TW202019908A - Pharmaceutically acceptable salt, crystalline form of azabicyclo substituted triazole derivative and preparation method thereof - Google Patents

Abstract

The present disclosure provides pharmaceutically acceptable salts, crystalline forms and preparation method of azabicyclo substituted triazole derivatives. In particular, the present invention provides a compound of formula A, 1-(2-chloro-4-fluorophenyl)-3-(5-(methoxymethyl)-4-(6-methoxypyridin -3-yl)-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane. Compared with free hydrazine, the pharmaceutically acceptable salts of the compound has higher purity and more excellent chemical stability, and is of great significance for developing medicine suitable for industrial production and of good biological activity.

Description

Medicinal salts, crystal forms and preparation methods of triazole derivatives substituted with azabicyclic groups

The present disclosure provides the compound 1- (2-chloro-4-fluorophenyl) -3- (5- (methoxymethyl) -4- (6-methoxy-3-yl) -4 H -1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane pharmaceutically acceptable salt and its preparation method.

This application requires the priority of Chinese patent application 201810676344.2 with the filing date of 2018/6/27. This application cites the entire text of the aforementioned Chinese patent application.

PCT/CN2017/118784 (application date December 27, 2017) describes a compound 1-(2-chloro-4-fluorophenyl)-3-(5-(methoxymethyl)-4-(6 -Methoxypyridin-3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane, showing high selectivity OTR as a free base Inhibition can effectively block the downstream function of oxytocin receptor mediated by oxytocin.

Nearly half of the drug molecules exist in the form of salts. At the same time, salt formation can improve some undesirable physical chemical or biological properties of drugs. Developed relative to 1-(2-chloro-4-fluorophenyl)-3-(5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4 H -1 ,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane, a salt with more excellent physical and chemical properties or pharmaceutical properties is of great significance. .

At the same time, in view of the importance of the solid drug crystal form and its stability in clinical treatment, the compound 1-(2-chloro-4-fluorophenyl)-3-(5-(methoxymethyl) Pharmaceutically acceptable salt of -4-(6-methoxypyridin-3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane The polymorphic form is of great significance for the development of drugs suitable for industrial production and with good biological activity.

其中，所述式A所示化合物的可藥用鹽選自鹽酸鹽，硫酸鹽、氫溴酸鹽、甲磺酸鹽、磷酸鹽、檸檬酸鹽、乙酸鹽、馬來酸鹽、酒石酸鹽、琥珀酸鹽、苯甲酸鹽或富馬酸鹽，優選鹽酸鹽、磷酸鹽、氫溴酸鹽。The present disclosure provides the compound represented by formula A (1 S ,5 R )-1-(2-chloro-4-fluorophenyl)-3-(5-(methoxymethyl)-4-(6- Methoxypyridin-3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane, a pharmaceutically acceptable salt,

Wherein, the pharmaceutically acceptable salt of the compound represented by Formula A is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, phosphate, citrate, acetate, maleate, tartrate , Succinate, benzoate or fumarate, preferably hydrochloride, phosphate, hydrobromide.

Preferably, the chemical ratio of the compound represented by the formula A to the acid molecule is 1:2~2:1, which may be 1:2, 1:1, 2:1.

In an alternative embodiment, the chemical ratio of the compound of formula A to hydrogen chloride is 1:1.

In an alternative embodiment, the chemical ratio of the compound of formula A to sulfuric acid is 1:1 or 2:1.

In an alternative embodiment, the chemical ratio of the compound of formula A to phosphoric acid is 1:1, 2:1.

In an alternative embodiment, the chemical ratio of the compound of formula A to methanesulfonic acid is 1:1.

The present disclosure also provides a method for preparing the aforementioned pharmaceutically acceptable salt, including: the step of forming a compound of Formula A with an acid, the acid selected from hydrochloric acid (or hydrogen chloride solution), sulfuric acid, hydrobromic acid, methanesulfonic acid , Phosphoric acid, citric acid, acetic acid, maleic acid, tartaric acid, succinic acid, benzoic acid or fumaric acid, preferably hydrochloric acid (or hydrogen chloride solution), phosphoric acid, hydrobromic acid.

The solvents used for salt formation in this disclosure are selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tertiary butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate At least one of them.

Further, in an alternative embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt further includes the steps of volatile solvent or crystallizing with stirring, filtration, and drying.

The present disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the aforementioned compound and a pharmaceutical adjuvant optionally selected from at least one of a pharmaceutically acceptable carrier, diluent or excipient.

The present disclosure also provides the use of the aforementioned pharmaceutically acceptable salts in the preparation of a medicament for the treatment or prevention of a disease or condition known or shown to inhibit oxytocin to produce a beneficial effect, the disease or condition being selected from sexual dysfunction, Hypoactive sexual desire disorder, sexual arousal disorder, orgasm disorder, sexual intercourse pain disorder, premature ejaculation, preterm delivery, complications of childbirth, appetite and eating disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertension, liver Sclerosis, renal hypertension, high intraocular pressure, obsessive-compulsive disorder and behavioral disorders, and neuropsychiatric diseases are preferably selected from sexual dysfunction, sexual arousal disorder, orgasm disorder, sexual intercourse pain disorder, and premature ejaculation.

The disclosure also provides the use of the aforementioned pharmaceutically acceptable salts in the preparation of a medicament for antagonizing oxytocin.

The present disclosure provides the crystalline form I of the hydrochloride salt of the compound represented by formula A, and the X-ray powder diffraction pattern expressed by the diffraction angle 2 θ is characterized at 7.98, 17.16, 21.74, 23.00, 25.00, 27.04, 32.54 peak.

In an alternative embodiment, the hydrochloride salt of the compound represented by formula A Form I, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 7.98, 8.44, 13.38, 17.16, 18.10, 19.02, There are characteristic peaks at 21.74, 23.00, 25.00, 27.04, 32.54.

Further, the hydrochloride salt of the compound represented by formula A Form I, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 7.98, 8.44, 12.62, 13.38, 15.22, 17.16, 18.10, 19.02, There are characteristic peaks at 19.80, 21.36, 21.74, 23.00, 25.00, 27.04, 32.54.

Preferably, the hydrochloride salt of the compound represented by formula A Form I, X- ray powder diffraction pattern at the diffraction angle 2 θ represents the angle shown in Figure 1.

The present disclosure also provides a preparation method of the crystalline form I of the hydrochloride of the compound represented by formula A, including: (A) Add the compound represented by formula A to the solvent (I), dissolve with stirring or heat to dissolve, the solvent (I) is selected from isopropanol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tris At least one of grade butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and; (B) Add hydrogen chloride solution dropwise and stir to crystallize. Wherein, the volume (ml) used for the solvent (I) is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (I) is preferably isopropanol/isopropyl ether.

In an alternative embodiment, the volume ratio of isopropyl alcohol/isopropyl ether is 1:1~1:2.

The hydrogen chloride solution in the present disclosure is selected from but not limited to hydrogen chloride isopropanol solution or hydrogen chloride tetrahydrofuran solution.

This disclosure provides the crystalline form II of the hydrochloride salt of the compound represented by formula A. The X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ is characterized at 7.98, 13.80, 17.10, 18.10, 18.92, 21.44, 26.50 peak.

In an alternative embodiment, the hydrochloride salt of the compound represented by formula A Form II, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 7.98, 8.34, 12.56, 13.80, 17.10, 18.10, There are characteristic peaks at 18.92, 21.44, 22.92, 26.50.

Preferably, the hydrochloride salt of the compound represented by formula A Form II, X- ray powder diffraction pattern at the diffraction angle 2 θ represents the angle shown in Figure 4.

The present disclosure also provides a method for preparing the crystalline form II of the hydrochloride of the compound represented by formula A, including: (A) Add the compound represented by formula A to the solvent (II), stir to dissolve or heat to dissolve, the solvent (II) is selected from isopropanol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tris At least one of grade butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and; (B) Add hydrogen chloride solution dropwise and stir to crystallize. Wherein, the volume (ml) used for the solvent (II) is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (I) is preferably isopropanol/isopropyl ether.

In an alternative embodiment, the volume ratio of isopropyl alcohol/isopropyl ether is 1:2~1:4, which may be 1:2, 1:2.5, 1:3, 1:3.5, 1:4.

The disclosure also provides the crystalline form III of the hydrochloride salt of the compound represented by formula A, and the X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ is available at 7.40, 14.02, 18.66, 22.14, 23.76, 27.06, 30.58 Characteristic peaks.

In an alternative embodiment, hydrochloride Form III compound represented by the formula A, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 7.40, 14.02, 15.16, 18.66, 19.60, 21.12, There are characteristic peaks at 22.14, 23.76, 27.06, 30.58.

In an alternative embodiment, hydrochloride Form III compound represented by the formula A, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 7.40, 13.16, 14.02, 14.80, 15.16, 16.88, There are characteristic peaks at 17.40, 18.66, 19.60, 21.12, 22.14, 23.76, 27.06, 30.58.

Further, the hydrochloride salt of the compound represented by formula A Form III, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle is shown in Fig.

The present disclosure also provides a preparation method of the crystalline form III of the hydrochloride salt of the compound represented by formula A, including: (A) The compound represented by formula A is added to a solvent (III), dissolved by stirring or heated, and the solvent (III) is selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tertiary At least one of butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and; (B) Add hydrogen chloride solution dropwise and stir to crystallize. Wherein, the volume (ml) used for the solvent (III) is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (III) is preferably isopropanol/tetrahydrofuran.

In an alternative embodiment, the volume ratio of isopropanol/tetrahydrofuran is 1:1~1:4, which may be 1:1, 2:3, 1:2, 1:3, 1:4.

The present disclosure also provides the crystal form IV of the hydrochloride salt of the compound represented by formula A, and the X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ is available at 12.26, 18.73, 20.34, 21.41, 23.72, 24.82, 32.58 Characteristic peaks.

In an alternative embodiment, Form IV of the hydrochloride salt of the compound represented by Formula A, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 9.59, 10.02, 12.26, 17.26, 18.73, 20.34, There are characteristic peaks at 21.41, 23.72, 24.82, 32.58.

