Crystalline form of compound suppressing protein kinase activity, and application thereof

Abstract

Provided are a compound as represented by structural formula (I) ({5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[((3S,5R)-3,5-di methylpiperazinyl)carbonyl]phenyl}carboxamide hydrochloride) and a novel crystalline form of a hydrate or solvate of the compound. Further provided are a manufacturing method of the compound and crystalline form, a related intermediate, a pharmaceutical composition comprising the compound, an application using the compound or the crystalline form for preparing a pharmaceutical product for treating a disease, symptom, or disorder, and a therapeutic method for treating a disease, symptom, or disorder. ##STR00001##

Claims

1. A crystalline form of a compound of formula I, hydrates and/or solvates thereof ##STR00008## wherein an X-ray powder diffraction pattern of the crystalline form has characteristic peaks at diffraction angles 2 of 4.90.2, 10.00.2 and 19.30.2.

2. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at diffraction angles 2 of 4.90.2, 10.00.2, 14.70.2, 16.90.2, 19.30.2 and 20.30.2.

3. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at diffraction angles 2 of 4.90.2, 10.00.2, 14.70.2, 16.90.2, 19.30.2, 20.30.2, 25.50.2 and 30.70.2.

4. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 1, wherein the crystalline form has the X-ray powder diffraction pattern approximately as shown in FIG. 1.

5. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 1, wherein the crystalline form is a dihydrate.

6. A crystalline form of a compound of formula I, hydrates and/or solvates thereof ##STR00009## wherein an X-ray powder diffraction pattern of the crystalline form has characteristic peaks at diffraction angles 2 of 10.50.2, 17.40.2 and 21.10.2.

7. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 6, wherein the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at diffraction angles 2 of 10.50.2, 17.40.2, 19.70.2, 21.10.2, 23.90.2 and 25.50.2.

8. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 6, wherein the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at diffraction angles 2 of 10.50.2, 17.40.2, 19.70.2, 21.10.2, 21.50.2, 23.90.2, 25.20.2 and 25.50.2.

9. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 6, wherein the X-ray powder diffraction pattern approximately as shown in FIG. 2.

10. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 6, wherein the crystalline form is a trihydrate.

11. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 3, wherein the crystalline form has a purity of 85%.

12. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 3, wherein the crystalline form has a purity of 95%.

13. The crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 3, wherein the crystalline form has a purity of 99%.

14. A pharmaceutical composition, comprising a therapeutically effective amount of the crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 3, and pharmaceutically acceptable excipients, adjuvants and/or carriers, and optionally at least one of other active ingredients.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is in a form of an oral preparation.

16. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is in a form of a tablet or a capsule.

17. The pharmaceutical composition according to claim 14, wherein 20 mg to 150 mg of the crystalline form is formulated with at least one excipient, adjuvant and/or carrier to a total amount of about 50 mg to 500 mg.

18. The pharmaceutical composition according to claim 14, wherein the excipient, adjuvant and/or carrier is microcrystalline cellulose, mannitol, crospovidone, croscarmellose sodium cellulose, sodium starch glycolate, povidone, hydroxypropyl cellulose, and/or stearic acid.

19. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition comprises 0.01% to 99% by weight of the crystalline form.

20. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition comprises 0.1% to 70% by weight of the crystalline form.

21. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition comprises 1% to 70% by weight of the crystalline form.

22. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition comprises 1% to 50% by weight of the crystalline form.

23. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition comprises 1% to 30% by weight of the crystalline form.

24. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition comprises 10% to 30% by weight of the crystalline form.

25. A method for treating a disease, disorder or condition in a patient, administering to a patient the crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 3 or the pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the compound of formula I, hydrates and/or solvates thereof, and pharmaceutically acceptable excipients, adjuvants and/or carriers, and optionally at least one of other active ingredients, wherein the disease, disorder or condition in a patient is selected from lung cancer, melanoma, colon cancer, breast cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, glioma, lymphoma, neuroblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, and/or head and neck squamous cell carcinoma.

26. The method for treating a disease, disorder or condition in a patient according to claim 25, wherein the disease, disorder or condition is non-small cell lung cancer resistant to crizotinib therapy.

27. The method for treating a disease, disorder or condition in a patient according to claim 25, wherein the disease, disorder or condition is melanoma.

28. The method for treating a disease, disorder or condition in a patient according to claim 25, wherein the disease, disorder or condition is neurological disease, psychiatric disease, obesity, diabetes, and/or cardiovascular disease.

29. The method for treating a disease, disorder or condition in a patient according to claim 28, wherein the psychotic disease is schizophrenia, depression, and/or addiction or abuse of substance.

30. The method for treating a disease, disorder or condition in a patient according to claim 29, wherein the addiction or abuse of substance is addiction or abuse of cocaine, tobacco or alcohol.

31. A method for preparing the crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 3, comprising following steps: an amorphous sample of the compound of formula I was placed in centrifuge tubes, and stored in an airtight ethanol or acetonitrile atmosphere for 6 to 10 days at room temperature to obtain the crystalline form; or an amorphous sample of the compound of formula I was added into ethanol, stirred at 4 C. to 25 C., and filtrated to give the crystalline form; or an amorphous sample of the compound of formula I was added into ethanol at 4 C. to 25 C., and dissolved to get a clear solution; the solution was filtered to give filtrate; then the filtrate was added with n-heptane under stirring until a large amount of crystal being observed, then filtered to obtain the crystalline form; or an amorphous sample of the compound of formula I was added into methyl tert-butyl ether/ethanol or n-heptane/ethanol at 55 C. to 70 C., and dissolved to get a clear solution; and the solution was filtered to give filtrate; then the filtrate was stirred at -20 C. until solid being observed, and filtered to obtain the crystalline form; or an amorphous sample of the compound of formula I was added into methanol, and dissolved to get a clear solution, filtrated, then exposed to 35 C. to 50 C. to evaporate solvent, giving the crystalline form; or an amorphous sample of the compound of formula I was added into methanol, and dissolved to get a clear solution; the solution was filtered to give filtrate; then the filtrate was added with carboxymethyl cellulose, and exposed to room temperature to evaporate solvent, obtaining the crystalline form.

