Crystal form of CGRP antagonist

Abstract

A crystal polymorphism form of CGRP antagonist (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiopyrano[2,3-b]pyridin-6-yl)piperidine-1-carboxamide, a preparation method therefor, a pharmaceutical composition containing the crystal form, and the use thereof in the treatment of related diseases.

Description

Crystalline form of CGRP antagonists Technical Field

[0001] This application relates to the crystalline polymorphic form of the CGRP antagonist (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiaro[2,3-b]pyridin-6-yl)piperidine-1-carboxamide, methods for its preparation, pharmaceutical compositions comprising said crystalline form, and its use in the treatment of related diseases. Background Technology

[0002] Migraine is a common neurovascular disease, mainly characterized by recurrent, mostly unilateral, moderate to severe throbbing headaches that usually last 4 to 72 hours and are accompanied by symptoms such as nausea, vomiting, and sensitivity to sound and light (phonophobia and photophobia) [1]. Before a migraine attack, there is often a period of sensory disturbance, which is called migraine with aura. One-seventh of migraine patients in my country have aura symptoms [2]. The main types of aura include visual disturbances such as scotomas, bright spots and flashes of light, as well as olfactory abnormalities, dizziness, tinnitus, and difficulty in speech. Currently, more than 1 billion people worldwide are affected by migraine [3]. The consultation rate of migraine patients in my country is only 52.9%, and the correct diagnosis rate by physicians is only 13.8%. There is also a general lack of preventive treatment and overuse of analgesics [2]. Migraine attacks can last for hours or even days and may seriously affect normal daily activities, which creates a significant need for acute treatments that can quickly relieve headaches. In recent years, with the progress of migraine research at home and abroad, new therapeutic targets such as calcitonin gene-related peptide (CGRP) have emerged, enriching the treatment methods for migraine.

[0003] Calcitonin gene-related peptide (CGRP) is a polypeptide composed of 37 amino acids. Its N-terminal disulfide bond and amino-terminal C-terminus play an important role in activating receptors [4]. CGRP is mainly located in the trigeminal ganglion, C-fibers and Aδ fibers in the dorsal root ganglion, and the central nervous system [5]. There are two forms of CGRP in the human body, namely α-CGRP and β-CGRP, which differ by only 1-3 amino acids in different species. α-CGRP is highly expressed in sensory neurons, while β-CGRP mainly functions in the enteric nervous system [6]. CGRP exerts its biological function by binding to receptors on the membrane. The CGRP receptor is mainly composed of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), and also requires receptor component protein (RCP) to perform signal transduction function [7]. CGRP mainly plays a role in vasodilating in the body. Studies suggest that CGRP plays an important role in the occurrence and development of migraine. Clinical evidence shows that the CGRP content in the jugular vein of migraine patients increases during an attack. Intravenous injection of CGRP can cause moderate to severe headache attacks, while the use of CGRP antagonists can relieve migraine pain and related symptoms[4].

[0004] PCT application PCT / CN2024 / 090110 provides a series of oxopyridine compounds with aliphatic or heterocyclic structures as CGRP antagonists, which can be used for the prevention and treatment of CGRP-mediated diseases, particularly migraine and neurogenic headache. Specifically, in Example 6 of this application, compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide is provided, which has the following structure and is referred to herein as compound I:

[0005] As demonstrated in PCT application PCT / CN2024 / 090110, the compound of formula I exhibits excellent CGRP antagonistic activity.

[0006] The solid-state form of the active pharmaceutical ingredient (API) of a particular drug is often a crucial factor determining the ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo. Crystalline form refers to the different lattice arrangements of substances of the same composition, resulting in different thermodynamic properties and stability for specific crystalline forms. Crystalline forms may also include different hydrates or solvates of the same compound. Determining which form is preferred requires comparing numerous properties of these forms and selecting the preferred form based on many physical property variables. In some cases, when certain aspects (e.g., ease of preparation, stability, etc.) are considered crucial, one form may be preferred, while in other cases, a different form may be preferred to obtain a higher dissolution rate and / or higher bioavailability.

[0007] Therefore, the ability of a chemical substance to crystallize into multiple crystalline forms can profoundly affect a drug's shelf life, solubility, formulation characteristics, and processing properties. Furthermore, drug efficacy can be influenced by molecular polymorphism. Different polymorphs may have varying absorption rates in vivo, leading to lower or higher than expected biological activity. The occurrence of unknown crystalline forms during manufacturing can also have significant impacts.

[0008] It is currently impossible to predict whether a particular compound or its salt will form polymorphs, whether those polymorphs are suitable for commercial use in therapeutic compositions, or which polymorphs will exhibit the desired properties. However, understanding which crystal forms a drug will produce under specific conditions allows researchers to optimize the desired properties of a compound, such as solubility, formulation characteristics, processing characteristics, and shelf life. Understanding these factors early in new drug development may mean producing more active, more stable, or cheaper drugs.

[0009] Invention Overview

[0010] On the one hand, this application provides polymorphic forms (including crystal forms A, B, C, D, E, and F of the compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) as well as amorphous forms.

[0011] On the other hand, this application provides a pharmaceutical composition comprising a polymorphic form (including crystal forms A, B, C, D, E, and F of the compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiaro[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) and / or an amorphous form, and a pharmaceutically acceptable carrier thereof.

[0012] On the other hand, this application provides the polymorphic form (including crystal forms A, B, C, D, E, and F of the compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiaro[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I), the amorphous form, and the above-described pharmaceutical compositions thereof, which are used as pharmaceuticals, particularly as pharmaceuticals for the prevention, treatment, or relief of diseases mediated and / or regulated by CGRP, such as migraines and / or neurogenic headaches.

[0013] On the other hand, this application provides the use of compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiaro[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) in polymorphic forms (including crystal forms A, B, C, D, E, and F of compound of formula I), amorphous forms, and the use of the above pharmaceutical compositions in the preparation of medicaments, particularly medicaments for the prevention, treatment, or relief of CGRP-mediated and / or regulated diseases, such as migraine and / or neurogenic headache.

[0014] On the other hand, this application also provides a method for preventing, treating, or alleviating CGRP-mediated and / or regulated diseases, comprising administering to a subject in need of prevention, treatment, or alleviation of the disease a therapeutically effective amount of compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidine-1-carboxamide (compound of formula I) in polymorphic forms (including crystal forms A, B, C, D, E, and F of compound of formula I), amorphous forms, and / or the above pharmaceutical composition. Alternatively, this application also provides polymorphic forms (including crystal forms A, B, C, D, E, and F of the compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I), amorphous forms, and / or the above pharmaceutical compositions for the prevention, treatment, or relief of CGRP-mediated and / or regulated diseases. Alternatively, this application also provides the use of compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiaro[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) in polymorphic forms (including crystal forms A, B, C, D, E, and F of compound of formula I), amorphous forms, and / or the above pharmaceutical compositions for the prevention, treatment, or relief of diseases mediated and / or regulated by CGRP. Such diseases include, for example, migraines and / or neuropathic pain.

[0015] On the other hand, this application also provides methods for preparing the polymorphic forms (including crystal forms A, B, C, D, E, and F of the compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) as well as the amorphous form.

[0016] Example 6 of PCT application PCT / CN2024 / 090110 describes the preparation of compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound I), and the preparation process is as follows:

[0017] The mass spectrometry and NMR data of the obtained compound of formula I are as follows:

[0018] MS(ESI)m / z(M+H) + =660.8.

