P2X3 inhibitor compounds and their salts, crystal polymorphs and uses

Abstract

The present invention relates to P2X3 inhibitor compounds and their salts, crystalline polymorphs and uses.The present invention provides the crystalline form of the compound of formula I with good medicinal properties.The present invention also obtains medicinal salts of the compound of formula I, and further obtains crystalline form products of salts, such as hydrochloride crystalline form A, maleate crystalline form A, p-toluenesulfonate crystalline form A, benzenesulfonate crystalline form A, malonate crystalline form A, etc., which has important significance for the development of effective therapeutic drugs.

Description

Detailed Description of the Invention

[0001] This application claims priority to a prior application, filed on March 29, 2022 with the State Intellectual Property Office of the People's Republic of China, bearing application number 202210326113.5 and entitled "P2X3 Inhibitor Compounds and Their Salts, Crystalline Polymorphs and Uses," and a prior application, filed on March 21, 2023 with the State Intellectual Property Office of the People's Republic of China, bearing application number 202310281376.3 and entitled "P2X3 Inhibitor Compounds and Their Salts, Crystalline Polymorphs and Uses," both of which are incorporated herein by reference in their entirety.

[0002] [Technical field] The present invention relates to a P2X3 inhibitor compound and its salt, crystal polymorphism, and a method for producing and using the same.

[0003] [Background technology] P2X receptors are non-selective ATP-gated ionotropic receptors, i.e. purinergic receptors, which can bind to extracellular ATP, mainly derived from damaged or inflamed tissues. These receptors are widely expressed in the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, endocrine and other systems, and are involved in various physiological processes, such as the regulation of cardiac rhythm and contractility, the regulation of vascular tone, the regulation of nociception, especially chronic pain, the contraction of the vas deferens during ejaculation, the contraction of the bladder during urination, platelet aggregation, macrophage activation, cell apoptosis and neuron-glia interaction. The above P2X receptors include seven homologous receptors, namely P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7, and three heterologous receptors, namely P2X2 / 3, P2X4 / 6 and P2X1 / 5.

[0004] P2X3 is an isoform of the P2X receptor family that is selectively expressed in dorsal root ganglia at nerve terminals, spinal cord and brain neurons, ie small to medium diameter primary sensory neurons.

[0005] Numerous studies have suggested that activation of P2X3 and P2X2 / 3 expressed in primary sensory neurons plays an important role in acute injury, hyperalgesia and hypersensitivity in rodents. Many studies have suggested that upregulation of P2X3 receptor expression may lead to the formation of hyperalgesia and be involved in pain signal transduction. P2X3 gene knockout mice show reduced pain response, and P2X3 receptor antagonists have shown the effect of reducing nociception in pain and inflammatory pain models.

[0006] P2X3 is distributed in the primary afferent nerves around the airway and can regulate coughing. Research suggests that ATP released from airway injury or inflammatory tissue acts on the P2X3 receptors of primary neurons, triggering depolarization and action potentials, and the transmission of these potentials causes the urge to cough, resulting in coughing. P2X3 receptors play an important role in cough reflex hypersensitivity, and antagonizing the binding to P2X3 receptors can inhibit cough reflex hypersensitivity, thereby inhibiting excessive coughing in patients with chronic cough. Research also suggests that P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary arterial hypertension or asthma, and therefore P2X3 antagonists are also expected to be new drugs for treating the above diseases.

[0007] P2X3 is related to the channel that controls bladder volume reflex, and it has been reported that P2X3 gene knockout mice have significantly reduced urination frequency and significantly increased bladder volume.Therefore, the inhibition of the binding of P2X3 receptor antagonist to P2X3 receptor has the effect of treating urine storage and urination disorder such as overactive bladder.Therefore, P2X3 antagonist may be a potential drug for treating related diseases such as overactive bladder.

[0008] P2X3 antagonists show great promise. Although the currently commonly used cough medications, such as gabapentin, morphine and amitriptyline, or treatment with speech pathology, can improve the cough of many patients, they are not applicable to all patients, and centrally acting drugs such as gabapentin may cause adverse side effects and are not suitable for long-term administration. There is a need to develop a drug for chronic refractory cough that can be administered clinically for a long period of time to provide doctors with a drug choice. Therefore, the development of P2X3 antagonists is of great clinical significance.

[0009] Chinese patent application CN202111165441.3 discloses the structure of the compound of formula I. [ka] The compound of formula I can effectively antagonize P2X3 receptor activity and has a wide range of applications in the manufacture of drugs for treating P2X3-related diseases. Therefore, further study of the compound of formula I and its salts and crystal forms is of great significance to the development of effective drugs for treating P2X3-related diseases.

[0010] Summary of the Invention To solve the problems existing in the prior art, in one aspect, the present invention provides a crystalline form of a compound of Formula I, the structure of which is shown below, or a pharma- ceutically acceptable salt thereof. [ka] In some embodiments, the present invention provides a free base crystalline form A of the compound of formula I, wherein the free base crystalline form A has an X-ray powder diffraction pattern expressed at diffraction angles of 2θ±0.2° having diffraction peaks at 7.44°, 14.87°, 15.77°, 17.81°, and 18.61°, and further wherein the free base crystalline form A has an X-ray powder diffraction pattern expressed at diffraction angles of 2θ±0.2° having diffraction peaks at 7.44°, 11.14°, 11.36°, 14.87°, 15.77°, 16.97°, 17.81°, 18.61°. The X-ray powder diffraction pattern of the free base crystalline form A expressed in 2θ±0.2° diffraction angles has diffraction peaks at 3.75°, 7.44°, 11.14°, 11.36°, 11.98°, 12.25°, 14.87°, 15.77°, 16.97°, 17.81°, 18.61°, and 22.36°, and the X-ray powder diffraction pattern of the free base crystalline form A expressed in 2θ±0.2° diffraction angles has diffraction peaks at 3.75°, 5.99°, 7.44°, 9.81°, 10.78°, 11.02°, 12.01°, 13.02°, 14.01°, 15.02°, 16.02°, 17.01°, 18.02°, and 22.03°. and further, the X-ray powder diffraction pattern of the free base crystalline form A has diffraction peaks at 2θ±0.2° diffraction angles of 3.75°, 5.99°, 7.44°, 9.01°, 9.93°, 11.14°, 11.36°, 11.98°, 12.25°, 13.88°, 14.20°, 14.87°, 15.77°, 16.97°, 17.81°, 18.61°, 22.36°, and 24.07°. 5°, 13.88°, 14.20°, 14.87°, 15.77°, 16.97°, 17.81°, 18.61°, 19.39°, 20.26°, 21.14°, 22.36°, 23.34°, 24.07°, 26.33°, 26.78°, 27.18°, 28.17°, 30.20°, 33.88°, 34.35°, 37.23°, and 37.70°, and further, the free base crystalline form A has an XRPD pattern essentially as shown in FIG. 1-1.

[0011] In some embodiments, the free base crystalline form A is (1) The weight loss at 150.0±3°C in the TGA curve of the free base crystalline form A is about 1.28±1%; (2) The DSC curve for the free base crystalline form A has an onset of one endothermic peak at 175.6±3°C; (3) The DSC curve of the free base crystalline form A has one, two or three characteristics, namely, a single endothermic peak at 176.4±3° C.

[0012] In some embodiments, the TGA / DSC pattern of the free base crystalline form A is shown in FIG. 1 The H NMR spectra are shown in Figures 1-3.

[0013] According to an embodiment of the present invention, the free base crystalline form A is an anhydrous crystalline form.

[0014] In some embodiments, the free base crystalline form A exhibits aggregated needle-like crystals.

[0015] In some embodiments, the present invention provides a free base crystalline form B of the compound of formula I, wherein the free base crystalline form B has an X-ray powder diffraction pattern expressed at diffraction angles 2θ±0.2° having diffraction peaks at 7.21°, 12.48°, 13.17°, 14.41°, 19.09°, 19.56°, 22.09°, and 26.49°, and further wherein the free base crystalline form B has an X-ray powder diffraction pattern expressed at diffraction angles 2θ±0.2° having diffraction peaks at 7. and the X-ray powder diffraction pattern of the free base crystalline form B, expressed as diffraction peaks at 2θ±0.2° diffraction angles, is 7.21°, 8.35°, 12.48°, 13.17°, 14.41°, 16.72°, 19.09°, 19.56°, 20.90°, 22.09°, and 26.49°. and the X-ray powder diffraction pattern of the free base crystalline form B, expressed as diffraction peaks at 2θ±0.2° diffraction angles, is 7.21°, 8.35°, 12.48°, 13.17°, 14.41°, 15.05°, 16.72°, 17.80°, 18.39°, 19.09°, 19.56°, 20.90°, 21.67°, 22.09°, 22.97°, 25.16°, 26.49°, and 27.49°. 0.90°, 21.67°, 22.09°, 22.97°, 25.16°, 25.45°, 26.49°, 27.49°, 28.66°, 29.10°, 29.35°, 31.71°, 32.00°, 32.85°, 33.70°, 34.23°, 36.78°, 38.26°, and 38.70°, and further, the free base crystalline form B has an XRPD pattern essentially as shown in FIG. 2-1.

[0016] In some embodiments, the free base crystalline form B has (1) The weight loss at 150.0±3°C in the TGA curve of the free base crystalline form B is about 2.36±1%; (2) The DSC curve of the free base crystalline form B has an endothermic peak at the onset of 177.0±3°C. (3) The DSC curve of the free base crystalline form B has one, two or three characteristics, namely, one endothermic peak at 179.4±3° C.

[0017] In some embodiments, the TGA / DSC pattern of the free base crystalline form B is shown in FIG. 1 The H NMR spectrum is shown in Figure 2-3.

[0018] According to an embodiment of the present invention, the free base crystalline form B is an anhydrous crystalline form.

[0019] In another aspect, the present invention provides a pharma- ceutically acceptable salt of a compound of formula I, which may be selected from salts formed by a compound of formula I with an inorganic or organic acid, for example, said inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, and said organic acids include, for example, maleic acid, L-aspartic acid, fumaric acid, L-tartaric acid, citric acid, D-glucuronic acid, L-malic acid, hippuric acid, D-gluconic acid, DL-lactic acid, succinic acid, L-ascorbic acid, adipic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, malonic acid, gentisic acid, benzoic acid.

[0020] According to a preferred embodiment of the present invention, the pharma- ceutically acceptable salt of the compound of formula I above is the hydrochloride, maleate, p-toluenesulfonate, benzenesulfonate or malonate salt of the compound of formula I.

[0021] According to an embodiment of the present invention, as can be understood by those skilled in the art, when the compound of formula I and an acid form a salt, the molar ratio of the compound of formula I to the acid may be 5:1 to 1:5, such as 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3. Preferably, the molar ratio of the compound of formula I to the acid is 1:1 or 2:1.

[0022] According to another aspect, the present invention provides a crystalline form of a pharma- ceutically acceptable salt of a compound of formula I above.

[0023] In some embodiments, the present invention provides a hydrochloride crystalline form A of the compound of formula I, wherein the X-ray powder diffraction pattern of the hydrochloride crystalline form A expressed at diffraction angles of 2θ±0.2° has diffraction peaks at 7.77°, 9.01°, 10.10°, 15.54°, 17.51°, 19.24°, and 24.49°, and further wherein the X-ray powder diffraction pattern of the hydrochloride crystalline form A expressed at diffraction angles of 2θ±0.2° has diffraction peaks at 7.77°, 9.01°, 10.10°, 15.54°, 17.51°, 18.01°, 19.24°, 20.05°, 21.28°, 23.38°, 23.02°, 24.01°, 24.02 ... and the X-ray powder diffraction pattern expressed as 2θ±0.2° diffraction angles of the hydrochloride crystalline form A has diffraction peaks at 7.77°, 9.01°, 10.10°, 15.54°, 17.51°, 18.01°, 19.24°, 20.05°, 21.28°, 21.59°, 22.67°, 23.38°, 23.79°, 24.49°, 26.07°, 27.17°, and 28.33°, and further, the hydrochloride crystalline form A has an XRPD pattern essentially as shown in FIG. 3-1.

[0024] In some embodiments, the molar ratio of the compound of formula I to hydrochloric acid in the hydrochloride salt crystalline form A is 2:1.

[0025] According to an embodiment of the present invention, the hydrochloride salt crystalline form A has a VT-XRPD pattern essentially as shown in Figure 9-4.

[0026] According to an embodiment of the present invention, the hydrochloride crystalline form A is an anhydrous crystalline form.

[0027] In some embodiments, the hydrochloride salt crystalline form A is (1) The weight loss at 100.0±3°C in the TGA curve of the hydrochloride crystalline form A is about 2.19±1%; (2) The weight loss of the hydrochloride crystalline form A in the TGA curve within the temperature range of 100.0±3°C to 160.0±3°C is about 3.90±1%; (3) The DSC curve of the hydrochloride crystalline form A has an endothermic peak at 143.6±3°C. (4) The DSC curve of the hydrochloride crystalline form A has one endothermic peak at 157.4±3°C; (5) The DSC curve of the hydrochloride crystalline form A has one endothermic peak at 176.0±3°C; (6) The DSC curve of the hydrochloride salt crystalline form A has one, two, three, four, five or six characteristics, namely, one endothermic peak at 179.0±3°C.

[0028] In some embodiments, the TGA / DSC pattern of the hydrochloride salt crystalline form A is shown in FIG. 1 The 1 H NMR spectrum is shown in Figure 3-2.

[0029] In some embodiments, the hydrochloride salt crystalline form A is free of residual solvent.

[0030] In some embodiments, the hydrochloride salt crystalline form A exhibits irregular particulate appearance.

[0031] In some embodiments, the present invention provides a maleate crystalline form A of the compound of formula I, wherein the maleate crystalline form A has an X-ray powder diffraction pattern expressed at diffraction angles of 2θ±0.2° having diffraction peaks at 6.73°, 10.84°, 14.68°, 16.26°, 18.23°, and 18.44°, and further has an X-ray powder diffraction pattern expressed at diffraction angles of 2θ±0.2° having diffraction peaks at 5.43°, 6.73°, 10.84°, 14.68°, 16.26°, 16.82°, 18.23°, and 18.44°. and further, the X-ray powder diffraction pattern, expressed as diffraction angles of 2θ±0.2°, of the maleate crystalline form A has diffraction peaks at 5.43°, 6.73°, 9.95°, 10.84°, 11.75°, 13.50°, 14.68°, 16.26°, 16.82°, 18.23°, 18.44°, 20.17°, 22.79°, 23.22°, 24.00°, 26.07°, 27.72°, and 28.86°, and further, the maleate crystalline form A has an XRPD pattern essentially as shown in FIG. 4-1.

[0032] In some embodiments, in the maleate salt crystalline form A, the molar ratio of the compound of formula I to maleic acid is 2:1.

[0033] According to an embodiment of the present invention, the maleate salt crystalline form A has a VT-XRPD pattern essentially as shown in FIG. 10-4.

[0034] According to an embodiment of the present invention, the maleate salt crystalline form A is an anhydrous crystalline form.