32. A method for preparing the crystalline form of the compound of formula I, hydrates and/or solvates thereof according to claim 8, comprising following steps: the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added into methanol, ethanol or water, dissolved to get a clear solution, filtered, then exposed to room temperature (20 C.) to 40 C. to evaporate solvent, obtaining the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added into methanol/water, methanol/acetone, methanol/ethyl acetate, methanol/methyl tert-butyl ether, methanol/tetrahydrofuran, methanol/dichloromethane, ethanol/water, ethanol/butanone, ethanol/isopropyl acetate, ethanol/n-heptane, trifluoroethanol/water, trifluoroethanol/ethyl acetate, trifluoroethanol/tetrahydrofuran, water/methanol , water/ethanol, water/trifluoroethanol, water/isopropanol, water/acetone, water/tetrahydrofuran, or water/acetonitrile, dissolved to get a clear solution; then the solution was filtrated and exposed to room temperature (20 C.) to 40 C. to evaporate solvent, obtaining the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added to a lower alcohol, water, nitromethane, butanone, diethyl ether, ethyl acetate, tetrahydrofuran, toluene or n-heptane to form a suspension; then the suspension was stirred for 4 to 5 days at room temperature to 40 C., and centrifuged to obtain the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added to water-saturated ethyl acetate layer, ethyl acetate saturated aqueous layer, ethanol/diethyl ether, toluene/acetonitrile, butanone/ethanol or toluene/isopropyl ether to form a suspension; then the suspension was stirred at 4 C. to 40 C. for 4 to 5 days and centrifuged to obtain the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added into methanol, acetone/water (3:1 v/v), or acetonitrile/water (3:2 v/v) at room temperature, and dissolved to get a clear solution; then the solution were added with hydroxypropylcellulose, ethylcellulose, povidone K30, polyallylamine hydrochloride, carboxymethyl cellulose, or polyvinyl alcohol, exposed to room temperature to evaporate solvent, obtaining the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added into a lower alcohol or water at 60 C. to 70 C., dissolved to get a clear solution, and stirred at 4 C. until crystals being observed, obtaining the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added into acetone/trifluoroethanol, acetone/water, dioxane/water, acetonitrile/water or methyl tert-butyl ether/n-propanol at 55 C. to 70 C., dissolved to get a clear solution; and the solution was filtered to give filtrate; then the filtrate was stirred at -20 C. until crystal being observed, then filtered to give the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added into nitromethane/methanol, acetonitrile/methanol, butanone/ethanol, ethyl acetate/ethanol, 1,4-dioxane/ethanol or tetrahydrofuran/water at 60 C. to 70 C., and dissolved to get a clear solution, filtered and exposed to room temperature to evaporate solvent, obtaining the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added into methanol, ethanol, water, trifluoroethanol, n-propanol or dimethyl sulfoxide at room temperature, and dissolved to get a clear solution; the solution was filtered, and the filtrate was added dropwise with acetone, ethyl acetate, methyl tert-butyl ether, isopropyl ether, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, n-heptane, methylene chloride or chloroform until a large amount of crystal being observed, obtaining the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was added into methanol or ethanol at room temperature, and dissolved to get a clear solution; and the solution was then filtrated to give filtrate; then the filtrate was added with dichloromethane or tetrahydrofuran, and exposed to room temperature to evaporate solvent, obtaining the crystalline form; or an amorphous sample of the compound of formula I was placed in centrifuge tubes, and then the centrifuge tubes were placed in the atmosphere of n-butanol, water, nitromethane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, chloroform and toluene to diffuse, to give the crystalline form; or an amorphous sample of the compound of formula I was added to n-propanol, water, butanone, ethyl acetate, tetrahydrofuran, dichloromethane, ethanol, isopropanol, n-butanol, acetone, ester, isopropyl acetate, 1,4-dioxane, acetonitrile, chloroform, sec-butanol, nitromethane or toluene, stirred at -4 C. to -40 C. for 30 minutes, then filtered to give the crystalline form; or an amorphous sample of the compound of formula I was added into isopropyl ether/methanol, ethyl acetate/methanol, 1,4-dioxane/methanol, butanone/ethanol, acetonitrile/ethanol, n-heptane/trifluoroethanol, nitromethane/trifluoroethanol, ether/trifluoroethanol, tetrahydrofuran/trifluoroethanol, acetone/water, tetrahydrofuran/water, acetonitrile/water, methyl tert-butyl ether/isopropanol, isopropyl acetate/n-propanol, methylcyclohexane/n-butanol, acetone/dimethylsulfoxide, ethyl acetate/dimethyl sulfoxide, acetonitrile/dimethyl sulfoxide, methyl tert-butyl ether/chloroform, or toluene/ethyl acetate to form a suspension, stirred at 4 C. to 40 C., then filtered to give the crystalline form; or an amorphous sample of the compound of formula I was placed at room temperature at a humidity of 85% RH to obtain the crystalline form; or the crystalline form of the compound of formula I of which the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 20 of 4.90.2 , 10.00.2 , 14.70.2 , 16.90.2 , 19.30.2 , 20.30.2 , 25.50.2 and 30.70.2 was dissolved into water or methanol to get a clear solution; the solution was filtered to give filtrate; then the filtrate was rotary evaporated to dry, obtaining the crystalline form.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: The X-ray powder diffraction pattern of Crystalline form A of the compound as shown in formula I.

(2) FIG. 2: The X-ray powder diffraction pattern of Crystalline form B of the compound as shown in formula I.

(3) FIG. 3: The X-ray powder diffraction pattern of Crystalline form C of the compound as shown in formula I.

(4) FIG. 4: The X-ray powder diffraction pattern of Crystalline form D of the compound as shown in formula I.

(5) FIG. 5: The X-ray powder diffraction pattern of Crystalline form E of the compound as shown in formula I.

(6) FIG. 6: The X-ray powder diffraction pattern of amorphous sample of the compound as shown in formula I.

(7) FIG. 7: Dynamic water adsorption pattern of Crystalline form A of the compound as shown in formula I.

(8) FIG. 8: Dynamic water adsorption pattern of Crystalline form B of the compound as shown in formula I.

(9) FIG. 9: Dynamic water adsorption pattern of amorphous sample of the compound as shown in formula I.

(10) FIG. 10: The differential thermal analysis of Crystalline form A of the compound as shown in formula I.

(11) FIG. 11: The differential thermal analysis of Crystalline form B of the compound as shown in formula I.

(12) FIG. 12: The differential thermal analysis of amorphous sample of the compound as shown in formula I.

(13) Table 6 summarizes the detection equipment and methods of the X-ray powder diffraction pattern shown in FIGS. 1-6.

(14) Table 7 summarizes the detection equipment and methods of the dynamic water adsorption pattern shown in FIGS. 7-9.

(15) Table 8 summarizes the detection equipment and methods of the differential thermal analysis of scanning pattern shown in FIGS. 10-12.

(16) TABLE-US-00006 TABLE 6 Device name X-ray powder diffractometer (XRD) & Hot stage XRD Equipment Bruker D8 Advance diffractometer Technical K radiation (40 Kv, 40 Ma) copper target Specifications wavelength: 1.54 nm, -2 goniometer, Mo monochromator, Lynxeye detector Calibrated substance Al.sub.2O.sub.3 Acquisition software Diffrac Plus XRD Commander Analysis software MDI Jade 6 Method Non reflective sample 24.6 mm diameter parameters plate specification 1.0 mm Thickness Variable temperature Copper plate hot stage sample plate Detection angle 3-402/3-302 (Hot stageXRD) Step length 0.022 Speed 0.2 s.step-1 detected sample >2 mg weight

(17) TABLE-US-00007 TABLE 7 Device name Dynamic Vapor Sorption (DVS) Instrument TA Instruments Q5000TGA Control Thermal Adventage software Analysis Universal Analysis software Sample plate Platinum crucible detected sample 1-10 mg weight Protective gas Nitrogen Gas flow rate 10 mL/min Detection Equilibrate at 20 C.; Humidity 0% ; Isothermal method for 180 min; Abort next iso if weight (%) < 0.0100 for 15.00 min; step humidity 10% every 120 min to 80.00%; Abort next iso if weight(%) <0.0100 for 15.00 min; step humidity 10% every 120 min to 0.00% Judgment non-hygroscopic Not more than 0.2% standard Mild More than 0.2% , but not hygroscopic more than 2.0% Hygroscopic More than 2% , but not more than 15% Extremely More than 15% hygroscopic

(18) TABLE-US-00008 TABLE 8 Device name Differential thermal analysis scanner (DSC) Instrument TA Instruments Q200 DSC Control software Thermal Adventage Analysis software Universal Analysis Sample plate Aluminum crucible (sealed and punched) detected sample weight 0.5-5 mg Protective gas Nitrogen Gas flow rate 40 mL/min Common detection methods Equilibrate at 20 C.; Ramp 10 C./min to 250/300 C.