[0019] 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),11.31(s,1H),7.96(s,1H),7.36(s,1H),7.00(s,1H),6.86(s,1H),6.64(d,J=8. 0,1H),4.80-4.72(m,1H),4.14-4.02(m,2H),3.57-3.53(m,1H),3.27-3.18(m,2H),3.14-3.08(m,1H),3.04-3.00(m,2H ),2.98-2.93(m,1H),2.92-2.86(m,1H),2.74-2.60(m,6H),2.56-2.54(m,1H),2.47(s,3H),2.37-2.31(m,1H),2.25-2. 19(m,1H),2.09(s,3H),2.01-1.89(m,4H),1.74-1.61(m,4H),1.55-1.49(m,1H),1.40-1.34(m,2H),1.30-1.13(m,4H).

[0020] Referring to a similar preparation process as the aforementioned compound of formula I, the following similar compounds were also prepared in PCT application PCT / CN2024 / 090110:

[0021] In the biological embodiments of this application, the activity or metabolic stability of compound (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) and its similar compounds (compounds of formulas II, III, and IV) were tested, and the specific results are as follows:

[0022] Test Example 1: Assay for Cellular Functional Antagonism - cAMP Assay

[0023] 1. Experimental Principle

[0024] The CGRP receptor complex is coupled to Gs in the G protein. The binding of CGRP to the CGRP receptor complex leads to the activation of Gs and the production of cAMP (3',5'-cyclic adenosine monophosphate).

[0025] 2. Experimental Materials

[0026] 2.1 Experimental cell lines:

[0027] SK-N-MC (neuroepithelial tumor cells), source: National Biomedical Experimental Cell Resource Bank.

[0028] 2.2 Reagents and Consumables

[0029] 3. Experimental Procedure

[0030] 3.1 Cell preparation:

[0031] Pre-resuscitate SK-N-MC cells, ensuring the cell confluence is 70%-80% before use.

[0032] 3.2 Prepare sample dilution solution, test compound and α-CGRP (human).

[0033] 3.3 Cell plating and drug effects:

[0034] SK-N-MC cells were digested, centrifuged, resuspended in sample dilution buffer, and seeded into 384-well plates. α-CGRP (human) and the test compound were added to each well, and the mixture was thoroughly mixed by pipetting. The plates were sealed with a sealing film and incubated at 25°C using an ELISA reader.

[0035] 3.4 cAMP assay: Performed according to the LANCE Ultra cAMP Kit instructions. Prepare Eu-cAMP tracer and Ultra-anti-cAMP working solutions in the dark. Add them separately to the wells of the plate and mix well by pipetting. Seal the plate with the sealing film and incubate at 25°C on an ELISA reader.

[0036] 3.5 Use the chemiluminescence module of the fully automated microplate reader to read the luminescence value.

[0037] 3.6 Data Analysis:

[0038] The IC was calculated using a nonlinear formula with the compound concentration (LOG) as the x-axis and inhibition as the y-axis. 50 The values ​​are shown in the table below.

[0039] Test Example 2: In vitro [ 125 Competitive binding assay of CGRP

[0040] 1. Experimental Principle:

[0041] SK-N-MCs endogenously express a CGRP receptor with the same sequence as the human CGRP receptor. Using SK-N-MC cell membrane homogenate as the receptor source, radiolabeled endogenous peptide human α-CGRP was added. 125 [I]CGRP) and compounds competitively bind to this receptor source, washing away unbound portions. 125 After CGRP, the binding of the reaction compound to the receptor can be detected by detecting radioactive signals.

[0042] 2. Experimental materials:

[0043] 2.1 Experimental cell line: SK-N-MC (human neuroepithelial tumor cells), source: Peking Union Medical College Cell Resource Center

[0044] 2.2 Detection equipment: MicroBeta2 (PerkinElmer), UNIFILTER-96-well cell collector (PerkinElmer, C961961)

[0045] 2.3 Experimental Reagents and Consumables

[0046] 2.4 Experimental Procedure

[0047] 2.4.1 Membrane Protein Extraction and Quantification: Fresh SK-N-MC cells were collected. The cell pellet was resuspended in experimental buffer (Tris-HCl 50mM, pH 7.4). The cells were homogenized 10 times using a homogenizer, centrifuged at 1000g, 4℃ for 10 minutes to remove nuclear / mitochondrial debris, and the supernatant tissue homogenate was collected. The supernatant was centrifuged at 50000g, 4℃ for 1 hour, and the supernatant was discarded. The particles were resuspended in an appropriate buffer (Tris-HCl 50mM, pH 7.4), and the protein concentration was determined. The suspension was then aliquoted and stored at -80℃.

[0048] 2.4.2 Determination of Compound Binding Ki (Inhibition Constant): Transfer 1 μl of serially diluted analyte to the assay plate. Add 50 μl of the membrane stock solution (i.e., the suspension prepared in section 2.4.1 above) (15 μg) and 50 μl of a final concentration of 200 pM to the plate. 125 I-CGRP (Human), vortex to mix. Add 50 μl of 0.3% PEI to each well of the plate and soak for 1 hour. Filter the reaction mixture using a UNIFILTER-96-well cell collector and wash the plate with pre-cooled buffer (Tris-HCl 50 mM, pH 7.4). After drying the plate, seal the bottom of the plate with Unifilter-96 backing seal tape, add 50 μl of Microscint 20-cocktail to each well, and seal the top of the plate with TopSeal-A sealing film. Capture cells using a MicroBeta2 Reader counting filter. 3 H signal.

[0049] 2.4.3 Data Analysis

[0050] Data were analyzed using Prism 5. A "log(inhibitor) vs. response-variable slope" model was used to fit the data, employing the slope determined in the saturation binding experiment. 125 The Kd value of I-CGRP (Human) is 240.6 pM. Calculations were performed on the compound and... 125 I-CGRP (Human) competitively binds to the IC50 of SK-N-MC cell membranes. 50 And Ki (Ki=IC50 / (1+[L] / Kd), [L]: Radioligand concentration(200pM)).

[0051] 3. Experimental Results

[0052] The Ki values ​​of the compounds binding to the CGRP receptor are shown in the table below:

[0053] Note: Ki ratio = Ki(compound) / Ki(Zavegepant).

[0054] Test Example 3: Liver Microsomal Stability Test

[0055] 1. Experimental Objective

[0056] The stability of the compound of this application in rat, monkey, and human liver microsomes was determined.

[0057] 2. Reagents and consumables

[0058] 3. Experimental Procedure

[0059] 3.1 Experimental incubation system

[0060] 3.2 Transfer an appropriate amount of liver microsome solution to a 1 mL 96-well plate, add the test drug solution (or probe substrate solution), and pre-incubate in a 37℃ hot mixer for 5 min. Take two aliquots of the mixture from the system, add 1×PBS instead of NADPH, and take the mixtures at 0 and 60 min respectively, adding methanol (containing internal standard) to terminate the reaction. Add NADPH to each well of the remaining mixture to start the reaction. Take the mixture from the system at 0, 5, 15, 30, 45, and 60 min for the test group, and at 0, 30, and 60 min for the control group, adding methanol (containing internal standard) to terminate the reaction. Mix all the terminated samples thoroughly, centrifuge at 3800 rpm for 15 min, and take the supernatant for LC-MS / MS analysis.

[0061] 3.3 Data Analysis

[0062] Peak areas were determined from the extracted ion chromatograms. The slope value k was determined by linear regression of the remaining percentage of the parent drug relative to the natural logarithm of the incubation time curve. The in vitro half-life (t) was calculated based on the slope. 1 / 2 ), and calculate the in vitro intrinsic clearance rate (CL) int (Expressed in μL / min / mg protein). The calculation formula is as follows:

[0063] t 1 / 2 =ln2 / k=0.693 / k;CL int =0.693 / t 1 / 2 / Hepatic microsomal protein concentration

[0064] The experimental results are shown in the table below:

[0065] Test Example 4: Plasma Protein Binding Rate Test

[0066] 1. Experimental Objective

[0067] The protein binding rate of the compound of this application in rat, monkey and human plasma was determined by balanced dialysis.