In an alternative embodiment, Form IV of the hydrochloride salt of the compound represented by Formula A, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 9.59, 10.02, 12.26, 17.26, 18.73, 20.34, There are characteristic peaks at 21.41, 22.93, 23.72, 24.82, 27.02, 32.58.

Further, the hydrochloride salt of the compound represented by formula A Form IV, X- ray powder diffraction pattern at the diffraction angle 2 θ represents the angle shown in Figure 14.

The disclosure also provides the crystalline form A of the compound salt hydrobromide represented by the formula A, the X-ray powder diffraction pattern expressed by the diffraction angle 2 θ , at 6.12, 7.91, 8.18, 17.12, 18.00, 18.86, 25.14 There are characteristic peaks.

In an alternative embodiment, the compound represented by the hydrobromide salt of formula A Form A, X-ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 6.12, 7.91, 8.18, 17.12, 18.00, There are characteristic peaks at 18.86, 25.14, 12.44, 15.98, 17.12.

In an alternative embodiment, the compound represented by the hydrobromide salt of formula A Form A, X-ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 6.12, 7.91, 8.18, 12.44, 13.57, There are characteristic peaks at 15.98, 17.12, 17.12, 18.00, 18.86, 21.28, 25.14, 26.04, 28.57.

Further, hydrobromic acid compound represented by the formula A salt of Form A, X-ray powder diffraction pattern at the diffraction angle 2 θ represents an angle is shown in Fig.

The present disclosure also provides a preparation method of the crystalline form A of the hydrobromide salt of the compound represented by formula A, which includes: (a)(1 S ,5 R )-1-(2-chloro-4-fluorophenyl)- 3-(5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo [3.1.0] Hexane is added to the solvent (IV), dissolved by stirring or heated, and the solvent (IV) is selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tertiary butyl At least one of ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, preferably isopropanol/isopropyl ether, isopropanol/isopropyl acetate, and; (b) dropwise hydrogenation Bromic acid, stirring and crystallization. Wherein, the volume (ml) used for the solvent (IV) is 1 to 40 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (IV) is preferably isopropanol/isopropyl ether, isopropanol/isopropyl acetate ester.

In an alternative embodiment, the volume ratio of isopropyl alcohol/isopropyl ether is 1:1~1:3, which may be 1:1, 1:2, 1:3.

In an alternative embodiment, the volume ratio of isopropyl alcohol/isopropyl acetate is 1:1~1:3, which may be 1:1, 1:2, 1:3.

The present disclosure also provides compounds of formula A phosphate salt Form A, X-ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 5.09, 10.29, 12.89, 16.26, 20.86, 22.67 characteristic peaks at.

In an alternative embodiment, the crystalline form A, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 5.09, 10.29, 12.89, 15.46, 16.26, 19.52, 20.86, 22.67, 25.46 at characteristic peak.

In an alternative embodiment, the crystalline form A, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 5.09, 10.29, 12.89, 15.46, 16.26, 19.52, 20.86, 22.67, 23.68, 24.08, There are characteristic peaks at 25.46, 26.54, 30.86.

Further, the Form A, X- ray powder diffraction pattern at the diffraction angle 2 θ denotes an angle of 16 as shown in FIG.

The present disclosure also provides a method for preparing the crystalline form A of the compound phosphate represented by formula A, including: (A) The compound represented by formula A is added to a solvent (V), dissolved by stirring or heated to dissolve, the solvent (V) is selected from at least one of acetone, ethyl acetate, and isopropanol, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. The volume (ml) of the solvent (V) used in this method is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.

The present disclosure also provides the crystal form B of the compound phosphate represented by the formula A, and the X-ray powder diffraction pattern expressed by the diffraction angle 2 θ is characterized at 5.00, 14.24, 16.18, 20.51, 21.54, 22.49, 30.54 peak.

In an alternative embodiment, the phosphate compound of Form B in the formula A, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of 5.00, 14.24, 15.26, 16.18, 17.23, 20.51, 21.54 , 22.49, 30.00, 30.54 have characteristic peaks.

In an alternative embodiment, the phosphate compound of Form B in the formula A, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of 5.00, 14.24, 15.26, 16.18, 17.23, 20.51, 21.54 , 22.49, 30.00, 30.54, 25.16, 26.44 have characteristic peaks.

Further, the compound represented by the formula A phosphate salt Form B, X- ray powder diffraction pattern at the diffraction angle 2 θ represents the angle shown in Figure 18.

The present disclosure also provides a preparation method of the crystalline form B of the compound phosphate represented by formula A, including: (A) adding the compound represented by formula A to the solvent (VI), stirring and dissolving or heating to dissolve, the solvent (VI) is selected from at least one of 1,4-dioxane and isopropanol, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. The volume (ml) of the solvent (VI) used in this method is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.

The present disclosure also provides the crystalline form C of the compound phosphate represented by the formula A, and the X-ray powder diffraction pattern expressed by the diffraction angle 2 θ is characterized by 4.92, 9.91, 11.08, 15.98, 20.18, 20.74, 22.44 peak.

In an alternative embodiment, the phosphate compound of Form C, X- ray powder diffraction pattern at the diffraction angle 2 θ angle as shown in the formula represented by A, at 4.92, 9.91, 11.08, 15.98, 18.11, 20.18, 20.74 , 22.44, 23.25 have characteristic peaks.

In an alternative embodiment, the phosphate compound of Form C, X- ray powder diffraction pattern at the diffraction angle 2 θ angle as shown in the formula represented by A, at 4.92, 9.91, 11.08, 11.94, 14.83, 15.98, 18.11 , 19.28, 20.18, 20.74, 22.44, 23.25 have characteristic peaks.

Further, the compound represented by the formula A phosphate salt Form C, X- ray powder diffraction pattern at the diffraction angle 2 θ denotes an angle of 20 as shown in FIG.

The present disclosure also provides a method for preparing the crystalline form C of the compound phosphate represented by formula A, including: (A) The compound represented by formula A is added to the solvent (VII), dissolved by stirring or heated to dissolve, the solvent (VII) is selected from tertiary butyl dimethyl ether, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. Wherein, the volume (ml) used for the solvent (VII) is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.

The present disclosure also provides the crystal form D of the compound phosphate represented by the formula A, and the X-ray powder diffraction pattern expressed by the diffraction angle 2 θ is characterized by 5.14, 9.98, 10.31, 16.49, 19.49, 20.94, 22.75 peak.

In an alternative embodiment, the phosphate compound of Form D, X- ray powder diffraction pattern at the diffraction angle 2 θ angle as shown in the formula represented by A, at 5.14, 9.98, 10.31, 12.67, 14.47, 15.66, 16.49 , 19.49, 20.94, 22.75 have characteristic peaks.

In an alternative embodiment, the phosphate compound of Form D, X- ray powder diffraction pattern at the diffraction angle 2 θ angle as shown in the formula represented by A, at 5.14, 9.98, 10.31, 12.67, 14.00, 14.47, 15.66 , 16.49, 19.49, 20.94, 21.64, 22.75 have characteristic peaks.

Further, the compound represented by the formula A phosphate salt Form D, X- ray powder diffraction pattern at the diffraction angle 2 θ angle of 22 represented in FIG.

The present disclosure also provides a method for preparing the crystal form D of the compound phosphate represented by formula A, which includes: (a) Compound (1 S ,5 R )-1-(2-chloro-4-fluorophenyl)- 3-(5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo [3.1.0] Hexane is added to the solvent (VIII), dissolved by stirring or heated, and the solvent (VIII) is selected from dichloromethane, and; (b) Phosphoric acid or phosphoric acid solution is added dropwise, and crystallized by stirring. Wherein, the volume (ml) used for the solvent (VIII) is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.

The present disclosure also provides compounds of formula A phosphate salt Form F, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 4.96, 5.35, 16.06, 20.39, 22.33, 25.19 characteristic peaks at.

In an alternative embodiment, shown in A of the compound of formula phosphate Form F, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 4.96, 5.35, 10.27, 12.77, 16.06, 20.39, 22.33 , There is a characteristic peak at 25.19.

In an alternative embodiment, shown in A of the compound of formula phosphate Form F, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 4.96, 5.35, 10.27, 12.77, 15.27, 16.06, 20.39 , 22.33, 23.28, 25.19, 26.34 have characteristic peaks.

Further, the compound represented by the formula A phosphate salt Form F, X- ray powder diffraction pattern at the diffraction angle 2 θ angle represented by Figure 24.

The present disclosure also provides a method for preparing the crystal form F of the compound phosphate represented by formula A, including: (A) The compound represented by formula A is added to a solvent (IX), dissolved by stirring or heated to dissolve, the solvent (IX) is selected from methyl isobutyl ketone, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. Wherein, the volume (ml) used for the solvent (IX) is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.

The present disclosure also provides the crystalline form G of the compound phosphate represented by formula A, and the X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ is characterized by 5.26, 16.08, 16.81, 19.60, 20.90, 23.01, 23.96 peak.

In an alternative embodiment, the phosphate compound of Form G, X- ray powder diffraction pattern at the diffraction angle 2 θ angle as shown in the formula represented by A, at 5.26, 10.33, 12.58, 16.08, 16.81, 19.60, 20.90 , 23.01, 23.96, 25.47 have characteristic peaks.

In an alternative embodiment, the phosphate compound of Form G, X- ray powder diffraction pattern at the diffraction angle 2 θ angle as shown in the formula represented by A, at 5.26, 10.33, 12.58, 16.08, 16.81, 19.60, 20.90 , 23.01, 23.96, 25.47, 26.58, 31.62 have characteristic peaks.

Further, the compound represented by the formula A phosphate salt Form G, X- ray powder diffraction pattern at the diffraction angle 2 θ denotes an angle of 26 as shown in FIG.

