; (b) bis(triphenylphosphine)palladium chloride, potassium carbonate, dioxane, 110°C, overnight; (c) n-hexabutyl Ditin, tetrakistriphenylphosphine palladium, toluene, 110°C, nitrogen protection, 10 hours; (d) Na ¹²⁵ I, 3% hydrogen peroxide, 1M hydrochloric acid, room temperature, 15 minutes.

Figure 7 shows probes [ ¹²⁵ I] 1-3, [ ¹²⁵ I] 8, [ ¹²⁵ I] 54 and [ ¹²⁵ I] 60 in Example 62 of the present invention, and probe [ ¹⁸ F] 4 in Example 64 in AD. Autoradiography results of patient brain tissue sections and their corresponding silver staining or 6E10 staining results (first row, female, 102 years old, temporal lobe), (second row, male, 95 years old, frontal lobe).

Figure 8 is an enlarged view of the autoradiography results of probe [ ^125I ]1 in AD patient brain tissue sections in Example 62 of the present invention and its corresponding silver staining or 6E10 staining results (A and B, female, 102 years old, temporal lobe ), (C and D, male, 95 years old, frontal lobe).

Figure 9 shows the autoradiography results of probe [ ¹²⁵ I] 1 in AD patient brain tissue sections in Example 62 of the present invention (A, male, 95 years old, temporal lobe), (B, male, 97 years old, striatum) , (C, male, 74 years old, frontal lobe), (D, male, 74 years old, temporal lobe), (E, male, 78 years old, temporal lobe), (F, male, 95 years old, hippocampus).

Figure 10 shows the general structural formula of the present invention, the autoradiography results of probe [ ¹⁸ F] 4 in AD patient brain tissue sections in Example 64, and the results of AT8 antibody, 4G8 antibody and silver staining of adjacent sections.

Detailed ways

The following examples are used to illustrate the invention but are not intended to limit the scope of the invention.

Example 1: Synthesis of Compound 1

Compound 8-amino-1,7-naphthyridine (75.0mg, 0.5mmol), 2'-bromo-4-iodoacetophenone (152.1mg, 0.7mmol) and NaHCO ₃ (70.2mg, 0.8mmol) were dissolved in into 20 mL of ethanol, and then heated to reflux in a 90°C oil bath for 6 hours. After the reaction is completed, the ethanol is distilled off under reduced pressure, water is added, and extracted three times with ethyl acetate. After the ethyl acetate is removed under reduced pressure, column chromatography is separated and developed. The volume ratio of the solvent was ethyl acetate: petroleum ether = 9:1, and 96.2 mg of light yellow solid was obtained. Yield 40.5%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.87 (d, J = 4.3Hz, 1H), 8.50 (s, 1H), 8.39 (d, J = 7.2Hz, 1H), 8.26 (d,J＝8.0Hz,1H),7.79(s,4H),7.61(dd,J＝8.1,4.5Hz,1H),7.25(d,J＝7.1Hz,1H).

Example 2: Synthesis of Compound 2

Compound 2 was synthesized as a starting material for 1-aminoisoquinoline according to the synthesis method of Example 1, and 15.2 mg of light yellow product was obtained with a yield of 29.0%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.48 (d, J = 5.7Hz, 1H), 8.42 (d, J = 2.3Hz, 1H), 8.30 (dd, J = 7.2, 2.3Hz,1H),7.84(d,J＝7.2Hz,1H),7.78(d,J＝2.2Hz,4H),7.68–7.58(m,2H),7.24(d,J＝7.2Hz,1H) .

Example 3: Synthesis of Compound 3

According to the method of synthesizing compound 1, compound 3 was synthesized using 2,7-naphthyridin-1-amine as raw material, and 59.6 mg of earthy yellow solid was obtained. The yield was 37.1%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ9.70 (s, 1H), 8.67 (d, J = 5.4Hz, 1H), 8.54–8.50 (m, 2H), 7.80 (s, 5H),7.27(d,J＝7.3Hz,1H).

Example 4: Synthesis of Compound 4

Compound 8-amino-1,7-naphthyridine (100.9mg, 0.7mmol), 2'-bromo-4-fluoroacetophenone (152.0mg, 0.7mmol) and NaHCO ₃ (67.2mg, 0.8mmol) were dissolved in into 50 mL of ethanol, and then heated to reflux in a 90°C oil bath for 5 hours. After the reaction is completed, the ethanol is distilled off under reduced pressure, water is added, and extracted three times with ethyl acetate. After the ethyl acetate is removed under reduced pressure, column chromatography is separated and developed. The volume ratio of the agent was ethyl acetate: methanol = 10:1, and 110.8 mg of white solid was obtained. Yield 79.4%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ ) δ9.00 (d, J = 4.4Hz, 1H), 8.10–8.06 (m, 2H), 8.02 (d, J = 8.0Hz, 1H), 8.00 (d ,J＝7.1Hz,1H),7.87(s,1H),7.50(dd,J＝8.0,4.5Hz,1H),7.10(t,J＝8.6Hz,2H),7.01(d,J＝7.0Hz ,1H).

Example 5: Synthesis of labeled precursor compound 5

Intermediate compound 1 (48.4 mg, 0.1 mmol), tetrakis triphenylphosphine palladium (18.2 mg, 0.016 mmol) and n-hexabutyl distin (0.23 g, 0.4 mmol) were dissolved in 8 mL of toluene, protected by nitrogen, 110°C The reaction was carried out overnight. After the reaction was completed, toluene was distilled off under reduced pressure, dichloromethane was added, suction filtered, dichloromethane was distilled off under reduced pressure, and separated by column chromatography. The volume ratio of the developing agent was petroleum ether: ethyl acetate = 3: 2. 10.2 mg of light yellow solid was obtained, with a yield of 18.7%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ ) δ8.09 (t, J = 8.9Hz, 1H), 7.60 (d, J = 5.6Hz, 1H), 7.57 (s, 1H), 7.55 (d, J ＝6.3Hz,1H),7.37(d,J＝5.8Hz,2H),7.06(dd,J＝6.0,3.5Hz,1H),7.00(t,J＝7.0Hz,2H),6.73(d,J ＝5.7Hz,1H),2.26–2.24(m,4H),2.09–2.05(m,7H),1.86(d,J＝6.3Hz,4H),1.70(t,J＝5.8Hz,12H).

Example 6: Synthesis of labeled precursor compound 6

Intermediate compound 2 (60.1 mg, 0.16 mmol), tetrakis triphenylphosphine palladium (28.1 mg, 0.024 mmol) and n-hexabutyl distin (0.36 g, 0.65 mmol) were dissolved in 9 mL of toluene, protected by nitrogen, 110°C The reaction was carried out overnight. After the reaction was completed, toluene was distilled off under reduced pressure, dichloromethane was added, suction filtered, dichloromethane was distilled off under reduced pressure, and separated by column chromatography. The volume ratio of the developing agent was petroleum ether: ethyl acetate = 3: 1. 14.4 mg of light yellow oily product was obtained with a yield of 16.4%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ ) δ7.96 (d, J = 4.7Hz, 2H), 7.90 (d, J = 7.1Hz, 1H), 7.82 (s, 1H), 7.70 (dd, J ＝5.7,3.2Hz,1H),7.69(s,1H),7.64(s,1H),7.57(d,J＝7.5Hz,1H),7.54(d,J＝7.8Hz,2H),7.51(dd ,J＝5.8,3.2Hz,1H),1.57–1.54(m,5H),1.35–1.32(m,6H),1.10–1.05(m,6H),0.89(t,J＝7.3Hz,11H).

Example 7: Synthesis of labeled precursor compound 7

Intermediate compound 3 (51.5 mg, 0.14 mmol), tetrakis triphenylphosphine palladium (23.4 mg, 0.02 mmol) and n-hexabutyl distin (0.32 g, 0.55 mmol) were dissolved in 10 mL of toluene, protected by nitrogen, 110°C The reaction was carried out overnight. After the reaction was completed, toluene was distilled off under reduced pressure, dichloromethane was added, suction filtered, dichloromethane was distilled off under reduced pressure, and separated by column chromatography. The volume ratio of the developing agent was petroleum ether: ethyl acetate = 8: 1. 21 mg of light yellow oily product was obtained with a yield of 28.1%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ10.06 (s, 1H), 8.71 (d, J = 5.5Hz, 1H), 8.14 (d, J = 7.3Hz, 1H), 7.96 (d, J ＝8.0Hz,2H),7.92(s,1H),7.58(dd,J＝12.6,6.4Hz,3H),7.05(d,J＝7.2Hz,1H),1.58–1.53(m,5H),1.33 (t,J＝8.3Hz,6H),1.11–1.05(m,5H),0.89(t,J＝7.3Hz,11H).

