CN118184660A - Benzodiazepine compound salt, salt crystal form, preparation method and application - Google Patents

Abstract

The present invention provides a benzodiazepineSalts of compounds, crystalline forms of the salts, methods of preparation and use, in particular 7-chloro-3- (5-dimethylaminomethyl- [1,2,4] oxadiazol-3-yl) -5-methyl-4, 5-dihydro-imidazo [1,5-a ] [1,4] benzodiazepineSalts of 6-ketones, crystalline forms of salts and methods for their preparation, and their use in the manufacture of a medicament for anxiolytic and/or anticonvulsant and/or non-sedative hypnotic agents. The invention provides 7-chloro-3- (5-dimethylaminomethyl- [1,2,4] oxadiazol-3-yl) -5-methyl-4, 5-dihydro-imidazo [1,5-a ] [1,4] benzodiazepineThe salt of the-6-ketone and the crystal form thereof have the advantages of good solubility, high stability, high biological activity, low toxicity and the like, and can be better used for clinic.

Description

Benzodiazepine compound salt, salt crystal form, preparation method and application

Technical Field

The invention belongs to the technical field of medicines, and relates to a benzodiazepineSalts of compounds, crystalline forms of salts, methods of preparation and use thereof, in particular to 7-chloro-3- (5-dimethylaminomethyl- [1,2,4] oxadiazol-3-yl) -5-methyl-4, 5-dihydro-imidazo [1,5-a ] [1,4] benzodiazepineSalts of 6-ketones, crystalline forms of salts and methods for their preparation, and their use in the manufacture of a medicament for anxiolytic and/or anticonvulsant and/or non-sedative hypnotic agents.

Background

Patent WO2000069858A1 discloses imidazodiazaDerivatives, one example of which is disclosed is 7-chloro-3- (5-dimethylaminomethyl- [1,2,4] oxadiazol-3-yl) -5-methyl-4, 5-dihydro-imidazo [1,5-a ] [1,4] benzodiazepine-6-Ones (compounds of formula I) which exhibit high in vivo and in vitro activity binding to benzodiazepine receptors and which exhibit rapid onset and powerful therapeutic effects in such indications as anxiety disorders, insomnia, affective disorders, psychotic symptoms and disorders.

For pharmaceutical compositions, the pharmaceutically active ingredient present in the composition exhibits suitable physical, physicochemical and chemical properties, for example, solubility, chemical purity and stability, crystalline purity and stability, hygroscopicity, tabletting properties, powder properties, and the like of the pharmaceutically active ingredient. Patent CN109134471B and its PCT application (PCT/CN 2018/092820) disclose that both crystalline forms and one amorphous form of the compound of formula I, the disclosed free base has a low solubility in water, which is detrimental to drug dissolution in animals or humans.

Disclosure of Invention

The invention aims at the defects existing in the prior art and provides 7-chloro-3- (5-dimethylaminomethyl- [1,2,4] oxadiazol-3-yl) -5-methyl-4, 5-dihydro-imidazo [1,5-a ] [1,4] benzodiazepine which meets the basic requirements of pharmaceutical active ingredientsSalts of 6-ones (compounds of formula I) and crystalline forms thereof, and processes for their preparation and use.

The present invention provides a salt of a compound of formula I:

The acid salt of the compound of formula I is a salt of the compound of formula I with an acidic reagent, including an organic acid salt or an inorganic acid salt. Wherein the organic acid salt is prepared from organic acid, and the organic acid can be acetic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, salicylic acid, citric acid, gluconic acid, L-lactic acid, D/L-lactic acid, malic acid, aspartic acid, glutamic acid or cinnamic acid; the inorganic acid salt is made of inorganic acid, and the inorganic acid can be hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid or phosphoric acid, etc.

In some embodiments, the salt of the compound of formula I may be a hydrochloride, hydrobromide, phosphate, nitrate, tartrate, mesylate, besylate, or L-lactate salt.

In some embodiments, the acid salt of the compound of formula I is a salt to which a non-toxic acid is added.

In some embodiments, the salt of the compound of formula I is a crystalline salt.

In some embodiments, the salt of the compound of formula I is a crystalline hydrochloride salt, and the X-ray powder diffraction pattern of the hydrochloride salt form a of the compound of formula I has characteristic peaks at five or more positions in 2θ 7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、22.82±0.2°、25.26±0.2°、26.4±0.2°.

In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt form a of the compound of formula I has characteristic peaks at 7.58±0.2°, 9.44±0.2°, 11.26±0.2°, 17.94±0.2° and 26.4±0.2°, optionally further comprising characteristic peaks at 13.58±0.2°, 15.68±0.2°, 16.20±0.2°, 22.82±0.1° and 25.26±0.2° in 2θ.

For example, the X-ray powder diffraction pattern of the hydrochloride salt form a of the compound of formula I optionally has characteristic peaks at the following positions in 2θ:

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、13.58±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、15.68±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、16.20±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、22.82±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、25.26±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、13.58±0.2°、15.68±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、13.58±0.2°、16.20±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、13.58±0.2°、22.82±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、13.58±0.2°、25.26±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、15.68±0.2°、16.20±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、15.68±0.2°、22.82±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、15.68±0.2°、25.26±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、16.20±0.2°、22.82±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、16.20±0.2°、25.26±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、17.94±0.2°、26.4±0.2°、22.82±0.2°、25.26±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、15.68±0.2°、17.94±0.2°、22.82±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、15.68±0.2°、17.94±0.2°、25.26±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、16.20±0.2°、17.94±0.2°、22.82±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、16.20±0.2°、17.94±0.2°、25.26±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、17.94±0.2°、22.82±0.2°、25.26±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、22.82±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、25.26±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、16.20±0.2°、17.94±0.2°、22.82±0.2°、25.26±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、22.82±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、25.26±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、22.82±0.2°、25.26±0.2°、26.4±0.2°；

7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、22.82±0.2°、25.26±0.2°、26.4±0.2°.

In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt form a of the compound of formula I is substantially the same as the peak at the diffraction angle (2θ) shown in fig. 1, and the X-ray powder diffraction data of the hydrochloride salt form a of the compound of formula I is shown in table 1:

TABLE 1

In some embodiments, the X-ray powder diffraction pattern of hydrochloride form B of the compound of formula I has characteristic peaks at five or more positions in 2θ of 7.60±0.2°, 12.78±0.2°, 16.76±0.2°, 18.02±0.2°, 18.70±0.2°, 21.48±0.2°, 26.42±0.2°, 27.38±0.2°, 31.00±0.2°.

In some embodiments, the present invention provides an X-ray powder diffraction pattern of the hydrochloride salt form B of the compound of formula I having characteristic peaks at 2Θ of 12.78±0.2 °, 16.76±0.2 °, 18.70±0.2 °, 21.84±0.2° and 24.72±0.2°, optionally further comprising characteristic peaks at 2Θ of 7.60±0.2 °, 18.02±0.2 °, 26.42±0.2 °, 27.38±0.2° and 31.00±0.2°.