The present disclosure also provides a method for preparing the crystalline form G of the compound phosphate represented by formula A, including: (a) Compound (1 S ,5 R )-1-(2-chloro-4-fluorophenyl)- 3-(5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo [3.1.0] Hexane is added to the solvent (X), stirred and dissolved or heated to dissolve, the solvent (X) is selected from methyl isobutyl ketone, and; (b) Phosphoric acid or phosphoric acid solution is added dropwise, and stirred for crystallization. Wherein, the volume (ml) used by the solvent (X) is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.

The present disclosure further provides a crystalline form of the compound of formula A H phosphates, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 5.32, 15.97, 16.16, 19.69, 20.10, 21.76 characteristic peaks at.

In an alternative embodiment, the compound of Formula A shown in phosphate Form H, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of, in 5.32, 10.31, 10.72, 12.56, 13.18, 15.97, 16.16 , 19.69, 20.10, 21.76 have characteristic peaks.

Further, the compound represented by the formula A phosphate salt Form H, X- ray powder diffraction pattern at the diffraction angle 2 θ angle of 27 represented in FIG.

The present disclosure also provides a pharmaceutical composition containing the aforementioned crystalline form of a pharmaceutically acceptable salt and a pharmaceutical excipient optionally selected from a pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, the method for preparing the crystalline form of the present disclosure further includes steps such as filtration, washing or drying.

The present disclosure also provides pharmaceutical compositions prepared from the aforementioned crystal forms.

The disclosure also provides the use of the aforementioned crystalline forms of pharmaceutically acceptable salts in the preparation of a medicament for the treatment or prevention of a disease or condition known to or which may exhibit beneficial effects in inhibiting oxytocin, the disease or condition being selected from Dysfunction, hyposexual disorder, sexual arousal disorder, orgasm disorder, painful intercourse, premature ejaculation, pre-term delivery, complication of delivery, appetite and eating disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertension Blood pressure, cirrhosis, renal hypertension, high intraocular pressure, obsessive-compulsive disorder and behavioral disorders and neuropsychiatric disorders are preferably selected from sexual dysfunction, sexual arousal disorder, orgasm disorder, painful intercourse and premature ejaculation.

The present disclosure also provides the use of the aforementioned crystalline form of a pharmaceutically acceptable salt in the preparation of a medicine for antagonizing oxytocin.

According to the description of the hygroscopicity characteristics and the definition of hygroscopicity gain in the "Guidelines for Moisture Absorption of 9103 Drugs" in the four parts of the 2015 edition of the Chinese Pharmacopoeia, Deliquescence: Absorb enough water to form liquid; Very hygroscopic: the weight gain of moisture absorption is not less than 15%; Moisture-inducing: the weight-increasing of moisture inducing is less than 15% but not less than 2% Slightly moisturizing: the weight gain of moistening is less than 2% but not less than 0.2%; No or almost no hygroscopicity: the hygroscopic weight gain is less than 0.2%.

(1 S ,5 R )-1-(2-chloro-4-fluorophenyl)-3-(5-(methoxymethyl)-4-(6-methoxypyridine- 3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride crystal form I at 10.0% RH-80.0% RH At the bottom, the moisture-increasing weight gain is 0.7188%, which is slightly moisture-absorbing.

(1 S ,5 R )-1-(2-chloro-4-fluorophenyl)-3-(5-(methoxymethyl)-4-(6-methoxypyridine- 3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride crystal form III at 10.0% RH-80.0% RH, Humidity increased weight by 1.9898%, slightly moisturizing.

The "X-ray powder diffraction pattern" described in this disclosure is measured using Cu-Ka radiation.

The “X-ray powder diffraction pattern or XRPD” mentioned in this disclosure refers to the Bragg formula 2d Sin θ = nλ (where, λ is the wavelength of X-ray, λ=1.54056 Å, the order of diffraction n is any positive Integer, generally take first-order diffraction peak, n=1), when X-rays enter the crystal or part of the crystal sample at a grazing angle θ (coincidence of incident angle, also known as Bragg angle) with a d-lattice plane spacing On the atomic plane, the Bragg equation can be satisfied, and thus the X-ray powder diffraction pattern is measured.

In this disclosure, "2 θ or 2 θ angle" refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 θ is ±0.30, which can be -0.30, -0.29 , -0.28, -0.27, -0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13,- 0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07 , 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, preferably ± 0.20.

The "crystal plane spacing or crystal plane spacing (d value)" mentioned in this disclosure means that the spatial lattice selects three non-parallel unit vectors a, b, c connecting two adjacent lattice points, which will The lattice is divided into juxtaposed parallelepiped units, called interplanar spacing. The spatial lattice is divided according to the determined parallel hexahedral unit connection to obtain a set of straight grids, called spatial lattices or lattices. Lattices and lattices use geometric dots and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar distances (that is, the distance between two adjacent parallel crystal planes); the unit is Å Or Egypt.

The "differential scanning calorimetry or DSC" mentioned in this disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference substance during the sample heating or constant temperature process to characterize all physical changes related to thermal effects and Chemical changes to get information on the phase change of the sample.

The drying temperature in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and can be dried under normal pressure or under reduced pressure. Preferably, the drying is done under reduced pressure.

For those skilled in the art, there is a certain degree of error in the determination of the chemical ratio of the compound to the acid molecule in this disclosure. Generally speaking, plus or minus 10% is within a reasonable error range. There is a certain degree of error change depending on the context in which it is used, and the error change does not exceed plus or minus 10%, preferably plus or minus 5%.

The reagents used in this disclosure are commercially available.

Test conditions of the instruments used in the experiments in this disclosure: 1. Differential Scanning Calorimeter (DSC) Instrument model: TA Q2000 Purge gas: Nitrogen heating rate: 10.0℃/min Temperature range: 25-250℃ 2 、X-ray Powder Diffraction (X-ray Powder Diffraction, XRPD) (1) Instrument model: Bruker D8 Discover A25 X-ray powder diffractometer Ray: monochromatic Cu-Ka ray (l=1.5406) Scanning method: q/ 2q, scanning range: 10-48 ^o Voltage: 40 KV, current: 40 mA 3. Thermogravimetric Analysis (Thermogravimetric Analysis, TGA) Instrument model: TAQ500 Purge gas: Nitrogen heating rate: 10.0°C/min Temperature range: 25 -250℃ 4. DVS adopts SMS DVA Advantage for dynamic moisture adsorption detection. At 25℃, the humidity change is 50%-95%-0%-95%-50%, the step is 10% (the last step is 5%) , The judgment criterion is that dm/dt is not more than 0.02%. 5. Ion Chromatography (HPIC): Instrument American DionexICS-5000 ion chromatograph; separation column: IonPac AS14A, detection method: conductivity; eluent: NaHCO ₃ 0.0010M+Na ₂ CO ₃ 0.0035 M; flow rate 1.0 mL/min.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shift (d) is given in units of 10 ^-6 (ppm). The measurement of NMR was performed by Bruker AVANCE-400 nuclear magnetic instrument. The solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four. Methyl silane (TMS).

The MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC was measured using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

For chiral HPLC analysis, LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.) was used.

In the examples, the reaction progress was monitored by thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of column chromatography used for purifying the compound, and the developing agent system of thin layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acetic acid can also be added Such as alkaline or acid reagents for adjustment.

In order to make the above and other objects, features and advantages of the present invention more comprehensible, the following describes the embodiments in detail with reference to the accompanying drawings.

The following will explain this disclosure in more detail in conjunction with examples or experimental examples. The examples or experimental examples in this disclosure are only used to illustrate the technical solutions in this disclosure, and do not limit the substance and scope of this disclosure.

Example 1: Compound A(1 S ,5 R )-1-(2-chloro-4-fluorophenyl)-3-(5-(methoxymethyl)-4-(6-methoxypyridine -3-yl)-4 H -1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane

The first step: (1 S )-1-(2-chloro-4-fluorophenyl)-2-(hydroxymethyl)cyclopropylnitrile: 1c 2-chloro-4-fluorophenylacetonitrile 1a (1 g, 5.9 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to -20°C in a dry ice-acetone bath, and slowly added sodium bis(trimethylsilyl) amide (5.9 mL, 11.8 mmol), after addition, stirring for 30 minutes, then ( R )-2-(chloromethyl)ethylene oxide 1b (600 mg, 6.49 mmol) was added, and after the addition was completed, the dry ice-acetone bath was removed, the temperature of the reaction solution was naturally raised to room temperature, and the reaction was stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (50 mL×3), and concentrated under reduced pressure to obtain a crude product The title product 1c (1.35 g), the product was directly subjected to the next step without purification.

MS m/z (ESI): 226.4 [M+1].

Step 2: ((2 S )-2-(aminomethyl)-2-(2-chloro-4-fluorophenyl)cyclopropyl)methanol: 1d Add lithium aluminum hydride (672 mg, 17.7 mmol) In 15 mL of tetrahydrofuran, cool in an ice bath, add the crude product 1c (1.33 g, 5.9 mmol), add it, and remove the ice bath. The temperature of the reaction solution was naturally raised to room temperature, and the reaction was stirred for 15 hours. To the reaction solution, water (0.7 mL), sodium hydroxide solution (10%, 0.7 mL) and water (2.1 mL) were added in this order. After the addition, the mixture was stirred for 30 minutes. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude title product 1d (1.4 g). The product was directly subjected to the next step without purification.

MS m/z (ESI): 230.3 [M+1].

The third step: (1 S ,5 R )-1-(2-chloro-4-fluorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride: 1e The crude product 1d (1.35 g, 5.9 mmol) and sulfonium chloride (1.05 g, 8.85 mmol) were added to 10 mL of dichloromethane. After the addition, the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 1e (1.3 g). The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 212.3 [M+1].

The fourth step: (1 S ,5 R )-1-(2-chloro-4-fluorophenyl)-N-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1.0 ]Hexane-3-thioamide: 1g 5-isothiocyano-2-methoxypyridine 1f (1.25 g, 7.5 mmol, using a well-known method "Bioo R ganic and Medicinal Chemistry Letters, 2010, 20 (2), prepared from 516-520" and the crude product 1e (1.06 g, 5.0 mmol) was added to 20 mL of tetrahydrofuran. After the addition, the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1 g (1.9 g) of the crude title product. The product was directly subjected to the next step without purification.