Example 8: Synthesis of Compound 8

Compound 2-aminoquinoline (100.7 mg, 0.7 mmol), 2'-bromo-4-iodoacetophenone (152.8 mg, 0.7 mmol) and NaHCO ₃ (67.0 mg, 0.8 mmol) were dissolved in 30 mL of ethanol, and then Heating and refluxing in a 90°C oil bath for 7 hours. After the reaction is completed, ethanol is distilled off under reduced pressure, water is added, and extracted three times with ethyl acetate. After the ethyl acetate is removed under reduced pressure, column chromatography is separated. The volume of the developing agent is ethyl acetate. Ester: methanol = 10:1, and 133.9 mg of yellow solid was obtained. Yield 51.4%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ9.17 (s, 1H), 8.30 (d, J = 8.4Hz, 1H), 7.95 (d, J = 7.7Hz, 1H), 7.79 (s,4H),7.72(dd,J＝14.7,8.7Hz,2H),7.52(dd,J＝15.7,8.4Hz,2H).

Example 9: Synthesis of labeled precursor compound 9

Intermediate compound 8 (78.3 mg, 0.21 mmol), tetrakis triphenylphosphine palladium (37.6 mg, 0.032 mmol) and n-hexabutyl distin (0.48 g, 0.84 mmol) were dissolved in 8 mL of toluene, protected by nitrogen, 110°C The reaction was carried out overnight. After the reaction was completed, toluene was distilled off under reduced pressure, dichloromethane was added, suction filtered, dichloromethane was distilled off under reduced pressure, and separated by column chromatography. The volume ratio of the developing agent was petroleum ether: ethyl acetate = 3: 1. 18.1 mg of light yellow solid was obtained, with a yield of 16.1%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.30 (s, 1H), 7.94 (t, J = 7.5Hz, 3H), 7.78 (d, J = 7.9Hz, 1H), 7.62 (dd, J ＝16.4,8.3Hz,2H),7.55(d,J＝8.0Hz,2H),7.50(d,J＝9.5Hz,1H),7.44(t,J＝7.5Hz,1H),1.59(s,4H ), 1.37 (d, J = 7.3Hz, 6H), 1.09 (s, 3H), 0.91 (q, J = 7.5Hz, 14H).

Example 10: Synthesis of labeled precursor compound 10

According to the synthesis method of Example 1, the labeled precursor compound 10 was synthesized to obtain 46.6 mg of white solid with a yield of 42.8%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.99 (dd, J＝4.5, 1.6Hz, 1H), 8.14 (d, J＝8.1Hz, 2H), 8.02 (dd, J＝8.0, 1.5Hz ,1H),7.99(d,J＝7.1Hz,1H),7.97(s,1H),7.88(d,J＝8.1Hz,2H),7.49(dd,J＝8.1,4.5Hz,1H),7.01 (d,J＝7.1Hz,1H),1.36(s,12H).

Example 11: Synthesis of intermediate compound 11

Compound 8-amino-1,7-naphthyridine (145.2mg, 1mmol), 2'-bromo-4-hydroxyacetophenone (258.7mg, 1.2mmol) and NaHCO ₃ (168.4mg, 2mmol) were dissolved in 20mL ethanol in, and then heated to reflux in a 90°C oil bath for 10 hours. After the reaction is completed, ethanol is distilled off under reduced pressure, water is added, and extracted three times with ethyl acetate. After the ethyl acetate is distilled off under reduced pressure, column chromatography is separated, and the volume of the developer is The ratio was ethyl acetate: petroleum ether = 5:1, and 101.9 mg of light yellow solid was obtained. Yield 42.1%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.95 (dd, J＝4.4, 1.6Hz, 1H), 8.51 (d, J＝7.1Hz, 1H), 8.43 (s, 1H) ,8.38(dd,J＝8.1,1.6Hz,1H),7.93–7.89(m,2H),7.70(dd,J＝8.1,4.5Hz,1H),7.34(d,J＝7.1Hz,1H), 6.96–6.90(m,2H).

Example 12: Synthesis of Compound 12

Dissolve intermediate compound 11 (50.2mg, 0.23mmol), 1-bromo-2-fluoroethane (88.6mg, 0.69mmol) and cesium carbonate (0.6g, 1.84mmol) in 4mL DMF, react at 80°C 13 hour, DMF was distilled off under reduced pressure, methylene chloride was added, and the After sonication, cesium carbonate was removed by suction filtration, and methylene chloride was removed by distillation under reduced pressure, followed by column chromatography separation. The volume ratio of the developing agent was ethyl acetate: petroleum ether = 1:4 to obtain 29.2 mg of light yellow solid, with a yield of 41.3%. . The structure is as follows: 1H-NMR (600MHz, CDCl ₃ ) δ8.99 (dd, J＝4.5, 1.5Hz, 1H), 8.05–8.01 (m, 4H), 7.91 (s, 1H), 7.50 (dd, J＝ 8.0,4.5Hz,1H),7.02(d,J＝7.2Hz,1H),6.95(d,J＝8.7Hz,2H),4.83–4.80(m,1H),4.75–4.71(m,1H), 4.28–4.25(m,1H),4.24–4.21(m,1H).

Example 13: Synthesis of intermediate compound 13

Dissolve intermediate compound 11 (50.3 mg, 0.23 mmol), bromoethanol (88.3 mg, 0.69 mmol) and cesium carbonate (0.6 g, 1.84 mmol) in 4 mL DMF, react at 80°C for 11 hours, and distill away DMF under reduced pressure. , add water and extract with ethyl acetate, remove the ethyl acetate by distillation under reduced pressure, and then separate by column chromatography. The volume ratio of the developing agent is ethyl acetate:petroleum ether = 6:1, and a yellow solid 44.3 mg is obtained, with a yield of 63.1%. . The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.86 (dd, J＝4.4, 1.6Hz, 1H), 8.39 (d, J＝7.2Hz, 1H), 8.35 (s, 1H) ,8.25(dd,J＝8.0,1.6Hz,1H),7.94–7.88(m,2H),7.59(dd,J＝8.0,4.5Hz,1H),7.22(d,J＝7.2Hz,1H), 7.03–6.97(m,2H),4.01(t,J＝5.0Hz,2H),3.70(t,J＝4.9Hz,2H).

Example 14: Synthesis of intermediate compound 14

Dissolve intermediate compound 11 (457.3mg, 2mmol), 2-(2-chloroethoxy)ethanol (752.2mg, 6mmol) and cesium carbonate (5g, 15mmol) in 8mL DMF and react at 80°C for 6 hours. DMF was removed by distillation under reduced pressure, water was added and extracted with ethyl acetate. After the ethyl acetate was removed by distillation under reduced pressure, column chromatography was performed. The volume ratio of the developing agent was ethyl acetate:methanol=9:1 to obtain 169.2 mg of orange solid. The yield was 24.3%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.81 (dd, J＝4.4, 1.6Hz, 1H), 8.34 (d, J＝7.1Hz, 1H), 8.30 (s, 1H) ,8.20(dd,J＝8.1,1.6Hz,1H),7.86(d,J＝8.7Hz,2H),7.54(dd,J＝8.1,4.5Hz,1H),7.17(d,J＝7.2Hz, 1H), 6.96 (d, J＝8.9Hz, 2H), 4.06 (dd, J＝5.4, 3.9Hz, 2H), 3.68 (dd, J＝5.2, 3.9Hz, 2H), 3.43 (s, 4H).

Example 15: Synthesis of intermediate compound 15

Intermediate compound 11 (260.6mg, 1.2mmol), 2-[2-(2-chloroethoxy)ethoxy]ethanol (604.8mg, 3.6mmol) and cesium carbonate (2.7g, 8mmol) were dissolved in 6mL DMF, react at 80°C for 11 hours, remove DMF by distillation under reduced pressure, add water and extract with ethyl acetate. After distilling off ethyl acetate under reduced pressure, separate by column chromatography. The volume ratio of the developer is ethyl acetate:methanol=9: 1. Obtain 212.2 mg of colorless oily product with a yield of 45.1%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.98 (dd, J＝4.5, 1.6Hz, 1H), 8.02 (dd, J＝8.0, 5.7Hz, 4H), 7.89 (s, 1H), 7.49 (dd,J＝8.1,4.5Hz,1H),7.01(d,J＝7.2Hz,1H),6.95(d,J＝8.8Hz,2H),4.19–4.15(m,2H),3.90–3.86( m,2H),3.75–3.73(m,4H),3.66–3.60(m,4H).

