Spiro compound and application thereof

Abstract

The invention discloses a spiro compound as well as a preparation method and pharmaceutical application thereof, the compound is a CGRP antagonist, and the compound has an application prospect of relieving migraine.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and provides a class of spiro compounds, a preparation method thereof and pharmaceutical uses thereof. This class of compounds is a CGRP antagonist and has an application prospect for relieving migraine. Background Art

[0002] Migraine is a common chronic episodic brain dysfunction disease. Long-term repeated attacks can lead to serious health losses, reduced quality of life and productivity losses, and has now become one of the major problems of global public health. Migraine is a common primary headache clinically, manifested as repeated pulsating moderate to severe headaches, often accompanied by symptoms such as nausea or vomiting, photophobia and phonophobia; Migraine has a high incidence and a long course, ranking second in the burden of neurological diseases.

[0003] Calcitonin gene-related peptide (CGRP) is a neuropeptide containing 37 amino acids. It was discovered 30 years ago and is produced during the alternative RNA processing of the calcitonin gene. CGRP is a potent vasodilator and thus has a protective mechanism that is very important for physiological and pathological conditions such as the cardiovascular system and wound healing. CGRP is mainly released by sensory nerves and is thus related to the pain pathway. It has been confirmed that CGRP antagonists can relieve migraine. Summary of the Invention

[0004] Technical problem to be solved: The present invention provides a class of spiro compounds, which have CGRP antagonistic activity and can be used to prepare drugs for treating migraine.

[0005] Technical solution: A class of spiro compounds represented by formula I, their stereoisomers or their pharmaceutically acceptable salts, hydrates or solvates,

[0006]

[0007] wherein,

[0008] The configurations of carbon atoms Z1, Z2, and Z3 are each independently selected from R or S configurations;

[0009] A is selected from a chain connection within 8 carbon atoms or a cyclic connection within 8 carbon atoms.

[0010] Preferably, wherein,

[0011] Carbon atom Z1 is in the R configuration, carbon atom Z2 is in the S configuration, and carbon atom Z3 is in the S configuration;

[0012] Or carbon atom Z1 is in the S configuration, carbon atom Z2 is in the R configuration, and carbon atom Z3 is in the R configuration;

[0013] A is selected from carbonyl, cyclohexanedicarbonyl, succinyl, -C(O)-CH2-, -C(O)-CH2-CH2- or -C(O)-CH2-CH2-CH2-CH2-.

[0014] Preferably, the compound is:

[0015]

[0016] Compound 1: as shown in S1;

[0017]

[0018] Compound 2: as shown in S2;

[0019]

[0020] Compound 3: as shown in S3;

[0021]

[0022]

[0023] Compound 4: as shown in S4;

[0024]

[0025] Compound 5: as shown in S5;

[0026]

[0027] Compound 6: as shown in S6;

[0028]

[0029] Compound 7: as shown in S7;

[0030]

[0031] Compound 8: as shown in S8.

[0032] The present invention provides an application of a compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, hydrate or solvate in the preparation of an anti-migraine drug.

[0033] The present invention provides a pharmaceutical composition comprising a compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt, hydrate or solvate and a pharmaceutically acceptable carrier. Detailed Description of the Invention

[0034] The present invention discloses a class of spiro compounds and their uses. Those skilled in the art can draw on the content of this article and appropriately improve process parameters to achieve them. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate variations and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0035] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way.

[0036] Example 1 Synthesis of Intermediates I1 and I2

[0037] Synthesis route:

[0038]

[0039] Synthesis process:

[0040] Intermediate A:

[0041]

[0042] 3-Bromo-6-hydroxy-2-methylpyridine (50 g, 265.9 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (80.19 g, 345.5 mmol) and cesium carbonate (103.97 g) were added to dioxane (500 ml), and the reaction was carried out at 50 °C for 16 hours under nitrogen protection. The reaction was monitored by LCMS until completion, concentrated, and the crude product was purified by silica gel column chromatography to obtain 37.7 g of white solid, with a yield of 53%.

[0043] LCMS: m / z(ES+)(M+H) + = 269.9, Rt = 0.742 min

[0044] Intermediate B:

[0045]

[0046] Compound A (28.6 g, 105.91 mmol) was dissolved in a mixed solution of dioxane (300 ml) and water (60 ml).

