Vanin enzyme inhibitor salt form, crystal form and preparation method and application thereof

Abstract

The present invention relates to a salt form and crystal form of a vaninase inhibitor represented by Formula I, as well as methods for preparing and using the same. The salt form is a salt formed by a compound of Formula I with an acid, and the crystal form is selected from the group consisting of L-tartrate crystal forms A, B, C, and D of the compound of Formula I. The salt of the compound of Formula I of the present invention has high stability and good water solubility, which facilitates enhanced oral absorption and improved bioavailability. The preparation method is simple to operate, easy to control, and highly reproducible, making it suitable for industrial production. The crystal form of the present invention has high stability, good solubility, and low hygroscopicity, and has promising drug development prospects. #imgabs0#

Description

[0001] This application claims priority to Chinese patent application No. CN 202210272562.6, filed on March 18, 2022, and Chinese patent application No. CN 202211104893.5, filed on September 9, 2022. The entire text of these applications is incorporated into this application by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a salt form and a crystal form of a Vanin enzyme inhibitor and a preparation method thereof, and the use of the salt form and the crystal form in the preparation of a drug for preventing and / or treating cardiovascular diseases and tumor diseases. Background Art

[0003] Vanin-1 (vascular non-inflammatory molecule-1) is an exoenzyme with ubiquitinase activity that primarily catalyzes the hydrolysis of pantothenic acid (VB5) to produce pantothenic acid (pantothenic acid) and mercaptoethylamine. Coenzyme A (CoA) synthesized from VB5 regulates biotransformations such as fatty acid synthesis and oxidation, as well as energy metabolism. The reversible reaction between mercaptoethylamine and cystamine is an important sensor of oxidative stress. A growing number of studies have found that the absence or reduction of mercaptoethylamine leads to enhanced γ-GCS activity, increasing endogenous GSH reserves in tissues, thereby preventing or eliminating tissue inflammation. Studies have found that Vanin-1 mRNA is highly expressed in the human colon, duodenum, endometrium, liver, kidney, gallbladder, and small intestine. In patients with ulcerative colitis (UC), Vanin-1 expression is diffusely elevated and restricted to the brush border. Furthermore, during the clinically quiescent phase of UC, Vanin-1 expression in the colon remains significantly elevated compared to controls. In a TNBS model, mice with Vanin-1 knockout (Vanin-1- / -) showed a significantly higher survival rate than the control group and showed no significant weight loss. Furthermore, 90% of Vanin-1- / - mice treated with cystamine died within 5 days, demonstrating that cystamine completely reverses the protective effects of Vanin-1 deficiency against colitis. In addition, histopathological analysis of mice found that inhibition or knockout of Vanin-1 could significantly improve the lesions in the mouse colon (Berruyer C, et al., Vanin-1- / - mice exhibit a glutathione mediated tissue resistance to oxidative stress. Mol. Cell Biol. 2004; 24: 7214-7224; Berruyer C, et al., Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptorγactivity. J. Exp. Med. 2006; 203: 2817-2827).

[0004] In addition, Vanin-1 is also believed to play a regulatory role in cardiovascular disease and tumor diseases. Studies have shown that Vanin-1 regulates the activation of smooth muscle cells in vitro and regulates the occurrence of neointimal hyperplasia in response to carotid artery ligation in vivo. Polymorphisms of the VNN1 gene are associated with blood pressure and HDL levels. In SF-1 transgenic mice, Vanin-1 deficiency prevents mice from developing adrenal cortical tumors, indicating the role of Vanin-1 in certain cancers. Studies in inflammatory diseases have found that Vanin-1 is highly upregulated in psoriasis skin lesions compared to normal individuals. VNN1 gene expression is also upregulated in the whole blood of patients with childhood immune thrombocytopenia (ITP), where overexpression of VNN1 is associated with the progression of chronic ITP. In addition, elevated Vanin-1 has been detected in the urine of patients with a variety of renal disorders, including systemic lupus erythematosus, nephrotoxicant-induced renal injury, and type 2 diabetes (Rommelaere S, et al. PPARalpha regulates the production of serum Vanin-1 by liver. FEBS Lett. 2013 Nov 15; 587(22): 3742-8).

[0005] Chinese patent application CN2021110954656 (WO2022063197A1) discloses the following structure I

[0006]

[0007] The compound of formula I is an effective Vanin enzyme inhibitor and has broad pharmaceutical prospects. Therefore, it is necessary to research and develop a pharmaceutically acceptable active ingredient with high efficiency, low toxicity and / or long-acting effect to improve the above technical problems. Summary of the Invention

[0008] In order to solve the problems existing in the prior art, the first aspect of the present invention provides a pharmaceutically acceptable salt of a compound of formula I, wherein the compound of formula I is as follows:

[0009]

[0010] The pharmaceutically acceptable salt of the compound of formula I is a salt formed by the compound of formula I and an acid.

[0011] The acid is selected from inorganic or organic acids, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfate, 3-phenylpropionic acid, bitter acid, acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid. As an example, the acid can be selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, succinic acid, ethanesulfonic acid, L-malic acid, L-glutamic acid, oxalic acid, D-malic acid, pamoic acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid.

[0012] In a preferred embodiment, the pharmaceutically acceptable salt of the compound of formula I is selected from one of its hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, fumarate, maleate, citrate, L-tartrate, succinate, ethanesulfonate, L-malate, L-glutamate, oxalate, D-malate, and pamoic acid.

[0013] In a preferred embodiment, in the pharmaceutically acceptable salt of the compound of formula I, the molar ratio of the compound of formula I to the acid can be selected from 1:1, 2:1 or 3:1, provided that the ions of the compound of formula I in the salt are charged in balance with the ions of the acid. For example, when the number of ionizable hydrogen atoms in the acid (e.g., hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid) is 1, the molar ratio of the compound of formula I to the acid is 1:1; when the number of ionizable hydrogen atoms in the acid (e.g., sulfuric acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, succinic acid, malic acid, L-glutamic acid, pamoic acid) is 2, the molar ratio of the compound of formula I to the acid can be 1:1 or 2:1; when the number of ionizable hydrogen atoms in the acid (e.g., phosphoric acid) is 3, the molar ratio of the compound of formula I to the acid is 1:1, 2:1 or 3:1.

[0014] In a more preferred embodiment, in the pharmaceutically acceptable salt of the compound of formula I, the molar ratio of the compound of formula I to the acid is 1:1; that is, when the acid is L-tartaric acid, fumaric acid, or malic acid, the pharmaceutically acceptable salt is selected from the monotartrate, monofumarate, and monomalate of the compound of formula I, more preferably the monoL-tartrate of the compound of formula I.

[0015] The second aspect of the present invention provides a method for preparing a pharmaceutically acceptable salt of a compound of formula I, comprising reacting the compound of formula I with an acid to prepare a pharmaceutically acceptable salt of the compound of formula I.

[0016] According to an embodiment of the present invention, the preparation method comprises dissolving the compound of formula I in an organic solvent A, adding an acid to react; and then adding an organic solvent B to prepare a pharmaceutically acceptable salt of the compound of formula I.

[0017] According to an embodiment of the present invention, the acid has the above-mentioned definition. In some embodiments, the acid is first dissolved in an organic solvent C to prepare an acid solution before being added to the reaction.

[0018] According to an embodiment of the present invention, the organic solvent A is selected from at least one of esters, ketones, and alcohols. The esters may be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, isopropyl acetate, or a combination thereof; the ketones may be selected from ketones having 3 to 10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone, or a combination thereof; the alcohols may be selected from alcohols having 1 to 8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination thereof.

[0019] According to an embodiment of the present invention, the organic solvent B is selected from nitriles, esters, ethers, or a combination thereof. The nitriles can be selected from nitriles with 2 to 6 carbon atoms, such as acetonitrile, propionitrile, isopropionitrile, butyronitrile, or a combination thereof; the esters can be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, ethylpropyl acetate, isopropyl acetate, or a combination thereof; the ethers can be selected from ethers with 2 to 6 carbon atoms, such as diethyl ether, propyl ether, isopropyl ether, tert-butyl ether, methyl tert-butyl ether, or a combination thereof.

[0020] According to an embodiment of the present invention, those skilled in the art will appreciate that the organic solvent C is selected from any organic solvent that can dissolve the acid.