Example 16: Synthesis of labeled precursor compound 16

Dissolve intermediate compound 13 (95.9 mg, 0.31 mmol), p-toluenesulfonyl chloride (70.3 mg, 0.36 mmol), and triethylamine (0.15 mL, 2 mmol) in 5 mL of methylene chloride, and react at room temperature for 6 hours. After the reaction is completed The methylene chloride was removed by distillation under reduced pressure and separated by column chromatography. The volume ratio of the developing agent was petroleum ether: ethyl acetate = 1:7, and 29.4 mg of pinkish-white solid was obtained with a yield of 20%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ9.04 (dd, J = 4.4, 1.5Hz, 1H), 8.19 (d, J = 7.2Hz, 2H), 8.13 (s, 1H), 7.97 (d ,J＝8.6Hz,2H),7.83(d,J＝8.3Hz,2H),7.59(dd,J＝8.1,4.5Hz,1H),7.36(d,J＝ 8.2Hz,2H),7.14(d,J＝7.0Hz,1H),6.67(d,J＝8.5Hz,2H),4.35(dd,J＝5.4,3.7Hz,2H),4.12–4.06(m, 2H),2.46(s,3H).

Example 17: Synthesis of labeled precursor compound 17

Dissolve intermediate compound 14 (150.4 mg, 0.43 mmol), p-toluenesulfonyl chloride (98.9 mg, 0.52 mmol), and triethylamine (0.2 mL, 2.5 mmol) in 6 mL of methylene chloride, and react at room temperature for 5 hours. The reaction is completed. Afterwards, methylene chloride was distilled off under reduced pressure and separated by column chromatography. The volume ratio of the developing solvent was petroleum ether: ethyl acetate = 1:9, and 57.1 mg of white solid was obtained with a yield of 26.3%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.91 (dd, J＝4.5, 1.7Hz, 1H), 8.46–8.39 (m, 2H), 8.30 (dd, J＝8.1, 1.6 Hz,1H),7.95(d,J＝8.7Hz,2H),7.78(d,J＝8.3Hz,2H),7.63(dd,J＝8.0,4.5Hz,1H),7.44(d,J＝8.1 Hz,2H),7.27(d,J＝7.2Hz,1H),7.02(d,J＝8.8Hz,2H),4.19–4.13(m,2H),4.09–4.04(m,2H),3.72–3.64 (m,4H),2.37(s,3H).

Example 18: Synthesis of labeled precursor compound 18

Dissolve intermediate compound 14 (240.6 mg, 0.61 mmol), p-toluenesulfonyl chloride (139.4 mg, 0.73 mmol), and triethylamine (0.3 mL, 2.8 mmol) in 6 mL of methylene chloride, and react at room temperature for 5 hours. The reaction is completed. Afterwards, dichloromethane was removed by distillation under reduced pressure and separated by column chromatography. The volume ratio of the developing agent was ethyl acetate:methanol=12:1, and 116.1 mg of light yellow solid was obtained with a yield of 35.3%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.97 (dd, J＝4.5, 1.6Hz, 1H), 8.97 (dd, J＝4.5, 1.6Hz, 1H), 8.03–7.95 (m, 5H) ,7.81(s,1H),7.77(d,J＝8.3Hz,2H),7.47(dd,J＝7.9,4.5Hz,1H),7.30(d,J＝8.2Hz,2H),6.96(dd, J＝7.8,5.7Hz,3H),4.15(dd,J＝8.5,3.7Hz,5H),3.85–3.81(m,2H),3.70–3.67(m,2H),3.67–3.64(m,2H) ,3.63–3.58(m,2H),2.40(s,3H).

Example 19: Synthesis of Compound 19

The synthetic precursor compound 17 (25.3 mg, 0.05 mmol) and TBAF (0.25 mL, 0.25 mmol) were reacted in 5 mL of anhydrous tetrahydrofuran at 60°C for 2 hours. After the reaction was completed, the tetrahydrofuran was removed by distillation under reduced pressure and separated by column chromatography. The volume ratio of the developing agent was methylene chloride: methanol = 12:1, and 14 mg of yellow solid was obtained with a yield of 81.6%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.98 (dd, J＝4.5, 1.6Hz, 1H), 8.01 (ddd, J＝5.2, 3.9, 2.2Hz, 4H), 7.87 (s, 1H) ,7.48(dd,J＝8.1,4.5Hz,1H),7.00(d,J＝7.2Hz,1H),6.95(d,J＝8.9Hz,2H),4.68–4.64(m,1H),4.55– 4.52(m,1H),4.20–4.15(m,2H),3.92–3.89(m,2H),3.89–3.85(m,1H),3.81–3.78(m,1H).

Example 20: Synthesis of Compound 20

The synthetic precursor compound 17 (61.6 mg, 0.11 mmol) and TBAF (1 mL, 1 mmol) were reacted in 5 mL of anhydrous tetrahydrofuran at 60°C for 3 hours. After the reaction was completed, the tetrahydrofuran was removed by distillation under reduced pressure and separated by column chromatography. The volume ratio of methylene chloride:ethyl acetate:methanol=12:4:1, and 12.5 mg of yellow solid was obtained with a yield of 31.6%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.96 (dd, J＝4.5, 1.5Hz, 1H), 7.99 (dd, J＝10.5, 4.2Hz, 3H), 7.95 (d, J＝7.2Hz ,1H),7.79(s,1H),7.46(dd,J＝8.0,4.5Hz,1H),6.96(d,J＝7.2Hz,3H),4.63–4.58(m,1H),4.52–4.46( m,1H),4.19–4.15(m,2H),3.90–3.85(m,2H),3.80–3.77(m,1H),3.73–3.68(m,4H),3.62(t,J＝5.8Hz, 1H).

The schematic diagram of the synthesis process of the compounds of the above Examples 1-20 is shown in Figure 1.

Example 21: Synthesis of intermediate compound 21

Compound 8-amino-1,7-naphthyridine (290.4mg, 1mmol), 3-(2-bromoacetyl)pyridine oxide (518.3mg, 2.4mmol) and NaHCO ₃ (252.5mg, 3mmol) were dissolved in 20mL ethanol in, and then heated to reflux in a 90°C oil bath for 9 hours. After the reaction was completed, the ethanol was distilled off under reduced pressure and separated by column chromatography. The volume ratio of the developing agent was ethyl acetate:methanol=7:3, and 173.5 mg of yellow solid was obtained. Yield 33.5%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.90 (dd, J = 4.4, 1.5Hz, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.43 (d, J＝7.2Hz,1H),8.30(dd,J＝8.1,1.4Hz,1H),8.15(d,J＝6.4Hz,1H),7.92(d,J＝7.9Hz,1H),7.64(dd, J＝8.0,4.4Hz,1H),7.49(dd,J＝7.8,6.6Hz,1H),7.30(d,J＝7.2Hz,1H).

Example 22: Synthesis of labeled precursor compound 22

Compound 21 (131.1 mg, 0.5 mmol) was dissolved in 3 mL of methylene chloride, then trimethylamine (1.5 mL, 3 mmol) and trifluoroacetic anhydride (315.7 mg, 1.5 mmol) were added to the reaction solution in sequence, and stirred at room temperature for half an hour. After the reaction, water was added, the water phase was distilled off under reduced pressure, ether and acetonitrile were added for ultrasonic washing, and then centrifuged to obtain 137.6 mg of brown solid in the lower layer, with a yield of 75.7%. The structure is as follows: 1H-NMR (600MHz, (CD ₃ ) ₂ SO) δ9.29 (d, J = 2.3Hz, 1H), 8.94 (d, J = 4.5Hz, 1H), 8.77 (dd, J = 8.6, 2.1Hz,1H),8.57(s,1H),8.36(d,J＝7.2Hz,1H),8.30(d,J＝8.1Hz,1H),8.05(d,J＝8.7Hz,1H),7.68 (dd,J＝8.0,4.5Hz,1H),7.30(d,J＝7.2Hz,1H),3.68(s,9H).

Example 23: Synthesis of Compound 23

Compound 22 (30.0 mg, 0.07 mmol) and tetrabutylammonium fluoride (0.2 mL, 0.21 mmol) were dissolved in 5 mL acetonitrile and reacted at 60°C for two hours. After the reaction was completed, column chromatography was performed. The developer ratio was acetic acid. Ethyl ester: methanol = 10:1, 13.3 mg of light yellow product was obtained, and the yield was 67.3%. The structure is as follows: 1H-NMR (600MHz, (CD ₃ ) ₂ SO) δ8.89 (dd, J＝4.4, 1.2Hz, 1H), 8.84 (d, J＝2.0Hz, 1H), 8.57 (s, 1H) ,8.53(td,J＝8.2,2.3Hz,1H),8.44(d,J＝7.1Hz,1H),8.29(dd,J＝8.1,1.0Hz,1H),7.63(dd,J＝8.0,4.4 Hz,1H),7.30–7.26(m,2H).