[0035] In some embodiments, the maleate salt crystalline form A is (1) The weight loss at 110.0±3°C in the TGA curve of the maleate crystalline form A is about 1.65±1%; (2) The weight loss of the maleate salt crystalline form A in the TGA curve within the temperature range of 110.0±3°C to 220.0±3°C is about 11.88±1%; (3) The DSC curve of the maleate salt crystalline form A has one endothermic peak at 107.8±3°C; (4) The DSC curve of the maleate salt crystalline form A has an endothermic peak at the onset of 143.4±3°C; (5) The DSC curve of the maleate salt crystalline form A has one endothermic peak at 144.1±3°C; (6) The maleate salt crystalline form A has one, two, three or more characteristics, such as a DSC curve having one endothermic peak at 160.2±3° C.

[0036] In some embodiments, the TGA / DSC pattern of the maleate salt crystalline form A is shown in FIG. 10-2. 1 The 1 H NMR spectrum is shown in Figure 4-2.

[0037] In some embodiments, the present invention provides a p-toluenesulfonate crystalline form A of the compound of formula I, wherein the p-toluenesulfonate crystalline form A has an X-ray powder diffraction pattern at diffraction angles of 2θ±0.2° having diffraction peaks at 4.99°, 7.26°, 8.70°, 8.87°, 15.40°, 17.73°, 21.01°, and 24.13°, and further has an X-ray powder diffraction pattern at diffraction angles of 2θ±0.2° of the p-toluenesulfonate crystalline form A having diffraction peaks at 4.99°, 7.26°, 8.70°, 8.87°, 15.40°, 17.73°, 21.01°, and 24.13°. The pattern has diffraction peaks at 4.99°, 7.26°, 8.70°, 8.87°, 15.20°, 15.40°, 16.68°, 17.73°, 19.71°, 21.01° and 24.13°, and further, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A expressed as 2θ±0.2° diffraction angles is 4.99°, 7.26°, 8.70°, 8.87°, 14.45°, 14.88°, 15.20°, 15.40°, 16.41°, 16. The p-toluenesulfonate crystalline form A has diffraction peaks at 68°, 17.45°, 17.73°, 19.16°, 19.71°, 20.66°, 21.01°, 21.76°, 22.41°, 24.13°, 25.76°, 26.18°, and 27.25°, and further has an X-ray powder diffraction pattern represented by diffraction angles of 2θ±0.2° of 4.99°, 7.26°, 8.70°, 8.87°, 14.45°, 14.88°, 15.20°, 15.40°, 16.02°, and 17.01°. and having diffraction peaks at 6.41°, 16.68°, 17.45°, 17.73°, 19.16°, 19.71°, 20.66°, 21.01°, 21.76°, 22.41°, 24.13°, 25.76°, 26.18°, 27.25°, 27.95°, 29.23°, 30.69°, 31.00°, 31.78°, and 38.41°, and further, the p-toluenesulfonate salt crystalline form A has an XRPD pattern essentially as shown in FIG. 5-1.

[0038] In some embodiments, the p-toluenesulfonate crystalline form A has a molar ratio of the compound of formula I to p-toluenesulfonic acid of 1:1.

[0039] According to an embodiment of the present invention, the p-toluenesulfonate crystalline form A is an anhydrous crystalline form.

[0040] In some embodiments, the p-toluenesulfonate crystalline form A is (1) The weight loss at 150.0±3°C in the TGA curve of the p-toluenesulfonate crystalline form A is about 0.73±1%; (2) The DSC curve of the p-toluenesulfonate salt crystalline form A has an endothermic peak at 157.1±3°C. (3) The DSC curve of the p-toluenesulfonate salt crystalline form A has one, two or three characteristics, namely, one endothermic peak at 159.2±3°C.

[0041] In some embodiments, the TGA / DSC pattern of the p-toluenesulfonate salt crystalline form A is shown in FIG. 11-2. 1 The 1 H NMR spectrum is shown in Figure 5-2.

[0042] In some embodiments, the present invention provides a benzenesulfonate crystalline form A of the compound of formula I, wherein the benzenesulfonate crystalline form A has an X-ray powder diffraction pattern expressed at diffraction angles of 2θ±0.2° having diffraction peaks at 5.36°, 7.28°, 8.34°, 9.64°, 16.20°, 18.55°, and 21.49°, and further has an X-ray powder diffraction pattern expressed at diffraction angles of 2θ±0.2° having diffraction peaks at 5.36°, 7.28°, 8.34°, 9.64°, 16.20°, 18.55°, 19.28°, 21.49°, 21.81°, 23.21°, 25.05°, and 25.74°. and the X-ray powder diffraction pattern, expressed as 2θ±0.2° diffraction angles, of the benzenesulfonate crystalline form A has diffraction peaks at 5.36°, 7.28°, 8.34°, 9.64°, 10.66°, 14.55°, 15.00°, 16.20°, 16.93°, 17.85°, 18.55°, 19.28°, 19.74°, 20.80°, 21.49°, 21.81°, 23.21°, 23.68°, 23.98°, 25.05°, 25.74°, 26.65°, and 27.82°. Furthermore, the benzenesulfonate crystalline form A has an XRPD pattern essentially as shown in FIG. 6-1.

[0043] In some embodiments, in the benzenesulfonate salt crystalline form A, the molar ratio of the compound of formula I to benzenesulfonic acid is 1:1.

[0044] According to an embodiment of the present invention, the benzenesulfonate crystalline form A is an anhydrous crystalline form.

[0045] In some embodiments, the benzenesulfonate salt crystalline form A is (1) The weight loss at 120.0±3°C in the TGA curve of the benzenesulfonate crystalline form A is about 1.35±1%; (2) The DSC curve of the benzenesulfonate salt crystalline form A has an endothermic peak at 159.6±3°C; (3) The benzenesulfonate salt crystalline form A has one, two or three characteristics, namely, a DSC curve having one endothermic peak at 160.9±3°C.

[0046] In some embodiments, the TGA / DSC pattern of the benzenesulfonate salt crystalline form A is shown in FIG. 1 The 1 H NMR spectrum is shown in Figure 6-3.

[0047] In some embodiments, the present invention provides a malonate crystalline form A of the compound of formula I, wherein the malonate crystalline form A has an X-ray powder diffraction pattern expressed by diffraction angles of 2θ±0.2° having diffraction peaks at 6.75°, 9.96°, 10.67°, 14.48°, 16.04°, 16.88°, 18.04°, and 18.29°, and further comprises: The X-ray powder diffraction pattern of the malonate crystalline form A has diffraction peaks at 5.34°, 6.75°, 9.96°, 10.67°, 11.83°, 13.49°, 14.48°, 16.04°, 16.88°, 17.04°, 18.04°, 18.29°, and 27.38°. Further, the X-ray powder diffraction pattern of the malonate crystalline form A expressed in terms of diffraction angles of 2θ±0.2° has diffraction peaks at 5.34°, 6.75°, 9.96°, 10.67°, 11.83°, 13.49°, 14.48°, 16.04°, 16.88°, 17.04°, 18.04°, 18.29°, and 27.38°. and the X-ray powder diffraction pattern of the malonate crystalline form A, expressed as diffraction peaks at 2θ±0.2° angles, is 5.34°, 6.75°, 9.96°, 10.67°, 11.83°, 13.49°, 14.48°, 16.04°, 16.88°, 17.04°, 18.04°, 18.29°, 20.27°, 22.57°, 22.95°, 27.38°, and 28.83°. 7-1. and further, the malonate crystalline form A has diffraction peaks at: 13.49°, 14.48°, 16.04°, 16.88°, 17.04°, 18.04°, 18.29°, 18.63°, 20.27°, 21.57°, 22.57°, 22.95°, 24.11°, 24.83°, 26.02°, 27.38°, and 28.83°, and further, the malonate crystalline form A has an XRPD pattern essentially as shown in FIG. 7-1.

[0048] In some embodiments, the molar ratio of the compound of formula I to malonic acid in the malonate crystalline form A is 2:1.

[0049] According to an embodiment of the present invention, the malonate crystalline form A has a VT-XRPD pattern essentially as shown in FIG. 7-4.

[0050] According to an embodiment of the present invention, the malonate crystalline form A is an anhydrous crystalline form.

[0051] In some embodiments, the Malonate crystalline form A is (1) The weight loss at 120.0±3°C in the TGA curve of the malonate crystalline form A is about 2.99±1%; (2) The weight loss of the malonate crystal form A in the TGA curve within the temperature range of 120.0±3°C to 200.0±3°C is about 11.02±1%; (3) The DSC curve of the malonate salt crystalline form A has an endothermic peak at the onset of 155.6±3°C; (4) The DSC curve of the malonate crystal form A has one endothermic peak at 156.4±3°C; (5) The DSC curve of the malonate salt crystalline form A has one, two, three, four or five characteristics, namely, one endothermic peak at 172.4±3°C.

[0052] In some embodiments, the TGA / DSC pattern of the malonate salt crystalline form A is shown in FIG. 1 The 1 H NMR spectrum is shown in Figure 7-3.

[0053] In another embodiment, the present invention provides methods for preparing the free base crystalline form A of the compound of formula I above, including several methods below.

[0054] Method 1: Add the compound of formula I to organic solvent I, dissolve, filter, and evaporate at room temperature; Preferably, the organic solvent I is one or more selected from acetone, tetrahydrofuran, dichloromethane, acetonitrile and ethyl acetate;

[0055] Method 2: completely dissolve the compound of formula I in organic solvent II, dropwise add anti-solvent to the clear solution under stirring until solid precipitates, if no solid precipitates, use suspension stirring, if no solid precipitates, lower the temperature, and evaporate the clear solution at room temperature after suspension stirring; The organic solvent II may be one or more selected from the group consisting of methanol, acetone, ethyl acetate, tetrahydrofuran, chloroform, N,N-dimethylacetamide, and N-methylpyrrolidone; The anti-solvent may be one or more selected from water, meta-xylene, n-hexane, isopropylbenzene, toluene, cyclohexane, n-heptane, n-pentane, and p-isopropyltoluene, for example, water, a mixture of water and meta-xylene, a mixture of water and n-hexane, a mixture of water and isopropylbenzene, a mixture of water and toluene, and a mixture of cyclohexane and p-isopropyltoluene.

[0056] Method 3: A first sample bottle containing the compound of formula I is placed in a second sample bottle containing a solvent so as to be open, and the second sample bottle is sealed and left to stand at room temperature so that the solvent does not exceed the opening of the first sample bottle; The solvent is one or more selected from ethanol, dichloromethane, acetonitrile, acetone, toluene, N,N-dimethylacetamide, and n-hexane; Preferably, the standing time is 1 to 8 days.

[0057] Method 4: A first sample bottle containing a solution of the compound of formula I is placed in a second sample bottle containing an anti-solvent so that the first sample bottle is opened and placed in a sealed container at room temperature so that the anti-solvent does not exceed the opening of the first sample bottle; The solvent in the solution of the compound of formula I is one or more selected from isopropanol, methyl isobutyl ketone, 1,4-dioxane and dimethyl sulfoxide, preferably dimethyl sulfoxide; The anti-solvent is one or more selected from n-pentane, methyl butyl ether, water and meta-xylene, and is preferably a mixture of n-pentane and methyl butyl ether, or a mixture of water and meta-xylene.

[0058] Method 5: adding the polymer to a solution of the compound of formula I and volatilizing at room temperature; The solvent in the solution of the compound of formula I is one or more selected from the group consisting of methanol, 2-butanone, methyl acetate, isopropyl acetate, ethanol, dichloromethane and 2-methyltetrahydrofuran; The polymer is one or more selected from polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropylmethylcellulose, methylcellulose, polycaprolactone, polyethylene glycol, polymethylmethacrylate, sodium alginate, and hydroxyethylcellulose; Preferably, the polymer is selected from mixed polymer A or mixed polymer B, the mixed polymer A is composed of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropylmethylcellulose and methylcellulose, and the mixed polymer B is composed of polycaprolactone, polyethylene glycol, polymethylmethacrylate, sodium alginate and hydroxyethylcellulose; Preferably, the mass ratio of the polymer to the compound of formula I is 1:(5-20).

[0059] Method 6: A first sample bottle containing the compound of formula I is placed open into a second sample bottle containing a saturated salt solution or water, the second sample bottle is sealed, and the bottle is left standing at room temperature so that the solvent does not exceed the opening of the first sample bottle; Preferably, the saturated salt solution is an inorganic salt saturated solution, for example selected from a saturated potassium acetate solution, a saturated potassium carbonate solution, a saturated sodium bromide solution or a saturated potassium bromide solution; The humidity of the system is preferably 15 to 100% RH.

[0060] Method 7, a suspension of a compound of formula I is stirred with temperature cycling, centrifuged, and the solid is collected; The solvent in the suspension is one or more selected from n-heptane, methyl butyl ether, anisole, dicyclohexylamine, acetone, ethanol, ethyl acetate, methylcyclohexane, chloroform, 2-butanone, meta-xylene, and water, for example, a mixture of n-heptane, methyl butyl ether, anisole, butanone and water, a mixture of ethanol and water, a mixture of ethyl acetate and methylcyclohexane, a mixture of chloroform and n-heptane, or a mixture of 2-butanone and meta-xylene; Preferably, the temperature cycling conditions include 50° C. to 5° C., 0.1 to 0.5° C. / min, and at least two cycles.

[0061] Method 8: completely dissolve the compound of formula I in a positive solvent, add anti-solvent dropwise to the clear solution under stirring until a solid precipitates, if no solid precipitates, use suspension stirring, if no solid precipitates, lower the temperature, and evaporate the clear solution at room temperature after suspension stirring; The positive solvent may be one or more selected from ethanol, ethyl acetate, 2-methyltetrahydrofuran, 2-butanone, acetonitrile, dichloromethane and 1,4-dioxane; The anti-solvent is one or more selected from n-heptane, tetrahydrofuran and water.

[0062] Method 9: A suspension of a compound of formula I is magnetically stirred at room temperature, centrifuged, and the solid is collected; The solvent of the suspension is one or more selected from isobutanol, methyl tert-butyl ether, cyclohexane, toluene, isopropyl acetate, water, methylcyclohexane, tetrahydrofuran, n-pentane, acetone, isopropanol, cyclopentyl methyl ether, methanol, p-isopropyl toluene, dichloromethane, n-heptane, acetonitrile, 1,4-dioxane, and N-methylpyrrolidone. For example, the solvent of the suspension is selected from isobutanol, methyl tert-butyl ether, cyclohexane, toluene, a mixture of isopropyl acetate and toluene, water, methylcyclohexane, a mixture of tetrahydrofuran and n-pentane, a mixture of acetone and isopropanol, a mixture of isopropanol and cyclopentyl methyl ether, a mixture of dichloromethane and n-heptane, a mixture of acetonitrile and water, a mixture of 1,4-dioxane and water, or a mixture of N-methylpyrrolidone and water; Preferably, the rotation speed of the magnetic stirring is 700 to 1200 rpm.

[0063] Method 10: weigh the compound of formula I into an HPLC vial, add a solvent to the HPLC vial, heat, stir, and equilibrate, then filter to obtain a supernatant, place the supernatant in a bioincubator, cool from 50°C to 5°C at 0.05°C / min, and maintain at 5°C, transfer the clear solution to a constant temperature of -20°C, collect the precipitated solid, and transfer the sample without precipitated solid to room temperature for volatilization; The solvent is one or more selected from isopropanol, anisole, isopropyl acetate, tetrahydrofuran, and water; Heat to a temperature of 45 to 55°C, preferably 50°C.