For example, the X-ray powder diffraction pattern of the hydrochloride salt form B of the compound of formula I optionally has characteristic peaks at the following positions in 2θ:

12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°；

12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°；

12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、26.42±0.2°；

12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、27.38±0.2°；

12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、31.00±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.70±0.2°、21.48±0.2°、21.84±0.2°、24.72±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、27.38±0.2°；

12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、26.42±0.2°；

12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、27.38±0.2°；

12.78±0.2°、16.76±0.2°、18.70±0.2°、21.48±0.2°、21.84±0.2°、24.72±0.2°、27.38±0.2°；

12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、7.60±0.2°、18.02±0.2°、21.48±0.2°；

12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、7.60±0.2°、18.02±0.2°、27.38±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、26.42±0.2°、27.38±0.2°；

12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、26.42±0.2°、27.38±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、26.42±0.2°、27.38±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、26.42±0.2°、31.00±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、27.38±0.2°、31.00±0.2°；

7.60±0.2°、12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、26.42±0.2°、27.38±0.2°、31.00±0.2°.

in some embodiments, the X-ray powder diffraction pattern of hydrochloride form B of the compound of formula I is substantially the same as the peak at the diffraction angle (2θ) shown in fig. 2, with X-ray powder diffraction data as shown in table 2:

TABLE 2

In some embodiments, the hydrochloride salt of the compound of formula I is a polymorph, comprising form a and form B described above.

In some embodiments, the salt of the compound of formula I is crystalline hydrobromide, and the X-ray powder diffraction pattern of the hydrobromide form a of the compound of formula I has characteristic peaks at five or more positions in 2θ 11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、26.14±0.2°、30.32±0.2°.

In some embodiments, the X-ray powder diffraction pattern of hydrobromide crystalline form a of the compound of formula I has characteristic peaks at 11.16±0.2°, 17.86±0.2°, 18.38±0.2°, 21.56±0.2°, 24.44±0.2° and 30.32±0.2°, optionally further including characteristic peaks at 12.74 ±0.2°, 15.58±0.2°, 16.50±0.2°, 21.44 ±0.2°, 25.54±0.2° and 26.14±0.2° in 2θ.

For example, the X-ray powder diffraction pattern of hydrobromide crystalline form a of the compound of formula I optionally has a2 theta:

11.16±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、12.74±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、15.58±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2°；

11.16±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2°；

11.16±0.2°、12.74±0.2°、15.58±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、12.74±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、12.74±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、12.74±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2°；

11.16±0.2°、12.74±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2°；

11.16±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、15.58±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2°；

11.16±0.2°、15.58±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2°；

11.16±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2°；

11.16±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2°；

11.16±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2°；

11.16±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2°；

11.16±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2°；

11.16±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、26.14±0.2°、30.32±0.2°；

11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、15.58±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、15.58±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、15.58±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、26.14±0.2°、30.32±0.2；

11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2;

11.16±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、26.14±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、26.14±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、26.14±0.2°、30.32±0.2;

11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、26.14±0.2°、30.32±0.2;

11.16±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、26.14±0.2°、30.32±0.2;

11.16±0.2°、17.86±0.2°、18.38±0.2°、21.56±0.2°、24.44±0.2°、30.32±0.2、12.74±0.2°、15.58±0.2°、16.50±0.2°、21.44±0.2°、25.54±0.2°、26.14±0.2° There is a characteristic peak.

In some embodiments, the hydrobromide of the compound of formula I is in the form of a polymorph comprising hydrobromide form a, the X-ray powder diffraction pattern of the hydrobromide form a of the compound of formula I being substantially the same as the peak at the diffraction angle (2θ) shown in fig. 3, the X-ray powder diffraction data of which are shown in table 3:

TABLE 3 Table 3

In some embodiments, the salt of the compound of formula I is a crystalline phosphate salt, and the X-ray powder diffraction pattern of phosphate form a of the compound of formula I has characteristic peaks at five or more positions in 2θ 9.74±0.2°、11.22±0.2°、11.84±0.2°、12.04±0.2°、12.40±0.2°、14.64±0.2°、15.92±0.2°、16.24±0.2°、19.54±0.2°、21.12±0.2°、22.80±0.2°、24.90±0.2°、25.24±0.2°、25.56±0.2°、25.78±0.2°.

In some embodiments, the X-ray powder diffraction pattern of phosphate form a of the compound of formula I has characteristic peaks at five or more positions in 2θ of 11.22±0.2°, 14.64±0.2°, 19.54±0.2°, 22.80±0.2°, 25.24 ±0.2°, 25.56±0.2° and 25.78±0.2°, optionally further including characteristic peaks at 9.74±0.2°, 11.84±0.2°, 12.04±0.2°, 12.40±0.2°, 15.92±0.2°, 16.24±0.2°, 21.12±0.2° and 24.90±0.2°.

In some embodiments, the present invention provides a compound of formula I as a polymorph comprising phosphate form a, wherein the X-ray powder diffraction pattern of phosphate form a of the compound of formula I is substantially the same as the peak at the diffraction angle (2θ) shown in fig. 4, and wherein the X-ray powder diffraction data are as shown in table 4:

TABLE 4 Table 4

In some embodiments, the salt of the compound of formula I is a crystalline nitrate salt, and the X-ray powder diffraction pattern of nitrate crystalline form a of the compound of formula I has characteristic peaks at five or more positions in 2Θ 7.82±0.2°、9.56±0.2°、11.02±0.2°、12.60±0.2°、15.88±0.2°、16.60±0.2°、17.60±0.2°、19.18±0.2°、22.10±0.2°、22.80±0.2°、24.62±0.2°、25.92±0.2°.

In some embodiments, the X-ray powder diffraction pattern of nitrate form a of the compound of formula I has characteristic peaks at 7.82±0.2°, 9.56±0.2°, 15.88±0.2°, 17.60±0.2°, 22.80±0.2° and 25.92±0.2°, optionally further including characteristic peaks at 11.02±0.2°, 12.60±0.2°, 16.60±0.2°, 19.18±0.2°, 22.10±0.2° and 24.62±0.2°.

In some embodiments, the present invention provides a nitrate salt of a compound of formula I as a polymorph comprising nitrate form a, wherein the nitrate salt of the compound of formula I has an X-ray powder diffraction pattern substantially the same as the peak at the diffraction angle (2θ) shown in fig. 5, and wherein the X-ray powder diffraction data are as shown in table 5:

TABLE 5

In some embodiments, the salt of the compound of formula I is a crystalline tartrate salt, and the tartrate salt of the compound of formula I, form a, has an X-ray powder diffraction pattern with characteristic peaks at five or more positions in 2Θ at 12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、22.86±0.2°、24.08±0.2°、24.50±0.2°、26.48±0.2°.