EXAMPLES

(19) The present invention is further exemplified, but not limited, by the following examples that illustrate the invention. In the examples of the present invention, the techniques or methods, unless expressly stated otherwise, are conventional techniques or methods in the art.

Abbreviations

(20) Boc: Butoxycarbonyl;

(21) DCC: Dicyclohexylcarbodiimide;

(22) DCM: Dichloromethane;

(23) DIPEA: Diisopropylethylamine;

(24) DMAP: 4-diMethylaMinopyridine;

(25) DMF: N,N-Dimethylformamide;

(26) EDCI: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride;

(27) HATU: 2-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate;

(28) HOBT: 1-Hydroxybenzotriazole;

(29) IPA: Isopropyl alcohol;

(30) MeOH: Methanol;

(31) MTBE: Methyl tert-butyl ether;

(32) NMM: N-methylmorpholine;

(33) N: mol/L;

(34) TFA: Trifluoroacetate;

(35) THF: Tetrahydrofuran.sub.

Example 1: Synthesis of the Compounds of Formula I

(36) Synthesis of Compound M1:

(37) 8.57 g (0.024 mol, 1.00 eq) of Compound SM1 was dissolved in 85.7 mL of anhydrous methanol and 5% palladium on carbon (0.86 g) was added under nitrogen. The mixture was replaced with hydrogen three times and reacted in the atmosphere of hydrogen for 3 hours. When the reaction of the raw materials was complete, the filtrate was collected by filtration, then concentrated to solid and dried under vacuum to give the white solid, that is compound M1 with a yield of 100% and a purity of 97.32%.

(38) LC-MS[M+H.sup.+]: 334.sub.

(39) Synthesis of Compound M2:

(40) The 9.60 g (0.017 mol, 1.00 eq) of compound SM2 was dissolved in 53 mL of THF, the reaction mixture was cooled to 5 to 5 C. 1N KOH aqueous solution (1.40 g KOH and 25 mL water) was added dropwise and the mixture was incubated at 1 to 10 C. and stirred for 4 hours. 1N dilute hydrochloric acid was added to adjust pH value to about 5. The mixture was extracted with ethyl acetate (50 mL2) twice. The organic layers were combined and washed with saturated salt water solution, dried over anhydrous sodium sulfate for 1 hour, followed by filtered, and concentrated under vacuum to obtain viscous oil, 23 mL of dichloromethane was add to dissolve the above viscous oil, and then concentrated under vacuum to get a thick oil again. 69 mL of dichloromethane was add to dissolve the thick oil again and concentrated under vacuum to obtain 9.10 g of intermediate M2 as a yellow solid with a yield of 99.7%.

(41) LC-MS[M+H.sup.+]: 546.sub.

(42) Synthesis of Compound M2:

(43) 9.60 g (0.017 mol, 1.00 eq) of compound SM2 was dissolved in 53 mL of THF and the reaction mixture was cooled to 0-10 C. 1N of LiOH aqueous solution (1.05 g LiOH+25 mL water) was added dropwise. After 30 minutes of addition, the temperature gradually increased to room temperature, and reaction mixture were stirred overnight. The reaction was completed and concentrated under vacuum. The resulting residue was dissolved in 100 mL of water, and 50 mL of methyl tert-butyl ether was added, stirred and separated. 1N of dilute hydrochloric acid was added dropwise to the water phase for adjusting pH value to about 5. The mixture was extracted with ethyl acetate (50 mL2) twice. The organic layers were combined and washed with saturated salt water solution and dried over anhydrous sodium sulfate for 1 hour. The mixture was filtered and evaporated under vacuum to obtain 8.58 g of intermediate M2 as a yellow solid. The yield was 94%.

(44) LC-MS[M+H.sup.+]: 546.sub.

(45) Synthesis of Compound M3:

(46) 8.23 g (0.015 mol, 1.15 eq) of compound M2 was dissolved in 66 mL of dichloromethane and cooled to 10 to 20 C. 4.30 g (0.013 mol, 1.00 eq) of compound M1, 3.00 g (0.022 mol, 1.69 eq) of Hydroxybenzotriazole (HOBT), 4.58 g (0.024 mol, 1.85 eq) of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 6.90 g (0.068 mol, 5.23 eq) of N-methylmorpholine (NMM) was added in turn. The mixture was incubated and stirred at 20 to 30 C. for 16 hours, 16 mL of water was added to the reaction mixture, stirred for 10-15 minutes, liquid was separation when still, 16 mL of 1N diluted hydrochloric acid was added to the organic layer, stirred for 5 minutes, liquid was separation when still; the organic layer was washed by 16 mL of 1N dilute hydrochloric acid, 5 mL of 1N KOH water solution and 30 mL of saturated salt water respectively, and the static liquid was separated. The organic phase was dried by anhydrous sodium sulfate, followed by filtered and concentrated in vacuum. The resulting residue was washed with methyl tert-butyl ether (20 mL+20 mL+6 mL) for three times, and filtration was to collected solid, the solid was dried to give 7.95 g of yellow-like solid as the compound M3 with a yield of 71.6%.

(47) LC-MS[M+H.sup.+]: 861.sub.

(48) Synthesis of Compound M3:

(49) 7.96 g (0.015 mol, 1.15 eq) of compound M2 was dissolved in 40 mL of DMF, to which was added 5.23 g (0.014 mol, 1.08 eq) of HATU, 4.17 g (0.013 mol, 1.00 eq) of compound M1 and 2.17 mL of diisopropylethyl amine. The reaction mixture was stirred overnight at room temperature. 50 mL of saturated sodium carbonate aqueous solution was added to the reaction system, followed by stirred and filtered. The resulting solid is beaten with 60 mL of water and then filtered. The solid was dissolved in 30 mL of dichloromethane, washed twice with water, and the organic phase was dried, filtered, concentrated in vacuum and dried to obtain 10.03 g of compound M3 as brown solid with a yield of 93.2%.

(50) LC-MS[M+H.sup.+]: 861.sub.

(51) Synthesis of Compound M3:

(52) The 9.77 g of (0.018 mol, 1.20 eq) compound M2 was dissolved in 75 mL of dichloromethane, to which was added 6.21 g (0.030 mol, 2.00 eq) of dicyclohexylcarbodiimide, 0.96 g (0.0079 mol, 0.53 eq) of DMAP, and 5.00 g (0.015 mol, 1.00 eq) of compound M1. The reaction mixture was stirred overnight at room temperature. 20 mL of water was added to the reaction system, stirred and the liquid was separation when still; 20 mL of 1N dilute hydrochloric acid was added to the organic phase, stirred for 5 minutes, the liquid was separation when still. The organic layer was washed by 20 mL of dilute hydrochloric acid, 6 mL of 1N KOH water solution and 35 mL of saturated salt water respectively, and the static liquid was separated. The organic phase was dried by anhydrous sodium sulfate, filtered, and concentrated in vacuum. The resulting residue was washed for three times by adding methyl tert-butyl ether (25 mL+25 mL+8 mL). Filtration was to collect solid, and the solid was dried to obtain 10.62 g of brown solid as the compound M3 with a yield of 82.3%.

(53) LC-MS[M+H.sup.+]: 861.sub.