[0068] 2. Test substrate

[0069] 3. Experimental Procedure

[0070] 3.1 Rinse the dried dialysis membrane 2-3 times with ultrapure water, then soak it in phosphate buffer for 1 hour. Soak the polytetrafluoroethylene module in 20% ethanol for 30 minutes, blot off surface moisture with lint-free paper, and air dry. Assemble the pretreated dialysis membrane into the dialysis plate according to the product instructions, and add 100 μL of receiving solution (100 mM phosphate buffer solution with 0.002% Tween 80) to one side (receiving chamber) of each dialysis well.

[0071] 3.2 Take plasma and place it in a centrifuge tube. Add the working solution of the analyte to the plasma to a final concentration of 1 μM. Mix by inverting the tube (this step is performed on an ice bath). Take 20 μL of the drug-containing plasma into each of the 96-well sample plates, make two parallel samples, and store them in a -20℃ freezer.

[0072] 3.3 Take another 100 μL of the drug-containing plasma and add it to the other side of the membrane (sample chamber) of the dialysis apparatus, making two parallel portions. Incubate at 37°C with shaking for 6 hours. After 6 hours of incubation, take 20 μL of each sample from the receiving chamber and sample chamber after equilibration to obtain sample B and sample A. Add the corresponding volume of blank plasma or phosphate buffer (containing 0.002% Tween 80) to sample B and sample A respectively, so that the plasma to buffer volume ratio in each sample well is 1:1.

[0073] 3.4 Add 250 μL of methanol solution containing internal standard to all sample wells, mix well, and centrifuge at 3800 rpm for 10 minutes. Take 20 μL of the supernatant, add 180 μL of methanol, vortex to mix, and then analyze by LC-MS / MS.

[0074] 3.5 Data Analysis

[0075] The plasma protein binding rate and recovery rate of the compound in plasma are calculated using the following formula: Free percentage (%) = C B / C A Plasma protein binding rate (f b %) = 1 - Free percentage (%); Recovery rate (%) = (C B +C A ) / C T0

[0076] Where C B C represents the concentration of the compound in the receiving solution after equilibration dialysis. A C represents the concentration of the compound in the plasma after equilibration dialysis; T0 This represents the initial concentration of the compound in plasma.

[0077] The experimental results are shown in the table below:

[0078] Test Example 5: In Vivo Pharmacokinetic Study of the Test Compound Administered by Intravenous and Intranasal Routes to SD Rats

[0079] 1. Experimental Animals

[0080] Species: SD rats, male, SPF grade. Source: Purchased from Chengdu Dashuo Experimental Animal Co., Ltd., License number for experimental animal production: SCXK (Sichuan) 2020 - 030. Quantity: 2 for intravenous administration and 4 for intranasal administration.

[0081] 2. Preparation of Test Samples

[0082] 2.1 Weigh an appropriate amount of the drug precisely, add 50 mM succinate buffer (diluted with D5W, pH = 5 - 6), and sonicate and vortex to mix and dissolve thoroughly to obtain a dosing solution of 0.2 mg / mL for intravenous injection (IV) administration.

[0083] 2.2 Weigh an appropriate amount of the drug precisely, add 50 mM succinate buffer (diluted with purified water, pH = 5 - 6), and sonicate and vortex to mix and dissolve thoroughly to obtain a dosing solution of 10 mg / mL for intranasal (IN) administration.

[0084] 3. Experimental Design

[0085] 4. Blood Sampling Time Points

[0086] 5 min, 10 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h after administration.

[0087] 5. Sample Collection and Disposal [[ID=3​​​​​​​​​​​​​In vivo pharmacokinetic data of the test compound administered intravenously and intranasally to SD rats

[0092] Test Example 6: In vivo pharmacodynamic study of the test compound on capsaicin-induced changes in blood flow in the forearm skin of cynomolgus monkeys.

[0093] 1. Experimental Principle

[0094] Capsaicin induces the release of CGRP after acting on the skin. CGRP binds to receptors, exerts a vasodilatory effect, and promotes increased blood flow. The test compound inhibits the binding of CGRP to receptors, inhibiting the increase in blood flow caused by the release of CGRP. Blood flow is detected by a blood flow meter to reflect the efficacy of the drug.

[0095] 2. Experimental Procedure

[0096] 2.1 Animal Information:

[0097] Species: Crab-eating macaque, male (5-8 kg), Animal use permit: SYXK(Su)2019-0004, hair removal treatment was performed 3 days before the experiment.

[0098] 2.2 Sample configuration:

[0099] Accurately weigh an appropriate amount of drug, dissolve it in sterile physiological saline, and use sonication and vortexing to mix and dissolve it thoroughly to obtain a 0.05 mg / ml drug solution for intravenous (IV) administration.

[0100] 2.3 Pre-test phase: After anesthetizing the animals, a flowmeter was used to scan the blood flow on the inner side of the forearm, and an O-ring was placed on the inner side of the arm, avoiding obvious blood vessels. After confirming the position of the rubber ring, the blood flow rate inside the ring was scanned as the baseline blood flow value. Subsequently, 2 mg of capsaicin was applied inside the rubber ring, and the blood flowmeter recorded the blood flow rate at 10 min, 20 min, and 30 min after capsaicin treatment.

[0101] 2.4 Administration phase: After anesthetizing the monkeys, a rubber band was placed on the same part of the arm. After collecting baseline blood flow data, the test compound (dose: 0.05 mg / kg) was injected intravenously at a dose of 1 ml / kg. After administration, 2 mg of capsaicin was applied to the rubber band. Blood flow was recorded at 10 min, 20 min and 30 min after capsaicin treatment using a blood flow meter.

[0102] 2.5 Data Processing: Blood flow during the pre-test phase is denoted as P, and blood flow in the rubber band at time t is denoted as Pt. t Baseline blood flow is denoted as P0; blood flow during the drug administration phase is denoted as D; and blood flow through the rubber band at time t is denoted as D0. t If the baseline blood flow is denoted as D0, then the blood flow inhibition rate at time t is I. t The calculation formula is as follows: I t=((P) t –P0) / P0–(D t –D0) / D0)*100%

[0103] 3. Experimental Results:

[0104] The blood flow inhibition rates at different time points are shown in Figure 18. At 10 min, the blood flow inhibition rate of compound I (Mean = 355.3%) was significantly higher than that of Zavegepant (Mean = 89.7%). Attached Figure Description

[0105] Figure 1 shows the XRPD spectrum of crystal form A of compound I.

[0106] Figure 2 is the TGA spectrum of crystal form A of compound of formula I.

[0107] Figure 3 is the DSC spectrum of crystal form A of compound of formula I.

[0108] Figure 4 shows the XRPD spectrum of crystal form B of compound I.

[0109] Figure 5 is the TGA spectrum of crystal form B of compound I.

[0110] Figure 6 is the DSC spectrum of crystal form B of compound I.

[0111] Figure 7 shows the XRPD spectrum of crystal form C of compound I.

[0112] Figure 8 is the TGA spectrum of crystal form C of compound I.

[0113] Figure 9 shows the XRPD spectrum of crystal form D of compound I.

[0114] Figure 10 is the TGA spectrum of crystal form D of compound I.

[0115] Figure 11 is the DSC spectrum of crystal form D of compound of formula I.

[0116] Figure 12 is the XRPD spectrum of crystal form E of compound I.

[0117] Figure 13 is the TGA spectrum of crystal form E of compound I.

[0118] Figure 14 is the DSC spectrum of crystal form E of compound I.

[0119] Figure 15 is the XRPD spectrum of crystal form F of compound I.

[0120] Figure 16 is the TGA spectrum of crystal form F of compound I.

[0121] Figure 17 shows the amorphous XRPD spectrum of compound I.

[0122] Figure 18 shows the comparison of the blood flow inhibition rates of compound I and Zavegepant in an in vivo pharmacodynamic study of capsaicin-induced changes in blood flow in the forearm skin of cynomolgus monkeys.

