ACID ADDITION SALT OF RORy REGULATOR

Abstract

An acid addition salt of a RORγ regulator. Specifically relating to the acid addition salt of the compound of formula II. More specifically relating to benzoate, oxalate, methanesulfonate, maleate, hydrobromate, hydrochloride salt, and acetate of the compound of formula II and the benzoate crystal form, benzoate amorphous form, oxalate crystal form, oxalate amorphous form, methanesulfonate amorphous form, maleate B crystal form, maleate C crystal form, maleate D crystal form, hydrobromate I crystal form, hydrochloride salt α crystal form, hydrochloride salt β crystal form, hydrochloride salt γ crystal form, and acetate crystal form of the compound of formula II.

##STR00001##

Claims

1. An acid addition salt of a compound of formula II or a pharmaceutically acceptable solvate of the acid addition salt, wherein the acid addition salt is an organic acid addition salt or an inorganic acid addition salt, ##STR00004##

2. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 1, wherein the organic acid addition salt is selected from the group consisting of benzoate, oxalate, methanesulfonate, maleate and acetate, and the inorganic acid addition salt is selected from the group consisting of hydrobromide and hydrochloride.

3.-8. (canceled)

9. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 2, wherein the hydrobromide is a crystalline form I having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 12.579, 16.414, 17.075, 17.780 and 20.733.

10. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 2, wherein the hydrobromide is a crystalline form I having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 12.579, 16.414, 17.075, 17.780, 19.675, 20.733, 21.262, 23.113, 23.906, 24.391, 26.550, 28.445, 28.930 and 29.547.

11. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 2, wherein the hydrobromide is a crystalline form I having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 8.128, 11.918, 12.579, 16.414, 17.075, 17.780, 18.750, 19.675, 20.733, 21.262, 23.113, 23.906, 24.391, 26.550, 28.445, 28.930, 29.547, 30.958, 32.236, 33.382, 38.670, 39.640, 40.830, 42.064, 43.342, 46.824, 48.190, 48.983 and 50.746.

12. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 2, wherein the hydrochloride is a crystalline form α having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 7.931, 10.115, 13.920, 15.224, 17.425 and 18.309.

13.-15. (canceled)

16. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 9, wherein the 2θ values of the crystalline forms have an error range of ±0.2.

17.-18. (canceled)

19. A pharmaceutical composition comprising the acid addition salt or the pharmaceutically acceptable solvate of the acid addition salt according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20.-24. (canceled)

25. A method for preparing a pharmaceutical composition, comprising: mixing the acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 1 with at least one pharmaceutically acceptable carrier, diluent or excipient.

26. (canceled)

27. A method for treating a disease or disorder mediated by RORγ in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of pharmaceutical composition according to claim 19.

28. The pharmaceutical composition according to claim 19, wherein the pharmaceutically acceptable solvate of the acid addition salt is hydrobromide.

29. The pharmaceutical composition according to claim 28, wherein the hydrobromide is a crystalline form I.

30. The method according to claim 25, wherein the acid addition salt is hydrobromide.

31. The method according to claim 30, wherein the hydrobromide is a crystalline form I.

32. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 10, wherein the 2θ values of the crystalline forms have an error range of ±0.2.

33. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 11, wherein the 2θ values of the crystalline forms have an error range of ±0.2.

34. The acid addition salt of the compound of formula II or the pharmaceutically acceptable solvate of the acid addition salt according to claim 12, wherein the 2θ values of the crystalline forms have an error range of ±0.2.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0121] FIG. 1 is an XRPD pattern of an amorphous form of a compound of formula II.

[0122] FIG. 2 is an XRPD pattern of an amorphous form of a benzoate of a compound of formula II.

[0123] FIG. 3 is an XRPD pattern of a crystalline form of a benzoate of a compound of formula II.

[0124] FIG. 4 is a DSC pattern of a crystalline form of a benzoate of a compound of formula II.

[0125] FIG. 5 is an XRPD pattern of an amorphous form of an oxalate of a compound of formula II.

[0126] FIG. 6 is an XRPD pattern of a crystalline form of an oxalate of a compound of formula II.

[0127] FIG. 7 is an XRPD pattern of an amorphous form of a methanesulfonate of a compound of formula II.

[0128] FIG. 8 is an XRPD pattern of a crystalline form B of a maleate of a compound of formula II.

[0129] FIG. 9 is a DSC pattern of a crystalline form B of a maleate of a compound of formula II.

[0130] FIG. 10 is a TGA pattern of a crystalline form B of a maleate of a compound of formula II.

[0131] FIG. 11 is a DVS vapor sorption plot of a crystalline form B of a maleate of a compound of formula II.

[0132] FIG. 12 is a comparison of XRPD patterns before and after DVS analysis of a crystalline form B of a maleate of a compound of formula II.

[0133] FIG. 13 is an XRPD pattern of a crystalline form C of a maleate of a compound of formula II.

[0134] FIG. 14 is a DSC pattern of a crystalline form C of a maleate of a compound of formula II.

[0135] FIG. 15 is a TGA pattern of a crystalline form C of a maleate of the compound of formula II.

[0136] FIG. 16 is an XRPD pattern of a crystalline form D of a maleate of a compound of formula II.

[0137] FIG. 17 is a DSC pattern of a crystalline form D of a maleate of a compound of formula II.

[0138] FIG. 18 is a TGA pattern of a crystalline form D of a maleate of a compound of formula II.

[0139] FIG. 19 is an XRPD pattern of a crystalline form I of a hydrobromide of a compound of formula II.

[0140] FIG. 20 is a DSC pattern of a crystalline form I of a hydrobromide of a compound of formula II.

[0141] FIG. 21 is a TGA pattern of a crystalline form I of a hydrobromide of a compound of formula II.

[0142] FIG. 22 is a DVS vapor sorption plot of a crystalline form I of a hydrobromide of a compound of formula II.

[0143] FIG. 23 is a comparison of XRPD patterns before and after DVS analysis of a crystalline form I of a hydrobromide of a compound of formula II.

[0144] FIG. 24 is an XRPD pattern of a crystalline form α of a hydrochloride of a compound of formula II.

[0145] FIG. 25 is a DSC pattern of a crystalline form α of a hydrochloride of a compound of formula II.

[0146] FIG. 26 is a TGA pattern of a crystalline form α of a hydrochloride of a compound of formula II.

[0147] FIG. 27 is a DVS vapor sorption plot of a crystalline form α of a hydrochloride of a compound of formula II.

