A triazole compound, preparation method and medical use thereof

Abstract

The present invention provides a triazole compound, a preparation method and a medical use thereof. The triazole compound has a structure of the following formula (I). The present invention claims a triazole compound of formula (I) or a pharmaceutically acceptable salt, a composite salt, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers thereof. The compound of the present invention has significant antagonistic activity against histamine H1 receptors, lower anti-M-choline side effects, and lower Herg toxicity. #imgabs0#

Description

(I) Technical field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a triazole compound, a preparation method and a pharmaceutical use thereof. Compared with the prior art, the compound of the present invention has significant antihistamine activity and extremely low choline inhibition effect, and Herg toxicity is significantly reduced. The present invention also provides the use of the compound in the preparation of drugs for preventing and treating allergic diseases. (II) Background technology

[0002] H1 receptor antagonists can competitively bind to H1 receptors and block the action of histamine on H1 receptors, thereby inhibiting the biological effect of histamine and playing an anti-allergic role [Zolaly MA. Histamine H1 antagonists and clinical characteristics of febrile seizures [J]. Int J Gen Med. 2012, 5: 277-281]. However, the third-generation H1 receptor antagonists currently in clinical use, such as desloratadine, have obvious side effects of inhibiting cholinergics, such as dry mouth and dry eyes, and can cause motor dysfunction in severe cases. Therefore, it is of great value to develop new H1 receptor blockers with higher safety, improve the deficiencies of existing therapeutic drugs, and reduce central nervous system, cardiac toxicity and cholinergic inhibitory activity.

[0003] The Chinese patent CN107602534B applied by the inventor discloses a series of desloratadine derivatives with dual antihistamine and anti-inflammatory activities, among which compound LHC-7 has the best activity.

[0004]

[0005] However, subsequent studies found that it has strong Herg toxicity.

[0006] The Chinese patent CN109096251A applied by the present inventor discloses a class of multi-target desloratadine derivatives, including compound LP-2.

[0007]

[0008] Patent WO9200293A1 also discloses a series of antihistamine compounds, including compound 1 having the following structure:

[0009]

[0010] However, the patent does not disclose the implementation method, activity data, etc. of Compound 1.

[0011] Through continuous efforts, the present invention has designed a series of new compounds and found that these compounds show excellent effects and functions. In particular, the compounds of the present invention retain significant anti-histamine activity while significantly reducing their ability to inhibit M-choline, and have higher safety. (III) Summary of the invention

[0012] The present invention aims at the deficiencies of the prior art and provides a compound having the following formula (I) or a pharmaceutically acceptable salt thereof through structural modification.

[0013]

[0014] in

[0015] Ring A is a benzene ring, a pyridine ring, or a thiophene ring;

[0016] X is R 5 , R 6 Substituted or unsubstituted diazoles, triazoles, tetrazoles, oxazolone, oxadiazolone, 1,2,4-triazol-3-one;

[0017] n = 1-6;

[0018] R 1 , R 4 Selected from H, C1-C6 alkyl, hydroxyl, halogen;

[0019] R 2 , R 3 Selected from H, C1-C6 alkyl, hydroxyl, =O;

[0020] R 5 , R 6 Selected from H, C1-C6 alkyl, COOR 7 ,CONR 7 , R 7 is H, an optionally substituted C1-C6 alkyl group.

[0021] Preferably, the compound of formula (I)

[0022] in

[0023] n = 1-4;

[0024] R 1 , selected from H, Cl;

[0025] R 2 , R 3 , selected from H, hydroxyl;

[0026] R 4 is H;

[0027] R 5, R 6 Selected from H, methyl, COOR 7 ,CONR 7 ,

[0028] R 7 It is H, methyl.

[0029] More preferably, the compound of formula (I)

[0030] in

[0031] Ring A is a pyridine ring.

[0032] The present invention further includes pharmaceutically acceptable salts of the compounds of the present invention, which are salts formed between the compound of formula (I) and an alkali metal or alkaline earth metal, an amino acid or a basic compound containing an amino group, or salts formed between the compound of formula (I) and an inorganic acid or an organic acid, or a composite salt of a polyacid alkali metal or alkaline earth metal salt of the compound of formula (I).

[0033] Specifically, it includes potassium salt, sodium salt, ammonium salt of the compound of formula (I) and salts formed by the compound of formula (I) and hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid or acetic acid; the polyacid alkali metal or alkaline earth metal salt composite salt of the compound of formula (I), wherein the polyacid is selected from citric acid, succinic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, oxalic acid, sulfuric acid, phosphoric acid, sulfurous acid, malic acid, and the alkali metal or alkaline earth metal is selected from sodium, potassium, calcium, magnesium, and zinc.

[0034] Particularly preferred compounds of the present invention are selected from the following compounds:

[0035]

[0036]

[0037]

[0038] The present invention further includes a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the dosage form is selected from tablets, capsules, granules, oral liquids, suppositories, transdermal preparations, and injections.

[0039] The present invention further includes the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and treating an allergic disease, wherein the allergic disease is selected from the group consisting of allergic rhinitis, urticaria, chronic urticaria, allergic purpura, asthma, allergic dermatitis, eczema, allergic conjunctivitis, atopic dermatitis, sinusitis, and chronic sinusitis.