[0064] Method 11. Stirring and centrifuging a suspension of a compound of Formula I and collecting the solid; The solvent in the suspension is one or more selected from n-butanol (n-BuOH), toluene, diisopropyl ether, methylcyclohexane, isopropylbenzene, anisole, water, petroleum ether, dicyclohexylamine, 2-methyltetrahydrofuran, n-hexane, 2-butanone, isopropyl acetate, chloroform, meta-xylene, tetrahydrofuran, methyl isobutyl ketone, cyclopentyl methyl ether, and benzyl alcohol, such as a mixture of n-butanol and toluene, diisopropyl ether, methylcyclohexane, isopropylbenzene, anisole, water, PET, dicyclohexylamine, a mixture of 2-butanone and isopropylbenzene, a mixture of isopropyl acetate and toluene, a mixture of chloroform and meta-xylene, a mixture of isopropyl acetate and water, a mixture of tetrahydrofuran and water, a mixture of methyl isobutyl ketone and cyclopentyl methyl ether, or a mixture of benzyl alcohol and toluene; The suspension is stirred at 45 to 55°C, preferably 50°C. Preferably, the stirring is magnetic stirring, and for example, the rotation speed of the magnetic stirring is 700 to 1200 rpm.

[0065] In another aspect, the present invention provides a method for preparing the free base crystalline form B of the compound of formula I above, The method includes dissolving the free base crystalline form A of the compound of formula I in 1,4-dioxane, followed by gas-liquid diffusion in an n-hexane atmosphere to obtain the free base crystalline form B of the compound of formula I.

[0066] The present invention further provides a process for preparing a pharma- ceutically acceptable salt of the compound of formula I, comprising the step of mixing the compound of formula I or the free base crystalline form A of the compound of formula I with a salt-forming agent (e.g., a corresponding acid) in a suitable solvent to obtain a mixture.

[0067] In some embodiments, the process further comprises stirring or pulping the mixture, isolating the solid, and vacuum drying to obtain the pharma- ceutically acceptable salt of the compound of formula I, preferably, the stirring, pulping, and vacuum drying are performed at room temperature.

[0068] In some embodiments, the method further comprises increasing the supersaturation of the mixture (eg, by adding an anti-solvent).

[0069] In some embodiments, the solvent is a mixture of one or more selected from ethanol, heptane, ethyl acetate, MTBE, acetonitrile, water, and acetone.

[0070] In a further aspect, the present invention provides pharmaceutical compositions comprising one or more of the free base crystalline forms of the compound of formula I above (e.g., free base crystalline form A, free base crystalline form B), pharma- ceutically acceptable salts of the compound of formula I (including crystalline forms thereof).

[0071] In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient or carrier.

[0072] In a further aspect, the present invention provides the use of the free base crystalline form (e.g., free base crystalline form A, free base crystalline form B) of the compound of formula I, a pharma- ceutically acceptable salt of the compound of formula I (including its crystalline form) or the pharmaceutical composition described above in the manufacture of a medicament for treating and / or preventing a P2X3-related disease.

[0073] According to an embodiment of the present invention, the use of the free base crystalline form of the compound of formula I (e.g., free base crystalline form A, free base crystalline form B), a pharma- ceutically acceptable salt of the compound of formula I (including its crystalline form) or the above-mentioned pharmaceutical composition according to the present invention can provide a better and more effective clinical treatment drug or treatment regimen to patients in need thereof.

[0074] The present invention further provides a method for treating and / or preventing P2X3-related diseases, comprising administering to a patient a therapeutically effective amount of a pharmaceutical formulation comprising the crystalline form of the compound of formula I, a pharma- ceutically acceptable salt of the compound of formula I, a crystalline form of the salt, or the pharmaceutical composition, preferably comprising the free base crystalline form of the compound of formula I (e.g., free base crystalline form A, free base crystalline form B), a pharma- ceutically acceptable salt of the compound of formula I (including its crystalline form) or the pharmaceutical composition.

[0075] In some preferred embodiments, the pharma- ceutically acceptable salts of the compounds of formula I include salts formed by compounds of formula I and an acid selected from hydrochloric acid, sulfuric acid, maleic acid, L-aspartic acid, phosphoric acid, fumaric acid, L-tartaric acid, citric acid, D-glucuronic acid, L-malic acid, hippuric acid, D-gluconic acid, DL-lactic acid, succinic acid, L-ascorbic acid, adipic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, malonic acid, gentisic acid, and benzoic acid.

[0076] Preferably, the pharma- ceutically acceptable salt of the compound of formula I comprises the above hydrochloride crystalline form A, maleate crystalline form A, p-toluenesulfonate crystalline form A, benzenesulfonate crystalline form A, malonate crystalline form A, or a combination of any two or more salts thereof.

[0077] According to an embodiment of the present invention, the P2X3-related disorder comprises pain, a genitourinary disorder or a respiratory disorder.

[0078] Preferably, said pain comprises inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, burn pain, migraine or cluster headache, preferably, said genitourinary system disease comprises urinary incontinence, overactive bladder, dysuria, cystitis, endometriosis, endometriosis-related pain, preferably, said respiratory system disease comprises cough, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), preferably, said cough comprises subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, cough associated with respiratory system diseases (e.g. COPD, asthma and bronchospasm).

[0079] According to an embodiment of the present invention, the P2X3-related disease includes at least one selected from chronic cough, particularly refractory chronic cough (RCC) and chronic cough of unknown etiology (UCC).

[0080] The present invention provides a method for detecting the quality of a crystalline form of a compound of formula I or a pharma- ceutically acceptable salt thereof, comprising: detecting the content of said crystalline form by using high performance liquid chromatography; and the mobile phase used in said high performance liquid chromatography comprises mobile phase A and mobile phase B; The method further provides, wherein said mobile phase A is an aqueous solution of formic acid (FA) and acetonitrile (ACN) and said mobile phase B is acetonitrile.

[0081] Preferably, the mobile phase A is an aqueous solution of 0.05 to 0.15% formic acid and 2 to 7% acetonitrile, illustratively an aqueous solution of 0.1% formic acid and 5% acetonitrile.

[0082] Preferably, the quality testing method includes a purity testing method, a solubility testing method, and a stability testing method.

[0083] Preferably, the high performance liquid chromatography uses gradient elution.

[0084] Preferably, the flow rate of the mobile phase is 1±0.2 mL / min, and the time of the gradient elution is 5 to 60 min, more preferably 10 to 30 min.

[0085] Preferably, in the gradient elution, the volume ratio of the mobile phase A to the mobile phase B is 1:9 to 9:1.

[0086] Definitions and Interpretations of Terms Although various terms and phrases used in the present invention have common meanings well known to those skilled in the art, the present invention still intends to explain and interpret these terms and phrases in more detail, and if the terms and phrases referred to do not coincide with their well-known meanings, the meanings described in the present invention shall prevail.

[0087] Unless otherwise specified, the numerical ranges described in the present specification and claims are equivalent to at least describing each specific integer value therein. For example, 2 or more means 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. When some numerical ranges are defined or understood as "numbers", it should be understood that the two end points of the range, each integer within the range, and each decimal within the range are described. For example, "numbers from 0 to 10" should be understood to describe not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least each integer and each sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

[0088] In the present specification and claims, when "about" is used in relation to a certain numerical value, it includes the numerical value itself, as well as numerical values ​​within a range around the numerical value that is acceptable in the art, such as numerical values ​​within ±15% of the numerical value, numerical values ​​within ±10% of the numerical value, numerical values ​​within ±5% of the numerical value, etc. For example, about 10 means that it includes numerical values ​​within the range of 10±1.5, i.e., within the range of 8.5 to 11.5, within the range of 10±1.0, i.e., within the range of 9.0 to 11.0, and within the range of 10±0.5, i.e., within the range of 9.5 to 10.5.

[0089] The salts and crystalline polymorphs of the compound of formula I of the present invention can be used in combination with other active ingredients, provided that no other adverse effects, such as allergic reactions, occur.

[0090] The term "composition" as used herein is meant to include a product containing the specified amounts of each specified ingredient, as well as any product that results directly or indirectly from the combination of the specified amounts of each specified ingredient.

[0091] The term "patient" refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, and most preferably a human.

[0092] The term "therapeutically effective amount" refers to an amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician, or other clinician is looking for in a tissue, system, animal, individual, or human, including one or more of the following: (1) prevention of disease, such as prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but has not yet experienced or developed the pathology or symptoms of the disease; (2) inhibition of disease, such as inhibition of a disease, disorder, or condition (i.e., preventing further progression of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition; (3) mitigation of disease, such as alleviation of a disease, disorder, or condition (i.e., reversal of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

[0093] The term "pharmaceutical acceptable" means that a formulation or active ingredient does not have undue adverse effects on the health of the general therapeutic target.

[0094] The term "pharmacologically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use and have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components of the composition can be mixed with the compounds of the present invention and with each other without appreciably reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipient or carrier moieties include cellulose and its derivatives (sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (stearic acid, magnesium stearate, etc.), calcium sulfate, vegetable oils (soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers, wetting agents (sodium dodecyl sulfate, etc.), colorants, flavor enhancers, stabilizers, antioxidants, preservatives, pyrogen-free water, etc. The pharmaceutical composition can be prepared in solid or liquid form for oral administration, parenteral gastrointestinal injection or rectal administration. The pharmaceutical composition can be prepared in various dosage forms for ease of administration, such as oral preparations (such as tablets, capsules, solutions or suspensions), injectable preparations (such as injectable solutions or suspensions, or injectable dry powders, ready to use after adding a drug solvent before injection).

[0095] When used for the above therapeutic and / or prophylactic uses, the total daily dose of the salts, crystalline polymorphs and pharmaceutical compositions of the compound of formula I of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level must be determined by various factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used, the age, weight, general health status, sex and diet of the patient, the administration time, route of administration and excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or simultaneously with the specific compound used, and similar factors well known in the medical field. For example, as is common practice in the art, the dose of the compound is gradually increased from a level lower than that required to obtain the desired therapeutic effect until the desired effect is obtained.

[0096] The term “API” refers to the free base, i.e., the compound of formula I.

[0097] Beneficial effects 1) The present invention provides a crystalline form of the compound of formula I having good medicinal properties, among which the free base crystalline form A has relatively low hygroscopicity, good solubility and physical and chemical stability, and said free base crystalline form A is a thermodynamically stable crystalline form at room temperature and 50°C, which is beneficial for the storage, quality stability and further formulation of the drug.

[0098] 2) The present invention obtains a medicinal salt of the compound of formula I through screening of optimization test, and further obtains crystalline form products of the salt such as hydrochloride crystalline form A, maleate crystalline form A, p-toluenesulfonate crystalline form A, benzenesulfonate crystalline form A, malonate crystalline form A, etc., among which, p-toluenesulfonate crystalline form A has almost no hygroscopicity, good physical and chemical stability, higher solubility in biological solvents, and better pharmaceutical value.

[0099] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1-1 is an XRPD pattern of the free base crystalline form A of the compound of formula I. FIG. 1-2 is a TGA / DSC pattern of the free base crystalline form A of the compound of formula I. FIG. 1-3 shows the free base crystalline form A of the compound of formula I. 1 1 H NMR spectrum. 1-4 are PLM patterns of the free base crystalline form A of the compound of formula I. FIG. 2-1 is an XRPD pattern of the free base crystalline form B of the compound of formula I. FIG. 2-2 is a TGA / DSC pattern of the free base crystalline form B of the compound of formula I. FIG. 2-3 shows the free base crystalline form B of the compound of formula I. 1 1 H NMR spectrum. Figures 2-4 are XRPD overlays of the free base crystalline Form A / B suspension versus the test sample. FIG. 3-1 is an XRPD pattern of the hydrochloride salt crystalline form A of the compound of formula I. FIG. 3-2 shows the hydrochloride crystalline form A of the compound of formula I. 1 1 H NMR spectrum. FIG. 4-1 is an XRPD pattern of the maleate salt crystalline form A of the compound of formula I. FIG. 4-2 shows the maleate crystalline form A of the compound of formula I. 1 1 H NMR spectrum. FIG. 5-1 is an XRPD pattern of the p-toluenesulfonate salt crystalline form A of the compound of formula I. FIG. 5-2 shows the crystal form A of the p-toluenesulfonate salt of the compound of formula I. 1 1 H NMR spectrum. FIG. 6-1 is an XRPD pattern of crystalline form A of the benzenesulfonate salt of the compound of formula I. FIG. 6-2 is a TGA / DSC pattern of crystalline form A of the benzenesulfonate salt of the compound of formula I. FIG. 6-3 shows the crystalline form A of the benzenesulfonate salt of the compound of formula I. 1 1 H NMR spectrum. FIG. 7-1 is an XRPD pattern of malonate crystalline form A of the compound of formula I. FIG. 7-2 is a TGA / DSC pattern of the malonate crystalline form A of the compound of formula I. FIG. 7-3 shows the malonate crystal form A of the compound of formula I. 1 1 H NMR spectrum. FIG. 7-4 is a VT-XRPD pattern of malonate crystalline form A of the compound of formula I. FIG. 8-1 is an XRPD overlay of samples 1 and 2. FIG. 8-2 is an XRPD overlay of samples 3, 4, 5 and 6. FIG. 9-1 is an XRPD pattern of the hydrochloride salt crystalline form A of compound of formula I prepared in a repeated run. FIG. 9-2 is a TGA / DSC pattern of the hydrochloride salt crystalline form A of compound of formula I prepared repeatedly. FIG. 9-3 shows the hydrochloride crystal form A of the compound of formula I, which was repeatedly prepared. 1 1 H NMR spectrum. FIG. 9-4 is a VT-XRPD pattern of the hydrochloride salt crystalline form A of compound of formula I prepared in a repeated run. FIG. 9-5 is a PLM pattern of the hydrochloride salt crystalline form A of compound of formula I prepared repeatedly. FIG. 10-1 is an XRPD pattern of a repeated preparation of the maleate salt crystalline form A of compound of formula I. FIG. 10-2 is a TGA / DSC pattern of the maleate salt crystalline form A of compound of formula I prepared in replicates. FIG. 10-3 shows the maleate crystalline form A of compound of formula I prepared in a repeated manner. 1 1 H NMR spectrum. FIG. 10-4 is a VT-XRPD pattern of a repeated preparation of maleate salt crystalline form A of compound of formula I. FIG. 10-5 is a PLM pattern of the maleate salt crystalline form A of compound of formula I prepared repeatedly. FIG. 11-1 is an XRPD pattern of p-toluenesulfonate crystalline form A of compound of formula I prepared repeatedly. FIG. 11-2 is a TGA / DSC pattern of the p-toluenesulfonate crystalline form A of the compound of formula I prepared repeatedly. FIG. 11-3 shows the crystal form A of the p-toluenesulfonate salt of the compound of formula I, which was repeatedly prepared. 1 1 H NMR spectrum. FIG. 11-4 is a PLM pattern of the p-toluenesulfonate crystal form A of the compound of formula I prepared repeatedly. FIG. 12 is a kinetic solubility curve at 37° C. FIG. 13 is an XRPD overlay of a solubility sample of free base crystalline form A in HO. FIG. 14 is an XRPD overlay of a solubility sample of free base crystalline form A in SGF. FIG. 15 is an XRPD overlay of a solubility sample of free base Form A in FaSSIF. FIG. 16 is an XRPD overlay of a solubility sample of free base Form A in FeSSIF. FIG. 17 is an XRPD overlay of a solubility sample of the hydrochloride salt crystalline form A in HO. FIG. 18 is an XRPD overlay of a solubility sample of the hydrochloride salt crystalline form A in SGF. FIG. 19 is an XRPD overlay of a solubility sample of the hydrochloride salt crystalline form A in FaSSIF. FIG. 20 is an XRPD overlay of a solubility sample of the hydrochloride salt crystalline form A in FeSSIF. FIG. 21 is an XRPD overlay of a solubility sample of maleate salt crystalline form A in HO. FIG. 22 is an XRPD overlay of a solubility sample of maleate salt crystalline form A in SGF. FIG. 23 is an XRPD overlay of a solubility sample of maleate salt crystalline form A in FaSSIF. FIG. 24 is an XRPD overlay of a solubility sample of maleate crystalline form A in FeSSIF. FIG. 25 is an XRPD overlay of a solubility sample of the p-toluenesulfonate salt crystalline form A in HO. FIG. 26 is an XRPD overlay of a solubility sample of the p-toluenesulfonate salt crystalline form A in SGF. FIG. 27 is an XRPD overlay of a solubility sample of p-toluenesulfonate salt crystalline form A in FaSSIF. FIG. 28 is an XRPD overlay of a solubility sample of p-toluenesulfonate crystalline form A in FeSSIF. FIG. 29 is a DVS pattern of free base crystalline form A. FIG. 30 is an XRPD overlay of free base crystalline form A before and after DVS measurement. FIG. 31 is a DVS pattern of the hydrochloride salt crystalline form A. FIG. 32 is an XRPD overlay of the hydrochloride salt crystalline form A before and after DVS measurement. FIG. 33 is a DVS pattern of maleate salt crystalline form A. FIG. 34 is an XRPD overlay of maleate salt crystalline form A before and after DVS measurement. FIG. 35 is a DVS pattern of p-toluenesulfonate crystalline form A. FIG. 36 is an XRPD overlay of the p-toluenesulfonate salt crystalline form A before and after DVS measurement. FIG. 37 is an XRPD overlay of a stability assessment sample of free base crystalline form A. FIG. 38 is an XRPD overlay of a stability assessment sample of the hydrochloride salt crystalline form A. FIG. 39 is an XRPD overlay of a stability assessment sample of maleate crystalline form A. FIG. 40 is an XRPD overlay of a stability evaluation sample of p-toluenesulfonate crystalline form A. FIG. 41 shows the results of a test on water / water quinine intake ratio when the corresponding compound was administered to animals. FIG. 42 shows the results of a test on the number of coughs induced by histamine / citric acid stimulation after administration of the corresponding compound to guinea pigs. FIG. 43 shows the results of a test on the number of coughs stimulated by ATP / citric acid after administration of the corresponding compounds to guinea pigs.