[0148] FIG. 28 is a comparison of XRPD patterns before and after DVS analysis of a crystalline form α of a hydrochloride of a compound of formula II.

[0149] FIG. 29 is an XRPD pattern of a crystalline form β of a hydrochloride of a compound of formula II.

[0150] FIG. 30 is a DSC pattern of a crystalline form β of a hydrochloride of a compound of formula II.

[0151] FIG. 31 is a TGA pattern of a crystalline form β of a hydrochloride of a compound of formula II.

[0152] FIG. 32 is a DVS vapor sorption plot of a crystalline form β of a hydrochloride of a compound of formula II.

[0153] FIG. 33 is a comparison of XRPD patterns before and after DVS analysis of a crystalline form β of a hydrochloride of a compound of formula II.

[0154] FIG. 34 is an XRPD pattern of a crystalline form γ of a hydrochloride of a compound of formula II.

[0155] FIG. 35 is an XRPD pattern of a crystalline form of an acetate of a compound of formula II.

[0156] FIG. 36 is a DSC pattern of a crystalline form of an acetate of a compound of formula II.

DETAILED DESCRIPTION

[0157] Hereinafter, the present disclosure will be explained in more details with reference to the examples. The examples are only used to illustrate the technical solutions of the present disclosure, rather than limit the essence and scope of the present disclosure.

[0158] Test Conditions for the Instruments Used in the Experiment:

[0159] The structure of the compounds was determined by nuclear magnetic resonance (NMR) analysis or/and mass spectrometry (MS). NMR shifts (δ) are given in a unit of 10.sup.−6 (ppm). NMR analysis was conducted with a Bruker AVANCE-400 system using deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3) and deuterated methanol (CD.sub.3OD) as solvents and tetramethylsilane (TMS) as internal standard.

[0160] MS was conducted with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0161] The HPLC was conducted with an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm chromatographic column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm chromatographic column).

[0162] XRPD refers to X-ray powder diffraction detection: The measurement was conducted using a BRUKER D8 X-ray diffractometer with a Cu anode (40 kV, 40 mA) and Cu-Kα radiation (λ=1.5418 Å). Scanning mode: θ/2θ, scanning range: 10-48°.

[0163] DSC refers to differential scanning calorimetry: The measurement was conducted using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a temperature ramping rate of 10° C./min, specific temperature ranges shown in corresponding patterns (mostly 25-300 or 25-350° C.) and a nitrogen purging speed of 50 mL/min.

[0164] TGA refers to thermogravimetric analysis: The measurement was conducted using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a temperature ramping rate of 10° C./min, specific temperature ranges shown in corresponding patterns (mostly 25-300° C.) and a nitrogen purging speed of 20 mL/min.

[0165] DVS refers to dynamic vapor sorption: The measurement was conducted with a Surface Measurement Systems advantage 2 at 25° C., starting from 50% humidity in humidity range of 0%-95% with a step size of 10%. The judging criterion was that the mass change of each gradient dM/dT is less than 0.002 and TMAX is less than 360 min in two circles.

[0166] The monitoring of the reaction progress in the examples was conducted by thin layer chromatography (TLC). The developing solvent for reactions, the eluent system for column chromatography purification and the developing solvent system for thin layer chromatography included: A: n-hexane/ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compound, or by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Comparative Example 1. Preparation Example of Compound of Formula II (Methods in Examples 152 and 153 of Patent Application No. PCT/US19/30526)

Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

Preparation of (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

[0167] ##STR00003##

Step I. Preparation of 6-chloro-2′-(difluoromethoxy)-[1,1′-biphenyl]-3,4-diamine

[0168] A mixture of 4-bromo-5-chlorobenzene-1,2-diamine (1.5 g, 6.78 mmol), 2-(2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 8.15 mmol), tris(dibenzylideneacetone)dipalladium (620 mg), tri-tert-butylphosphonium tetrafluoroborate (393 mg), sodium carbonate (1.7 g, 13.7 mmol), 1,4-dioxane (50 mL) and water (10 mL) was deoxygenated, heated to 90° C., and stirred for 3 h. The reaction solution was concentrated at reduced pressure. The residue was directly loaded on an ISCO solid column, and eluted with a mixed solvent of n-hexane/ethyl acetate to give a white solid product (1.0 g, 51.9% yield). MS (+) ES: 285 (M+H).sup.+.

Step II. Preparation of ethyl 4-((4-amino-6-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate

Preparation of ethyl 4-((5-amino-2-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate

[0169] EDCl (560 mg, 2.93 mmol), HOBT (447 mg, 2.93 mmol) and DIPEA (380 mg, 2.94 mmol) were added to a solution of 6-chloro-2′-(difluoromethoxy)-[1,1′-biphenyl]-3,4-diamine (543 mg, 1.9 mmol), 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-ethoxy-4-oxobutanoic acid (500 mg, 1.47 mmol) and DMF (5 mL), and the reaction system was stirred at room temperature for 2 h. The reaction solution was adsorbed on 5 g of silica gel, loaded onto a silica gel column, and eluted with 45% ethyl acetate in n-hexane to obtain a mixture of ethyl 4-((4-amino-6-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate as a white solid (600 mg, 62.3% yield). MS (ESI): 607 (M+H).sup.+.

Step III. Preparation of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate

[0170] A solution of the mixture of ethyl 4-((4-amino-6-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2′-(dichloromethoxy)-[1,1′-biphenyl]-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate (800 mg) in acetic acid (15 mL) was heated to 80° C. and stirred for 2 h for reaction. The reaction solution was concentrated at reduced pressure, and the obtained residue was purified by column chromatography with an eluent of 60% ethyl acetate in n-hexane to obtain ethyl 3-(6-chloro-5-(2-(dichloromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate as an off-white solid (600 mg, 77.3% yield). MS (ESI): 589 (M+H).sup.+.

Step IV. Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

Preparation of (R)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

[0171] A 7 N solution of ammonia in methanol (4.8 mL, 33.9 mmol) was added to a solution of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propionate (400 mg, 0.68 mmol) in methanol (5 mL). The reaction system was heated to 60° C. and stirred for 12 h for reaction. The reaction solution was concentrated at reduced pressure, and the resulting crude product was purified by column chromatography with a n-hexane/ethyl acetate eluent system to obtain 3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide (177 mg).