In some embodiments, the X-ray powder diffraction pattern of tartrate form a of the compound of formula I has characteristic peaks at 12.36±0.2°, 16.20±0.2°, 19.56±0.2°, 21.12±0.2°, 22.12±0.2°, 24.50±0.2° and 26.48±0.2°, optionally further comprising characteristic peaks at 14.12±0.2°, 14.64±0.2°, 17.62±0.2°, 20.98 ±0.2°, 22.52±0.2°, 22.86±0.2° and 24.08±0.2° of 2θ.

For example, the tartrate salt form a of the compound of formula I has an X-ray powder diffraction pattern, optionally at 2θ:

12.36±0.2°、16.20±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、14.12±0.2°、16.20±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、16.20±0.2°、14.64±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、16.20±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、22.86±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、16.20±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°、14.12±0.2°、14.64±0.2°；

12.36±0.2°、14.12±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、14.12±0.2°、16.20±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、14.64±0.2°、16.20±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、14.64±0.2°、16.20±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、24.50±0.2°、26.48±0.2°；

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、22.86±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、22.86±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、19.56±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、22.86±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、24.08±0.2°、24.50±0.2°、26.48±0.2°;

12.36±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、°、22.52±0.2°、22.86±0.2°24.50±0.2°、26.48±0.2;

12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、22.86±0.2°、24.08±0.2°、24.50±0.2°、26.48±0.2°、;

In some embodiments, the tartrate salt of the compound of formula I provided herein is polymorphic form, comprising tartrate salt form a, the tartrate salt form a of the compound of formula I having an X-ray powder diffraction pattern substantially the same as the peaks at the diffraction angle (2Θ) shown in fig. 6, and having X-ray powder diffraction data as shown in table 6:

TABLE 6

In some embodiments, the salt of the compound of formula I is crystalline mesylate, and the mesylate form a of the compound of formula I has an X-ray powder diffraction pattern with characteristic peaks at five or more positions in 2Θ 12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°、24.66±0.2°、25.37±0.2°、27.22±0.2°.

In some embodiments, the X-ray powder diffraction pattern of mesylate form a of the compound of formula I has characteristic peaks at 2θ of 12.02±0.2°, 15.36±0.2°, 16.06±0.2°, 18.52±0.2°, 22.44±0.2° and 22.82±0.2°, optionally further including characteristic peaks at 2θ of 14.52±0.2°, 15.58±0.2°, 19.86±0.2°, 23.98±0.2°, 24.66±0.2°, 25.37±0.2° and 27.22±0.2°.

For example, the mesylate salt of the compound of formula I has an X-ray powder diffraction pattern of form a, optionally at 2θ:

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、24.66±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、25.37±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、27.22±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、24.66±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、25.37±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、27.22±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、24.66±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、25.37±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、27.22±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、24.66±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、25.37±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、27.22±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°、24.66±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°、25.37±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°、27.22±0.2°；

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、25.37±0.2°、27.22±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、24.66±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、24.66±0.2°；

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、25.37±0.2°；

12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°;

12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、24.66±0.2°;

12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、27.22±0.2°;

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°、24.66±0.2°;

12.02±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°、25.37±0.2°;

12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°、24.66±0.2°、25.37±0.2°;

12.02±0.2°、15.36±0.2°、16.06±0.2°、18.52±0.2°、22.44±0.2°、22.82±0.2°、14.52±0.2°、15.58±0.2°、19.86±0.2°、23.98±0.2°、24.66±0.2°、25.37±0.2°、27.22±0.2°;

in some embodiments, the present invention provides a mesylate salt of a compound of formula I in a polymorph form comprising mesylate form a, wherein the mesylate salt of the compound of formula I has an X-ray powder diffraction pattern substantially the same as the peak at the diffraction angle (2θ) shown in fig. 7, and wherein the X-ray powder diffraction data are as shown in table 7:

TABLE 7

In some embodiments, the salt of the compound of formula I is crystalline benzenesulfonate salt, and the X-ray powder diffraction pattern of benzenesulfonate salt form a of the compound of formula I has characteristic peaks at five or more positions in degrees 2Θ of 10.30±0.2°、12.88±0.2°、13.80±0.2°、14.86±0.2°、15.12±0.2°、15.50±0.2°、15.68±0.2°、18.06±0.2°、21.66±0.2°、22.02±0.2°、23.70±0.2°、25.00±0.2° and 26.54 ± 0.2 °.

In some embodiments, the X-ray powder diffraction pattern of the besylate crystalline form a of the compound of formula I has characteristic peaks at 15.12±0.2°, 15.68±0.2°, 21.66±0.2°, 22.02±0.2° and 26.54±0.2°, optionally further comprising characteristic peaks at 10.30±0.2°, 12.88±0.2°, 13.80±0.2°, 14.86±0.2°, 15.50±0.2°, 18.06±0.2°, 23.70±0.2° and 25.00±0.2°.

In some embodiments, the present invention provides a benzenesulfonate salt of a compound of formula I in the form of a polymorph comprising benzenesulfonate salt form a, wherein the X-ray powder diffraction pattern of form a of the benzenesulfonate salt of the compound of formula I is substantially the same as the peak at the diffraction angle (2θ) shown in fig. 8, and wherein the X-ray powder diffraction data are as shown in table 8:

TABLE 8

In some embodiments, the salt of the compound of formula I is crystalline L-lactate, and the X-ray powder diffraction pattern of L-lactate form a of the compound of formula I has characteristic peaks at five or more positions in 2θ 6.63±0.2°、9.12±0.2°、12.57±0.2°、12.98±0.2°、13.28±0.2°、14.68±0.2°、16.96±0.2°、19.84±0.2°、20.94±0.2°、23.70±0.2°.

In some embodiments, the X-ray powder diffraction pattern of crystalline form a of the L-lactate salt of the compound of formula I has characteristic peaks at 2θ of 6.63±0.2°, 9.12±0.2°, 14.68±0.2°, 20.94±0.2° and 23.70±0.2°, optionally further including characteristic peaks at 2θ of 12.57±0.2°, 12.98±0.2°, 13.28±0.2°, 16.96±0.2° and 19.84±0.2°.

In some embodiments, the present invention provides a compound of formula I wherein the L-lactate salt is polymorphic form a, comprising L-lactate salt form a, wherein the L-lactate salt form a of the compound of formula I has an X-ray powder diffraction pattern substantially the same as the peak at the diffraction angle (2θ) shown in fig. 9, and wherein the X-ray powder diffraction data is as shown in table 9:

TABLE 9

In some embodiments, the present invention also provides a method of preparing a salt of a compound of formula I, comprising:

step 1, placing a free base of a compound of a formula I in a solvent, adding an acidic reagent, and reacting to generate a salt of the compound of the formula I;

step 2, obtaining a solid product of the salt of the compound of formula I from the system obtained in step 1.

In some embodiments, the acidic reagent used in step 1 may be an organic acid, for example, acetic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, salicylic acid, citric acid, gluconic acid, L-lactic acid, D/L-lactic acid, malic acid, aspartic acid, glutamic acid, cinnamic acid, or the like. The acidic reagent used in step 1 may be a mineral acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, or the like. The acidic reagent may be a liquid or a solid or a solution.