(54) Synthesis of the Compound of Formula I:

(55) The 7.95 g (0.092 mol) of compound M3 was dissolved in 30 mL of dichloromethane, the reaction solution was cooled to 5 C. to 5 C., to which was dropped 15 mL of trifluoroacetate with stirring at room temperature for 2 hours. After the mixture was cooled to 10 to 20 C., to which the reaction mixture was slowly added 60 mL of saturated potassium carbonate aqueous solution, followed by stirred and static stratification. The organic layer was washed with saturated salt water, and dried over by anhydrous sodium sulfate, followed by filtered and concentrated. The resulting residue was dissolved in 41.2 g of isopropanol, after the mixture was cooled to 10 to 20 C., to which the reaction mixture was added 5 mL of concentrated hydrochloric acid with stirring at room temperature. Filtration was to collect solid, and the solid was washed by isopropanol, dried in vacuum to obtain 5.75 g of compound of formula I.

(56) LC-MS[M+H.sup.+]: 561.sub.

(57) 1H-NMR (300 MHz, CDCl.sub.3): =1.25-1.43 (m, 6H), 1.91 (d, 3H), 3.15-3.48 (m, 4H), 3.66-3.89 (m, 0.5H), 4.55-4.78 (m, 0.5H), 5.49 (s, 2H), 6.26 (q, 1H), 7.10 (t, 1H), 7.33-7.44 (m, 4H), 7.78 (d, 2H), 9.93 (s, 1H).

Example 2: Preparation Method of Crystalline Form A

(58) Preparation Method 1 of Crystalline Form A

(59) About 5 to 10 mg of the amorphous compound of the Formula I was dissolved into sec-butanol to get a clear solution, followed by filtration, the solution was exposed to 40 C. to get the Crystalline Form A.

(60) Preparation Method 2 of Crystalline Form A

(61) About 10 mg of amorphous compound of the Formula I was dissolved into methanol to get a clear solution, followed by filtration, to which was added 1 mg of carboxymethyl cellulose. The mixture was exposed to room temperature to get the Crystalline Form A.

(62) Preparation Method 3 and 4 of Crystalline Form A

(63) At the corresponding temperature, about 10 mg of amorphous compound of the Formula I was added to Solvent 2, followed by added to Solvent 1 to get a clear solution and then filtered, stirred under 20 C. to precipitate solid, The precipitate was collected by filtration to obtain the Crystalline Form A.

(64) TABLE-US-00009 Sample Solvent 1 Solvent 2 Temperature weight (volume, (volume, No. ( C.) (mg) Solvent 1 mL) Solvent 2 mL) preparation method 55 10 Ethanol 0.8 Methyl 1.0 3 of the Crystalline tert-butyl ether Form A preparation method 70 10 Ethanol 0.8 N-heptane 0.8 4 of the Crystalline Form A

(65) Preparation Method 5 of Crystalline Form A

(66) At room temperature, about 10 mg of amorphous compound of Formula I was dissolved into ethanol to get a clear solution, followed by filtration. n-heptane was dropped to the solution under stirring until a large amount of solid being observed, filtered and recovered the Crystalline Form A.

(67) Preparation Method 6 and 7 of Crystalline Form A

(68) Approximately 10 mg of the amorphous compound of Formula I was placed in 2.0 mL centrifuge tube and exposed at room temperature for 6 days in corresponding closed solvent atmosphere. The crystalline form A was obtained.

(69) TABLE-US-00010 Sample Solvent weight (Volume, No. (mg) Solvent mL) ) preparation method 10 Ethanol 4.0 6 of the Crystalline Form A preparation method 10 Acetonitrile 4.0 7 of the Crystalline Form A 7

(70) Preparation Method 8 of Crystalline Form A

(71) Approximately 15 mg of the amorphous compound of Formula I was added to 0.2 mL of ethanol at 4 C., the mixture was stirred at the corresponding temperature for 30 minutes and filtered to obtain the Crystalline form A.

Example 3: Preparation Method of Crystalline Form B

(72) The First Experiment Method

(73) About 5 to 10 mg of Crystalline form A was dissolved into the appropriate solvent to get a clear solution and then filtered. The mixture was exposed to the corresponding temperature for volatilization to get the Crystalline form B.

(74) TABLE-US-00011 Crystalline Tempera- Form A Solvent ture Weight (Volume, No. ( C.) (mg) Solvent mL) Preparation method Room 5 Methanol 0.4 1 of Crystalline temperature Form B Preparation method Room 5 Ethanol 1.0 2 of Crystalline temperature Form B Preparation method Room 5 Water 0.1 3 of Crystalline temperature Form B Preparation method 40 10 Ethanol 1.5 4 of Crystalline Form B Preparation method 40 10 Water 0.4 5 of Crystalline Form B

(75) The Second Experiment Method

(76) About 10 mg of Crystalline form A was added to solvent 1, followed by added to solvent 2 to get a clear solution and filtered, then exposed to the corresponding temperature for volatilization to obtain the Crystalline form B.

(77) TABLE-US-00012 Crystalline Solvent 1 Solvent 2 Temperature Form A (Volume, (Volume, No. ( C.) Weight (mg) Solvent 1 mL) Solvent 2 mL) Preparation Room 10 Methanol 0.4 Water 0.1 method 6 of temperature Crystalline Form B Preparation Room 10 Methanol 0.4 Acetone 0.4 method 7 of temperature Crystalline Form B Preparation Room 10 Methanol 0.6 Ethyl 0.4 method 8 of temperature acetate Crystalline Form B Preparation Room 10 Methanol 1.0 Methyl 0.4 method 9 of temperature tert-butyl Crystalline Form B ether Preparation Room 10 Methanol 0.6 Tetrahydrofuran 0.6 method 10 of temperature Crystalline Form B Preparation Room 10 Methanol 0.4 Dichloromethane 0.4 method 11 of temperature Crystalline Form B Preparation Room 10 Ethanol 1.2 Water 0.2 method 12 of temperature Crystalline Form B Preparation Room 10 Ethanol 1.2 Butanone 0.4 method 13 of temperature Crystalline Form B Preparation Room 10 Ethanol 1.2 Isopropyl 0.4 method 14 of temperature acetate Crystalline Form B Preparation Room 10 Ethanol 1.2 n-Heptane 0.4 method 15 of temperature Crystalline Form B Preparation Room 10 Trifluoro 0.2 Water 0.2 method 16 of temperature ethanol Crystalline Form B Preparation Room 10 Trifluoro 0.2 Ethyl 0.2 method 17 of temperature ethanol acetate Crystalline Form B Preparation Room 10 Trifluoro 0.2 Tetrahydrofuran 0.4 method 18 of temperature ethanol Crystalline Form B Preparation 40 10 Water 0.2 Methanol 0.6 method 19 of Crystalline Form B Preparation 40 10 Water 0.2 Ethanol 0.6 method 20 of Crystalline Form B Preparation 40 10 Water 0.2 Trifluoroethanol 0.4 method 21 of Crystalline Form B Preparation 40 10 Water 0.2 Isopropanol 0.4 method 22 of Crystalline Form B Preparation 40 10 Water 0.2 Acetone 1.0 method 23 of Crystalline Form B Preparation 40 10 Water 0.2 Tetrahydrofuran 0.6 method 24 of Crystalline Form B Preparation 40 10 Water 0.2 Acetonitrile 0.4 method 25 of Crystalline Form B

(78) The Third Experiment Method

(79) About 15 to 30 mg of Crystalline form A was added to the corresponding solvent to form suspension, stirred at room temperature for 5 days, filtered to obtain the Crystalline form B.