[0040] Pharmacodynamic experiments show that the compounds of the present invention significantly antagonize histamine H1 receptor activity, significantly reduce or substantially eliminate the anticholinergic activity of the compounds disclosed in the prior art, and reduce the Herg toxicity of the compounds. The present invention also includes prodrugs, tautomers, stereoisomers or mixtures of stereoisomers of the compounds of the present invention.

[0041] (IV) Biological activity

[0042] 1. Inhibitory effect of the compounds of the present invention on histamine-induced vascular permeability in mice

[0043] ICR mice weighing 18-22g were taken and adaptively fed for 7 days, and randomly divided into 10 groups, namely, model group, compound group of the present invention, positive drug desloratadine group, LHC-7 control group, and compound 1 control group. The mice were intragastrically administered 1h before modeling, the control group was given the corresponding solvent, the compound group was given 5mg / kg of the corresponding compound, and the desloratadine group was given 5mg / kg of the corresponding drug. The back of mice was depilated with 10% sodium sulfide (3cm×3cm). One hour after administration, 1ug / 0.1mL of histamine phosphate saline solution was intradermally injected into the depilated area. Immediately after injection, 4ml / kg of 0.25% Evans blue solution was injected through the tail vein. The mice were killed by dislocation 30 minutes later. The blue-stained part of the skin was punched (15mm in diameter), cut into pieces and immersed in 1ml of acetone-saline (7:3) solution. After 24 hours, centrifugation (3000r / min, 10min) was performed, and the supernatant was taken. The absorbance value of the sample was measured by ultraviolet spectrophotometer at a wavelength of 610nm and calibrated to zero with acetone-saline solution blank.

[0044] The results are shown in Table 1. Compared with the model group, each compound group and the desloratadine group significantly inhibited histamine-induced mouse skin vascular permeability (P < 0.01); compared with the control group, the inhibition rate of the compound of the present invention was equivalent to that of desloratadine, LHC-7, and LP-2 compounds, and was superior to compound 1 (P < 0.05). This shows that the compound of the present invention has a strong antihistamine activity.

[0045] Table 1 Inhibitory effect of the compounds of the present invention on histamine-induced vascular permeability in mice

[0046]

[0047]

[0048] 2. Experimental results of the compounds of the present invention on pilocarpine-induced salivation in rats

[0049] Wistar male rats, 180-220 g, were divided into a blank group, a model group, a desloratadine group, a compound of the present invention group, an LHC-7 control group, and a compound 1 control group, with 10 rats in each group. The rats in each group were given the corresponding drugs by gavage, and 15 minutes later, pilocarpine (1 mg / kg, dissolved in saline) was intraperitoneally injected to induce saliva secretion. The rats were immediately anesthetized by intraperitoneal injection of 10% chloral hydrate. After the rats were anesthetized, the saliva remaining in the oral cavity was removed with a cotton ball, and then the weighed cotton balls (M1) were placed in the oral cavity (two under the tongue, one on each side), and the weight of the cotton balls (M2) was immediately measured after 10 minutes.

[0050] Saliva secretion = M2-M1

[0051] Inhibition rate = saliva secretion of the drug group / saliva secretion of the model group × 100%

[0052] The experimental results are shown in the following table. The model group was injected with 1 mg / kg of pilocarpine intraperitoneally, and the saliva secretion increased significantly, and the model was successful. The saliva secretion of desloratadine (1 mg / kg), LHC-1 (10 mg / kg), LP-2 (10 mg / kg), and compound 1 (10 mg / kg) was reduced by oral administration (P<0.01), indicating that desloratadine, LHC-1, LP-2, and compound 1 have obvious inhibitory effects on choline. The saliva secretion of the compound of the present invention (10 mg / kg) administered by oral administration had no statistical difference compared with the model group (P>0.05), and had a significant difference compared with the control group (P<0.05). It shows that compared with desloratadine, LHC-7, LP-2, and compound 1, the activity of the compound of the present invention in inhibiting choline is extremely low.

[0053] Table 2 Inhibitory effect of the compounds of the present invention on pilocarpine-induced salivation in rats

[0054]

[0055]

[0056] 3. Herg toxicity test of the compounds of the present invention

[0057] Compared with the comparative technical compounds LHC-7, LP-2, compound 1 and desloratadine, the Herg toxicity of the compounds of the present invention is significantly reduced, especially the IC values ​​of Examples 3, 5, 7, 13, 19, 22, 23 and 25 for inhibiting Herg 50 >30μM, with higher safety.

[0058] Example No. Herg(μM) 1 6.511 2 15.243 3 >30 5 >30 7 >30 8 15.323 13 >30 19 >30 22 >30 23 >30 25 >30 LHC-7 0.248 LP-2 4.032 Compound 1 2.033 Desloratadine 1.214

[0059] (V) Specific implementation method

[0060] Example 1

[0061] Synthesis of 8-chloro-11-(1-((5-methyl-1H-imidazol-4-yl)methyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,22-b]pyridine

[0062] Compound desloratadine (310mg, 1mmol) and 5-methyl-1H-imidazole-4-carboxaldehyde (330mg, 3mmol) were dissolved in 1.2-dichloroethane (50ml), stirred at room temperature for 10min, then sodium triacetoxyborohydride (626mg, 3mmol) and acetic acid (3 drops) were added. The temperature was raised to 25℃ and stirred overnight. LC (DCM:MeOH = 10:1) detected that the raw material had reacted completely. Concentrate, mix, and column chromatography to obtain the target compound (190mg, 47% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δppm 8.36 (dd, J1=1.2Hz, J2=4.8Hz, 1H), 7.74 (s, 1H), 7.47 (dd, J1=0.8Hz, J2=7.8Hz, 1H), 7.47 (d, J=2.0Hz, 1H), 7.10-7.14 (m,2H),7.04(d,J=8.0Hz,1H),4.09(s,2H),3.31-3.39(m,2H),3.06-3.20(m,4H), 2.61-2.89(m,6H),2.28(s,3H).