In some embodiments, the acidic reagent used in step1 may be hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, L-lactic acid, fumaric acid, maleic acid, succinic acid, meso-tartaric acid, L-tartaric acid, D-tartaric acid, citric acid.

In some embodiments, the compound of formula I in step 1 may be dissolved in a solvent, or suspended in a solvent. The solvent may comprise at least one organic solvent, or water, or a mixture of organic solvents and water. Suitable organic solvents are various, for example, methanol, acetonitrile, acetone, ethyl acetate, and the like.

For example, the hydrochloride salt form a of the compound of formula I may be prepared by the following method: adding a proper solvent (including but not limited to methanol, acetonitrile, acetone, ethyl acetate or a mixture thereof) into the free base of the compound of the formula I, adding hydrochloric acid with the same or excessive molar equivalent, mixing and stirring, and carrying out solid-liquid separation after the salification reaction is completed to obtain the hydrochloride crystal form A of the compound of the formula I.

In some embodiments, the manner in which the solid product of the salt of the compound of formula I is obtained varies based on the system at the end of step 1. The solid product precipitated at the end of step 1 may be collected, specifically, the precipitated solid product may be collected by filtration, drying or the like. When no solid product is precipitated at the end of step 1, or the amount of solid product precipitated is particularly small, the solid product of the salt of the compound of formula I can be precipitated from the system of step 1 by constructing a salt system supersaturation. There are various ways of constructing the supersaturation of the salt system, such as cooling, solvent evaporation, addition of antisolvent, etc. For some cases, by constructing the salt system supersaturation, crystalline salts of the compound of formula I may be obtained.

In some embodiments, after the crystalline salt of the compound of formula I is prepared using step 1 and step 2 above, one crystal form of the acid salt may also be converted to the other crystal form of the salt by a process of crystal form conversion. For example, the conversion of the crystalline form may be achieved by seeding or recrystallising the suspension in a suitable solvent, or by heating or milling.

In some embodiments, the acid salt of the compound of formula I may be a non-solvated crystal.

In some embodiments, the acid salt crystals of the compound of formula I are solvates, i.e., partial crystals in which the solvent molecules form the crystal structure, the solvent forming the solvent compound may be water, in which case the solvent compound is commonly referred to as a hydrate, and the solvent compound may be formed from other solvents such as ethanol, acetone, ethyl acetate, and the like. The exact amount of solvent compound will generally depend on a variety of conditions.

The acid salts of the present invention may exist in more than one solid form, i.e., they may exist in one crystalline form or in a polymorphic form. If multiple crystalline forms are present, a polymorph is formed. The present invention is intended to cover both pure compounds and also two or more polymorphs of their mixtures.

It should be understood that modifications and equivalents of the technical solutions of the present invention, for example, some organic solvents exemplified in the foregoing section of the present invention, may be adopted, and the spirit and scope of the technical solutions of the present invention should be included in the present invention.

In some embodiments, the invention provides a pharmaceutical composition comprising a salt of a compound of formula I.

The pharmaceutical compositions may comprise crystalline or amorphous salts of the compounds of formula I. For example, the pharmaceutical composition comprises one or more of the crystalline hydrochloride, crystalline hydrobromide, crystalline phosphate, crystalline nitrate, crystalline tartrate, crystalline mesylate, crystalline besylate, crystalline L-lactate of the compound of formula I.

In some embodiments, the present invention provides the use of a salt of a compound of formula I in the manufacture of a medicament for anxiolytic and/or anticonvulsant and/or non-sedative hypnotic. In terms of pharmaceutical use, the crystalline acid salts of the compounds of formula I and/or hydrates and/or solvates thereof of the present invention may be prepared by methods conventional in the art and administered by convenient methods, for example, orally, injectable, parenterally, buccally, sublingually, rectally or transdermally, and the pharmaceutical composition may be adapted accordingly.

The invention provides 7-chloro-3- (5-dimethylaminomethyl- [1,2,4] oxadiazol-3-yl) -5-methyl-4, 5-dihydro-imidazo [1,5-a ] [1,4] benzodiazepineThe salt of the-6-ketone (the compound in the formula I) and the crystal form thereof have the advantages of good solubility, high stability, high biological activity, low toxicity and the like, and can be better used for clinic.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of crystalline form A of the hydrochloride salt of the compound of formula I, wherein the abscissa is the angle 2 θ (°), and the ordinate is the intensity (CPS);

FIG. 2 is an X-ray powder diffraction pattern of crystalline form B of the hydrochloride salt of the compound of formula I, wherein the abscissa is the angle 2θ (°), and the ordinate is the intensity (CPS);

FIG. 3 is an X-ray powder diffraction pattern of crystalline form A of the hydrobromide salt of compound of formula I, wherein the abscissa is angle 2 θ (°), and the ordinate is intensity (CPS);

FIG. 4 is an X-ray powder diffraction pattern of a compound of formula I, phosphate form A, wherein the abscissa is angle 2 θ (°), and the ordinate is intensity (CPS);

FIG. 5 is an X-ray powder diffraction pattern of crystalline form A of the compound nitrate salt of formula I, wherein the abscissa is angle 2 θ (°), and the ordinate is intensity (CPS);

FIG. 6 is an X-ray powder diffraction pattern of crystalline form A of the tartrate salt of the compound of formula I, in which the abscissa represents angle 2 θ (°) and the ordinate represents intensity (CPS);

FIG. 7 is an X-ray powder diffraction pattern of crystalline form A of the mesylate salt of compound of formula I, wherein the abscissa is angle 2 θ (°), and the ordinate is intensity (CPS);

FIG. 8 is an X-ray powder diffraction pattern of crystalline form A of the benzenesulfonate salt of the compound of formula I, wherein the abscissa is angle 2 theta (°), and the ordinate is intensity (CPS);

FIG. 9 is an X-ray powder diffraction pattern of crystalline form A of compound L-lactate of formula I, wherein the abscissa is angle 2 θ (°), and the ordinate is intensity (CPS);

FIG. 10 is a DSC plot of form A of the hydrochloride of the compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is heat flow (W/g);

FIG. 11 is a DSC plot of form B of the hydrochloride salt of the compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is heat flow (W/g);

FIG. 12 is a DSC plot of form A of the hydrobromide of the compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is heat flow (W/g);

FIG. 13 is a DSC graph of compound phosphate form A of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is heat flow (W/g);

FIG. 14 is a DSC graph of form A of the nitrate salt of the compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is heat flow (W/g);

FIG. 15 is a DSC plot of tartrate form A of the compound of formula I, wherein the abscissa represents temperature (degrees Celsius) and the ordinate represents heat flow (W/g);

FIG. 16 is a DSC of form A of the mesylate of compound of formula I, wherein the abscissa represents temperature (degrees Celsius) and the ordinate represents heat flow (W/g);

FIG. 17 is a DSC graph of form A of the benzenesulfonate salt of the compound of formula I, wherein the abscissa indicates temperature (degrees Celsius) and the ordinate indicates heat flow (W/g);