Example 24: Synthesis of intermediate compound 24

Intermediate compound 4 (131.3 mg, 0.5 mmol) was used as raw material, dissolved in 40 mL of methylene chloride, mCPBA (127.2 mg, 0.75 mmol) was added, and the reaction was carried out at room temperature for 3 hours, and the methylene chloride was evaporated under reduced pressure. 41.5 mg of light yellow solid was obtained, with a yield of 50.2%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.53–8.47 (m, 3H), 8.04 (dd, J = 8.7, 5.6Hz, 2H), 7.77 (d, J = 8.0Hz, 1H),7.52(dd,J＝8.1,6.4Hz,1H),7.32–7.26(m,3H).

Example 25: Synthesis of labeled precursor compound 25

According to the synthesis method of Example 22, the labeled precursor compound 25 was synthesized using the intermediate compound 24 as the raw material. 26.1 mg of brown-white solid was obtained, with a yield of 68.6%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.74 (d, J = 8.8Hz, 1H), 8.61 (d, J = 4.5Hz, 2H), 8.31 (d, J = 8.8Hz ,1H),8.10–8.03(m,2H),7.43(d,J＝7.1Hz,1H), 7.30(t,J＝8.1Hz,2H),3.71(s,9H).

Example 26: Synthesis of Compound 26

According to the synthesis method of Example 22, compound 26 was synthesized using labeled precursor compound 25 as raw material, and 9.7 mg of white solid was obtained with a yield of 78.5%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ ) δ8.16–8.12(m,1H),8.07(dd,J＝8.9,5.4Hz,2H),8.03(d,J＝7.1Hz,1H),7.90 (s,1H),7.16(dd,J＝8.5,2.7Hz,1H),7.12(t,J＝8.7Hz,2H),7.05(d,J＝7.1Hz,1H).

Example 27: Synthesis of intermediate compound 27

According to the synthesis method of Example 1, intermediate compound 34 was synthesized using 8-amino-1,7-naphthyridine and 5-(2-bromoacetyl)-2-chloropyridine as raw materials to obtain 172.8 mg of white product, yield is 61.3%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ9.06 (d, J = 2.0Hz, 1H), 8.93 (d, J = 4.5Hz, 1H), 8.67 (s, 1H), 8.48 (d,J＝7.2Hz,1H),8.44(dd,J＝8.5,1.5Hz,1H),8.33(d,J＝8.0Hz,1H),7.67(dd,J＝7.7,4.5Hz,1H) ,7.63(d,J＝8.3Hz,1H),7.33(d,J＝7.0Hz,1H).

Example 28: Synthesis of intermediate compound 28

Compound 28 (30.9 mg, 0.1 mmol) was dissolved in 6 mL DMF, and NaH (50.1 mg, 1.25 mmol) was added to it. After stirring in ice bath for half an hour, diethylene glycol (3 mL, 5 mmol) was added, and heated to 130°C, 3 After an hour, add water to quench the reaction, add methylene chloride for extraction, distill the methylene chloride under reduced pressure, and separate by column chromatography. The volume ratio of the developing agent is ethyl acetate:methylene chloride:methanol=10:2:1. 18.1 mg of product was obtained, with a yield of 51.7%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.88 (dd, J＝4.5, 1.6Hz, 1H), 8.77 (d, J＝2.4Hz, 1H), 8.46 (s, 1H) ,8.43(d,J＝7.1Hz,1H),8.30–8.24(m,2H),7.61(dd,J＝7.3,3.7Hz,1H),7.26(d,J＝7.2Hz,1H),6.92( d,J＝8.6Hz,1H),4.42–4.37(m,2H),3.76–3.72(m,2H),3.47(t,J＝3.6Hz,4H).

Example 29: Synthesis of labeled precursor compound 29

According to the synthesis method of Example 16, the labeled precursor compound 29 was synthesized using the intermediate compound 28 as the raw material, and 50.3 mg of white product was obtained with a yield of 66.7%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ ) δ9.01 (dd, J = 4.5, 1.4Hz, 1H), 8.75 (d, J = 2.4Hz, 1H), 8.42 (dd, J = 8.6, 2.3Hz ,1H),8.07(t,J＝8.2Hz,2H),7.98(s,1H),7.79(d,J＝8.2Hz,2H),7.54(dd,J＝8.0,4.5Hz,1H),7.30 (d,J＝8.4Hz,2H),7.08(d,J＝7.2Hz,1H),6.81(d,J＝8.6Hz,1H),4.44–4.40(m,2H),4.22–4.18(m, 2H),3.80–3.77(m,2H),3.76–3.73(m,2H),2.40(s,3H).

Example 30: Compound 30

The synthetic precursor compound 29 (25.7 mg, 0.05 mmol) and TBAF (0.25 mL, 0.25 mmol) were reacted in 5 mL of anhydrous tetrahydrofuran at 60°C for 2 hours. After the reaction was completed, the tetrahydrofuran was removed by distillation under reduced pressure and separated by column chromatography. The volume ratio of the developing agent was methylene chloride: methanol = 12:1, and 14.1 mg of yellow solid was obtained with a yield of 81.6%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ9.01(dd,J＝4.5,1.4Hz,1H),8.69(d,J＝2.1Hz,1H),8.32(dd,J＝8.6,2.4Hz,1H),8.07(dd,J＝8.2, 1.6Hz,1H),8.06–8.02(m,1H),7.94(s,1H),7.55(dd,J＝8.0,4.5Hz,1H),7.09(d,J＝7.2Hz,1H),6.79( d,J＝8.6Hz,1H),4.68–4.65(m,1H),4.57–4.53(m,1H),4.52–4.48(m,2H),3.93–3.89(m,2H),3.88–3.85( m,1H),3.81–3.77(m,1H).

The schematic diagram of the synthesis process of the compounds of the above Examples 21-30 is shown in Figure 2.

Example 31: Synthesis of intermediate compound 31

According to the synthesis method of Example 1, intermediate compound 31 was synthesized to obtain 167.9 mg of product with a yield of approximately 62.7%. Without purification, proceed directly to the next reaction.

Example 32: Synthesis of intermediate compound 32

Dissolve intermediate compound 31 (1.2g, 3mmol) in 10mL of dichloromethane, then add 5mL of trifluoroacetic acid, and react at room temperature for 3 hours. After the reaction is completed, the dichloromethane and trifluoroacetic acid are distilled off under reduced pressure and added diethyl ether, and suction filtration to obtain 680.1 mg of white solid, with a yield of approximately 91.3%. Without purification, proceed directly to the next reaction.

Example 33: Synthesis of intermediate compound 33

Intermediate compound 32 (490.3 mg, 2 mmol), 3-bromo-1-propanol (1.9 g, 12 mmol) and cesium carbonate (3.3 g, 10 mmol) were dissolved in 25 mL acetonitrile and heated at 90°C overnight to obtain a light yellow solid 86.3 mg, the yield is approximately 14.0%. Without purification, proceed directly to the next reaction.

Example 34: Synthesis of Compound 34

Compound 34 was synthesized according to the synthesis method of Example 33, and 16.7 mg of light yellow solid was obtained with a yield of 17.9%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ ) δ8.92 (dd, J＝4.5, 1.5Hz, 1H), 7.97 (dd, J＝8.1, 1.4Hz, 1H), 7.91 (d, J＝7.0Hz ,1H),7.44(dd,J＝8.0,4.6Hz,1H),7.35(s,1H),6.96–6.90(m,1H),4.55(t,J＝6.1Hz,1H),4.47(t, J＝6.0Hz,1H),3.02(d,J＝11.2Hz,2H),2.90(tt,J＝11.7,3.5Hz,1H),2.51(t,J＝7.4Hz,2H),2.24(d, J＝12.6Hz,2H),2.14(t,J＝11.2Hz,2H),1.98–1.86(m,2H),1.85–1.76(m,2H).

Example 35: Synthesis of labeled precursor compound 35

According to the synthesis method of Example 16, labeled precursor compound 35 was synthesized to obtain 12.5 mg of white solid with a yield of 10.0%. The structure is as follows: 1H-NMR (600MHz, CD ₃ OD) δ8.94 (dd, J＝4.5, 1.5Hz, 1H), 8.01 (dd, J＝8.0, 1.5Hz, 1H), 7.97 (d, J＝7.0 Hz,1H),7.80(d,J＝8.0Hz,2H),7.61(s,1H),7.48(dd,J＝8.0,4.4Hz,1H),7.13(d,J＝8.0Hz,2H), 6.97(d,J＝7.2Hz,1H),4.56(t,J＝8.4Hz,2H),4.38(t,J＝8.3Hz,2H),3.90(s,2H),3.88(d,J＝3.4 Hz,1H),2.76–2.69(m,2H),2.44(s,1H),2.32(s,4H),1.71(s,3H).

