Pharmaceutically acceptable salt of compound of formula i and crystal form thereof

Abstract

The present invention belongs to the technical field of chemical drugs, and provides a pharmaceutically acceptable salt of a compound of formula I and a crystal form thereof, and a pharmaceutical composition comprising the pharmaceutically acceptable salt of the compound of formula I and the crystal form thereof. In addition, the present invention also relates to use of the pharmaceutically acceptable salt of the compound of formula I and the crystal form thereof in the preparation of a drug for treating or preventing related diseases caused by an increased level of CYP11B2 activity.

Description

A pharmaceutically acceptable salt of a compound of formula I and its crystal form Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, and provides a pharmaceutically acceptable salt of a compound of formula I and its crystal form, as well as a pharmaceutical composition containing the pharmaceutically acceptable salt of a compound of formula I and its crystal form. In addition, this invention also relates to the use of the pharmaceutically acceptable salt of a compound of formula I and its crystal form in the preparation of a medicament for treating or preventing diseases caused by elevated CYP11B2 activity levels. Background Technology

[0002] Aldosterone is a steroid hormone with mineralocorticoid activity. It is primarily produced in response to angiotensin II, adrenocorticotropic hormone (ACTH), and the zona glomerulosa of the adrenal gland, which increases serum potassium levels. Its main physiological role in the kidneys is to maintain sodium and potassium balance by regulating cation exchange (Na+ reabsorption and K+ secretion) in the distal nephron. However, aldosterone has also been shown to be a pro-inflammatory and pro-fibrotic hormone in the blood vessels, heart, and kidneys. The effects of aldosterone on gene expression are regulated through binding to the mineralocorticoid receptor (MR) and typical nuclear hormone receptor pathways.

[0003] CYP11B2 (aldosterone synthase) is a cytochrome P450 enzyme known as an enzyme that catalyzes a series of reactions from 11-deoxycorticosterone (i.e., the aldosterone precursor) to aldosterone. CYP11B2 is primarily expressed in the zona glomerulosa of the adrenal cortex, and plasma aldosterone levels are regulated by the activity of this enzyme in the adrenal glands. Furthermore, aldosterone expression has been confirmed in sites outside the adrenal glands, such as the cardiovascular system, kidneys, adipose tissue, and brain. The finding that locally produced aldosterone in various organs is associated with organ dysfunction has attracted attention. Reports indicate that CYP11B2 inhibitors can inhibit aldosterone production in studies using enzymes and cultured cells, and have shown inhibitory and therapeutic effects in studies using various experimental animal models. In addition, CYP11B2 inhibitors have been confirmed to reduce plasma and urinary aldosterone levels and have an antihypertensive effect in patients with hypertension and primary aldosteronism. Finding ways to block the biosynthetic pathway of aldosterone is a highly feasible approach to establishing effective treatments for various aldosterone-related diseases.

[0004] PCT / CN2024 / 142727 discloses an aldosterone synthase inhibitor, its preparation method, and its uses, specifically disclosing compound (R)-N-(4-(2-cyanoquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide (i.e., compound I), whose structural formula is: However, the patent application did not disclose the specific medicinal salt of the compound, nor did it disclose the microstructure of the medicinal salt.

[0005] It is well known in this field that drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different polymorphs of the same drug may differ significantly in appearance, solubility, melting point, dissolution rate, and bioavailability, and may also have different impacts on drug stability, bioavailability, and efficacy. Therefore, the issue of drug polymorphism should be comprehensively considered in drug development. Studying the polymorphism of pharmaceutically usable salts of Formula I compounds is also of great significance for developing drugs suitable for industrial production and with good biological activity.

[0006] On the other hand, salt formation can improve some undesirable physicochemical or biological properties of drugs. Developing salts with superior physicochemical or pharmaceutical properties compared to compounds of Formula I is of great significance. Further research into the polymorphism of salts of Formula I compounds is also important for developing drugs suitable for industrial production and with good biological activity. Summary of the Invention

[0007] In view of the problems existing in the prior art, the present invention aims to provide a pharmaceutically acceptable salt of the compound of formula I or its crystal form, so as to solve the problems existing in the prior art.

[0008] This invention is achieved through the following technical solution:

[0009] This invention provides a pharmaceutically usable salt of a compound of formula I, characterized in that the structure of the compound of formula I is as follows:

[0010] The pharmaceutically usable salt is independently selected from: hydrochloride, hydrobromide, phosphate, nitrate, sulfate, acetate, propionate, malonate, succinate, valerate, glutarate, adipate, oxalate, L-proline, lactobionate, glycine, alanine, arginine, lactate, cinnamate, fumarate, mandelate, maleate, hippurate, tartrate, citrate, malate, succinate, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, camphorsulfonate, benzoate, salicylate, benzenesulfonate, methanesulfonate, or p-toluenesulfonate.

[0011] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt is independently selected from: hydrochloride, hydrobromide, phosphate, sulfate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, oxalate, succinate, or adipate.

[0012] Furthermore, as a preferred embodiment of the present invention, the molar ratio of the compound of formula I to the pharmaceutically acceptable salt is 1:0.3 to 1:3.5; preferably, the molar ratio of the compound of formula I to the pharmaceutically acceptable salt is 1:1, 1:2, 1:3, 2:1, or 3:1.

[0013] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: hydrochloride, hydrobromide, phosphate, sulfate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, oxalate, succinate, or adipate of the compound of formula I, wherein the molar ratio of the compound of formula I to hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, oxalic acid, succinate, or adipate is 1:1.

[0014] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the hydrochloride salt of the compound of formula I, wherein the molar ratio of the compound of formula I to hydrochloric acid is 1:1.

[0015] Furthermore, the present invention also provides a crystal form of hydrochloride A of the compound of formula I, characterized in that the crystal form of hydrochloride A of the compound of formula I has characteristic peaks at 11.58°, 22.82°, 26.11° and 27.46° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the crystal form of hydrochloride A of the compound of formula I has characteristic peaks at 7.94°, 11.58°, 21.69°, 22.82°, 26.11° and 27.46° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the crystal form of hydrochloride A of the compound of formula I has characteristic peaks at 7.52°, 7.94°, 11.58°, 14.74°, 16.89°, 17.91°, 20.53° and 27.46° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; Characteristic peaks are observed at 1.69°, 22.82°, 24.26°, 25.21°, 26.11°, and 27.46°, with an error of ±0.2°; more preferably, the hydrochloride A crystal form of the compound of formula I, represented by 2θ angles in the X-ray diffraction pattern, is at 7.52°, 7.94°, 11.58°, 12.79°, 13.86°, 14.74°, and 16.89°. Characteristic peaks are observed at 17.91°, 19.23°, 19.62°, 20.53°, 21.69°, 21.96°, 22.82°, 24.26°, 25.21°, 26.11°, 27.46°, and 29.97°, with an error of ±0.2°; most preferably, the hydrochloride A crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 1.

[0016] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the hydrochloride A crystal form of the compound of formula I has an endothermic peak at 209.6±10℃; preferably, the hydrochloride A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 22.

[0017] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the hydrobromide salt of the compound of formula I, wherein the molar ratio of the compound of formula I to hydrobromic acid is 1:1.

[0018] Furthermore, the present invention also provides a hydrobromide A crystal form of the compound of formula I, characterized in that the hydrobromide A crystal form of the compound of formula I has characteristic peaks at 7.96° and 22.37° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the hydrobromide A crystal form of the compound of formula I has characteristic peaks at 7.96°, 13.69°, 21.81°, 22.37°, 22.66°, 25.27°, 26.40°, and 27.7° in the X-ray diffraction pattern, represented by a 2θ angle. A characteristic peak is observed at 7°, with an error of ±0.2°; more preferably, the hydrobromide A crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, exhibits characteristic peaks at 7.96°, 11.14°, 13.69°, 16.73°, 16.92°, 17.27°, 21.81°, 22.37°, 22.66°, 23.59°, 24.32°, 25.27°, 25.70°, 26.40°, 26.77°, and 27.77°, with an error of ±0.2°;

[0019] More preferably, the hydrobromide A crystal form of the compound of formula I is represented by a 2θ angle in the X-ray diffraction pattern at 7.35°, 7.96°, 11.14°, 12.60°, 13.69°, 14.57°, 16.73°, 16.92°, 17.27°, 18.96°, 19.20°, 20.15°, 21.50°, 21.81°, and 22.37°. Characteristic peaks are observed at 22.66°, 23.59°, 24.32°, 25.27°, 25.70°, 26.40°, 26.77°, 27.77°, 29.11°, 29.79°, 32.33°, and 33.50°, with an error of ±0.2°; most preferably, the hydrobromide A crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 2.

[0020] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the hydrobromide A crystal form of the compound of formula I has an endothermic peak at 177.7±10℃; preferably, the hydrobromide A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 23.

[0021] Furthermore, the present invention also provides a hydrobromide B crystal form of the compound of formula I, characterized in that the hydrobromide B crystal form of the compound of formula I has characteristic peaks at 6.99°, 10.39°, 13.80° and 20.67° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the hydrobromide B crystal form of the compound of formula I has characteristic peaks at 3.59°, 6.99°, 10.39°, 13.80°, 15.01°, 17.22°, 20.67°, 25.04° and 27.61° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the hydrobromide B crystal form of the compound of formula I has an XRPD pattern substantially as shown in FIG. 17.

[0022] Furthermore, the present invention also provides a hydrobromide C crystal form of the compound of formula I, characterized in that the hydrobromide C crystal form of the compound of formula I has characteristic peaks at 6.78°, 16.00°, 16.65°, 23.13° and 25.02° in the X-ray diffraction pattern, with an error of ±0.2°; preferably, the hydrobromide C crystal form of the compound of formula I has characteristic peaks at 6.78°, 13.52°, 15.55°, 16.00°, 16.65°, 19.83°, 21.70°, 22.42°, 23.13°, and 23.72° in the X-ray diffraction pattern, with an angle of 2θ. Characteristic peaks are observed at 24.53°, 25.02°, 25.46°, 25.81°, 26.47°, and 27.26°, with an error of ±0.2°; more preferably, the hydrobromide C crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, is at 3.80°, 6.78°, 10.94°, 13.52°, 14.11°, 15.55°, 16.00°, 16.65°, 17.03°, 18.77°, 19.83°, 20.12°, 20.32°, 21.18°, 21.70°, 22.42°, 23.13°, and 23.72°. Characteristic peaks are observed at 24.53°, 25.02°, 25.46°, 25.81°, 26.47°, 27.26°, 27.58°, 28.10°, and 28.71°, with an error of ±0.2°. More preferably, the hydrobromide C crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, is found at 3.80°, 6.78°, 7.67°, 10.94°, 12.20°, 13.52°, 14.11°, 14.66°, 14.96°, 15.55°, 16.00°, 16.65°, 17.03°, 18.77°, and 19.20°. Characteristic peaks are observed at 19.83°, 20.12°, 20.32°, 21.18°, 21.70°, 22.42°, 23.13°, 23.72°, 24.53°, 25.02°, 25.46°, 25.81°, 26.47°, 27.26°, 27.58°, 28.10°, 28.71°, 29.56°, 30.77°, 31.93°, 32.25°, 33.74°, and 36.17°, with an error of ±0.2°; most preferably, the hydrobromide C crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 18.

[0023] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the hydrobromide C crystal form of the compound of formula I has endothermic peaks at 64.0±10℃, 80.0±10℃ and 234.1±10℃; preferably, the hydrobromide C crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 31.

[0024] Furthermore, the present invention also provides an amorphous hydrobromide of a compound of formula I, characterized in that the amorphous hydrobromide of the compound of formula I has an X-ray diffraction pattern substantially as shown in FIG32.

[0025] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from the sulfate of the compound of formula I, wherein the molar ratio of the compound of formula I to sulfuric acid is 1:1.

[0026] Furthermore, the present invention also provides a sulfate A crystal form of the compound of formula I, characterized in that the sulfate A crystal form of the compound of formula I has characteristic peaks at 20.35°, 21.31°, 24.14° and 24.50° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the sulfate A crystal form of the compound of formula I has characteristic peaks at 5.59° and 7.10° in the X-ray diffraction pattern, represented by a 2θ angle. Characteristic peaks are observed at 7.39°, 16.19°, 19.83°, 20.35°, 21.31°, 22.23°, 22.91°, 24.14°, and 24.50° in the X-ray diffraction pattern, with an error of ±0.2°. More preferably, the sulfate A crystal form of the compound of Formula I is represented by a 2θ angle at 5.59°, 7.10°, 7.39°, 10.21°, 16.19°, and 19.4° in the X-ray diffraction pattern. Characteristic peaks are observed at 4°, 19.83°, 20.35°, 21.31°, 22.23°, 22.91°, 23.54°, 24.14°, 24.50°, and 25.48°, with an error of ±0.2°; more preferably, the sulfate A crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, is at 5.59°, 7.10°, 7.39°, 10.21°, 10.91°, and 1... Characteristic peaks are present at 6.19°, 16.47°, 17.48°, 19.44°, 19.83°, 20.35°, 21.31°, 22.23°, 22.91°, 23.54°, 24.14°, 24.50°, 25.48°, and 26.87°, with an error of ±0.2°; most preferably, the sulfate A crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 3.