[0063] Example 2

[0064] Step 1 Synthesis of 2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethan-1-ol (2)

[0065]

[0066] The raw material 1 (400 mg, 1.29 mmol) and N, N-diisopropylethylamine (417 mg, 3.23 mmol) were dissolved in DCM (7 mL), stirred at room temperature for 30 min, and then 2-bromoethanol (404 mg, 3.23 mmol) was added. The mixture was stirred at room temperature for 22 h. TLC (V acetone: V dichloromethane: V triethylamine = 1: 2: 0.1) detected that the raw material 1 was completely reacted. The reaction was stopped, the solvent was dried under reduced pressure, and separated by column chromatography (V dichloromethane: V ethyl acetate: V triethylamine = 2: 1: 0.05) to obtain 412 mg of a white solid with a yield of 90.0%. 1H-NMR (300MHz, CDCl3) δ (ppm): 8.42 (d, J=4.2Hz, 1H, ArH), 7.46 (d, J=7.5Hz, 1H, ArH), 7.19-7.12 (m, 4H, ArH), 3.78-3.75(m,2H,CH2OH),3.45-3.34(m,2H,Ar CH2 ),2.97-2.57(m,12H,Ar CH2 , N (CH2)3 ,C (CH2)2 ).

[0067] Step 2

[0068] Synthesis of ethyl 2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methanesulfonate (3)

[0069]

[0070] 2 (520 mg, 1.47 mmol) was dissolved in dichloromethane (8 mL), and methanesulfonyl chloride (253 mg, 2.21 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C for 1 h. After the reaction of raw material 2 was complete, saturated ammonium chloride solution (10 mL) was added to the reaction solution and stirred for 5 min before separation. The aqueous layer was further extracted with dichloromethane (10 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and the mixture was directly used for the next step without purification.

[0071] Step 3

[0072] Synthesis of 11-(1-(2-azidoethyl)piperidin-4-ylidene)-8-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (4)

[0073]

[0074] Dissolve 3 (636 mg, 1.47 mmol) in DMF (5 mL), cool to 0 °C in an ice bath, add sodium azide (191 mg, 2.94 mmol) in batches, stir at low temperature for 10 min after addition, and heat to 50 °C for 12 h. TLC (V dichloromethane: V methanol = 20:1) detected that the reaction of raw material 3 was complete. Stop heating, cool to room temperature, add saturated sodium hypochlorite solution (5 mL) to quench, add ethyl acetate to extract, extract the aqueous layer with ethyl acetate (10 mL x 3), combine the organic layers, add anhydrous sodium sulfate to dry, filter, and reduce the pressure to spin dry the filtrate. Column chromatography (eluent: V dichloromethane: V methanol = 200: 1 ~ 50: 1) to obtain 370 mg of white solid, with a yield of 66.3%.

[0075] 1 H-NMR (300MHz, CDCl3) δ (ppm): 8.42 (d, J = 4.5 Hz, 1H, ArH), 7.46 (d, J = 7.6 Hz, 1H, ArH), 7.18-7.10 (m, 4H, ArH), 3.46-3.38 (m, 2H, Ar CH2 ),2.89-2.35(m,12H, Ar CH2 ,N (CH2)3 ,C (CH2)2 ),1.88-1.78(m,2H, CH2 N3).

[0076] Step 4

[0077] Synthesis of 1-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester

[0078]

[0079] 4 (500 mg, 1.32 mmol) was dissolved in a mixed solution of acetonitrile and water (V acetonitrile: V water = 6:1, 8 mL), and 9 (130 mg, 1.55 mmol) and cuprous iodide (50 mg, 0.26 mmol) were added in turn under an ice bath. After the addition, the mixture was stirred at low temperature for 30 min and then moved to room temperature for reaction for 2 h. TLC (V dichloromethane: V methanol = 20:1) detected that the reaction of raw material 4 was complete, the reaction was stopped, the solvent was dried under reduced pressure, methanol (5 mL) was added to slurry, and suction was filtered. The solid was slurried with dichloromethane (5 mL), suction was filtered, the filtrate was combined, the solvent was dried under reduced pressure, and the residue was separated by column chromatography (eluent: V dichloromethane: V methanol = 200:1-50:1) to obtain 298 mg of light gray-yellow solid, yield: 48.7%, mp 185.8-187.5 °C.1 H-NMR (300MHz, CDCl3) δ (ppm): 8.45-8.44(m,1H,ArH),8.28(s,1H,ArH),7.51(d,J=7.2Hz,1H,ArH),7.16-7.13(m, 4H,ArH),4.52(t,J=6.0Hz,1H,triazole- CH2 ),3.98(s,3H,O CH3 ),3.41-3.35(m,2H, ArH- CH2 CH2), 2.87-2.79(m,6H,ArH-CH2 CH2 ,N (CH2)2 ),2.56-2.31(m,6H,N CH2 , C (CH2)2 ).