[0123] Invention Details

[0124] definition

[0125] Unless otherwise stated or separately defined, the terms used in the specification and claims shall have the following meanings.

[0126] "Antagonist" refers to a drug that does not have intrinsic activity but can block the action mediated by receptor agonists after binding to the receptor.

[0127] As used herein, the term “pharmaceutical acceptable” means a molecular entity or composition that is approved or can be approved by the relevant authorities of each country, or is listed in a generally accepted pharmacopoeia for use in animals and more specifically in humans, or that will not produce adverse, allergic or other adverse reactions when administered appropriately to animals, such as humans.

[0128] As used herein, the term "substantially pure" when applied to a particular crystal form of a compound of Formula I means having a crystal form purity of more than 50% by weight, for example, more than 60% by weight, more than 70% by weight, more than 80% by weight, more than 90% by weight, more than 95% by weight, more than 97% by weight, and more preferably more than 99% by weight.

[0129] As used in this article, "polymorphism" or "crystal form" refers to a crystal form that has the same chemical composition but different spatial arrangements of molecules that form crystals.

[0130] As used herein, "solvent" or "solvent compound" refers to a crystalline form of a molecule that further comprises molecules of one or more solvents bound to a lattice structure. Solvent molecules in a solvate may exist in a regular and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate with non-stoichiometric amounts of solvent molecules may arise from the partial loss of solvent from the solvate. The solvent may be water, in which case the solvate may be referred to as a hydrate.

[0131] As used in this article, "amorphous" refers to a solid form of molecules that is not crystalline. Amorphous solids do not exhibit defined X-ray diffraction patterns.

[0132] As used herein, the terms “about” and “substantially” indicate that their values ​​can vary for characteristics such as endothermic, endothermic peaks, exothermic, baseline shifts, etc. Regarding X-ray diffraction peak positions, “about” or “substantially” means taking into account typical peak position and intensity variability. For example, those skilled in the art will understand that peak position (2θ) can indicate variability between certain devices, typically up to 0.2°. Furthermore, those skilled in the art will understand that relative peak intensities will show variability between devices as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be used only as qualitative measurements. For DSC, the observed temperature variation will depend on the rate of temperature change and the sample preparation technique and the specific instrument used. Therefore, the endothermic / melting point values ​​reported herein for DSC / TGA thermal analysis plots can vary by ±5°C (and are still considered characteristic of the specific crystalline form described herein). When used in the context of other characteristics such as weight percentage (by weight%) and reaction temperature, the term “about” indicates a variation of ±5%.

[0133] Zavegepant, also known as Vazegepant, is a nasal spray that was launched in the United States in March 2023 by Pfizer under the brand name ZAVZPRET.

[0134] Unless otherwise stated, the terms “comprise”, “comprises”, and “comprising” or their equivalents (contain, contain, containing, include, include, including) used herein are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0135] Unless the context clearly indicates otherwise, singular terms in this document cover the plural referents, and vice versa.

[0136] The term “prevention” means administering the crystalline, amorphous or compositional form of the compound of Formula I described in this application to prevent the disease described in this application or one or more symptoms associated with the disease, including: preventing the occurrence of the disease or disease state in a subject, particularly when such subjects are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0137] The term "treatment" means administering a crystalline, amorphous, or compositional form of a compound of Formula I described in this application to improve or eliminate one or more symptoms of the disease described in this application or related to the disease, including: suppressing the disease or disease state, i.e., curbing its development, or causing the disease or disease state to subside.

[0138] The term "relief" refers to administering the crystalline, amorphous, or compositional form of the compound of Formula I described in this application to reduce or decrease one or more symptoms of the disease described in this application or related to the disease, including: reducing the severity of the disease described in this application, delaying the progression of the disease, or reducing the frequency or duration of the disease.

[0139] The term "therapeutic effective amount" means (i) the amount of a crystalline, amorphous, or compositional form of a compound of Formula I described herein used to treat the specific disease, condition, or disorder described herein, (ii) reduce, improve, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) prevent or delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of a crystalline, amorphous, or compositional form of a compound of Formula I described herein constituting a "therapeutic effective amount" varies depending on the crystalline, amorphous, or compositional form of the compound of Formula I, the disease state and its severity, the route of administration, and the age of the subject to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

[0140] Unless otherwise stated, the terms “patient,” “subject,” and “individual” are used interchangeably in this document and refer to human or non-human animals (e.g., primates, rodents, etc.), such as, but not limited to, mice, rats, guinea pigs, dogs, pigs, chickens, rabbits, monkeys (e.g., rhesus monkeys, cynomolgus monkeys, etc.), humans, etc.

[0141] The term "pharmaceutically acceptable carrier" refers to carriers, such as excipients, diluents, or transporters, that do not significantly irritate the organism and do not impair the biological activity and properties of the active compound.

[0142] For purposes of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or contents of these documents. Detailed Implementation

[0143] Implementation Scheme 1. Crystalline form of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of Formula I), optionally said crystalline form is an anhydrous crystalline form.

[0144] Implementation Scheme 2. Crystal form A of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I).

[0145] Implementation Scheme 3. The crystal form A of the compound of formula I according to Implementation Scheme 2 is in essentially pure form.

[0146] Implementation Scheme 4. Crystal form A of the compound of formula I according to Implementation Scheme 2 or Implementation Scheme 3, having an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 7.1 ± 0.2°, 8.9 ± 0.2°, 10.0 ± 0.2°, 11.1 ± 0.2°, 13.6 ± 0.2°, 17.1 ± 0.2°.

[0147] Implementation Scheme 5. Crystal form A of the compound of formula I according to Implementation Scheme 2 or Implementation Scheme 3, having an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 6.2±0.2°, 7.1±0.2°, 8.9±0.2°, 10.0±0.2°, 11.1±0.2°, 12.4±0.2°, 13.6±0.2°, 15.1±0.2°, 16.1±0.2°, 17.1±0.2°, 18.0±0.2°, 19.3±0.2°, 21.1±0.2°, 22.3±0.2°, 25.3±0.2°.

[0148] Implementation Scheme 6. Crystal form A of the compound of formula I according to Implementation Scheme 2 or Implementation Scheme 3, having an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

[0149] Implementation Scheme 7. The crystal form A of the compound of formula I according to any one of Implementation Schemes 2 to 6 has a TGA spectrum that is substantially the same as that shown in Figure 2.

[0150] Implementation Scheme 8. The crystal form A of the compound of formula I according to any one of Implementation Schemes 2 to 7 has a DSC spectrum that is substantially the same as that shown in Figure 3.

[0151] Implementation scheme 9. Crystal form B of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I).

[0152] Implementation Scheme 10. The crystal form B of the compound of formula I according to Implementation Scheme 9 is in essentially pure form.

[0153] Implementation Scheme 11. Crystal form B of the compound of formula I according to Implementation Scheme 9 or Implementation Scheme 10, having an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.9 ± 0.2°, 7.2 ± 0.2°, 8.9 ± 0.2°, 10.3 ± 0.2°, 13.6 ± 0.2°, 16.1 ± 0.2°, 16.9 ± 0.2°, 21.8 ± 0.2°.

[0154] Implementation Scheme 12. Crystal form B of the compound of formula I according to Implementation Scheme 9 or Implementation Scheme 10, having an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.9 ± 0.2°, 7.2 ± 0.2°, 8.9 ± 0.2°, 10.3 ± 0.2°, 10.7 ± 0.2°. 0.2°, 11.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.6±0.2°, 14.6±0.2°, 16.1±0.2°, 16.9±0.2°, 17.9±0.2°, 18.5±0.2°, 19.3±0.2°, 20.4±0.2°, 20.9±0.2°, 21.8±0.2°, 26.8±0.2°.