Example 36: Synthesis of intermediate compound 36

According to the synthesis method of Example 1, intermediate compound 36 was synthesized using 8-amino-1,7-naphthyridine and chloroacetaldehyde as raw materials. 177.5 mg of white product was obtained, with a yield of 71.3%. The structure is as follows: 1H-NMR (600MHz, CD ₃ OD) δ8.94 (dd, J＝4.3, 1.3Hz, 1H), 8.01–7.98 (m, 2H), 7.70 (s, 1H), 7.63 (d, J ＝0.9Hz,1H),7.47(dd,J＝8.0,4.5Hz,1H),6.99(d,J＝7.2Hz,1H).

Example 37: Synthesis of intermediate compound 37

According to the synthesis method of Example 24, intermediate compound 36 was used as raw material to synthesize intermediate compound 37. 237.9 mg of white solid was obtained, with a yield of 87.8%. Without purification, proceed directly to the next reaction.

Example 38: Synthesis of labeled precursor compound 38

According to the synthesis method of Example 22, the labeled precursor compound 38 was synthesized using the intermediate compound 37 as a raw material. 209.7 mg of white powder was obtained, with a yield of 49.1%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.75 (d, J = 8.9Hz, 1H), 8.64 (d, J = 7.2Hz, 1H), 8.30 (d, J = 8.8Hz ,1H),8.19(s,1H),7.75(s,1H),7.43(d,J=7.2Hz,1H),3.68(s,9H).

Example 39: Synthesis of Compound 39

Compound 39 was synthesized according to the synthesis method of Example 23, using labeled precursor compound 38 as raw material. 36.2 mg of white solid was obtained, with a yield of 50.3%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ8.48 (dd, J = 12.9, 7.2Hz, 2H), 8.07 (s, 1H), 7.63 (s, 1H), 7.40 (d, J＝8.5Hz,1H),7.30(d,J＝7.0Hz,1H).

The schematic diagram of the synthesis process of the compounds in Examples 31-39 above is shown in Figure 3.

Example 40: Collectively named intermediate compound 40

Dissolve 2-amino-3-nitro-4-methylpyridine (1.5g, 10mmol) and chloroacetaldehyde (1.5g, 30mmol) in 25mL ethanol. After refluxing for 3 hours, remove the solvent by distillation under reduced pressure and add 100mL The mixture was extracted three times with water and methylene chloride, and the solvent was evaporated under reduced pressure to obtain a yellow solid crude product, which was directly put into the next reaction without identification.

Example 41: Synthesis of intermediate compound 41

Intermediate compound 40 (870.4 mg, 5 mmol) was used as raw material, and N,N-dimethylformamide dimethyl acetal (1.2 g, 10 mmol) was dissolved in 15 mL DMF. After reacting at 130°C for 2 hours, the pressure was reduced The solvent was removed by distillation, 100 mL of water was added and extracted three times with dichloromethane. The solvent was distilled off under reduced pressure to obtain a dark red solid crude product, which was directly put into the next reaction without identification.

Example 42: Synthesis of intermediate compound 42

Intermediate compound 41 (1.2g, 5mmol) and sodium periodate (5.0g, 21mmol) were dissolved in 45mL THF/45mL water. After reacting at room temperature for 24 hours, the solvent was evaporated under reduced pressure, 100mL of water was added and extracted with dichloromethane. Three times, the solvent was distilled off under reduced pressure to obtain a yellow solid crude product, which was directly put into the next reaction without identification.

Example 43: Synthesis of intermediate compound 43

Dissolve intermediate compound 42 (900.4 mg, 5 mmol) and iron powder (560.2 mg, 10 mmol) in 30 mL ethanol/3 mL water. Add five drops of concentrated hydrochloric acid to the stirred solution. After refluxing for 3 hours, filter with suction. Most of the solvent was removed by pressure distillation, and saturated sodium bicarbonate solution was added to neutralize until the pH was neutral. 100 mL of water was added and extracted three times with methylene chloride. The solvent was removed by distillation under reduced pressure to obtain light yellow solid intermediate compound 53 (388.2 mg, 2.5mmol), yield 51.4%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ9.80 (s, 1H), 7.58 (d, J = 0.6Hz, 1H), 7.52 (d, J = 0.7Hz, 1H), 7.44 (d, J =6.9Hz,1H),6.83(d,J=7.0Hz,1H).

Example 44: Synthesis of Compound 44

Dissolve intermediate compound 43 (155.1 mg, 1 mmol) and p-iodoacetophenone (258.6 mg, 1 mmol) in 30 mL of ethanol. Add 3 g of potassium hydroxide. After refluxing for 6 hours, add 1 M hydrochloric acid to neutralize. The solvent was distilled off under reduced pressure and separated by column chromatography. The developing solvent was ethyl acetate: dichloromethane: methanol = 8:2:1 to obtain a light yellow solid (100.9 mg, 0.27 mmol). The yield was 27.2%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.34–8.31(m,2H),8.07(d,J＝8.4Hz,1H),7.99(dd,J＝7.8,3.6Hz,2H),7.75(d, J＝1.2Hz,1H),7.65(d,J＝1.2Hz,1H),7.49(d,J＝7.5Hz,1H),7.03(d,J＝7.1Hz,1H).

Example 45: Synthesis of Precursor Compound 45

According to the synthesis method of Example 5, the labeled precursor compound 45 was synthesized using the intermediate compound 44 as the raw material, and 20.3 mg of light yellow solid was obtained with a yield of 39.1%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.25 (d, J = 8.1Hz, 2H), 8.05 (d, J = 8.4Hz, 1H), 7.97 (d, J = 7.3Hz, 2H), 7.74(d,J＝1.2Hz,1H),7.64(d,J＝1.2Hz,1H),7.59(d,J＝8.1Hz,2H),7.02(d,J＝7.1Hz,1H),1.58– 1.54(m,4H),1.36–1.31(m,4H),1.08(d,J＝6.3Hz,7H),0.93–0.88(m,12H).

Example 46: Synthesis of intermediate compound 46

According to the synthesis method of Example 40, the intermediate compound 57 was synthesized using 2-methyl-3-nitro-6-aminopyridine as raw material to obtain a yellow solid crude product, which was directly put into the next reaction without purification and identification.

Example 47: Synthesis of intermediate compound 47

According to the synthesis method of Example 41, intermediate compound 46 was used as raw material to synthesize intermediate compound 47 to obtain a dark red solid crude product, which was directly put into the next reaction without purification and identification.

Example 48: Synthesis of intermediate compound 48

According to the synthesis method of Example 42, using intermediate compound 47 as raw material, intermediate compound 59 was synthesized to obtain a brown solid crude product, which was directly put into the next reaction without purification and identification.

Example 49: Synthesis of intermediate compound 49

According to the synthesis method of Example 43, using intermediate compound 48 as raw material, intermediate compound 49 was synthesized to obtain 97.3 mg of yellow solid with a yield of 42.1%. The structure is as follows: 1H-NMR (400MHz, CD ₃ OD) δ10.19 (s, 1H), 7.62 (d, J = 9.6Hz, 1H), 7.41 (d, J = 1.0Hz, 1H), 6.87 (d, J＝9.6Hz,1H).

Example 50: Synthesis of Compound 50

According to the synthesis method of Example 44, using intermediate compound 49 as raw material, compound 50 was synthesized to obtain 12.6 mg of yellow-green solid with a yield of 17.3%. The structure is as follows: 1H-NMR (600MHz, (CD ₃ ) ₂ SO) δ8.87 (d, J＝8.7Hz, 1H), 8.73 (s, 1H), 8.31 (dd, J＝8.7, 2.0Hz, 1H) ,8.22(d,J＝7.4Hz,1H),8.03(d,J＝8.3Hz,1H),7.89(d,J＝8.3Hz,1H),7.81(d,J＝9.6Hz,1H),7.76 (t,J＝9.9Hz,1H),7.68(s,1H),7.53(t,J＝7.5Hz,1H).

Example 51: Synthesis of Precursor Compound 51

According to the synthesis method of Example 45, using compound 50 as raw material, the precursor compound 51 was synthesized to obtain 8.0 mg of light yellow solid with a yield of 22.8%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ ) δ8.28 (d, J = 8.7Hz, 1H), 8.07–8.03 (m, 4H), 7.99 (d, J = 8.7Hz, 1H), 7.82 (t ,J＝9.7Hz,3H),7.36(d,J＝4.3Hz,1H),1.61–1.54(m,4H),1.39–1.32(m,5H),1.13–1.07(m,9H),0.90( dd,J＝12.1,5.0Hz,8H).