MS m/z (ESI): 378.2 [M+1].

Step 5: (1 S ,5 R ,E)-1-(2-chloro-4-fluorophenyl)-N-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1 .0] Hexan-3-thioimidic acid methyl ester: 1h The crude product 1g (1.86 g, 5.0 mmol) was added to 30 mL of tetrahydrofuran, cooled in an ice bath, potassium tert-butoxide (2.2 g, 20 mmol) was added After the addition, the reaction was stirred for 2 hours. Methyl p-toluenesulfonate (1.86 g, 10.0 mmol) was added, the addition was completed, the ice bath was removed, the temperature of the reaction solution was naturally raised to room temperature, and the reaction was stirred for 15 hours. Ice water (90 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B, The title product was obtained in 1 h (700 mg), yield: 32.2%.

MS m/z (ESI): 392.2 [M+1].

The sixth step: Add 1h (180 mg, 0.46 mmol), methoxyacetohydrazide 1i (239 mg, 2.3 mmol) and trifluoroacetic acid (52 mg, 0.46 mmol) to 8 mL of tetrahydrofuran. After addition, heat to 70°C and stir React for 3 hours. The heating was stopped, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography to obtain compound A (50 mg), yield: 24.21%.

MS m/z (ESI): 430.2 [M+1].

1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.66 (d, 1H), 7.27 (t, 1H), 7.10 (d, 1H), 6.91-6.89 (m, 2H), 4.24 (s , 2H), 4.01 (s, 3H), 3.78 (d, 1H), 3.57-3.55 (m, 2H), 3.53 (d, 1H), 3.25 (s, 3H), 1.81-1.79 (m, 1H), 1.10 (t, 1H), 0.95 (t, 1H).

Test Example 1: Determination of human OTR inhibitory activity

1. Experimental materials and instruments 1. Fluo-4 NW calcium analysis kit (F36206, invitrogen) 2. MEM (Hyclone, SH30024.01B) 3. G418 sulfate (Enzo, ALX-380-013-G005) 4. Fetal bovine serum (GIBCO, 10099) 5. Sodium pyruvate solution (sigma, S8636-100ML) 6. MEM non-essential amino acid solution (100×) (sigma, M7145-100ML) 7. Flexstation 3 Multifunctional Microplate Reader (Molecular Devices) 8. Poly-D-lysine 96-well plate, black/clean (356692, BD) 9. Oxytocin (synthesized by Jill Biochemical Co., Ltd.) 10. pcDNA3.1 (invitrogen, V79020) 11. pcDNA3.1-hOTR (NM-000916) (Jin Weizhi Biotechnology Co., Ltd. synthesized and constructed into pcDNA3.1 plastid) 12. HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)

2. Experimental procedure

The pcDNA3.1-hOTR plasmid was transfected into HEK293 cells with Lipofectamine® 3000 transfection reagent; G418 screening was started the next day to select monoclonal cell lines.

One day in advance, HEK293/human OTR stable transfectant cells were planted in 96-well plates at a density of 25,000 cells/well. The next day, first prepare the loading buffer containing Fluo-4 dye using the reagents in the Fluo-4 NW calcium analysis kit, then remove the medium, add 100 µl of loading buffer containing Fluo-4 dye to each well, 37 Incubate at 30°C for 30 minutes. When the time is up, move the board to room temperature and equilibrate for 10 minutes. Compounds were prepared into 10 ⁶ , 10 ⁵ , 10 ⁴ , 10 ³ , 10 ² , and 10 ¹ nM, 1 µl was added to each well, and incubated at room temperature for 10 minutes. The flexstation 3 microplate reader was used for the detection. The machine automatically added 3 nM of oxytocin peptide 50 µl and immediately read the value at 494/516 nM. The IC ₅₀ value of the compound can be the fluorescence value corresponding to different concentrations, calculated by Graphpad Prism, IC ₅₀ = 28 nM, indicating that the compound has a significant inhibitory effect on human OTR activity.

Test Example 2: Determination of human V1aR inhibitory activity

1. Experimental materials and instruments 1. Fluo-4 NW calcium analysis kit (F36206, invitrogen) 2. MEM (Hyclone, SH30024.01B) 3. G418 sulfate (Enzo, ALX-380-013-G005) 4. Fetal bovine serum (GIBCO, 10099) 5. Sodium pyruvate solution (sigma, S8636-100ML) 6. MEM non-essential amino acid solution (100×) (sigma, M7145-100ML) 7. Flexstation 3 Multifunctional Microplate Reader (Molecular Devices) 8. Poly-D-lysine 96-well plate, black/clean (356692, BD) 9. Vasopressin (Tocris, 2935) 10. pcDNA3.1 (invitrogen, V79020) 11. pcDNA3.1-V1aR (NM-000706) (Jin Weizhi Biotechnology Co., Ltd. synthesized and constructed into pcDNA3.1 plastid) 12. HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)

2. Experimental procedure

The pcDNA3.1-V1aR plasmid was transfected into HEK293 cells with Lipofectamine® 3000 transfection reagent; G418 screening was started the next day to select monoclonal cell lines.

One day in advance, HEK293/human V1aR stable transfectant cells were planted in 96-well plates at a density of 25,000 cells/well. The next day, first prepare the loading buffer containing Fluo-4 dye using the reagents in the Fluo-4 NW calcium analysis kit, then remove the medium, add 100 µl of loading buffer containing Fluo-4 dye to each well, 37 Incubate at 30°C for 30 minutes. When the time is up, move the board to room temperature and equilibrate for 10 minutes. Compounds were prepared into 10 ⁶ , 10 ⁵ , 10 ⁴ , 10 ³ , 10 ² , and 10 ¹ nM, 1 µl was added to each well, and incubated at room temperature for 10 minutes. The flexstation 3 microplate reader was used for detection. The machine automatically added 3 nM of vasopressin polypeptide 50 µl and immediately read the value at 494/516 nM. The IC ₅₀ value of the compound can be the fluorescence value corresponding to different concentrations, calculated by Graphpad Prism, IC ₅₀ = 2885 nM, indicating that the compound has no inhibitory effect on human V1aR activity, indicating that it has selective inhibitory effect on OTR activity.

Test Example 3: Determination of human V1bR inhibitory activity

1. Experimental materials and instruments 1. Fluo-4 NW calcium analysis kit (F36206, invitrogen) 2. MEM (Hyclone, SH30024.01B) 3. G418 sulfate (Enzo, ALX-380-013-G005) 4. Fetal bovine serum (GIBCO, 10099) 5. Sodium pyruvate solution (sigma, S8636-100ML) 6. MEM non-essential amino acid solution (100×) (sigma, M7145-100ML) 7. Flexstation 3 Multifunctional Microplate Reader (Molecular Devices) 8. Poly-D-Lysine 96-well Microplates, black/clear (356692, BD) 9. Vasopressin (Tocris, 2935) 10. pcDNA3.1 (invitrogen, V79020) 11. pcDNA3.1-V1bR (NM-000706) (Jin Weizhi Biotechnology Co., Ltd. synthesized and constructed into pcDNA3.1 plastid) 12. HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)

2. Experimental procedure

The pcDNA3.1-V1bR plastid was transfected into HEK293 cells with Lipofectamine® 3000 transfection reagent; G418 was added the next day to obtain HEK293/human-derived V1bR pool cell line.

One day in advance, HEK293/human V1bR pool cells were seeded in 96-well plates at a density of 25,000 cells/well. The next day, first prepare the loading buffer containing Fluo-4 dye using the reagents in the Fluo-4 NW calcium analysis kit, then remove the medium, add 100 µl of loading buffer containing Fluo-4 dye to each well, 37 Incubate at 30°C for 30 minutes. When the time is up, move the board to room temperature and equilibrate for 10 minutes. Compounds were prepared into 10 ⁶ , 10 ⁵ , 10 ⁴ , 10 ³ , 10 ² , and 10 ¹ nM, 1 µl was added to each well, and incubated at room temperature for 10 minutes. The flexstation 3 microplate reader was used for detection. The machine automatically added 3 nM of vasopressin polypeptide 50 µl and immediately read the value at 494/516 nM. The IC ₅₀ value of the compound can be the fluorescence value corresponding to different concentrations, calculated by Graphpad Prism software, IC ₅₀ = 37568 μM, indicating that the compound has no significant inhibitory effect on human V1bR activity, indicating that it has selective inhibitory effect on OTR activity.

Test Example 4: Determination of the inhibitory activity of compounds on human V2R

1. Experimental materials and instruments 1. cAMP Dynamic 2 Kit-1,000 experiments (62AM4PEB, Cisbio) 2. MEM (Hyclone, SH30024.01B) 3. G418 sulfate (Enzo, ALX-380-013-G005) 4. Fetal bovine serum (GIBCO, 10099) 5. Sodium pyruvate solution (sigma, S8636-100ML) 6. MEM non-essential amino acid solution (100×) (sigma, M7145-100ML) 7. PheraStar Multi-function Microplate Reader (BMG) 8. Corning/Costar 384-well non-adsorption microplate-black NBS plate (4514, Corning) 9. Cell dissociation solution, enzyme-free, PBS (13151014-100ml, Thermo Fisher Scientific) 10. HBSS, calcium, magnesium, phenol red free (14025-092, Invitrogen) 11. HEPES, 1M buffer solution (15630-080, GIBCO) 12. BSA (0219989725, MP Biomedicals) 13. IBMX (I7018-250MG, sigma) 14. Vasopressin (Tocris, 2935) 15. pcDNA3.1 (invitrogen, V79020) 16. pcDNA3.1-V2R (NM-000054) (Jin Weizhi Biotechnology Co., Ltd. synthesized and constructed into pcDNA3.1 plastid) 17. HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)

2. Experimental procedure The pcDNA3.1-V2R plastid was transfected into HEK293 cells with Lipofectamine® 3000 transfection reagent; G418 was added the next day to obtain HEK293/human-derived V2R pool cell line.