[0155] Implementation Scheme 13. Crystal form B of the compound of formula I according to Implementation Scheme 9 or Implementation Scheme 10, having an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

[0156] Implementation Scheme 14. Crystal form B of the compound of formula I according to any one of Implementation Schemes 9 to 13, having a TGA spectrum substantially the same as that shown in Figure 5.

[0157] Implementation Scheme 15. Crystal form B of the compound of formula I according to any one of Implementation Schemes 9 to 14, having a DSC spectrum substantially the same as that shown in Figure 6.

[0158] Implementation scheme 16. Crystal form C of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I).

[0159] Implementation Scheme 17. The crystal form C of the compound of formula I according to Implementation Scheme 16 is in essentially pure form.

[0160] Implementation Scheme 18. Crystal form C of the compound of formula I according to Implementation Scheme 16 or Implementation Scheme 17, having an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.4 ± 0.2°, 7.9 ± 0.2°, 11.0 ± 0.2°, 15.6 ± 0.2°, 18.2 ± 0.2°.

[0161] Implementation Scheme 19. Crystal form C of the compound of Formula I according to Implementation Scheme 16 or Implementation Scheme 17, having an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.4 ± 0.2°, 7.9 ± 0.2°, 10.2 ± 0.2°, 11.0 ± 0.2°, 12.2 ± 0.2°, 12.7 ± 0.2°, 14.3 ± 0.2°, 15.6 ± 0.2°, 17.7 ± 0.2°, 18.2 ± 0.2°, 19.1 ± 0.2°, 20.6 ± 0.2°, 21.9 ± 0.2°, 22.9 ± 0.2°, 23.7 ± 0.2°.

[0162] Implementation Scheme 20. Crystal form C of the compound of formula I according to Implementation Scheme 16 or Implementation Scheme 17, having an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

[0163] Implementation Scheme 21. The crystal form C of the compound of formula I according to any one of Implementation Schemes 16 to 20 has a TGA spectrum that is substantially the same as that shown in Figure 8.

[0164] Implementation scheme 22. Crystal form D of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I).

[0165] Implementation Scheme 23. The crystal form D of the compound of formula I according to Implementation Scheme 22 is in a substantially pure form.

[0166] Implementation Scheme 24. Crystal form D of the compound of formula I according to Implementation Scheme 22 or Implementation Scheme 23, having an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 7.4 ± 0.2°, 8.1 ± 0.2°, 10.7 ± 0.2°, 12.5 ± 0.2°, 16.2 ± 0.2°, 17.5 ± 0.2°, 18.5 ± 0.2°, 22.4 ± 0.2°.

[0167] Implementation Scheme 25. Crystal form D of the compound of formula I according to Implementation Scheme 22 or Implementation Scheme 23, having an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 7.4 ± 0.2°, 8.1 ± 0.2°, 10.7 ± 0.2°, 11.6 ± 0.2°, 12.5 ± 0.2°, 13.6 ± 0.2°, 14.6 ± 0.2°, 15.2 ± 0.2°, 16.2 ± 0.2°, 17.5 ± 0.2°, 18.5 ± 0.2°, 20.7 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 25.2 ± 0.2°.

[0168] Implementation Scheme 26. Crystal form D of the compound of formula I according to Implementation Scheme 22 or Implementation Scheme 23, having an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

[0169] Implementation Scheme 27. The crystal form D of the compound of formula I according to any one of Implementation Schemes 22 to 26 has a TGA spectrum that is substantially the same as that shown in FIG10.

[0170] Implementation Scheme 28. The crystal form D of the compound of formula I according to any one of Implementation Schemes 22 to 27 has a DSC spectrum that is substantially the same as that shown in FIG11.

[0171] Implementation scheme 29. Crystal form E of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I).

[0172] Implementation Scheme 30. The crystal form E of the compound of formula I according to Implementation Scheme 29 is in a substantially pure form.

[0173] Implementation Scheme 31. Crystal form E of the compound of formula I according to Implementation Scheme 29 or Implementation Scheme 30, having an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 4.0 ± 0.2°, 8.9 ± 0.2°, 10.5 ± 0.2°, 11.2 ± 0.2°, 11.8 ± 0.2°, 18.1 ± 0.2°, 20.3 ± 0.2°.

[0174] Implementation Scheme 32. Crystal form E of the compound of formula I according to Implementation Scheme 29 or Implementation Scheme 30, having an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 4.0 ± 0.2°, 7.8 ± 0.2°, 8.9 ± 0.2°, 10.5 ± 0.2°, 11.2 ± 0.2°, 11.8 ± 0.2°, 13.5 ± 0.2°, 16.6 ± 0.2°, 17.5 ± 0.2°, 18.1 ± 0.2°, 18.9 ± 0.2°, 20.3 ± 0.2°, 21.4 ± 0.2°, 22.0 ± 0.2°, 22.5 ± 0.2°, 23.7 ± 0.2°.

[0175] Implementation Scheme 33. Crystal form E of the compound of formula I according to Implementation Scheme 29 or Implementation Scheme 30, having an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

[0176] Implementation Scheme 34. The crystal form E of the compound of formula I according to any one of Implementation Schemes 29 to 33 has a TGA spectrum that is substantially the same as that shown in Figure 13.

[0177] Implementation Scheme 35. The crystal form E of the compound of formula I according to any one of Implementation Schemes 29 to 34, which has a DSC spectrum substantially the same as that shown in FIG14.

[0178] Implementation scheme 36. Crystal form F of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I).

[0179] Implementation Scheme 37. The crystal form F of the compound of formula I according to Implementation Scheme 36 is in essentially pure form.

[0180] Implementation Scheme 38. Crystal form F of the compound of formula I according to Implementation Scheme 36 or Implementation Scheme 37, having an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.8 ± 0.2°, 7.3 ± 0.2°, 8.9 ± 0.2°, 11.6 ± 0.2°, 13.9 ± 0.2°, 17.0 ± 0.2°.

[0181] Implementation Scheme 39. Crystal form F of the compound of formula I according to Implementation Scheme 36 or Implementation Scheme 37, having an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.8±0.2°, 7.3±0.2°, 8.9±0.2°, 10.2±0.2°, 10.8±0.2°, 11.6±0.2°, 13.9±0.2°, 16.1±0.2°, 17.8±0.2°, 17.0±0.2°, 20.5±0.2°, 21.2±0.2°, 22.2±0.2°, 27.3±0.2°.

[0182] Implementation Scheme 40. Crystal form F of the compound of formula I according to Implementation Scheme 36 or 37, having an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

[0183] Implementation Scheme 41. The crystal form F of the compound of formula I according to any one of Implementation Schemes 36 to 40, having a TGA spectrum substantially the same as that shown in FIG16.

[0184] Implementation scheme 42. Amorphous form of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I).

[0185] Implementation Scheme 43. A pharmaceutical composition comprising, as an active ingredient, a compound of formula I according to any one of Implementation Schemes 1 to 42 in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F and / or amorphous form, and one or more pharmaceutically acceptable carriers.

[0186] Implementation Scheme 44. A compound of Formula I according to any one of Implementation Schemes 1 to 42, in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F or amorphous form, or a pharmaceutical composition according to Implementation Scheme 43, used as a medicament, particularly a medicament for the prevention, treatment or relief of diseases mediated and / or regulated by CGRP, said diseases preferably including migraine and / or neurogenic headache.

[0187] Implementation Scheme 45. Use of a compound of Formula I according to any one of Implementation Schemes 1 to 42, in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F or amorphous form, or in the preparation of a pharmaceutical composition according to Implementation Scheme 43, in the preparation of a medicament, particularly a medicament for the prevention, treatment or relief of CGRP-mediated and / or regulated diseases, wherein said diseases preferably include migraine and / or neurogenic headache.

[0188] Implementation Scheme 46. A method for preventing, treating, or alleviating a CGRP-mediated and / or regulated disease, comprising administering to a subject requiring prevention, treatment, or alleviation of the disease a therapeutically effective amount of a compound of formula I according to any one of Implementation Schemes 1 to 42, in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, or an amorphous form, or a pharmaceutical composition according to Implementation Scheme 43, wherein the disease preferably includes migraine and / or neurogenic headache.