The schematic diagram of the synthesis process of the compounds in Examples 40-51 above is shown in Figure 4.

Example 52: Synthesis of Compound 52

According to the synthesis method of Example 1, using 8-amino-1,7-naphthyridine and α-bromo-m-fluoroacetophenone as raw materials, 33.2 mg of light yellow solid was obtained with a yield of 47.2%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ )δ9.00(d,J＝4.3Hz,1H),8.01(d,J＝7.8Hz,1H),7.98(d,J＝7.1Hz,1H),7.89(s,1H) ,7.85(d,J＝7.8Hz,2H),7.49(dd,J＝8.0,4.5Hz,1H),7.38–7.34(m,1H),7.00(d,J＝7.0Hz,2H).

Example 53: Synthesis of Compound 53

According to the synthesis method of Example 1, using 8-amino-1,7-naphthyridine and α-bromo-iodoacetophenone as raw materials, 12.1 mg of brown solid was obtained with a yield of 30.9%. The structure is as follows: 1H-NMR (600MHz, CDCl ₃ )δ9.00(s,1H),8.53(s,1H),8.03(d,J＝7.8Hz,2H),7.99(d,J＝7.1Hz,1H),7.90(s, 1H),7.63(d,J＝7.7Hz,1H),7.51(s,1H),7.14(t,J＝7.7Hz,1H),7.01(s,1H).

Example 54: Synthesis of Compound 54

According to the synthesis method of Example 1, using 4-aminoquinazoline and 2'-bromo-4-iodoacetophenone as raw materials, 29.2 mg of earthy yellow solid was obtained with a yield of 33.0%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ9.24 (s, 1H), 8.53 (s, 1H), 8.43 (d, J = 7.7Hz, 1H), 7.90 (d, J = 8.1Hz,1H),7.82(s,4H),7.75–7.68(m,2H).

Example 55: Synthesis of Precursor Compound 55

According to the synthesis method of Example 5, the labeled precursor compound 55 was synthesized using the intermediate compound 53 as a raw material to obtain 6.3 mg of light yellow solid with a yield of 27.7%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.99 (dd, J＝4.5, 1.6Hz, 1H), 8.14 (s, 1H), 8.08 (d, J＝7.3Hz, 1H), 8.02 (d ,J＝7.3Hz,2H),7.93(s,1H),7.51–7.47(m,1H),7.41(d,J＝2.2Hz,1H),7.38(d,J＝7.2Hz,1H),7.01 (d,J＝7.1Hz,1H),1.61–1.50(m,6H),1.36–1.30(m,6H),1.12–1.08(m,4H),0.92–0.85(m,11H).

Example 56: Synthesis of Precursor Compound 56

According to the synthesis method of Example 5, the labeled precursor compound 56 was synthesized using the intermediate compound 54 as a raw material to obtain 11.3 mg of light yellow solid with a yield of 35.9%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.88 (s, 1H), 8.67 (s, 1H), 7.99–7.92 (m, 3H), 7.89 (s, 1H), 7.68 (t, J＝ 7.0Hz,2H),7.56(d,J＝8.0Hz,2H),1.59(d,J＝7.2Hz,8H),1.38–1.32(m,8H),1.10(dd,J＝10.1,4.6Hz, 5H),0.95–0.88(m,6H).

Example 57: Synthesis of Precursor Compound 57

Using 53 (285.1mg, 0.75mmol), potassium peroxymonosulfonate (300.4mg, 1mmol), 6.10-dioxaspiro[4.5]decane-7,9-dione (192.5mg, 1.1mmol) as raw materials , first dissolve 53 and potassium peroxymonosulfonate in 6mL of chloroform, add 3.5mL of TFA dropwise, and stir at room temperature for half an hour. After the reaction is completed, remove the solvent by distillation under reduced pressure, dissolve in ethanol, add ketone, and use sodium bicarbonate Adjust the pH of the saturated solution until it is greater than 10, react at room temperature for 3 hours, remove the solvent by distillation under reduced pressure, add 20 mL of water, extract three times with dichloromethane, remove the solvent by distillation under reduced pressure, and separate by column chromatography. The developing solvent system is ethyl acetate: Dichloromethane: methanol = 8:4:1, 19.4 mg of white solid was obtained, with a yield of 5.1%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.99 (s, 1H), 8.60 (s, 1H), 8.24 (s, 1H), 8.03 (dd, J = 18.1, 7.5Hz, 2H), 7.95 (s,1H),7.70(d,J＝6.2Hz,1H),7.53(dd,J＝7.0,4.1Hz,1H),7.41(s,1H),7.05(d,J＝7.0Hz,1H) ,2.17(s,4H),1.79(s,4H).

Example 58: Synthesis of Precursor Compound 58

According to the synthesis method of Example 57, compound 1 was used as raw material to synthesize the labeled precursor compound 58, and 21.9 mg of light yellow solid was obtained with a yield of 8.3%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ9.01 (d, J = 4.6Hz, 1H), 8.14 (d, J = 8.4Hz, 2H), 8.06 (d, J = 8.1Hz, 1H), 8.03–7.98(m,2H),7.92(d,J＝8.4Hz,2H),7.54(dd,J＝8.0,4.6Hz,1H),7.06(d,J＝7.3Hz,1H),2.16(s ,4H),1.79(s,4H).

The schematic diagram of the synthesis process of the compounds in Examples 52-58 above is shown in Figure 5.

Example 59: Synthesis of intermediate compound 59

Use intermediate compound 36 (281.3 mg, 1.7 mmol) and N-bromosuccinimide (600.9 mg, 3.5 mmol) as raw materials, dissolve them in 20 mL acetonitrile, and add TMS-OTf (390.9 mg, 1.8 mmol) dropwise. After reacting at 40°C for half an hour, 400.3 mg of light yellow solid was obtained with a yield of 93.9%. The structure is as follows: 1H-NMR (400MHz, (CD ₃ ) ₂ SO) δ 8.91 (dd, J = 4.5, 1.6Hz, 1H), 8.36(dd,J＝8.1,1.6Hz,1H),8.27(d,J＝7.3Hz,1H),7.76(s,1H),7.66(dd,J＝8.1,4.5Hz,1H),7.43(d ,J＝7.3Hz,1H).

Example 60: Synthesis of Compound 60

Use intermediate compound 59 (204.1 mg, 0.8 mmol) and 4-iodophenylboronic acid (202.3 mg, 1 mmol) as raw materials, dissolve them in 15 mL dioxane, and add bis(triphenylphosphine) palladium chloride (49.5 mg ,0.07mmol) and potassium carbonate (350.8mg, 2.5mmol), under nitrogen protection, at 110°C overnight. After the reaction is completed, the solvent is distilled off under reduced pressure and separated by column chromatography. The developing solvent is ethyl acetate:dichloromethane=1:1 , 67.7 mg of light yellow solid was obtained with a yield of 22.5% and the structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.99 (dd, J=4.5, 1.6Hz, 1H), 8.10 (d, J=7.3Hz, 1H),8.04(dd,J＝8.0,1.6Hz,1H),7.88(d,J＝8.5Hz,2H),7.76(s,1H),7.51(dd,J＝8.1,4.5Hz,1H), 7.33(d,J＝8.4Hz,2H),7.04(d,J＝7.4Hz,1H).

Example 61: Synthesis of Precursor Compound 61

According to the synthesis method of Example 5, the labeled precursor compound 61 was synthesized using intermediate compound 60 as raw material to obtain a light yellow solid, 9.0 mg, with a yield of 29.9%. The structure is as follows: 1H-NMR (400MHz, CDCl ₃ ) δ8.98 (d, J = 4.4Hz, 1H), 8.20 (d, J = 7.3Hz, 1H), 8.02 (d, J = 8.0Hz, 1H), 7.76(s,1H),7.63(d,J＝7.8Hz,2H),7.53(d,J＝7.2Hz,3H),7.01(d,J＝7.4Hz,1H),1.61–1.55(m,6H ), 1.36 (d, J = 7.3Hz, 6H), 1.12 (d, J = 8.4Hz, 5H), 0.90 (t, J = 7.3Hz, 10H).

The schematic diagram of the synthesis process of the compounds in Examples 59-61 above is shown in Figure 6.