[0027] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the sulfate A crystal form of the compound of formula I has an endothermic peak at 182.4±10℃; preferably, the sulfate A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 24.

[0028] Furthermore, the present invention also provides an amorphous sulfate form of a compound of formula I, characterized in that the amorphous sulfate form of the compound of formula I has an X-ray diffraction pattern substantially as shown in FIG33.

[0029] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the phosphate of the compound of formula I, wherein the molar ratio of the compound of formula I to phosphate is 1:1.

[0030] Furthermore, the present invention also provides a phosphate A crystal form of the compound of formula I, characterized in that the phosphate A crystal form of the compound of formula I has characteristic peaks at 7.35°, 11.02°, 16.00°, 18.77° and 19.73° in the X-ray diffraction pattern, with an error of ±0.2°; preferably, the phosphate A crystal form of the compound of formula I has characteristic peaks at 6.59°, 7.35°, and 19.73° in the X-ray diffraction pattern, with an error of ±0.2°; Characteristic peaks are observed at 10.66°, 11.02°, 13.86°, 16.00°, 18.77°, 19.73°, 21.91°, and 23.73°, with an error of ±0.2°; more preferably, the phosphate A crystal form of the compound of Formula I is represented by 2θ angles at 5.43°, 6.59°, 7.35°, 10.66°, 11.02°, 13.86°, 15.67°, and 16.00° in the X-ray diffraction pattern. Characteristic peaks are observed at 0°, 18.77°, 19.73°, 21.91°, 23.73°, 25.02°, and 26.74°, with an error of ±0.2°; more preferably, the phosphate A crystal form of the compound of formula I, represented by a 2θ angle in the X-ray diffraction pattern, is at 5.43°, 6.59°, 7.35°, 10.66°, 11.02°, 12.54°, 13.86°, 14.48°, 15.67°, 1... Characteristic peaks are present at 6.00°, 17.51°, 17.84°, 18.77°, 19.73°, 20.56°, 21.21°, 21.91°, 23.07°, 23.73°, 24.43°, 25.02°, 25.82°, 26.74°, and 27.97°, with an error of ±0.2°; most preferably, the phosphate A crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 4.

[0031] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the phosphate A crystal form of the compound of formula I has endothermic peaks at 199.5±10℃ and 221.9±10℃; preferably, the phosphate A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 25.

[0032] Furthermore, the present invention also provides a phosphate amorphous form of a compound of formula I, characterized in that the phosphate amorphous form of the compound of formula I has an X-ray diffraction pattern substantially as shown in FIG34.

[0033] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the benzenesulfonate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to benzenesulfonic acid is 1:1.

[0034] Furthermore, the present invention also provides a benzenesulfonate A crystal form of the compound of formula I, characterized in that the benzenesulfonate A crystal form of the compound of formula I has characteristic peaks at 4.79° and 22.28° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the benzenesulfonate A crystal form of the compound of formula I has characteristic peaks at 4.79°, 12.06°, 15.44° and 22.28° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°. The error is ±0.2°; more preferably, the benzenesulfonate A crystal form of the compound of formula I has characteristic peaks at 4.79°, 12.06°, 13.20°, 13.89°, 14.67°, 15.44°, 18.11°, 20.39° and 22.28° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; most preferably, the benzenesulfonate A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 5.

[0035] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the p-toluenesulfonate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1.

[0036] Furthermore, the present invention also provides a p-toluenesulfonate A crystal form of the compound of formula I, characterized in that the p-toluenesulfonate A crystal form of the compound of formula I has characteristic peaks at 5.19° and 21.46° in the X-ray diffraction pattern, represented by 2θ angles, with an error of ±0.2°; preferably, the p-toluenesulfonate A crystal form of the compound of formula I has characteristic peaks at 5.19°, 15.53° and 21.46° in the X-ray diffraction pattern, represented by 2θ angles, with an error of ±0.2°; more preferably, the p-toluenesulfonate A crystal form of the compound of formula I has characteristic peaks at 5.19°, 15.53° and 21.46° in the X-ray diffraction pattern, represented by 2θ angles, with an error of ±0.2°; and more preferably, the p-toluenesulfonate A crystal form of the compound of formula I has characteristic peaks at 5.19°, 10.00° and 21.46° in the X-ray diffraction pattern, represented by 2θ angles. Characteristic peaks are observed at 5.19°, 10.00°, 12.90°, 14.83°, 15.53°, 21.46°, and 21.94°, with an error of ±0.2°, in the X-ray diffraction pattern of the p-toluenesulfonate A crystal form of the compound of Formula I, represented by a 2θ angle. Characteristic peaks are observed at 5.19°, 10.00°, 12.90°, 14.83°, 15.53°, 18.40°, 21.46°, 21.94°, 22.43°, 23.80°, and 24.55°, with an error of ±0.2°, in the X-ray diffraction pattern. Most preferably, the p-toluenesulfonate A crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 6.

[0037] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the p-toluenesulfonate A crystal form of the compound of formula I has an endothermic peak at 114.6±10℃; preferably, the p-toluenesulfonate A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 26.

[0038] Furthermore, the present invention also provides a p-toluenesulfonate B crystal form of the compound of formula I, characterized in that the p-toluenesulfonate B crystal form of the compound of formula I has characteristic peaks at 5.16°, 5.36°, and 13.81° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the p-toluenesulfonate B crystal form of the compound of formula I has characteristic peaks at 5.16°, 5.36°, 13.66°, 13.81°, 14.92°, 20.55°, 21.03°, 21.70°, and 25.69° in the X-ray diffraction pattern, with an error of ±0.2°; more preferably, the p-toluenesulfonate B crystal form of the compound of formula I has characteristic peaks at 5.16°, 5.36°, 13.66°, and 13.81° in the X-ray diffraction pattern, represented by a 2θ angle. Characteristic peaks are observed at 14.92°, 20.55°, 21.03°, 21.70°, 25.69°, and 27.27° in the X-ray diffraction pattern, with an error of ±0.2°. More preferably, the p-toluenesulfonate B crystal form of the compound of Formula I exhibits characteristic peaks at 5.16°, 5.36°, 13.66°, 13.81°, 14.92°, 15.85°, 17.66°, 18.30°, 18.97°, 20.55°, 21.03°, 21.70°, 22.89°, 24.47°, 25.69°, 26.77°, 27.27°, and 30.13° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°. Most preferably, the p-toluenesulfonate B crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 7.

[0039] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the p-toluenesulfonate B crystal form of the compound of formula I has an endothermic peak at 181.9±10℃; preferably, the p-toluenesulfonate B crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 27.

[0040] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the maleate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to maleic acid is 1:1.

[0041] Furthermore, the present invention also provides a maleate A crystal form of the compound of formula I, characterized in that the maleate A crystal form of the compound of formula I has characteristic peaks at 9.14° and 19.10° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the maleate A crystal form of the compound of formula I has characteristic peaks at 9.14°, 13.64° and 19.10° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the maleate A crystal form of the compound of formula I has characteristic peaks at 4° in the X-ray diffraction pattern, represented by a 2θ angle... Characteristic peaks are observed at 0.67°, 9.14°, 13.64°, and 19.10° with an error of ±0.2°; more preferably, the maleate A crystal form of the compound of formula I has characteristic peaks at 4.67°, 9.14°, 13.64°, 15.02°, 18.13°, 19.10°, 19.75°, 23.23°, 23.97°, and 24.90° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; most preferably, the maleate A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 8.

[0042] Furthermore, the present invention also provides a maleate B crystal form of the compound of formula I, characterized in that the maleate B crystal form of the compound of formula I has characteristic peaks at 5.20°, 15.54°, and 21.49° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the maleate B crystal form of the compound of formula I has characteristic peaks at 5.20°, 10.02°, 14.84°, 15.54°, 21.49°, 21.96°, 22.45°, and 23.81° in the X-ray diffraction pattern, represented by a 2θ angle. The compound of Formula I has characteristic peaks at 5.20°, 10.02°, 12.91°, 14.84°, 15.54°, 18.46°, 21.49°, 21.96°, 22.45°, 22.76°, 23.81°, and 24.56° in its X-ray diffraction pattern, with an error of ±0.2°. Most preferably, the compound of Formula I has an XRPD pattern substantially as shown in Figure 9.

[0043] Furthermore, the present invention also provides a maleate C crystal form of the compound of formula I, characterized in that the maleate C crystal form of the compound of formula I has characteristic peaks at 9.54°, 18.14°, 18.46°, 18.94°, 20.12°, 20.31°, 22.33°, 22.69°, 24.29°, and 25.14° in the X-ray diffraction pattern, with an error of ±0.2°; preferably, ...46°, 18.94°, 20.12°, 20.31°, 22.33°, 22.69°, 24.29°, and 25.14° in the X-ray diffraction pattern, with an error of ±0.2°. Characteristic peaks are observed at 4°, 14.31°, 18.14°, 18.46°, 18.94°, 20.12°, 20.31°, 21.24°, 22.33°, 22.69°, 24.29°, 24.66°, and 25.14° in the X-ray diffraction pattern, with an error of ±0.2°. More preferably, the maleate C crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, is at 7.43°, 9.54°, 11.84°, 14.31°, 17.51°, 18.14°, 18.46°, and 18.94°. Characteristic peaks are observed at 20.12°, 20.31°, 20.74°, 21.24°, 22.33°, 22.69°, 23.24°, 23.48°, 24.29°, 24.66°, 25.14°, and 26.28°, with an error of ±0.2°. More preferably, the maleate C crystal form of the compound of Formula I is represented by a 2θ angle in the X-ray diffraction pattern at 4.78°, 7.03°, 7.43°, 9.54°, 11.84°, 14.31°, 14.84°, 15.97°, and 17. Characteristic peaks are present at 51°, 18.14°, 18.46°, 18.94°, 20.12°, 20.31°, 20.74°, 21.24°, 22.33°, 22.69°, 23.24°, 23.48°, 24.29°, 24.66°, 25.14°, 25.71°, 26.28°, 27.07°, 28.52°, and 29.95°, with an error of ±0.2°; most preferably, the maleate C crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 19.

[0044] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the fumarate of the compound of formula I, wherein the molar ratio of the compound of formula I to fumarate is 1:1.

[0045] Furthermore, the present invention also provides a fumarate A crystal form of the compound of formula I, characterized in that the fumarate A crystal form of the compound of formula I exhibits characteristic peaks at 7.59°, 9.70°, 14.41°, 18.31°, 18.64°, and 25.27° in the X-ray diffraction pattern, with an error of ±0.2°; preferably, the fumarate A crystal form of the compound of formula I exhibits characteristic peaks at 7.59°, 9.70°, 14.41°, 18.31°, 18.64°, 19.00°, 19.10°, and 20.3° in the X-ray diffraction pattern, with an angle of 2θ. Characteristic peaks are observed at 0°, 20.48°, 21.38°, 22.49°, 22.85°, 23.40°, 24.48°, 24.77°, and 25.27°, with an error of ±0.2°; more preferably, the fumarate A crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, is at 7.17°, 7.59°, 9.70°, 9.95°, 12.01°, 14.41°, 16.09°, 17.44°, 18.31°, 18.64°, 19.00°, 19.10°, 19.70°, 20.30°, 25.27°, with an error of ±0.2°; Characteristic peaks are observed at 0.48°, 20.85°, 21.38°, 22.49°, 22.85°, 23.40°, 23.61°, 24.48°, 24.77°, 25.27°, and 25.79°, with an error of ±0.2°. More preferably, the fumarate A crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, occurs at 4.94°, 7.17°, 7.59°, 8.61°, 9.70°, 9.95°, 11.78°, 12.01°, 12.35°, 14.41°, 14.98°, and 16.0°. Characteristic peaks are present at 9°, 17.44°, 18.31°, 18.64°, 19.00°, 19.10°, 19.70°, 20.30°, 20.48°, 20.85°, 21.38°, 21.91°, 22.49°, 22.85°, 23.40°, 23.61°, 24.48°, 24.77°, 25.27°, 25.79°, 26.47°, and 27.01°, with an error of ±0.2°; most preferably, the fumarate A crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 10.