[0100] [Mode for carrying out the invention] The technical solution of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included in the scope of the claims of the present invention.

[0101] Unless otherwise specified, all materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0102] The instruments and inspection methods used in the present invention are as follows.

[0103] 1. X-ray powder diffraction (XRPD) XRPD patterns were collected on a PANalytacal X-ray powder diffraction analyzer and the scan parameters are shown in Table A-1 below. [Table 1]

[0104] 2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) TGA and DSC patterns were collected on a TA 5500 Thermogravimetric Analyzer and a TA 2500 Differential Scanning Calorimeter, respectively, and the measurement parameters are listed in Table A-2 below. [Table 2]

[0105] 3. Dynamic moisture sorption (DVS) Dynamic moisture sorption (DVS) curves were collected with a Surface Measurement Systems (SMS) DVS IntrInsic. Relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. DVS measurement parameters are listed in Table A-3 below. [Table 3]

[0106] 4. Polarized Light Microscope (PLM) Polarized light micrographs were taken at room temperature using a Zeiss Axio Scope.A1 microscope.

[0107] 5. Liquid nuclear magnetism ( 1 H NMR) Liquid state nuclear magnetic resonance spectra were collected on a Bruker 400M nuclear magnetic resonance instrument using DMSO-d6 as the solvent.

[0108] 6. High performance liquid chromatography (HPLC) The purity, dynamic solubility and stability in the test were measured by Agilent 1260 high performance liquid chromatograph, and the salt formation molar ratio of ions was measured by ion chromatography. The analytical conditions are shown in Tables A-4 and A-5 below.

[0109] [Table 4]

[0110] [Table 5]

[0111] The reagents used in the present invention are shown in Table A-6 below. [Table 6]

[0112] Example 1 Synthesis of Intermediate A-1 [ka] Step 1: Synthesis of 3-bromo-2-fluoro-5-iodobenzoic acid 3-Bromo-2-fluorobenzoic acid (10 g, 45.7 mmol) was dissolved in concentrated sulfuric acid (40 mL), and NIS (10.27 g, 45.7 mmol) was added in portions at 0°C and stirred at room temperature for 3 hours. The mixture was quenched with ice water (200 mL), filtered, and the filter cake was washed five times with water (200 mL) and then dried in vacuum to obtain 3-bromo-2-fluoro-5-iodobenzoic acid (10.9 g, white solid, 69.2% yield).

[0113] Step 2: Synthesis of 3-bromo-2-fluoro-5-hydroxybenzoic acid Cuprous oxide (0.656 g, 4.74 mmol) was added to a solution of 3-bromo-2-fluoro-5-iodobenzoic acid (10.9 g, 31.6 mmol) and sodium hydroxide (6.32 g, 158 mmol) in water (100 mL), and the mixture was allowed to react overnight at 100° C. After cooling to room temperature, the mixture was filtered, and the filtrate was adjusted to pH=1 with 2 M hydrochloric acid solution, extracted with ethyl acetate (60 mL×3), and the organic phase was concentrated and dried to obtain 3-bromo-2-fluoro-5-hydroxybenzoic acid (7.2 g, yellow solid, yield 96.8%).

[0114] Step 3: Synthesis of methyl 3-bromo-2-fluoro-5-hydroxybenzoate To a solution of 3-bromo-2-fluoro-5-hydroxybenzoic acid (7.2 g, 30.6 mmol) in methanol (120 mL) was added thionyl chloride (10.9 g, 91.8 mmol) and stirred for 16 h at 55° C. The solvent was then removed under reduced pressure and concentrated to give the solid compound methyl 3-bromo-2-fluoro-5-hydroxybenzoate (3.1 g, 40.8% yield), which was used in the next step without further purification.

[0115] Step 4: Synthesis of methyl 2-fluoro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate Methyl 3-bromo-2-fluoro-5-hydroxybenzoate (3.1 g, 12.45 mmol), bis(pinacolato)diboron (3.48 g, 13.69 mmol) and potassium acetate (3.67 g, 37.3 mmol) were dissolved in 1,4-dioxane (50 mL) and the solution was degassed with nitrogen gas for 2 minutes. Pd(dppf)Cl2 (0.455 g, 0.622 mmol) was added and the resulting solution was degassed with nitrogen gas for another 2 minutes, then the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated in vacuum, and the residue was purified by separation on a silica gel column to give methyl 2-fluoro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate (3.4 g, white solid, 92% yield).

[0116] Step 5: Synthesis of methyl 2-fluoro-5-hydroxy-3-(5-methylthiazol-2-yl)benzoate (Intermediate A-1) At room temperature, 2-fluoro-5-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)methyl benzoate (3.4 g, 11.48 mmol), 2-bromo-5-methylthiazole (2.453 g, 13.78 mmol), potassium carbonate (3.81 g, 27.6 mmol) in THF (30 mL) and water (10 mL) were added to Pd(dppf)Cl2 (1.260 g, 1.722 mmol), and the mixture was purged with nitrogen gas three times under vacuum, followed by reaction at 90 °C for 16 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL×3). The organic phase was concentrated and dried, and the residue was purified by separation using a silica gel column to obtain methyl 2-fluoro-5-hydroxy-3-(5-methylthiazol-2-yl)benzoate (intermediate A-1, 1.41 g, yellow solid, yield 45.9%). LC-MS, M / Z: 268.2 [M+H] + .

[0117] Example 2 Preparation of Compounds of Formula I [ka] Step 1: Synthesis of (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane-2-oxide (2R,3R)-(-)-2,3-butanediol (2 g, 22.19 mmol) and pyridine (3.86 g, 48.8 mmol) were dissolved in dry tetrahydrofuran (20 mL), the reaction temperature was adjusted to 0-5°C, thionyl chloride (2.9 g, 24.41 mmol) was gradually added, the mixture was warmed to room temperature and stirred for 16 h, the reaction was quenched with water (30 mL), 20 mL of ethyl acetate was added, the liquid was separated, the organic phase was washed with saturated ammonium chloride (20 mL) and saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane-2-oxide (2.4 g, colorless liquid, 79% yield). 1 H NMR (400 MHz, Chloroform-d) δ 4.63 (dq, J=9.0, 6.1 Hz, 1H), 4.07 (dq, J=9.0, 6.1 Hz, 1H), 1.52 (d, J=6.2 Hz, 3H), 1.43 (d, J=6.1 Hz, 3H).

[0118] Step 2: Synthesis of methyl 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoate Under nitrogen gas protection, cesium carbonate (1.22 g, 3.74 mmol) was added to a solution of 2-fluoro-5-hydroxy-3-(5-methylthiazol-2-yl)methyl benzoate (intermediate A-1, 500 mg, 1.871 mmol) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 30 min. (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane-2-oxide (382 mg, 2.81 mmol) was added, the temperature was raised to 80°C, and the reaction was continued for 16 h, then cooled to room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and chloroform (20 mL) and 4 M sulfuric acid solution (20 mL) were added. The mixture was stirred at 70°C for 5 h, separated, and the aqueous phase was adjusted to pH 7-8 with sodium bicarbonate. Extraction with dichloromethane (20 mL x 3) was performed. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain methyl 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoate (380 mg, white solid, yield 60%). LC-MS, M / Z: 340.1 [M+H] + .

[0119] Step 3: Synthesis of 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid 2-Fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)methyl benzoate (200 mg, 0.589 mmol) was dissolved in methanol (4 mL), lithium hydroxide monohydrate (70.7 mg, 1.765 mmol) and water (0.4 mL) were further added, and the reaction was continued with stirring at room temperature for 16 h. The reaction solution was directly concentrated to dryness, water (5 mL) was added, and the pH was adjusted to 2-3 with 1 M aqueous hydrochloric acid solution, and the aqueous phase was extracted with dichloromethane (5 mL x 3), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to obtain 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (190 mg, white solid, yield 99%). LC-MS, M / Z: 326.1 [M+H] + .

[0120] Step 4: 2-Fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide [ka] Under nitrogen gas protection, 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)benzoic acid (190 mg, 0.584 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine hydrochloride (160 mg, 0.701 mmol), N,N-diisopropylethylamine (226 mg, 1.752 mmol) and N,N-dimethylformamide (5 mL) were added in that order to a reaction flask, cooled to about 0°C, and a solution of 1-propylphosphoric acid anhydride in N,N-dimethylformamide (50%, 557 mg, 0.876 mmol) was added dropwise. After the addition, the mixture was returned to room temperature and reacted for 16 h. The mixture was quenched by adding saturated sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (10 The organic phase was combined, the organic phase was washed with saturated saline (30 mL×2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by separation on a silica gel plate (petroleum ether:ethyl acetate (V / V)=1:1) to obtain a white solid 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (compound of formula I, 110 mg, yield 37.8%). 1 H NMR (400 MHz, CDCl3) δ 8.94 (s, 2H), 7.86 (dd, J=5.9, 3.3 Hz, 1H), 7.63-7.58 (m, 1H), 7.50 (dd, J=5.8, 3.4 Hz, 1H), 7.10 (dd, J=12.3, 6.5 Hz, 1H), 5.38 (ddd, J=7.7, 4.4, 1.5 Hz, 1H), 4.40 (qd, J=6.3, 3.3 Hz, 1H), 4.01 (ddd, J=6.5, 4.8, 3.3 Hz, 1H), 2.56 (d, J=1.2 Hz, 3H), 2.07 (d, J=4.9 Hz, 1H), 1.72 (d, J=7.1 Hz, 3H), 1.26 (d, J=6.3 Hz, 3H), 1.23 (d, J=6.5 Hz, 3H). LC-MS, M / Z: 499.1 [M+H] + .

[0121] Example 3 Preparation of the free base crystalline form A of the compound of formula I About 20 mg of the compound of formula I sample was weighed into an HPLC glass vial, 0.5 mL of toluene was added, and the resulting suspension was magnetically stirred (1000 rpm) at room temperature for about 4 days, then centrifuged (10000 rpm, 2 min), the solid was collected, and XRPD measurement was performed. The measurement results show that the solid product is designated as free base crystalline form A, as shown in Figure 1-1. The TGA / DSC results (Figure 1-2) show that the sample has a weight loss of 1.28% when heated to 150°C, and has one endothermic peak at 175.6°C (onset temperature). The free base crystalline form A 1 H NMR results are shown in Figure 1-3. PLM (Figure 1-4) shows that the sample exhibits aggregated needle-like crystals.

[0122] The XRPD analytical data of the obtained free base crystalline form A of the compound of formula I is shown in Table 3-1 below. [Table 7]

[0123] Example 4 Preparation of the free base crystalline form B of the compound of formula I The free base crystalline form A of the compound of formula I was dissolved in 1,4-dioxane, and then subjected to gas-liquid diffusion in an n-hexane atmosphere. The solid was dried at room temperature to obtain the free base crystalline form B.

[0124] The XRPD of free base crystalline form B is shown in Figure 2-1. The TGA / DSC results (Figure 2-2) show that the sample has a weight loss of 2.36% when heated to 150°C and has one endothermic peak at 177.0°C (onset temperature). 1 The H NMR results are shown in Figures 2-3.