(80) TABLE-US-00013 Crystalline Tempera- form A Solvent ture weight (volume, No. ( C.) (mg) Solvent mL) Preparation method Room 15 Ethanol 1.0 26 of Crystalline temperature Form B Preparation method Room 15 Isopropanol 2.0 27 of Crystalline temperature Form B Preparation method Room 15 Propanol 1.0 28 of Crystalline temperature Form B Preparation method Room 30 Water 0.4 29 of Crystalline temperature Form B Preparation method Room 15 Nitro- 2.0 30 of Crystalline temperature methane Form B Preparation method Room 15 Butanone 2.0 31 of Crystalline temperature Form B Preparation method Room 15 Ether 2.0 32 of Crystalline temperature Form B

(81) The Fourth Experiment Method

(82) About 15 to 20 mg of Crystalline form A was added to the corresponding solvent to form suspension, stirred for 5 days at 40 C., filtered to obtain the Crystalline form B.

(83) TABLE-US-00014 Crystalline Tempera- form A Solvent ture weight (Volume, No. ( C.) (mg) Solvent mL) Preparation method 40 20 Ethanol 1.0 33 of Crystalline Form B Preparation method 40 15 Ethyl acetate 2.0 34 of Crystalline Form B Preparation method 40 15 Tetra- 2.0 35 of Crystalline hydrofuran Form B Preparation method 40 15 Toluene 2.0 36 of Crystalline Form B Preparation method 40 15 n-Heptane 2.0 37 of Crystalline Form B

(84) The Fifth Experiment Method

(85) About 15 to 40 mg of Crystalline form A was added to Solvent 2 first, then added to Solvent 1 to form suspension, and stirred at the corresponding temperature for 4 days, filtered to obtain the Crystalline form B.

(86) TABLE-US-00015 Crystalline Solvent 1 Solvent 2 Temperature form A (Volume, (Volume, No. ( C.) weight (mg) Solvent 1 mL) Solvent 2 mL) Preparation method Room 20 Water-saturated 2.0 Non Non 38 of Crystalline temperature ethyl Form B acetate layer Preparation method Room 40 Ethyl 0.5 Non Non 39 of Crystalline temperature acetate-saturated Form B water layer Preparation method 4 15 Ether 1.0 Ethanol 1.0 40 of Crystalline Form B Preparation method 40 15 Acetonitrile 1.0 Toluene 1.0 41 of Crystalline Form B Preparation method 40 15 Ethanol 0.5 Butanone 1.5 42 of Crystalline Form B Preparation method 40 15 Isopropyl 1.0 Toluene 1.0 43 of Crystalline ether Form B

(87) The Sixth Experiment Method

(88) About 10 mg of Crystalline form A was added to the corresponding solvent wherein, Acetone:Water=3:1 (volume ratio), Acetonitrile:Water=3:2 (volume ratio) to get a clear solution by ultrasonic, followed by filtration, to which was added 1 mg of polymer. The mixture was exposed to room temperature for volatilization to get the Crystalline form B.

(89) TABLE-US-00016 Crystalline Tempera- form A Solvent ture weight (Volume, No. ( C.) (mg) Solvent mL) Polymer Preparation method Room 10 Methanol 0.5 Hydroxypropyl 44 of Crystalline temperature cellulose Form B Preparation method Room 10 Methanol 0.5 Ethyl 45 of Crystalline temperature cellulose Form B Preparation method Room 10 Acetone- 0.4 Hydroxypropyl 46 of Crystalline temperature Water cellulose Form B Preparation method Room 10 Acetone- 0.4 Ethyl 47 of Crystalline temperature Water cellulose Form B Preparation method Room 10 Acetone- 0.4 Povidone 48 of Crystalline temperature Water K30 Form B Preparation method Room 10 Acetone- 0.4 Polyallylamine 49 of Crystalline temperature Water hydrochloride Form B Preparation method Room 10 Acetone- 0.4 Carboxymethyl 50 of Crystalline temperature Water cellulose Form B Preparation method Room 10 Acetone- 0.4 Polyvinyl 51 of Crystalline temperature Water alcohol Form B Preparation method Room 10 Acetonitrile- 0.5 Hydroxypropyl 52 of Crystalline temperature Water cellulose Form B Preparation method Room 10 Acetonitrile- 0.5 Ethyl 53 of Crystalline temperature Water cellulose Form B Preparation method Room 10 Acetonitrile- 0.5 Povidone 54 of Crystalline temperature Water K30 Form B Preparation method Room 10 Acetonitrile- 0.5 Polyallylamine 55 of Crystalline temperature Water hydrochloride Form B Preparation method Room 10 Acetonitrile- 0.5 Carboxymethyl 56 of Crystalline temperature Water cellulose Form B Preparation method Room 10 Acetonitrile- 0.5 Polyvinyl 57 of Crystalline temperature Water alcohol Form B

(90) The Seventh Experiment Method

(91) About 15 to 50 mg of Crystalline form A was dissolved into corresponding solvent at corresponding temperature to get a clear solution, followed by filtration, the filtrate was placed at 4 C. being kept stirring until solid being observed and filtered to obtain the Crystalline form B. Among them, crystalline form not being observed into isopropanol at 4 C. with stirring, and then exposed to room temperature for volatilization to get the Crystalline form B.

(92) TABLE-US-00017 The weight of Tempera- Crystalline Solvent ture form A (Volume, No. ( C.) (mg) Solvent mL) Preparation method 60 50 Methanol 1.0 58 of Crystalline Form B Preparation method 70 15 Ethanol 1.2 59 of Crystalline Form B Preparation method 70 15 n- 1.4 60 of Crystalline Propanol Form B Preparation method 70 10 n-Butanol 2.0 61 of Crystalline Form B Preparation method 70 50 Water 0.4 62 of Crystalline Form B Preparation method 70 10 Iso- 2.0 63 of Crystalline propanol Form B

(93) The Eighth Experiment Method

(94) About 10 to 15 mg of Crystalline form A was added to Solvent 2 first, then added to Solvent 1 to get a clear solution at the corresponding temperature, followed by filtration, then the filtrate was stirred at 20 C. until solid being observed, recovering the Crystalline form B. Among them, crystalline form not being observed with stirring using preparation method 69 to 74 of Crystalline form B, the filtrate was exposed to room temperature for volatilization to get the Crystalline form B.

(95) TABLE-US-00018 The weight Solvent 1 Solvent 2 Temperature of Crystalline (Volume, (Volume, No. ( C.) form A (mg) Solvent 1 mL) Solvent 2 mL) Preparation method 55 15 Trifluoro- 0.1 Acetone 0.3 64 of Crystalline ethanol Form B Preparation method 55 15 Water 0.2 Acetone 1.0 65 of Crystalline Form B Preparation method 70 15 Water 0.3 Dioxane 2.0 66 of Crystalline Form B Preparation method 70 15 Water 0.3 Acetonitrile 3.0 67 of Crystalline Form B Preparation method 55 10 n-Propanol 0.8 Methyl 0.7 68 of Crystalline tert-butyl Form B ether Preparation method 60 15 Methanol 0.2 Nitromethane 1.0 69 of Crystalline Form B Preparation method 60 15 Methanol 0.3 Acetonitrile 0.5 70 of Crystalline Form B Preparation method 70 10 Ethanol 1.0 Butanone 0.5 71 of Crystalline Form B Preparation method 70 10 Ethanol 1.6 Ethyl 0.5 72 of Crystalline acetate Form B Preparation method 70 10 Ethanol 1.0 1,4- 0.5 73 of Crystalline dioxane Form B Preparation method 70 15 Water 0.3 Tetrahydrofuran 2.0 74 of Crystalline Form B

(96) The Ninth Experiment Method

(97) About 10 to 15 mg of Crystalline form A was added to solvent 1 to get a clear solution by ultrasonic at room temperature, then filtered, and added to solvent 2 dropwise with stirring until a large amount of solid being observed, and filtered to obtain the Crystalline form B. Among them, no solid being observed using the preparation methods 89 and 90 of Crystalline form B, then the mixture was exposed to room temperature for volatilization to get the Crystalline form B.