[0080] Example 3

[0081] Synthesis of 1-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-1H-1,2,3-triazole-5-carboxylic acid methyl ester

[0082] Referring to the synthesis method of Example 2, column chromatography (eluent: V dichloromethane: V methanol = 200: 1-50: 1) was used to separate and obtain 210 mg of the compound as a light brown solid. The yield was 43.1%, and the mp was 186.2-188.1°C.

[0083] Example 4

[0084] Synthesis of 1-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid

[0085] The compound of Example 2 (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (2 mL), and an aqueous solution of LiOH.H2O (23 mg, 2 mL) was added dropwise under ice bath. After the addition, the mixture was stirred at low temperature for 10 min and then moved to room temperature for reaction for 1 h. TLC (V dichloromethane: V methanol = 30:1) detected that the reaction of the raw material DL-1 was complete, the solvent was dried under reduced pressure, 1 mL of water was added and stirred to dissolve, 6N HCl was used under ice bath to adjust the pH to 4-5, and solid was precipitated. The solid was filtered and dried to obtain 62 mg of white solid, with a yield of 62.6%, and mp 80.1-82.0°C.

[0086] Example 5

[0087] Synthesis of 1-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-1H-1,2,3-triazole-5-carboxylic acid

[0088] Using the raw material of Example 3 (200 mg, 0.44 mmol), the same synthesis method as Example 4 was used to obtain 121 mg of a white solid with a yield of 61.1% and mp>250°C.

[0089] Example 6

[0090] Referring to the synthesis method of Example 4, 64 mg of compound was obtained with a yield of 34.1%. 1 H-NMR(300MHz, CD3OD)δ(ppm):2.44~2.55(m,2H),2.64~2.66(m,2H),2.82~2.92(m,2H),3.04~ 3.06(m,2H),3.35~3.37(m,2H),3.39~3.42(m,2H),4.45(s,2H),5.48(s,1H),7.11(d, 1H),7.19(d,1H),7.25(s,1H),7.27(t,1H),7.65(d,1H),8.33(d,1H).

[0091] Example 7

[0092] Referring to the synthesis method of Example 4, 58 mg of compound was obtained with a yield of 26.3%. 1 H-NMR(300MHz, CD3OD)δ(ppm):2.17~2.23(m,2H),2.26~2.35(m,2H),2.39~2.44(m,2H), 2.78~2.81(m,2H),2.84~2.90(m,4H),3.37~3.42(m,2H),3.58~3.60(m,2H), 3.65~3.67(m,2H),4.51~4.54(m,2H),4.64(s,2H),7.07(d,1H),7.13(d,1H),7.20(s, 1H),7.25(t,1H),7.65(d,1H),8.03(s,1H),8.32(s,1H).

[0093] Example 8

[0094] Synthesis of 1-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide

[0095] The compound of Example 2 (50 mg, 0.11 mmol) was dissolved in ammonia water (2 ml), sealed and reacted at 78°C for 3 h. After cooling to room temperature, TLC (V dichloromethane: V methanol = 20:1) detected that the reaction of raw material DL-1 was complete, the reaction solution was filtered, the white solid was washed with water and dried to obtain 30 mg, yield: 60.7%, mp 234.5~236.1°C.

[0096] 1 H-NMR (300MHz, CDCl3) δ (ppm): 8.43-8.42 (m, 1H, ArH), 8.26 (s, 1H, ArH), 7.46 (d, J=6.8Hz, 1H, ArH), 7.18-7.09 (m, 4H, ArH), 4.53 (t, J=6.6Hz, 1H, triazole-CH2),3.46-3.34(m,2H,ArH-CH2CH2),2.87-2.74(m,6H,ArH-CH2CH2, N(CH2)2),2.56-2.32(m,6H,NCH2,C(CH2)2).

[0097] Example 9

[0098] Synthesis of 1-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-1H-1,2,3-triazole-5-carboxamide

[0099] Using the compound of Example 3 (100 mg, 0.22 mmol) as the starting material, the same operation as Example 8 was performed to obtain 70 mg of an off-white solid with a yield of 70.9% and mp 220.1-221.8°C.

[0100] 1H-NMR (300MHz, CDCl3) δ (ppm): 8.43-8.41 (m, 1H, ArH), 8.26 (s, 1H, ArH), 7.46 (d, J = 8.1Hz, 1H, ArH), 7.18-7.10 (m, 4H, ArH), 4.53 (t, J = 6.3Hz, 1H, triazole-CH2),3.46-3.35(m,2H,ArH-CH2CH2),2.88-2.73(m,6H,ArH-CH2CH2, N(CH2)2),2.60-2.30(m,6H,NCH2,C(CH2)2).