[0125] The XRPD analytical data of the obtained free base crystalline form B of the compound of formula I is shown in Table 4-1 below. [Table 8]

[0126] In order to confirm the thermodynamic conversion relationship of free base anhydrous crystalline forms A and B under different temperature conditions, a suspension competition test was set up in n-heptane and toluene at room temperature and 50°C. The specific steps are as follows: 1) First, prepare a saturated solution of the starting sample free base crystalline form A at the corresponding temperature and solvent; 2) Weigh out an appropriate amount of mixed crystal sample and add it to the saturated solution after filtration to form a suspension; 3) Suspend and stir at the corresponding temperature conditions. The results are summarized in Table 4-2, and the XRPD results are summarized in Figure 2-4. The results show that after suspension competition at 50°C in n-heptane system and room temperature / 50°C in toluene system, both are converted to free base crystalline form A, and after suspension competition at room temperature in n-heptane system for 42 days, it is converted to free base crystalline form A. The experiment shows that free base crystalline form A is a thermodynamically stable crystalline form at room temperature and 50°C. [Table 9]

[0127] Example 5 Preparation and Screening of Salt Forms of Compounds of Formula I Approximately 20 mg of the compound of formula I and equimolar amounts of different salt-forming preparations (i.e., acids that form salts with the free base) were weighed into HPLC vials, and 0.5 mL of solvent was added and mixed to obtain a suspension. The salt-forming preparations were first diluted with the corresponding solvent and then mixed with the starting sample. After about 5 days of suspension stirring at room temperature, the solid was centrifuged and vacuum dried overnight at room temperature. 0.5-1.0 mL of antisolvent n-heptane was added to the room temperature clear system to improve the supersaturation of the solution and accelerate the crystallization. The obtained solid XRPD characterization results show that a total of five salt forms are obtained in the salt form screening test (Table 5-1). [Table 10] JPEG2025510348000017.jpg255164 JPEG2025510348000018.jpg151169

[0128] Example 6 Preparation of Crystalline Form A of the Hydrochloride Salt of Compound of Formula I After pulping a sample of compound of formula I and an equimolar amount of hydrochloric acid with MTBE at room temperature for 5 days, the solid was centrifuged and dried under vacuum at room temperature to obtain hydrochloride salt crystalline form A.

[0129] The XRPD pattern of the hydrochloride salt crystalline form A sample is shown in Figure 3-1. 1 H NMR was performed in DMSO-d6 and the results are shown in Figure 3-2, no residual MTBE solvent was observed in the sample. HPLC / IC results show that the molar ratio of HCl to API (i.e., free base) is 0.5:1.

[0130] The XRPD analysis data of the obtained hydrochloride salt crystalline form A of compound of formula I is shown in Table 6-1 below. [Table 11]

[0131] Example 7 Preparation of Crystalline Form A of the Maleate Salt of Compound of Formula I A sample of the compound of formula I and an equimolar amount of maleic acid were stirred in EtOAc at room temperature for 3 hours, and then 0.5 mL of n-heptane was added to the resulting clear solution, which was then stirred at room temperature for 5 days. The solid was centrifuged and dried in vacuum at room temperature to obtain the maleate salt form A of the compound of formula I.

[0132] The XRPD pattern of the maleate salt crystalline form A sample is shown in Figure 4-1. 1H NMR was measured in DMSO-d6, and the results are shown in Figure 4-2. The results show that the molar ratio of maleic acid to API (i.e., free base) is 0.5:1, and no solvent residue of EtOAc or n-heptane is observed.

[0133] The XRPD analytical data of the obtained maleate crystalline form A of the compound of formula I is shown in Table 7-1 below. [Table 12]

[0134] Example 8 Preparation of crystalline form A of the p-toluenesulfonate salt of the compound of formula I After stirring a sample of the compound of formula I and an equimolar amount of p-toluenesulfonic acid in EtOAc at room temperature for 5 days, the solid was centrifuged and dried under vacuum at room temperature to obtain p-toluenesulfonic acid salt crystalline form A of the compound of formula I.

[0135] The XRPD pattern of the p-toluenesulfonate salt crystalline form A sample is shown in Figure 5-1. 1 H NMR was measured in DMSO-d6 and the results are shown in Figure 5-2. The results show that the molar ratio of p-toluenesulfonic acid to API (i.e., free base) is 1.0:1 and no solvent residue of EtOAc is observed.

[0136] The XRPD analysis data of the obtained p-toluenesulfonate crystalline form A of the compound of formula I is shown in Table 8-1 below. [Table 13]

[0137] Example 9 Preparation of crystalline form A of the benzenesulfonate salt of the compound of formula I A sample of the compound of formula I and an equimolar amount of benzenesulfonic acid were stirred in MTBE at room temperature for 5 days, and the solid was centrifuged and dried under vacuum at room temperature to obtain benzenesulfonate salt crystalline form A of the compound of formula I.

[0138] The XRPD diagram of the benzenesulfonate salt crystalline form A is shown in Figure 6-1. The details of the TGA / DSC results are shown in Figure 6-2. The TGA results show that the sample has a weight loss of 1.35% when heated to 120°C, and the DSC results show that the sample has one endothermic peak with an onset temperature of 159.6°C and a peak temperature of 160.9°C. 1 H NMR was measured in DMSO-d6 and the results are shown in Figure 6-3. The results show that the molar ratio of benzenesulfonic acid to API (i.e., free base) is 0.9:1 and no solvent residue of MTBE is observed.

[0139] The XRPD analysis data of the obtained benzenesulfonate crystal form A of the compound of formula I is shown in Table 9-1 below. [Table 14]

[0140] Example 10 Preparation of Malonate Crystalline Form A of the Compound of Formula I The compound of formula I and an equimolar amount of malonic acid were stirred in EtOAc at room temperature for 3 hours, and then 0.5 mL of n-heptane was added to the resulting clear solution, which was then stirred at room temperature for 5 days. The solid was then centrifuged and dried under vacuum at room temperature to obtain malonate crystal form A of the compound of formula I.

[0141] The XRPD diagram of the malonate salt crystalline form A is shown in Figure 7-1. The details of the TGA / DSC results are shown in Figure 7-2. The TGA results show that the sample has a weight loss of 2.99% when heated to 120°C, and the weight loss of the sample is 11.02% when heated from 120°C to 200°C, and the DSC results show that the sample has an endothermic peak at 156.4°C (peak value temperature). 1 H NMR was measured in DMSO-d6 and the results are shown in Figure 7-3. The results show that the molar ratio of malonic acid to API (i.e., free base) is 0.7:1 and no solvent residue of EtOAc is observed.

[0142] The crystal form of the malonate salt Form A was identified by VT-XRPD (Figure 7-4), and the results show that the sample was purged with N2 for 20 min, heated to 120°C, and cooled to room temperature, and no change in crystal form was observed.

[0143] The XRPD analysis data of the obtained malonate crystal form A of the compound of formula I is shown in Table 10-1 below. [Table 15]

[0144] Example 11 Repetitive preparation of polymorphs of the compound of formula I (1) Repeated production of free base crystalline form B [Table 16]

[0145] As shown in Table 11-1, free base form A did not give free base form B in TFE, but remained free base form A (XRPD patterns of Samples 1 and 2 are shown in Figure 8-1), while mixed crystals of free base form A+B were obtained in 1,4-dioxane (XRPD patterns of Samples 3, 4, 5, and 6 are shown in Figure 8-2).

[0146] (2) Repeated production of salt molds Hydrochloride crystal form A, maleate crystal form A and p-toluenesulfonate crystal form A were selected for 300 mg repeat production. The results showed that the repeat production of all three salt forms was successful, and the repeat production steps of the salt form samples are summarized in Table 11-2. [Table 17]

[0147] 1. Hydrochloride Crystal Form A The XRPD patterns of the repeated preparations of the hydrochloride salt crystalline form A sample are shown in Figure 9-1. The TGA / DSC results are shown in Figure 9-2, where the TGA results show that the sample has a weight loss of 2.2% when heated to 100°C and a weight loss of 3.9% when heated from 100°C to 160°C, and the DSC results show that the sample has endothermic peaks at 157.4°C and 179.0°C (peak temperature). 1 H NMR was measured in DMSO-d6, the results are shown in Figure 9-3, no residual MTBE solvent was observed. HPLC / IC results show that the molar ratio of the hydrochloride form A sample is 0.5:1 (HCl:API). PLM (Figure 9-5) shows that the hydrochloride form A exhibits small irregular particles. VT-XRPD (Figure 9-4) identifies the crystal form of the hydrochloride form A, the results show that the sample is purged with N2 for 20 min, heated to 100°C and cooled to room temperature, and no change in crystal form is observed.

[0148] 2. Maleate Crystal Form A The XRPD patterns of the repeated preparations of the maleate salt crystalline form A samples are shown in Figure 10-1. The TGA / DSC results are shown in Figure 10-2. The TGA results show that the sample has a weight loss of 1.65% when heated to 110°C and a weight loss of 11.88% when heated from 110°C to 220°C, and the DSC results show that the sample has an endothermic peak at 144.1°C (peak value temperature). 1 H NMR was measured in DMSO-d6, and the results are shown in Figure 10-3. The results indicate that the molar ratio of maleic acid to API in the sample is 0.5:1, and 0.3 wt% of EtOAc solvent residue is observed. PLM (Figure 10-5) shows that irregular particles of maleate salt form A are aggregated. VT-XRPD (Figure 10-4) identifies the crystal form of maleate salt form A, and the results show that the sample is purged with N2 for 20 min, heated to 120°C, and cooled to room temperature, and no change in crystal form is observed.

[0149] 3. p-Toluenesulfonate Crystal Form A The XRPD pattern of the repeatedly prepared p-toluenesulfonate crystalline form A sample is shown in Figure 11-1. The TGA / DSC results are shown in Figure 11-2. The TGA results show that the sample has a weight loss of 0.73% when heated to 150°C, and the DSC results show that the sample has one endothermic peak with an onset temperature of 157.1°C and a peak temperature of 159.2°C. 1 H NMR was measured in DMSO-d6 and the results are shown in Figure 11-3. The results indicate that the molar ratio of p-toluenesulfonic acid to API in the sample is 1.0:1, and no EtOAc solvent residue is observed. PLM (Figure 11-4) shows that p-toluenesulfonate salt crystalline form A exhibits irregular granularity.

[0150] Example 12 Dynamic Solubility Experiments The solubility of each sample was measured in four systems, water, SGF, FaSSIF and FeSSIF, at different time points (1, 4 and 24 hours) with rotational mixing at 37°C with a solid input concentration of 10 mg / mL (as free base). After sampling at each time point, the samples were filtered (0.45 μm PTFE filter head) by centrifugation (10000 rpm), and the HPLC concentration and pH value of the filtrate were measured. The solubility test results are summarized in Table 12-1, and the solubility curves are shown in Figure 12. The results show that the maleate crystalline form A has the highest solubility in HO, and the p-toluenesulfonate crystalline form A has the highest solubility in the three biological solvents other than HO at 1 hour. 13-28 are XRPD overlays of solubility samples of free base form A, hydrochloride salt form A, maleate salt form A, and p-toluenesulfonate salt form A in HO, SGF, FaSSIF, and FeSSIF, respectively. The changes in crystal form are shown in Table 12-1. Dynamic solubility measurements of free base form A showed no change in crystal form, indicating very high stability. [Table 18]

[0151] Biological Solvent Preparation Instructions: Simulated gastric fluid preparation (SGF): 100.2 mg of NaCl and 50.3 mg of Triton X-100 were weighed into a 50 mL flask, and purified water was added until the solution became clear. 816 μL of 1 M hydrochloric acid was added, and the pH was adjusted to 1.8 with 1 M hydrochloric acid or 1 M NaOH solution. The volume was adjusted to the constant level by adding purified water.

[0152] Preparation of intestinal fluid simulating fasting state (FaSSIF): 170.5 mg of anhydrous NaH2PO4, 22.2 mg of NaOH, and 310.9 mg of NaCl were weighed into a 50 mL flask. Purified water was added until the solution became clear, and the pH was adjusted to 6.5 with 1 M hydrochloric acid or 1 M NaOH solution. Purified water was added to the volume. Then, 55.1 mg of SIF powder was weighed into a 25 mL flask, and the solution was dissolved and the volume was adjusted to the volume.

[0153] Preparation of intestinal fluid simulating fed state (FeSSIF): 0.21 mL of glacial acetic acid, 101.6 mg of NaOH, and 295.4 mg of NaCl were taken in a 25 mL flask. Approximately 20 mL of purified water was added until the solution became clear, and the pH was adjusted to 5.0 with 1 M hydrochloric acid or 1 M NaOH solution. Purified water was added to the volume, and 280.8 mg of SIF powder was added until the solution became clear.

[0154] Example 13 Hygroscopicity The hygroscopicity of the free base crystalline form A prepared in Example 3, the hydrochloride crystalline form A, the maleate crystalline form A and the p-toluenesulfonate crystalline form A prepared repeatedly in Example 11 was evaluated using a dynamic moisture sorption apparatus (DVS). The measurement was started at 0% RH, and the mass change percentage of the samples was collected as the humidity was changed (0% RH to 95% RH to 0% RH) at a constant temperature of 25° C. The DVS measurement results and the XRPD results of the samples before and after the DVS measurement are shown in Figures 29 to 36. As a result, the moisture adsorption of the free base crystal form A at 25°C / 80%RH was ~0.91%, indicating slight hygroscopicity, the moisture adsorption of the hydrochloride crystal form A at 25°C / 80%RH was ~0.49%, indicating slight hygroscopicity, the moisture adsorption of the maleate crystal form A at 25°C / 80%RH was ~0.41%, indicating slight hygroscopicity, rapid moisture absorption of the maleate crystal form A was observed when humidity was >80%RH, and the moisture adsorption of the p-toluenesulfonate crystal form A sample at 25°C / 80%RH was ~0.12%, indicating almost no hygroscopicity. The crystal forms of the free base crystal form A, hydrochloride crystal form A, maleate crystal form A and p-toluenesulfonate crystal form A samples did not change after DVS measurement.

[0155] Example 14 Solid state stability The free base crystalline form A prepared in Example 3, the hydrochloride crystalline form A, the maleate crystalline form A and the p-toluenesulfonate crystalline form A prepared repeatedly in Example 11 were respectively left at 60°C in a closed state for 1 day, and left at 25°C / 60%RH and 40°C / 75%RH in an open state for 1 week and 1 month (wherein the hydrochloride crystalline form A and the maleate crystalline form A were left only for 1 week), and then the physical and chemical stability of the samples was examined by XRPD and HPLC. The purity data is listed in Table 14-1, and the XRPD results are listed in Figures 37 to 40. The results show that the HPLC purity of the free base crystalline form A, the hydrochloride crystalline form A, the maleate crystalline form A and the p-toluenesulfonate crystalline form A after being left under the corresponding conditions does not change obviously. [Table 19]

[0156] Example 15 Different processes for preparing the free base crystalline form of the compound of formula I The compound of formula I can be prepared according to the process method of Example 2, and the free base crystalline form A or the free base crystalline form B (identified by XRPD) can be prepared according to the following method.