(98) TABLE-US-00019 Sample Solvent 1 Solvent 2 weight (Volume, (Volume, No. (mg) Solvent 1 mL) Solvent 2 mL) Preparation method 15 Methanol 0.4 Acetone 5.0 75 of Crystalline Form B Preparation method 15 Methanol 0.4 Ethylacetate 3.6 76 of Crystalline Form B Preparation method 15 Methanol 0.4 Methyl 1.6 77 of Crystalline tert-butyl Form B ether Preparation method 10 Ethanol 0.8 Isopropyl ether 3.0 78 of Crystalline Form B Preparation method 10 Ethanol 0.8 Isopropyl acetate 5.0 79 of Crystalline Form B Preparation method 15 Trifluoroethanol 0.2 Acetone 5.0 80 of Crystalline Form B Preparation method 15 Water 0.4 Acetone 13.0 81 of Crystalline Form B Preparation method 15 Water 0.4 Tetrahydrofuran 12.0 82 of Crystalline Form B Preparation method 15 Water 0.4 1,4-dioxane 13.0 83 of Crystalline Form B Preparation method 15 Water 0.4 Acetonitrile 5.0 84 of Crystalline Form B Preparation method 10 n-Propanol 0.8 Isopropyl acetate 5.0 85 of Crystalline Form B Preparation method 10 n-Propanol 0.8 n-Heptane 12.0 86 of Crystalline Form B Preparation method 15 Dimethyl 0.2 Dichloromethane 5.0 87 of Crystalline sulfoxide Form B Preparation method 15 Methanol 0.2 Chloroform 5.0 88 of Crystalline Form B Preparation method 15 Methanol 0.4 Dichloromethane 5.0 89 of Crystalline Form B Preparation method 10 Ethanol 0.8 Tetrahydrofuran 5.0 90 of Crystalline Form B

(99) The Tenth Experiment Method

(100) About 10 mg of amorphous sample of the compound of formula I was placed in a 2.0 mL of centrifuge tube. The centrifuge tube was then placed in the corresponding solvent atmosphere at room temperature for 6 days to obtain the Crystalline form B.

(101) TABLE-US-00020 Sample Solvent weight (Volume, No. (mg) Solvent mL) Preparation method 10 n-Butanol 4.0 91 of Crystalline Form B Preparation method 10 Water 4.0 92 of Crystalline Form B Preparation method 10 Nitromethane 4.0 93 of Crystalline Form B Preparation method 10 Ethyl acetate 4.0 94 of Crystalline Form B Preparation method 10 Methyl tert-butyl ether 4.0 95 of Crystalline Form B Preparation method 10 Tetrahydrofuran 4.0 96 of Crystalline Form B Preparation method 10 Dichloromethane 4.0 97 of Crystalline Form B Preparation method 10 Chloroform 4.0 98 of Crystalline Form B Preparation method 10 Toluene 4.0 99 of Crystalline Form B

(102) The Eleventh Experiment Method

(103) About 15 to 30 mg of amorphous sample of the compound of formula I was added to the corresponding solvent at the corresponding temperature, and stirred for 30 minutes, followed by filtration to obtain the Crystalline Form B.

(104) TABLE-US-00021 Tempera- Sample Solvent ture weight (Volume, No. ( C.) (mg) Solvent mL) Preparation method 4 15 n-Propanol 0.2 100 of Crystalline Form B Preparation method 4 30 Water 0.1 101 of Crystalline Form B Preparation method 4 10 Butanone 0.4 102 of Crystalline Form B Preparation method 4 10 Ethyl acetate 0.4 103 of Crystalline Form B Preparation method 4 10 Tetra- 0.4 104 of Crystalline hydrofuran Form B Preparation method 4 10 Dichloro- 0.4 105 of Crystalline methane Form B Preparation method Room 15 Ethanol 0.2 106 of Crystalline temperature Form B Preparation method Room 15 Isopropanol 0.2 107 of Crystalline temperature Form B Preparation method Room 15 n-Butanol 0.2 108 of Crystalline temperature Form B Preparation method Roomv 30 Water 0.1 109 of Crystalline temperature Form B Preparation method Room 10 Acetone 0.4 110 of Crystalline temperature Form B Preparation method Room 10 Ether 0.4 111 of Crystalline temperature Form B Preparation method Room 10 Isopropyl 0.4 112 of Crystalline temperature acetate Form B Preparation method Room 10 1,4-dioxane 0.4 113 of Crystalline temperature Form B8 Preparation method Room 10 Acetonitrile 0.4 114 of Crystalline temperature Form B Preparation method Room 10 Chloroform 0.4 115 of Crystalline temperature Form B Preparation method 40 10 Sec-butanol 0.4 116 of Crystalline Form B Preparation method 40 10 Nitromethane 0.4 117 of Crystalline Form B Preparation method 40 10 Ethyl acetate 0.4 118 of Crystalline Form B Preparation method 40 10 Tetra- 0.4 119 of Crystalline hydrofuran Form B Preparation method 40 10 Acetonitrile 0.4 120 of Crystalline Form B Preparation method 40 10 Toluene 0.4 121 of Crystalline Form B

(105) The Twelfth Experiment Method

(106) About 15 to 30 mg of amorphous sample of the compound of formula I was added to solvent 2 first, and then added to solvent 1 to get a suspension, stirred for 30 minutes at the corresponding temperature, filtered to obtain the Crystalline Form B.

(107) TABLE-US-00022 Sample Solvent 1 Solvent 2 Temperature weight (Volume, (Volume, No. ( C.) (mg) Solvent 1 mL) Solvent 2 mL) Preparation method Room 15 Methanol 0.2 Isopropyl 0.6 122 of Crystalline temperature ether Form B Preparation method 40 15 Methanol 0.1 Ethyl 0.6 123 of Crystalline acetate Form B Preparation method 4 15 Methanol 0.05 1,4-dioxane 1.0 124 of Crystalline Form B Preparation method 4 10 Ethanol 0.1 Butanone 1.0 125 of Crystalline Form B Preparation method Room 10 Ethanol 0.2 Acetonitrile 3.0 126 of Crystalline temperature Form B Preparation method 40 10 Ethanol 0.2 n-Heptane 0.8 127 of Crystalline Form B Preparation method Room 15 Trifluoro 0.05 Nitromethane 0.6 128 of Crystalline temperature ethanol Form B Preparation method 4 15 Trifluoro 0.1 Ether 0.8 129 of Crystalline ethanol Form B Preparation method 40 15 Trifluoro 0.05 Tetrahydrofuran 0.8 130 of Crystalline ethanol Form B Preparation method Room 15 Water 0.05 Acetone 1.0 131 of Crystalline temperature Form B Preparation method 4 15 Water 0.05 Tetrahydrofuran 1.0 132 of Crystalline Form B Preparation method Room 15 Water 0.05 Acetonitrile 1.0 133 of Crystalline temperature Form B Preparation method Room 10 Isopropanol 0.2 Methyl 0.6 134 of Crystalline temperature tert-butyl Form B ether Preparation method 4 10 n-Propanol 0.2 Isopropyl 0.6 135 of Crystalline acetate Form B Preparation method 40 10 n-Butanol 0.2 Methyl 0.8 136 of Crystalline cyclohexane Form B Preparation method 4 15 Dimethyl 0.1 Acetone 1.6 137 of Crystalline sulfoxide Form B Preparation method 40 15 Dimethyl 0.05 Ethyl 1.0 138 of Crystalline sulfoxide acetate Form B Preparation method Room 15 Dimethyl 0.05 Acetonitrile 1.0 139 of Crystalline temperature sulfoxide Form B Preparation method Room 10 Chloroform 0.4 Methyl 0.4 140 of Crystalline temperature tert-butyl Form B ether Preparation method Room 10 Ethyl 0.4 Toluene 0.4 141 of Crystalline temperature acetate Form B

(108) The Thirteenth Experiment Method Preparation Method 142 of Crystalline Form B

(109) About 10 mg of amorphous sample of the compound of formula I was placed in an atmosphere of 85% RH humidity for 10 days at room temperature to obtain the Crystalline form B.