[0047] Add phenylboronic acid (15.5 g, 127.09 mmol), sodium carbonate (28.1 g, 264.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (8.65 g, 10.59 mmol). React at 100 °C for 16 h under nitrogen protection. Monitor the reaction completion by LCMS. Concentrate and purify by silica gel column chromatography to obtain 26.9 g of a gray solid with a yield of 95%.

[0048] LCMS: m / z (ES+) (M + H) + = 268.1, Rt = 0.891 min

[0049] Intermediate C:

[0050]

[0051] Dissolve compound B (30 g, 112.25 mmol) and N-bromosuccinimide (20.18 g, 113.4 mmol) in DCM. React at 25 °C for 16 h. Monitor the reaction completion by LCMS. Concentrate and obtain 27.5 g of a white solid by silica gel column chromatography with a yield of 79%.

[0052] LCMS: m / z (ES+) (M + H) + = 246.0

[0053] Intermediate D:

[0054]

[0055] Add compound C (27.50 g, 79.45 mmol), cesium carbonate (77.65 g, 238.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (7.28 g, 7.94 mmol), tert-butyl carbamate (13.96 g, 119.17 mmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (5.56 g, 11.92 mmol) to dioxane (300 ml). Stir at 100 °C for 16 h. Monitor the reaction completion by LCMS. Concentrate and purify by silica gel column chromatography to obtain 21 g of a white solid with a yield of 69%.

[0056] LCMS: m / z (ES+) (M + H)+ = 382.2

[0057] Intermediate E:

[0058]

[0059] Compound D (5 g, 13.1 mmol) and palladium-loaded catalyst (5 g, 47.0 mmol) were added to acetic acid (100 ml) and stirred at 100 °C for 16 hours. The reaction was monitored by LCMS until completion, then filtered and concentrated. Purification by silica gel column chromatography gave 2 g of white solid with a yield of 45%.

[0060] LCMS: m / z (ES+) (M + H) + = 329.3, Rt = 0.834 min

[0061] Intermediate F:

[0062]

[0063] Compound E (4.55 g, 13.86 mmol) and triethylamine (4.21 g, 41.6 mmol) were added to acetonitrile (200 ml). Subsequently, di-tert-butyl dicarbonate (14.1 g, 64.55 mmol) and 4-dimethylaminopyridine (169 mg, 1.39 mmol) were added. The reaction was carried out at 80 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and purified by silica gel column chromatography to give 5.6 g of white solid with a yield of 94%.

[0064] LCMS: m / z (ES+) (M + H) + = 329.3, Rt = 1.091 min

[0065] Intermediate G:

[0066]

[0067] Compound F (3.40 g, 7.94 mmol) was dissolved in methanol (34 ml), and sodium methoxide (171 mg, 3.17 mmol) was added. The mixture was stirred at 25 °C for 2 h. LCMS showed that the reaction was complete. The reaction solution was concentrated together with the last two batches (E0025 - 275, E0025 - 276: batch 1 g, 3.4 g, two batches obtained after this experiment). Ethyl acetate (200 ml) and water (100 ml) were added to the concentrated crude product. The aqueous phase was extracted with ethyl acetate (100 ml × 3), and the organic phases were combined. Washed with brine (100 ml × 1), dried over anhydrous sodium sulfate, and concentrated. Purification of the crude product by silica gel column chromatography gave 6.6 g of white solid with a yield of 94%.

[0068] LCMS: m / z (ES+) (M + H - 56) + = 331.3, Rt = 1.043 min

[0069] Intermediates H1 and H2:

[0070]

[0071] A pair of enantiomers G (6.6 g, 17 mmol) was separated by supercritical liquid chromatography to obtain white solid H1 (1.5 g, 3.88 mmol) and white solid H2 (1.6 g, 4.14 mmol).

[0072] Intermediates I1 and I2:

[0073]

[0074] Compound H1 (1.50 g, 3.88 mmol) was added to 1 M HCl (28 ml), and the mixture was stirred at 10 °C for 12 hours. The mixture was concentrated and lyophilized to obtain white solid I1 (1.17 g, yield 93%).