[0021] In some embodiments, when the acid is selected from L-tartaric acid, the organic solvent C is selected from alcohols, which can be selected from alcohols having 1-8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination thereof.

[0022] In the preparation method, the volume ratio of the organic solvent A to the organic solvent B is 1:1 to 5, preferably 1:1.

[0023] In the preparation method, the molar ratio of the compound of formula I to the acid is 1:0.8 to 1:1.5, preferably 1:0.9 to 1:1.3, and more preferably 1:1.0 to 1:1.1.

[0024] According to an embodiment of the present invention, the reaction temperature is 20°C to 80°C, preferably 20°C to 60°C.

[0025] According to an embodiment of the present invention, the preparation method further comprises the steps of filtering and / or drying after the reaction is completed to prepare a pharmaceutically acceptable salt of the compound of formula I.

[0026] In the preparation method, the drying temperature may be 30°C to 60°C, more preferably 40°C to 50°C.

[0027] In the preparation method, the drying pressure is 0 to 20 KPa, preferably 0 to 10 KPa, and more preferably 5 to 10 KPa.

[0028] The present invention also provides a crystal of the mono-L-tartrate salt of the compound of formula I, preferably a single crystal. The unit cell parameters of the single crystal are as follows:

[0029] Monoclinic system, space group is P21,

[0030]

[0031] β=96.577,

[0032]

[0033] Z=2.

[0034] The present invention also provides a method for preparing crystals, especially single crystals, of the mono-L-tartrate of the compound of formula I, which comprises dissolving the mono-L-tartrate of the compound of formula I in solvent D and then diffusing the solution in an atmosphere of solvent E.

[0035] The solvent D is selected from alcohol solvents, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol or a combination thereof.

[0036] The solvent E is selected from an ester solvent, an ether solvent, an alkane solvent, or a combination thereof. The ester solvent can be selected from an organic carboxylic acid ester, such as ethyl acetate, isopropyl acetate, etc.; the ether solvent can be selected from ethers with 2 to 6 carbon atoms, such as diethyl ether, propyl ether, isopropyl ether, tert-butyl ether, methyl tert-butyl ether, etc.; the alkane solvent can be selected from hydrocarbons with 1 to 8 carbon atoms, such as n-hexane, n-heptane, etc.

[0037] The third aspect of the present invention provides a crystalline form of a pharmaceutically acceptable salt of the compound of formula I.

[0038] According to a preferred embodiment of the present invention, a crystalline form of the mono L-tartrate salt of the compound of formula I is provided, selected from the crystalline form A, crystalline form B, crystalline form C and crystalline form D described below.

[0039] In some embodiments, a crystalline form A of a mono L-tartrate salt of the compound of Formula I is provided. The crystalline form A has characteristic peaks at 17.06±0.20°, 20.06±0.20°, and 22.58±0.20° in X-ray powder diffraction using Cu-Kα radiation expressed in 2θ angles.

[0040] Preferably, the crystalline form A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.06±0.20°, 18.00±0.20°, 18.80±0.20°, 19.22±0.20°, 20.06±0.20°, 22.58±0.20°, 23.72±0.20°, and 24.38±0.20°.

[0041] Preferably, the crystalline form A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.30±0.20°, 14.24±0.20°, 17.06±0.20°, 18.00±0.20°, 18.80±0.20°, 19.22±0.20°, 20.06±0.20°, 20.52±0.20°, 22.58±0.20°, 23.72±0.20°, 24.38±0.20°, and 25.70±0.20°.

[0042] Preferably, the X-ray powder diffraction of the crystalline form A using Cu-Kα radiation, expressed in 2θ angles, is shown in Table 1, with an error range of ±0.20°:

[0043] Table 1 XRPD analysis data of Form A

[0044]

[0045]

[0046] Preferably, the crystalline form A has substantially Figure 1 The powder X-ray diffraction pattern is shown.

[0047] According to an embodiment of the present invention, the crystalline form A is an anhydrate of the mono-L-tartrate of the compound of formula I.

[0048] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystalline form A shows that the first endothermic peak appears near the peak temperature of 150.14°C when heated.

[0049] Preferably, the crystalline form A has substantially Figure 2 The DSC graph shown.

[0050] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the crystalline form A shows a weight loss of about 0.069% in the range of 22.03°C to 120°C.

[0051] Preferably, the crystalline form A has substantially Figure 3 TGA graph shown.

[0052] According to an embodiment of the present invention, the crystal form A is an irregular morphology crystal. Preferably, the particle size of the crystal form A does not exceed 10 μm.

[0053] Preferably, the crystalline form A has substantially Figure 4 The PLM diagram shown.

[0054] In some embodiments, a crystalline form B of a mono-L-tartrate salt of the compound of Formula I is provided. The crystalline form B has characteristic peaks at 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, and 23.72±0.20° using Cu-Kα radiation and X-ray powder diffraction expressed in 2θ angles.

[0055] Preferably, the crystalline form B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.56±0.20°, 17.36±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, and 26.02±0.20°.

[0056] Preferably, the crystalline form B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.56±0.20°, 17.36±0.20°, 18.14±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, 24.52±0.20°, 26.02±0.20°, and 29.52±0.20°.

[0057] Preferably, the crystalline form B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.78±0.20°, 7.56±0.20°, 17.36±0.20°, 18.14±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, 24.52±0.20°, 26.02±0.20°, and 29.52±0.20°.

[0058] Preferably, the X-ray powder diffraction of the crystalline form B using Cu-Kα radiation, expressed in 2θ angles, is shown in Table 2, with an error range of ±0.20°:

[0059] Table 2 XRPD analysis data of Form B

[0060]

[0061]

[0062] Preferably, the crystalline form B has substantially Figure 5 The powder X-ray diffraction pattern is shown.

[0063] According to an embodiment of the present invention, the crystalline form B is a hydrate of mono-L-tartrate of the compound of formula I.

[0064] According to an embodiment of the present invention, the hydrate contains 0.5 to 1 mol of water.

[0065] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystalline form B shows a first endothermic peak near a peak temperature of 61.57° C. and a second endothermic peak near a peak temperature of 152.18° C. The first endothermic peak is a dehydration peak, and the second endothermic peak is a melting peak.

[0066] Preferably, the crystalline form B has substantially Figure 6 The DSC graph shown.

[0067] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the crystalline form B shows a weight loss of about 2.76% in the range of 21.34°C to 120°C.

[0068] Preferably, the crystalline form B has substantially Figure 7 TGA graph shown.

[0069] In some embodiments, a mono L-tartrate crystalline form C of the compound of Formula I is provided. The crystalline form C has characteristic peaks at 17.88±0.20°, 19.40±0.20°, and 21.38±0.20° in X-ray powder diffraction using Cu-Kα radiation and expressed in 2θ angles.

[0070] Preferably, the crystalline form C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.14±0.20°, 17.88±0.20°, 19.40±0.20°, 20.06±0.20°, 21.38±0.20°, 23.76±0.20°, and 25.92±0.20°.

[0071] Preferably, the crystalline form C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.58±0.20°, 7.14±0.20°, 13.96±0.20°, 17.10±0.20°, 17.88±0.20°, 19.40±0.20°, 20.06±0.20°, 21.38±0.20°, 25.92±0.20°, and 29.38±0.20°.

[0072] Preferably, the X-ray powder diffraction of the crystalline form C using Cu-Kα radiation, expressed in 2θ angles, is shown in Table 3, with an error range of ±0.20°:

[0073] Table 3 XRPD analysis data of Form C

[0074]

[0075]

[0076] Preferably, the crystalline form C has substantially Figure 8 The powder X-ray diffraction pattern is shown.

[0077] According to an embodiment of the present invention, the crystalline form C is a mono-L-tartrate solvate of the compound of formula I, preferably an ethanol solvate of the mono-L-tartrate of the compound of formula I.

[0078] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystalline form C shows a first endothermic peak near a peak temperature of 129.45° C. and a second endothermic peak near a peak temperature of 151.90° C. The first endothermic peak is a desolvation peak, and the second endothermic peak is a melting peak.

[0079] Preferably, the crystalline form C has substantially Figure 9 The DSC graph shown.

[0080] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the crystalline form C shows a weight loss of about 4.59% in the range of 21.47°C to 150°C.