[0172] The resulting product was subjected to chiral resolution (conditions: CHIRALCEL OZ-H (OZH00CD-VC005), 0.46 cm I.D.×15 cm L; mobile phase: 100% methanol; flow rate: 1.0 mL/min). The corresponding fractions were collected and concentrated at reduced pressure to obtain the target compound (67 mg, 60 mg).

[0173] Single-Component Compounds (Shorter Retention Time)

[0174] MS (+) ES: 560 (M+H).sup.+

[0175] Chiral analysis methodology: retention time: 3.919 min, chiral purity: 100% (column: OD Phenomenex Lux Cellulose-1 150×4.6 mm, 5 μm; mobile phase: ethanol/n-hexane=80:20 (v:v)).

[0176] 1H NMR (400 mHz, CD.sub.3OD): 7.92 (d, 8.0 Hz, 2H), 7.51-7.49 (s, 1H), 7.65 (d, 8.0 Hz, 2H), 7.56-7.54 (m, 1H), 7.48-7.44 (m, 1H), 7.33-7.32 (m, 2H), 7.28-7.26 (d, 8.0 Hz, 1H), 6.86 (d, 8.0 Hz, 1H), 4.96-4.92 (t, 8.0 Hz, 1H), 3.41-3.35 (dd, 8.0 Hz, 1H), 3.13-3.11 (d, 8.0 Hz, 2H), 3.12-3.06 (dd, 8.0 Hz, 1H), 0.93-0.91 (m, 1H), 0.52-0.50 (d, 8.0 Hz, 2H), 0.13-0.11 (d, 8.0 Hz, 2H).

[0177] Single-Component Compound (Longer Retention Time, Compound of Formula II)

[0178] MS (+) ES: 560 (M+H).sup.+

[0179] Chiral analysis methodology: retention time: 8.942 min, chiral purity: 100% (column: OD Phenomenex Lux Cellulose-1 150×4.6 mm, 5 μm; mobile phase: ethanol/n-hexane=80:20 (v:v)).

[0180] 1H NMR (400 mHz, CD.sub.3OD): 7.92 (d, 8.0 Hz, 2H), 7.51-7.49 (s, 1H), 7.65 (d, 8.0 Hz, 2H), 7.56-7.54 (m, 1H), 7.48-7.44 (m, 1H), 7.33-7.32 (m, 2H), 7.28-7.26 (d, 8.0 Hz, 1H), 6.86 (d, 8.0 Hz, 1H), 4.96-4.92 (t, 8.0 Hz, 1H), 3.41-3.35 (dd, 8.0 Hz, 1H), 3.13-3.11 (d, 8.0 Hz, 2H), 3.12-3.06 (dd, 8.0 Hz, 1H), 0.93-0.91 (m, 1H), 0.52-0.50 (d, 8.0 Hz, 2H), 0.13-0.11 (d, 8.0 Hz, 2H).

Test Example 1. Biochemical Assay of LanthaScreen TR-FRET RORγ-LBD and Co-Activation Peptide

[0181] Materials and Reagents

[0182] 1. RORγ LBD-GST tagged (Cat No. RORC-114H, Creative Biomart)

[0183] 2. Fluorescein-D22 coactivator (Cat No. PV4386, Invitrogen)

[0184] 3. LanthaScreen™ Tb anti-GST antibody (Cat No. PV3550, Invitrogen)

[0185] 4. TR-FRET coregulatory buffer D (Cat No. PV4420, Invitrogen)

[0186] 5. DTT (Cat No. P2325, Fisher)

[0187] 6. 384 well assay plate (Cat No. 6008280, Perkin Elmer)

[0188] 7. Tecan Infinite M1000 plate reader (Tecan)

[0189] Procedures

[0190] Complete TR-FRET Coregulator Buffer D was prepared by diluting 1 M DTT with TR-FRET Coregulator Buffer D to a final concentration of 5 mM DTT. The compounds were diluted in Complete TR-FRET Coregulator Buffer D. The solutions were serially 7-fold diluted from an initial concentration of 3 μM to the 7.sup.th concentration. 10 μL of the dilutions was added to each well of the 384-well plate. For negative and positive controls, 10 μL of Complete TR-FRET Coregulator Buffer D was added.

[0191] A RORγ LBD solution was prepared using Complete TR-FRET Coregulator Buffer D. The final concentration of the RORγ LBD solution in each reaction was 25 ng. Other than the negative wells receiving 5 μL of Complete TR-FRET Coregulator Buffer D, 5 μL of the RORγ LBD solution was added to the remaining wells of the 384-well assay plate.

[0192] Complete TR-FRET Coregulator Buffer D was used to prepare a solution containing 0.6 μM Fluorescein-D22 and 8 nM Tbanti-GST antibody, and 5 μL of the prepared solution was added to all wells of the 384-well assay plate.

[0193] The 384-well plate was mixed gently on a plate shaker and let stand at room temperature for 1 h away from light. The 384-well plate was sealed with a plastic film to avoid evaporation.

[0194] The plate was measured on a Tecan Infinite M1000 plate reader at wavelengths of 520 nm and 495 nm. IC.sub.50 values were calculated using GraphPad Prism by plotting log compound concentration versus percentage inhibition. The IC.sub.50 values for the compounds are shown in Table 1.

Test Example 2. Assay for Inhibiting Cytokine IL-17A Production in Human Peripheral Blood Mononuclear Cells

[0195] Materials and Instruments

[0196] 1. Human PBMC (Stemcell, Cat No. 70025.1)

[0197] 2. Lymphocyte medium (Zenbio, Cat No. LYMPH-1)

[0198] 3. TexMACS (Miltenyi Biotec, Cat No. 130-097-196)

[0199] 4. Human Cytostim (Miltenyi Biotec, Cat No. 130-092-173)

[0200] 5. Human IL-17 ELISA, human IL-17 enzyme-linked immunosorbent assay kit (R&D Systems, D1700)

[0201] 6. 96-well cell culture plate (Fisher Scientific, Cat No. 07-200-80)

[0202] 7. Tecan SPARK plate reader (Tecan)