[0189] Implementation Scheme 47. A compound of Formula I according to any one of Implementation Schemes 1 to 42, in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F or amorphous form, or a pharmaceutical composition according to Implementation Scheme 43, for the prevention, treatment or relief of diseases mediated and / or regulated by CGRP, wherein the diseases preferably include migraine and / or neurogenic headache.

[0190] Implementation Scheme 48. A compound of Formula I according to any one of Implementation Schemes 1 to 42, in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F or amorphous form, or a pharmaceutical composition according to Implementation Scheme 43, which is used as a medicine, particularly for the prevention, treatment or relief of diseases mediated and / or regulated by CGRP, wherein the diseases preferably include migraine and / or neurogenic headache.

[0191] Implementation Scheme 49. Use of a compound of Formula I according to any one of Implementation Schemes 1 to 42, in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F or amorphous form, or in the pharmaceutical composition according to Implementation Scheme 43, for the prevention, treatment or relief of diseases mediated and / or regulated by CGRP, wherein the diseases preferably include migraine and / or neurogenic headache.

[0192] Implementation Scheme 50. A method for preparing crystal form A of a compound of formula I according to any one of Implementation Schemes 2 to 8, comprising dispersing the amorphous form of the compound of formula I in acetonitrile, stirring overnight at room temperature, and filtering.

[0193] Implementation Scheme 51. A method for preparing crystal form B of a compound of formula I according to any one of Implementation Schemes 9 to 15, comprising dispersing the amorphous form of the compound of formula I in isopropanol, stirring overnight, and filtering.

[0194] Implementation Scheme 52. A method for preparing crystal form C of the compound of formula I according to any one of Implementation Schemes 16 to 21, comprising dispersing the amorphous form of the compound of formula I in tetrahydrofuran, stirring overnight, and filtering.

[0195] Implementation Scheme 53 is a method for preparing crystal form D of the compound of formula I according to any one of Implementation Schemes 22 to 28, comprising dispersing the amorphous form of the compound of formula I in butyl acetate, stirring overnight, and filtering.

[0196] Implementation Scheme 54. A method for preparing crystal form E of a compound of formula I according to any one of Implementation Schemes 29 to 35, comprising dispersing the amorphous form of the compound of formula I in tert-butanol, stirring overnight, and filtering.

[0197] Implementation Scheme 55. A method for preparing crystal form F of a compound of formula I according to any one of Implementation Schemes 36 to 41, comprising dispersing the amorphous form of the compound of formula I in toluene, stirring overnight, and filtering.

[0198] The following embodiments further illustrate this application. These embodiments are only for illustrating the technical solutions of this application and are not intended to limit the scope of this application. Unless otherwise specified in the embodiments, conventional conditions or manufacturer-recommended conditions shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0199] Example

[0200] Instruments and testing methods:

[0201] ●X-ray powder diffractometer (XRPD):

[0202] Instrument Model: DX-2700

[0203] Detection method: Diffraction source: copper target (40KV, 30mA); Scanning rate: 0.04° / s; Scanning range: 3~40°(2θ)

[0204] ●Differential Scanning Calorimeter (DSC):

[0205] Instrument Model: Mettler Toledo DSC 3

[0206] Test method: Heating rate: 10K / min; Temperature range: 30~300℃

[0207] ●Simultaneous Thermal Analyzer (TGA / DSC)

[0208] Instrument Model: Mettler Toledo TGA / DSC 3 +

[0209] Test method: Heating rate: 10K / min; Temperature range: 30~300℃

[0210] Example 1. Preparation of the amorphous form of compound I

[0211] 10.0 g of compound I ((R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide) was dispersed in 100 mL of a 1:1 mixture of dichloromethane and methanol and stirred at room temperature until the solution became clear. The solution was then concentrated under reduced pressure (approximately 0.09 MPa) in a water bath at 45 °C to obtain a yellow-brown solid. The XRPD spectrum of the obtained solid showed no obvious characteristic peaks (Figure 17), indicating a diffuse, amorphous appearance.

[0212] Example 2. Preparation of crystal form A of compound of formula I

[0213] Take 100 mg of the amorphous form of compound I, disperse it in 1.5 ml of acetonitrile, and stir overnight at room temperature. Filter to obtain a powdery solid, which is the crystalline form A of compound I.

[0214] XRPD analysis of the solid revealed the following characteristic peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 7.1 ± 0.2°, 8.9 ± 0.2°, 10.0 ± 0.2°, 11.1 ± 0.2°, 13.6 ± 0.2°, and 17.1 ± 0.2°.

[0215] In addition, the X-ray powder diffraction pattern also includes the following characteristic peaks (Bragg angle 2θ, expressed in degrees ±0.2°): 6.2±0.2°, 12.4±0.2°, 15.1±0.2°, 16.1±0.2°, 18.0±0.2°, 19.3±0.2°, 21.1±0.2°, 22.3±0.2°, and 25.3±0.2°.

[0216] The representative XRPD spectrum of crystal form A of the compound of formula I is shown in Figure 1, and the important spectral lines are shown in the table below:

[0217] The TGA spectrum (Figure 2) of crystal form A of compound I shows no significant weight loss during heating; the DSC spectrum (Figure 3) shows a single sharp endothermic peak at 261.50℃ (onset). Therefore, crystal form A of compound I is amorphous.

[0218] Example 3. Preparation of crystal form B of compound of formula I

[0219] Take 100 mg of the amorphous form of compound I, disperse it in 1.5 ml of isopropanol, and stir overnight. Filter to obtain a powdery solid, which is the crystal form B of compound I.

[0220] XRPD analysis of the solid revealed the following characteristic peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.9 ± 0.2°, 7.2 ± 0.2°, 8.9 ± 0.2°, 10.3 ± 0.2°, 13.6 ± 0.2°, 16.1 ± 0.2°, 16.9 ± 0.2°, and 21.8 ± 0.2°.

[0221] In addition, the X-ray powder diffraction pattern also includes the following characteristic peaks (Bragg angle 2θ, expressed in degrees ±0.2°): 10.7±0.2°, 11.1±0.2°, 11.9±0.2°, 12.3±0.2°, 14.6±0.2°, 17.9±0.2°, 18.5±0.2°, 19.3±0.2°, 20.4±0.2°, 20.9±0.2°, and 26.8±0.2°.

[0222] The representative XRPD spectrum of crystal form B of compound I is shown in Figure 4, and the important spectral lines are shown in the table below:

[0223] The TGA spectrum (Figure 5) of crystalline form B of compound I shows a weight loss of approximately 7.1% at around 100–220 °C; the DSC spectrum (Figure 6) shows a broad endothermic peak at 176.08 °C (onset), followed by an exothermic peak, and then a sharp endothermic peak. Crystalline form B exhibits a significant desolvation process between 100 and 220 °C, indicating it is a solvate.

[0224] Example 4. Preparation of the crystal form C of compound of formula I

[0225] Take 150 mg of the amorphous form of compound I, disperse it in 1.5 ml of tetrahydrofuran, and stir overnight. Filter to obtain a powdery solid, which is the crystalline form C of compound I.

[0226] XRPD analysis of the solid produced the following characteristic peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.4 ± 0.2°, 7.9 ± 0.2°, 11.0 ± 0.2°, 15.6 ± 0.2°, and 18.2 ± 0.2°.

[0227] In addition, the X-ray powder diffraction pattern also includes the following characteristic peaks (Bragg angle 2θ, expressed in degrees ±0.2°): 10.2±0.2°, 12.2±0.2°, 12.7±0.2°, 14.3±0.2°, 17.7±0.2°, 19.1±0.2°, 20.6±0.2°, 21.9±0.2°, 22.9±0.2°, and 23.7±0.2°.