[0157] Method 1: Slow evaporation A total of six slow volatilization tests were set up using different solvent systems. Approximately 20 mg of the compound of formula I sample per part was weighed into a 5 mL vial, and 0.4-0.6 mL of the solvent in Table 15-1 was added, respectively. After dissolution, the vial was filtered, sealed with a sealing film, and two pinholes were pierced into it, and allowed to slowly volatilize at room temperature. The obtained solid was collected and subjected to XRPD measurement. The test results are shown in Table 15-1, and free base crystalline form A / B was obtained. [Table 20]

[0158] Method 2: Gas-solid infiltration A total of eight gas-solid permeation tests were set up using different solvents. 20 mg of compound of formula I sample per portion was weighed into a 3 mL vial, and about 3 mL of solvent was added to the 20 mL vial, and the 3 mL vial was placed in an open position in the 20 mL vial, and then the 20 mL vial was sealed. After standing at room temperature for 1 to 8 days, the solid was collected and XRPD measurement was performed. The test results are shown in Table 15-2, and free base crystalline form A and free base crystalline form A+B were obtained. [Table 21]

[0159] Method 3: Gas-liquid infiltration A total of eight gas-liquid permeation tests were set up using different solvents. Approximately 20 mg of the compound of formula I sample per part was weighed into a 3 mL vial, and 0.4-2.2 mL of solvent was added to dissolve (filtered with a 0.45 μm PTFE filter head), and approximately 3 mL of antisolvent was added to a 20 mL vial. The 3 mL vial containing the clear liquid was placed in a 20 mL vial so that it was open, and then the 20 mL vial was sealed and left to stand at room temperature. The solid obtained was collected and XRPD measurement was performed. The test results are shown in Table 15-3, and free base crystalline form A / B and low crystallinity were obtained. [Table 22]

[0160] Method 4: High polymer derivatization A total of eight high polymer induction tests were set up in different solvents using two kinds of mixed high polymers. Approximately 20 mg of compound of formula I sample per part was weighed into a 3 mL vial, and dissolved by adding 0.4-1.0 mL of solvent. After dissolution, the sample was filtered, and ~2 mg of mixed polymer was added, the vial was sealed with a sealing film, and two pinholes were pierced into it, and the sample was allowed to slowly evaporate at room temperature. The test results are shown in Table 15-4, and free base crystalline form A and free base crystalline form A+B were obtained. [Table 23] Mixed High Polymer A: Polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose and methylcellulose (mixed in equal amounts) Mixed High Polymer B: Polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose (mixed in equal amounts)

[0161] Method 5, humidity induction A total of five humidity induction tests were set up using different solvents. Approximately 20 mg of compound of formula I sample per portion was weighed into each 3 mL vial, and saturated salt solution was prepared in a 20 mL vial at room temperature, and the 3 mL vial was placed in the 20 mL vial so that it was open, and then the 20 mL vial was sealed. After standing at room temperature for 8 days, the solid was collected and XRPD measurement was performed. The test results are shown in Table 15-5, and free base crystalline form A was obtained. [Table 24]

[0162] Method 6, cyclic heating / cooling A total of nine temperature cycling tests were set up using different solvents. Approximately 20 mg of compound of formula I sample per part was weighed into an HPLC glass vial, and 0.5 mL of the solvent listed in Table 15-6 was added, respectively. The resulting suspension was temperature cycled (50°C to 5°C, 0.1°C / min, 2 cycles) with magnetic stirring (1000 rpm), centrifuged (10000 rpm, 2 min), and the solid was collected and subjected to XRPD measurement. The test results are shown in Table 15-6, and the free base crystalline form A was obtained. [Table 25]

[0163] Method 7, Antisolvent Addition A total of 12 anti-solvent addition tests were set up using different solvents. Approximately 20 mg of the compound of formula I sample per portion was weighed into a 20 mL vial, and the solid was completely dissolved in 0.4-0.6 mL of solvent (see Table 15-7). The anti-solvent in Table 15-7 was added dropwise to the clear solution while stirring (1000 rpm) until the solid precipitated, or the sample in which no solid precipitated even after adding the anti-solvent until the total volume of the anti-solvent reached 5 mL was suspended and stirred at 5°C, and if no solid precipitated, it was suspended and stirred at -20°C, and the final clear sample was evaporated at room temperature. The precipitated solid was separated and XRPD measurement was performed, and the results are shown in Table 15-7. The free base crystalline form A and a clear solution were obtained by the anti-solvent addition test. [Table 26]

[0164] Method 8, Reverse-Antisolvent Addition A total of eight reverse-antisolvent addition tests were set up using different solvents. Approximately 20 mg of a sample of the compound of formula I per part was weighed into a 20 mL vial, and the solid was completely dissolved in 0.4-0.6 mL of a solvent (see Table 15-8). The clear solution was dropped into 5 mL of the antisolvent in Table 15-8 while stirring (1000 rpm). Samples in which no solid precipitated were suspended and stirred at 5°C, and if no solid still precipitated, suspended and stirred at -20°C, and the final clear sample was evaporated at room temperature. The precipitated solid was separated and XRPD measurement was performed, and the results are shown in Table 15-8. Free base crystalline form A was obtained by reverse-antisolvent addition measurement. [Table 27]

[0165] Method 9: Suspension stirring at room temperature A total of 15 suspension stirring tests were set up at room temperature using different solvents. Approximately 20-40 mg of the compound of formula I sample per part was weighed into an HPLC glass vial, and 0.5 mL of the solvent listed in Table 15-9 was added, respectively. The resulting suspension was magnetically stirred (1000 rpm) at room temperature for about 4 days, then centrifuged (10000 rpm, 2 min), the solid was collected, and XRPD measurement was performed. The test results are shown in Table 15-9, and the free base crystalline form A was obtained. [Table 28]

[0166] Method 10, slow cooling A total of five slow cooling tests were set up using different solvent systems. Approximately 20 mg of a sample of the compound of formula I per part was weighed into an HPLC vial, 1.0 mL of the solvent in Table 15-10 was added, and the sample was stirred at 50°C for about 2 hours to equilibrate, then filtered (filtered with a 0.45 μm PTFE filter head) and the supernatant was taken. The obtained supernatant was left in a bioincubator, cooled from 50°C to 5°C at 0.05°C / min, and then kept at a constant temperature of 5°C, and the clear solution was transferred to a constant temperature of -20°C. The precipitated solid was collected and XRPD measurement was performed, and the sample without precipitated solid was transferred to room temperature to volatilize. The test results are shown in Table 15-10, and the free base crystalline form A and the free base crystalline form B+ multi-peak were obtained by the slow cooling test. [Table 29]

[0167] Method 11, Suspension Stirring at 50°C A total of 16 suspension stirring tests were set up at 50°C using different solvents. Approximately 20-40 mg of the compound of formula I sample per part was weighed into an HPLC glass vial, and 0.5 mL of the solvent listed in Table 15-11 was added, respectively. The resulting suspension was magnetically stirred (1000 rpm) at 50°C for about 3 days, then centrifuged (10000 rpm, 2 min), the solid was collected, and XRPD measurement was performed. The test results are shown in Table 15-11, and the free base crystalline form A was obtained. [Table 30]

[0168] Example 16 Control compound 1 and control compound 2 were synthesized with reference to patent application WO2016 / 091776A1. [ka] 1. Measurement of hP2X3 antagonist antagonist activity against hP2X3 by FLIPR method To evaluate the antagonistic activity of human P2X3 receptor (hP2X3) antagonists against hP2X3, calcium flow signals were detected using a FLIPR Calcium 4 Assay Kit (Molecular Devices, R8141) and a FLIPR TETRA instrument (Molecular Devices, 0296). 24 h before the experiment, human cells stably transfected with hP2X3 receptor were cultured at 2 × 10 5 Cell suspension was seeded into 384-well plates at a density of 1000 cells / mL with 50 μL / well and incubated in a 5% CO2, 37°C incubator for 16-24 h. Test compounds were prepared in DMSO at 180-fold the required concentration (20-50 mM DMSO stock solution) and added to the 384-well plate at 500 nL / well and 30 μL of FLIPR Assay buffer (1.26 mM Ca 2+The plates were supplemented with 1xHBSS containing 1xHBSS+20mM HEPES containing 2mM CaCl2) and shaken for 20-40 min to mix evenly. Agonist (α,β-meATP) was prepared at 3x the required concentration (final required concentration 400nM) in FLIPR Assay buffer, and the agonist was added at 45μL / well to another 384-well plate. The cell incubation plate seeded the day before was taken, the cell supernatant was aspirated and discarded, and Dye (FLIPR® Calcium 4 Assay Kit, diluted with FLIPR buffer) was added at 30μL / well and incubated for 1h. 15μL of compound was added to the cells in each well (injected by the FLIPR instrument), and after 15 minutes, agonist was added at 22.5μL / well, and the fluorescent signal (excitation wavelength 470nm-495nm, emission wavelength 515nm-575nm) was measured. The difference between the signal peak value and the trough value was taken as the base data, the highest concentration data of the positive drug was taken as 100% inhibition rate, and the DMSO data was taken as 0% inhibition rate. The compound inhibition effect curve was fitted using the software Graphpad Prism 6, and the IC 50 values ​​were calculated. [Table 31]

[0169] 2. Pharmacokinetic study in mice In the mouse pharmacokinetic study, male ICR mice weighing 20-25 g were fasted overnight. Three mice were taken and orally administered intragastrically at 10 mg / kg, and blood was collected before and after administration at 15, 30 min and 1, 2, 4, 8, and 24 h. Blood samples were taken at 6800 g and centrifuged at 2-8 °C for 6 min, plasma was collected and stored at -80 °C. Plasma at each time point was taken, mixed with 3-5 volumes of acetonitrile solution containing internal standard, mixed by vortexing for 1 min, centrifuged at 13000 rpm for 10 min at 4 °C, the supernatant was mixed with 3 volumes of water, and an appropriate amount of the mixture was taken for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by a non-compartmental model using WinNonlin 7.0 software.

[0170] The test results show that the pharmacokinetic properties of the compound of formula I of the present invention are improved to some extent compared with the control compounds 1 and 2 in a mouse model. [Table 32]

[0171] 3. Taste test on rats The SD rats were administered the compound after three days of overnight water deprivation training. Half an hour after administration, each animal was administered one bottle of water and one bottle of 0.3 mM quinine solution. 15 minutes after administration of the water, the water bottles were removed and the amount of water and 0.3 mM quinine solution ingested by the rats were measured. The effect of the compound on the taste of the SD rats was evaluated based on the difference between the amount of water and the amount of quinine solution ingested (Figure 41). [Table 33]

[0172] 4. Efficacy test of histamine / citric acid on cough in guinea pigs Before entering the groups, the animals were acclimated for 3 to 7 days and then numbered and randomly assigned to groups after passing body weight (300 to 400 g).

[0173] Guinea pigs were administered the compound or vehicle by nasal instillation 0.25-24 hours prior to the start of cough evaluation. The dose range of the test article was 0.17 mg / kg-1.5 mg / kg. For cough evaluation, animals were placed in a whole body volume scan case for adaptation, followed by histamine atomization and citric acid atomization. The number of coughs and cough latency of the animals were recorded for a total of 22 min from the start of histamine atomization to the end of the observation period.

[0174] For statistical analysis of experimental data, one-way ANOVA was used to analyze and compare each data set. Significant differences were observed at p<0.05. For pairwise comparisons, the t-test method was used to compare the differences. [Table 34]

[0175] The data show that, compared with the control compound 1, the compounds of the present invention significantly reduced the number of coughs in animals and extended the cough latency period in the citric acid / histamine-stimulated guinea pig cough model, and have good antitussive effects (Figure 42).

[0176] 5. Efficacy test of ATP / citric acid on cough in guinea pigs Before entering the groups, the animals were acclimated for 3-7 days and randomly assigned to groups after body weight (300-400 g) by numbering. Compounds or vehicle were administered nasally to the guinea pigs 0.25-24 hours before the start of cough evaluation. The dose range of the test product was 0.17 mg / kg-1.5 mg / kg. For cough evaluation, the animals were placed in a whole body volume scan case for acclimation, and then ATP atomization was performed, followed by a further citric acid atomization after a few minutes interval. The number of coughs and cough latency of the animals within 15 min from the start of citric acid atomization were recorded.

[0177] One-way ANOVA was used to analyze and compare each data set. Significant differences were observed at p<0.05. For pairwise comparisons, the t-test method was used to compare the differences. [Table 35]

[0178] The data show that, compared with the control compound 1, the compounds of the present invention significantly reduced the number of coughs in animals and extended the cough latency period in the citrate / ATP-stimulated guinea pig cough model, and have good antitussive effects (Figure 43).

[0179] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention are intended to be included in the scope of the claims of the present invention. [Brief description of the drawings]