FIG. 18 is a DSC plot of form A of the L-lactate compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is heat flow (W/g);

FIG. 19 is a TGA graph of the hydrochloride salt form A of the compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is percent (%) weight loss;

FIG. 20 is a TGA graph of the hydrochloride salt form B of the compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is percent (%) weight loss;

Fig. 21 is a TGA profile of compound hydrobromide form a of formula I, wherein the abscissa is temperature (degrees celsius) and the ordinate is percent weight loss (%);

FIG. 22 is a TGA graph of the phosphate form A of the compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is percent weight loss (%);

FIG. 23 is a TGA graph of crystalline form A of a compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is percent weight loss (%);

FIG. 24 is a TGA graph of tartrate form A of the compound of formula I, wherein the abscissa represents temperature (degrees Celsius) and the ordinate represents percent (%) weight loss;

FIG. 25 is a TGA graph of form A of the mesylate salt of compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is percent (%) weight loss;

FIG. 26 is a TGA graph of the benzenesulfonate salt form A of the compound of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is percent (%) weight loss;

FIG. 27 is a TGA graph of compound L-lactate form A of formula I, wherein the abscissa is temperature (degrees Celsius) and the ordinate is percent weight loss (%);

FIG. 28 is an ORTEP (Single Crystal structural analysis) diagram of hydrochloride form A;

fig. 29 is an ORTEP (single crystal structure analysis) diagram of tartrate form a.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

In the examples described below, the free base crystalline forms of the compounds of formula I used may be prepared by methods described in the prior art documents of the patents CN1350538A and CN109134471B, etc.

The invention relates to an instrument for detecting salt crystal forms and properties of a compound of a formula I, which comprises the following steps:

Powder X-ray diffraction (PXRD) characterization: instrument: rigaku D/Max-2550 PC powder diffractometer, cuK alpha radiation, power 40kV×250mA, scanning range 2 theta 3-50 deg., step width 0.02 deg., scanning speed 5 deg/min. The data were analyzed and presented using MDI-Jade version 7.5.1 software.

Single crystal X-ray diffraction (SXRD) characterization: instrument: bruker APEX-IICCD single crystal diffractometer using MoK alphaThe rays were analyzed and corrected for structure with ShelXL and ShelXT 2015. Analysis and presentation using Mercury software.

Differential scanning calorimetric analysis (DSC) characterization: instrument: TA DSC Q100, purge gas: nitrogen 50ml/min, heating rate: 10 ℃/min, temperature range: room temperature to 230 ℃. Plotting the endothermic peak upward, the data were analyzed and shown with TA Universal Analysis, and there may be a margin of error of + -3 ℃.

Thermogravimetric analysis (TG) characterization: instrument: TA company SDT Q600, purge gas: nitrogen 120mL/min, heating rate: 10 ℃/min, temperature range: room temperature to 400 ℃. The data were analyzed and presented with TA Universal Analysis.

EXAMPLE 1 preparation of hydrochloride form A of the Compound of formula I

2G (5.36 mmol) of the free base of the compound of formula I (purity 99.0% by HPLC) are taken up in 30ml of ethyl acetate, heated to dissolve the free base of the compound of formula I, then 0.46ml of 37% hydrochloric acid is added, a white solid is precipitated with stirring, the suspension is cooled to room temperature while being stirred, the white solid obtained is collected by filtration and washed with ethyl acetate and then dried overnight with air at 40℃to give the hydrochloride salt of the compound of formula I as form A.

The X-ray powder diffraction pattern of the hydrochloride form a prepared in example 1 is shown in fig. 1, and a DSC curve thereof is shown in fig. 10, and comprises endothermic peaks having peak top values of about 83 ℃ and 248 ℃, wherein the endothermic peak at about 83 ℃ is caused by dehydration, and the endothermic peak at 248 ℃ is a melting endothermic peak; the TGA profile is shown in fig. 19, showing 8.1% loss of weight in the range of room temperature to 130 c, with the hydrochloride form a of the compound of formula I being the hydrate form. The purity was 99.96% as measured by HPLC.

Regarding the hydrochloride form A of the compound of formula I, the solubility in water is greater than 33.9mg/ml, much greater than the solubility in water (4.5 mg/ml) of the free base form A of the compound of formula I;

The hydrochloride obtained by the preparation method is subjected to single crystal culture to obtain perfect crystals suitable for X-ray single crystal diffraction. The specific method for single crystal cultivation is as follows:

weighing 0.2g of the prepared compound hydrochloride of the formula I, adding 20ml of acetone and 4ml of water, heating for dissolving, and standing for 1-3 days to obtain perfect crystals suitable for X-ray single crystal diffraction.

The single crystal structural analysis of the hydrochloride shows that the hydrochloride of the compound of the formula I belongs to a monoclinic system (monoclinic), a C2/C space group, a minimum asymmetric unit contains 1 cation of the formula I, 1 chloride ion and 2 water molecules, namely a dihydrate crystal form (the theoretical water content is 8.12%), the cations of the formula I and the chloride ions are connected through N-H.O charge hydrogen bonds, the water molecules are connected through the hydrogen bonds, and the crystallographic parameters are as follows:β＝101.318(15)°， Z=8, dx=1.461 g/cm ³; the analysis chart of the single crystal structure is shown in fig. 28. The characteristic diffraction lines obtained by calculation of the single crystal diffraction results are completely consistent with those of fig. 1.

EXAMPLE 2 preparation of hydrochloride form B of the Compound of formula I

2G (5.36 mmol) of the free base of the compound of formula I (purity 99.0% by HPLC) are dissolved in 10ml of ethanol, heated to dissolve the free base of the compound of formula I, then 0.46ml of 37% hydrochloric acid is added, a white solid is precipitated with stirring, the suspension is cooled to room temperature while being stirred, the white solid obtained is collected by filtration and washed with ethanol, and then dried overnight with air at 40℃to give the hydrochloride form B of the compound of formula I.

The X-ray powder diffraction pattern of the hydrochloride form B prepared in example 2 is shown in fig. 2, and a DSC curve thereof is shown in fig. 11, comprising endothermic peaks having peak top values of 45 ℃ and 250 ℃, wherein the endothermic peak at about 45 ℃ is caused by dehydration, and the endothermic peak at 250 ℃ is a melting endothermic peak; the TGA profile is shown in fig. 20, showing a weight loss of 0.8% over the range of room temperature to 100 ℃. The purity was 99.96% as measured by HPLC.

Regarding the hydrochloride salt form B of the compound of formula I, the solubility in water is greater than 34.8mg/ml, which is much greater than the solubility of the free base form A of the compound of formula I in water (4.5 mg/ml).

EXAMPLE 3 preparation of hydrochloride form A of the Compound of formula I

0.5G of the hydrochloride crystal form B prepared in the embodiment 2 is added with 20ml of acetone and 4ml of water, the mixture is heated, stirred and dissolved, the temperature is reduced, a white solid is precipitated, the white solid is collected by filtration and washed with acetone, and the obtained solid is the hydrochloride crystal form A.