[0046] Furthermore, the present invention also provides a fumarate B crystal form of the compound of formula I, characterized in that the fumarate B crystal form of the compound of formula I has characteristic peaks at 9.20°, 9.87°, 10.92°, 17.66°, 18.99°, 19.18°, 22.96°, and 28.96° in the X-ray diffraction pattern, with an error of ±0.2°; preferably, the fumarate B crystal form of the compound of formula I has characteristic peaks at 9.20° in the X-ray diffraction pattern, with an error of ±0.2°. Characteristic peaks are observed at 9.87°, 10.92°, 17.66°, 18.80°, 18.99°, 19.18°, 22.96°, 23.60°, 28.96°, and 29.54° in the X-ray diffraction pattern, with an error of ±0.2°. More preferably, the fumarate B crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, exhibits characteristic peaks at 9.20°, 9.87°, 10.92°, 13.71°, 14.61°, 15.00°, 17.66°, 18.2°, and 29.54°. Characteristic peaks are observed at 9°, 18.80°, 18.99°, 19.18°, 22.96°, 23.60°, 24.94°, 28.96°, and 29.54°, with an error of ±0.2°. More preferably, the fumarate B crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, is at 4.68°, 7.24°, 8.29°, 9.20°, 9.87°, 10.92°, 13.18°, 13.31°, 13.71°, and 14°. Characteristic peaks are present at 0.61°, 15.00°, 15.61°, 16.07°, 17.66°, 18.29°, 18.80°, 18.99°, 19.18°, 20.72°, 22.96°, 23.60°, 24.94°, 25.79°, 28.39°, 28.96°, and 29.54°, with an error of ±0.2°; most preferably, the fumarate B crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 11.

[0047] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the fumarate B crystal form of the compound of formula I has an endothermic peak at 173.8±10℃; preferably, the fumarate B crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 28.

[0048] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the oxalate of the compound of formula I, wherein the molar ratio of the compound of formula I to oxalic acid is 1:1.

[0049] Furthermore, the present invention also provides an oxalate A crystal form of the compound of formula I, characterized in that the oxalate A crystal form of the compound of formula I has characteristic peaks at 8.32° and 11.47° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the oxalate A crystal form of the compound of formula I has characteristic peaks at 8.32°, 11.47°, 18.54°, 19.64°, 21.07°, 24.59°, and 25.97° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the oxalate A crystal form of the compound of formula I has characteristic peaks at 5.08°, 8.32°, 9.98°, 11.47°, 14.91°, 18.54°, and 19.64° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; Characteristic peaks are observed at 9.64°, 21.07°, 22.87°, 24.17°, 24.59°, 25.97°, and 26.38°, with an error of ±0.2°. More preferably, the oxalate A crystal form of the compound of Formula I has characteristic peaks at 5.08°, 8.32°, 9.98°, 11.47°, 14.91°, 18.54°, 19.64°, 21.07°, 21.54°, 21.70°, 22.87°, 24.17°, 24.59°, 25.10°, 25.97°, and 26.38° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°. Most preferably, the oxalate A crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 12.

[0050] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the oxalate A crystal form of the compound of formula I has an endothermic peak at 166.0±10℃; preferably, the oxalate A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 29.

[0051] Furthermore, the present invention also provides a crystal form of oxalate B of the compound of formula I, characterized in that the crystal form of oxalate B of the compound of formula I has characteristic peaks at 7.64°, 10.24°, 17.54°, 18.72° and 23.00° in the X-ray diffraction pattern, with an error of ±0.2°; preferably, the crystal form of oxalate B of the compound of formula I has characteristic peaks at 7.64°, 10.24°, 15.40° and 23.00° in the X-ray diffraction pattern, with an error of ±0.2°; Characteristic peaks are observed at 15.56°, 17.54°, 18.72°, 22.28°, 22.61°, 23.00°, 23.39°, and 24.36°, with an error of ±0.2°; more preferably, the oxalate B crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, is at 7.64°, 8.82°, 10.24°, 13.05°, 15.40°, 15.56°, 17.54°, 18.72°, and 20.49°. Characteristic peaks are observed at 22.28°, 22.61°, 23.00°, 23.39°, 24.36°, and 24.49°, with an error of ±0.2°; more preferably, the oxalate B crystal form of the compound of formula I, represented by a 2θ angle in the X-ray diffraction pattern, has characteristic peaks at 5.24°, 7.64°, 8.82°, 10.24°, 12.33°, 12.45°, 13.05°, 15.40°, 15.56°, 16.78°, 1... Characteristic peaks are present at 7.54°, 18.12°, 18.72°, 19.98°, 20.49°, 21.48°, 21.85°, 22.28°, 22.61°, 23.00°, 23.39°, 24.36°, 24.49°, 25.52°, 25.92°, and 31.15°, with an error of ±0.2°; most preferably, the oxalate B crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 13.

[0052] Furthermore, as a preferred embodiment of the present invention, the DSC spectrum of the oxalate B crystal form of the compound of formula I has endothermic peaks at 89.2±10℃ and 168.2±10℃; preferably, the oxalate B crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 30.

[0053] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the succinate of the compound of formula I, wherein the molar ratio of the compound of formula I to succinic acid is 1:1.

[0054] Furthermore, the present invention also provides a succinate A crystal form of the compound of formula I, characterized in that the succinate A crystal form of the compound of formula I exhibits characteristic peaks at 10.27°, 17.24°, and 18.09° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the succinate A crystal form of the compound of formula I exhibits characteristic peaks at 7.32°, 10.27°, 12.23°, 15.31°, 17.24°, and 18.09° in the X-ray diffraction pattern, represented by a 2θ angle. Characteristic peaks are observed at 7.32° and 24.38°, with an error of ±0.2°; more preferably, the succinate A crystal form of the compound of Formula I has characteristic peaks at 7.32°, 10.27°, 12.23°, 14.44°, 15.31°, 17.24°, 18.09°, 24.38° and 25.50° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; most preferably, the succinate A crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 14.

[0055] Furthermore, the present invention also provides a succinate B crystal form of the compound of formula I, characterized in that the succinate B crystal form of the compound of formula I has characteristic peaks at 9.45°, 9.92°, 10.99°, 17.60° and 18.87° in the X-ray diffraction pattern, with an error of ±0.2°; preferably, the succinate B crystal form of the compound of formula I has characteristic peaks at 9.45°, 9.92°, 10.99°, 17.60°, 18.34° and 18.87° in the X-ray diffraction pattern, with an error of ±0.2°; more preferably, the succinate B crystal form of the compound of formula I has characteristic peaks at 7.20°, 9.45°, 9.92°, 10.99°, 17.60° and 18.87° in the X-ray diffraction pattern, with an error of ±0.2°; Characteristic peaks are observed at 3.28°, 14.72°, 15.60°, 15.96°, 17.60°, 18.34°, and 18.87° in the X-ray diffraction pattern, with an error of ±0.2°. More preferably, the succinate B crystal form of the compound of Formula I exhibits characteristic peaks at 7.20°, 9.45°, 9.92°, 10.99°, 13.28°, 14.72°, 15.11°, 15.60°, 15.96°, 17.60°, 18.34°, 18.87°, 20.12°, 22.83°, 26.24°, and 28.40° in the X-ray diffraction pattern, with an error of ±0.2°. Most preferably, the succinate B crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 15.

[0056] Furthermore, the present invention also provides a succinate C crystal form of the compound of formula I, characterized in that the succinate C crystal form of the compound of formula I exhibits characteristic peaks at 9.79°, 16.97°, and 22.04° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the succinate C crystal form of the compound of formula I exhibits characteristic peaks at 4.92°, 9.79°, 11.95°, 16.37°, 16.97°, 17.23°, 19.72°, 20.96°, 22.04°, and 25.22° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the succinate C crystal form of the compound of formula I exhibits characteristic peaks at 4.92°, 7.01°, 9.79°, 11.95°, 14.69°, and 16.3° in the X-ray diffraction pattern, represented by a 2θ angle. Characteristic peaks are observed at 7°, 16.97°, 17.23°, 18.45°, 19.72°, 20.96°, 22.04°, and 25.22°, with an error of ±0.2°; more preferably, the succinate C crystal form of the compound of formula I, represented by a 2θ angle in the X-ray diffraction pattern, is at 4.92°, 7.01°, 8.48°, 9.79°, 11.95°, 14.69°, and 1... Characteristic peaks are present at 6.37°, 16.97°, 17.23°, 18.45°, 19.72°, 20.04°, 20.96°, 22.04°, 22.38°, 24.17°, 25.22°, 25.92°, and 26.30°, with an error of ±0.2°; most preferably, the succinic acid C crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 20.

[0057] Furthermore, the present invention also provides a succinate D crystal form of the compound of formula I, characterized in that the succinate D crystal form of the compound of formula I exhibits characteristic peaks at 12.17° and 15.83° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the succinate D crystal form of the compound of formula I exhibits characteristic peaks at 6.95°, 8.27°, 8.67°, 9.72°, 12.17°, 13.67°, 15.83°, and 17.3° in the X-ray diffraction pattern, represented by a 2θ angle. Characteristic peaks are observed at 8°, 18.01°, 18.96°, 20.44°, 23.00°, and 25.19°, with an error of ±0.2°; more preferably, the D crystal form of the succinate of Formula I compound is represented by 2θ angles at 6.95°, 8.27°, 8.67°, 9.72°, 12.17°, 13.67°, 15.83°, 16.05°, 17.38°, 18.01°, 18.96°, 19.67°, 20.44°, 25.19°, and 20.44° in the X-ray diffraction pattern. Characteristic peaks are observed at 0.76°, 21.96°, 22.34°, 23.00°, 23.64°, 23.93°, 24.15°, and 25.19°, with an error of ±0.2°. More preferably, the succinate D crystal form of the compound of Formula I is represented by 2θ angles at 6.95°, 8.27°, 8.67°, 9.72°, 10.31°, 12.17°, 13.67°, 13.96°, 15.83°, 16.05°, and 16. Characteristic peaks are present at 57°, 17.38°, 18.01°, 18.96°, 19.67°, 20.44°, 20.76°, 21.96°, 22.34°, 23.00°, 23.64°, 23.93°, 24.15°, 25.19°, 25.81°, 26.43°, 26.87°, and 27.42°, with an error of ±0.2°; most preferably, the succinic acid D crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 21.

[0058] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically usable salt of the compound of formula I is selected from: the adipic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to adipic acid is 1:1.

[0059] Furthermore, the present invention also provides an adipate A crystal form of the compound of formula I, characterized in that the adipate A crystal form of the compound of formula I has characteristic peaks at 8.90°, 9.17°, 13.58°, and 20.34° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the adipate A crystal form of the compound of formula I has characteristic peaks at 8.90°, 9.17°, 10.48°, 10.68°, 13.58°, 18.00°, 20.34°, 20.75°, and 23.84° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the adipate A crystal form of the compound of formula I has characteristic peaks at 8.90°, 9.17°, 10.48°, 10.68°, 13.58°, 18.00°, 20.34°, 20.75°, and 23.84° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; Characteristic peaks are observed at 0.68°, 13.58°, 17.81°, 18.00°, 20.34°, 20.75°, and 23.84° in the X-ray diffraction pattern, with an error of ±0.2°. More preferably, the adipic acid A crystal form of the compound of formula I exhibits characteristic peaks at 8.90°, 9.17°, 10.48°, 10.68°, 12.24°, 13.58°, 15.25°, 15.47°, 17.81°, 18.00°, 19.30°, 20.34°, 20.75°, 22.66°, 23.84°, 24.70°, and 26.44° in the X-ray diffraction pattern, with an error of ±0.2°. Most preferably, the adipic acid A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 16.

[0060] Furthermore, the present invention also provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a pharmaceutically acceptable salt of the aforementioned compound of formula I or its crystal form, and one or more pharmaceutically acceptable excipients and / or carriers.

[0061] Furthermore, the present invention also provides a pharmaceutically acceptable salt of the aforementioned compound of formula I or its crystal form, or the use of the aforementioned pharmaceutical composition in the preparation of a medicament for treating or preventing diseases related to elevated CYP11B2 activity levels; preferably, the diseases related to elevated CYP11B2 activity levels are selected from: hypertension, chronic kidney disease, primary aldosteronism, diabetic nephropathy, congestive heart failure, or Cushing's syndrome.

[0062] For clarity, this article defines the general terminology used in the description of compounds.

[0063] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0064] The term "medicinal salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a medicinal acid or base.