[0081] Preferably, the crystalline form C has substantially Figure 10 TGA graph shown.

[0082] According to an embodiment of the present invention, the crystal form C is an irregular morphology crystal. Preferably, the particle size of the crystal form C does not exceed 10 μm.

[0083] Preferably, the crystalline form C has substantially Figure 11 The PLM diagram shown.

[0084] In some embodiments, a mono L-tartrate crystalline form D of the compound of Formula I is provided, wherein the crystalline form D has characteristic peaks at 3.50±0.20°, 7.46±0.20°, and 23.04±0.20° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation.

[0085] Preferably, the crystalline form D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.50±0.20°, 6.92±0.20°, 7.46±0.20°, 17.22±0.20°, 18.20±0.20°, 19.88±0.20°, and 23.04±0.20°.

[0086] Preferably, the crystalline form D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.50±0.20°, 6.92±0.20°, 7.46±0.20°, 17.22±0.20°, 18.20±0.20°, 19.88±0.20°, 20.76±0.20°, 23.04±0.20°, and 25.62±0.20°.

[0087] Preferably, the X-ray powder diffraction of the crystalline form D using Cu-Kα radiation, expressed in 2θ angles, is shown in Table 4, with an error range of ±0.20°:

[0088] Table 4 XRPD analysis data of Form D

[0089]

[0090]

[0091] Preferably, the crystalline form D has substantially Figure 12 The powder X-ray diffraction pattern is shown.

[0092] According to an embodiment of the present invention, the crystalline form D is a mono-L-tartrate solvate of the compound of formula I, preferably a tetrahydrofuran solvate of the mono-L-tartrate of the compound of formula I.

[0093] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystalline form D shows a first endothermic peak near a peak temperature of 94.15° C., a second endothermic peak near a peak temperature of 118.79° C., and a third endothermic peak near a peak temperature of 146.04° C. The first and second endothermic peaks are desolvation peaks, and the third endothermic peak is a melting peak.

[0094] Preferably, the crystalline form D has substantially Figure 13 The DSC graph shown.

[0095] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the crystalline form D shows a weight loss of about 5.25% in the range of 23.19°C to 120°C.

[0096] Preferably, the crystalline form D has substantially Figure 14 TGA graph shown.

[0097] The fourth aspect of the present invention provides a method for preparing the crystalline form of the pharmaceutically acceptable salt of the compound of formula I.

[0098] According to a preferred embodiment of the present invention, a method for preparing the mono L-tartrate crystalline form of the compound of formula I is provided.

[0099] In some embodiments, a preparation method for the mono L-tartrate salt of the compound of Formula I, Form A, is provided, comprising: stirring the mono L-tartrate salt of the compound of Formula I in a solvent to obtain the Form A.

[0100] The stirring temperature is 20-80°C, preferably 25-55°C.

[0101] The solvent is selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, alkane solvents, halogenated hydrocarbon solvents and nitrile solvents or a combination thereof.

[0102] The alcohol solvent is selected from one of methanol, ethanol and isopropanol.

[0103] The ester solvent is selected from one of ethyl acetate, propyl acetate and isopropyl acetate.

[0104] The ketone solvent is selected from one of acetone, 2-butanone, methyl isobutyl ketone and 4-methyl-2-pentanone.

[0105] The ether solvent is selected from one of diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether and tetrahydrofuran.

[0106] The alkane solvent is selected from one of toluene, n-heptane and cyclohexane.

[0107] The nitrile solvent is selected from one of acetonitrile, benzyl cyanide and benzonitrile.

[0108] The mass volume ratio of the mono L-tartrate salt of the compound of formula I to the solvent is 1 g: (20-40) ml, preferably 1 g: (20-30) ml.

[0109] In some embodiments, a second method for preparing the mono L-tartrate salt of the compound of formula I, crystalline form A, is provided, comprising: dissolving the mono L-tartrate salt of the compound of formula I in an alcohol solvent, and then adding an anti-solvent and stirring to obtain the crystalline form A.

[0110] The alcohol solvent is selected from one of methanol, ethanol, propanol and isopropanol.

[0111] The anti-solvent is one or more of an ether solvent or an ester solvent. The ether solvent is selected from one of diethyl ether, propyl ether, isopropyl ether, and methyl tert-butyl ether. The ester solvent is selected from one of ethyl acetate, propyl acetate, and isopropyl acetate.

[0112] The mass volume ratio of the mono L-tartrate salt of the compound of formula I to the alcohol solvent and the anti-solvent is 1g:(10-30)ml:(80-120)ml, preferably 1g:(15-25)ml:(90-110)ml.

[0113] According to an embodiment of the present invention, the preparation method one or two of Form A further includes post-processing steps such as filtration and drying.

[0114] In some embodiments, a method for preparing the mono L-tartrate crystalline form B of the compound of Formula I is provided, comprising placing the crystalline form A under high humidity conditions to obtain the crystalline form B. Preferably, the crystalline form A is placed for more than 2 days, more preferably, for more than 3 days.

[0115] The high humidity condition is 80% to 100% RH, preferably 90% to 100% RH.

[0116] In some embodiments, a second method for preparing the mono L-tartrate salt of the compound of formula I, Form B, is provided, comprising dissolving the mono L-tartrate salt of the compound of formula I in an alcohol solvent, and obtaining Form B after evaporation of the solvent.

[0117] The alcohol solvent is selected from one of methanol, ethanol and isopropanol.

[0118] The dissolving temperature is 15-45°C, preferably 25-35°C.

[0119] The mass volume ratio of the mono L-tartrate salt of the compound of formula I to the alcohol solvent is 1 g: (10-30) ml, preferably 1 g: (15-25) ml.

[0120] In some embodiments, a method for preparing the mono L-tartrate crystalline form C of the compound of formula I is provided, comprising dissolving the mono L-tartrate of the compound of formula I in an alcohol solvent and crystallizing to obtain the crystalline form C.

[0121] The alcohol solvent is selected from methanol, ethanol and / or isopropanol, preferably methanol.

[0122] The mass volume ratio of the mono L-tartrate of the compound of formula I to the alcohol solvent is 1 g: (20-40) ml, preferably 1 g: (20-30) ml.

[0123] According to an embodiment of the present invention, the preparation method of the crystal form C further includes post-processing steps such as filtration and drying.

[0124] In some embodiments, a method for preparing the mono L-tartrate salt of the compound of formula I, crystalline form D, is provided, comprising dissolving the mono L-tartrate salt of the compound of formula I in an ether solvent, heating and stirring, cooling, and precipitating a solid to obtain the crystalline form D.

[0125] The ether solvent is selected from one of diethyl ether, tetrahydrofuran, and methyl tert-butyl ether, preferably tetrahydrofuran.

[0126] The heating temperature is 30°C to 80°C, preferably 45°C to 75°C.

[0127] The cooling temperature is 20°C to 30°C.

[0128] The mass volume ratio of the mono L-tartrate salt of the compound of formula I to the ether solvent is 1 g: (20-40) ml, preferably 1 g: (20-30) ml.

[0129] According to an embodiment of the present invention, the preparation method of the crystal form D includes post-processing steps such as filtration and drying.

[0130] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt or a crystalline form thereof of the compound of Formula I, and optionally a pharmaceutically acceptable excipient. According to a preferred embodiment of the present invention, the pharmaceutically acceptable salt is a mono-L-tartrate salt of the compound of Formula I; the crystalline form is selected from the group consisting of mono-L-tartrate salt Form A, Form B, Form C, and Form D of the compound of Formula I. Preferably, the pharmaceutical composition is in the form of a preparation.

[0131] The present invention also provides a formulation comprising a pharmaceutically acceptable salt or a crystalline form thereof of the compound of Formula I, and optionally a pharmaceutically acceptable excipient. According to a preferred embodiment of the present invention, the pharmaceutically acceptable salt is a mono-L-tartrate salt of the compound of Formula I; the crystalline form is selected from the group consisting of mono-L-tartrate salt Form A, Form B, Form C, and Form D of the compound of Formula I.

[0132] The present invention also provides the use of a pharmaceutically acceptable salt or a crystalline form thereof of the compound of formula I, or the pharmaceutical composition, in the preparation of a drug for preventing and / or treating diseases or conditions associated with Vanin enzyme inhibitors.