[0203] Procedures

[0204] Frozen human peripheral blood mononuclear cells (PBMCs) were rapidly thawed in a pre-warmed lymphocyte medium and centrifuged at 1000 rpm for 10 min. The cell culture supernatant was discarded, and the cells were gently suspended in the TexMACS medium and counted. T cell activating reagent cytostim (10 μL/mL) was added to the cell suspension in certain proportions, and then the cells were seeded in a 96-well cell culture plate at a density of 1×10.sup.5 PBMCs/well. Test compounds were diluted in gradient using TexMACS medium and added to the treatment wells in 2-3 replicates. Negative control wells containing cells only without cytostim were prepared to obtain background readings. The cell culture plate was incubated in a 5% carbon dioxide/37° C. incubator for 3 days. Cell culture supernatant was collected 3 days after treatment and centrifuged to remove the suspended matter. IL-17A in the supernatant was then quantified using an IL-17A enzyme-linked immunosorbent assay kit. The log(inhibitor) vs. response—Variable slope (four parameters) algorithm in GraphPad Prism 6.0 was used to plot the curve for calculating the IC.sub.50 values of the compounds. The calculation equation of inhibition is as follows:

[00001]$\mathrm{Inhibition}\%=\left[100-\frac{\mathrm{OD}\left(\mathrm{Compound}\right)-\mathrm{OD}\left(\mathrm{NC}\right)}{\mathrm{OD}\left(\mathrm{PC}\right)-\mathrm{OD}\left(\mathrm{NC}\right)}\times 100\right]/-1$

[0205] In the calculation equation, inhibition % is inhibition rate; OD(NC) is the reading of cells in negative control groups with no cytostim and no compound; OD(PC) is the reading of cells in positive control groups with cytostim but no compound; OD(compound) is the reading of cells with cytostim and compound.

TABLE-US-00001 TABLE 1 Binding of compounds of formula II to RORγ and IL-17 production in human peripheral blood mononuclear cells RORγ coactivation IL-17 production Compound assay (IC.sub.50, μM) (IC.sub.50, μM) Those with longer retention 0.013 0.010 time in Examples 152 and 153 (compound of formula II)

Example 1. Preparation of Amorphous Form of Compound of Formula II

[0206] The compound of formula II (30 mg, 53.57 μmol) was added to isopropyl ether (1.5 mL). The mixture was heated to 70° C. to obtain an opaque white suspension. The suspension was slowly cooled to room temperature, stirred for 16 h and filtered. The filter cake was collected and dried in vacuo to obtain a product (20 mg, 66% yield). The product was in an amorphous form with XRPD pattern shown in FIG. 1.

Example 2. Preparation of Amorphous Form of Compound of Formula II

[0207] The compound of formula II (30 mg, 53.57 μmol) was added to toluene (1.5 mL). The mixture was heated to 70° C. and stirred to obtain a clarified solution. The solution was slowly cooled to room temperature and a solid was precipitated on the inner wall of the container. The mixture was stirred for 16 h at room temperature and filtered. The filter cake was collected and dried in vacuo to obtain a product (20 mg, 66% yield). The product was in an amorphous form as determined by X-ray powder diffraction.

Example 3. Preparation of Amorphous Form of Compound of Formula II

[0208] The compound of formula II (30 mg, 53.57 μmol) was added to a 1.5 mL mixture of isopropyl acetate/n-hexane (v:v=1:3). The mixture was heated to 70° C. and a viscous solid was precipitated. The solution was slowly cooled to room temperature and a solid was precipitated. The mixture was stirred for 16 h at room temperature and filtered. The filter cake was collected and dried in vacuo to obtain a product (20 mg, 66% yield). The product was in an amorphous form as determined by X-ray powder diffraction.

Example 4. Preparation of Amorphous Form of Compound of Formula II

[0209] The compound of formula II (5 g, 8.93 mmol) was purified by high performance liquid chromatography (Waters-2767, eluent system: ammonium bicarbonate, water and acetonitrile) to obtain a product (2.5 g, 50% yield). The product was in an amorphous form as determined by X-ray powder diffraction.

Example 5. Influencing Factor Study of Amorphous Form of Compound of Formula II

[0210] A sample of the amorphous form of the compound of formula II (Example 4) was let stand open to examine the stability of the sample in conditions of heating (40° C. and 60° C.), illumination (4500 Lux) and high humidity (RH 75% and RH 90%) in a period of 30 days.

[0211] Results:

TABLE-US-00002 TABLE 2 Results of influencing factor study Amorphous Weight Time Color and form Purity gain Chiral Conditions (days) appearance (%) (%) purity Initial 0 White solid 99.91 / 99.4 4500 Lux 5 White solid 99.91 / / 10 White solid 99.91 / 99.3 30 White solid 99.93 / 99.3 40° C. 5 White solid 99.93 / / 10 White solid 99.90 / 99.4 30 White solid 99.92 / 99.5 60° C. 5 White solid 99.95 / / 10 White solid 99.95 / 99.4 30 White solid 99.95 / 99.4 RH 75% 5 White solid 99.92 10.42 / 10 White solid 99.90 13.2  99.3 30 White solid 99.90 23.24 99.4 RH 90% 5 White solid 99.91 21.67 / 10 White solid 99.92 26.49 99.4 30 White solid 99.89 37.24 99.4

[0212] Conclusion:

[0213] The results of influencing factor study in Table 2 showed that: the amorphous form of the compound of the formula II has good chemical stability after standing for 30 days in conditions of illumination, high temperature of 40° C., high temperature of 60° C., high humidity of 75% and high humidity of 90%.

Example 6. Long-Term/Accelerated Stability Study of Amorphous Form of Compound of Formula II

[0214] The amorphous form of the compound of formula II (Example 4) was subjected to a long-term (25° C., 60% RH)/accelerated (40° C., 75% RH) stability study with a period of 3 months.

[0215] Results

TABLE-US-00003 TABLE 3 Result of long-term/accelerated stability study of amorphous form of compound of formula II Purity Purity Purity Chiral Purity/chiral (%) (%) (%) purity (%) Condition of purity Month Month Month Month Sample standing Initial 1 2 3 3 Amorphous 25° C., 60% RH 99.87/99.2 99.86 99.86 99.85 99.2 form 40° C., 75% RH 99.87/99.2 99.87 99.86 99.88 99.1 5° C. 99.87/99.2 99.86 99.86 99.85 99.1

[0216] The results of the long-term/accelerated stability study in Table 3 showed that: the amorphous form of the compound of formula II has good chemical stability in conditions of a long term (25° C., 60% RH) and acceleration (40° C., 75% RH) in a period of 3 months.

Example 7. Preparation of Amorphous Form of Benzoate of Compound of Formula II

[0217] 0.5 mL of n-hexane was added to 10 mg of the compound of formula II before 2.3 mg of benzoic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as an amorphous form of the benzoate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 2.