[0228] The representative XRPD spectrum of crystal form C of compound I is shown in Figure 7, and the important spectral lines are shown in the table below:

[0229] The TGA spectrum of crystalline form C of Formula I (Figure 8) shows that it continuously loses weight, approximately 6.9%, between 50 and 200 °C. Crystalline form C exhibits a significant desolvation process between 50 and 200 °C, indicating that it is a solvate.

[0230] Example 5. Preparation of crystal form D of compound of formula I

[0231] Take 150 mg of the amorphous form of compound I, disperse it in 1.5 ml of butyl acetate, and stir overnight. Filter to obtain a powdery solid, which is the crystal form D of compound I.

[0232] XRPD analysis of the solid revealed the following characteristic peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 7.4 ± 0.2°, 8.1 ± 0.2°, 10.7 ± 0.2°, 12.5 ± 0.2°, 16.2 ± 0.2°, 17.5 ± 0.2°, 18.5 ± 0.2°, and 22.4 ± 0.2°.

[0233] In addition, the X-ray powder diffraction pattern also includes the following characteristic peaks (Bragg angle 2θ, expressed in degrees ±0.2°): 11.6±0.2°, 13.6±0.2°, 14.6±0.2°, 15.2±0.2°, 20.7±0.2°, 21.8±0.2°, and 25.2±0.2°.

[0234] The representative XRPD spectrum of crystal form D of the compound of formula I is shown in Figure 9, and the important spectral lines are shown in the table below:

[0235] The TGA spectrum (Figure 10) of crystal form D of compound I shows a sustained weight loss of approximately 12.5% ​​between 90 and 160 °C; the DSC spectrum (Figure 11) shows a broad, shallow endothermic peak at 127 ± 5 °C. Crystal form D exhibits a significant desolvation process between 90 and 160 °C, indicating it is a solvate.

[0236] Example 6. Preparation of crystal form E of compound of formula I

[0237] Take 150 mg of the amorphous form of compound I, disperse it in 1.5 ml of tert-butanol, and stir overnight. Filter to obtain a powdery solid, which is the crystal form E of compound I.

[0238] XRPD analysis of the solid produced an X-ray powder diffraction pattern with the following characteristic peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 4.0 ± 0.2°, 8.9 ± 0.2°, 10.5 ± 0.2°, 11.2 ± 0.2°, 11.8 ± 0.2°, 18.1 ± 0.2°, and 20.3 ± 0.2°.

[0239] In addition, the X-ray powder diffraction pattern also includes the following characteristic peaks (Bragg angle 2θ, expressed in degrees ±0.2°): 7.8±0.2°, 13.5±0.2°, 16.6±0.2°, 17.5±0.2°, 18.9±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, and 23.7±0.2°.

[0240] The representative XRPD spectrum of crystal form E of the compound of formula I is shown in Figure 12, and the important spectral lines are shown in the table below:

[0241] The TGA spectrum (Figure 13) of crystal form E of compound I shows a rapid weight loss of approximately 16.3% between 100 and 150 °C. The DSC spectrum (Figure 14) shows a distinct endothermic peak at 110 ± 5 °C, an exothermic peak at 172 ± 5 °C, and an endothermic peak at 214.7 ± 5 °C. Crystal form E exhibits a significant desolvation process between 100 and 150 °C, indicating it is a solvate.

[0242] Example 7. Preparation of crystal form F of compound of formula I

[0243] Take 150 mg of the amorphous form of compound I, disperse it in 1.5 ml of toluene, and stir overnight. Filter to obtain a powdery solid, which is the crystalline form F of compound I.

[0244] XRPD analysis of the solid produced an X-ray powder diffraction pattern with the following characteristic peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.8 ± 0.2°, 7.3 ± 0.2°, 8.9 ± 0.2°, 11.6 ± 0.2°, 13.9 ± 0.2°, and 17.0 ± 0.2°.

[0245] In addition, the X-ray powder diffraction pattern also includes the following characteristic peaks (Bragg angle 2θ, expressed in degrees ±0.2°): 10.2±0.2°, 10.8±0.2°, 16.1±0.2°, 17.8±0.2°, 20.5±0.2°, 21.2±0.2°, 22.2±0.2°, and 27.3±0.2°.

[0246] The representative XRPD spectrum of crystal form F of compound I is shown in Figure 15, and the important spectral lines are shown in the table below:

[0247] The TGA spectrum (Figure 16) of crystal form F of compound I shows that it continuously loses approximately 8.81% of its weight between 40 and 210 °C. Crystal form F undergoes a desolvation process between 40 and 210 °C, and is a solvate.

[0248] Example 8. Stability Test

[0249] 1) Crystal form stability and chemical stability

[0250] The crystal form stability and chemical stability of representative crystal forms of this application were determined using methods known in the art. The results are shown below:

[0251] The results show that crystal forms A and B exhibit good crystal stability under light and high temperature conditions, respectively. Furthermore, under humid and hot conditions (40℃, 75% RH), crystal form A is stable, while crystal form B slowly transforms into an amorphous form.

[0252] The results show that, compared with the amorphous form, crystal form A and crystal form B have better chemical stability under light and high temperature conditions, respectively.

[0253] 2) Hygroscopicity

[0254] The hygroscopicity of a drug refers to the ability or degree to which a substance absorbs moisture under certain temperature and humidity conditions.

[0255] Test method:

[0256] 1. Take a dry, stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and place it in a suitable 25℃±1℃ constant temperature desiccator (with ammonium chloride or ammonium sulfate saturated solution at the bottom) or artificial climate chamber (set temperature 25℃±1℃, relative humidity 80%±2%) one day before the test, and accurately weigh it (m1).

[0257] 2. Take an appropriate amount of the test sample and spread it evenly in the weighing bottle mentioned above. The thickness of the test sample is generally about 1 mm. Accurately weigh the sample (m2).

[0258] 3. Leave the weighing bottle open and place it, along with the cap, under the above-mentioned constant temperature and humidity conditions for 24 hours.

[0259] 4. Close the weighing bottle cap and accurately weigh the contents (m³). Weight gain percentage = (m³ - m²) / (m² - m¹) × 100%

[0260] 5. Description of hygroscopic characteristics and definition of hygroscopic weight gain

[0261] Deliquescence: The process of absorbing sufficient water to form a liquid.

[0262] Extremely hygroscopic: the weight gain due to moisture absorption is not less than 15%.

[0263] It has hygroscopic properties: the weight gain due to moisture absorption is less than 15% but not less than 2%.

[0264] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0265] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0266] Hygroscopicity of compound I in crystal form A, crystal form B, and amorphous form was investigated according to the above guidelines for drug hygroscopicity. The results are as follows:

[0267] The results showed that crystal form A had significantly better hygroscopicity than crystal form B and amorphous form.

[0268] The compound of formula I of this application exhibits excellent stability and hygroscopicity, and can effectively inhibit CGRP-stimulated cAMP production, with a significantly lower IC50 value. 50 It has good liver microsomal stability and better PK properties, thus it can be used as a CGRP antagonist to prevent, alleviate or treat CGRP-mediated and / or regulated diseases, especially migraine or neuropathic pain.

[0269] For purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0270] This application is not limited to the optional embodiments described above, and anyone can derive other various forms of products based on the guidance of this application. The specific embodiments described above should not be construed as limiting the scope of protection of this application, which shall be determined by the claims, and the description can be used to interpret the claims.

[0271] Cited references:

[0272] [1]Ashina M, Terwindt GM, Al-Karagholi MA, et al. Migraine: disease characterization, biomarkers, and precision medicine. Lancet.2021;397(10283):1496-1504.doi:10.1016 / S0140-6736(20)32162-0

[0273] [2] Neurology Branch of Chinese Medical Doctor Association, Headache and Sensory Disorders Committee of Chinese Research Hospital Association. Chinese Guidelines for the Diagnosis and Treatment of Migraine (2022 Edition) [J]. Chinese Journal of Pain Medicine, 2022, 28(12):881-898.