(110) The Fourteenth Experiment Method

(111) The appropriate amount of sample was added to the corresponding solvent, to get a clear solution by ultrasonic, followed by filtration, then the filtrate was spin-dried rapidly at the corresponding water bath temperature to obtain the Crystalline form B.

(112) TABLE-US-00023 Tempera- Sample Solvent 1 ture weight (Volume, No. ( C.) (mg) Solvent mL) Preparation method 60 15 Water 0.4 143 of Crystalline Form B Preparation method 40 1000 Methanol 40.0 144 of Crystalline Form B

Example 4: Preparation Method of Crystalline form C

(113) Preparation Method 1 of Crystalline Form C:

(114) 100 mg of Crystalline form A of the compound of formula I was added to 2.8 mL of isopropyl ether, followed by added to 2.8 mL of methanol to form a suspension. The mixture was stirred for 4 days at room temperature and filtered in vacuum to obtain 73 mg of the Crystalline form C.

(115) Preparation Method 2 of Crystalline Form C:

(116) 100 mg of Crystalline form A of the compound of formula I was added to 1.0 mL of isopropyl ether, followed by added to 3.0 mL of methanol to form a suspension. The mixture was stirred at room temperature for 5 days and filtered in vacuum to obtain 63 mg of the Crystalline form C.

(117) Preparation method 3 and 4 of Crystalline form C:

(118) About 15 mg of Crystalline Form A of the compound of formula I was dissolved into solvent 2, followed by dissolved into solvent 1 to get a clear solution, filtered and stirred at 20 C. until solid being observed, recovering the Crystalline Form C.

(119) TABLE-US-00024 Sample Temperature weight Solvent 1 Solvent 2 No. ( C.) (mg) Solvent 1 (mL) Solvent 2 (mL) Preparation 60 15 Methanol 1.1 Isopropyl 0.5 method 3 ether Preparation 60 15 Methanol 0.6 Isopropyl 0.5 method 4 acetate

(120) Preparation Method 5 of Crystalline Form C:

(121) About 10 mg of Crystalline Form A of the compound of formula I was placed in a 2.0 mL of centrifuge tube, and exposed to 4 mL of methanol closed solvent atmosphere for 6 days at room temperature to obtain the Crystalline form C.

Example 5: Preparation Method of Crystalline Form D

(122) Preparation Method 1 of Crystalline form D:

(123) 100 mg of Crystalline form A of the compound of formula I was added to 2.0 mL of ethyl acetate, then added to 1.0 mL of dimethyl sulfoxide to form a suspension. The suspension was stirred at room temperature for 1 day to obtain the Crystalline form D.

(124) Preparation Method 2 of Crystalline form D:

(125) About 5 mg of Crystalline form A of the compound of formula I was dissolved into 0.1 mL of dimethylsulfoxide to get a clear solution, followed by filtration, and exposed to 40 C. for volatilization to get the Crystalline form.

(126) Preparation Method 3 of Crystalline Form D:

(127) About 20 mg of Crystalline form A of the compound of formula I was added to solvent 2, then added to solvent 1 to form a suspension. The mixture was stirred at the corresponding temperature for 4 days to obtain the Crystalline form D.

(128) TABLE-US-00025 Tempera- Sample Solvent Solvent ture weight Solvent 1 2 ( C.) (mg) 1 (mL) Solvent 2 (mL) 40 20 Ethyl 1.0 Dimethyl 0.5 acetate sulfoxide

(129) Preparation Method 4 and 5 of Crystalline Form D:

(130) About 15 mg of Crystalline form A of the compound of formula I was added to solvent 1 to get a clear solution by ultrasonic at room temperature, followed by filtration, and then the solvent 2 was added dropwise to the solution with stirring until a large amount of solid being observed, recovering the Crystalline form D.

(131) TABLE-US-00026 Sample Solvent Solvent weight 1 2 No. (mg) Solvent 1 (mL) Solvent 2 (mL) preparation 15 Dimethyl 0.2 Acetone 3.0 method 4 sulfoxide preparation 15 Dimethyl 0.2 Ethyl 5.0 method 5 sulfoxide acetate

Example 6: Preparation Method of Crystalline Form E

(132) About 20 mg of Crystalline form A of the compound of formula I was placed in 85% RH Humidity Apparatus for 26 days at room temperature to get the Crystalline form E.

Example 7: Preparation Method of Amorphis

(133) Preparation Method 1 of Amorphis:

(134) 200 mg of Crystalline form A of the compound of formula I was added to 0.6 mL of trifluoroethanol to get a clear solution by ultrasonic, followed by filtration, and the filtrate was spin-dried rapidly in vacuum at 40 C. to obtain the amorphis.

(135) Preparation Method 2 of Amorphis:

(136) 200 mg of Crystalline form A of the compound of formula I was added to 7.0 mL of methanol to get a clear solution by ultrasonic, followed by filtration, and spin-dried rapidly in vacuum at 40 C. to obtain the amorphis.

(137) Preparation Method 3-5 of Amorphis:

(138) 5 to 10 mg of Crystalline form A of the compound of formula I was dissolved into the corresponding solvent to get a clear solution, followed by filtration, and exposed to the corresponding temperature for volatilization to obtain the amorphis.

(139) TABLE-US-00027 Tempera- Sample ture weight Solvent No. ( C.) (mg) Solvent (mL) Preparation Room 5 Trifluoroethanol 0.4 method 3 temperature Preparation 40 5 n-Propanol 1.0 method 4 Preparation 40 10 Trifluoroethanol 0.4 method 5
Preparation Method 6-9 of Amorphis:

(140) About 10 mg of Crystalline form A of the compound of formula I was dissolved into the corresponding solvent to get a clear solution, followed by filtration, and exposed to the corresponding temperature for volatilization to obtain the amorphis.

(141) TABLE-US-00028 Sample Temperature weight Solvent 1 Solvent 2 No. ( C.) (mg) Solvent 1 (mL) Solvent 2 (mL) Preparation Room 10 Trifluoro-ethanol 0.2 Acetonitrile 0.2 method 6 temperature Preparation 60 10 n-Propanol 1.0 Toluene 0.4 method 7 Preparation 60 10 Sec-butanol 2.0 1,4-dioxane 0.4 method 8 Preparation 60 10 n-Butanol 2.0 n-Heptane 0.6 method 9
Preparation Method 10 of Amorphis:

(142) About 15 mg of Crystalline form A of the compound of formula I was added to 2.0 mL of n-heptane, the mixture was stirred at room temperature for 5 days to obtain the amorphis.