[0133] According to an embodiment of the present invention, the diseases or conditions associated with the Vanin enzyme inhibitor include one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases; for example, Crohn's disease, inflammatory bowel disease and ulcerative colitis.

[0134] The present invention also provides a method for preventing and / or treating diseases or conditions associated with Vanin enzyme inhibitors, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt or a crystalline form thereof of the compound of formula I, or the pharmaceutical composition, to an individual in need thereof.

[0135] According to an embodiment of the present invention, the diseases or conditions associated with Vanin enzyme inhibitors include one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases; for example, Crohn's disease, inflammatory bowel disease and ulcerative colitis.

[0136] The therapeutic methods of the present invention may include administering one, two, or more pharmaceutically acceptable salts of the compounds of Formula I of the present invention, or their crystalline forms, alone, or administering one, two, or more pharmaceutically acceptable salts of the compounds of Formula I of the present invention, or their crystalline forms, in combination with other chemotherapeutic agents. The combined administration may be performed simultaneously or sequentially with the different drugs.

[0137] Those skilled in the art will understand that the terms "... or a combination thereof" and "one or more of..." appearing in this document are equivalent to "one, two or more of...", and all indicate that each of the options and every combination of two or more can be adopted (i.e., combining two of the options is not excluded).

[0138] Beneficial effects

[0139] (1) The salts of the compound of formula I of the present invention are highly stable, especially the mono-L-tartrate salt, which has high solubility in water, thereby enhancing oral absorption and improving bioavailability;

[0140] (2) The method for preparing the salt of the compound of formula I of the present invention is simple to operate, easy to control, has good reproducibility, and is suitable for industrial production;

[0141] (3) The four crystalline forms of the mono-L-tartrate salt of the compound of formula I of the present invention have high stability, good solubility, low hygroscopicity, and good drug development prospects;

[0142] (4) The preparation methods of the four crystalline forms of the mono-L-tartrate salt of the compound of formula I of the present invention are simple, the reaction conditions are mild, and the product yield is high, which is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0143] Figure 1 The XRPD pattern of the mono L-tartrate form A of the compound of formula I is shown in FIG.

[0144] Figure 2 The DSC spectrum of the mono L-tartrate crystalline form A of the compound of formula I is shown in FIG.

[0145] Figure 3 The figure is the TGA spectrum of the mono L-tartrate form A of the compound of formula I.

[0146] Figure 4 The figure is the PLM spectrum of the mono L-tartrate form A of the compound of formula I.

[0147] Figure 5 The XRPD pattern of the mono L-tartrate form B of the compound of formula I is shown in FIG.

[0148] Figure 6 The DSC spectrum of the mono L-tartrate form B of the compound of formula I is shown in FIG.

[0149] Figure 7 The figure is the TGA spectrum of the mono L-tartrate form B of the compound of formula I.

[0150] Figure 8 The XRPD pattern of the mono L-tartrate form C of the compound of formula I is shown in FIG.

[0151] Figure 9 The DSC spectrum of the mono L-tartrate crystal form C of the compound of formula I is shown in FIG.

[0152] Figure 10 The figure is the TGA spectrum of the mono L-tartrate form C of the compound of formula I.

[0153] Figure 11 The figure is the PLM spectrum of the mono L-tartrate form C of the compound of formula I.

[0154] Figure 12 The XRPD pattern of the mono L-tartrate crystalline form D of the compound of formula I is shown in FIG.

[0155] Figure 13 The DSC spectrum of the mono L-tartrate crystalline form D of the compound of formula I is shown in FIG.

[0156] Figure 14 The figure is the TGA spectrum of the mono L-tartrate form D of the compound of formula I.

[0157] Figure 15 This is the XRPD pattern of the mono L-tartrate form A of the compound of formula I in Example 7.

[0158] Figure 16 This is the XRPD pattern of the mono L-tartrate form B of the compound of formula I in Example 9.

[0159] Figure 17 This is the XRPD pattern of the mono L-tartrate form A of the compound of formula I after being placed under high temperature and high humidity conditions for 3 days.

[0160] Figure 18 This is the XRPD pattern of the mono L-tartrate form A of the compound of formula I after being placed under high temperature and high humidity conditions for 2 weeks.

[0161] Figure 19 This is a single crystal image of the mono L-tartrate salt of the compound of formula I. DETAILED DESCRIPTION

[0162] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0163] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0164] 40℃ / 75%RH-open means placing the product in the open at 40℃ and 75% humidity.

[0165] 60℃-open means placing it in the open at 60℃.

[0166] 80% RHopen means placing it in the open at 80% humidity.

[0167] 92.5% RH-open means that the container is placed openly at a humidity of 80%.

[0168] 40℃ / 75%RH-closed-2wks means the container is sealed and placed at 40℃ and 75% humidity for 2 weeks.

[0169] 40℃ / 75%RH-open-2wks means placing the product in the open at 40℃ and 75% humidity for 2 weeks.

[0170] 60℃-closed-2wks means sealed and placed at 60℃ for 2 weeks.

[0171] STD-1 refers to the control sample.

[0172] Initial refers to the initial state.

[0173] SGF refers to simulated gastric fluid.

[0174] FaSSIF refers to fasting state simulated intestinal fluid

[0175] FeSSIF stands for fed state simulated intestinal fluid.

[0176] 1d means 1 day; 3d means 3 days.

[0177] Experimental instrument parameters

[0178] X-ray powder diffraction (XRPD)

[0179] The equipment is Shimadzu XRD-6000, and the sample is scanned according to the following parameters:

[0180] The ray source is Cu~Kα target

[0181] The minimum operating voltage and current of the fluorescent tube are 40kV and 30mA respectively.

[0182] The 2-Theta value of the sample scan range is from 2 o to 50 o The scanning speed is 5deg / min.

[0183] Thermogravimetric analysis (TGA)

[0184] About 5 mg of sample was weighed and placed in a crucible. Under nitrogen protection, the temperature was raised from 30°C to 300°C at a heating rate of 20°C / min and maintained at 300°C for 1 min.

[0185] Differential Scanning Calorimetry (DSC)

[0186] Weigh about 1 to 5 mg of powder sample and place it in a sealed aluminum crucible with a pinhole on the crucible lid. Under nitrogen protection, perform differential thermal scanning from 30°C to 300°C. o ℃ and hold for 1 minute. The heating rate is 20℃ / min.

[0187] Polarized Light Microscopy (PLM)

[0188] The sample was dispersed in a medium (silicone oil), and the sample was observed using a 10X eyepiece and a 10X objective lens, and the image was recorded using a camera computer system.

[0189] Dynamic moisture sorption (DVS)

[0190] Under 0% to 95% to 0% relative humidity (RH) cycle, weigh about 10 mg of sample and test the moisture absorption / desorption characteristics at 25°C. The parameters are as follows:

[0191]

[0192] Hygroscopicity classification:

[0193]

[0194] “*”: At 25±1°C and 80±2%RH (European Pharmacopoeia 10.0)

[0195] "W": weight gain after moisture absorption at 80% RH.

[0196] Single crystal testing equipment and test conditions:

[0197] Instrument model: D8 Venture

[0198] Instrument parameters:

[0199] Light source: Cu target X-ray: Detector: CMOS area detector Resolution: Current and voltage: 50kV, 1.2mA Exposure time: 50s

[0200] Distance from surface detector to sample: 40mm Test temperature: 170(2)K

[0201] Preparation of intermediate 1f and compound of formula I

[0202] (1) Preparation of intermediate 1f

[0203]

[0204] 2-Chloropyrimidine-5-carboxylic acid (284 g, 1.78 mol) and 8-oxa-2-azaspiro[4.5]decane hydrochloride (310 g, 1.78 mol) were dissolved in dichloromethane and cooled to -10°C. T3P (625 g, 1.78 mol) was slowly added dropwise. After complete addition, the reaction was continued at this temperature for 2 hours. After completion of the reaction, as determined by LCMS, water was added and stirred. Solids precipitated, which were filtered and dried to afford compound 1f (350 g, 98% purity).

[0205] 1 H NMR (400MHz, CDCl3): δ8.80(s,2H),3.81-3.57(m,7H),3.36(s,1H),1.93(td, J=14.58,7.25Hz,2H),1.66(t,J=5.35Hz,2H),1.58(dd,J=11.10,4.64Hz,2H).