[0101] Example 10

[0102] Step 1

[0103]

[0104] Desloratadine (8.00 g, 25.7 mmol), potassium carbonate (7.12 g, 51.5 mmol), acetone (200 mL) and 1-bromo-2-chloroethane (9.67 g, 51.5 mmol) were added to a 500 mL single-mouth bottle in sequence. The mixture was reacted at room temperature overnight under nitrogen protection. After the reaction was completed, the mixture was concentrated by TLC (DCM: MeOH = 10:1). Ethyl acetate (100 mL) was added to the residue, filtered, concentrated and purified by column chromatography (DCM: MeOH = 100:1 to 25:1) to obtain intermediate 1 (2.60 g, 27.1% yield) as a light red solid. 1 H NMR (400MHz, CDCl3): δppm 8.39-8.41 (dd, J1=1.6Hz, J2=4.8Hz, 1H), 7.42-7.44 (m, 1H), 7.14-7.15 (m, 1H), 7.13(d,J=1.2Hz,2H),7.07-7.10(m,1H),3.58(t,J=7.2Hz,2H),3.32-3.44(m,2 H),2.76-2.87(m,4H),2.73(t,J=7.2Hz,2H),2.50-2.57(m,1H),2.40-2.47(m,1H),2.23-2.39(m,4H).

[0105] Step 2

[0106]

[0107] 2,2-Dimethylbut-3-ynoic acid (2.00 g, 17.8 mmol), dichloromethane (40 mL), DMAP (261 mg, 2.14 mmol), DCC (4.41 g, 21.4 mmol) and benzyl alcohol (2.31 g, 21.4 mmol) were added to a 100 mL three-necked flask in sequence, and the reaction was allowed to proceed overnight at room temperature under nitrogen protection. After the reaction was completed by monitoring by TLC (PE:EA=20:1), the reaction solution was filtered, concentrated, and purified by flash preparative chromatography (40 g, PE:EA=200:1) to obtain intermediate 2 (3.25 g, 90.0% yield) as a light yellow oil. 1 HNMR (400MHz, CDCl3): δppm 7.33-7.38 (m, 5 H), 5.20 (s, 2H), 2.29 (s, 1H), 1.53 (s, 6H).

[0108] Step 3

[0109]

[0110] To a 100mL three-necked flask, add intermediate 2 (2.00g, 9.89mmol), (DMF:MeOH=9:1, 40 mL), CuI (94mg, 0.49mmol) and TMSN3 (1.71g, 14.8mmol) in sequence. Under nitrogen protection, slowly heat to 100℃ and keep warm overnight. The reaction solution is cooled to room temperature and monitored by TLC (PE:EA=20:1) to complete the reaction. The reaction system is quenched with water (120mL), extracted with ethyl acetate (30mL×6), washed with saturated sodium chloride solution (30 mL×3), and the organic phase is collected and dried over anhydrous sodium sulfate. Filter, concentrate and purify by flash preparative chromatography (40g, PE:EA=4:1) to obtain intermediate 3 (1.87g, 76.9%yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6): δppm 14.80 (s, 1H), 7.76 (s, 1H), 7.24-7.36 (m, 5H), 5.10 (s, 2 H), 1.56 (s, 6H).

[0111] Step 4

[0112]

[0113] Add intermediate 3 (1.60 g, 6.52 mmol) and anhydrous tetrahydrofuran (24 mL) to a 100 mL three-necked flask, and cool to 0 ° C under nitrogen protection. Add sodium hydride (60%, 391 mg, 9.78 mmol) to the above reaction solution in three batches, keep warm and stir for 30 min, then slowly add 2-(trimethylsilyl)ethoxymethyl chloride (1.63 g, 9.78 mmol), and react at room temperature for 8 h. After the reaction is completed, monitor the reaction by TLC (PE:EA=4:1), and cool the reaction solution to 0 ° C. Quench with water (100 mL), extract with ethyl acetate (20 mL×3), wash with saturated sodium chloride solution (20 mL×3), collect the organic phase, and dry with anhydrous sodium sulfate. Filter and concentrate to obtain intermediate 4 (2.45 g, 100% yield, N-position isomer mixture), oily substance, which is directly used in the next step. 1 H NMR (400MHz, CDCl3): δppm 7.56(s,1H),7.25-7.36(s,5H),5.61(s,2H),5.13(s,2H),3.60-3.64(m,2H ),1.64(m,6H),0.87-0.92(m,2H),-0.04(s,9H).(YWF41-12-1,20190606). 1HNMR(400 MHz, CDCl3): δppm 7.56(s,1H),7.27-7.36(s,5H),5.61(s,2H),5.14(s,2H),

[0114] 3.55-3.59(s,2H),1.68(s,6H),0.87-0.91(s,2H),-0.03(s,9H).

[0115] Step 5

[0116]

[0117] 4 (2.45 g, 6.52 mmol), methanol (50 mL) and 10% Pd / C (0.98 g, 40% Wt) were added to a 250 mL single-mouth bottle in sequence, and reacted at 45°C overnight (15 Psi) under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered under diatomaceous earth pad and concentrated to obtain 5 (1.86 g, 100% yield, a mixture of positional isomers) as a light yellow oil, which was directly used in the next step.

[0118] Step 6

[0119]

[0120] 5 (1.86 g, 6.52 mmol) and (DCM:MeOH = 10:1, 44 mL) were added to a 100 mL single-mouth bottle, and trimethylsilyldiazomethane (3.6 mL, 7.17 mmol) was slowly added dropwise at 0°C. After the addition was completed, the mixture was reacted at room temperature for 4 h. After the reaction was completed as monitored by TLC (PE:EA = 7.5:1) and the color development of bromocresol green showed, the mixture was concentrated and purified by flash preparative chromatography (40 g, PE:EA = 20:1-10:1) to obtain 6 (630 mg, 70% purity) as a colorless oil. 1 H NMR (400MHz, CDCl3): δppm 7.60(s,1H),5.63(s,2H),3.69(s,3H),3.57-3.61(s,2H), 1.66(s,6H),0.88-0.92(s,2H),-0.03(s,9H).