[0075] LCMS: m / z (ES+) (M + H) + = 287.1, Rt = 2.265 min

[0076] 1 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.33–7.28 (m, 1H), 7.23–7.16 (m, 2H), 4.73–4.59 (m, 1H), 4.25–4.16 (m, 1H), 3.99–3.85 (m, 1H), 3.82–3.73 (m, 1H), 3.67–3.55 (m, 1H), 2.62–2.51 (m, 1H), 2.34–2.23 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).

[0077] Compound H2 (1.60 g, 4.14 mmol) was added to 1 M HCl (28.9 mmol), and the mixture was stirred at a temperature of 10 °C for 12 hours. The mixture was concentrated and lyophilized to obtain white solid I2 (1.31 g, yield 98%).

[0078] LCMS: m / z (ES+) (M + H) + = 287.1, Rt = 1.698 min

[0079] 11H NMR (400 MHz, DMSO-d6) δ 8.70–8.50 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 7.33–7.28 (m, 1H), 7.20 (d, J = 7.6 Hz, 2H), 4.74–4.59 (m, 1H), 4.25–4.16 (m, 1H), 3.98–3.86 (m, 1H), 3.82–3.75 (m, 1H), 3.69–3.59 (m, 1H), 2.63–2.52 (m, 1H), 2.36–2.23 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).

[0080] Example 2: Synthesis of Compound S1

[0081] Synthesis route:

[0082]

[0083] Synthesis process:

[0084] Compound S1: Dissolve Compound I2 (0.11 g, 0.35 mmol) and N,N-diisopropylethylamine (0.09 g, 0.70 mmol) in 10 ml of dichloromethane, and add a dichloromethane solution (10 ml) of bis(trichloromethyl) carbonate (0.035 g, 0.117 mmol). React under an ice bath for 3 h, and add J (0.077 g, 0.35 mmol). Raise the temperature to room temperature and react overnight. Monitor the reaction by TLC until completion, concentrate, add ethyl acetate (10 ml) and water (10 ml) for extraction. Take the organic phase, wash with brine (10 ml), dry over anhydrous sodium sulfate, and filter. Purify the crude product by silica gel column chromatography to obtain 0.13 g of a white solid with a yield of 71.4%.

[0085] LCMS: m / z (ES+) (M + H) + = 532.2

[0086] 11H NMR (500 MHz, Chloroform-d) δ 9.73 (s, 1H), 8.28 (dd, J = 4.0, 2.2 Hz, 1H), 7.67 (dd, J = 7.7, 2.2 Hz, 1H), 7.29–7.15 (m, 5H), 6.72 (d, J = 9.0 Hz, 1H), 4.34 (dddd, J = 9.0, 7.6, 5.1, 2.5 Hz, 1H), 4.08–3.96 (m, 2H), 3.90 (dq, J = 17.0, 9.0 Hz, 1H), 3.65 (ddd, J = 12.3, 7.0, 4.3 Hz, 2H), 3.53 (ddd, J = 12.5, 7.0, 4.4 Hz, 2H), 3.15 (dddd, J = 11.3, 6.7, 3.2, 2.3 Hz, 1H), 2.52–2.46 (m, 1H), 2.49–2.44 (m, 1H), 2.44–2.39 (m, 1H), 2.41–2.35 (m, 1H), 2.20 (ddd, J = 12.5, 9.0, 7.8 Hz, 1H), 2.07 (ddd, J = 12.3, 6.2, 5.1 Hz, 1H), 1.17 (d, J = 7.0 Hz, 3H).

[0087] Example 3: Synthesis of Compound S2

[0088] Synthetic Route:

[0089]

[0090] Synthesis Process:

[0091] Compound S2: Dissolve Compound I1 (0.11 g, 0.35 mmol) and N,N-diisopropylethylamine (0.09 g, 0.70 mmol) in 10 ml of dichloromethane, and add a dichloromethane solution (10 ml) of bis(trichloromethyl) carbonate (0.035 g, 0.117 mmol). React under an ice bath for 3 h, and add J (0.077 g, 0.35 mmol). Raise the temperature to room temperature and react overnight. Monitor the reaction by TLC until completion, concentrate, add ethyl acetate (10 ml) and water (10 ml) for extraction. Take the organic phase, wash with brine (10 ml), dry over anhydrous sodium sulfate, and filter. Purify the crude product by silica gel column chromatography to obtain 0.14 g of white solid with a yield of 76.0%.