[0206] (2) Preparation of compound of formula I

[0207]

[0208] first step

[0209] Compound 1b (385 g, 3.18 mol) and tetraethyl titanate (905 g, 3.97 mol) were dissolved in toluene (3 L), stirred, heated to 110°C, and refluxed; a toluene solution (500 mL) of compound 1a (352 g, 2.65 mol) was added dropwise to the reaction mixture. After the addition was complete, heating and reflux were continued for 1 hour. After the reaction was completed, the reaction was stopped, cooled to room temperature, and concentrated to remove toluene. The residue was quenched with water (400 mL), diluted with 1000 mL of ethyl acetate, and filtered through celite. The filtrate was separated, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The residue was stirred with MTBE (100 mL) and petroleum ether (300 mL), filtered, and the filtrate was concentrated to obtain compound 1c (500 g, yield: 80%).

[0210] Step 2

[0211] Compound 1c (500 g, 2.1 mol) was dissolved in THF (3000 mL), cooled to -60°C, and then lithium L-tri-sec-butylborohydride (2510 mL, 2.51 mol) was slowly added dropwise. The mixture was stirred at -60°C. After the reaction was complete, 1000 mL of water was slowly added to quench the reaction. Most of the THF was removed by concentration. Extraction was performed with ethyl acetate (500 mL x 3), and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), and dried. The solvent was removed by distillation under reduced pressure, and the crude product 1d was used directly in the next step.

[0212] Step 3

[0213] The crude product 1d was dissolved in methanol (500 mL) and HCl / MeOH (200 mL 4 M) was slowly added. The reaction mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated to obtain an oil, which was then added with ethyl acetate (100 mL) and stirred. After filtration, compound 1e was obtained as a red solid powder (300 g, ee value 98%, purity 99%).

[0214] Step 4

[0215] Compound 1e (284 g, 1.375 mol), compound 1f (350 g, 1.25 mol), and K2CO3 (862.5 g, 6.25 mol) were dissolved in isopropanol (400 mL) and heated under reflux overnight. After completion of the reaction, the mixture was cooled, filtered, and the filtrate concentrated. The residue was dissolved in water (300 mL) and adjusted to a pH of 8-9 with dilute hydrochloric acid (2N). The mixture was extracted with dichloromethane (200 mL x 3), washed with saturated sodium chloride solution (200 mL x 1), dried, and concentrated to yield the compound of Formula I (374 g).

[0216] 1 H NMR (400MHz, CD3OD) δ8.58(s,2H),8.37(d,J=5.1Hz,1H),7.77(s,1H),7.26(d,J=2.5Hz, 1H),5.72(t,J=7.7Hz,1H),4.53(s,2H),3.80–3.58(m,7H),3.54(d,J=18.8Hz,2H),3.15 (ddd,J=16.9,9.2,3.7Hz,1H),3.02(dt,J=16.8,8.5Hz,1H),2.68(dq,J=12.8,4.4Hz,1H ), 2.14–2.02(m,1H),1.93(q,J=8.1Hz,2H),1.67(d,J=5.8Hz,2H),1.59(d,J=5.7Hz,2H).

[0217] Example 1 Preparation of the Mono-L-Tartrate of the Compound of Formula I

[0218]

[0219] Dissolve 1 g of the compound of formula I in 18 ml of acetone, add 1.24 ml of a 2 mol / L ethanol solution of L-tartaric acid, and stir overnight. Then, add 18 ml of isopropyl acetate to obtain a solid, filter, and dry under reduced pressure to obtain the L-tartrate salt of the compound of formula I (the molar ratio of the compound of formula I to L-tartaric acid is 1:1, i.e., the mono-L-tartrate salt is obtained).

[0220] 50 mg of the L-tartrate salt of the compound of Formula I was placed in an 8 mL glass vial. 1 mL of methanol was added and dissolved by sonication. The resulting solution was filtered, and the filtrate was transferred to a new 8 mL glass vial. The open 8 mL glass vial was placed in a 40 mL glass vial containing 4 mL of methyl tert-butyl ether. The cap of the 40 mL glass vial was tightened and allowed to stand to grow single crystals. The single crystal data for the mono-L-tartrate salt of the compound of Formula I are as follows:

[0221]

[0222]

[0223] Single crystals of the mono L-tartrate salt of the compound of formula I are as follows Figure 19 shown.

[0224] Example 2 Preparation of Fumarate Salt of Formula I Compound

[0225] Dissolve 536 mg of the compound of formula I in 10 ml of acetone, add 161.4 mg of fumaric acid, and stir overnight. Then add 10 ml of isopropyl acetate and stir to obtain a solid. Filter and dry under reduced pressure to obtain a fumarate salt of the compound of formula I.

[0226] Example 3 Preparation of D-malate of Formula I Compound

[0227] 517 mg of the compound of formula I was dissolved in 10 ml of isopropyl acetate, 187.4 mg of D-malic acid was added, and the solution became viscous after stirring. 10 ml of isopropyl acetate was then added to obtain a white viscous solid, which was filtered and dried under reduced pressure to obtain D-malate of the compound of formula I.

[0228] Example 4 Stability Test of Mono L-Tartrate, Fumarate, and D-Malate of Formula I Compound

[0229] The stability of the mono L-tartrate, fumarate and D-malate salts of the compound of formula I obtained in Examples 1-3 was investigated.

[0230] Stability test conditions: 40℃ / 75%RH-closed, 40℃ / 75%RH-open, 60℃-closed; Stability test content: changes in related substances and crystal forms.

[0231] Related Substance Detection: Weigh approximately 5 mg of sample into a 40 mL vial, dissolve in 10 mL of 50% acetonitrile aqueous solution, dilute to volume, and inject 5 μL. Chromatographic conditions are shown in Table 5.

[0232] The results of the stability test of the mono L-tartrate, fumarate and D-malate salts of the compound of formula I are shown in Table 6.

[0233] Table 5 Chromatographic conditions for related substance testing

[0234]

[0235]

[0236] Table 6 Results of stability study of mono-L-tartrate, fumarate and D-malate salts of Formula I

[0237]

[0238] As can be seen from Table 6, the chemical stability of the L-tartrate, fumarate and D-malate salts of the compound of formula I remains good after being subjected to accelerated high humidity and high temperature conditions, especially the L-tartrate salt of the compound of formula I.

[0239] Example 5 Solubility Test of Formula I Compound and Its L-Tartrate, Fumarate, and D-Malate

[0240] The solubility of the compound of formula I and its L-tartrate, fumarate and D-malate in water, SGF, FaSSIF and FeSSIF at pH 7.4 at 37°C was investigated.

[0241] Experimental Method: Weigh 30 mg (in water) or 15 mg of sample into a 4 mL vial. Add 3 mL of the test medium and stir continuously at 37°C. After 1 hour and 24 hours, remove 0.5 mL of the sample and centrifuge at 12,000 rpm for 5 minutes. Dilute the supernatant with 50% acetonitrile and determine its concentration. Chromatographic conditions for the solubility test are shown in Table 7.

[0242] Reference Standard and Linearity: Because Formula I is highly hygroscopic and contains numerous impurities, it is not suitable for use as a reference. Therefore, weigh 13 mg of the fumarate salt of Formula I into a 25 mL volumetric flask (approximately 10 mg of the free base per 25 mL volumetric flask). Dissolve in 50% acetonitrile solution and dilute to volume. Prepare two replicates. Dilute STD-1 to 200 μg / mL, 50 μg / mL, and 10 μg / mL with 50% acetonitrile solution. Inject 5 μL of each sample to plot the standard curve.

[0243] The solubility test results of the compound of formula I and its L-tartrate, fumarate, and D-malate are shown in Table 8.

[0244] Table 7 Solubility test chromatographic conditions

[0245]

[0246] Table 8 Solubility test results of the compound of formula I and its L-tartrate, fumarate, and D-malate

[0247]

[0248]

[0249] As can be seen from Table 8, the compound of Formula I and its mono-L-tartrate, fumarate, and D-malate salts all have good solubility and are completely soluble in each medium to the target concentration of 5 mg / mL or 10 mg / mL, calculated as the free base.