The hydrochloride salt form a prepared in example 3 was crystalline and had an X-ray powder diffraction pattern substantially in accordance with figure 1 (example 1). The purity was 99.97% as measured by HPLC.

EXAMPLE 4 preparation of hydrochloride form A of the Compound of formula I

0.5G of the hydrochloride crystal form B prepared in the embodiment 2 is added with 6ml of water, heated, stirred and dissolved, cooled and precipitated to obtain a white solid, the white solid is collected by filtration and washed with water, and the obtained solid is the hydrochloride crystal form A.

The hydrochloride salt form a prepared in example 4 was crystalline and had an X-ray powder diffraction pattern substantially in accordance with figure 1 (example 1).

EXAMPLE 5 preparation of hydrobromide form A of the Compound of formula I

2G (5.36 mmol) of the free base of the compound of formula I (purity 99.0% by HPLC) are dissolved in 10ml of ethanol, heated to dissolve the free base of the compound of formula I, then 0.73ml of 40% hydrobromic acid are added, a white solid is precipitated with stirring, the suspension is cooled to room temperature while stirring, the white solid obtained is collected by filtration and washed with ethanol and then dried overnight with air at 40℃to give the hydrobromide crystalline form A.

The X-ray powder diffraction pattern of the hydrobromide crystalline form a prepared in example 5 is shown in fig. 3, and the DSC curve thereof is shown in fig. 12, and comprises endothermic peaks having peak top values of about 64 ℃, 75 ℃,215 ℃ and 239 ℃, wherein the endothermic peak at about 64 ℃, 75 ℃ is caused by dehydration, the endothermic peak at 215 ℃ is the endothermic peak caused by phase transition, and the endothermic peak at 248 ℃ is the melting endothermic peak; the TGA profile is shown in fig. 21, showing a loss of weight of 3.2% in the range of room temperature to 130 ℃, hydrobromide form a as a hydrate form, with a purity of 99.955% as measured by HPLC.

Regarding the hydrobromide form A of the compound of formula I, the solubility in water is greater than 25.7mg/ml, much greater than the solubility in water (4.5 mg/ml) of the free base form A of the compound of formula I;

EXAMPLE 6 preparation of phosphate Crystal form A of Compound of formula I

2G (5.36 mmol) of the free base of the compound of formula I (purity 99.0% by HPLC) are dissolved in 40ml of ethanol, heated to dissolve the free base of the compound of formula I, then 0.33ml of phosphoric acid is added, a white solid is precipitated by stirring, the suspension is cooled to room temperature while being stirred, the white solid obtained is collected by filtration and washed with ethanol, and then dried overnight by air blow at 40℃to give the phosphate form A.

The X-ray powder diffraction pattern of the phosphate form a prepared in example 6 is shown in fig. 4, and a DSC curve is shown in fig. 13, comprising endothermic peaks having peak top values of about 77 ℃ and 194 ℃, wherein the endothermic peak at about 77 ℃ is caused by dehydration, and the endothermic peak at 194 ℃ is a melting endothermic peak; the TGA profile is shown in fig. 22, showing a loss of weight of 2.0% over the range of room temperature to 130 ℃, with phosphate form a being a hydrate. The purity was 99.859% as measured by HPLC.

Regarding the phosphate form A of the compound of formula I, the solubility in water is greater than 142.0mg/ml, which is much greater than the solubility of the free base form A of the compound of formula I in water (4.5 mg/ml).

EXAMPLE 7 preparation of nitrate form A of the Compound of formula I

2G (5.36 mmol) of the free base of the compound of formula I (purity 99.0% by HPLC) are dissolved in 20ml of ethanol, heated to dissolve the free base of the compound of formula I, then 0.33ml of nitric acid is added, a white solid is precipitated by stirring, the suspension is cooled to room temperature while being stirred, the white solid obtained is collected by filtration and washed with ethanol, and then dried overnight by air blast at 40℃to obtain the nitrate form A.

The X-ray powder diffraction pattern of nitrate form a prepared in example 7 is shown in fig. 5, and the DSC curve is shown in fig. 14, and comprises an endothermic peak with a peak top value of about 85 ℃ for dehydration, and no obvious melting point is found after decomposition; the TGA profile is shown in fig. 23, showing a loss of weight of 2.9% over the range of room temperature to 100 ℃, with nitrate form a as the hydrate. The purity was 99.845% as measured by HPLC.

Regarding the nitrate form A of the compound of formula I, the solubility in water is greater than 17.2mg/ml, much greater than the solubility in water (4.5 mg/ml) of the free base form A of the compound of formula I;

EXAMPLE 8 preparation of tartrate salt form A of the Compound of formula I

2G (5.36 mmol) of the free base of the compound of formula I (purity 99.0% by HPLC) are dissolved in 10ml of ethanol, heated to dissolve the free base of the compound of formula I, then 0.81g L-tartaric acid is added, stirred for a while to precipitate a white solid, the suspension is stirred while it is cooled to room temperature, the white solid obtained is collected by filtration and then dried overnight with air at 40℃to give tartrate form A.

The X-ray powder diffraction pattern of tartrate form a prepared in example 8, as shown in figure 6, has a DSC curve as shown in figure 15, and contains an endothermic peak with a peak top value of 184 ℃ as a melting endothermic peak; the TGA profile is shown in fig. 24, showing little loss of weight at temperatures below 120 ℃, and tartrate form a was in the anhydrous form. The purity was 99.95% as measured by HPLC.

Regarding tartrate salt form A of the compound of formula I, the solubility in water is greater than 74.2mg/ml, much greater than the solubility in water (4.5 mg/ml) of the free base form A of the compound of formula I;

The tartrate obtained by the preparation method is subjected to single crystal cultivation to obtain perfect crystals suitable for X-ray single crystal diffraction. The specific method for single crystal cultivation is as follows:

Weighing 0.5g of tartrate of the compound shown in the formula I prepared by the method, adding 20ml of ethanol and 4ml of water, heating for dissolving, and standing for 1-3 days to obtain perfect crystals suitable for X-ray single crystal diffraction.

Analysis of the single crystal structure of tartrate shows that the tartrate of the compound shown in the formula I belongs to an orthorhombic system (orthorhombic), the P212121 space group contains 2 molecules shown in the formula I and 2 tartaric acid molecules in the minimum asymmetric unit, 2 carboxyl groups on the tartaric acid molecules, and protons of one carboxyl group are transferred to the molecules shown in the formula I to form N-H.cndot.O charge hydrogen bonds, and the crystallographic parameters are as follows: Z=4, dx=1.570 g/cm ³; the analysis chart of the single crystal structure is shown in fig. 28. The characteristic diffraction lines obtained by calculation of the single crystal diffraction results are completely consistent with those of fig. 6.