[0092] LCMS: m / z (ES+) (M + H) + = 532.2

[0093] 11H NMR (500 MHz, Chloroform-d) δ 9.73 (s, 1H), 8.28 (dd, J = 4.0, 2.2 Hz, 1H), 7.67 (dd, J = 7.7, 2.2 Hz, 1H), 7.29–7.15 (m, 5H), 6.72 (d, J = 9.0 Hz, 1H), 4.34 (dddd, J = 9.0, 7.6, 5.1, 2.5 Hz, 1H), 4.08–3.96 (m, 2H), 3.90 (dq, J = 17.0, 9.0 Hz, 1H), 3.65 (ddd, J = 12.3, 7.0, 4.3 Hz, 2H), 3.53 (ddd, J = 12.5, 7.0, 4.4 Hz, 2H), 3.15 (dddd, J = 11.3, 6.7, 3.2, 2.3 Hz, 1H), 2.52–2.46 (m, 1H), 2.49–2.44 (m, 1H), 2.44–2.39 (m, 1H), 2.41–2.35 (m, 1H), 2.20 (ddd, J = 12.5, 9.0, 7.8 Hz, 1H), 2.07 (ddd, J = 12.3, 6.2, 5.1 Hz, 1H), 1.17 (d, J = 7.0 Hz, 3H).

[0094] Example 4: Synthesis of Compound S3

[0095] Synthetic route:

[0096]

[0097] Synthesis process:

[0098] Intermediate K: Dissolve compound I1 (0.097 g, 0.3 mmol) in dichloromethane and cool to 0 °C. Dropwise add chloroacetyl chloride (0.036 g, 0.32 mmol). After reacting at room temperature for 2 h, monitor by TLC until the reaction is complete. Add ethyl acetate (20 ml), wash with water (10 ml × 3), dry over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography to obtain 0.098 g of white solid, with a yield of 90%.

[0099] LCMS: m / z (ES+) (M + H) + = 263.1

[0100] Compound S3: Dissolve J (0.024 g, 0.11 mmol) in N,N-dimethylformamide (5 ml) at room temperature. Add cesium carbonate (0.036 g, 0.11 mmol) and crown ether (0.0058 g, 0.022 mmol). Heat the mixture to 45 °C and react for 1.5 h. Then cool it to 0 °C and slowly add a solution of K (0.11 mmol, 0.04 g) in N,N-dimethylformamide (5 ml). Add potassium iodide (0.022 mmol, 0.0037 g) and let the reaction proceed overnight at room temperature. Monitor the reaction by TLC until completion. Add ethyl acetate (20 ml), wash with water (10 ml × 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain 0.053 g of a white solid with a yield of 88%.

[0101] LCMS: m / z (ES+) (M + H) + = 546.7

[0102] 1 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.75 - 7.63 (m, 3H), 7.44–7.05 (m, 6H), 4.71 - 4.56 (m, 1H), 4.43–4.28 (m, 1H), 4.19–4.08 (m, 2H), 3.87–3.69 (m, 2H), 3.61–3.53 (d, J = 13.7 Hz, 1H), 3.13–2.95 (m, 2H), 2.92–2.78 (m, 2H), 2.32–1.88 (m, 6H), 1.03 - 0.91 (m, 3H).

[0103] Example 5: Synthesis of Compound S4

[0104] Synthesis route:

[0105]

[0106] Synthesis process:

[0107] Compound S4: Succinic anhydride (12 mg, 0.12 mmol) was dissolved in dichloromethane. The temperature was lowered to 0 °C in an ice bath. I1 (38.65 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.079 ml, 0.48 mmol) were added. After reacting at room temperature for 3 h, N,N-diisopropylethylamine (0.079 ml, 0.48 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (42.38 mg, 0.13 mmol) were added, and then J (26.31 mg, 0.12 mmol) was added. TLC detection showed that the reaction was complete. 80 ml of water was added, and the mixture was extracted with ethyl acetate (20 ml × 4). The organic phases were combined, washed with water (100 ml × 1), washed with an aqueous sodium bicarbonate solution (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 0.059 g of a gray solid with a yield of 83.3%.