[0180] [Figure 1-1] 1 is an XRPD pattern of the free base crystalline form A of the compound of formula I. [Figure 1-2] 1 is a TGA / DSC pattern of the free base crystalline form A of the compound of formula I. [Figure 1-3] 1 is a 1H NMR spectrum of the free base crystalline form A of the compound of formula I. [Figure 1-4] 1 is a PLM pattern of the free base crystalline form A of the compound of formula I. [Figure 2-1] 1 is an XRPD pattern of the free base crystalline form B of the compound of formula I. [Figure 2-2] 1 is a TGA / DSC pattern of the free base crystalline form B of the compound of formula I. [Figure 2-3] 1 is a 1H NMR spectrum of the free base crystalline form B of the compound of formula I. [Figure 2-4] 1 is an XRPD overlay of the free base crystalline form A / B suspension versus a test sample. [Figure 3-1] 1 is an XRPD pattern of the hydrochloride salt crystalline form A of the compound of formula I. [Figure 3-2] 1 is a 1H NMR spectrum of the hydrochloride salt crystalline form A of the compound of formula I. [Figure 4-1] 1 is an XRPD pattern of the maleate salt crystalline form A of the compound of formula I. [Figure 4-2] 1 is a 1H NMR spectrum of the maleate salt crystalline form A of the compound of formula I. [Figure 5-1] 1 is an XRPD pattern of the p-toluenesulfonate salt of the compound of formula I, crystalline form A. [Figure 5-2] 1 is a 1H NMR spectrum of the p-toluenesulfonate salt crystalline form A of the compound of formula I. [Figure 6-1] 1 is an XRPD pattern of crystalline form A of the benzenesulfonate salt of compound of formula I. [Figure 6-2] 1 is a TGA / DSC pattern of crystalline form A of the benzenesulfonate salt of compound of formula I. [Figure 6-3] 1 is a 1H NMR spectrum of crystalline form A of the benzenesulfonate salt of compound of formula I. [Figure 7-1] 1 is an XRPD pattern of crystalline form A of the malonate salt of compound of formula I. [Figure 7-2] 1 is a TGA / DSC pattern of malonate crystalline form A of compound of formula I. [Figure 7-3] 1 is a 1H NMR spectrum of the malonate crystalline form A of the compound of formula I. [Figure 7-4] VT-XRPD pattern of malonate crystalline form A of compound of formula I. [Figure 8-1] 1 is an XRPD overlay of samples 1 and 2. [Figure 8-2] XRPD overlay of samples 3, 4, 5 and 6. [Figure 9-1] 1 is an XRPD pattern of the hydrochloride salt crystalline form A of compound of formula I prepared in a repeated run. [Figure 9-2] 1 is a TGA / DSC pattern of the hydrochloride salt crystalline form A of compound of formula I prepared in a repeated run. [Figure 9-3] 1 is a 1H NMR spectrum of the hydrochloride salt crystalline form A of compound of formula I prepared in a repeated run. [Figure 9-4] 1 is a VT-XRPD pattern of the hydrochloride salt crystalline form A of compound of formula I prepared in a repeated run. [Figure 9-5] 1 is a PLM pattern of repeatedly prepared hydrochloride salt crystalline form A of compound of formula I. [Figure 10-1]1 is an XRPD pattern of a repeated preparation of the maleate salt crystalline form A of compound of formula I. [Figure 10-2] 1 is a TGA / DSC pattern of the maleate salt crystalline form A of compound of formula I prepared in replicates. [Figure 10-3] 1 is a 1H NMR spectrum of the maleate salt crystalline form A of compound of formula I prepared in a repeated run. [Figure 10-4] 1 is a VT-XRPD pattern of a replicate preparation of crystalline Form A of the maleate salt of compound of formula I. [Figure 10-5] 1 is a PLM pattern of the maleate salt of compound of formula I in a repeated preparation of crystalline form A. [Figure 11-1] 1 is an XRPD pattern of p-toluenesulfonate crystalline form A of compound of formula I prepared in a repeated run. [Figure 11-2] 1 is a TGA / DSC pattern of p-toluenesulfonate crystalline form A of compound of formula I prepared repeatedly. [Figure 11-3] 1 is a 1H NMR spectrum of p-toluenesulfonate crystalline form A of compound of formula I prepared repeatedly. [Figure 11-4] 1 is a PLM pattern of p-toluenesulfonate crystalline form A of compound of formula I prepared repeatedly. [Figure 12] FIG. 2 is a kinetic solubility curve at 37° C. [Figure 13] 1 is an XRPD overlay of a solubility sample of free base crystalline Form A in HO. [Figure 14] 1 is an XRPD overlay of a solubility sample of free base Form A in SGF. [Figure 15] 1 is an XRPD overlay of a solubility sample of free base Form A in FaSSIF. [Figure 16] FIG. 13 is an XRPD overlay of a solubility sample of free base Form A in FeSSIF. [Figure 17] 1 is an XRPD overlay of a solubility sample of the hydrochloride salt crystalline form A in HO. [Figure 18]1 is an XRPD overlay of a solubility sample of the hydrochloride salt crystalline form A in SGF. [Figure 19] 1 is an XRPD overlay of a solubility sample of the hydrochloride salt crystalline form A in FaSSIF. [Figure 20] FIG. 13 is an XRPD overlay of a solubility sample of the hydrochloride salt crystalline form A in FeSSIF. [Figure 21] 1 is an XRPD overlay of a solubility sample of maleate salt crystalline form A in HO. [Figure 22] 1 is an XRPD overlay of a solubility sample of maleate salt crystalline form A in SGF. [Figure 23] 1 is an XRPD overlay of a solubility sample of maleate salt Form A in FaSSIF. [Figure 24] FIG. 13 is an XRPD overlay of a solubility sample of maleate crystalline form A in FeSSIF. [Diagram 25] 1 is an XRPD overlay of a solubility sample of the p-toluenesulfonate salt crystalline form A in HO. [Figure 26] 1 is an XRPD overlay of a solubility sample of the p-toluenesulfonate salt crystalline form A in SGF. [Figure 27] 1 is an XRPD overlay of a solubility sample of the p-toluenesulfonate salt crystalline form A in FaSSIF. [Figure 28] FIG. 13 is an XRPD overlay of a solubility sample of p-toluenesulfonate crystalline form A in FeSSIF. [Figure 29] 1 is a DVS pattern of the free base crystalline form A. [Diagram 30] 1 is an XRPD overlay of free base crystalline form A before and after DVS measurement. [Diagram 31] 1 shows the DVS pattern of the hydrochloride salt crystalline form A. [Diagram 32] 1 is an XRPD overlay of the hydrochloride salt crystalline form A before and after DVS measurement. [Diagram 33] 1 is a DVS pattern of the maleate salt crystalline form A. [Diagram 34]1 is an XRPD overlay of maleate crystalline form A before and after DVS measurement. [Diagram 35] 1 is a DVS pattern of p-toluenesulfonate crystalline form A. [Diagram 36] 1 is an XRPD overlay of the p-toluenesulfonate salt crystalline form A before and after DVS measurement. [Figure 37] 1 is an XRPD overlay of a stability assessment sample of free base crystalline form A. [Figure 38] 1 is an XRPD overlay of a stability evaluation sample of the hydrochloride salt crystalline form A. [Figure 39] 1 is an XRPD overlay of a stability evaluation sample of maleate crystalline form A. [Diagram 40] 1 is an XRPD overlay of a stability evaluation sample of p-toluenesulfonate crystalline form A. [Diagram 41] 4 shows the results of a test on the water / water quinine intake ratio when the corresponding compound was administered to animals. [Diagram 42] 4 shows the results of a test on the number of coughs induced by histamine / citric acid stimulation after administration of the corresponding compound to guinea pigs. [Diagram 43] 1 shows the results of a test on the number of coughs induced by ATP / citric acid stimulation after administration of the corresponding compound to guinea pigs.

Claims

1. A crystalline form of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula I is: 【Chemistry 1】 As shown in A crystalline form of the compound of formula I or a pharmaceutically acceptable salt thereof.

2. the crystalline form is free base crystalline form A of the compound of formula I, and the X-ray powder diffraction pattern of free base crystalline form A, expressed as diffraction angles 2θ±0.2°, has diffraction peaks at 7.44°, 14.87°, 15.77°, 17.81°, and 18.61°; Preferably, the free base crystalline form A has an X-ray powder diffraction pattern expressed as diffraction angles 2θ±0.2°, with diffraction peaks at 7.44°, 11.14°, 11.36°, 14.87°, 15.77°, 16.97°, 17.81°, and 18.61°; Preferably, the free base crystalline form A has an X-ray powder diffraction pattern expressed as diffraction angles 2θ±0.2°, having diffraction peaks at the following angles: 3.75°, 7.44°, 11.14°, 11.36°, 11.98°, 12.25°, 14.87°, 15.77°, 16.97°, 17.81°, 18.61°, and 22.36°; Preferably, the free base crystalline form A has an X-ray powder diffraction pattern expressed as diffraction angles 2θ±0.2°, having diffraction peaks at the following angles: 3.75°, 5.99°, 7.44°, 9.01°, 9.93°, 11.14°, 11.36°, 11.98°, 12.25°, 13.88°, 14.20°, 14.87°, 15.77°, 16.97°, 17.81°, 18.61°, 22.36°, and 24.07°; Preferably, the free base crystalline form A has an X-ray powder diffraction pattern, expressed as diffraction angles 2θ±0.2°, having diffraction peaks at the following angles: 3.75°, 5.99°, 7.44°, 9.01°, 9.93°, 11.14°, 11.36°, 11.98°, 12.25°, 13.88°, 14.20°, 14.87°, 15.77°, 16.97°, 17.81°, 18.61°, 19.39°, 20.26°, 21.14°, 22.36°, 23.34°, 24.07°, 26.33°, 26.78°, 27.18°, 28.17°, 30.20°, 33.88°, 34.35°, 37.23°, and 37.70°; Preferably, the free base crystalline form A has an XRPD pattern essentially as shown in Figure 1-1; Preferably, the free base crystalline form A is (1) The weight loss of the free base crystalline form A in the TGA curve at 150.0±3°C is approximately 1.28±1%; (2) The DSC curve of the free base crystalline form A has an endothermic peak at the onset of 175.6±3°C. (3) The free base crystalline form A has one, two, or three characteristics, namely, a DSC curve having one endothermic peak at 176.4±3°C; Preferably, the TGA / DSC pattern of the free base crystalline form A is shown in Figure 1-2; Preferably, the free base crystalline form A 1 The H NMR spectrum is shown in Figures 1-3. The crystalline form of claim 1.

3. the crystalline form is free base crystalline form B of the compound of formula I, wherein the X-ray powder diffraction pattern of the free base crystalline form B, expressed as a diffraction angle of 2θ±0.2°, has diffraction peaks at 7.21°, 12.48°, 13.17°, 14.41°, 19.09°, 19.56°, 22.09°, and 26.49°; Preferably, the free base crystalline form B has an X-ray powder diffraction pattern expressed as diffraction angles 2θ±0.2°, having diffraction peaks at 7.21°, 12.48°, 13.17°, 14.41°, 16.72°, 19.09°, 19.56°, 20.90°, 22.09°, and 26.49°; Preferably, the free base crystalline form B has an X-ray powder diffraction pattern expressed as diffraction angles 2θ±0.2°, having diffraction peaks at the following angles: 7.21°, 8.35°, 12.48°, 13.17°, 14.41°, 15.05°, 16.72°, 17.80°, 18.39°, 19.09°, 19.56°, 20.90°, 21.67°, 22.09°, 22.97°, 25.16°, 26.49°, and 27.49°; Preferably, the free base crystalline form B has an X-ray powder diffraction pattern, expressed as diffraction angles 2θ±0.2°, having diffraction peaks at the following angles: 7.21°, 8.35°, 12.48°, 13.17°, 14.41°, 15.05°, 16.72°, 17.80°, 18.39°, 19.09°, 19.56°, 20.90°, 21.67°, 22.09°, 22.97°, 25.16°, 25.45°, 26.49°, 27.49°, 28.66°, 29.10°, 29.35°, 31.71°, 32.00°, 32.85°, 33.70°, 34.23°, 36.78°, 38.26°, and 38.70°; Preferably, the free base crystalline form B has an XRPD pattern essentially as shown in Figure 2-1; Preferably, the free base crystalline form B is (1) The weight loss of the free base crystalline form B at 150.0±3°C in the TGA curve is about 2.36±1%; (2) The DSC curve of the free base crystalline form B has an endothermic peak at 177.0±3°C. (3) The DSC curve of the free base crystalline form B has one, two, or three characteristics, namely, an endothermic peak at 179.4±3°C. The crystalline form of claim 1.

4. The pharmaceutically acceptable salts of the compounds of formula I include salts formed by compounds of formula I with inorganic or organic acids, The inorganic acid includes hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and hydrobromic acid; The organic acid includes maleic acid, L-aspartic acid, fumaric acid, L-tartaric acid, citric acid, D-glucuronic acid, L-malic acid, hippuric acid, D-gluconic acid, DL-lactic acid, succinic acid, L-ascorbic acid, adipic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, malonic acid, gentisic acid, and benzoic acid; Preferably, the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride, maleate, p-toluenesulfonate, benzenesulfonate, or malonate salt of the compound of formula I. The crystalline form of claim 1.

5. The crystalline forms of the pharmaceutically acceptable salts of the compound of formula I are hydrochloride crystalline form A, maleate crystalline form A, p-toluenesulfonate crystalline form A, benzenesulfonate crystalline form A, and malonate crystalline form A of the compound of formula I. The crystalline form of claim 1.

6. The X-ray powder diffraction pattern of the hydrochloride salt crystalline form A, expressed as a diffraction angle of 2θ±0.2°, has diffraction peaks at 7.77°, 9.01°, 10.10°, 15.54°, 17.51°, 19.24°, and 24.49°; Preferably, the X-ray powder diffraction pattern of the hydrochloride salt crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at the following angles: 7.77°, 9.01°, 10.10°, 15.54°, 17.51°, 18.01°, 19.24°, 20.05°, 21.28°, 23.38°, 23.79°, 24.49°, 26.07°, and 28.33°; Preferably, the X-ray powder diffraction pattern of the hydrochloride salt crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at the following angles: 7.77°, 9.01°, 10.10°, 15.54°, 17.51°, 18.01°, 19.24°, 20.05°, 21.28°, 21.59°, 22.67°, 23.38°, 23.79°, 24.49°, 26.07°, 27.17°, and 28.33°; Preferably, the hydrochloride salt crystalline form A has an XRPD pattern essentially as shown in Figure 3-1; Preferably, in the hydrochloride salt crystalline form A, the molar ratio of the compound of formula I to hydrochloric acid is 2:1; Preferably, the hydrochloride salt crystalline form A has a VT-XRPD pattern essentially as shown in Figure 9-4; Preferably, the hydrochloride crystalline form A is (1) The weight loss of the hydrochloride crystalline form A in the TGA curve at 100.0±3°C is approximately 2.19±1%; (2) The weight loss of the hydrochloride crystalline form A in the TGA curve within the temperature range of 100.0±3°C to 160.0±3°C is approximately 3.90±1%; (3) The DSC curve of the hydrochloride salt crystalline form A has an endothermic peak at 143.6±3°C. (4) The DSC curve of the hydrochloride salt crystalline form A has one endothermic peak at 157.4±3°C; (5) The DSC curve of the hydrochloride salt crystalline form A has one endothermic peak at 176.0±3°C; (6) The DSC curve of the hydrochloride salt crystalline form A has one, two, three, four, five, or six characteristics, namely, one endothermic peak at 179.0±3°C; The crystalline form of claim 5.

7. The X-ray powder diffraction pattern of the maleate salt crystalline form A, expressed as a diffraction angle of 2θ±0.2°, has diffraction peaks at 6.73°, 10.84°, 14.68°, 16.26°, 18.23°, and 18.44°; Preferably, the X-ray powder diffraction pattern of the maleate salt crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at 5.43°, 6.73°, 10.84°, 14.68°, 16.26°, 16.82°, 18.23°, and 18.44°; Preferably, the maleate salt crystalline form A has an X-ray powder diffraction pattern, expressed as diffraction angles 2θ±0.2°, having diffraction peaks at the following angles: 5.43°, 6.73°, 9.95°, 10.84°, 11.75°, 13.50°, 14.68°, 16.26°, 16.82°, 18.23°, 18.44°, 20.17°, 22.79°, 23.22°, 24.00°, 26.07°, 27.72°, and 28.86°; Preferably, the maleate salt crystalline form A has an XRPD pattern essentially as shown in Figure 4-1; Preferably, in the maleate salt crystalline form A, the molar ratio of the compound of formula I to maleic acid is 2:1; Preferably, the maleate salt crystalline form A has a VT-XRPD pattern essentially as shown in Figure 10-4; Preferably, the maleate crystalline form A is (1) The weight loss of the maleate salt crystalline form A in the TGA curve at 110.0±3°C is approximately 1.65±1%; (2) The weight loss of the maleate salt crystalline form A in the TGA curve within the temperature range of 110.0±3°C to 220.0±3°C is approximately 11.88±1%; (3) The DSC curve of maleate crystalline form A has one endothermic peak at 107.8±3°C; (4) The DSC curve of maleate crystalline form A has an endothermic peak at 143.4±3°C. (5) The DSC curve of maleate crystalline form A has one endothermic peak at 144.1±3°C; (6) The DSC curve of maleate crystalline form A has one, two, three or more characteristics, including an endothermic peak at 160.2±3°C. The crystalline form of claim 5.