[0121] Step 7

[0122]

[0123] Add 6 (893 mg, 2.98 mmol), tetrahydrofuran (31 mL) and tetrabutylammonium fluoride (3.89 g, 14.9 mmol) to a 100 mL single-mouth bottle, and react at 66 ° C for 4 h under nitrogen protection. After the reaction is completed, monitor the reaction by TL C (PE: EA = 2: 1) and concentrate. Add ethyl acetate (40 mL) to the residue, wash with saturated sodium chloride solution (40 mL × 6), collect the organic phase, and dry it over anhydrous sodium sulfate. Filter, concentrate and purify by flash preparative chromatography (12 g, PE: EA = 2: 1) to obtain 7 (400 mg, 79.3% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3): δppm 7.65 (s, 1H), 3.71 (s, 3H), 1.66 (s, 6H).

[0124] Step 8

[0125]

[0126] 7 (250 mg, 1.48 mmol), DMF (16 mL), potassium carbonate (409 mg, 2.96 mmol), 1 (552 mg, 1.48 mmol) and potassium iodide (25 mg, 0.15 mmol) were added to a 100 mL single-mouth bottle in sequence, and the mixture was reacted at 70 °C for 4 h under nitrogen protection. After the reaction was completed by monitoring by TLC (DCM: MeOH = 20: 1), the reaction system was quenched with water (90 mL) at 0 °C. The mixture was extracted with ethyl acetate (10 mL × 6), washed with saturated sodium chloride solution (20 mL × 3), and the organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated and chromatographed by column chromatography (EA: MeOH = 25: 1) to obtain Example 10 compound (497 mg, 41.4% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3): δppm 8.38-8.40 (dd, J1=1.6Hz, J2=4.8Hz, 1H), 7.46 (s, 1H), 7.41-7.43 (dd, J1=1.6Hz, J2=7.6Hz,1H),7.14(s,1H),7.10-7.12(m,2H),7.06-7.09(m,1H),4.50 (t,J=7.2Hz,2H),3.65(s,3H),3.31-3.46(m,2H),2.93(t,J=6.8Hz,2H),2.71-2.86 (m,4H),2.45-2.52(m,1H),2.27-2.41(m,3H),2.18-2.25(m,2H),1.59(s,6H).

[0127] Embodiment 11

[0128] Referring to the synthesis method of Example 10, the compound of Example 11 (172 mg, 14.3% yield) was prepared as a yellow oil. 1 H NMR (400MHz, CDCl3): δppm 8.39-8.40 (dd, J1=1.6Hz, J2=4.8Hz, 1H), 7.50 (s, 1H), 7.42-7.44 (dd, J1=1.6Hz, J2=7.6Hz, 1H), 7.15 (br, 1H), 7.12 (br, 2H),7.07-7.10(m,1H),4.21(t,J=7.6Hz,2H),3.71(s,3H),3.32-3.44(m,2H), 2.94(t,J=7.6Hz,2H),2.76-2.87(m,4H),2.47-2.54(m,1H),2.31-2.44(m,3H), 2.20-2.29 (m, 2H), 1.63 (s, 6H).

[0129] Example 12

[0130] Referring to the synthesis method of Example 10, the compound of Example 12 (48 mg, 4.00% yield) was prepared as a yellow oil. 1 H NMR (400MHz, CDCl3): δppm 8.38-8.40 (dd, J1=1.6Hz, J2=4.8Hz, 1H), 7.59 (s, 1H), 7.42-7.44 (dd, J1=1.6Hz, J2=7.6Hz, 1H), 7.15 (br, 1H), 7.12 (br, 2H),7.07-7.10(m,1H),4.43(t,J=6.4Hz,2H),3.67(s,3H),3.31-3.44(m,2H),2. 73-2.87(m,6H),2.48-2.55(m,1H),2.31-2.44(m,3H),2.21-2.31(m,2H),1.63(s, 6H).

[0131] Embodiment 13

[0132]

[0133] To a 25 mL single-mouth bottle, add the compound of Example 10 (120 mg, 0.24 mmol), methanol (4 mL) and an aqueous solution (1 mL) of lithium hydroxide monohydrate (40 mg, 0.95 mmol) in sequence, and react at room temperature overnight under nitrogen protection. After the reaction is completed, monitor the reaction by TLC (EA: MeOH = 20: 1), and concentrate to remove the organic solvent. Dilute the residual liquid with water (1 mL), adjust the pH (5) with 1N hydrochloric acid, and a large amount of solid precipitates. Stir at room temperature for 1 h. Filter, wash the filter cake with water (2 mL × 4), collect the filter cake, and air dry (50 ° C, 4 h) to obtain the compound of Example 13 (100 mg, 84.7% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δppm 8.47-8.49 (dd, J1=1.2 Hz, J2=4.8Hz, 1H), 7.56 (s, 1H), 7.52-7.54 (dd, J1=0.8Hz, J2=7.6Hz, 1H), 7.16-7.19(m,3H),7.10(s,1H),4.82-4.90(m,1H),4.36-4.41(m,1H),3.24-3.36 (m,4H),3.13(t,J=10.0Hz,1H),2.75-2.81(m,3H),2.53-2.57(m,1H),2.22- 2.29(m,1H),2.01-2.10(m,2H),1.78-1.89(m,2H),1.72(s,3H),1.64(s,3H). (YWF42-01-1,20190622). 13 C NMR (100MHz, CDCl3): δ177.81,156.29,152.26, 144.66,138.46,137.82,137.55,136.50,133.68,132.48,131.58,130.80,130.57, 128.73,125.74,122.22,55.49,51.32,50.76,50.49,41.22,31.17,30.35,29.77,24.93,24.28.