1) Digest cells: Use cell dissociation solution to digest HEK293/human-derived V2R pool cells without enzymes to dissociate cells from the cell culture dish, dissociate the cells into a single, pipette evenly after termination, centrifuge, remove the supernatant with experimental buffer 1 (1x HBSS+20 mM HEPES+0.1% BSA) Resuspend the cells and count, adjust the cell density to 1250 cells/5 µl, which is 2.5*10 ⁵ /ml.

2) Dispensing 1. Compounds are formulated with pure DMSO into a series of 20 mM, 6.67 mM, 2.22 mM, 0.74 mM, 0.25 mM, 0.0 8 mM, 27.4 µM, 9.14 µM, 3.05 µM, 1.02 µM, 0.34 µM and 0 µM (DMSO) concentration. The compound was then made up to 4 times the use concentration using Experiment Buffer 2 (Experiment Buffer 1+1 mM IBMX). 2. Agonist: Use 460 µM vasopressin mother liquor, first make up 2 µM with DMSO, then dilute to 0.5 nM concentration with experiment buffer 2. 3. Standard: The first point is a stock solution of 20 µl (2848 nM). From the second point, dilute it in 4 times with experiment buffer 1, a total of 11 concentrations.

3) Incubation with medicine: 1. Add the mixed cells to a 384-well plate at 5 µl/well without changing the tip. 2. Add 2.5 µl/well of the compound to be tested and the positive compound. The tip needs to be replaced. 3. Centrifuge at 1000 rpm for 1 min, shake for 30 sec to mix, and incubate at room temperature for 30 min. 4. For standard curve wells, add 5 µl/well of experiment buffer 2. 5. Add 2.5 µl per well of the prepared agonist. Need to change the tip, centrifuge at 1000 rpm for 1 min, mix by shaking for 30 sec, and incubate at room temperature for 30 min. 6. Prepare cAMP-d2 (component in the cAMP dynamic 2 kit) and Anti-cAMP-Eu-Cryptate (component in the cAMP dynamic 2 kit) in the dark, according to the ratio of 1:4 and cAMP lysate ( cAMP Dynamic 2 kit components) and mix well. Add 5 μl/well of the prepared cAMP-d2 liquid to each well, add Anti-cAMP-Eu-Cryptate 5 μl/well, mix by shaking for 30 sec, and incubate at room temperature in the dark for 1 h.

4) Plate reading: PheraStar multi-function microplate reader performs HTRF signal reading.

5) Data processing The data in this experiment was processed using the data processing software Graphpad Prism, and IC ₅₀ =32604 μM was obtained, indicating that the compound had no significant inhibitory effect on human V2R activity, indicating that it had selective inhibitory effect on OTR activity.

Test Example 5: Pharmacokinetic test of the compound

1. Summary Using the rat as the test animal, the drug concentration in the plasma at different times after the compound was intragastrically administered by the LC/MS/MS method was determined. Study the pharmacokinetic behavior of the compounds in this disclosure in rats and evaluate their pharmacokinetic characteristics.

2. Test plan

2.1 Experimental animals There were 12 healthy adult SD rats, half male and half female, divided into 3 groups on average, 4 rats in each group, purchased from Shanghai Jie Si Jie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.

2.2 Drug preparation Weigh a certain amount of drug, add 2.5% volume of DMSO and 97.5% volume of 10% solutol HS-15 to make 0.2 mg/mL colorless clear transparent liquid.

2.3 Administration The SD rats were fasted and administered by gavage overnight, the dosage was 2.0 mg/kg, and the dosage volume was 10.0 mL/kg.

3. Operation Rats were administered intragastrically. Before and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours, 0.2 mL of blood was collected from the orbit and placed in a heparinized test tube at 4°C and 3500 rpm. Centrifuge for 10 minutes to separate plasma, store at -20°C, and eat 2 hours after administration. Determination of test compound content in rat plasma after intragastric administration of different concentrations of drugs: take 25 μL of rat plasma at each time after administration, add internal standard solution camptothecin 50 μL (100 ng/mL), acetonitrile 200 μL, vortex to mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 1.0 μL of the supernatant of the plasma sample for LC/MS/MS analysis.

結論：化合物的藥代吸收較好，具有藥代動力學優勢。4. Pharmacokinetic parameters results The pharmacokinetic parameters of the compounds are as follows:

Conclusion: The compound has good pharmacokinetic absorption and has pharmacokinetic advantages.

Example 2: Compound A hydrochloride crystal form I

Compound A　 (100 mg, 0.233 mmol) was dissolved in a mixed solvent of 0.8 mL isopropanol and 1.6 mL isopropyl ether, 4 M hydrogen chloride in isopropanol solution (0.064 mL, 0.256 mmol) was added dropwise, heated and stirred, and cooled to The crystal was stirred at room temperature, filtered, and dried in vacuo to obtain the product (60 mg, yield: 55.3%).

The ion chromatography (HPIC) test result of the obtained product: the chloride ion content is 7.52%, indicating that the molar ratio of the compound in the salt to hydrochloric acid is about 1:1.

The XRPD pattern of the crystalline sample is shown in Figure 1, the DSC pattern is shown in Figure 2, the TGA pattern is shown in Figure 3, the melting peak point is near 198.54℃, and the characteristic peak position is shown in Table 1 below: Table 1

Example 3: Form I of the hydrochloride salt of Compound A

Compound A (40 mg, 0.093 mmol) was dissolved in 0.33 mL of isopropanol, 4 M hydrogen chloride in isopropanol solution (0.05 mL, 0.2 mmol) was added, the temperature was stirred, and 0.66 mL of isopropyl ether was added, the solution was slightly cloudy, Naturally cooled to room temperature and stirred for 16 hours, crystallized, filtered, and dried to obtain the product (30 mg, yield: 69.14%), which was detected as Form I by X-powder diffraction.

Example 4: Form II of the hydrochloride salt of Compound A

Compound A (75 g, 174.47 mmol) was dissolved in a mixed solvent of 150 mL of isopropanol and 450 mL of isopropyl ether, heated to 45°C, and a 4 M solution of hydrogen chloride in isopropanol (92 mL, 366.39 mmol) was added dropwise. Stir at 45°C for about 5 minutes, change from clear to slightly mixed, let cool to room temperature and stir for 3 hours, crystallize, filter, and vacuum dry to obtain product (74 g, yield: 90.95%).

The ion chromatography (HPIC) test result of the obtained product: the chloride ion content is 7.54%, indicating that the molar ratio of the compound in the salt to hydrochloric acid is about 1:1.

The XRPD spectrum of the crystalline sample is shown in Figure 4, the DSC spectrum is shown in Figure 5, the TGA spectrum is shown in Figure 6, the melting peak point is near 187.58℃, and the characteristic peak position is shown in Table 2 below: Table 2

test: In the process of DSC detection, the aforementioned sample was heated to 65°C or 110°C and taken out. It was detected by X-powder diffraction as crystal form II, and the crystal form did not change.

Example 5: Form III of the hydrochloride salt of Compound A

Compound A (40 mg, 0.093 mmol) was dissolved in a mixed solvent (V:V = 1:1) of 0.5 mL isopropanol and 0.5 mL tetrahydrofuran, and a 4 M hydrogen chloride solution in isopropanol (0.05 mL, 0.2 mmol) was added dropwise ), heated and stirred, cooled to room temperature and stirred for crystallization, filtered, and dried in vacuo to obtain the product (20 mg, yield: 46.09%).

The ion chromatography (HPIC) test result of the obtained product: the chloride ion content is 7.61%, indicating that the molar ratio of the compound in the salt to hydrochloric acid is about 1:1.

The XRPD spectrum of the crystalline sample is shown in Figure 7, the DSC is shown in Figure 8, the TGA is shown in Figure 9, the melting peak is near 197.29℃, and the characteristic peak position is shown in Table 3 below: Table 3

Example 6: Compound A hydrochloride crystal form III

Compound A (200 mg, 0.465 mmol) was dissolved in 4 mL of a mixed solvent of isopropanol and tetrahydrofuran (V:V = 2:3), the temperature was raised to 30°C, and a 4 M solution of hydrogen chloride in isopropanol (0.14 mL) was added dropwise , 0.56 mmol), heated and stirred, cooled to room temperature and stirred for crystallization, filtered, and dried in vacuo to obtain the product (68 mg, yield: 31.3%). Form III was detected by X-powder diffraction.

Example 7: Form I of the hydrochloride salt of Compound A

Compound A hydrochloride crystal form II (37.1 mg, 0.07956 mmol) was dissolved in 0.5 mL of isopropanol, stirred at room temperature, filtered, and dried in vacuo to obtain the product (30 mg, yield: 80.86%).

The ion chromatography (HPIC) test result of the obtained product: the chloride ion content is 7.46%, indicating that the molar ratio of the compound in the salt to hydrochloric acid is about 1:1.

Form X was detected by X-powder diffraction.

Example 8: Compound A hydrochloride crystal form I

Compound A hydrochloride crystal form II (37.1 mg, 0.07956 mmol) was dissolved in 0.5 mL of isopropyl acetate, stirred at room temperature, filtered, and dried in vacuo to obtain the product (30 mg, yield: 80.86%).

The ion chromatography (HPIC) test result of the obtained product: the chloride ion content is 7.54%, indicating that the molar ratio of the compound in the salt to hydrochloric acid is about 1:1. Form X was detected by X-powder diffraction.

Example 9: Form I of the hydrochloride salt of Compound A

Compound A hydrochloride crystal form II (37.1 mg, 0.07956 mmol) was dissolved in 0.3 mL ethanol and 0.3 mL isopropyl ether, and stirred at room temperature for 16 hours. Stir at room temperature, filter, and vacuum dry to obtain the product (30 mg, yield: 80.86%).

The ion chromatography (HPIC) test result of the obtained product: the chloride ion content is 7.44%, indicating that the molar ratio of the compound in the salt to hydrochloric acid is about 1:1. Form X was detected by X-powder diffraction.