[0108] LCMS: m / z (ES+)(M + H) + = 588.8

[0109] 1 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.41 - 8.31 (m, 1H), 8.23–8.09 (dd, J = 5.0, 1.6 Hz, 1H), 7.75 - 7.66 (m, 1H), 7.43 - 6.96 (m, 6H), 4.70 - 4.51 (t, J = 12.4 Hz, 1H), 4.47 - 4.37 (m, 1H), 4.32 - 4.20 (m, 1H), 3.96–3.85 (d, J = 12.5, 1H), 3.84–3.68 (m, 2H), 3.58–3.46 (m, 1H), 3.31–3.27 (m, 3H), 3.20–3.12 (m, 1H), 2.98–2.83 (m, 1H), 2.58–2.52 (m, 1H), 2.49 - 2.44 (m, 5H), 2.37 - 2.30 (m, 1H), 2.20 - 1.76 (m, 6H), 1.01 - 0.89 (d, J = 5.7 Hz, 3H).

[0110] Example 6: Synthesis of Compound S5

[0111] Synthesis route:

[0112]

[0113] Synthesis process:

[0114] Intermediate L: Dissolve J (263 mg, 1.2 mmol) in 15 ml of N,N-dimethylformamide, add N,N-diisopropylethylamine (0.31 g, 2.4 mmol), then add O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (466 mg, 1.45 mmol), add 4-(methoxycarbonyl)cyclohexanecarboxylic acid (223 mg, 1.2 mmol), and react at room temperature overnight. Monitor the reaction by TLC. After the reaction is complete, add 30 ml of ice water, extract with ethyl acetate (20 ml × 3), combine the organic phases, wash once with 50 ml of saturated brine, dry, and concentrate. Purify the crude product by silica gel column chromatography to obtain 0.39 g of white solid with a yield of 83.0%.

[0115] LCMS: m / z (ES+) (M + H) + = 388.2

[0116] 1 1H NMR (500 MHz, Chloroform-d) δ 9.73 (s, 1H), 8.28 (dd, J = 4.0, 2.2 Hz, 1H), 7.67 (dd, J = 7.7, 2.2 Hz, 1H), 7.23 (dd, J = 7.7, 4.0 Hz, 1H), 3.53 (t, J = 5.8 Hz, 4H), 2.51 (q, J = 6.6 Hz, 1H), 2.50–2.37 (m, 4H), 2.23 (p, J = 6.3 Hz, 1H), 1.92–1.81 (m, 4H), 1.81–1.71 (m, 2H), 1.64–1.53 (m, 2H).

[0117] Intermediate M: Dissolve L (263 mg, 0.6 mmol) in 10 ml of tetrahydrofuran, add an aqueous solution (3.3 ml) of lithium hydroxide (28.7 mg, 1.2 mmol), and react at room temperature overnight. Monitor the reaction by TLC. After the reaction is complete, dilute with ethyl acetate (100 ml), wash with water (30 ml × 2), wash with brine (30 ml × 1), dry, and concentrate. Purify the crude product by silica gel column chromatography to obtain 0.20 g of white solid with a yield of 90.0%.

[0118] LCMS: m / z (ES+) (M + H) + = 374.2

[0119] Compound S5: I2 (41.9 mg, 0.13 mmol) was dissolved in 5 ml of N,N-dimethylformamide, and N,N-diisopropylethylamine (0.043 ml, 0.26 mmol) was added. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.09 mg, 0.16 mmol) was then added. L (49 mg, 0.13 mmol) was then added, and the mixture was allowed to react overnight at room temperature. TLC indicated that the reaction was complete. 20 ml of ice water was added, and the mixture was extracted with ethyl acetate (10 ml x 3). The organic phases were combined, washed once with 50 ml of saturated brine, dried, and concentrated. The crude product was purified by silica gel column chromatography to yield 0.064 g of a white solid (76.9% yield).