[0274] [3]Ashina M,Katsarava Z,Do TP,et al.Migraine:epidemiology and systems of care.Lancet.2021;397(10283):1485-1495.doi:10.1016 / S0140-6736(20)32160-7

[0275] [4]Russo AF.Calcitonin gene-related peptide(CGRP):a new target for migraine.Annu Rev Pharmacol Toxicol.2015;55:533-552.doi:10.1146 / annurev-pharmtox-010814-124701.

Claims

1. (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) in crystalline or amorphous form, optionally in anhydrous crystalline form, 2. The crystalline or amorphous form of the compound of formula I according to claim 1, wherein, The crystalline form of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) has an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 7.1±0.2°, 8.9±0.2°, 10.0±0.2°, 11.1±0.2°, 13.6±0.2°, 17.1±0.2°; Optionally, the crystal form is in a substantially pure form; Optionally, the crystal form has an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 6.2±0.2°, 7.1±0.2°, 8.9±0.2°, 10.0±0.2°, 11.1±0.2°, 12.4±0.2°, 13.6±0.2°, 15.1±0.2°, 16.1±0.2°, 17.1±0.2°, 18.0±0.2°, 19.3±0.2°, 21.1±0.2°, 22.3±0.2°, 25.3±0.2°; Optionally, the crystal form has an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

3. The crystalline or amorphous form of the compound of formula I according to claim 2, wherein, The crystal form has a TGA spectrum that is substantially the same as that shown in Figure 2; Optionally, the crystal form has a DSC spectrum that is substantially the same as that shown in Figure 3.

4. The crystalline or amorphous form of the compound of formula I according to claim 1, wherein, The crystalline form of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) has an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.9±0.2°, 7.2±0.2°, 8.9±0.2°, 10.3±0.2°, 13.6±0.2°, 16.1±0.2°, 16.9±0.2°, 21.8±0.2°; Optionally, the crystal form is in a substantially pure form; Optionally, the crystal form has an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.9 ± 0.2°, 7.2 ± 0.2°, 8.9 ± 0.2°, 10.3 ± 0.2°, 10.7 ± 0.2°, 11.1 ± 0.2°. °, 11.9±0.2°, 12.3±0.2°, 13.6±0.2°, 14.6±0.2°, 16.1±0.2°, 16.9±0.2°, 17.9±0.2°, 18.5±0.2°, 19.3±0.2°, 20.4±0.2°, 20.9±0.2°, 21.8±0.2°, 26.8±0.2°; Optionally, the crystal form has an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

5. The crystalline or amorphous form of the compound of formula I according to claim 4, wherein, The crystal form has a TGA spectrum that is substantially the same as that shown in Figure 5; Optionally, the crystal form has a DSC spectrum that is substantially the same as that shown in Figure 6.

6. The crystalline or amorphous form of the compound of formula I according to claim 1, wherein, The crystalline form of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) has an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.4 ± 0.2°, 7.9 ± 0.2°, 11.0 ± 0.2°, 15.6 ± 0.2°, 18.2 ± 0.2°; Optionally, the crystal form is in a substantially pure form; Optionally, the crystal form has an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.4±0.2°, 7.9±0.2°, 10.2±0.2°, 11.0±0.2°, 12.2±0.2°, 12.7±0.2°, 14.3±0.2°, 15.6±0.2°, 17.7±0.2°, 18.2±0.2°, 19.1±0.2°, 20.6±0.2°, 21.9±0.2°, 22.9±0.2°, 23.7±0.2°; Optionally, the crystal form has an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): Optionally, the crystal form has a TGA spectrum that is substantially the same as that shown in Figure 8.

7. The crystalline or amorphous form of the compound of formula I according to claim 1, wherein, The crystalline form of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) has an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 7.4±0.2°, 8.1±0.2°, 10.7±0.2°, 12.5±0.2°, 16.2±0.2°, 17.5±0.2°, 18.5±0.2°, 22.4±0.2°; Optionally, the crystal form is in a substantially pure form; Optionally, the crystal form has an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 7.4±0.2°, 8.1±0.2°, 10.7±0.2°, 11.6±0.2°, 12.5±0.2°, 13.6±0.2°, 14.6±0.2°, 15.2±0.2°, 16.2±0.2°, 17.5±0.2°, 18.5±0.2°, 20.7±0.2°, 21.8±0.2°, 22.4±0.2°, 25.2±0.2°; Optionally, the crystal form has an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

8. The crystalline or amorphous form of the compound of formula I according to claim 7, wherein, The crystal form has a TGA spectrum that is substantially the same as that shown in Figure 10. Optionally, the crystal form has a DSC spectrum that is substantially the same as that shown in FIG11.

9. The crystalline or amorphous form of the compound of formula I according to claim 1, wherein, The crystalline form of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) has an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 4.0±0.2°, 8.9±0.2°, 10.5±0.2°, 11.2±0.2°, 11.8±0.2°, 18.1±0.2°, 20.3±0.2°; Optionally, the crystal form is in a substantially pure form; Optionally, the crystal form has an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 4.0±0.2°, 7.8±0.2°, 8.9±0.2°, 10.5±0.2°, 11.2±0.2°, 11.8±0.2°, 13.5±0.2°, 16.6±0.2°, 17.5±0.2°, 18.1±0.2°, 18.9±0.2°, 20.3±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.7±0.2°; Optionally, the crystal form has an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

10. The crystalline or amorphous form of the compound of formula I according to claim 9, wherein, The crystal form has a TGA spectrum that is substantially the same as that shown in Figure 13; Optionally, the crystal form has a DSC spectrum that is substantially the same as that shown in Figure 14.

11. The crystalline or amorphous form of the compound of formula I according to claim 1, wherein, The crystalline form of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropyl-2-yl)-4-(7-oxo-3,4,7,8-tetrahydro-2H-thiarano[2,3-b]pyridin-6-yl)piperidin-1-carboxamide (compound of formula I) has an X-ray powder diffraction pattern showing at least the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.8 ± 0.2°, 7.3 ± 0.2°, 8.9 ± 0.2°, 11.6 ± 0.2°, 13.9 ± 0.2°, 17.0 ± 0.2°; Optionally, the crystal form is in a substantially pure form; Optionally, the crystal form has an X-ray powder diffraction pattern showing at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°): 5.8±0.2°, 7.3±0.2°, 8.9±0.2°, 10.2±0.2°, 10.8±0.2°, 11.6±0.2°, 13.9±0.2°, 16.1±0.2°, 17.8±0.2°, 17.0±0.2°, 20.5±0.2°, 21.2±0.2°, 22.2±0.2°, 27.3±0.2°; Optionally, the crystal form has an X-ray powder diffraction pattern showing the following diffraction peaks (Bragg angle 2θ, expressed in degrees ± 0.2°):

12. The crystalline or amorphous form of the compound of formula I according to claim 13, wherein, The crystal form F has a TGA spectrum that is substantially the same as that shown in Figure 16.

13. A pharmaceutical composition comprising, as an active ingredient, a compound of formula I according to any one of claims 1 to 12 in crystalline and / or amorphous form, and one or more pharmaceutically acceptable carriers.

14. A crystalline or amorphous form of a compound of formula I according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13, for the prevention, treatment or relief of diseases mediated and / or regulated by CGRP, wherein the diseases preferably include migraine and / or neurogenic headache.

15. A method for preparing the crystalline form of the compound of formula I according to any one of claims 1 to 12, comprising: The amorphous form of the compound of formula I is dispersed in any solvent selected from the group consisting of acetonitrile, isopropanol, tetrahydrofuran, butyl acetate and tert-butanol, stirred overnight, and filtered.

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