(143) Preparation Method 11-12 of Amorphis:

(144) About 10 to 15 mg of Crystalline form A of the compound of formula I was dissolved into the corresponding solvent to get a clear solution at the corresponding temperature, followed by filtration, and stirred at 20 C. until solid being observed, recovering the amorphis.

(145) TABLE-US-00029 Temperature Sample Solvent 1 Solvent 2 No. ( C.) weight (mg) Solvent 1 (mL) Solvent 2 (mL) Preparation 70 15 Trifluoroethanol 0.1 Acetonitrile 2.0 method 11 Preparation 70 10 Sec-butanol 2.0 n-Heptane 0.8 method 12
Preparation Method 13 of Amorphis:

(146) About 15 mg of Crystalline form A of the compound of formula I was added to 0.2 mL of trifluoroethanol to get a clear solution by ultrasonic at room temperature, followed by filtration, 1.0 mL of isopropyl ether was added dropwise to the solution with stirring until a large amount of solid being observed, recovering the amorphis.

(147) Preparation Method 14-17 of Amorphis:

(148) About 10 to 15 mg of Crystalline form A of the compound of formula I was dissolved into the corresponding solvent to get a clear solution, followed by filtration, and the filtrate was spin-dried rapidly at the corresponding temperature to obtain the amorphis.

(149) TABLE-US-00030 Sample Temperature weight Solvent 1 Solvent 2 No. ( C.) (mg) Solvent 1 (mL) Solvent 2 (mL) Preparation 40 10 Ethanol 1.0 NA NA method 14 Preparation 40 15 Methanol 0.4 Dichloromethane 0.4 method 15 Preparation 40 10 Ethanol 1.5 Chloroform 0.5 method 16 Preparation 40 15 Trifluoro-ethanol 0.2 Acetonitrile 0.4 method 17

Example 8: Stability of the Crystalline Form

(150) Samples of Crystalline form A and B were placed at 80 C. for 24 hours, 25 C.-60% RH for 10 days and 40 C.-75% RH for 10 days respectively, there were no change in crystalline form.

(151) Crystalline form C was almost completely converted to Crystalline form A under the condition of being dried in vacuum at room temperature overnight.

(152) Most of the Crystalline form D transformed into Crystalline form B under conditions of being dried at room temperature or being dried in vacuum at room temperature, which can not exist stably.

(153) Most of the Crystalline form E transformed into Crystalline form A. under the condition of being placed in a desiccator for 2 days, which is unstable.

Example 9: Assay of Dynamic Vapor Sorption (DVS)

(154) Crystalline form A: There was about 2.3% weight change in the range of 0% to 80% RH. The hydrate of Crystalline form A removed about 1.5% of moisture in the 0% RH drying stage, and absorbed about 2.3% of moisture in the 0% RH-80% RH range. In the desorption stage, 1.5% of moisture could be removed under the condition of 30% RH and the change of the weight was less than 2% in the range of 30-80% RH.

(155) Crystalline form B: There was about 2.3% weight change in the range of 0% to 80% RH. The hydrate of Crystalline form B could remove about 4% of moisture under 10% RH, and absorbed about 4% of moisture under the condition of 10% RH in the adsorption stage and the change of weight was less than 2% in the range of 10-80% RH.

(156) Amorphis: There was about 15.7% weight change in the range of 0-80% RH, extremely hygroscopic.

Example 10: Solubility Determination

(157) The solubility of Crystalline form A of the compound as shown in formula I in water is 20 to 100 mg/mL at room temperature, and the solubility of the free base amorphis of the compound as shown in formula I in water is less than 1 mg/mL.

Example 11. Capsule Formulation

(158) As an explicit embodiment of an oral medication, about 20 to 150 mg of the polymorphs described in example 1 and/or example 2 are formulated with finely divided microcrystalline cellulose and/or stearic acid to obtain a total amount of about 50 mg to 500 mg to fill 0 type capsule.

Example 12. Formulation of Tablets or Capsules

(159) As an explicit embodiment of an oral medication, about 20 to 150 mg of the polymorphs described in example 1 and/or example 2 are formulated with the two or more of the following excipient: finely divided microcrystalline cellulose, mannitol, crospovidone, croscarmellose sodium, sodium starch glycolate, povidone, hydroxypropylcellulose and/or stearic acid to allocate a total amount of about 50 mg to 500 mg of tablet or capsule.

Example 13: Pharmacokinetic Data

(160) 6 female SD rats were divided into two groups, three rats in each group. 50 mg/kg of Crystalline form A of the compound of formula I and free base amorphis of the compound of formula I were administered by intragastric gavage at single dose to each female SD rat respectively; the blood samples were collected through the jugular vein at the specified time, and the plasma from these samples was separated and stored in the refrigerator at 80 C.

(161) For the above plasma from these samples, protein was precipitated using acetonitrile, the supernatant was diluted 3-fold by water, then took 5 L of the solution for LC-MS/MS test, and data is shown in Table 9:

(162) TABLE-US-00031 TABLE 9 Administra- tion Dose T.sub.max C.sub.max AUC.sub.last Compound methods (mg/kg) (h) (ng/mL) (h*ng/mL) Free base PO 50 4.67 890 8165 amorphous of the compound as shown in formula I Crystalline form A PO 50 2.67 1440 11551 of the compound as shown in formula I

(163) 50 mg/kg of Crystalline form A of the compound as shown in formula I and free base amorpphis of the compound as shown in formula I were administered orally to the rats, T.sub.max were 2.67 and 4.67 h respectively, C.sub.max were 1440 and 890 ng/mL respectively, and AUC.sub.last were 11551 and 8165 h*ng/mL, respectively.

(164) From the above results, it is suggested that Crystalline form A of the compound as shown in formula I showed higher absorption in vivo than the free base amorphis of the compound as shown in formula I.

Example 14: Biochemical Kinase Activity of the Compound of Formula I

(165) Biochemical kinase activity of the compound as shown in formula I was tested by Reaction Biology Corp located in Malvern, Pa., USA. The testing rules is described in Nat Biotechnol. 2011; 29(11):1039-45 by Anastassiadis et al. It was found that the compound of Formula I could potentially inhibit the following kinases:

(166) TABLE-US-00032 Kinase IC.sub.50 (nM) ALK 0.16 ALK (C1156Y) 0.28 ALK (F1174L) 0.16 ALK (Fl 174L)-EML4 0.53 ALK (Fl 174L)-NPM1 0.47 ALK (F1174S) 0.17 ALK (G1202R) 3.83 ALK (G1269A) 1.14 ALK (G1269S) 1.39 ALK(L1152R) 0.58 ALK(L1196M) 0.32 ALK (R1275Q) 1.06 ALK (S1206R) 0.17 ALK (T1151-L1152insT) 0.26 ALK (T1151M) 0.13 ALK-NPM1 0.68 c-MET 9.59 EPHA1 6.22 EPHA2 1.14 EPHB1 8.59 CSF1R (FMS) 13.44 NEK1 6.08 ROS/ROS1 1.41 ROS1-GOPC 0.98 TRKA 8.00 TRKA-TFG (TRK-T3) 0.46 TRKA-TPM3 0.62 TRKA-TPR 1.22 TRKB 3.39 TRKC 0.46 ALK-TFG 0.73 ALK-TPM3 0.21

(167) Although the present invention has been fully described in connection with the preferred embodiments thereof with reference to the accompanying drawings, it is to be noted that various changes and modifications are apparent to those skilled in the art. Such changes and modifications are to be understood as included within the scope of the present invention.