Example 10: Compound A Hydrochloride Form I

Compound A hydrochloride crystal form II (1 g, 2.14 mmol) was dissolved in a mixed solvent of 10 mL of isopropanol and isopropyl acetate (V:V=1:2), stirred at room temperature, filtered, and dried in vacuum, The product was obtained (600 mg, yield: 60%).

The ion chromatography (HPIC) detection result of the obtained product: the chloride ion content is 7.55%, indicating that the molar ratio of the compound in the salt to hydrochloric acid is about 1:1. Form X was detected by X-powder diffraction.

Test 1: During the DSC detection process, the aforementioned sample was heated to 65°C or 110°C and taken out. It was still crystalline form II by X-powder diffraction, and the crystalline form did not change.

Test 2: Place the sample under the conditions of 25℃, 10.0% RH-80.0% RH, as the humidity increases, the water absorption also increases, the weight change is 0.7188%, less than 2% but not less than 0.2%, the sample is slightly Hygroscopicity; during the humidity change of 0%-95%, the desorption process of this sample basically coincides with the adsorption process. The DVS spectrum is shown in Figure 10, and the X-ray powder diffraction comparison before and after DVS is shown in Figure 11.

Example 11: Form I of the hydrochloride salt of Compound A

Dissolve Compound A Hydrochloride Form I (30 mg, 0.064 mmoL), Compound A Hydrochloride Form II (30 mg, 0.064 mmoL), Compound A Hydrochloride Form III (30 mg, 0.064 mmoL) 1 mL of a mixed solvent of isopropyl alcohol and isopropyl acetate (V:V=1:2), protected from light, stirred at room temperature, filtered, and dried in vacuo to obtain the product (60 mg, yield: 66.6%).

The ion chromatography (HPIC) test result of the obtained product: the chloride ion content is 7.50%, indicating that the molar ratio of the compound in the salt to hydrochloric acid is about 1:1. Form X was detected by X-powder diffraction.

Example 12: Form III of Compound A Hydrochloride

Compound A hydrochloride crystal form II (37.1 mg, 0.07956 mmol) was dissolved in 0.5 mL of acetone, stirred at room temperature, filtered, and dried in vacuo to obtain the product (30 mg, yield: 80.86%). The ion chromatography (HPIC) test result of the obtained product: the chloride ion content was 7.59%. Form III was detected by X-powder diffraction.

Example 13: Form III of Compound A hydrochloride

Compound A hydrochloride crystal form II (37.1 mg, 0.07956 mmol) was dissolved in 0.5 mL of tetrahydrofuran, stirred at room temperature, filtered, and dried in vacuo to obtain the product (30 mg, yield: 80.86%). Form III was detected by X-powder diffraction.

Example 14: Form III of Compound A hydrochloride

Compound A hydrochloride crystal form II (37.1 mg, 0.07956 mmol) was dissolved in 0.3 mL 1,4-dioxane and 0.3 mL tetrahydrofuran, stirred at room temperature, filtered, and dried in vacuo to give the product (30 mg, produced Rate: 80.86%). Form III was detected by X-powder diffraction.

Example 15: Form III of Compound A hydrochloride

Compound A hydrochloride crystal form II (37.1 mg, 0.07956 mmol) was dissolved in 0.3 mL of tetrahydrofuran and 0.3 mL of isopropanol, stirred at room temperature, filtered, and dried in vacuo to give the product (30 mg, yield: 80.86%) . Form III was detected by X-powder diffraction.

Example 16: Form III of Compound A Hydrochloride

Compound A hydrochloride crystal form II (37.1 mg, 0.07956 mmol) was dissolved in 0.5 mL 1,4-dioxane, stirred at room temperature, filtered, and dried in vacuo to give the product (30 mg, yield: 80.86%) ). Form III was detected by X-powder diffraction.

Example 17: Form III of Compound A Hydrochloride

Compound A hydrochloride crystal form II (1 g, 2.14 mmol) was dissolved in 10 mL 1,4-dioxane, stirred at room temperature, filtered, and dried in vacuo to give the product (600 mg, yield: 60%) ). Form III was detected by X-powder diffraction. The ion chromatography (HPIC) test result of the obtained product: the chloride ion content was 7.41%.

Test 1: During the DSC detection process, the aforementioned sample was heated to 65°C or 110°C and taken out, which was detected by X-powder diffraction as crystal form III, and the crystal form did not change.

Test 2: Place the sample under the conditions of 25℃, 10.0% RH-80.0% RH, the water absorption also increases with the increase of humidity, the weight change is 1.9898%, less than 2% but not less than 0.2%, the sample is slightly Hygroscopicity; the sample is slightly hygroscopic; during the humidity change of 0%-95%, the desorption process of this sample basically coincides with the adsorption process; the DVS spectrum is shown in Figure 12, X-ray powder diffraction comparison before and after DVS See Figure 13.

Example 18: Form IV of the hydrochloride salt

After placing the crystal form III of Compound A hydrochloride under RH 90% for 24 days, the XRPD pattern of the crystalline sample is shown in Figure 14, and the characteristic peak positions are shown in Table 4 below: Table 4

Example 19: Form A of Compound A hydrobromide salt

Compound A (84 mg, 0.195 mmol) was dissolved in 1 mL of isopropanol, and 47% hydrobromic acid (0.027 mL, 0.234 mmol) was slowly added dropwise, stirred at room temperature for 4 hours, and concentrated under reduced pressure to obtain a crude product (100 mg) , Dissolve the crude product in 0.4 mL isopropyl alcohol, add 1.2 mL isopropyl ether dropwise, stir at 60°C for 1 hour, slowly cool to room temperature, stir, crystallize, filter, and vacuum dry to obtain the product (90 mg, yield: 90%).

The ion chromatography (HPIC) detection result of the obtained product: the bromide ion content was 15.77%, indicating that the molar ratio of the compound in the salt to hydrochloric acid was about 1:1.

The XRPD pattern of the crystalline sample is shown in Figure 15, and the characteristic peak positions are shown in Table 5 below: Table 5

Example 20: Form A of Compound A hydrobromide salt

Compound A (84 mg, 0.195 mmol) was dissolved in 1 mL of isopropanol, and 47% hydrobromic acid (0.027 mL, 0.234 mmol) was slowly added dropwise, stirred at room temperature for 4 hours, and the crude product (100 mg), dissolve the crude product in 0.4 mL isopropanol, slowly add 1.2 mL isopropyl acetate dropwise, stir at 60°C for 1 hour, slowly cool to room temperature, stir, crystallize, filter, and vacuum dry to obtain the product (90 mg , Yield: 90%). Form A of hydrobromide salt was detected by X-powder diffraction.

Example 21: Experiments on the influencing factors of crystal forms I and III of the hydrochloride salt of compound A

Place Form I and III of the hydrochloride crystals of Compound A flatly and open them, and examine the samples under heating (40℃, 60℃), light (4500 Lux), high humidity (RH 75%, RH 90%) The stability of the sampling period is 24 days. Table 6

in conclusion: The experimental results of the influencing factors in Table 6 show that the crystal forms I and III of Compound A hydrochloride were placed under the conditions of 40 ℃, 60 ℃, light (4500 Lux) and RH 75% for 24 days, and the crystal structure of the compound did not change. , There is no crystal form transition, and it has good stability.

Example 22: Long-term accelerated stability experiment

The crystal forms I and III of Compound A hydrochloride were placed at 25°C, 60% RH and 40°C, 75% RH for 1 month, 3 months and 6 months stability inspection. The data are as follows: Table 7

Experimental results: The experimental results in Table 7 show that at 25°C and 60% RH, the hydrochloride crystal forms I and III have good stability, but at 40°C and 75% RH, the hydrochloride crystals Form I has better stability than Form III.

Example 23: Compound A Phosphate Form A

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of acetone, heated to 45°C and stirred to dissolve, and phosphoric acid (0.0517 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid.

The ion chromatography (HPIC) detection result of the obtained product: the phosphate content was 22.92%, indicating that the molar ratio of the compound in the salt to the phosphate was about 1:1.

The XRPD pattern of the crystalline sample is shown in Figure 16, and its DSC pattern is shown in Figure 17. The melting peak is around 165.33℃, and the characteristic peak position is shown in Table 8 below: Table 8

Example 24: Compound A Phosphate Form A

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of ethyl acetate, heated to 45°C with stirring and dissolved, and phosphoric acid (0.0517 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. Form A of phosphate was detected by X-powder diffraction.

Example 25: Compound A Phosphate Form A

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of isopropanol, heated to 45°C and stirred to dissolve, and phosphoric acid (0.0517 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. Form A of phosphate was detected by X-powder diffraction.

Example 26: Compound A Phosphate Form A

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of acetone, heated to 45°C and stirred to dissolve, and phosphoric acid (0.0987 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered and dried to obtain a solid. Form A of phosphate was detected by X-powder diffraction.

Example 27: Compound A Phosphate Form A

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of ethyl acetate, heated to 45°C with stirring to dissolve, and phosphoric acid (0.0987 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. Form A of phosphate was detected by X-powder diffraction.

Example 28: Compound A Phosphate Form B

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of 1,4-dioxane, heated to 45°C with stirring and dissolved, and phosphoric acid (0.0517 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered and dried to obtain a solid. The ion chromatography (HPIC) detection result of the obtained product: the phosphate content was 21.94%, indicating that the molar ratio of the compound in the salt to the phosphate was about 1:1.

The XRPD pattern of the crystalline sample is shown in Figure 18, and its DSC pattern is shown in Figure 19. The melting peak is around 162.50℃, and the characteristic peak position is shown in Table 9 below: Table 9

Example 29: Compound A Phosphate Form B

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of 1,4-dioxane, heated to 45°C and stirred to dissolve. Phosphoric acid (0.0987 mmol) was slowly added dropwise, the reaction was stirred, cooled, filtered, and dried to obtain a solid. Form X of the phosphate was detected by X-powder diffraction.

Example 30: Compound A Phosphate Form B

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of isopropanol, heated to 45°C and stirred to dissolve, and phosphoric acid (0.0987 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. Form X of the phosphate was detected by X-powder diffraction.