Example 8. Preparation of Crystalline Form of Benzoate of Compound of Formula II

[0218] 0.5 mL of methyl tert-butyl ether was added to 10 mg of the compound of formula II before 2.3 mg of benzoic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form of the benzoate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 3. The DSC pattern is shown in FIG. 4, with a first endothermic peak value at 178.46° C. and a second endothermic peak value at 237.42° C.

TABLE-US-00004 TABLE 4 Characteristic peaks of crystalline form of benzoate of conpound of formula II No. 2-Theta d (A) I % Peak 1 5.305 16.64444 100.0 Peak 2 7.411 11.91828 43.6 Peak 3 19.140 4.63321 1.3 Peak 4 22.031 4.03134 23.9

Example 9. Preparation of Amorphous Form of Oxalate of Compound of Formula II

[0219] 0.5 mL of methyl tert-butyl ether was added to 10 mg of the compound of formula II before 2 mg of oxalic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as an amorphous form of the oxalate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 5.

Example 10. Preparation of Crystalline Form of Oxalate of Compound of Formula II

[0220] 0.5 mL of n-hexane was added to 10 mg of the compound of formula II before 2 mg of oxalic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form of the oxalate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 6.

TABLE-US-00005 TABLE 5 Characteristic peaks of crystalline form of oxalate of comound of formula II No. 2-Theta d (A) I % Peak 1 14.378 6.15525 100.0 Peak 2 18.463 4.80158 51.5 Peak 3 21.670 4.09779 70.9 Peak 4 23.075 3.85126 50.6 Peak 5 28.127 3.17003 21.6

Example 11. Preparation of Amorphous Form of Methanesulfonate of Compound of Formula II

[0221] 0.5 mL of methyl tert-butyl ether was added to 10 mg of the compound of formula II before 1.8 μL of methanesulfonic acid was added. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as an amorphous form of the methanesulfonate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 7.

Example 12. Preparation of Crystalline Form B of Maleate of Compound of Formula II

[0222] 100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 30 min to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form B of the maleate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 8. The DSC pattern is shown in FIG. 9, with a first endothermic peak value at 138.04° C.; the TGA pattern is shown in FIG. 10.

[0223] DVS characterization: the vapor sorption of the crystalline form B of the maleate at 25° C. increased along with the increase of humidity in a range of 20.0% RH to 80.0% RH, with a weight change of 1.731%, less than 2% but not less than 0.2%, indicating that the sample is slightly hygroscopic. In a normal storage condition (i.e., 60% humidity/25° C.), the vapor sorption was about 1.438%; in an accelerated test condition (i.e., 70% humidity), the vapor sorption was about 1.809%; in an extreme condition (i.e., 90% humidity), the vapor sorption was about 3.077%.

[0224] The comparison of X-ray powder diffraction patterns before and after DVS showed that crystalline form did not change during DVS. The DVS pattern is shown in FIG. 11, and the comparison of X-ray powder diffraction patterns before and after DVS is shown in FIG. 12.

TABLE-US-00006 TABLE 6 Characteristic peaks of crystalline form B of maleate of compound of formula II No. 2-Theta d (A) I % Peak 1 7.624 11.58707 74.9 Peak 2 9.659 9.14922 40.7 Peak 3 13.815 6.40503 41.2 Peak 4 15.844 5.58882 56.9 Peak 5 17.391 5.09522 100.0 Peak 6 18.619 4.76186 31.5 Peak 7 21.802 4.07319 76.4 Peak 8 23.667 3.75633 49.8 Peak 9 26.441 3.36816 13.2

Example 13. Preparation of Crystalline Form B of Maleate of Compound of Formula II

[0225] 100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 10 min to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form B of the maleate of the compound of formula II as determined by X-ray powder diffraction.

Example 14. Preparation of Crystalline Form B of Maleate of Compound of Formula II

[0226] 100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 20 min to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form B of the maleate of the compound of formula II as determined by X-ray powder diffraction.

Example 15. Preparation of Crystalline Form B of Maleate of Compound of Formula II

[0227] 100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 1 h to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form B of the maleate of the compound of formula II as determined by X-ray powder diffraction.

Example 16. Preparation of Crystalline Form B of Maleate of Compound of Formula II

[0228] 100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 2 h to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form B of the maleate of the compound of formula II as determined by X-ray powder diffraction.

Example 17. Preparation of Crystalline Form C of Maleate of Compound of Formula II

[0229] 100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 1 d to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form C of the maleate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 13. The DSC pattern is shown in FIG. 14, with a first endothermic peak value at 154.58° C.; the TGA pattern is shown in FIG. 15.

TABLE-US-00007 TABLE 7 Characteristic peaks of crystalline form C of maleate of compound of formula II No. 2-Theta d (A) I % Peak 1 7.325 12.05902 24.9 Peak 2 8.635 10.23231 46.0 Peak 3 9.809 9.00970 38.0 Peak 4 11.661 7.58265 14.6 Peak 5 13.649 6.48261 27.1 Peak 6 16.133 5.48950 23.5 Peak 7 16.765 5.28383 27.8 Peak 8 18.346 4.83192 100.0 Peak 9 21.689 4.09421 37.3 Peak 10 23.586 3.76901 31.9 Peak 11 25.303 3.51708 15.5

Example 18. Preparation of Crystalline Form D of Maleate of Compound of Formula II

[0230] 100 mg of the compound of formula II and 22 mg of maleic acid were added to 5 mL of methyl tert-butyl ether. The mixture was stirred at 600 rpm at 50° C. for 3 d to obtain a suspension. The suspension was filtered in vacuo and the residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form D of the maleate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 16. The DSC pattern is shown in FIG. 17, with a first endothermic peak value at 159.27° C.; the TGA pattern is shown in FIG. 18.