[0134] Embodiment 14

[0135] Referring to the synthesis method of Example 13, the compound of Example 14 (110 mg, 65.8% yield) was prepared as a white solid. 1H NMR (400MHz, CDCl3): δppm 8.47-8.49 (dd, J1=1.6Hz, J2=4.8Hz, 1 H), 7.74 (s, 1H), 7.48-7.50 (dd, J1=1.6Hz, J2=7.6Hz, 1H), 7.11-7.16 (m, 3H), 7.05-7.07(d,J=8.4Hz,1H),4.45-4.57(m,2H),3.31-3.41(m,2H),2.97-3.09(m, 2H),2.75-2.86(m,3H),2.53-2.57(m,1H),2.27-2.50(m,5H),2.16-2.21(m,1H), 1.69(s,3H),1.66(s,3H). 13 C NMR (100MHz, CDCl3): δ178.66,156.57,152.44, 145.84,139.32,138.13,137.35,137.24,133.83,133.00,132.47,130.63,129.06, 126.18,122.60,122.13,56.56,53.81,53.75,47.15,42.01,31.61,31.22,29.99,29.90,26.27,25.82.

[0136] Embodiment 15

[0137] Referring to the synthesis method of Example 13, the compound of Example 15 (83 mg, 94.3% yield) was prepared as an off-white solid. 1 H NMR (400MHz, CDCl3): δppm 8.35 (d, J=4.0Hz, 1H), 7.52 (s, 1H), 7.46(d,J=7.2Hz,1H),7.09-7.16(m,3H),6.98(d,J=8.4Hz,1H),4.55-4.69(m,2 H),3.69-3.76(m,1H),3.55-3.61(m,1H),3.29-3.39(m,2H),3.15-3.18(m,1H), 2.74-2.89(m,5H),2.47-2.59(m,2H),2.28-2.40(m,2H),1.64(s,3H),1.61(s,3H). 13C NMR (100MHz, CDC3): δ174.56,151.54,141.90,139.03,135.10,133.67, 132.57,130.15,129.95,129.18,128.88,127.28,125.67,124.61,121.90,118.2 3,50.31,49.22,49.06,40.36,37.32,27.05,27.00,24.15,23.88,22.20,22.14.

[0138] Examples 16-22

[0139] Referring to the synthetic method of Example 13, the compounds of Examples 16-22 were prepared as follows

[0140]

[0141]

[0142] Embodiment 23

[0143] Synthesis of 5-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0144]

[0145] Desloratadine (500 mg, 1.6 mmol) and DIEA (520 mg, 4.0 mmol) were dissolved in methanol (8 mL), stirred at room temperature for 30 min, and then 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (215 mg, 1.6 mmol) was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature for 4 h. TLC (V dichloromethane: V methanol = 15:1) detected that the reaction of raw material 1 was complete, the reaction was stopped, methanol (10 mL) was added, stirred for 30 min, filtered, and dried to obtain 402 mg of a white solid, with a yield of 63.4%, and mp>250°C.

[0146] 1 H-NMR (300MHz, CDCl3) δ (ppm): 8.43-8.41 (m, 1H, ArH), 7.47 (d, J = 8.4Hz, 1H, ArH), 7.19-7.14 (m, 4H, ArH), 3.59 (s, 1H, N CH2 ),3.43-3.36(m,2H, ArH- CH2CH2), 2.95-2.81(m,4H,ArH-CH2 CH2 ,N (CH2)2 ),2.70-2.45(m,6H,N (CH2)2 , C (CH2)2 ).

[0147] Embodiment 24

[0148] Referring to the synthesis method of Example 23, 123 mg of compound was obtained with a yield of 46.1%. 1 H-NMR (300 MHz, CD3OD) δ (ppm): 2.24~2.34(m,2H), 2.44~2.50(m,2H), 2.83~2.85(m, 2H),2.86~2.92(m,2H),3.21~3.25(m,2H),3.34(s,3H),3.54(s,2H),3.70~3.76(m,2H), 7.11(d,1H),7.16(d,1H),7.22(s,1H),7.27(q,1H),7.68(d,1H),8.32(d,1H).

[0149] Embodiment 25

[0150] Referring to the synthesis method of Example 23, 136 mg of compound was obtained with a yield of 38.3%. 1 H-NMR (300 MHz, CD3OD) δ (ppm): 2.31~2.39(m,2H), 2.41~2.45(m,2H), 2.49~2.52(m,2H), 2.83~2.84(m,2H),2.90~2.92(m,2H),3.45~3.47(m,2H),3.69(s,2H),7.16(d,1H), 7.21(d,1H),7.27(s,1H),7.29(q,1H),7.70(d,1H),8.36(d,1H).