8. The X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form A, expressed as a diffraction angle of 2θ±0.2°, has diffraction peaks at 4.99°, 7.26°, 8.70°, 8.87°, 15.40°, 17.73°, 21.01°, and 24.13°; Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at 4.99°, 7.26°, 8.70°, 8.87°, 15.20°, 15.40°, 16.68°, 17.73°, 19.71°, 21.01°, and 24.13°; Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at the following angles: 4.99°, 7.26°, 8.70°, 8.87°, 14.45°, 14.88°, 15.20°, 15.40°, 16.41°, 16.68°, 17.45°, 17.73°, 19.16°, 19.71°, 20.66°, 21.01°, 21.76°, 22.41°, 24.13°, 25.76°, 26.18°, and 27.25°; Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at the following angles: 4.99°, 7.26°, 8.70°, 8.87°, 14.45°, 14.88°, 15.20°, 15.40°, 16.41°, 16.68°, 17.45°, 17.73°, 19.16°, 19.71°, 20.66°, 21.01°, 21.76°, 22.41°, 24.13°, 25.76°, 26.18°, 27.25°, 27.95°, 29.23°, 30.69°, 31.00°, 31.78°, and 38.41°; Preferably, the p-toluenesulfonate salt crystalline form A has an XRPD pattern essentially as shown in Figure 5-1; Preferably, in the p-toluenesulfonate crystalline form A, the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1; Preferably, the p-toluenesulfonate crystalline form A is (1) The weight loss of the p-toluenesulfonate salt crystalline form A in the TGA curve at 150.0±3°C is approximately 0.73±1%; (2) The DSC curve of the p-toluenesulfonate salt crystalline form A has an endothermic peak at 157.1±3°C. (3) The DSC curve of the p-toluenesulfonate salt crystalline form A has one, two, or three characteristics, namely, an endothermic peak at 159.2±3°C; The crystalline form of claim 5.

9. The X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A, expressed as a diffraction angle of 2θ±0.2°, has diffraction peaks at 5.36°, 7.28°, 8.34°, 9.64°, 16.20°, 18.55°, and 21.49°; Preferably, the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A, expressed as a diffraction angle of 2θ±0.2°, has diffraction peaks at 5.36°, 7.28°, 8.34°, 9.64°, 16.20°, 18.55°, 19.28°, 21.49°, 21.81°, 23.21°, 25.05°, and 25.74°; Preferably, the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at the following angles: 5.36°, 7.28°, 8.34°, 9.64°, 10.66°, 14.55°, 15.00°, 16.20°, 16.93°, 17.85°, 18.55°, 19.28°, 19.74°, 20.80°, 21.49°, 21.81°, 23.21°, 23.68°, 23.98°, 25.05°, 25.74°, 26.65°, and 27.82°; Preferably, the benzenesulfonate salt crystalline form A has an XRPD pattern essentially as shown in Figure 6-1; Preferably, in the benzenesulfonate salt crystalline form A, the molar ratio of the compound of formula I to benzenesulfonic acid is 1:1; Preferably, the benzenesulfonate salt crystalline form A is (1) The weight loss at 120.0±3°C in the TGA curve of crystalline form A of the benzenesulfonate salt is approximately 1.35±1%; (2) The DSC curve of the benzenesulfonate salt crystalline form A has an endothermic peak at 159.6±3°C. (3) The DSC curve of crystalline form A of the benzenesulfonate salt has one, two, or three characteristics, namely, an endothermic peak at 160.9±3°C; The crystalline form of claim 5.

10. The X-ray powder diffraction pattern of the malonate crystalline form A, expressed as a diffraction angle of 2θ±0.2°, has diffraction peaks at 6.75°, 9.96°, 10.67°, 14.48°, 16.04°, 16.88°, 18.04°, and 18.29°; Preferably, the X-ray powder diffraction pattern of the malonate crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at the following angles: 5.34°, 6.75°, 9.96°, 10.67°, 11.83°, 13.49°, 14.48°, 16.04°, 16.88°, 17.04°, 18.04°, 18.29°, and 27.38°; Preferably, the X-ray powder diffraction pattern of the malonate crystalline form A, expressed as a diffraction angle range of 2θ±0.2°, has diffraction peaks at the following angles: 5.34°, 6.75°, 9.96°, 10.67°, 11.83°, 13.49°, 14.48°, 16.04°, 16.88°, 17.04°, 18.04°, 18.29°, 20.27°, 22.57°, 22.95°, 27.38°, and 28.83°; Preferably, the X-ray powder diffraction pattern of the malonate crystalline form A, expressed in terms of diffraction angles 2θ±0.2°, has diffraction peaks at the following angles: 5.34°, 6.75°, 9.96°, 10.67°, 11.83°, 13.49°, 14.48°, 16.04°, 16.88°, 17.04°, 18.04°, 18.29°, 18.63°, 20.27°, 21.57°, 22.57°, 22.95°, 24.11°, 24.83°, 26.02°, 27.38°, and 28.83°; Preferably, the malonate salt crystalline form A has an XRPD pattern essentially as shown in Figure 7-1; Preferably, in the Malonate Crystalline Form A, the molar ratio of the compound of Formula I to malonic acid is 2:1; Preferably, the malonate salt crystalline form A has a VT-XRPD pattern essentially as shown in Figure 7-4; Preferably, the malonate crystalline form A is (1) The weight loss of the malonate crystalline form A at 120.0±3°C in the TGA curve is approximately 2.99±1%; (2) The weight loss of the malonate crystalline form A in the TGA curve within the temperature range of 120.0±3°C to 200.0±3°C is approximately 11.02±1%; (3) The DSC curve of malonate crystalline form A has an endothermic peak at 155.6±3°C; (4) The DSC curve of malonate crystalline form A has one endothermic peak at 156.4±3°C; (5) The DSC curve of malonate crystalline form A has one, two, three, four or five characteristics, namely, one endothermic peak at 172.4±3°C; The crystalline form of claim 5.

11. Salts of compounds of formula I, wherein the pharmaceutically acceptable salts of the compounds of formula I include salts formed by compounds of formula I with inorganic or organic acids, wherein the structure of the compounds of formula I is: 【Chemistry 2】 As shown in The inorganic acid includes hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and hydrobromic acid; The organic acid includes maleic acid, L-aspartic acid, fumaric acid, L-tartaric acid, citric acid, D-glucuronic acid, L-malic acid, hippuric acid, D-gluconic acid, DL-lactic acid, succinic acid, L-ascorbic acid, adipic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, malonic acid, gentisic acid, and benzoic acid; Preferably, the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride, maleate, p-toluenesulfonate, benzenesulfonate, or malonate salt of the compound of formula I; Preferably, the molar ratio of the compound of formula I to the acid is 5:1 to 1:5, for example 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, and preferably the molar ratio of the compound of formula I to the acid is 1:1 or 2:

1. A salt of a compound of formula I.

12. A method for preparing the free base crystalline form A of the compound of formula I according to claim 2, comprising the steps of: Method 1: Add the compound of formula I to organic solvent I, dissolve it, filter it, and evaporate it at room temperature; Preferably, the organic solvent I is one or more selected from acetone, tetrahydrofuran, dichloromethane, acetonitrile, and ethyl acetate; Method 2: completely dissolve the compound of formula I in organic solvent II, add anti-solvent dropwise to the clear solution under stirring until a solid precipitates, use suspension stirring if no solid precipitates, lower the temperature if no solid precipitates, and evaporate the clear solution at room temperature after suspension stirring; the organic solvent II is one or more selected from the group consisting of methanol, acetone, ethyl acetate, tetrahydrofuran, chloroform, N,N-dimethylacetamide, and N-methylpyrrolidone; the anti-solvent is one or more selected from the group consisting of water, meta-xylene, n-hexane, isopropylbenzene, toluene, cyclohexane, n-heptane, n-pentane, and p-isopropyltoluene; Method 3: A first sample bottle containing the compound of formula I is placed in a second sample bottle containing a solvent, the first sample bottle is sealed, and the second sample bottle is left standing at room temperature so that the solvent does not exceed the opening of the first sample bottle; the solvent is one or more selected from ethanol, dichloromethane, acetonitrile, acetone, toluene, N,N-dimethylacetamide, and n-hexane; Method 4: A first sample bottle containing a solution of the compound of formula I is placed in a second sample bottle containing an anti-solvent so that the first sample bottle is open, the second sample bottle is sealed, and the anti-solvent is allowed to stand at room temperature so that the anti-solvent does not exceed the opening of the first sample bottle; The solvent in the solution of the compound of formula I is one or more selected from the group consisting of isopropanol, methyl isobutyl ketone, 1,4-dioxane, and dimethyl sulfoxide; the anti-solvent is one or more selected from n-pentane, methyl butyl ether, water, and meta-xylene; Method 5: Add the polymer to a solution of the compound of formula I and evaporate at room temperature; The solvent in the solution of the compound of formula I is one or more selected from the group consisting of methanol, 2-butanone, methyl acetate, isopropyl acetate, ethanol, dichloromethane, and 2-methyltetrahydrofuran; the polymer is one or more selected from polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, and hydroxyethyl cellulose; Method 6: A first sample bottle containing the compound of formula I is placed in a second sample bottle containing a saturated salt solution or water so that the first sample bottle is open, and the second sample bottle is sealed and left to stand at room temperature so that the solvent does not exceed the opening of the first sample bottle; Preferably, the saturated salt solution is an inorganic salt saturated solution; Preferably, the saturated inorganic salt solution is a saturated potassium acetate solution, a saturated potassium carbonate solution, a saturated sodium bromide solution, or a saturated potassium bromide solution; Preferably, the humidity of the system is 15 to 100% RH; Method 7, temperature cycling a suspension of a compound of Formula I, centrifuging, and collecting the solid; the solvent in the suspension is one or more selected from n-heptane, methyl butyl ether, anisole, dicyclohexylamine, acetone, ethanol, ethyl acetate, methylcyclohexane, chloroform, 2-butanone, meta-xylene, and water; Preferably, the temperature cycling conditions include 50°C to 5°C, 0.1 to 0.5°C / min, and at least two cycles; Method 8: The compound of formula I is completely dissolved in a normal solvent, and the anti-solvent is added dropwise to the clear solution under stirring until a solid precipitates. If no solid precipitates, use suspension stirring. If no solid precipitates, lower the temperature. After suspension stirring, evaporate the clear solution at room temperature. the positive solvent is one or more selected from ethanol, ethyl acetate, 2-methyltetrahydrofuran, 2-butanone, acetonitrile, dichloromethane, and 1,4-dioxane; the anti-solvent is one or more selected from n-heptane, tetrahydrofuran, and water; Method 9: A suspension of a compound of Formula I is magnetically stirred at room temperature, centrifuged, and the solid is collected; the solvent of the suspension is one or more selected from isobutanol, methyl tert-butyl ether, cyclohexane, toluene, isopropyl acetate, water, methylcyclohexane, tetrahydrofuran, n-pentane, acetone, isopropanol, cyclopentyl methyl ether, methanol, p-isopropyltoluene, dichloromethane, n-heptane, acetonitrile, 1,4-dioxane, and N-methylpyrrolidone; Method 10: Weigh the compound of formula I into an HPLC vial, add a solvent to the HPLC vial, heat, stir, and equilibrate, then filter to obtain a supernatant, place the supernatant in a bioincubator, cool from 50°C to 5°C at a rate of 0.05°C / min, and maintain at 5°C, transfer the clear solution to a constant temperature of -20°C, collect the precipitated solid, and transfer the sample without precipitated solid to room temperature for evaporation; the solvent is one or more selected from isopropanol, anisole, isopropyl acetate, tetrahydrofuran, and water; Preferably, heating to a temperature of 45-55°C, preferably 50°C, Method 11, stirring and centrifuging a suspension of a compound of Formula I and collecting the solid; the solvent in the suspension is one or more selected from n-butanol, toluene, diisopropyl ether, methylcyclohexane, isopropylbenzene, anisole, water, petroleum ether, dicyclohexylamine, 2-methyltetrahydrofuran, n-hexane, 2-butanone, isopropyl acetate, chloroform, meta-xylene, tetrahydrofuran, methyl isobutyl ketone, cyclopentyl methyl ether, and benzyl alcohol; Preferably, the method is any one selected from the following methods: method.

13. A method for preparing the free base crystalline form B of the compound of formula I according to claim 3, comprising the steps of: dissolving free base crystalline form A of the compound of formula I in 1,4-dioxane, followed by gas-liquid diffusion in an n-hexane atmosphere to obtain free base crystalline form B of said compound of formula I; method.

14. 12. A method for preparing a pharmaceutically acceptable salt of the compound of formula I according to claim 11, comprising mixing the compound of formula I or the free base crystalline form A of the compound of formula I with a salt-forming agent in a suitable solvent to obtain a mixture, Preferably, the salt-forming reagent is an inorganic or organic acid as defined in claim 4, The free base crystalline form A of the compound of formula I is the free base crystalline form A in the crystalline form of claim 2. method.

15. A pharmaceutical composition comprising one or more of the crystalline forms of the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, or a pharmaceutically acceptable salt of the compound of formula I according to claim 11, Preferably, the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride, maleate, p-toluenesulfonate, benzenesulfonate, or malonate salt of the compound of formula I; Preferably, the crystalline form of the salt is hydrochloride crystalline form A, maleate crystalline form A, p-toluenesulfonate crystalline form A, benzenesulfonate crystalline form A, or malonate crystalline form A of the compound of formula I. Pharmaceutical compositions.

16. 12. Use of a crystalline form of a compound of formula I according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a compound of formula I according to claim 11, in the manufacture of a therapeutic medicament, comprising: Preferably, the medicament is used for the treatment and / or prevention of a P2X3-related disease, Preferably, the P2X3-related disease comprises pain, a genitourinary system disease or a respiratory system disease; Preferably, the pain comprises inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, burn pain, migraine or cluster headache; preferably, the genitourinary system disease comprises urinary incontinence, overactive bladder, dysuria, cystitis, endometriosis, endometriosis-related pain; preferably, the respiratory system disease comprises cough, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease; Preferably, the cough includes subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, and cough associated with respiratory diseases; use.

17. Use of the pharmaceutical composition of claim 15 in the manufacture of a therapeutic medicament, comprising: Preferably, the medicament is used for the treatment and / or prevention of a P2X3-related disease, Preferably, the P2X3-related disease comprises pain, a genitourinary system disease or a respiratory system disease; Preferably, the pain comprises inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, burn pain, migraine or cluster headache; preferably, the genitourinary system disease comprises urinary incontinence, overactive bladder, dysuria, cystitis, endometriosis, endometriosis-related pain; preferably, the respiratory system disease comprises cough, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease; Preferably, the cough includes subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, and cough associated with respiratory diseases; use.

18. A method for treating and / or preventing a P2X3-related disease, comprising administering to a patient a therapeutically effective amount of a crystalline form of the compound of formula I according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the compound of formula I according to claim 11. method.

19. A method for treating and / or preventing a P2X3-related disease, comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of claim 15. method.

20. The method for detecting the quality of a crystalline form according to any one of claims 1 to 10, comprising detecting the content of the crystalline form using high performance liquid chromatography, wherein the fluid phase used in the high performance liquid chromatography comprises fluid phase A and fluid phase B; The mobile phase A is an aqueous solution of formic acid (FA) and acetonitrile (ACN), and the mobile phase B is acetonitrile; Preferably, the mobile phase A is an aqueous solution of 0.05-0.15% formic acid and 2-7% acetonitrile, illustratively an aqueous solution of 0.1% formic acid and 5% acetonitrile; Preferably, the quality inspection method includes a purity inspection method, a solubility inspection method, and a stability inspection method; Preferably, the high performance liquid chromatography uses gradient elution; Preferably, the flow rate of the mobile phase is 1±0.2 mL / min, and the time of the gradient elution is 5 to 60 min, more preferably 10 to 30 min; Preferably, in the gradient elution, the volume ratio of mobile phase A to mobile phase B is 1:9 to 9:

1. method.

Images