TABLE-US-00008 TABLE 8 Characteristic peaks of crystalline form D of maleate of compound of formula II No. 2-Theta d (A) I % Peak 1 4.486 19.68368 65.1 Peak 2 5.998 14.72391 35.9 Peak 3 7.288 12.12061 48.6 Peak 4 9.067 9.74591 49.9 Peak 5 10.001 8.83770 50.9 Peak 6 13.914 6.35938 59.0 Peak 7 15.026 5.89121 34.9 Peak 8 16.227 5.45786 27.0 Peak 9 18.229 4.86287 100.0 Peak 10 18.940 4.68174 84.8 Peak 11 23.076 3.85108 58.0 Peak 12 25.612 3.47535 60.6 Peak 13 28.102 3.17274 12.9

Example 19. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

[0231] 5 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before 20 μL of hydrobromic acid was added. The mixture was stirred at 600 rpm at 25° C. for 3 days and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form I of the hydrobromide of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 19. The DSC pattern is shown in FIG. 20, with a first endothermic peak value at 201.73° C.; the TGA pattern is shown in FIG. 21. DVS characterization: the vapor sorption of the crystalline form I of the hydrobromide at 25° C. increased along with the increase of humidity in a range of 20.0% RH to 80.0% RH, with a weight change of 0.636%, less than 2% but not less than 0.2%, indicating that the sample is slightly hygroscopic. In a normal storage condition (i.e., 60% humidity/25° C.), the vapor sorption was about 0.589%; in an accelerated test condition (i.e., 70% humidity), the vapor sorption was about 0.702%; in an extreme condition (i.e., 90% humidity), the vapor sorption was about 1.094%.

[0232] The desorption process and the sorption process of the sample basically overlapped in the process of 0-95% humidity change; the comparison of X-ray powder diffraction patterns before and after DVS showed that crystalline form did not change during DVS. The DVS pattern is shown in FIG. 22, and the comparison of X-ray powder diffraction patterns before and after DVS is shown in FIG. 23.

TABLE-US-00009 TABLE 9 Characteristic peaks of crystalline form I of hydrobromide of compound of formula II No. 2-Theta d (A) I % Peak 1 8.128 10.86905 68.5 Peak 2 11.918 7.41964 7.5 Peak 3 12.579 7.03116 19.0 Peak 4 16.414 5.39626 54.1 Peak 5 17.075 5.18879 15.6 Peak 6 17.780 4.98456 39.3 Peak 7 18.750 4.72892 7.8 Peak 8 19.675 4.50851 9.9 Peak 9 20.733 4.28082 27.1 Peak 10 21.262 4.17552 100.0 Peak 11 23.113 3.84512 36.8 Peak 12 23.906 3.71929 15.0 Peak 13 24.391 3.64645 67.5 Peak 14 26.550 3.35455 14.5 Peak 15 28.445 3.13522 29.4 Peak 16 28.930 3.08378 26.0 Peak 17 29.547 3.02077 55.8 Peak 18 30.958 2.88630 27.7 Peak 19 32.236 2.77471 19.3 Peak 20 33.382 2.68204 1.4 Peak 21 38.670 2.32653 2.4 Peak 22 39.640 2.27183 3.3 Peak 23 40.830 2.20832 12.6 Peak 24 42.064 2.14635 5.4 Peak 25 43.342 2.08597 5.2 Peak 26 46.824 1.93865 4.0 Peak 27 48.190 1.88683 6.2 Peak 28 48.983 1.85811 4.1 Peak 29 50.746 1.79762 9.3

Example 20. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

[0233] 5 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before a 500 μL mixture of hydrobromic acid/ethanol (v:v=1:50) was added. The mixture was stirred at 600 rpm at 25° C. for 3 days and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form I of the hydrobromide of the compound of formula II as determined by X-ray powder diffraction.

Example 21. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

[0234] 5 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before a 40 μL mixture of hydrobromic acid/ethanol (v:v=1:1) was added. The mixture was stirred at 600 rpm at 25° C. for 3 days and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form I of the hydrobromide of the compound of formula II as determined by X-ray powder diffraction.

Example 22. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

[0235] 15 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before a 1000 μL mixture of hydrobromic acid/ethanol (v:v=1:99) was added. The mixture was stirred at 600 rpm at 25° C. overnight and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form I of the hydrobromide of the compound of formula II as determined by X-ray powder diffraction.

Example 23. Preparation of Crystalline Form I of Hydrobromide of Compound of Formula II

[0236] 5 mL of methyl tert-butyl ether was added to 100 mg of the compound of formula II before a 1000 μL mixture of hydrobromic acid/ethanol (v:v=1:99) was added. The mixture was stirred at 600 rpm at 25° C. overnight and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was a crystalline form I of the hydrobromide of the compound of formula II as determined by X-ray powder diffraction.

Example 24. Preparation of Crystalline Form α of Hydrochloride of Compound of Formula II

[0237] 5 mL of methyl tert-butyl ether and 15.6 μL of concentrated hydrochloric acid were added to 100 mg of the compound of formula II. The mixture was stirred at 50° C. for 2 d and dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form α of the hydrochloride of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 24. The DSC pattern is shown in FIG. 25, with a first endothermic peak value at 192.13° C.; the TGA pattern is shown in FIG. 26.

[0238] DVS characterization: the vapor sorption of the sample at 25° C. increased along with the increase of humidity in a range of 20.0% RH to 80.0% RH, with a weight change of 0.549%, less than 2% but not less than 0.2%, indicating that the sample is slightly hygroscopic. In a normal storage condition (i.e., 60% humidity/25° C.), the vapor sorption was about 0.463%; in an accelerated test condition (i.e., 70% humidity), the vapor sorption was about 0.574%; in an extreme condition (i.e., 90% humidity), the vapor sorption was about 1.040%.

[0239] The desorption process and the sorption process of the sample basically overlapped in the process of 0-95% humidity change; the comparison of X-ray powder diffraction patterns before and after DVS showed that crystalline form did not change during DVS. The DVS pattern is shown in FIG. 27, and the comparison of X-ray powder diffraction patterns before and after DVS is shown in FIG. 28.

TABLE-US-00010 TABLE 10 Characteristic peaks of crystalline form α of hydrochloride of compound of formula II No. 2-Theta d (A) I % Peak 1 7.931 11.13829 53.4 Peak 2 10.115 8.73832 19.9 Peak 3 12.166 7.26910 15.4 Peak 4 13.920 6.35673 24.2 Peak 5 15.224 5.81523 33.9 Peak 6 16.041 5.52078 13.9 Peak 7 16.315 5.42854 12.6 Peak 8 16.748 5.28930 12.2 Peak 9 17.425 5.08526 21.3 Peak 10 18.309 4.84177 64.7 Peak 11 19.624 4.52003 15.9 Peak 12 20.235 4.38496 19.6 Peak 13 21.491 4.13138 36.6 Peak 14 22.340 3.97642 67.3 Peak 15 23.359 3.80507 65.0 Peak 16 23.905 3.71950 48.0 Peak 17 24.570 3.62032 100.0 Peak 18 25.320 3.51464 20.1 Peak 19 25.811 3.44896 13.9 Peak 20 26.096 3.41194 10.5 Peak 21 27.624 3.22652 24.8 Peak 22 28.213 3.16057 24.6 Peak 23 29.190 3.05697 5.1 Peak 24 29.760 2.99971 2.4 Peak 25 31.266 2.85855 10.1 Peak 26 31.795 2.81217 5.5 Peak 27 32.324 2.76732 8.1 Peak 28 35.906 2.49902 3.7 Peak 29 37.291 2.40939 8.3