EXAMPLE 9 preparation of mesylate form A of the Compound of formula I

2G (5.36 mmol) of the free base of the compound of formula I (purity 99.0% by HPLC) are dissolved in 10ml of ethanol, heated to dissolve the free base of the compound of formula I, then 0.348ml of methanesulfonic acid is added, a white solid is precipitated with stirring, the suspension is cooled to room temperature while being stirred, the white solid obtained is collected by filtration and then dried overnight with air blow at 40℃to give the mesylate form A.

The X-ray powder diffraction pattern of the mesylate salt form a prepared in example 9 is shown in fig. 7, and the DSC curve thereof is shown in fig. 16, and comprises an endothermic peak having a peak top value of 262 ℃ which is a melting endothermic peak; the TGA profile is shown in fig. 25, showing little weight loss at temperatures below 120 ℃, and the mesylate salt form a is the anhydrous form. The purity was 99.88% as measured by HPLC.

Regarding the mesylate salt form A of the compound of formula I, the solubility in water is greater than 169.5mg/ml, much greater than the solubility of the free base form A of the compound of formula I in water (4.5 mg/ml).

EXAMPLE 10 preparation of benzenesulfonate salt of Compound of formula I form A

2G (5.36 mmol) of the free base of the compound of formula I (HPLC purity: 99.0%) are dissolved in 10ml of ethanol, heated to dissolve the free base of the compound of formula I, then 0.85g of benzenesulfonic acid is added, and a white solid is precipitated by stirring, the suspension is cooled to room temperature while being stirred, the resulting white solid is collected by filtration and then dried overnight with air blow at 40℃to obtain a white solid.

The X-ray powder diffraction pattern of the benzenesulfonate crystal form a prepared in example 10 is shown in fig. 8, and its DSC curve is shown in fig. 17, and comprises endothermic peaks having peak top values of about 57 ℃ and 219 ℃, wherein the endothermic peak at about 57 ℃ is caused by dehydration, and the endothermic peak at 219 ℃ is a melting endothermic peak; the TGA profile is shown in fig. 26, showing a loss of weight of 3.1% in the range of room temperature to 100 ℃, and the besylate salt form a is a hydrate form. The purity was 98.91% as measured by HPLC.

Regarding the benzenesulfonate salt form a of the compound of formula I, the solubility in water is greater than 28.9mg/ml, much greater than the solubility of the free base form a of the compound of formula I in water (4.5 mg/ml).

EXAMPLE 11 preparation of L-lactate form A of the Compound of formula I

2G (5.36 mmol) of the free base of the compound of formula I (HPLC purity: 99.0%) are dissolved in 10ml of ethanol, heated to dissolve the free base of the compound of formula I, then 0.5ml of L-lactic acid is added, stirred with heat preservation, subsequently cooled to room temperature, after 3 days of standing a white solid is precipitated, the white solid obtained is collected by filtration and then dried by air blast at 40℃overnight to obtain the crystalline form A of L-lactate.

The X-ray powder diffraction pattern of the L-lactate crystal form A prepared in example 11 is shown in FIG. 9, and a DSC curve thereof is shown in FIG. 18, and the DSC curve comprises an endothermic peak having a peak top value of about 156 ℃ and is a melting endothermic peak; the TGA profile is shown in fig. 27, showing little weight loss over the range of room temperature to 100 ℃, and the L-lactate form a is the anhydrous form. The purity was 99.80% as measured by HPLC.

The solubility of the L-lactate form A of the compound of formula I in water is about 1.6mg/ml, which is less than the solubility of the free base form A of the compound of formula I in water (4.5 mg/ml).

Claims (22)

1. A salt of a compound of formula I:

The salt is organic acid salt or inorganic acid salt; the organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, salicylic acid, citric acid, gluconic acid, L-lactic acid, D/L-lactic acid, malic acid, aspartic acid, glutamic acid or cinnamic acid; the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid or phosphoric acid.

2. The salt according to claim 1, wherein the salt is a crystalline salt.

3. The salt according to claim 2, wherein the salt is a crystalline hydrochloride salt, and the X-ray powder diffraction pattern of the hydrochloride salt form a of the compound of formula I has characteristic peaks at five or more positions in the 2Θ range 7.58±0.2°、9.44±0.2°、11.26±0.2°、13.58±0.2°、15.68±0.2°、16.20±0.2°、17.94±0.2°、22.82±0.2°、25.26±0.2°、26.4±0.2°;

The X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound of the formula I has characteristic peaks at more than five positions in the 2 theta of 7.60±0.2°、12.78±0.2°、16.76±0.2°、18.02±0.2°、18.70±0.2°、21.84±0.2°、24.72±0.2°、26.42±0.2°、27.38±0.2°、31.00±0.2°.

4. A salt according to claim 3, wherein the X-ray powder diffraction pattern of the hydrochloride salt form a of the compound of formula I has characteristic peaks at 2Θ of 7.58 ± 0.2 °, 9.44 ± 0.2 °, 11.26 ± 0.2 °, 17.94 ± 0.2 ° and 26.4 ± 0.2 °, optionally further comprising characteristic peaks at 2Θ of 13.58 ± 0.2 °, 15.68 ± 0.2 °, 16.20 ± 0.2 °, 22.82 ± 0.1 ° and 25.26 ± 0.2 °;

The X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound of the formula I has characteristic peaks at 12.78+/-0.2 DEG, 16.76+/-0.2 DEG, 18.70+/-0.2 DEG, 21.84+/-0.2 DEG and 24.72+/-0.2 DEG of 2 theta, and optionally has characteristic peaks at 7.60+/-0.2 DEG, 18.02+/-0.2 DEG, 26.42+/-0.2 DEG, 27.38+/-0.2 DEG and 31.00+/-0.2 DEG of 2 theta.

5. The salt according to claim 2, wherein the salt is crystalline hydrobromide and the X-ray powder diffraction pattern of the hydrobromide crystalline form of the compound of formula I has characteristic peaks at five or more positions in the 2Θ range 11.16±0.2°、12.74±0.2°、15.58±0.2°、16.50±0.2°、17.86±0.2°、18.38±0.2°、21.44±0.2°、21.56±0.2°、24.44±0.2°、25.54±0.2°、26.14±0.2°、30.32±0.2°.

6. The salt of claim 5, wherein the X-ray powder diffraction pattern of the hydrobromide crystalline form of the compound of formula I has characteristic peaks at 11.16±0.2°, 17.86±0.2°, 18.38±0.2°, 21.56±0.2°, 24.44±0.2° and 30.32±0.2°, optionally further comprising characteristic peaks at 12.74 ±0.2°, 15.58±0.2°, 16.50±0.2°, 21.44 ±0.2°, 25.54±0.2° and 26.14±0.2° in 2Θ.

7. The salt according to claim 2, wherein the salt is a crystalline phosphate salt and the X-ray powder diffraction pattern of the phosphate crystalline form of the compound of formula I has characteristic peaks at five or more positions in the 2Θ range 9.74±0.2°、11.22±0.2°、11.84±0.2°、12.04±0.2°、12.40±0.2°、14.64±0.2°、15.92±0.2°、16.24±0.2°、19.54±0.2°、21.12±0.2°、22.80±0.2°、24.90±0.2°、25.24±0.2°、25.56±0.2°、25.78±0.2°.