[0065] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0066] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0067] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0068] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur. Attached Figure Description

[0069] 1) Figure 1 is the X-ray diffraction pattern of the hydrochloride A crystal form of the compound of formula I obtained in Example 2;

[0070] 2) Figure 2 is the X-ray diffraction pattern of the hydrobromide A crystal form of the compound of formula I obtained in Example 3;

[0071] 3) Figure 3 is the X-ray diffraction pattern of the sulfate A crystal form of the compound of formula I obtained in Example 4;

[0072] 4) Figure 4 is the X-ray diffraction pattern of phosphate A crystal form of the compound of formula I obtained in Example 5;

[0073] 5) Figure 5 is the X-ray diffraction pattern of the benzenesulfonate A crystal form of the compound of formula I obtained in Example 6;

[0074] 6) Figure 6 is the X-ray diffraction pattern of the p-toluenesulfonate A crystal form of the compound of formula I obtained in Example 7;

[0075] 7) Figure 7 is the X-ray diffraction pattern of the p-toluenesulfonate B crystal form of the compound of formula I obtained in Example 8;

[0076] 8) Figure 8 shows the X-ray diffraction pattern of maleate A crystal form of the compound of formula I obtained in Example 9;

[0077] 9) Figure 9 is the X-ray diffraction pattern of maleate B crystal form of compound I obtained in Example 10;

[0078] 10) Figure 10 is the X-ray diffraction pattern of the fumarate A crystal form of the compound of formula I obtained in Example 11;

[0079] 11) Figure 11 is the X-ray diffraction pattern of the B crystal form of the compound of formula I obtained in Example 12;

[0080] 12) Figure 12 is the X-ray diffraction pattern of the oxalate A crystal form of the compound of formula I obtained in Example 13;

[0081] 13) Figure 13 is the X-ray diffraction pattern of the oxalate B crystal form of the compound of formula I obtained in Example 14;

[0082] 14) Figure 14 is the X-ray diffraction pattern of the succinate A crystal form of the compound of formula I obtained in Example 15;

[0083] 15) Figure 15 is the X-ray diffraction pattern of the succinate B crystal form of the compound of formula I obtained in Example 16;

[0084] 16) Figure 16 is the X-ray diffraction pattern of adipate A crystal form of the compound of formula I obtained in Example 17;

[0085] 17) Figure 17 is the X-ray diffraction pattern of the hydrobromide B crystal form of the compound of formula I obtained in Example 18;

[0086] 18) Figure 18 is the X-ray diffraction pattern of the hydrobromide C crystal form of the compound of formula I obtained in Example 19;

[0087] 19) Figure 19 is the X-ray diffraction pattern of the maleate C crystal form of the compound of formula I obtained in Example 20;

[0088] 20) Figure 20 is the X-ray diffraction pattern of the C crystal form of the succinate of the compound of formula I obtained in Example 21;

[0089] 21) Figure 21 is the X-ray diffraction pattern of the D crystal form of the succinate of the compound of formula I obtained in Example 22;

[0090] 22) Figure 22 is the DSC spectrum of the hydrochloride A crystal form of the compound of formula I obtained in Example 2;

[0091] 23) Figure 23 is the DSC spectrum of the hydrobromide A crystal form of the compound of formula I obtained in Example 3;

[0092] 24) Figure 24 is the DSC spectrum of the sulfate A crystal form of the compound of formula I obtained in Example 4;

[0093] 25) Figure 25 is the DSC spectrum of phosphate A crystal form of the compound of formula I obtained in Example 5;

[0094] 26) Figure 26 is the DSC spectrum of the p-toluenesulfonate A crystal form of the compound of formula I obtained in Example 7;

[0095] 27) Figure 27 is the DSC spectrum of the p-toluenesulfonate B crystal form of the compound of formula I obtained in Example 8;

[0096] 28) Figure 28 is the DSC spectrum of the B crystal form of the fumarate of the compound of formula I obtained in Example 12;

[0097] 29) Figure 29 is the DSC spectrum of the oxalate A crystal form of the compound of formula I obtained in Example 13;

[0098] 30) Figure 30 is the DSC spectrum of the oxalate B crystal form of the compound of formula I obtained in Example 14;

[0099] 31) Figure 31 is the DSC spectrum of the hydrobromide C crystal form of the compound of formula I obtained in Example 19;

[0100] 32) Figure 32 is the XRD pattern of the hydrobromide amorphous form of the compound of formula I obtained in Example 23;

[0101] 33) Figure 33 is the XRD pattern of the sulfate amorphous form of compound I obtained in Example 24;

[0102] 34) Figure 34 is the XRD pattern of the phosphate amorphous compound of Formula I obtained in Example 25. Detailed Implementation

[0103] The present invention will be further described in detail below with reference to the embodiments, but the content of the invention is not limited to the embodiments.

[0104] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-III NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0105] MS measurements were performed using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).

[0106] High-performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD HPLC system and an Agilent 1260 HPLC system.

[0107] The CombiFlash rapid preparation system uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).

[0108] Thin-layer chromatography silica gel plates used are from Yantai Yinlong HSGF. 254 or GF 254 Silica gel plates: The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.17 mm to 0.23 mm, while those used for TLC separation and purification of products have a size of 0.4 mm to 0.5 mm.

[0109] Silica gel column chromatography generally uses 100-200 mesh silica gel from Rushan Shangbang as the carrier.

[0110] Unless otherwise stated, the crystal form of the present invention was detected using the following equipment and conditions: X-ray powder diffraction (XRPD). The XRPD pattern was acquired on an X-ray powder diffractometer manufactured by PANalytacal, and the scanning parameters are shown in the table below:

[0111] X-ray powder diffraction conditions:

[0112] The X-ray powder diffraction (XRPD) pattern shown in this invention was obtained using an Empyrean X-ray powder diffractometer under the following conditions: Cu-Kα radiation, wavelength... The divergence slit is 1 / 4°, the X-ray tube voltage is 45kV, the X-ray tube current is 40mA, the scanning range is 3-40° (2θ), the step size is 0.026°, and the dwell time per step is about 30s.

[0113] Differential scanning calorimetry (DSC) was performed. The DSC images were acquired using a NETZSCH DSC200F3 differential scanning calorimeter. The test parameters are shown in the table below:

[0114] DSC test conditions:

[0115] Dynamic moisture adsorption test conditions:

[0116] The dynamic moisture adsorption map described in this invention was acquired using an Intrinsic dynamic moisture adsorption analyzer from SMS Corporation. The parameters of the dynamic moisture adsorption test method described in this invention are as follows:

[0117] Humidity range 0-95% RH

[0118] Temperature: 25℃

[0119] Protective gas and flow rate: N2, 200 ml / min

[0120] Maximum test time for each humidity level: 6 hours

[0121] Sample collection time interval: 5 seconds.

[0122] Example 1

[0123] (R)-N-(4-(2-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0124] The specific synthesis route is as follows:

[0125] Step A: Synthesis of ethyl 5-bromo-4-methylnicotinate

[0126] 5-Bromo-4-methylnicotinic acid (50.0 g, 231.45 mmol) and iodoethane (39.7 g, 254.59 mmol) were dissolved in 500 mL of N,N-dimethylformamide, and potassium bicarbonate (46.3 g, 462.90 mmol) was added. The mixture was degassed and protected with nitrogen, and the reaction was stirred at room temperature for 12 hours.

[0127] After the reaction was complete, the mixture was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate (300 mL × 3 times). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to give 54.6 g of ethyl 5-bromo-4-methylnicotinate. [M+H] + =244.05.

[0128] Step B: Synthesis of methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate

[0129] At -78°C, LDA (123 mL, 246.06 mmol, 2M) was added dropwise to a tetrahydrofuran (500 mL) solution of ethyl 5-bromo-4-methylnicotinate (54.6 g, 223.69 mmol). The mixture was stirred for 30 minutes, followed by the addition of a tetrahydrofuran (200 mL) solution of methyl acrylate (48.1 g, 559.22 mmol). The mixture was then stirred at -78°C for 2 hours.

[0130] After the reaction was complete, 400 mL of 10% acetic acid aqueous solution was added to the mixture to quench the reaction. The organic solvent was removed by evaporation, and the mixture was extracted with ethyl acetate (300 mL × 3 times). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to give 31.5 g of methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate. [M+H] + =284.06.

[0131] Step C: Synthesis of 4-bromo-6,7-dihydroisoquinoline-8(5H)-one

[0132] 31.5 g (110.87 mmol) of methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate was dissolved in 300 mL of hydrochloric acid (6 M), and the mixture was refluxed at 105 °C for 16 hours.

[0133] After the reaction was complete, the solvent was evaporated, 300 mL of water was added, and the pH was adjusted to approximately 9 with 1 N sodium hydroxide aqueous solution. The mixture was extracted with ethyl acetate (200 mL × 3 times), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 8) to give 19.6 g of 4-bromo-6,7-dihydroisoquinoline-8(5H)-one. [M+H] + =226.05.

[0134] Step D: Synthesis of (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-ylidene)-2-methylpropane-2-sulfonamide

[0135] 4-Bromo-6,7-dihydroisoquinoline-8(5H)-one (10.0 g, 44.23 mmol) was dissolved in 200 mL of tetrahydrofuran, and (S)-tert-butylsulfinamide (5.9 g, 48.66 mmol) and tetraisopropyl titanate (37.7 g, 132.70 mmol) were added. The mixture was heated to 65 °C under nitrogen protection and stirred for 24 hours.

[0136] After the reaction was complete, 100 mL of water was added to quench the reaction, and the solid was filtered. The filtrate was concentrated, and 100 mL of water was added to the residue. The residue was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The residue was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 13.3 g of (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-ylidene)-2-methylpropane-2-sulfonamide. [M+H] + =329.12.

[0137] Step E: Synthesis of (S)-N-((R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)-2-methylpropane-2-sulfonamide

[0138] Sodium borohydride (2.3 g, 60.59 mmol) was added in portions to a methanol (400 mL) solution of (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-ylidene)-2-methylpropane-2-sulfonamide (13.3 g, 40.39 mmol), and the mixture was stirred at -42 °C for 1 hour.

[0139] After the reaction was complete, 100 mL of water was added to quench the reaction, the solvent was evaporated, and 100 mL of water was added to the residue. The mixture was extracted with ethyl acetate (100 mL × 3 times), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to give 11.1 g of (S)-N-((R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)-2-methylpropane-2-sulfonamide. [M+H] + =331.06. 1 HNMR(400MHz, CDCl3)δ8.58(s,1H),8.57(s,1H),4.59–4.51(m,1H),3.41(d,J=10.0Hz,1H) ,2.83–2.68(m,2H),2.38–2.28(m,1H),2.05–1.95(m,2H),1.94–1.84(m,1H),1.29(s,9H).

[0140] Step F: Synthesis of (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine

[0141] In a solution of (S)-N-((R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)-2-methylpropane-2-sulfonamide (11.1 g, 9.86 mmol) in dichloromethane (100 mL), 40 mL of hydrogen chloride-dioxane solution (4 M) was added, and the mixture was stirred at room temperature for 5 hours.

[0142] After the reaction was complete, the solvent was evaporated from the mixture, and 100 mL of water was added to the residue. The pH was adjusted to 9 with sodium hydroxide solution (1 M), and the mixture was extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give 7.2 g of (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine. [M+H] + =227.11.

[0143] Step G: Synthesis of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0144] (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (7.2 g, 31.70 mmol) and triethylamine (8.8 mL, 63.41 mmol) were dissolved in dichloromethane (100 mL), and propionyl chloride (3.1 mL, 34.87 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 5 minutes.

[0145] After the reaction was complete, water was added to the mixture, and the mixture was extracted with dichloromethane (100 mL × 3 times). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to give 8.5 g of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide. [M+H] + =283.12.

[0146] Step H: Synthesis of (R)-N-(4-(2-cyanoquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide

[0147] (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (100 mg, 0.35 mmol) and pinacol ester of 2-cyanoquinoline-6-borate (119 mg, 0.42 mmol) were dissolved in a mixed solvent of 5.0 mL dioxane and 1.0 mL water. Sodium carbonate (76 g, 0.71 mmol) and tetrakis(triphenylphosphine)palladium (8 mg, 0.0071 mmol) were added. The mixture was reacted under nitrogen protection at 85 °C for 6 hours.

[0148] After the reaction was completed, the resulting suspension was filtered, the filter cake was washed with dichloromethane, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to give 109 mg (R)-N-(4-(2-cyanoquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)propionamide.

[0149] [M+H] + =357.00. NMR data: 1 HNMR (400MHz, DMSO-d6) δ8.74(d,J=8.5Hz,1H),8.45(s,1H),8.39(s,1H),8.34(d,J=8.4Hz,1H),8.25(d,J=8.7Hz,1H),8.18(d,J=2.0Hz,1H),8.14( d,J=8.4Hz,1H),7.99(dd,J=8.7,2.0Hz,1H),5.15(q,J=6.5Hz,1H),2.71– 2.63(m,2H),2.26–2.12(m,2H),1.99–1.66(m,4H),1.09(t,J=7.6Hz,3H).