Example 25. Preparation of Crystalline Form β of Hydrochloride of Compound of Formula II

[0240] 5 mL of methyl tert-butyl ether and a 0.6 mL solution of concentrated hydrochloric acid in ethanol (0.1 mL of concentrated hydrochloric acid was added to 9.9 mL of ethanol and the mixture was well mixed) were added to 100 mg of the compound of formula II. The mixture was stirred at 25° C. for 1 h and at 50° C. for 2 d, and filtered in vacuo. The residue was dried for 2 h at 40° C. to obtain a product. The product was identified as a crystalline form β of the hydrochloride of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 29. The DSC pattern is shown in FIG. 30, with a first endothermic peak value at 194.04° C.; the TGA pattern is shown in FIG. 31.

[0241] DVS characterization: the vapor sorption of the sample at 25° C. increased along with the increase of humidity in a range of 20.0% RH to 80.0% RH, with a weight change of 1.235%, less than 2% but not less than 0.2%, indicating that the sample is slightly hygroscopic. In a normal storage condition (i.e., 60% humidity/25° C.), the vapor sorption was about 1.755%; in an accelerated test condition (i.e., 70% humidity), the vapor sorption was about 1.954%; in an extreme condition (i.e., 90% humidity), the vapor sorption was about 2.534%.

[0242] The desorption process and the sorption process of the sample basically overlapped in individual processes of 0-95% humidity change, but the desorption process and the sorption process of the first and second cycles could not overlap; the comparison of X-ray powder diffraction patterns before and after DVS showed that crystalline form changed during DVS. The DVS pattern is shown in FIG. 32, and the comparison of X-ray powder diffraction patterns before and after DVS is shown in FIG. 33.

TABLE-US-00011 TABLE 11 Characteristic peaks of crystalline form β of hydrochloride of compound of formula II No. 2-Theta d (A) I % Peak 1 5.386 16.39621 39.0 Peak 2 8.191 10.78576 77.6 Peak 3 10.818 8.17156 29.1 Peak 4 12.688 6.97098 42.8 Peak 5 13.980 6.32982 20.9 Peak 6 14.915 5.93499 26.6 Peak 7 16.607 5.33388 19.7 Peak 8 18.076 4.90345 12.8 Peak 9 19.056 4.65352 12.9 Peak 10 20.036 4.42814 20.8 Peak 11 21.372 4.15427 100.0 Peak 12 22.040 4.02986 35.2 Peak 13 23.465 3.78826 25.0 Peak 14 24.355 3.65171 28.5 Peak 15 25.869 3.44132 36.7 Peak 16 26.582 3.35068 21.8 Peak 17 27.383 3.25440 12.0 Peak 18 29.253 3.05045 29.5 Peak 19 29.832 2.99256 39.9 Peak 20 30.946 2.88740 22.9 Peak 21 31.480 2.83959 41.4 Peak 22 32.504 2.75242 7.6 Peak 23 33.439 2.67755 8.5

Example 26. Preparation of Crystalline Form γ of Hydrochloride of Compound of Formula II

[0243] A small amount of the crystalline form β of the hydrochloride of the compound of formula II was loaded on a DVS system and subjected to a detection with parameters of dm/dt=0.002, 50-95-0-95-50% RH, Max 360 min, 25° C. The product was identified as a crystalline form β of the hydrochloride of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 34.

TABLE-US-00012 TABLE 12 Characteristic peaks of crystalline form γ of hydrochloride of compound of formula II No. 2-Theta d (A) I % Peak 1 8.114 10.88737 89.0 Peak 2 11.997 7.37097 42.5 Peak 3 12.640 6.99748 77.7 Peak 4 13.772 6.42501 45.7 Peak 5 16.478 5.37549 25.8 Peak 6 17.897 4.95221 45.6 Peak 7 19.671 4.50933 9.7 Peak 8 20.337 4.36327 52.8 Peak 9 21.422 4.14464 79.1 Peak 10 22.156 4.00903 62.3 Peak 11 23.228 3.82632 79.1 Peak 12 24.472 3.63450 100.0 Peak 13 25.882 3.43968 26.9 Peak 14 27.567 3.23307 27.4 Peak 15 28.277 3.15351 14.1 Peak 16 29.830 2.99281 38.1 Peak 17 31.160 2.86797 15.9 Peak 18 32.269 2.77189 17.0 Peak 19 33.334 2.68576 13.6

Example 27. Preparation of Crystalline Form of Acetate of Compound of Formula II

[0244] 1 mL of water was added to 20 mg of the compound of formula II before a solution of acetic acid in ethanol (0.1 mL of acetic acid was added to 9.9 mL of ethanol and the mixture was well mixed) was added in a molar ratio of 1:1. The mixture was stirred overnight at 50° C. and filtered in vacuo. The residue was dried for 1 h at 40° C. to obtain a product. The product was identified as a crystalline form of the acetate of the compound of formula II by X-ray powder diffraction, with an XRPD pattern shown in FIG. 35. The DSC pattern is shown in FIG. 36, with a first endothermic peak value at 206.96° C., a first exothermic peak value at 213.49° C. and a second endothermic peak value at 246.30° C.

TABLE-US-00013 TABLE 13 Characteristic peaks of crystalline form of acetate of compound of formula II No. 2-Theta d (A) I % Peak 1 11.651 7.58948 96.9 Peak 2 12.495 7.07863 38.2 Peak 3 14.323 6.17872 29.8 Peak 4 15.121 5.85472 28.9 Peak 5 15.636 5.66274 100.0 Peak 6 15.965 5.54704 66.5 Peak 7 18.075 4.90394 58.9 Peak 8 19.247 4.60782 20.4 Peak 9 19.903 4.45730 25.1 Peak 10 20.935 4.23993 38.5 Peak 11 22.107 4.01768 29.1 Peak 12 22.998 3.86402 47.4 Peak 13 23.842 3.72910 52.3 Peak 14 24.733 3.59676 59.9 Peak 15 25.530 3.48623 35.2 Peak 16 26.843 3.31862 11.7 Peak 17 28.719 3.10600 12.9 Peak 18 29.750 3.00061 6.1 Peak 19 30.829 2.89805 18.2 Peak 20 32.142 2.78260 14.6 Peak 21 35.143 2.55155 3.6 Peak 22 39.973 2.25369 2.6

Example 28. Influencing Factor Study of Crystalline Form α of Hydrochloride and Crystalline Form I of Hydrobromide of Compound of Formula II

[0245] Sample of the crystalline form α of the hydrochloride and the crystalline form I of the hydrobromide of the compound of formula II were let stand open to examine the stability of the samples in conditions of illumination (4500 Lux), high temperature (40° C. and 60° C.) and high humidity (RH 75% and RH 92.5%) in a period of 30 days.