[0250] Example 6 Preparation Method of Crystal Form A

[0251] 400 mg of the mono-L-tartrate salt of the compound of formula I (prepared according to Example 1) was added with 10 mL of acetone, stirred, centrifuged, and dried under reduced pressure and vacuum at 40° C. to obtain Form A.

[0252] Form A was characterized by XRPD, DSC, TGA and PLM.

[0253] The crystal form A is anhydrous. The XRPD characteristic peak positions and intensities are shown in Table 1, and the XRPD spectrum is shown in Table 1. Figure 1 .

[0254] DSC shows that the first endothermic peak appears near the peak temperature of 150.14 °C. Figure 2 shown.

[0255] TGA showed a weight loss of about 0.069% in the range of 22.03°C to 120°C. Figure 3 shown.

[0256] The PLM image shows that the sample is an irregular morphology crystal with a diameter less than 10 μm, such as Figure 4 shown.

[0257] The XRPD pattern of Form A is an X-ray powder diffraction pattern expressed in 2θ angles, and the 2θ values are shown in Table A:

[0258] Table A XRPD analysis data of Form A

[0259] Peak number <![CDATA[2θ[ ° ]]]> Relative strength % Peak number <![CDATA[2θ[ ° ]]]> Relative strength % 1 8.30 28.3 17 26.90 10.2 2 10.22 11.9 18 28.44 11.9 3 12.44 8 19 28.92 19.4 4 14.24 24.2 20 30.30 9.1 5 15.60 20.4 21 31.10 8.4 6 17.06 70.8 22 32.52 17.2 7 18.00 54.4 23 34.60 15.7 8 18.80 60 24 35.16 13.4 9 19.22 51 25 36.28 10.7 10 20.06 95.8 26 38.12 11 11 20.52 32.6 27 39.28 8.2 12 22.58 100 28 39.88 5.6 13 23.72 63.4 29 40.90 8.7 14 24.38 55.2 30 41.54 4.8 15 25.32 18.7 31 45.52 6.2 16 25.70 31.1 32 49.06 4.4

[0260] Example 7 Preparation Method of Form A

[0261] 500 mg of the mono-L-tartrate of the compound of formula I (prepared according to Example 1) was dissolved in 10 ml of methanol, and then 60 ml of methyl tert-butyl ether was added and stirred for 1.5 h. The mixture was centrifuged, filtered, and dried to obtain the crystalline form A.

[0262] The XRPD pattern of the crystalline form A is as follows Figure 15 shown.

[0263] Example 8 Preparation Method of Form B

[0264] Form B was obtained by exposing 500 mg of the mono L-tartrate Form A of the compound of Formula I to 92.5% RH for 3 days.

[0265] Form B was characterized by XRPD, DSC, TGA and PLM.

[0266] The crystal form B is a hydrate containing 0.5 to 1 mol of water. The XRPD characteristic peak positions and intensities are shown in Table B, and the XRPD spectrum is shown in Table B. Figure 5 .

[0267] DSC shows that the first endothermic peak appears near the peak temperature of 61.57℃, and the second endothermic peak appears near the peak temperature of 152.18℃. Figure 6 shown.

[0268] TGA showed a weight loss of about 2.76% in the range of 22.03°C to 120°C. Figure 7 shown.

[0269] The XRPD pattern of Form B is an X-ray powder diffraction pattern expressed in 2θ angles, and the 2θ values are shown in Table B:

[0270] Table B XRPD analysis data of Form B

[0271] Peak number <![CDATA[2θ[ ° ]]]> Relative strength % Peak number <![CDATA[2θ[ ° ]]]> Relative strength % 1 3.78 23 21 26.72 22 2 7.56 58.2 22 28.56 15.6 3 10.62 7.7 23 29.52 37.9 4 14.16 16.5 24 30.66 16.5 5 15.06 19.6 25 31.20 15.4 6 15.62 14.1 26 33.16 17.5 7 16.48 22.4 27 33.78 17 8 17.36 60.1 28 34.58 12.7 9 18.14 27.2 29 35.12 20.4 10 18.58 21.6 30 35.60 8.6 11 19.28 100 31 36.42 7.9 12 19.94 98.2 32 38.20 11.3 13 21.30 72.9 33 39.60 4 14 22.56 16 34 40.36 7.3 15 22.90 4.6 35 41.02 3.5 16 23.72 70.9 36 42.20 5.8 17 24.52 28 37 43.98 8.5 18 25.00 14 38 45.08 6.7 19 25.42 11.3 39 47.32 6.1 20 26.02 51.3

[0272] Example 9 Preparation Method of Form B

[0273] 414 mg of the mono-L-tartrate salt of the compound of formula I (prepared according to Example 1) was added to 10 mL of methanol to completely dissolve it. The solvent was then evaporated naturally to obtain a white solid, which was dried under reduced pressure to obtain Form B.

[0274] The XRPD of the crystalline form B is as follows Figure 16 shown.

[0275] Example 10 Preparation method of crystal form C

[0276] 410 mg of the mono-L-tartrate salt of the compound of Formula I (prepared according to Example 1) was added to 16 mL of ethanol and stirred at 50°C for 1 day. After cooling to room temperature, a white solid precipitated, which was filtered and dried under reduced pressure to obtain Form C.

[0277] Form C was characterized by XRPD, DSC, TGA and PLM.

[0278] The crystalline form C is an ethanol solvate.

[0279] The XRPD characteristic peak positions and intensities are shown in Table C, and the XRPD patterns are shown in Table Figure 8 .

[0280] DSC shows that the first endothermic peak appears near the peak temperature of 129.45℃. Figure 9 shown.

[0281] TGA showed a weight loss of about 4.59% in the range of 21.47°C to 150°C. Figure 10 shown.

[0282] The XRPD pattern of Form C is an X-ray powder diffraction pattern expressed in 2θ angles, and the 2θ values are shown in Table C:

[0283] Table C XRPD analysis data of Form C

[0284] Peak number <![CDATA[2θ[ ° ]]]> Relative strength % Peak number <![CDATA[2θ[ ° ]]]> Relative strength % 1 3.58 28.6 13 24.38 12.5 2 7.14 51.6 14 25.00 7.7 3 10.46 17.3 15 25.92 36.6 4 12.22 9.2 16 27.58 9.1 5 13.96 26.5 17 28.06 11 6 14.56 17.5 18 29.38 21 7 17.10 35 19 30.22 5.1 8 17.88 77.1 20 30.78 12.3 9 19.40 75 21 33.66 9.1 10 20.06 48.8 22 35.24 8.9 11 21.38 100 23 37.40 5.6 12 23.76 49.1 24 38.86 4.2

[0285] The PLM image shows that the sample is an irregular morphology crystal with a diameter less than 10 μm, such as Figure 11 shown.

[0286] Example 11 Preparation method of crystal form D

[0287] 410 mg of the mono-L-tartrate salt of the compound of formula I (prepared according to Example 1) was added to 12 mL of tetrahydrofuran and stirred at 50°C for 1 day. After cooling to room temperature, a white solid precipitated, which was filtered and dried under reduced pressure to obtain Form D.

[0288] Form D was characterized by XRPD, DSC and TGA.

[0289] The crystalline form D is a tetrahydrofuran solvate.

[0290] The XRPD characteristic peak positions and intensities are shown in Table D, and the XRPD patterns are shown in Table D. Figure 12 .

[0291] DSC shows that the first endothermic peak appears near the peak temperature of 94.15℃. Figure 13 shown.

[0292] TGA showed a weight loss of about 5.25% in the range of 23.19°C to 120°C. Figure 14 shown.

[0293] The XRPD pattern of Form D is an X-ray powder diffraction pattern expressed in 2θ angles, and the 2θ values are shown in Table D:

[0294] Table D XRPD analytical data of Form D

[0295]

[0296]

[0297] Example 12 Stability Study of Form A

[0298] Form A was placed under 40°C / 75% RH-open, 60°C-open, 80% RH-open, and 92.5% RH-open conditions, and taken out after 3 days to observe whether its crystal form changed.

[0299] In addition, samples stored at 40°C / 75% RH-closed, 40°C / 75% RH-open, and 60°C-open were taken out after 2 weeks for stability testing, including related substances and crystal forms.

[0300] Method for detecting related substances in stability samples: Weigh approximately 5 mg of sample, add 5 mL of 20% methanol, sonicate for a few seconds until the compound can be completely dissolved, and inject 5 μL for related substance testing.