[0150] Example 2

[0151] Preparation of the A crystal form of the hydrochloride salt of compound I:

[0152] Weigh 27 mg of hydrochloric acid (concentration 36-38%), add 2 ml of acetone, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection. Dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid with a purity of 99.21%.

[0153] The X-ray diffraction pattern of the hydrochloride A crystal form of the obtained compound of formula I is shown in Figure 1. The specific characteristic peaks are shown in Table 1 below, with an error of ±0.2°.

[0154] The DSC spectrum of the hydrochloride A crystal form of the obtained compound of formula I is shown in Figure 22, which has an endothermic peak at 209.6±10℃.

[0155] Table 1. X-ray diffraction data of the hydrochloride A crystal form of compound I.

[0156] Example 3

[0157] Preparation of the hydrobromide A crystal form of compound I:

[0158] Weigh 42 mg of hydrobromic acid (concentration 48%), add 2 ml of acetone, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection. Dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid with a purity of 99.01%.

[0159] The X-ray diffraction pattern of the hydrobromide A crystal form of the obtained Formula I compound is shown in Figure 2. The specific characteristic peaks are shown in Table 2 below, with an error of ±0.2°.

[0160] The DSC spectrum of the hydrobromide A crystal form of the obtained compound of formula I is shown in Figure 23, which has an endothermic peak at 177.7±10℃.

[0161] Table 2 shows the X-ray diffraction data of hydrobromide A crystal form of compound I.

[0162] Example 4

[0163] Preparation of the sulfate A crystal form of compound I:

[0164] Weigh 25 mg of sulfuric acid, add 2 ml of acetone, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection. Dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid with a purity of 97.61%.

[0165] The X-ray diffraction pattern of the sulfate A crystal form of the obtained compound of formula I is shown in Figure 3. The specific characteristic peaks are shown in Table 3 below, with an error of ±0.2°.

[0166] The DSC spectrum of the sulfate A crystal form of the obtained compound of formula I is shown in Figure 24, which has an endothermic peak at 182.4±10℃.

[0167] Table 3. X-ray diffraction data of sulfate A crystal form of compound I.

[0168] Example 5

[0169] Preparation of phosphate A crystal form of compound I:

[0170] Weigh 25 mg of phosphoric acid, add 2 ml of acetone and 100 μl of water, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection. Dry the filter cake under vacuum at 50 °C for 1 day to obtain a white solid with a purity of 98.95%.

[0171] The X-ray diffraction pattern of the phosphate A crystal form of the obtained compound of formula I is shown in Figure 4. The specific characteristic peaks are shown in Table 4 below, with an error of ±0.2°.

[0172] The DSC spectrum of the phosphate A crystal form of the obtained compound of formula I is shown in Figure 25, which has endothermic peaks at 199.5±10℃ and 221.9±10℃.

[0173] Table 4. X-ray diffraction data of phosphate A crystal form of compound I.

[0174] Example 6

[0175] Preparation of the benzenesulfonate A crystal form of compound I:

[0176] Weigh 39.5 mg of benzenesulfonic acid, add 2 ml of ethyl acetate, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0177] The X-ray diffraction pattern of the benzenesulfonate A crystal form of the obtained Formula I compound is shown in Figure 5. The specific characteristic peaks are shown in Table 5 below, with an error of ±0.2°.

[0178] Table 5. X-ray diffraction data of benzenesulfonate A crystal form of compound I.

[0179] Example 7

[0180] Preparation of p-toluenesulfonate A crystal form of compound I:

[0181] Weigh 47.6 mg of p-toluenesulfonic acid, add 2 ml of acetone, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then add 4 ml of isopropyl ether and continue to react at room temperature for 1 day. Then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0182] The X-ray diffraction pattern of p-toluenesulfonate A crystal form of the obtained compound of formula I is shown in Figure 6. The specific characteristic peaks are shown in Table 6 below, with an error of ±0.2°.

[0183] The DSC spectrum of the p-toluenesulfonate A crystal form of the obtained compound of formula I is shown in Figure 26, which has an endothermic peak at 114.6±10℃.

[0184] Table 6 shows the X-ray diffraction data of p-toluenesulfonate A crystal form of compound I.

[0185] Example 8

[0186] Preparation of p-toluenesulfonate B crystal form of compound I:

[0187] Weigh 47.6 mg of p-toluenesulfonic acid, add 2 ml of ethyl acetate, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0188] The X-ray diffraction pattern of the p-toluenesulfonate B crystal form of the obtained Formula I compound is shown in Figure 7. The specific characteristic peaks are shown in Table 7 below, with an error of ±0.2°.

[0189] The DSC spectrum of the p-toluenesulfonate B crystal form of the obtained compound of formula I is shown in Figure 27, which has an endothermic peak at 181.9±10℃.

[0190] Table 7. X-ray diffraction data of p-toluenesulfonate B crystal form of compound I.

[0191] Example 9

[0192] Preparation of maleate A crystal form of compound I:

[0193] Weigh 29.8 mg of maleic acid, add 2 ml of acetone, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then add 4 ml of isopropyl ether and continue to react at room temperature for 1 day. Then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0194] The X-ray diffraction pattern of the maleate A crystal form of the obtained compound of formula I is shown in Figure 8. The specific characteristic peaks are shown in Table 8 below, with an error of ±0.2°.

[0195] Table 8. X-ray diffraction data of maleate A crystal form of compound I.

[0196] Example 10

[0197] Preparation of maleate B crystal form of compound I:

[0198] Weigh 29.8 mg of maleic acid, add 2 ml of isopropanol, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then add 4 ml of n-heptane and continue to react at room temperature for 1 day. Then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0199] The X-ray diffraction pattern of the maleate B crystal form of the obtained compound of formula I is shown in Figure 9. The specific characteristic peaks are shown in Table 9 below, with an error of ±0.2°.

[0200] Table 9. X-ray diffraction data of maleate B crystal form of compound I.

[0201] Example 11

[0202] Preparation of the fumarate A crystal form of compound I:

[0203] Weigh 29.8 mg of fumaric acid, add 2 ml of acetone, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0204] The X-ray diffraction pattern of the fumarate A crystal form of the obtained compound of formula I is shown in Figure 10. The specific characteristic peaks are shown in Table 10 below, with an error of ±0.2°.

[0205] Table 10. X-ray diffraction data of fumarate A crystal form of compound I.

[0206] Example 12

[0207] Preparation of the B crystal form of the fumarate of compound I:

[0208] Weigh 29.8 mg of fumaric acid, add 2 ml of ethyl acetate, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0209] The X-ray diffraction pattern of the fumarate B crystal form of the obtained Formula I compound is shown in Figure 11. The specific characteristic peaks are shown in Table 11 below, with an error of ±0.2°.

[0210] The DSC spectrum of the fumarate B crystal form of the obtained compound of formula I is shown in Figure 28, which has an endothermic peak at 173.8±10℃.

[0211] Table 11. X-ray diffraction data of fumarate B crystal form of compound I.

[0212] Example 13

[0213] Preparation of the oxalate A crystal form of compound I:

[0214] Weigh 22.5 mg of oxalic acid, add 2 ml of acetone, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection. Dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0215] The X-ray diffraction pattern of the oxalate A crystal form of the obtained compound of formula I is shown in Figure 12. The specific characteristic peaks are shown in Table 12 below, with an error of ±0.2°.

[0216] The DSC spectrum of the oxalate A crystal form of the obtained compound of formula I is shown in Figure 29, which has an endothermic peak at 166.0±10℃.

[0217] Table 12 shows the X-ray diffraction data of the alumina crystal form of compound I.

[0218] Example 14

[0219] Preparation of the oxalate B crystal form of compound I:

[0220] Weigh 22.5 mg of oxalic acid, add 2 ml of isopropanol, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0221] The X-ray diffraction pattern of the oxalate B crystal form of the obtained Formula I compound is shown in Figure 13. The specific characteristic peaks are shown in Table 13 below, with an error of ±0.2°.

[0222] The DSC spectrum of the oxalate B crystal form of the obtained compound of formula I is shown in Figure 30, with endothermic peaks at 89.2±10℃ and 168.2±10℃.

[0223] Table 13. X-ray diffraction data of oxalate B crystal form of compound I.

[0224] Example 15

[0225] Preparation of the A crystal form of succinate of compound I:

[0226] Weigh 29.5 mg of succinic acid, add 2 ml of acetone, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection. Dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0227] The X-ray diffraction pattern of the succinate A crystal form of the obtained Formula I compound is shown in Figure 14. The specific characteristic peaks are shown in Table 14 below, with an error of ±0.2°.

[0228] Table 14. X-ray diffraction data of succinate A crystal form of compound I.

[0229] Example 16

[0230] Preparation of the B crystal form of succinate of compound I:

[0231] Weigh 29.5 mg of succinic acid, add 2 ml of ethyl acetate, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0232] The X-ray diffraction pattern of the succinate B crystal form of the obtained Formula I compound is shown in Figure 15. The specific characteristic peaks are shown in Table 15 below, with an error of ±0.2°.

[0233] Table 15. X-ray diffraction data of succinate B crystal form of compound I.

[0234] Example 17

[0235] Preparation of adipate A crystal form of compound I:

[0236] Weigh 36.5 mg of adipic acid, add 2 ml of ethyl acetate, stir, and then add 89 mg of the compound of formula I prepared in Example 1. React at room temperature for 1 day, then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid.

[0237] The X-ray diffraction pattern of adipate A crystal form of the obtained compound I is shown in Figure 16. The specific characteristic peaks are shown in Table 16 below, with an error of ±0.2°.

[0238] Table 16 shows the X-ray diffraction data of adipate A crystal form of compound I.

[0239] Example 18

[0240] Preparation of the hydrobromide B crystal form of compound I:

[0241] Weigh 6g of the compound of formula I prepared in Example 1, add 50ml of acetone, stir at room temperature, dilute 2.84g of hydrobromic acid (concentration 48%) with 10ml of acetone, mix, and add dropwise to the acetone solution of the compound of formula I prepared in Example 1. After reacting at room temperature for 1 day, filter, add 60ml of isopropyl ether to the filtrate, add a small amount of the solid from Example 3 as seed crystals, stir at room temperature for 7h, then filter under nitrogen protection, and dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid with a purity of 98.33%.

[0242] The X-ray diffraction pattern of the hydrobromide B crystal form of the obtained Formula I compound is shown in Figure 17. The specific characteristic peaks are shown in Table 17 below, with an error of ±0.2°.

[0243] Table 17. X-ray diffraction data of hydrobromide B crystal form of compound I.

[0244] Example 19

[0245] Preparation of the C-crystal form of the hydrobromide of compound I:

[0246] Weigh 947 mg of hydrobromic acid (concentration 48%), add 10 ml of acetone, stir, add 2 g of the compound of formula I prepared in Example 1, react at room temperature for 1 day, add the solid of Example 18 as seed crystals, continue stirring for 1 day, then filter under nitrogen protection, dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid with a purity of 99.53%.

[0247] The X-ray diffraction pattern of the hydrobromide C crystal form of the obtained Formula I compound is shown in Figure 18. The specific characteristic peaks are shown in Table 18 below, with an error of ±0.2°.

[0248] The DSC spectrum of the hydrobromide C crystal form of the obtained Formula I compound is shown in Figure 31. It has endothermic peaks at 64.0±10℃, 80.0±10℃ and 234.1±10℃.

[0249] Table 18 shows the X-ray diffraction data of the C crystal form of compound I hydrobromide.

[0250] Example 20

[0251] Preparation of the maleate C crystal form of compound I:

[0252] Weigh 652 mg of maleic acid, add 10 ml of acetone, stir, and then add 2 g of the compound of formula I prepared in Example 1. React at room temperature for 2 days, then filter under nitrogen protection. The filter cake is dried under vacuum at 50°C for 1 day to obtain a white solid with a purity of 95.94%.

[0253] The X-ray diffraction pattern of the maleate C crystal form of the obtained compound of formula I is shown in Figure 19. The specific characteristic peaks are shown in Table 19 below, with an error of ±0.2°.

[0254] Table 19 shows the X-ray diffraction data of the maleate C crystal form of compound I.

[0255] Example 21

[0256] Preparation of the C-type succinate of compound I:

[0257] Weigh 663 mg of succinic acid, add 10 ml of acetone, stir, add 2 g of the compound of formula I prepared in Example 1, react at room temperature for 30 minutes, add 3 ml of acetone, react at room temperature for one day, add another 3 ml of acetone, continue to react at room temperature for one day, filter under nitrogen protection, dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid with a purity of 99.63%.

[0258] The X-ray diffraction pattern of the succinate C crystal form of the obtained Formula I compound is shown in Figure 20. The specific characteristic peaks are shown in Table 20 below, with an error of ±0.2°.