TABLE-US-00014 TABLE 14 Stability data of the influencing factor study Crystalline form α of hydrochloride of compound of formula II Main peak Chiral Chloride Color and purity purity ion content Crystalline Conditions Time (days) appearance (%) (%) (%) form Initial 0 White solid 96.925 99.14 5.75 Crystalline form α 40° C. 7 White solid 96.915 99.131 / Not changed 14 White solid 96.921 99.115 / Not changed 30 White solid 96.824 99.207 5.75 Not changed 60° C. 7 White solid 96.884 99.136 / Not changed 14 White solid 96.907 99.106 / Not changed 30 White solid 96.814 99.232 5.65 Not changed 75% RH 7 White solid 96.916 99.138 / Not changed 14 White solid 96.908 99.130 / Not changed 30 White solid 96.903 99.220 5.68 Not changed 92.5% RH 7 White solid 96.912 99.132 / Not changed 14 White solid 96.908 99.111 / Not changed 30 White solid 96.880 99.211 5.67 Not changed 4500 Lux 7 White solid 96.911 99.137 / Not changed 14 White solid 96.911 99.139 / Not changed 30 White solid 96.810 99.216 5.71 Not changed Crystalline form I of hydrobromide of compound of formula II Main peak Chiral Bromide Color and purity purity ion content Crystalline Conditions Time (days) appearance (%) (%) (%) form Initial 0 White solid 97.689 99.298 11.75 Crystalline form I 40° C. 7 White solid 97.716 99.293 / Not changed 14 White solid 97.727 99.165 / Not changed 30 White solid 97.644 99.251 11.73 Not changed 60° C. 7 White solid 97.645 99.299 / Not changed 14 White solid 97.671 99.187 / Not changed 30 White solid 97.630 99.263 11.50 Not changed 75% RH 7 White solid 97.687 99.293 / Not changed 14 White solid 97.705 99.179 / Not changed 30 White solid 97.676 99.274 11.73 Not changed 92.5% RH 7 White solid 97.706 99.294 / Not changed 14 White solid 97.701 99.175 / Not changed 30 White solid 97.653 99.268 11.55 Not changed 4500 Lux 7 White solid 97.683 99.297 / Not changed 14 White solid 97.660 99.152 / Not changed 30 White solid 97.626 99.243 11.18 Not changed

[0246] Conclusions: the influencing factor study showed that: the crystalline form α of the hydrochloride and the crystalline form I of the hydrobromide of the compound of formula II have good physical and chemical stabilities in conditions of illumination, high temperatures of 40° C. and 60° C. and high humidities of 75% and 92.5%.

Example 29. Long-Term/Accelerated Stability Study of Crystalline Form α of Hydrochloride and Crystalline Form I of Hydrobromide of Compound of Formula II

[0247] The crystalline form α of the hydrochloride of the compound of formula II was let stand in conditions of 25° C./60% RH and 40° C./75% RH to examine its stability.

TABLE-US-00015 TABLE 15 Long term/accelerated stability study data for the crystalline form α of the hydrochloride of the compound of formula II Crystalline form α of hydrochloride of compound of formula II Chiral Color and Main peak purity Chloride ion Crystalline Conditions Time appearance purity (%) (%) content (%) form Initial 0 White solid 96.925 99.14 5.75 Crystalline form α 25° C., Day 7 White solid 96.915 99.131 / Not changed 60% RH Day 14 White solid 96.831 99.111 / Not changed Month 1 White solid 96.906 99.225 5.75 Not changed Month 2 White solid 96.883 99.332 5.74 Not changed Month 3 White solid 96.749 99.239 / Not changed Month 6 White solid 96.170 99.187 5.85 Not changed 40° C., Day 7 White solid 96.906 99.137 / Not changed 75% RH Day 14 White solid 96.902 99.104 / Not changed Month 1 White solid 96.846 99.206 5.44 Not changed Month 2 White solid 96.780 99.292 5.86 Not changed Month 3 White solid 96.664 99.149 / Not changed Month 6 White solid 95.990 98.972 5.98 Not changed

[0248] The long-term/accelerated stability study showed that: the crystalline form α of the hydrochloride of the compound of formula II has good physical and chemical stability in conditions of a long term and acceleration in a period of 6 months.

[0249] The crystalline form I of the hydrobromide of the compound of formula II was let stand in conditions of 25° C./60% RH and 40° C./75% RH to examine its stability.

TABLE-US-00016 TABLE 16 Long term/accelerated stability study data for the crystalline form I of the hydrobromide of the compound of formula II Crystalline form I of hydrobromide of compound of formula II Chiral Color and Main peak purity Bromide ion Crystalline Conditions Time appearance purity (%) (%) content (%) form Initial 0 White solid 97.689 99.298 11.75 Crystalline form I 25° C., Day 7 White solid 97.689 99.297 / Not changed 60% RH Day 14 White solid 97.697 99.198 / Not changed Month 1 White solid 97.649 99.255 11.20 Not changed Month 2 White solid 97.661 99.363 11.05 Not changed Month 3 White solid 97.552 99.283 / Not changed Month 6 White solid 96.981 99.228 11.82 Not changed 40° C., Day 7 White solid 97.661 99.295 / Not changed 75% RH Day 14 White solid 97.660 99.174 / Not changed Month 1 White solid 97.558 99.262 11.49 Not changed Month 2 White solid 97.561 99.328 10.93 Not changed Month 3 White solid 97.259 99.275 / Not changed Month 6 White solid 96.412 99.199 11.91 Not changed

[0250] The long-term/accelerated stability study showed that: the crystalline form I of the hydrobromide of the compound of formula II has good physical and chemical stability in conditions of a long term and acceleration in a period of 6 months.