Example 62: Preparation of ¹²⁵ I labeled compounds

(a) Compound [ ¹²⁵ I] 1, [ ¹²⁵ I] 2, [ ¹²⁵ I] 3, [ ¹²⁵ I] 8, [ ¹²⁵ I] 44, [ ¹²⁵ I] 50, [ ¹²⁵ I] 53, [ ¹²⁵ I] Preparation of 54 and [ ^125I ]60

Dissolve 0.1 mg of labeled precursor compounds (compounds 5, 6, 7, 9, 45, 51, 55, 56 and 61 respectively) in 100 μL ethanol, add about 70 μCi Na ¹²⁵ I solution, 100 μL hydrochloric acid (1M) and 50 μL of 3% hydrogen peroxide solution was reacted at room temperature for 15 minutes, and NaHCO ₃ was added until the pH was neutral. Then it is separated and purified by HPLC. The separation conditions are: Venusil MP C18 chromatographic column (5 μm, 4.6 mm × 250 mm). Collect the target product effluent, remove acetonitrile with nitrogen, and prepare the obtained product into the required solution.

Example 63: Preparation of ¹⁸ F-labeled compounds

(1) Preparation of compound [ ^18F ]4

(a) [ ¹⁸ F]F ^- ions are enriched on the QMA column, rinse the QMA column with 3 mL of methanol, and then use 1 mL of eluent (containing 0.5 mg TEAB, methanol solution) to remove [ ¹⁸ F]F ^- from the QMA column. Wash it off. Add about 20 mCi of fluoride ion solution into a 10 mL glass reaction tube, heat it in a 120°C metal bath, continuously pass in N ₂ and blow dry to ensure that the reaction system is anhydrous. Dissolve 3.5 mg of labeled precursor compound (Compound 10) and 6 mg of Cu(OTf) ₂ (Py) ₄ in 100 μL of 1-butanol and 200 μL of DMA, and transfer the solution to a glass reaction tube containing [ ^{18F ]} F- middle. The reaction was heated at 110°C for 20 minutes. After cooling, 10 mL of deionized water was added to dilute the reaction mixture. The mixture was purified through a pretreated Sep-Pak C18 solid-phase extraction cartridge, and the column was washed with 20 mL of deionized water to remove unreacted [ ¹⁸ F]F ^- and inorganic salts. Elute the column with 1 mL of anhydrous acetonitrile to elute the labeled compounds and labeled precursor compounds adsorbed on the column. After concentration, they are separated and purified by HPLC. The separation conditions are: Venusil MP C18 reverse column (5 μm, 10 mm × 250 mm), collect the effluent of the target product, blow dry the solvent with nitrogen, dissolve the obtained product in 10% ethanol, and prepare it with purified water to the required concentration.

(b) [ ¹⁸ F]F ^- ions are concentrated on the QMA column, and then use 1 mL of eluent (containing 2 mg of TEAB, acetonitrile/water = 7/3) to elute [ ¹⁸ F]F ^- from the QMA column. Come down. Add about 20 mCi of fluoride ion solution into a 10 mL glass reaction tube, heat it in a 120°C metal bath, continuously pass in N ₂ and blow dry to ensure that the reaction system is anhydrous. Dissolve 2 mg of the labeled precursor compound (compound 58) in 400 μL of DMF, and transfer the solution to a glass reaction tube containing [ ^18F ] ^F- . Heat the reaction at 110°C for 10 minutes. After cooling, separate and purify by HPLC. Separation conditions: Venusil MP C18 reverse column (5 μm, 10 mm × 250 mm). Collect the effluent of the target product, blow dry the solvent with nitrogen, dissolve the obtained product in 10% ethanol and prepare it with purified water. required concentration.

(2) Preparation of compounds [ ¹⁸ F] 12, [ ¹⁸ F] 19, [ ¹⁸ F] 20, [ ¹⁸ F] 40 and [ ¹⁸ F] 34

[ ¹⁸ F]F ^- ions are enriched on the QMA column, and [ ¹⁸ F]F - is concentrated with 1 mL of eluent (containing 13 mg of Kryptofix-2.2.2, 1.1 mg of K ₂ CO ₃ , acetonitrile/water = 4/1) ^. Elute from the QMA column. Add about 20 mCi of fluoride ion solution into a 10 mL glass reaction tube, heat it in a 120°C metal bath, continuously pass in N ₂ and blow dry to ensure that the reaction system is anhydrous. Dissolve 1.5 mg of labeled precursor compounds (compounds 16, 17, 18, 29 and 35) in 300 μL of anhydrous acetonitrile, and transfer the solution to a glass reaction tube containing [ ^18F ] ^F- . Heat the reaction at 100°C for 5-10 minutes. After cooling, separate and purify by HPLC. Separation conditions: Venusil MP C18 reverse column (5 μm, 10 mm × 250 mm). Collect the effluent of the target product, blow dry the solvent with nitrogen, dissolve the obtained product in 10% ethanol and prepare it with purified water. to the required concentration.

(3) Preparation of compounds [ ¹⁸ F] 23, [ ¹⁸ F] 26, and [ ¹⁸ F] 39

[ ¹⁸ F]F ^- ions are concentrated on the QMA column, and 1 mL of eluent (containing 6.8 mg of TBAB, acetonitrile/water = 7/3) is used to elute [ ¹⁸ F]F ^- from the QMA column. Add about 20 mCi of fluoride ion solution into a 10 mL glass reaction tube, heat it in a 120°C metal bath, continuously pass in N ₂ and blow dry to ensure that the reaction system is anhydrous. Dissolve 1 mg of labeled precursor compounds (compounds 22, 25 and 38) in 300 μL of anhydrous DMSO and transfer the solution to a glass reaction tube containing [ ^18F ] ^F- . Heat the reaction at 100°C for 6 minutes. After cooling, separate and purify by HPLC. Separation conditions: Venusil MP C18 reverse column (5 μm, 10 mm × 250 mm). Collect the effluent of the target product, blow dry the solvent with nitrogen, dissolve the obtained product in 10% ethanol and prepare it with purified water. to the required concentration.

(4) Preparation of compound [ ^18F ]52

[ ¹⁸ F]F ^- ions are concentrated on the QMA column, and then use 1 mL of eluent (containing 2 mg of TEAB, acetonitrile/water = 7/3) to elute [ ¹⁸ F]F ^- from the QMA column. Add about 20 mCi of fluoride ion solution into a 10 mL glass reaction tube, heat it in a 120°C metal bath, continuously pass in N ₂ and blow dry to ensure that the reaction system is anhydrous. Dissolve 2 mg of labeled precursor compound (compound 57) in 400 μL of DMF, and transfer the solution to a glass reaction tube containing [ ^18F ] ^F- . Heat the reaction at 110°C for 10 minutes. After cooling, separate and purify by HPLC. Separation conditions: Venusil MP C18 reverse column (5 μm, 10 mm × 250 mm). Collect the effluent of the target product, blow dry the solvent with nitrogen, dissolve the obtained product in 10% ethanol and prepare it with purified water. required concentration.

Two experimental results

[ ^125I ]1,[ ^125I ]2,[ ^125I ]3,[ ^18F ]4,[ ^125I ]8,[ ^18F ]12,[ ^18F ]19,[ ^18F ]20,[ ¹⁸ F]23, [ ^18F ]26, [ ^18F ]30, [ ^18F ]34, [ ^18F ]39, [ ^125I ]44, [ ^125I ]50, [ ^18F ]52, [ ^125I ] The labeling rates of 53, [ ^125I ]54 and [ ^125I ]60 are as follows. After HPLC separation and purification, the radiochemical purity is greater than 95%. The chromatographic column is a Venusil MP C18 reverse column (5 μm, 10 mm × 250 mm). The mobile phase flow rate is 4 mL/min. The labeling rate is shown in Table 1.

Table 1: Labeling rates of labeled compounds

Example 64: Autoradiography Experiment

A certain concentration of the labeled product (10% ethanol solution) was incubated with AD patient brain slices at room temperature for a certain period of time. After the incubation, the products were exposed through a phosphor screen, and the images were analyzed using a phosphor screen storage system.

1. Experimental steps:

(1) Preprocess AD human brain slices;

(2) Cover AD human brain slices with 1 mL of 5 μCi/mL ¹²⁵ I-labeled or 20 μCi/mL ¹⁸ F-labeled compound solution, and incubate at room temperature for 1.5 hours or 1 hour;

(3) Soak in 50% ethanol solution for 30 minutes, or rinse with 50% ethanol for 5 minutes;

(4) After drying, wrap it in plastic wrap and place it under a phosphor screen for exposure for 24 hours ( ¹²⁵ I-labeled compound) or 1 hour ( ¹⁸ F-labeled compound), and then use a phosphorus screen system to analyze the image.

2. Experimental results:

The experimental results are shown in Figures 7, 8 and 9, fully demonstrating that the compound of the present invention, after being labeled with radionuclides, can be used as an imaging agent for Tau protein in the AD brain and has potential application prospects in clinical diagnosis.