Example 31: Compound A Phosphate Form C

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL tertiary butyl dimethyl ether, heated to 45°C with stirring and dissolved, and phosphoric acid (0.0517 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. The ion chromatography (HPIC) detection result of the obtained product: the phosphate content was 21.54%, indicating that the molar ratio of the compound in the salt to the phosphate was about 1:1.

The XRPD pattern of the crystalline sample is shown in Figure 20, and the DSC pattern is shown in Figure 21. The melting peak is around 162.26℃, and the characteristic peak position is shown in Table 10 below: Table 10

Example 32: Compound A Phosphate Form C

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL tertiary butyl dimethyl ether, heated to 45°C with stirring and dissolved, and phosphoric acid (0.0987 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. Form C of phosphate was detected by X-powder diffraction.

Example 33: Compound A Phosphate Form D

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of dichloromethane, heated to 45°C with stirring to dissolve, and phosphoric acid (0.0517 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered and dried to obtain a solid. The ion chromatography (HPIC) test result of the obtained product: the phosphate content was 18.18%, indicating that the molar ratio of the compound in the salt to the phosphate was about 1:1.

The XRPD pattern of the crystalline sample is shown in FIG. 22, and the DSC pattern is shown in FIG. 23. The melting peak point is around 159.44°C, and the characteristic peak positions are shown in Table 11 below: Table 11

Example 34: Compound A Phosphate Form F

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of methyl isobutyl ketone, heated to 45°C with stirring and dissolved, and phosphoric acid (0.0517 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. The ion chromatography (HPIC) test result of the obtained product: the phosphate content was 21.98%, indicating that the molar ratio of the compound in the salt to the phosphate was about 1:1.

The XRPD pattern of the crystalline sample is shown in Figure 24, and its DSC pattern is shown in Figure 25. The melting peak is around 160.16℃, and the characteristic peak position is shown in Table 12 below: Table 12

Example 35: Compound A Phosphate Form F

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of methyl isobutyl ketone, heated to 45°C with stirring and dissolved, and phosphoric acid (0.0987 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. The crystal form F of phosphate was detected by X-powder diffraction.

Example 36: Compound A Phosphate Form G

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of acetonitrile, heated to 45°C and stirred to dissolve, and phosphoric acid (0.0517 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. The ion chromatography (HPIC) detection result of the obtained product: the phosphate content was 21.95%, indicating that the molar ratio of the compound in the salt to the phosphate was about 1:1.

The XRPD pattern of the crystalline sample is shown in Figure 26, and the characteristic peak positions are shown in Table 13 below:

Example 37: Compound A Phosphate Form G

Compound A (20 mg, 0.047 mmol) was added to 0.2 mL of acetonitrile, heated to 45°C and stirred to dissolve, and phosphoric acid (0.0987 mmol) was slowly added dropwise. The reaction was stirred, cooled, filtered, and dried to obtain a solid. The crystal form G of phosphate was detected by X-powder diffraction.

Example 38: Crystal form H of compound A phosphate

The crystal form A of Compound A phosphate was placed at 40°C and RH75% for 7 days. The XRPD pattern of the crystalline sample is shown in FIG. 27, and the characteristic peak positions are as follows: Table 14

Although the present invention has been disclosed as above with examples, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention belongs can make some modifications and retouching without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the scope defined in the appended patent application.

no

Figure 1: The XRPD pattern of Form I of the hydrochloride salt of the compound of formula A. Figure 2: DSC spectrum of Form I of the hydrochloride salt of the compound of formula A. Figure 3: TGA spectrum of Form I of the hydrochloride salt of the compound represented by formula A. Figure 4: XRPD pattern of the crystalline form II of the hydrochloride salt of the compound represented by formula A. Figure 5: DSC pattern of the crystalline form II of the hydrochloride salt of the compound represented by formula A. Figure 6: TGA pattern of crystalline form II of the hydrochloride salt of the compound represented by formula A. Figure 7: XRPD pattern of the crystalline form III of the hydrochloride salt of the compound of formula A. Figure 8: DSC pattern of Form III of the hydrochloride salt of the compound of formula A. Figure 9: TGA pattern of Form III of the hydrochloride salt of the compound represented by Formula A. Figure 10: DVS pattern of Form I of the hydrochloride salt of the compound of formula A. Figure 11: Comparison of X-ray powder diffraction before and after DVS of Form I of the hydrochloride salt of the compound of formula A. Figure 12: DVS pattern of the crystalline form III of the hydrochloride salt of the compound represented by formula A. Figure 13: Comparison of X-ray powder diffraction before and after DVS of Form III of the hydrochloride salt of the compound of formula A. Figure 14: XRPD pattern of Form IV of the hydrochloride salt of the compound of formula A. Figure 15: XRPD pattern of Form A of the hydrobromide salt of the compound of formula A. Figure 16: The XRPD pattern of Form A of the phosphate salt of the compound represented by Formula A. Fig. 17: DSC pattern of the crystalline form A of the compound phosphate represented by formula A. Figure 18: XRPD pattern of the crystalline form B of the compound phosphate of formula A. Figure 19: DSC pattern of Form B of the phosphate salt of the compound represented by Formula A. Figure 20: XRPD pattern of Form C of the phosphate salt of the compound represented by Formula A. Figure 21: DSC pattern of Form C of the phosphate salt of the compound represented by Formula A. Figure 22: XRPD pattern of crystalline form D of the compound phosphate of formula A. Figure 23: DSC pattern of the crystalline form D of the phosphate salt of the compound represented by formula A. Figure 24: XRPD pattern of the crystalline form F of the compound phosphate represented by formula A. Figure 25: DSC pattern of the crystalline form F of the compound phosphate represented by formula A. Figure 26: XRPD pattern of the crystalline form G of the compound phosphate of formula A. Figure 27: XRPD pattern of Form H of the compound phosphate of formula A.

Claims (37)

A pharmaceutically acceptable salt of a compound of formula A, said pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, methanesulfonate, phosphate, citrate, acetate, maleic acid Salt, tartrate, succinate, benzoate or fumarate, preferably hydrochloride, phosphate, hydrobromide

. The pharmaceutically acceptable salt of the compound represented by formula A according to item 1 of the patent application range, characterized in that the chemical ratio of the compound to the acid molecule is 1:2 to 2:1, preferably 1:2, 1:1, 2:1. The method for preparing a pharmaceutically acceptable salt of the compound represented by formula A according to item 1 or 2 of the patent application includes the step of forming a salt of the compound represented by formula A with an acid. The preparation method according to item 3 of the patent application range, characterized in that the solvent used in the salt formation reaction is selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tertiary butyl ether , At least one of acetonitrile, ethanol, 1,4-dioxane, ethyl acetate. A pharmaceutical composition containing a pharmaceutically acceptable salt of a compound represented by formula A according to item 1 of the patent application scope and optionally medicinal from at least one of a pharmaceutically acceptable carrier, diluent or excipient Accessories. The use of a pharmaceutically acceptable salt of the compound represented by formula A as described in item 1 of the scope of the patent application for the preparation of a medicament for the treatment or prevention of a disease or condition known to be or which may show a beneficial effect by inhibiting oxytocin, The disease or disorder is selected from sexual dysfunction, hyposexual disorder, sexual arousal disorder, orgasm disorder, sexual intercourse pain disorder, premature ejaculation, pre-term delivery, complications of childbirth, appetite and eating disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, Congestive heart failure, arterial hypertension, cirrhosis, renal hypertension, high intraocular pressure, obsessive-compulsive disorder and behavioral disorders, and neuropsychiatric diseases, preferably sexual dysfunction, sexual arousal disorder, orgasm disorder, painful intercourse and premature ejaculation. The use of a pharmaceutically acceptable salt of a compound represented by formula A as described in item 1 of the patent application scope in the preparation of a medicine for antagonizing oxytocin. A crystalline form I of the hydrochloride salt of a compound of formula A, characterized by an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ , characterized at 7.98, 17.16, 21.74, 23.00, 25.00, 27.04, 32.54 peak

. The crystalline form I of the hydrochloride salt of the compound represented by formula A according to item 8 of the patent application range is characterized in that the X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ is at 7.98, 8.44, 13.38, 17.16 , 18.10, 19.02, 21.74, 23.00, 25.00, 27.04, 32.54 have characteristic peaks. The crystalline form I of the hydrochloride salt of the compound represented by formula A as described in item 8 or 9 of the patent application range is characterized by an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ at 7.98, 8.44, 12.62 , 13.38, 15.22, 17.16, 18.10, 19.02, 19.80, 21.36, 21.74, 23.00, 25.00, 27.04, 32.54 have characteristic peaks. The crystalline form I of the hydrochloride salt of the compound represented by formula A according to any one of the patent application ranges from 8 to 10, characterized in that the X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ is shown in FIG. 1 . A method for preparing the crystalline form I of the hydrochloride of the compound represented by formula A as described in item 8 of the scope of the patent application includes: (A) Add the compound represented by formula A to the solvent (I), dissolve with stirring or heat to dissolve, the solvent (I) is selected from isopropanol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tris At least one of grade butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, preferably isopropanol/isopropyl ether, and; (B) Add hydrogen chloride solution dropwise and stir to crystallize. A crystalline form II of the hydrochloride salt of a compound of formula A, characterized by an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ , characterized at 7.98, 13.80, 17.10, 18.10, 18.92, 21.44, 26.50 peak

. A method for preparing the crystal form II of the hydrochloride of the compound represented by formula A as described in item 13 of the patent application scope includes: (A) Add the compound represented by formula A to the solvent (II), stir to dissolve or heat to dissolve, the solvent (II) is selected from isopropanol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tris At least one of grade butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and; (B) Add hydrogen chloride solution dropwise and stir to crystallize. A crystalline form III of the hydrochloride salt of a compound of formula A, characterized by an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ , characterized at 7.40, 14.02, 18.66, 22.14, 23.76, 27.06, 30.58 peak