[0301] The XRPD patterns of Form A after being placed under high temperature and high humidity conditions for 3 days and 2 weeks are Figure 17 and Figure 18 shown.

[0302] Chromatographic conditions:

[0303]

[0304] Table 9 Stability test results of Form A

[0305]

[0306]

[0307] From Table 9, Figure 17 and Figure 18 As shown, the crystal form A did not change under the conditions of 60°C and 80% RH, which indicates that the crystal form A has good stability.

[0308] Example 13 Solubility Study of Form A

[0309] The solubility of Form A in SGF, FaSSIF, and FeSSIF at pH 7.4 was evaluated.

[0310] Weigh 20 mg of the raw material into a vial, add 3 mL of the medium, and observe its dissolution at 37°C.

[0311] Table 10 Solubility test results of the mono-L-tartrate crystal form A of the compound of formula I (37°C)

[0312]

[0313] As can be seen from Table 10, the solubility of Form A in various media is good.

[0314] The above is a description of specific embodiments of the present invention. It should be understood that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for the purpose of illustrating the principles of the present invention. Those skilled in the art may make various non-substantial changes and improvements to the present invention without departing from the scope of the present invention, and all of these fall within the scope of protection claimed in the present invention.

Claims

1. A pharmaceutically acceptable salt of a compound of formula I, wherein the compound of formula I is as follows: The pharmaceutically acceptable salt of the compound of formula I is a salt formed by the compound of formula I and an acid, wherein the acid is selected from L-tartrate, fumarate and D-malate.

2. The pharmaceutically acceptable salt of the compound of formula I according to claim 1, characterized in that: The pharmaceutically acceptable salt of the compound of formula I is selected from the monotartrate, monofumarate and monomalate of the compound of formula I.

3. A method for preparing a pharmaceutically acceptable salt of a compound of formula I according to claim 1 or 2, comprising reacting the compound of formula I with the acid to prepare the pharmaceutically acceptable salt of the compound of formula I.

4. The preparation method according to claim 3, characterized in that The preparation method comprises dissolving a compound of formula I in an organic solvent A, adding an acid to react; and then adding an organic solvent B to prepare a pharmaceutically acceptable salt of the compound of formula I; the organic solvent A is selected from at least one of esters, ketones, and alcohols; and the organic solvent B is selected from nitriles, esters, ethers, or a combination thereof.

5. The preparation method according to claim 4, characterized in that The acid is first dissolved in an organic solvent C to prepare an acid solution and then added to the reaction.

6. The preparation method according to claim 5, characterized in that When the acid is selected from L-tartaric acid, the organic solvent C is selected from alcohols.

7. A crystalline form of a pharmaceutically acceptable salt of a compound of formula I according to claim 1, characterized in that: The crystal form is the crystal form A of the mono L-tartrate salt of the compound of formula I. The crystal form A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.06±0.20°, 18.00±0.20°, 18.80±0.20°, 19.22±0.20°, 20.06±0.20°, 22.58±0.20°, 23.72±0.20°, and 24.38±0.20°.

8. The crystalline form A of the mono-L-tartrate salt of the compound of formula I according to claim 7, characterized in that: The crystalline form A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.30±0.20°, 14.24±0.20°, 17.06±0.20°, 18.00±0.20°, 18.80±0.20°, 19.22±0.20°, 20.06±0.20°, 20.52±0.20°, 22.58±0.20°, 23.72±0.20°, 24.38±0.20°, and 25.70±0.20°.

9. The crystalline form A of the mono-L-tartrate salt of the compound of formula I according to claim 7, characterized in that: The X-ray powder diffraction of the crystalline form A using Cu-Kα radiation and expressed in 2θ angles is shown in Table 1, with an error range of ±0.20°.

10. The crystalline form A of the mono L-tartrate salt of the compound of formula I according to claim 7, characterized in that: The crystalline form A has a powder X-ray diffraction pattern substantially as shown in FIG1 ; The crystalline form A is the anhydrate of L-tartrate of the compound of formula I.

11. The crystalline form A of the mono L-tartrate salt of the compound of formula I according to claim 7, characterized in that: Differential scanning calorimetry (DSC) analysis of the crystalline form A showed that the first endothermic peak appeared near the peak temperature of 150.14°C.

12. The crystalline form A of the mono L-tartrate salt of the compound of formula I according to claim 7, characterized in that: The crystalline form A has a DSC graph substantially as shown in FIG2 .

13. The crystalline form A of the mono L-tartrate salt of the compound of formula I according to claim 7, characterized in that: Thermogravimetric analysis (TGA) of the crystalline form A showed a weight loss of about 0.069% in the range of 22.03°C to 120°C.

14. The crystalline form A of the mono L-tartrate salt of the compound of formula I according to claim 7, characterized in that: The crystalline form A has a TGA graph substantially as shown in FIG3 .

15. The crystalline form of a pharmaceutically acceptable salt of the compound of formula I according to claim 1, characterized in that: The crystal form is the crystal form B of the mono L-tartrate salt of the compound of formula I. The crystal form B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.56±0.20°, 17.36±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, and 26.02±0.20°.

16. The crystalline form B of the mono L-tartrate salt of the compound of formula I according to claim 15, characterized in that: The crystalline form B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.56±0.20°, 17.36±0.20°, 18.14±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, 24.52±0.20°, 26.02±0.20°, and 29.52±0.20°.

17. The crystalline form B of the mono L-tartrate salt of the compound of formula I according to claim 15, characterized in that: The crystalline form B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.78±0.20°, 7.56±0.20°, 17.36±0.20°, 18.14±0.20°, 19.28±0.20°, 19.94±0.20°, 21.30±0.20°, 23.72±0.20°, 24.52±0.20°, 26.02±0.20°, and 29.52±0.20°.

18. The crystalline form B of the mono-L-tartrate salt of the compound of formula I according to claim 15, characterized in that: The X-ray powder diffraction of the crystalline form B using Cu-Kα radiation and expressed in 2θ angles is shown in Table 2, with an error range of ±0.20°.

19. The crystalline form B of the mono-L-tartrate salt of the compound of formula I according to claim 15, characterized in that: The crystalline form B has a powder X-ray diffraction pattern substantially as shown in FIG5 ; The crystalline form B is a hydrate of L-tartrate of the compound of formula I.

20. The crystalline form B of the mono L-tartrate salt of the compound of formula I according to claim 15, characterized in that: Differential scanning calorimetry (DSC) analysis of the crystalline form B showed that a first endothermic peak appeared near the peak temperature of 61.57°C when heated, and a second endothermic peak appeared near the peak temperature of 152.18°C when heated.

21. The crystalline form B of the mono-L-tartrate salt of the compound of formula I according to claim 15, characterized in that: The crystalline form B has a DSC graph substantially as shown in FIG6 .

22. The crystalline form B of the mono-L-tartrate salt of the compound of formula I according to claim 15, characterized in that: Thermogravimetric analysis (TGA) of the crystalline form B showed a weight loss of about 2.76% in the range of 21.34°C to 120°C.

23. The crystalline form B of the mono L-tartrate salt of the compound of formula I according to claim 15, characterized in that: The crystalline form B has a TGA graph substantially as shown in FIG7 .

24. A crystalline form of a pharmaceutically acceptable salt of a compound of formula I according to claim 1, characterized in that: The crystal form is the crystal form C of the mono L-tartrate salt of the compound of formula I. The crystal form C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.14±0.20°, 17.88±0.20°, 19.40±0.20°, 20.06±0.20°, 21.38±0.20°, 23.76±0.20°, and 25.92±0.20°.

25. The crystalline form C of the mono L-tartrate salt of the compound of formula I according to claim 24, characterized in that The crystalline form C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.58±0.20°, 7.14±0.20°, 13.96±0.20°, 17.10±0.20°, 17.88±0.20°, 19.40±0.20°, 20.06±0.20°, 21.38±0.20°, 25.92±0.20°, and 29.38±0.20°.

26. The crystalline form C of the mono-L-tartrate salt of the compound of formula I according to claim 24, characterized in that The X-ray powder diffraction of the crystalline form C using Cu-Kα radiation and expressed in 2θ angles is shown in Table 3, with an error range of ±0.20°.