[0151] The composition embodiments of the present invention, taking the compound of Example 33 as an example, include but are not limited to the excipients and prescription ratios used in the following embodiments.

[0152] Embodiment 26

[0153] Example 1 Compound coated tablets (1000 tablets)

[0154] Tablet prescription

[0155]

[0156] Coating liquid prescription

[0157]

[0158] Preparation method: The compound of Example 1 and magnesium stearate are sieved through a 120-mesh sieve, and microcrystalline cellulose, calcium hydrogen phosphate, and pregelatinized starch are sieved through a 100-mesh sieve for later use; the compound of Example 1, microcrystalline cellulose, calcium hydrogen phosphate, and pregelatinized starch in the prescribed amount are weighed, and mixed by passing through an 80-mesh sieve in an equal-incremental manner, and a 30% ethanol solution is used as a wetting agent to prepare a soft material, granulated through a 20-mesh sieve, dried at 50-60° C. for 3-4 hours, granulated through a 20-mesh sieve, and the prescribed amount of magnesium stearate is added, mixed, and tableted.

[0159] Embodiment 27

[0160] Ordinary tablets of the compound of Example 1 (1000 tablets)

[0161]

[0162] Preparation method: the compound of Example 1 and magnesium stearate are sieved through a 120-mesh sieve, and microcrystalline cellulose, sodium carboxymethyl starch, and lactose are sieved through an 80-mesh sieve for later use; the compound of Example 1, microcrystalline cellulose, sodium carboxymethyl starch, and lactose in the prescribed amount are weighed, and mixed by 80-mesh sieve in equal increments, a 30% ethanol solution is used as a wetting agent to prepare a soft material, granulated with a 30-mesh sieve, dried at 50-60° C. for 3-4 hours, granulated with a 30-mesh sieve, and the prescribed amount of magnesium stearate is added, mixed, and tableted.

[0163] Embodiment 28

[0164] Capsules of the compound of Example 1 (1000 capsules)

[0165]

[0166] Preparation method: The compound of Example 1 and magnesium stearate are sieved through a 120-mesh sieve, and low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and lactose are sieved through an 80-mesh sieve for later use; the compound of Example 1, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and lactose in the prescribed amount are weighed, and mixed by 80-mesh sieve in equal increments, and a 30% ethanol solution is used as a wetting agent to prepare a soft material, and granulated with a 30-mesh sieve, dried at 50-60°C for 3-4 hours, granulated with a 30-mesh sieve, and the prescribed amount of magnesium stearate is added, mixed, and filled into capsules.

[0167] Embodiment 29

[0168] Granules of the compound of Example 1 (1000 packets)

[0169]

[0170] Preparation method: the compound of Example 1, microcrystalline cellulose, sucrose powder, sodium carboxymethyl starch, lactose, and aspartame are sieved through a 100-mesh sieve, and the orange flavor and sodium lauryl sulfate are sieved through an 80-mesh sieve for later use; the compound of Example 1, microcrystalline cellulose, sucrose powder, sodium carboxymethyl starch, lactose, and aspartame in the prescribed amount are weighed and mixed in equal amounts in an increasing manner, a 30% ethanol solution of 3% povidone is used to prepare a soft material, granulated with a 20-mesh sieve, dried at 50-60° C. for 3-4 hours, granulated with an 18-mesh sieve, and the prescribed amount of orange flavor and sodium lauryl sulfate is added, mixed, and bagged and sealed to obtain the product.

[0171] Embodiment 30

[0172] Example 1 Compound oral solution (1000 bottles)

[0173]

[0174] Preparation method: Aspartame, orange flavor and sodium citrate are dissolved in freshly prepared water for injection, filtered, and the compound of Example 1 in the prescribed amount is added at room temperature, dissolved, filtered and filled.

[0175] Embodiment 31

[0176] Example 1 Compound Syrup

[0177]

[0178]

[0179] Preparation method: add sucrose to 900 ml of water for injection, heat to boil, dissolve, filter while hot, cool to room temperature for use; dissolve the prescribed amount of Example 1 compound, aspartame, orange flavor, and sodium citrate in 60 ml of water for injection, filter, add to the above syrup, add water for injection to 1000 ml, mix well, and fill to obtain the product.

Claims

1. A compound having the following formula (I) or a pharmaceutically acceptable salt thereof in Ring A is a pyridine ring; X is R 5 , R 6 Substituted triazoles; n＝1-4； R 1 Selected from H, Cl; R 2 , R 3 Selected from H, hydroxyl; R 4 is H; R 5 , R 6 Selected from H, methyl, COOR 7 ,CONR 7 , R 7 It is H or methyl.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that The pharmaceutically acceptable salt is a potassium salt, sodium salt or ammonium salt of the compound of formula (I), or a salt formed by the compound of formula (I) and hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid or acetic acid.

3. A compound or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from the following compounds:

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4, wherein the dosage form is selected from tablets, capsules, granules, oral solutions, suppositories, transdermal preparations, injections, and eye drops.

6. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and treating allergic diseases.

7. The use according to claim 6, wherein the allergic disease is selected from the group consisting of allergic rhinitis, urticaria, chronic urticaria, allergic purpura, asthma, allergic dermatitis, eczema, allergic conjunctivitis, atopic dermatitis, sinusitis, and chronic sinusitis.

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