[0120] LCMS: m / z (ES+) (M+H) + =642.6

[0121] 1 H NMR(500MHz,Chloroform-d)δ10.82(s,1H),8.28(dd,J=4.0,2.2Hz,1H),7.97–7.95(d,J=10,1H),7,68-7. 66(m,1H),7.29–7.15(m,6H),4.36(dddd,J=9.8,7.5,4.9,2.6Hz,1H),4.08–3.96(m,2H),3.91(dq,J=17.0 ,9.0Hz,1H),3.53(t,J=5.8Hz,4H),3.19–3.11(m,1H),2.53(p,J=6.2Hz,1H),2.50–2.37(m,4H),2.35–2.2 8(m,1H),2.31–2.24(m,1H),1.99(ddd,J=12.5,9.0,7.6Hz,1H),1.88–1.65(m,9H),1.17(d,J=7.0Hz,3H).

[0122] Example 7: Synthesis of Compound S6

[0123] Synthesis route:

[0124]

[0125] Synthesis process:

[0126] Compound S6: Dissolve I2 (45.1 mg, 0.14 mmol) in 5 ml of dichloromethane, add triethylamine (28.3 mg, 0.28 mmol), cool the temperature to 0 °C, and dropwise add a solution of chloropropionyl chloride (18.66 mg, 0.15 mmol) in dichloromethane (5 ml). Add potassium iodide (4.7 mg, 0.028 mmol), add J (30.7 mg, 0.14 mmol), and react at room temperature overnight. Monitor by TLC until the reaction is complete. Dilute with 30 ml of ethyl acetate, wash with water (10 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by silica gel column chromatography to obtain 0.062 g of white solid with a yield of 78.6%.

[0127] LCMS: m / z(ES+)(M+H) + = 560.2

[0128] 1 H NMR(500 MHz, Chloroform-d) δ 10.77(s, 1H), 7.73 - 7.64(m, 3H), 7.40 - 7.02(m, 6H), 4.37(dddd, J = 9.5, 7.8, 5.0, 2.5 Hz, 1H), 4.08–3.96(m, 2H), 3.91(dq, J = 17.0, 9.0 Hz, 1H), 3.19–

[0129] 3.11(m, 1H), 2.91(t, J = 5.5 Hz, 4H), 2.78–2.65(m, 2H), 2.43–2.23(m, 6H), 1.98(ddd, J = 12.5, 8.9, 7.8 Hz, 1H), 1.17(d, J = 7.0 Hz, 3H).

[0130] Example 8: Synthesis of Compound S7

[0131] Synthesis route:

[0132]

[0133] Synthesis process:

[0134] Compound S7: Dissolve J (30.7 mg, 0.14 mmol) in 5 ml of dichloromethane, add triethylamine (28.3 mg, 0.28 mmol), cool the temperature to 0 °C, and dropwise add a solution of chloroacetyl chloride (17.0 mg, 0.15 mmol) in dichloromethane (5 ml). Add potassium iodide (4.7 mg, 0.028 mmol), add I2 (45 mg, 0.14 mmol), and react at room temperature overnight. Monitor by TLC until the reaction is complete. Add 50 ml of ethyl acetate for dilution, wash with water (15 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by silica gel column chromatography to obtain 0.060 g of white solid with a yield of 78.6%.

[0135] LCMS: m / z(ES+)(M+H) + = 546.4

[0136] 1 H NMR(500MHz,Chloroform-d)δ10.77(s,1H),8.28(dd,J = 4.0,1.8Hz,1H),7.67(dd,J = 7.7,1.8Hz,1H),7.29–7.15(m,6H),4.08–3.86(m,4H),3.82(dddd,J = 8.8,7.1,4.7,2.5Hz,1H),3.65–3.52(m,4H),3.48–3.35(m,2H),3.13–3.05(m,1H),2.54–2.48(m,1H),2.50–

[0137] 2.46(m,1H),2.45–2.40(m,1H),2.43–2.37(m,1H),2.15(ddd,J = 12.5,6.0,4.6Hz,1H),1.88(ddd,J = 12.5,8.8,7.3Hz,1H),1.16(d,J = 7.0Hz,3H).