[0259] Table 20 shows the X-ray diffraction data of the C crystal form of succinate of compound I.

[0260] Example 22

[0261] Preparation of the D crystal form of the succinate of compound I:

[0262] Weigh 663 mg of succinic acid, add 10 ml of methanol, stir, add 2 g of the compound of formula I prepared in Example 1, react at room temperature for 30 minutes, add 3 ml of acetone, react at room temperature for 2 days, filter under nitrogen protection, dry the filter cake under vacuum at 50°C for 1 day to obtain a white solid with a purity of 99.89%.

[0263] The X-ray diffraction pattern of the D crystal form of the succinate of the obtained Formula I compound is shown in Figure 21. The specific characteristic peaks are shown in Table 21 below, with an error of ±0.2°.

[0264] Table 21. X-ray diffraction data of succinate D crystal form of compound I.

[0265] In Table 1-21, No. = serial number, Rel.Int. = Relative Intensity, Pos.[°2θ] = Position[°2θ], with an error of ±0.2°. Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak and should not be used as a limitation on a specific crystal form.

[0266] Example 23

[0267] Preparation of the amorphous hydrobromide of compound I:

[0268] Weigh 947 mg of hydrobromic acid aqueous solution (concentration 48%), add 20 ml of water, stir, add 2 g of compound of formula I prepared in Example 1, react at room temperature for 30 minutes, freeze dry, and obtain a white solid with a purity of 99.50%.

[0269] The amorphous X-ray diffraction pattern of the hydrobromide of the obtained compound of formula I is shown in Figure 32.

[0270] Example 24

[0271] Preparation of amorphous sulfates of compounds of formula I:

[0272] Weigh 550 mg of concentrated sulfuric acid, add 20 ml of water, stir, and then add 2 g of the compound of formula I prepared in Example 1. React at room temperature for 30 minutes, freeze dry, and a white solid with a purity of 99.49% is obtained.

[0273] The amorphous X-ray diffraction pattern of the sulfate of the obtained compound I is shown in Figure 33.

[0274] Example 25

[0275] Preparation of amorphous phosphates of compounds of formula I:

[0276] Weigh 550 mg of solid phosphoric acid, add 20 ml of water, stir, add 2 g of the compound of formula I prepared in Example 1, then add 10 ml of ethanol, 6 ml of methanol, and 14 ml of tetrahydrofuran. React at room temperature for 30 minutes, freeze dry, and obtain a white solid with a purity of 99.40%.

[0277] The amorphous X-ray diffraction pattern of the phosphate of the obtained compound I is shown in Figure 34.

[0278] Example 26

[0279] Preparation of the hydrochloride salt of compound I:

[0280] Weigh 569 mg of hydrochloric acid (concentration 36%-38%), add 20 ml of water, stir, and then add 2 g of the compound of formula I prepared in Example 1. React at room temperature for 30 minutes, freeze dry, and a white solid with a purity of 99.43% is obtained.

[0281] Example 27 Bioactivity Assessment

[0282] Detection methods

[0283] In this paper, the inventors used the H295R Steroidogenesis Assay System to test the enzyme activities of human CYP11B1, human CYP11B2, etc. The in vitro H295R Steroidogenesis Assay System utilizes the human adrenal cancer cell line (NCI-H295R cells) to construct a level 2 "in vitro assay, providing mechanistic data" for screening and prioritization purposes. The development and standardization of this method were carried out in a multi-step process for screening the chemical effects of steroidogenesis. The H295R assay method has been optimized and validated according to the OECD test guideline (Test Guideline No. 456 H295R Steroidogenesis Assay).

[0284] Inhibition of aldosterone synthase

[0285] NCI-H295R cells can be purchased from ATCC. After culturing H295R cells from the original ATCC batch, the cells should be cultured for five generations (i.e., the cells divide four times), and then the cells that have been passaged five times should be frozen and stored in liquid nitrogen.

[0286] H295R cells were cultured in a 37°C, 5% CO2 incubator, with the culture medium changed 2-3 times per week. Cells were passaged when they reached approximately 85-90% confluence. The culture medium was then aspirated and replaced with DPBS (calcium-free). 2+Mg 2+ Wash three times, digest with trypsin for 1-3 min, add 3 mL of culture medium to stop digestion and blow off the cells, then wash off the remaining cells with 1 mL of culture medium and add to a 15 mL centrifuge tube. Centrifuge at 800 rpm for 5 min at room temperature, discard the supernatant, resuspend the pellet with 3 mL of culture medium, and count the cell suspension. Discard the edge wells of the 96-well plate, and seed 50,000 cells into each of the remaining wells. Add 100 μL of 10% FBSDMEM:F12 (1:1) basal medium per well and incubate overnight. Replace with 150 μL of basal medium containing 10 μM Forskolin and incubate for 48 h. After 48 h, replace with basal medium containing 10 μM deoxycorticosterone. The compound is dissolved in DMSO to prepare a 100 mM stock solution. Starting at 100 mM, perform a 3-fold serial dilution in DMSO to obtain 10 concentration points. Ten concentration points were further diluted 10-fold with DMEM:F12 (1:1) blank medium, with an initial concentration of 10 mM. 1.5 μL of each concentration of the compound was added to the cells, with a final DMSO concentration of 0.1% and an initial compound concentration of 100 μM. After incubation for 48 h, 40 μL of cell supernatant was collected, and aldosterone and cortisol levels were analyzed using LCMS.

[0287] Cell viability assay

[0288] After collecting the supernatant, add 100 μL of 10% CCK8 assay reagent to each well, incubate at 37°C for 10 min, mix thoroughly by tapping, and then measure the OD value at 405 nm using a microplate reader. A 70% methanol group was set as a negative control, and DMSO solvent controls were set as a positive control. The following formula was used to calculate:

[0289] %viable cells=(OD cmpd–OD Avg MeOH[=100%dead])÷(OD Avg SCs[=100%viability]–OD Avg MeOH[=100%dead])

[0290] Wells with cell viability below 80% should not be included in the final data analysis. In cases of cytotoxicity approaching 20%, inhibition of steroid production should be carefully evaluated to ensure that cytotoxicity is not the cause of inhibition. Furthermore, data with cell viability exceeding 120% should be labeled to identify potential false positives.

[0291] The inhibition rate was calculated using the following formula in the results analysis:

[0292] Inhibition rate % = (PeakArea Avg SCs - PeakArea cmpd) / (PeakArea Avg SCs - Peak Areablank) × 100

[0293] Plotting the logarithm of compound concentration on the x-axis and the inhibition rate on the y-axis, a nonlinear regression curve was fitted using Graphpad 9.0 to calculate the IC50 value (Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)). 50 -X)*HillSlope))),Ki=IC 50 / (1+[S] / Km), the test results are shown in Table 22. Unless otherwise specified, it is assumed that all proteases are competitively inhibited. Selectivity = CYP11B1Ki(nM) / CYP11B2 Ki(nM); where A represents a selectivity value between 0 and 50;

[0294] Table 22 Inhibitory effects of compounds on CYP11B2

[0295] As shown in Table 22, the compound of the present invention has a good inhibitory effect on CYP11B2, which is better than that of the control compound Baxdrostat. In addition, the compound of the present invention has excellent selectivity for CYP11B2, which can selectively inhibit CYP11B2 while weakly inhibiting CYP11B1.

[0296] Example 28: Rat Pharmacokinetic Study

[0297] Experimental materials

[0298] SD rats: male, 180-250g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0299] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0300] Instrument: AB SCIEX QTRAP 5500+.

[0301] Experimental methods

[0302] The compounds from Examples 1-49 of this invention were weighed and dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After intravenous or gavage administration to rats, 200 μL of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h (an additional 5 min for the IV group) into EDTA-K2 anticoagulant tubes. The tubes were centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test sample was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. Accurately pipette 10 μL of each of the above standard series solutions, add 90 μL of blank plasma, vortex to mix, and prepare plasma samples with concentrations equivalent to 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Perform dual-sample analysis for each concentration to establish a standard curve. Take 30 μL of plasma (diluted 5-fold after intravenous administration at 5 min, 15 min, and 30 min), add 150 μL of acetonitrile solution of propranolol (50 ng / mL) as internal standard, vortex to mix, add 100 μL of purified water, vortex again, centrifuge at 4000 rpm for 5 min, and analyze the supernatant by LC-MS. The LC-MS detection conditions are as follows:

[0303] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0304] Mobile phase: water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below.

[0305] Data processing

[0306] After LC-MS detection of blood drug concentration, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The test results are shown in Table 23.

[0307] Table 23 Pharmacokinetics of the compounds of the present invention in rats

[0308] As shown in Table 23, the compounds of this invention exhibit good pharmacokinetic characteristics in SD rats, with C0.05 being the largest C0.05 after intravenous and gavage administration. max and AUC last All were superior to the positive control, with good absorption, high absolute bioavailability, and half-life comparable to or better than the control compound.

[0309] Example 29: Pharmacokinetic Study of Compound in Crab-Eating Monkeys

[0310] Experimental materials

[0311] Crab-eating macaque: Male, 180-250g, purchased from Guangxi Xiongsen Primate Experimental Animal Breeding and Development Co., Ltd.

[0312] Reagents: DMSO (dimethyl sulfoxide), PEG400, physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) were all commercially available.

[0313] Instrument: AB SCIEX 7500.

[0314] Experimental methods

[0315] The compound was dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After administration by gavage to cynomolgus monkeys, 200 μL of venous blood was collected at 30 min, 60 min, 90 min, 2 h, 3 h, 5 h, 8 h, and 24 h in EDTA-K2 anticoagulant tubes. The tubes were centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test sample was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. Accurately pipette 10 μL of each of the above standard series solutions and add 90 μL of blank plasma. Vortex to mix, preparing plasma samples with concentrations equivalent to 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng / mL, and quality control samples with concentrations of 2.4, 120, and 2400 ng / mL. Perform dual-sample analysis for each concentration and establish a standard curve. Take 30 μL of plasma and add 150 μL of acetonitrile solution containing propranolol (50 ng / mL) as internal standard. Vortex to mix, then add 100 μL of purified water, vortex again, centrifuge at 4000 rpm for 5 min, and analyze the supernatant by LC-MS. The LC-MS detection conditions are as follows:

[0316] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0317] Mobile phase: water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below.

[0318] Data processing

[0319] After LC-MS detection of blood drug concentration, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The test results are shown in Table 24.

[0320] Table 24. Pharmacokinetic results of the compounds of this invention in cynomolgus monkeys.

[0321] As shown in Table 24, the series of compounds of this invention all exhibit good pharmacokinetic characteristics in cynomolgus monkeys. The post-oral absorption exposure levels were higher or comparable to the positive control Baxdrostat. max and AUC last All are superior to the positive control, with a better half-life, better absorption, and higher absolute bioavailability.

[0322] Example 27 Solubility Test

[0323] (1) Pipette 0.5 ml of water into a 2.5 ml centrifuge tube, add the solid form of compound I hydrochloride A while vortexing, add until 454 mg is reached, and the sample is still completely dissolved within 30 min.

[0324] (2) Pipette 0.5 ml of water into a 2.5 ml centrifuge tube, add the solid sulfate A of compound I while vortexing, and add until the sample is completely dissolved within 30 min.

[0325] (3) Pipette 0.5 ml of water into a 2.5 ml centrifuge tube, add the solid form of hydrobromide B of Formula I while vortexing, and add up to 97 mg. The sample will still be completely dissolved within 30 min.

[0326] (4) Pipette 0.5 ml of water into a 2.5 ml centrifuge tube, add the solid phosphate A of compound I while vortexing. After adding 7 mg of solid, the mixture becomes turbid. Then add 1 ml of water. The sample does not completely dissolve within 30 min.

[0327] (5) Pipette 0.5 ml of water into a 2.5 ml centrifuge tube, add 500 mg of compound I hydrochloride solid, and vortex while adding. The sample will be completely dissolved within 30 min.

[0328] (6) Pipette 0.5 ml of water into a 2.5 ml centrifuge tube, add 500 mg of amorphous solid sulfate of compound I, and vortex while adding. The sample will be completely dissolved within 30 min.

[0329] (7) Pipette 0.5 ml of water into a 2.5 ml centrifuge tube, add 500 mg of amorphous solid hydrobromide of compound I, and vortex while adding. The sample will be completely dissolved within 30 min.

[0330] (8) Pipette 0.5 ml of water into a 2.5 ml centrifuge tube, add the amorphous solid of phosphate of Formula I while vortexing, add 7 mg, and the sample will not completely dissolve within 30 min.

[0331] The results are shown in Table 25.