. A method for preparing the crystalline form III of the hydrochloride of the compound represented by formula A as described in item 15 of the patent application scope includes: (A) Add the compound represented by formula A to the solvent (III), stir to dissolve or heat to dissolve, the solvent (III) is selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tri At least one of grade butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, preferably isopropanol/tetrahydrofuran, and; (B) Add hydrogen chloride solution dropwise and stir to crystallize. The crystal form IV of the hydrochloride salt of a compound represented by formula A is characterized by an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ at 12.26, 18.73, 20.34, 21.41, 23.72, 24.82, 32.58 peak

. The crystalline form A of the hydrobromide salt of a compound of formula A has an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ and has characteristic peaks at 6.12, 7.91, 8.18, 17.12, 18.00, 18.86, 25.14

. A method for preparing the crystalline form A of the compound hydrobromide salt represented by the formula A as described in item 18 of the patent application scope includes: (A) The compound represented by formula A is added to a solvent (IV), dissolved by stirring or heated, and the solvent (IV) is selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tertiary At least one of butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, preferably isopropyl alcohol/isopropyl ether, isopropyl alcohol/isopropyl acetate, (B) Add hydrobromic acid dropwise and stir to crystallize. The crystalline form A of a compound phosphate represented by formula A has an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ and has characteristic peaks at 5.09, 10.29, 12.89, 16.26, 20.86, 22.67

. A method for preparing the crystalline form A of the compound phosphate represented by the formula A as described in item 20 of the patent application scope includes: (A) The compound represented by the formula A is added to a solvent (V), dissolved by stirring or heated to dissolve, the solvent (V) is selected from at least one of acetone, ethyl acetate, and isopropanol, (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. The crystalline form B of a compound of formula A phosphate has an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ , with characteristic peaks at 5.00, 14.24, 16.18, 20.51, 21.54, 22.49, 30.54

. A method for preparing crystalline form B of the compound phosphate represented by formula A as described in item 22 of the patent application scope includes: (A) The compound represented by formula A is added to a solvent (VI), dissolved by stirring or heated to dissolve, the solvent (VI) is selected from at least one of 1,4-dioxane and isopropanol, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. The crystalline form C of a compound of formula A phosphate has an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ and has characteristic peaks at 4.92, 9.91, 11.08, 15.98, 20.18, 20.74, 22.44

. A method for preparing the crystalline form C of the compound phosphate represented by formula A as described in item 24 of the patent application scope includes: (A) The compound represented by formula A is added to a solvent (VII), dissolved by stirring or heated to dissolve, the solvent (VII) is selected from tertiary butyl dimethyl ether, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. The crystalline form D of a compound of formula A phosphate has an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ and has characteristic peaks at 5.14, 9.98, 10.31, 16.49, 19.49, 20.94, 22.75

. A method for preparing the crystal form D of the compound phosphate represented by formula A as described in item 26 of the patent application scope includes: (A) The compound represented by formula A is added to the solvent (VIII), dissolved by stirring or heated to dissolve, the solvent (IX) is selected from dichloromethane, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. The crystalline form F of a compound of formula A phosphate has an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ and has characteristic peaks at 4.96, 5.35, 16.06, 20.39, 22.33, 25.19

. A method for preparing crystal form F of the compound phosphate represented by formula A as described in item 28 of the patent application scope includes: (A) The compound represented by formula A is added to a solvent (IX), and dissolved by stirring or heating, the solvent (IX) is selected from methyl isobutyl ketone, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. The crystalline form G of a compound phosphate represented by formula A has an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ and has characteristic peaks at 5.26, 16.08, 16.81, 19.60, 20.90, 23.01, 23.96

. A method for preparing the crystalline form G of the compound phosphate represented by the formula A as described in item 30 of the patent application scope includes: (A) The compound represented by formula A is added to a solvent (IX), and dissolved by stirring or heating, the solvent (IX) is selected from methyl isobutyl ketone, and; (B) Add phosphoric acid or phosphoric acid solution dropwise and stir to crystallize. The crystalline form H of a compound phosphate represented by formula A has an X-ray powder diffraction pattern expressed at a diffraction angle of 2 θ and has characteristic peaks at 5.32, 15.97, 16.16, 19.69, 20.10, 21.76

. According to the crystalline form I of the hydrochloride of the compound represented by the formula A described in any one of the patent application scope 8-11, the crystalline form II of the hydrochloride of the compound represented by the formula A described in the patent application scope 13 The crystalline form III of the hydrochloride of the compound represented by the formula A described in item 15 of the patent scope, the crystalline form IV of the hydrochloride of the compound represented by the formula A described in item 17 of the patent scope, and the The crystalline form A of the hydrobromide salt of the compound represented by formula A described above, the crystalline form A of the compound phosphate represented by formula A described in item 20 of the patent application, and the formula A described in item 22 of the patent application Form B of the compound phosphate, Form C of the compound phosphate represented by the formula A described in item 24 of the patent application, Form D of the compound phosphate represented by the formula A described in item 26 of the patent application, The crystalline form F of the compound phosphate represented by the formula A described in item 28 of the patent scope, the crystalline form G of the compound phosphate represented by the formula A described in item 30 of the patent scope or the item 32 described in the patent scope The crystal form H of the compound phosphate represented by the formula A, wherein the 2 θ angle error range is ±0.30, preferably ±0.20. A pharmaceutical composition containing the crystalline form I of the hydrochloride salt of the compound represented by formula A as described in any of claims 8-11, and the hydrochloride salt of the compound represented by formula A as described in claim 13 Form II of the patent, Form III of the hydrochloride of the compound of formula A as described in item 15 of the patent application, Form IV of the hydrochloride of the compound of formula A as described in item 17 of the patent application The crystalline form A of the compound of formula A hydrobromide according to item 18 of the patent scope, the crystalline form A of the compound phosphate of formula A according to item 20 of the patent scope, and the The crystalline form B of the compound phosphate represented by formula A, the crystalline form C of the compound phosphate represented by formula A described in item 24, and the phosphoric acid compound of formula A described in item 26 of patent application The crystal form D of the salt, the crystal form F of the compound phosphate represented by the formula A described in item 28 of the patent scope, the crystal form G of the compound phosphate represented by the formula A described in item 30 of the patent scope, or the patent application The crystalline form H of the phosphate of the compound represented by the formula A described in the item 32 of the scope is optionally selected from a pharmaceutically acceptable carrier, diluent or excipient. A crystal form I of the hydrochloride salt of the compound represented by formula A according to any one of claims 8-11, and a crystal form II of the hydrochloride salt of compound represented by formula A according to claim 13 , Form III of the hydrochloride salt of the compound of formula A as described in item 15 of the patent scope, Form IV of the hydrochloride salt of the compound of formula A as described in item 17 of the patent scope Form A of the hydrobromide salt of the compound represented by the formula A described in the item, Form A of the phosphate salt of the compound represented by the formula A described in the item 20 of the patent application, Formula A described in the item 22 of the patent application The crystalline form B of the compound phosphate shown, the crystalline form C of the compound phosphate represented by formula A described in item 24 of the patent application, and the crystalline form of the compound phosphate represented by formula A described in item 26 of the patent application D. The crystalline form F of the compound phosphate represented by the formula A described in item 28 of the patent scope, the crystalline form G of the compound phosphate represented by the formula A described in item 30 of the patent scope or the 32nd item applied for in the patent scope The pharmaceutical composition prepared by the crystalline form H of the compound phosphate represented by the formula A. A crystal form I of the hydrochloride salt of the compound represented by formula A according to any one of claims 8-11, a crystal form II of the hydrochloride salt of the compound represented by formula A according to item 13 of the patent application Form III of the hydrochloride salt of the compound of formula A as described in item 15 of the patent application, Form IV of the hydrochloride salt of the compound of formula A as described in item 17 of the patent application, and item 18 of the patent application The crystalline form A of the hydrobromide salt of the compound represented by the formula A, the crystalline form A of the compound phosphate represented by the formula A described in item 20 of the patent application, and the formula A described in the item 22 of the patent application range The crystalline form B of the compound phosphate, the crystalline form C of the compound phosphate represented by formula A described in item 24 of the patent application, and the crystalline form D of the compound phosphate represented by formula A described in item 26 of the patent application , Form F of the compound phosphate represented by the formula A described in item 28 of the patent scope, Form G of the compound phosphate represented by the formula A described in item 30 of the patent scope The use of the crystalline form H of the phosphate of the compound represented by formula A in the preparation of a medicament for the treatment or prevention of a disease or condition known or shown to inhibit the beneficial effects of oxytocin, the disease or condition selected from sexual function Disorders, hyposexual disorder, sexual arousal disorder, orgasm disorder, painful intercourse, premature ejaculation, pre-term delivery, complications of delivery, appetite and eating disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertension , Liver cirrhosis, renal hypertension, high intraocular pressure, obsessive-compulsive disorder and behavioral disorders and neuropsychiatric diseases, preferably sexual dysfunction, sexual arousal disorder, orgasm disorder, sexual intercourse pain disorder and premature ejaculation. A crystal form I of the hydrochloride salt of the compound represented by formula A according to any one of claims 8-11, a crystal form II of the hydrochloride salt of the compound represented by formula A according to item 13 of the patent application Form III of the hydrochloride salt of the compound of formula A as described in item 15 of the patent application, Form IV of the hydrochloride salt of the compound of formula A as described in item 17 of the patent application, and item 18 of the patent application The crystalline form A of the hydrobromide salt of the compound represented by the formula A, the crystalline form A of the compound phosphate represented by the formula A described in item 20 of the patent application, and the formula A described in the item 22 of the patent application range The crystalline form B of the compound phosphate, the crystalline form C of the compound phosphate represented by formula A described in item 24 of the patent application, and the crystalline form D of the compound phosphate represented by formula A described in item 26 of the patent application , Form F of the compound phosphate represented by the formula A described in item 28 of the patent scope, Form G of the compound phosphate represented by the formula A described in item 30 of the patent scope The use of the crystalline form H of the compound phosphate represented by the formula A in the preparation of a medicine for antagonizing oxytocin.

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