27. The crystalline form C of the mono-L-tartrate salt of the compound of formula I according to claim 24, characterized in that The Form C has a powder X-ray diffraction pattern substantially as shown in FIG8 .

28. The crystalline form C of the mono-L-tartrate salt of the compound of formula I according to claim 24, characterized in that: The crystalline form C is an ethanol solvate of L-tartrate of the compound of formula I.

29. The crystalline form C of the mono-L-tartrate salt of the compound of formula I according to claim 24, characterized in that: Differential scanning calorimetry (DSC) analysis of the crystalline form C showed that a first endothermic peak appeared near a peak temperature of 129.45° C. when heated, and a second endothermic peak appeared near a peak temperature of 151.90° C. when heated.

30. The crystalline form C of the mono L-tartrate salt of the compound of formula I according to claim 24, characterized in that The crystalline form C has a DSC graph substantially as shown in FIG9 .

31. The crystalline form C of the mono-L-tartrate salt of the compound of formula I according to claim 24, characterized in that: Thermogravimetric analysis (TGA) of the Form C showed a weight loss of about 4.59% in the range of 21.47°C to 150°C.

32. The crystalline form C of the mono-L-tartrate salt of the compound of formula I according to claim 24, characterized in that: The crystalline form C has a TGA graph substantially as shown in FIG10 .

33. A crystalline form of a pharmaceutically acceptable salt of a compound of formula I according to claim 1, characterized in that: The crystal form is the crystal form D of the mono L-tartrate salt of the compound of formula I. The crystal form D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.50±0.20°, 6.92±0.20°, 7.46±0.20°, 17.22±0.20°, 18.20±0.20°, 19.88±0.20°, and 23.04±0.20°.

34. The crystalline form D of the mono-L-tartrate salt of the compound of formula I according to claim 33, characterized in that: The crystalline form D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.50±0.20°, 6.92±0.20°, 7.46±0.20°, 17.22±0.20°, 18.20±0.20°, 19.88±0.20°, 20.76±0.20°, 23.04±0.20°, and 25.62±0.20°.

35. The crystalline form D of the mono-L-tartrate salt of the compound of formula I according to claim 33, characterized in that: The X-ray powder diffraction of the crystalline form D using Cu-Kα radiation and expressed in 2θ angles is shown in Table 4, with an error range of ±0.20°.

36. The crystalline form D of the mono L-tartrate salt of the compound of formula I according to claim 33, characterized in that The crystalline form D has a powder X-ray diffraction pattern substantially as shown in FIG12 .

37. The crystalline form D of the mono-L-tartrate salt of the compound of formula I according to claim 33, characterized in that The crystalline form D is a tetrahydrofuran solvate of L-tartrate of the compound of formula I.

38. The crystalline form D of the mono L-tartrate salt of the compound of formula I according to claim 33, characterized in that: Differential scanning calorimetry (DSC) analysis of the crystalline form D showed that a first endothermic peak appeared near the peak temperature of 94.15°C, a second endothermic peak appeared near the peak temperature of 118.79°C, and a third endothermic peak appeared near the peak temperature of 146.04°C.

39. The crystalline form D of the mono-L-tartrate salt of the compound of formula I according to claim 33, characterized in that: The crystalline form D has a DSC graph substantially as shown in FIG13 .

40. The crystalline form D of the mono L-tartrate salt of the compound of formula I according to claim 33, characterized in that Thermogravimetric analysis (TGA) of the crystalline form D showed a weight loss of about 5.25% in the range of 23.19°C to 120°C.

41. The crystalline form D of the mono-L-tartrate salt of the compound of formula I according to claim 33, characterized in that The crystalline form D has a TGA graph substantially as shown in FIG14 .

42. The method for preparing the crystal form according to any one of claims 7 to 14, characterized in that: The first method for preparing the mono L-tartrate crystalline form A of the compound of formula I comprises: stirring the mono L-tartrate crystalline form A of the compound of formula I in a solvent to obtain the mono L-tartrate crystalline form A; The stirring temperature is 20-80° C.; the solvent is selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, alkane solvents, halogenated hydrocarbon solvents and nitrile solvents or a combination thereof.

43. The method for preparing the crystal form according to claim 42, wherein: The mass volume ratio of the mono L-tartrate salt of the compound of formula I to the solvent is 1 g: (20-40) ml.

44. The method for preparing the crystal form according to any one of claims 7 to 14, characterized in that: The second method for preparing the L-tartrate crystal form A of the compound of formula I comprises: dissolving the mono-L-tartrate of the compound of formula I in an alcohol solvent, and then adding an anti-solvent and stirring to obtain the crystal form A; The alcohol solvent is selected from one of methanol, ethanol, propanol and isopropanol; the anti-solvent is one or more of ether solvents or ester solvents.

45. The method for preparing the crystal form according to claim 44, wherein: The mass volume ratio of the mono-L-tartrate salt of the compound of formula I to the alcohol solvent and the anti-solvent is 1 g: (10-30) ml: (80-120) ml.

46. The method for preparing the crystal form according to any one of claims 42 to 45, characterized in that: The preparation method one or two of the crystal form A further includes filtration and drying post-processing steps.

47. The method for preparing the crystal form according to any one of claims 15 to 23, wherein: The first method for preparing the mono L-tartrate crystal form B of the compound of formula I comprises placing the crystal form A under high humidity conditions to obtain the crystal form B; the high humidity conditions are 80% to 100% RH.

48. The method for preparing the crystal form according to claim 47, wherein: The high humidity condition is 90% to 100% RH.

49. The method for preparing the crystal form according to any one of claims 15 to 23, wherein: The second method for preparing the mono-L-tartrate crystalline form B of the compound of formula I comprises dissolving the mono-L-tartrate crystalline form B of the compound of formula I in an alcohol solvent, and obtaining the crystalline form B after evaporation of the solvent; The alcohol solvent is selected from one of methanol, ethanol and isopropanol; and the dissolution temperature is 15-45°C.

50. The method for preparing the crystal form according to claim 49, wherein: The mass volume ratio of the mono L-tartrate of the compound of formula I to the alcohol solvent is 1g:(10-30)ml.

51. The method for preparing the crystal form according to any one of claims 24 to 32, wherein: The preparation method of the mono L-tartrate crystal form C of the compound of formula I comprises dissolving the mono L-tartrate of the compound of formula I in an alcohol solvent and crystallizing to obtain the crystal form C; the alcohol solvent is selected from methanol, ethanol and / or isopropanol.

52. The method for preparing the crystal form according to claim 51, wherein: The mass volume ratio of the mono L-tartrate of the compound of formula I to the alcohol solvent is 1g:(20-40)ml.

53. The method for preparing the crystal form according to claim 51 or 52, wherein: The preparation method of the crystal form C further includes filtering and drying post-processing steps.

54. The method for preparing the crystal form according to any one of claims 33 to 41, characterized in that: The preparation method of the mono L-tartrate crystalline form D of the compound of formula I comprises dissolving the mono L-tartrate of the compound of formula I in an ether solvent, heating and stirring, cooling, and precipitating a solid to obtain the crystalline form D; the ether solvent is selected from one of diethyl ether, tetrahydrofuran, and methyl tert-butyl ether.

55. The method for preparing the crystal form according to claim 54, wherein: The heating temperature is 30°C to 80°C; the cooling temperature is 20°C to 30°C; the mass volume ratio of the mono L-tartrate salt of the compound of formula I to the ether solvent is 1g:(20-40)ml.

56. The method for preparing the crystal form according to claim 54 or 55, wherein: The preparation method of the crystal form D includes filtration and drying post-processing steps.

57. A pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula I according to any one of claims 1-2 or a crystalline form according to any one of claims 7-41, and optionally a pharmaceutically acceptable excipient.

58. The pharmaceutical composition according to claim 57, characterized in that The pharmaceutical composition is in the form of a preparation.

59. Use of a pharmaceutically acceptable salt of the compound of formula I according to any one of claims 1 to 2, or a crystalline form according to any one of claims 7 to 41, or a pharmaceutical composition according to claim 57 in the preparation of a medicament for preventing and / or treating diseases or conditions associated with Vanin enzyme inhibitors.

60. The use according to claim 59, characterized in that The disease or condition is selected from one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases.

61. The use according to claim 59, characterized in that The disease or disorder is selected from Crohn's disease, inflammatory bowel disease, ulcerative colitis.

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