[0332] Table 25 Solubility of pharmaceutically acceptable salts of compounds of Formula I in water

[0333] As can be seen from the results in Table 25, the hydrochloride, sulfate and hydrobromide of compound A of formula I of the present invention have good solubility, which is significantly better than that of phosphate.

[0334] Example 30 Moisture Adsorption Test

[0335] The sample was placed on an SMS Intrinsic dynamic moisture adsorption analyzer to collect data. Starting from 0 RH, a humidity gradient of 5% RH was used, with the final humidity at 95% RH. The weight change was collected every 5 seconds, and the weight change under 95% RH conditions was taken as the final moisture absorption of the product. The results are shown in Table 26.

[0336] Table 26. Hygroscopicity of pharmaceutically acceptable salts of compounds of Formula I of the present invention

[0337] As can be seen from the results in Table 26, most of the pharmaceutically acceptable salts of the compounds of Formula I of the present invention have relatively low hygroscopicity, among which the phosphates of the compounds of Formula I have high hygroscopicity.

[0338] Example 31 Stability Test

[0339] The pharmaceutically acceptable salts of the compounds of formula I prepared in Examples 2-22 were placed at high temperature (60°C) and high humidity (92.5% RH) for 6 days, and the chemical stability of the samples was determined by HPLC. The results are shown in Table 27.

[0340] Table 27 Stability of pharmaceutically acceptable salts of compounds of Formula I of the present invention

[0341] Note: " / " indicates that it has not been tested.

[0342] As can be seen from the results in Table 27, most of the pharmaceutically usable salts of the compounds of Formula I of the present invention have good stability. However, the phosphates of the compounds of Formula I have poor stability under high temperature and high humidity.

[0343] Example 32 Pharmacokinetic Study of Compound I of the Invention in Beagle Dogs

[0344] 1. Experimental Materials

[0345] Beagle: Male, 8-13kg, Beijing Mars Biotechnology Co., Ltd.

[0346] Test substances: Compound I hydrobromide, Compound I phosphate, Compound I sulfate, Compound I hydrochloride.

[0347] Reagents: Methanol, formic acid, and propranolol (internal standard) are all commercially available. Compound I and Compound I-D5 (internal standard) were prepared by our company.

[0348] Instrument: AB SCIEX TripleQuad5500+ triple quadrupole mass spectrometer.

[0349] 2. Experimental Methods

[0350] Beagle dogs were used for capsule administration experiments of each test substance. The dose of each test substance was 50 mg based on the free amount of compound I. Three dogs were administered each test substance. Venous blood samples of approximately 0.5 mL were collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration in anticoagulant tubes containing EDTA-K2. The samples were centrifuged at 4000 rpm for 10 min at 2–8 °C, and the plasma was stored at -80 °C for later analysis. A precise amount of compound I was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. The stock solution of compound I was accurately pipetted and diluted with acetonitrile-water to prepare a series of standard solutions. 10 μL of each of the above standard solutions was accurately pipetted and added to 90 μL of blank plasma. The mixture was vortexed to prepare plasma samples with concentrations equivalent to 1–10000 ng / mL. Two-sample analysis was performed for each concentration to establish a standard curve. Take 30 μL of plasma, add 200 μL of acetonitrile methanol solution containing internal standard, vortex to mix, centrifuge at 6000 rpm for 10 min at 2–8 °C, take 150 μL of supernatant, add 150 μL of purified water, vortex to mix again, and detect compound I using LC-MS / MS.

[0351] 3. Data Processing

[0352] After detecting blood drug concentrations by LC-MS, pharmacokinetic parameters were calculated using WinNonlin software and a non-compartmental model method.

[0353] 4. Experimental Results

[0354] Table 28 shows the comparison of the absorption of different salt forms of compound I administered as gastric-coated capsules in beagle dogs.

[0355] Table 28 Comparison of different salt forms of the present invention administered to Beagle PK dogs.

[0356] As can be seen from the results in Table 28, the hydrochloride, sulfate, and hydrobromide salts of the compound of formula I of this invention exhibit good pharmacokinetics, with Cmax, AUClast, and T... 1 / 2 Both are significantly superior to the phosphate of compound I.

[0357] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims of the present invention.

Claims

1. A pharmaceutically acceptable salt of a compound of formula I, characterized in that, The structure of the compound of formula I is shown below: The pharmaceutically usable salt is independently selected from: hydrochloride, hydrobromide, phosphate, nitrate, sulfate, acetate, propionate, malonate, succinate, valerate, glutarate, adipate, oxalate, L-proline, lactobionate, glycine, alanine, arginine, lactate, cinnamate, fumarate, mandelate, maleate, hippurate, tartrate, citrate, malate, succinate, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, camphorsulfonate, benzoate, salicylate, benzenesulfonate, methanesulfonate, or p-toluenesulfonate; preferably, the pharmaceutically usable salt is independently selected from: hydrochloride, hydrobromide, phosphate, sulfate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, oxalate, succinate, or adipate.

2. The pharmaceutically acceptable salt of the compound of formula I according to claim 1, characterized in that, The molar ratio of the compound of formula I to the pharmaceutically acceptable salt is 1:0.3 to 1:3.5; preferably, the molar ratio of the compound of formula I to the pharmaceutically acceptable salt is 1:1, 1:2, 1:3, 2:1, or 3:

1.

3. A pharmaceutically acceptable salt of the compound of formula I according to any one of claims 1-2, characterized in that, The pharmaceutically usable salt of the compound of formula I is selected from: hydrochloride, hydrobromide, phosphate, sulfate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, oxalate, succinate, or adipate of the compound of formula I, wherein the molar ratio of the compound of formula I to hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, benzenesulfonate, p-toluenesulfonate, maleic acid, fumarate, oxalic acid, succinate, or adipate is 1:

1.

4. A crystal form of the hydrochloride salt A of a compound of formula I, characterized in that, The hydrochloride A crystal form of the compound of Formula I exhibits characteristic peaks at 11.58°, 22.82°, 26.11°, and 27.46° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the hydrochloride A crystal form of the compound of Formula I exhibits characteristic peaks at 7.94°, 11.58°, 21.69°, 22.82°, 26.11°, and 27.46° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the... The hydrochloride A crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, has characteristic peaks at 7.52°, 7.94°, 11.58°, 14.74°, 16.89°, 17.91°, 20.53°, 21.69°, 22.82°, 24.26°, 25.21°, 26.11°, and 27.46°, with an error of ±0.2°; most preferably, the hydrochloride A crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 1.

5. A crystal form of the hydrochloride salt A of a compound of formula I, characterized in that, The DSC spectrum of the hydrochloride A crystal form of the compound of formula I has an endothermic peak at 209.6±10℃; preferably, the hydrochloride A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 22.

6. A hydrobromide crystal form of a compound of formula I, characterized in that, The hydrobromide A crystal form of the compound of Formula I exhibits characteristic peaks at 7.96° and 22.37° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the hydrobromide A crystal form of the compound of Formula I exhibits characteristic peaks at 7.96°, 13.69°, 21.81°, 22.37°, 22.66°, 25.27°, 26.40°, and 27.77° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the hydrobromide A crystal form of the compound of Formula I exhibits characteristic peaks at 7.96°, 13.69°, 21.81°, 22.37°, 22.66°, 25.27°, 26.40°, and 27.77° in the X-ray diffraction pattern ... The form, represented by a 2θ angle in the X-ray diffraction pattern, has characteristic peaks at 7.96°, 11.14°, 13.69°, 16.73°, 16.92°, 17.27°, 21.81°, 22.37°, 22.66°, 23.59°, 24.32°, 25.27°, 25.70°, 26.40°, 26.77°, and 27.77°, with an error of ±0.2°; most preferably, the hydrobromide A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 2.

7. A hydrobromide crystal form of a compound of formula I, characterized in that, The DSC spectrum of the hydrobromide A crystal form of the compound of formula I has an endothermic peak at 177.7±10℃; preferably, the hydrobromide A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 23.

8. A hydrobromide B crystal form of a compound of formula I, characterized in that, The hydrobromide B crystal form of the compound of Formula I has characteristic peaks at 6.99°, 10.39°, 13.80° and 20.67° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the hydrobromide B crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 17.

9. A hydrobromide C crystal form of a compound of formula I, characterized in that, The C crystal form of the hydrobromide of the compound of Formula I exhibits characteristic peaks at 6.78°, 16.00°, 16.65°, 23.13°, and 25.02° in the X-ray diffraction pattern, with an error of ±0.2°. Preferably, the C crystal form of the hydrobromide of the compound of Formula I exhibits characteristic peaks at 6.78°, 13.52°, 15.55°, 16.00°, 16.65°, 19.83°, 21.70°, 22.42°, 23.13°, 23.72°, 24.53°, 25.02°, 25.46°, 25.81°, 26.47°, and 27.26° in the X-ray diffraction pattern, with an error of ±0.2°. More preferably, the C crystal form of the hydrobromide of the compound of Formula I exhibits characteristic peaks at 6.78°, 13.52°, 15.55°, 16.00°, 16.65°, 19.83°, 21.70°, 22.42°, 23.13°, 23.72°, 24.53°, 25.02°, 25.46°, 25.81°, 26.47°, and 27.26° in the X-ray diffraction pattern, with an error of ±0.2°. The form, represented by a 2θ angle in the X-ray diffraction pattern, has characteristic peaks at 3.80°, 6.78°, 10.94°, 13.52°, 14.11°, 15.55°, 16.00°, 16.65°, 17.03°, 18.77°, 19.83°, 20.12°, 20.32°, 21.18°, 21.70°, 22.42°, 23.13°, 23.72°, 24.53°, 25.02°, 25.46°, 25.81°, 26.47°, 27.26°, 27.58°, 28.10°, and 28.71°, with an error of ±0.2°; most preferably, the hydrobromide C crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 18.

10. A hydrobromide C crystal form of a compound of formula I, characterized in that, The DSC spectrum of the hydrobromide C crystal form of the compound of formula I has an endothermic peak at 234.1±10℃; preferably, the hydrobromide C crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 31.

11. A sulfate crystal form A of a compound of formula I, characterized in that, The sulfate A crystal form of the compound of Formula I exhibits characteristic peaks at 20.35°, 21.31°, 24.14°, and 24.50° in the X-ray diffraction pattern, indicated by a 2θ angle, with an error of ±0.2°; preferably, the sulfate A crystal form of the compound of Formula I exhibits characteristic peaks at 5.59°, 7.10°, 7.39°, 16.19°, 19.83°, 20.35°, 21.31°, 22.23°, 22.91°, 24.14°, and 24.50° in the X-ray diffraction pattern, indicated by a 2θ angle, with an error of ±0. 2°; more preferably, the sulfate A crystal form of the compound of formula I has characteristic peaks at 5.59°, 7.10°, 7.39°, 10.21°, 16.19°, 19.44°, 19.83°, 20.35°, 21.31°, 22.23°, 22.91°, 23.54°, 24.14°, 24.50° and 25.48° in the X-ray diffraction pattern, with an error of ±0.2°; most preferably, the sulfate A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 3.

12. A sulfate crystal form of a compound of formula I, characterized in that, The DSC spectrum of the sulfate A crystal form of the compound of formula I has an endothermic peak at 182.4±10℃; preferably, the sulfate A crystal form of the compound of formula I has a DSC spectrum basically as shown in Figure 24.

13. A phosphate crystal form of a compound of formula I, characterized in that, The phosphate A crystal form of the compound of Formula I exhibits characteristic peaks at 7.35°, 11.02°, 16.00°, 18.77°, and 19.73° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the phosphate A crystal form of the compound of Formula I exhibits characteristic peaks at 6.59°, 7.35°, 10.66°, 11.02°, 13.86°, 16.00°, 18.77°, 19.73°, 21.91°, and 23.73° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of... ±0.2°; more preferably, the phosphate A crystal form of the compound of formula I has characteristic peaks at 5.43°, 6.59°, 7.35°, 10.66°, 11.02°, 13.86°, 15.67°, 16.00°, 18.77°, 19.73°, 21.91°, 23.73°, 25.02° and 26.74° in the X-ray diffraction pattern, with an error of ±0.2°; most preferably, the phosphate A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 4.

14. A benzenesulfonate A crystal form of a compound of formula I, characterized in that, The benzenesulfonate A crystal form of the compound of formula I has characteristic peaks at 4.79° and 22.28° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the benzenesulfonate A crystal form of the compound of formula I has characteristic peaks at 4.79°, 12.06°, 15.44° and 22.28° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the benzenesulfonate A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 5.

15. A crystal form of p-toluenesulfonate of a compound of formula I, characterized in that, The p-toluenesulfonate A crystal form of the compound of formula I has characteristic peaks at 5.19° and 21.46° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the p-toluenesulfonate A crystal form of the compound of formula I has characteristic peaks at 5.19°, 15.53° and 21.46° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the p-toluenesulfonate A crystal form of the compound of formula I has characteristic peaks at 5.19°, 10.00°, 14.83°, 15.53°, 21.46° and 21.94° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; most preferably, the p-toluenesulfonate A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 6.