[0138] Example 9: Synthesis of Compound S8

[0139] Synthesis route:

[0140]

[0141] Synthesis process:

[0142] Compound S8: Dissolve I1 (32 mg, 0.10 mmol) in 5 ml of N,N-dimethylformamide, add triethylamine (20.2 mg, 0.20 mmol), cool down to 0 °C, and dropwise add a DMF (5 ml) solution of 5-chlorovaleryl chloride (16.3 mg, 0.11 mmol). React at room temperature overnight. Add cesium carbonate (65.2 mg, 0.20 mmol), 18-crown-6 (5.3 mg, 0.02 mmol), add potassium iodide (3.3 mg, 0.02 mmol), and add 10 (21.9 mg, 0.10 mmol). Monitor by TLC until the reaction is complete. Dilute with 50 ml of ethyl acetate, wash with water (15 ml × 2), dry over anhydrous sodium sulfate, and concentrate. Purify the crude product by silica gel column chromatography to obtain 0.047 g of white solid with a yield of 80.0%.

[0143] LCMS: m / z (ES+) (M + H) + = 588.3

[0144] 1 1H NMR (500 MHz, Chloroform-d) δ 10.77 (s, 1H), 8.35 - 8.33 (d, J = 9.4, 1H), 8.27 (m, 1H), 7.67 (m, 1H), 7.30 - 7.15 (m, 6H), 4.37 (dddd, J = 9.3, 7.6, 5.1, 2.6 Hz, 1H), 4.08–3.99 (m, 1H), 4.02–3.95 (m, 1H), 3.91 (dq, J = 17.0, 9.0 Hz, 1H), 3.19–3.11 (m, 1H), {2.93–2.84 (m, 4H), 2.50–

[0145] 2.44 (m, 2H), 2.44–2.37 (m, 1H), 2.40–2.35 (m, 1H), 2.35–2.16 (m, 5H), 1.98 (ddd, J = 12.4, 8.9, 7.8 Hz, 1H), 1.57–1.44 (m, 4H), 1.17 (d, J = 7.0 Hz, 3H).

[0146] Example 10: Activity detection of the compound:

[0147] Experimental method: Use a stably expressed CGRP cell line (CALCRL / RAMP1 / CRCP combination) and detect the activity of the test substance with a FlexStation3 Multi-Mode Microplate Reader (Molecular Devices). Detection compound concentration setting: 10 detection concentrations for each sample, duplicate wells, 3-fold serial dilution, and the starting detection concentration is 10 μM. The results are shown in Table 1.

[0148] Table 1 Results of CGRP activity of compounds

[0149]

[0150] Note: "++" indicates that the compound activity is 200 nM

Claims

1. A class of spiro compounds represented by formula I, their stereoisomers, or their pharmaceutically acceptable salts, hydrates or solvates, characterized in that, wherein, the configurations of carbon atoms Z1, Z2, Z3 are each independently selected from R or S configurations; A is selected from a chain connection within 8 carbon atoms or a cyclic connection within 8 carbon atoms.

2. The compound according to claim 1, and its stereoisomers or pharmaceutically acceptable salts, hydrates or solvates thereof, characterized in that, wherein, carbon atom Z1 is in the R configuration, carbon atom Z2 is in the S configuration, and carbon atom Z3 is in the S configuration; or carbon atom Z1 is in the S configuration, carbon atom Z2 is in the R configuration, and carbon atom Z3 is in the R configuration; A is selected from carbonyl, p-cyclohexanedicarbonyl, succinyl, -C(O)-CH2-, -C(O)-CH2-CH2- or -C(O)-CH2-CH2-CH2-CH2-.

3. The compound according to claim 1, and its stereoisomers or pharmaceutically acceptable salts, hydrates or solvates thereof, characterized in that, The compounds are: Compound 1: as shown in S1; Compound 2: as shown in S2; Compound 3: as shown in S3; Compound 4: as shown in S4; Compound 5: as shown in S5; Compound 6: as shown in S6; Compound 7: as shown in S7; Compound 8: as shown in S8.

4. Use of the compound according to any one of claims 1 to 4, its stereoisomers, or its pharmaceutically acceptable salts, hydrates or solvates in the preparation of an anti-migraine drug.

5. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 4, its stereoisomers, or its pharmaceutically acceptable salts, hydrates or solvates and a pharmaceutically acceptable carrier.

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