8. The salt of claim 7, wherein the X-ray powder diffraction pattern of the phosphate crystalline form of the compound of formula I has characteristic peaks at more than five positions in 2Θ of 11.22 ± 0.2 °, 14.64 ± 0.2 °, 19.54 ± 0.2 °, 22.80 ± 0.2 °, 25.24 ± 0.2 °, 25.56 ± 0.2 ° and 25.78 ± 0.2 °, optionally further comprising characteristic peaks at 9.74 ± 0.2 °, 11.84 ± 0.2 °, 12.04 ± 0.2 °, 12.40 ± 0.2 °, 15.92 ± 0.2 °, 16.24 ± 0.2 °, 21.12 ± 0.2 ° and 24.90 ± 0.2 °.

9. The salt according to claim 2, wherein the salt is crystalline nitrate and the nitrate crystalline form of the compound of formula I has an X-ray powder diffraction pattern with characteristic peaks at five or more positions in the 2Θ range 7.82±0.2°、9.56±0.2°、11.02±0.2°、12.60±0.2°、15.88±0.2°、16.60±0.2°、17.60±0.2°、19.18±0.2°、22.10±0.2°、22.80±0.2°、24.62±0.2°、25.92±0.2°.

10. The salt of claim 9, wherein the nitrate crystalline form of the compound of formula I has an X-ray powder diffraction pattern with characteristic peaks at 7.82±0.2°, 9.56±0.2°, 15.88±0.2°, 17.60±0.2°, 22.80±0.2° and 25.92±0.2°, optionally further comprising characteristic peaks at 11.02±0.2°, 12.60±0.2°, 16.60±0.2°, 19.18±0.2°, 22.10±0.2° and 24.62±0.2°.

11. The salt according to claim 2, wherein the salt is crystalline tartrate salt, and the tartrate salt form of the compound of formula I has an X-ray powder diffraction pattern with characteristic peaks at five or more positions in the 2Θ range 12.36±0.2°、14.12±0.2°、14.64±0.2°、16.20±0.2°、17.62±0.2°、19.56±0.2°、20.98±0.2°、21.12±0.2°、22.12±0.2°、22.52±0.2°、22.86±0.2°、24.08±0.2°、24.50±0.2°、26.48±0.2°.

12. The salt of claim 11, wherein the tartrate salt form of the compound of formula I has an X-ray powder diffraction pattern with characteristic peaks at 2Θ of 12.36 ± 0.2 °, 16.20 ± 0.2 °, 19.56 ± 0.2 °, 21.12 ± 0.2 °, 22.12 ± 0.2 °, 24.50 ± 0.2 ° and 26.48 ± 0.2 °, optionally further comprising characteristic peaks at 2Θ of 14.12 ± 0.2 °, 14.64 ± 0.2 °, 17.62 ± 0.2 °, 20.98 ± 0.2 °, 22.52 ± 0.2 °, 22.86 ± 0.2 ° and 24.08 ± 0.2 °.

13. The salt according to claim 2, wherein the salt is crystalline mesylate salt and the mesylate salt form of the compound of formula I has an X-ray powder diffraction pattern with characteristic peaks at five or more positions in the 2Θ range 12.02±0.2°、14.52±0.2°、15.36±0.2°、15.58±0.2°、16.06±0.2°、18.52±0.2°、19.86±0.2°、22.44±0.2°、22.82±0.2°、23.98±0.2°、24.66±0.2°、25.37±0.2°、27.22±0.2°.

14. The salt of claim 13, wherein the mesylate salt form of the compound of formula I has an X-ray powder diffraction pattern with characteristic peaks at 2Θ of 12.02 ± 0.2 °, 15.36 ± 0.2 °, 16.06 ± 0.2 °, 18.52 ± 0.2 °, 22.44 ± 0.2 ° and 22.82 ± 0.2 °, optionally further comprising characteristic peaks at 2Θ of 14.52 ± 0.2 °, 15.58 ± 0.2 °, 19.86 ± 0.2 °, 23.98 ± 0.2 °, 24.66 ± 0.2 °, 25.37 ± 0.2 ° and 27.22 ± 0.2 °.

15. The salt according to claim 2, wherein the salt is crystalline benzenesulfonate salt and the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form of the compound of formula I has characteristic peaks at five or more positions in the 2Θ range 10.30±0.2°、12.88±0.2°、13.80±0.2°、14.86±0.2°、15.12±0.2°、15.50±0.2°、15.68±0.2°、18.06±0.2°、21.66±0.2°、22.02±0.2°、23.70±0.2°、25.00±0.2°、26.54±0.2°.

16. The salt of claim 15, wherein the X-ray powder diffraction pattern of the besylate crystalline form of the compound of formula I has characteristic peaks at 15.12±0.2°, 15.68±0.2°, 21.66±0.2°, 22.02±0.2° and 26.54±0.2°, optionally further comprising characteristic peaks at 10.30±0.2°, 12.88±0.2°, 13.80±0.2°, 14.86±0.2°, 15.50±0.2°, 18.06±0.2°, 23.70±0.2° and 25.00±0.2°.

17. The salt according to claim 2, wherein the salt is crystalline L-lactate and the X-ray powder diffraction pattern of the crystalline form of the L-lactate of the compound of formula I has characteristic peaks at five or more positions in 2-theta 6.63±0.2°、9.12±0.2°、12.57±0.2°、12.98±0.2°、13.28±0.2°、14.68±0.2°、16.96±0.2°、19.84±0.2°、20.94±0.2°、23.70±0.2°.

18. The salt of claim 17, wherein the L-lactate crystalline form of the compound of formula I has an X-ray powder diffraction pattern with characteristic peaks at 6.63±0.2°, 9.12±0.2°, 14.68±0.2°, 20.94±0.2° and 23.70±0.2°, optionally further comprising characteristic peaks at 12.57±0.2°, 12.98±0.2°, 13.28±0.2°, 16.96±0.2° and 19.84±0.2° in 2Θ.

19. A process for the preparation of a salt of a compound of formula I according to any one of claims 1 to 18, comprising:

step 1, placing the free base of the compound of the formula I in a solvent, adding an acidic reagent, and reacting to generate salt of the compound of the formula I;

step 2, obtaining a solid product of the salt of the compound of formula I from the system obtained in step 1.

20. The process according to claim 19, wherein said obtaining a solid product of a salt of said compound of formula I from the system obtained in step 1 comprises:

Collecting the solid product of the salt of the compound of formula I precipitated in step 1 and/or precipitating the solid product of the salt of the compound of formula I from the system of step 1 by constructing a salt system supersaturation.

21. A pharmaceutical composition comprising a salt of a compound of formula I according to any one of claims 1 to 18.

22. Use of a salt of a compound of formula I according to any one of claims 1 to 18 for the manufacture of a medicament for anxiolytic and/or anticonvulsant and/or non-sedative hypnotic.