16. A p-toluenesulfonate B crystal form of a compound of formula I, characterized in that, The p-toluenesulfonate B crystal form of the compound of Formula I exhibits characteristic peaks at 5.16°, 5.36°, and 13.81° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the p-toluenesulfonate B crystal form of the compound of Formula I exhibits characteristic peaks at 5.16°, 5.36°, 13.66°, 13.81°, 14.92°, 20.55°, 21.03°, 21.70°, and 25.69° in the X-ray diffraction pattern, represented by a 2θ angle. The error is ±0.2°; more preferably, the p-toluenesulfonate B crystal form of the compound of Formula I has characteristic peaks at 5.16°, 5.36°, 13.66°, 13.81°, 14.92°, 20.55°, 21.03°, 21.70°, 25.69° and 27.27° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; most preferably, the p-toluenesulfonate B crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 7.

17. A maleate crystal form of a compound of formula I, characterized in that, The maleate A crystal form of the compound of formula I has characteristic peaks at 9.14° and 19.10° in X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the maleate A crystal form of the compound of formula I has characteristic peaks at 9.14°, 13.64° and 19.10° in X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the maleate A crystal form of the compound of formula I has characteristic peaks at 4.67°, 9.14°, 13.64° and 19.10° in X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; most preferably, the maleate A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 8.

18. A maleate B crystal form of a compound of formula I, characterized in that, The maleate B crystal form of the compound of Formula I has characteristic peaks at 5.20°, 15.54°, and 21.49° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the maleate B crystal form of the compound of Formula I has characteristic peaks at 5.20°, 10.02°, 14.84°, 15.54°, 21.49°, 21.96°, 22.45°, and 23.81° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the maleate B crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 9.

19. A maleate crystal form of a compound of formula I, characterized in that, The maleate C crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, exhibits characteristic peaks at 9.54°, 18.14°, 18.46°, 18.94°, 20.12°, 20.31°, 22.33°, 22.69°, 24.29°, and 25.14°, with an error of ±0.2°. Preferably, the maleate C crystal form of the compound of Formula I, represented by a 2θ angle in the X-ray diffraction pattern, exhibits characteristic peaks at 9.54°, 11.84°, 14.31°, 18.14°, 18.46°, 18.94°, 20.12°, 20.31°, 21.24°, 22.33°, 22.69°, 24.29°, 24.66°, and 25.14°. A characteristic peak is observed at 7.43°, 9.54°, 11.84°, 14.31°, 17.51°, 18.14°, 18.46°, 18.94°, 20.12°, 20.31°, 20.74°, 21.24°, 22.33°, 22.69°, 23.24°, 23.48°, 24.29°, 24.66°, 25.14°, and 26.28° in the X-ray diffraction pattern, with an error of ±0.2°. Most preferably, the maleate C crystal form of the compound I has an XRPD pattern substantially as shown in Figure 19.

20. A fumarate A crystal form of a compound of formula I, characterized in that, The fumarate A crystal form of the compound of Formula I exhibits characteristic peaks at 7.59°, 9.70°, 14.41°, 18.31°, 18.64°, and 25.27° in the X-ray diffraction pattern, with an error of ±0.2°. Preferably, the fumarate A crystal form of the compound of Formula I exhibits characteristic peaks at 7.59°, 9.70°, 14.41°, 18.31°, 18.64°, 19.00°, 19.10°, 20.30°, 20.48°, 21.38°, 22.49°, 22.85°, 23.40°, 24.48°, 24.77°, and 25.27° in the X-ray diffraction pattern, with an error of ±0.2°. More preferably, the fumarate A crystal form of the compound of Formula I exhibits characteristic peaks at 7.59°, 9.70°, 14.41°, 18.31°, 18.64°, 19.00°, 19.10°, 20.30°, 20.48°, 21.38°, 22.49°, 22.85°, 23.40°, 24.48°, 24.77°, and 25.27° in the X-ray diffraction pattern, with an error of ±0.2°. The fumarate A crystal form of compound I, represented by a 2θ angle in its X-ray diffraction pattern, exhibits characteristic peaks at 7.17°, 7.59°, 9.70°, 9.95°, 12.01°, 14.41°, 16.09°, 17.44°, 18.31°, 18.64°, 19.00°, 19.10°, 19.70°, 20.30°, 20.48°, 20.85°, 21.38°, 22.49°, 22.85°, 23.40°, 23.61°, 24.48°, 24.77°, 25.27°, and 25.79°, with an error of ±0.2°. Most preferably, the fumarate A crystal form of compound I has an XRPD pattern substantially as shown in Figure 10.

21. A fumarate B crystal form of a compound of formula I, characterized in that, The fumarate B crystal form of the compound of Formula I exhibits characteristic peaks at 9.20°, 9.87°, 10.92°, 17.66°, 18.99°, 19.18°, 22.96°, and 28.96° in the X-ray diffraction pattern, with an error of ±0.2°. Preferably, the fumarate B crystal form of the compound of Formula I exhibits characteristic peaks at 9.20°, 9.87°, 10.92°, 17.66°, 18.80°, 18.99°, 19.18°, 22.96°, 23.60°, 28.96°, and 29.54° in the X-ray diffraction pattern, with an error of ±0.2°. The characteristic peaks are shown in the X-ray diffraction pattern at 9.20°, 9.87°, 10.92°, 13.71°, 14.61°, 15.00°, 17.66°, 18.29°, 18.80°, 18.99°, 19.18°, 22.96°, 23.60°, 24.94°, 28.96°, and 29.54°, with an error of ±0.2°. Most preferably, the fumarate B crystal form of the compound I has an XRPD pattern substantially as shown in Figure 11.

22. An oxalate A crystal form of a compound of formula I, characterized in that, The oxalate A crystal form of the compound of Formula I exhibits characteristic peaks at 8.32° and 11.47° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the oxalate A crystal form of the compound of Formula I exhibits characteristic peaks at 8.32°, 11.47°, 18.54°, 19.64°, 21.07°, 24.59°, and 25.97° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the compound of Formula I... The oxalate A crystal form of the compound has characteristic peaks at 5.08°, 8.32°, 9.98°, 11.47°, 14.91°, 18.54°, 19.64°, 21.07°, 22.87°, 24.17°, 24.59°, 25.97°, and 26.38° in the X-ray diffraction pattern, with an error of ±0.2°. Most preferably, the oxalate A crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 12.

23. A crystal form of oxalate B of a compound of formula I, characterized in that, The oxalate B crystal form of the compound of Formula I exhibits characteristic peaks at 7.64°, 10.24°, 17.54°, 18.72°, and 23.00° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the oxalate B crystal form of the compound of Formula I exhibits characteristic peaks at 7.64°, 10.24°, 15.40°, 15.56°, 17.54°, 18.72°, 22.28°, 22.61°, 23.00°, 23.39°, and 24.36° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of... ±0.2°; more preferably, the oxalate B crystal form of the compound of Formula I has characteristic peaks at 7.64°, 8.82°, 10.24°, 13.05°, 15.40°, 15.56°, 17.54°, 18.72°, 20.49°, 22.28°, 22.61°, 23.00°, 23.39°, 24.36° and 24.49° in the X-ray diffraction pattern, with an error of ±0.2°; most preferably, the oxalate B crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 13.

24. A succinate A crystal form of a compound of formula I, characterized in that, The succinate A crystal form of the compound of Formula I has characteristic peaks at 10.27°, 17.24°, and 18.09° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the succinate A crystal form of the compound of Formula I has characteristic peaks at 7.32°, 10.27°, 12.23°, 15.31°, 17.24°, 18.09°, and 24.38° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; more preferably, the succinate A crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 14.

25. A succinate B crystal form of a compound of formula I, characterized in that, The succinate B crystal form of the compound of Formula I exhibits characteristic peaks at 9.45°, 9.92°, 10.99°, 17.60°, and 18.87° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the succinate B crystal form of the compound of Formula I exhibits characteristic peaks at 9.45°, 9.92°, 10.99°, 17.60°, 18.34°, and 18.87° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°. °; More preferably, the succinate B crystal form of the compound of Formula I has characteristic peaks at 7.20°, 9.45°, 9.92°, 10.99°, 13.28°, 14.72°, 15.60°, 15.96°, 17.60°, 18.34° and 18.87° in the X-ray diffraction pattern, with an error of ±0.2°; Most preferably, the succinate B crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 15.

26. A succinate C crystal form of a compound of formula I, characterized in that, The C crystal form of the succinate of Formula I exhibits characteristic peaks at 9.79°, 16.97°, and 22.04° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the C crystal form of the succinate of Formula I exhibits characteristic peaks at 4.92°, 9.79°, 11.95°, 16.37°, 16.97°, 17.23°, 19.72°, 20.96°, 22.04°, and 25.22° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0. 2°; more preferably, the succinate C crystal form of the compound of formula I has characteristic peaks at 4.92°, 7.01°, 9.79°, 11.95°, 14.69°, 16.37°, 16.97°, 17.23°, 18.45°, 19.72°, 20.96°, 22.04° and 25.22° in the X-ray diffraction pattern, with an error of ±0.2°; most preferably, the succinate C crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 20.

27. A succinate D crystal form of a compound of formula I, characterized in that, The D crystal form of succinate of Formula I exhibits characteristic peaks at 12.17° and 15.83° in X-ray diffraction patterns, represented by a 2θ angle, with an error of ±0.2°; preferably, the D crystal form of succinate of Formula I exhibits characteristic peaks at 6.95°, 8.27°, 8.67°, 9.72°, 12.17°, 13.67°, 15.83°, 17.38°, 18.01°, 18.96°, 20.44°, 23.00°, and 25.19° in X-ray diffraction patterns, represented by a 2θ angle, with an error of ±0.2°; more preferably, the D crystal form of succinate of Formula I exhibits characteristic peaks at 6.95°, 8.27°, 8.67°, 9.72°, 12.17°, 13.67°, 15.83°, 17.38°, 18.01°, 18.96°, 20.44°, 23.00°, and 25.19° in X-ray diffraction patterns ... The crystal form, represented by a 2θ angle in the X-ray diffraction pattern, exhibits characteristic peaks at 6.95°, 8.27°, 8.67°, 9.72°, 12.17°, 13.67°, 15.83°, 16.05°, 17.38°, 18.01°, 18.96°, 19.67°, 20.44°, 20.76°, 21.96°, 22.34°, 23.00°, 23.64°, 23.93°, 24.15°, and 25.19°, with an error of ±0.2°. Most preferably, the succinic acid D crystal form of the compound of Formula I has an XRPD pattern substantially as shown in Figure 21.

28. An adipate A crystal form of a compound of formula I, characterized in that, The adipate A crystal form of the compound of Formula I exhibits characteristic peaks at 8.90°, 9.17°, 13.58°, and 20.34° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°; preferably, the adipate A crystal form of the compound of Formula I exhibits characteristic peaks at 8.90°, 9.17°, 10.48°, 10.68°, 13.58°, 18.00°, 20.34°, 20.75°, and 23.84° in the X-ray diffraction pattern, represented by a 2θ angle. The characteristic peaks are shown with an error of ±0.2°. More preferably, the adipate A crystal form of the compound of formula I has characteristic peaks at 8.90°, 9.17°, 10.48°, 10.68°, 13.58°, 17.81°, 18.00°, 20.34°, 20.75° and 23.84° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°. Most preferably, the adipate A crystal form of the compound of formula I has an XRPD pattern substantially as shown in Figure 16.

29. An amorphous hydrobromide salt of a compound of formula I, characterized in that, The hydrobromide amorphous form of the compound of formula I has an X-ray diffraction pattern as shown in Figure 32.

30. An amorphous sulfate of a compound of formula I, characterized in that, The sulfate amorphous form of the compound of formula I has an X-ray diffraction pattern as shown in Figure 33.

31. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula I according to any one of claims 1-3, or a crystalline form according to any one of claims 4-28, or an amorphous form according to any one of claims 29-30, and one or more pharmaceutically acceptable excipients and / or carriers.

32. The use of a pharmaceutically acceptable salt of the compound of formula I according to any one of claims 1-3, or the crystalline form according to any one of claims 4-28, or the amorphous form according to any one of claims 29-30, or the use of the pharmaceutical composition according to claim 31 in the preparation of a medicament for treating or preventing diseases associated with elevated CYP11B2 activity levels; preferably, the diseases associated with elevated CYP11B2 activity levels are selected from: hypertension, chronic kidney disease, primary aldosteronism, diabetic nephropathy, congestive heart failure, or Cushing's syndrome.

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