Example 65: Biodistribution experiment in normal mice

1. Experimental steps:

5-10 μCi ¹⁸ F-labeled compound or 1-2 μCi ¹²⁵ I-labeled compound (100 μL physiological saline solution, containing 10% ethanol) was injected into normal mice (ICR, male, 18-20 g, 3-4 weeks old) through the tail vein. In vivo (n=3 or 5), the relevant organs were dissected and removed at 2 minutes, 10 minutes, 30 minutes and 60 minutes after injection, and the wet weight and radioactivity count were measured. Data are expressed as percent dose of radioactivity per gram of organ (%ID/g).

2. Experimental results:

The experimental results are shown in Table 2. The probes [ ^125I ]1, [ ^125I ]2, and [ ^18F ]4 of the present invention can all pass through the blood-brain barrier smoothly, and the brain uptake reaches the peak in 2 minutes. Clearance occurs rapidly in normal mouse brains.

Table 2: Animal distribution results of some compounds in normal mice

Example 66: Tau activity assay

1. Experimental steps:

(1) Preprocess AD human brain slices;

(2) Cover AD human brain slices with 1 mL of ¹²⁵ I-labeled compound solution at 10 μCi/mL, add stable cold ligands (final concentrations are 0.1 nM, 1 nM, 5 nM, 10 nM, 50 nM, 100 nM and 500 nM) at room temperature. Incubate for 2 hours;

(3) Soak in 50% ethanol solution for 30 minutes, or rinse with 50% ethanol solution for 5 minutes;

(4) After drying, cover it with plastic wrap and expose it to a phosphor screen for 24 hours. Use a phosphor screen system to analyze the image and obtain the quantitative values of Region of interests (ROIs) (Digital Light Unit/mm ² , DLU/mm ² ), according to the numerical value and the corresponding cold ligand concentration fitting curve, the half-inhibition constant (IC ₅₀ ) is calculated through fitting.

2. Experimental results:

Experimental results show that the IC ₅₀ value of compound 1 is 1.63 nM, and the IC ₅₀ value of compound 4 is 8.22 nM. As shown in Table 3, the activity of some compounds was evaluated by inhibition experiments (the final concentration of cold ligand is 10 nM), indicating that this compound The inventive probes, especially compounds 1 and 4, have particularly high activity against Tau protein.

Table 3: Evaluation of Tau activity of some compounds

Example 67: Aβ activity assay

1. Experimental steps

(1) Mix 100 μL radioligand ([ ¹²⁵ I]IMPY, 100000CPM/100 μL), 100 μL ethanol solutions of compounds 1, 4, 12, 19 and 20 (10 ^-4 M to 10 ^-10 M), 700 μL BSA (0.1 % PBS solution) and Aβ _1-42 aggregates (100 μL, final concentration 0.7 μM) were added to the borosilicate glass test tube in sequence.

(2) Incubate at 37°C for 2 hours.

(3) Filter and separate using MP-48T cell collector from Brandel Company of the United States, and wash three times with 10% ethanol.

(4) Collect glass fiber filter paper containing ¹²⁵ I ligands bound to Aβ _1-42 aggregates and place them at the bottom of numbered counting tubes, and measure the radioactivity count of each counting tube with a Wizard2 2480 γ counter from Perkinelmer Company of the United States. The half-inhibition constant (IC ₅₀ ) is calculated through fitting, and the inhibition constant (K _i ) is calculated according to the Cheng-Prusoff equation: K _i =IC ₅₀ /(1+[L]/K _d ).

2. Experimental results

The experimental results are shown in Table 4. The activity (K _i ) of compounds 1, 4, 12, 19 and 20 against Aβ is basically in the micromolar level, which basically shows that the binding ability to Aβ is very poor.

Table 4: Activity test results of some compounds Aβ _1-42

Example 68: MAO-A/B activity assay

1. Experimental steps

(1) Prepare substrate solution, dissolve 10μL 4-(trifluoromethyl)benzylamine in 9990μL PBS (1X).

(2) Prepare a chromogenic solution. Dissolve 2.03 mg 4-aminoantipyrine, 3.36 mg vanillic acid, and 400 μL horseradish peroxidase aqueous solution (2 mg/mL) in 19.6 mL PBS.

(3) Prepare an inhibitor solution, that is, prepare selegiline and chlorhydrin into a 1000nM aqueous solution.

(4) In the 96-well plate, add 50 μL of the extracted enzyme solution and 50 μL of the inhibitory solution, and incubate at 37°C for 30 minutes. After the incubation, add 50 μL of the sample to be tested at different concentrations, and incubate at 37°C for another 30 minutes. After the incubation is completed, proceed in sequence Add 100 μL substrate and 40 μL chromogenic solution and incubate at 37°C for 90 minutes.

(5) After incubation, use a microplate reader to measure the UV absorbance at 490nm. The abscissa is the negative logarithm of the final concentration of the sample to be tested, the ordinate is the absorbance, and the IC ₅₀ value is calculated using one-site mode.

2. Experimental results

Experimental results show that the IC ₅₀ values of compounds 1, 2, 3, 8, 44, 53, 54 and 60 are all greater than 1000nM, indicating that they are inactive with MAO-A/B, and it is predicted that there will be no corresponding non-target uptake in the brain. .

Although the present invention has been described in detail with general descriptions and specific embodiments above, it is obvious to those skilled in the art that some modifications or improvements can be made based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention. The above are only preferred embodiments of the present invention, and therefore cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made based on the patent scope of the present invention and the content of the specification should still be covered by the present invention. In the range.

Industrial applicability

The invention provides an imidazonaphthyridine compound with high affinity to Tau protein and its preparation method and application. The imidazonaphthyridine compound has a structure of general formula (I). After being labeled with radionuclides, the compound and its derivatives can be used for nuclear medicine clinical diagnosis of neurodegenerative diseases, especially for the diagnosis of diseases characterized by Tau protein deposition, including Alzheimer's disease. economic value and application prospects.

Claims (10)

An imidazonaphthyridine compound, characterized in that it has the following general formula (I) structure:
in: X ₁ ~ X ₇ independently represent N or CH; R ₁ is located at positions 1 and 2, R ₂ is located at positions 3 and 4; R ₁ and R ₂ independently represent H, Where R ₃ represents ^123/125/127 I, ^18/19 F, OH, O ^11/12 CH ₃ , (OCH ₂ CH ₂ ) _m ^18/19 F, m is an integer between 1-6. The imidazonaphthyridine compound according to claim 1, wherein X ₁ , X ₃ and X ₆ all represent N, and the imidazonaphthyridine compound has the following general formula (II) structure:
Wherein, X ₂ , X ₄ , X ₅ , X ₇ , R ₁ and R ₂ are as defined in claim 1. The imidazonaphthyridine compound according to claim 1 or 2, wherein R ₁ is located at position 1; preferably, R ₂ is located at position 3; preferably, R ₁ represents Preferably, R ₂ represents H, R ₃ represents ^123/125/127 I, ^18/19 F, O ^11/12 CH ₃ , (OCH ₂ CH ₂ ) _m ^18/19 F; preferably, m is 1-3 integers between. The imidazonaphthyridine compound according to claim 1 or 2, characterized in that X ₁ , X ₃ and X ₆ all represent N, X ₂ represents C, and X ₄ , X ₅ and X ₇ all represent CH. The imidazonaphthyridine compound according to claim 1, characterized in that it is selected from the following compounds:

Among them, I in compound 1-4, compound 14-17, and compound 19 is ¹²³ I, ¹²⁵ I or ¹²⁷ I; F in compound 5-13 and compound 18 is ¹⁸ F or ¹⁹ F. The preparation method of imidazonaphthyridine compounds according to claim 5, characterized in that when I is ¹²³ I or ¹²⁵ I, compounds 1-4, compounds 14-17 and compound 19 are composed of trialkyl tin, trialkyl silicon , obtained by reacting boric acid or borate ester precursor compound with [123/125]NaI solution in the presence of oxidant; When F is ¹⁸ F, compounds 5-13 and 18 are obtained by reacting OTs, trimethyl quaternary ammonium salts, boric acid, borate esters or hypervalent iodine prosthetic group precursor compounds with [18F]F anion in the presence of a phase transfer catalyst. . The derivative of the imidazonaphthyridine compound according to any one of claims 1 to 5, characterized in that it includes a pharmaceutically acceptable salt, ester or amide compound. A diagnostic or detection reagent for neurofibrillary tangle diseases caused by Tau protein deposition, characterized in that its active ingredient is the imidazonaphthyridine compound described in any one of claims 1 to 5, and/or the claim Derivatives described in 7. The diagnostic or detection reagent according to claim 8, characterized in that the diseases include Alzheimer's disease, frontotemporal degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration change or Pick's disease. The application of the imidazonaphthyridine compound according to any one of claims 1 to 5, or the derivative according to claim 7 in the preparation of nuclear medicine imaging agents.