CRYSTAL FORMS OF FUSED RING COMPOUND, AND COMPOSITION THEREOF, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF

Abstract

Disclosed in the present disclosure are crystal forms of a fused ring compound, and a composition thereof, a preparation method therefor and use thereof. The crystal forms comprise a crystal form I, a crystal form II, a crystal form III, a crystal form IV and a crystal form V, which have, when using X-ray diffraction, characteristic diffraction peaks at about 11.3 degrees, 17.2 degrees and 21.1 degrees, at about 25.1 degrees, 21.2 degrees and 14.1 degrees, or at about 6.6 degrees, 13.4 degrees and 8.0 degrees, at about 11.8 degrees, 13.3 degrees and 16.7 degrees, and at about 6.5 degrees, 13.3 degrees and 20.0 degrees. The crystal form I or IV is obtained by dissolving a fused ring compound in a proper solvent, followed by stirring, filtering and drying. The use of crystal form I or crystal form IV in preparation of anti-cancer drugs for inhibiting phosphatidylinositol 3-kinase. The use thereof for targeted therapy for tumors, and for anti-inflammation or treatment of autoimmune diseases.

Claims

1. A crystal form of a fused ring compound having a structural formula of: ##STR00004## wherein, the crystal form is: crystal form I, having characteristic diffraction peaks at 2θ angles of 11.3°, 17.2° and 21.1° using X-ray diffraction; crystal form II, having characteristic diffraction peaks at 2θ angles of 25.1°, 21.2° and 14.1° using X-ray diffraction; crystal form III, having characteristic diffraction peaks at 2θ angles of 6.6°, 13.4° and 8.0° using X-ray diffraction; crystal form IV, having characteristic diffraction peaks at 2θ angles of 11.8°, 13.3° and 16.7° using X-ray diffraction; or crystal form V, having characteristic diffraction peaks at 2θ angles of 6.5°, 13.3° and 20.0° using X-ray diffraction; wherein the error in the 2θ angles is ±0.5°.

2. The crystal form according to claim 1, wherein, crystal form I further has characteristic diffraction peaks at 2θ angles of 22.7°, 18.5°, and 13.8° using X-ray diffraction; crystal form II further has characteristic diffraction peaks at 2θ angles of 16.0°, 7.0°, and 18.4° using X-ray diffraction; crystal form III further has characteristic diffraction peaks at 2θ angles of 20.0°, 21.1°, and 10.5° using X-ray diffraction; crystal form IV further has characteristic diffraction peaks at 2θ angles of 17.8°, 21.8°, and 24.4° using X-ray diffraction; crystal form V further has characteristic diffraction peaks at 2θ angles of 10.4°, 24.0°, and 24.8° using X-ray diffraction; wherein the error in the 2θ angles is ±0.5°.

3. A composition comprising one of crystal form I, crystal form II, crystal form III, crystal form IV and crystal form V defined in claim 1, or any combination thereof, and crystal form I or crystal form IV accounts for 50% by weight or more of the composition.

4. The composition according to claim 3, wherein crystal form I or crystal form IV accounts for 80% by weight or more of the composition.

5. The composition according to claim 3, wherein crystal form I or crystal form IV accounts for 90% by weight or more of the composition.

6. The composition according to claim 3, comprising crystal form I, crystal form II, crystal form III, crystal form IV or crystal form V, and a pharmaceutically acceptable carrier or excipient.

7-10. (canceled)

11. A method for preparing crystal form IV defined in claim 1, characterized in that, the method comprises dissolving the fused ring compound in an organic solvent and/or water under heating, followed by stirring for crystallization, filtering and drying.

12. The method for preparing crystal form IV according to claim 11, wherein, the method comprises dissolving the fused ring compound in a mixture of acetonitrile and water, wherein the amount of acetonitrile is 30-90 times the weight of the fused ring compound and the amount of water is 0-20 times the weight of the fused ring compound.

13. The method for preparing crystal form IV according to claim 11, wherein, the stirring for crystallization is carried out at a temperature of 0-40° C. for a time period of 0.5-30 hours, and the drying is carried out at a temperature of 60-150° C. for a time period of 1-20 hours.

14. The composition according to claim 3, wherein the composition is an agent for inhibiting phosphatidylinositol 3-kinase.

15. The method according to claim 18, wherein the cancer is selected from the group consisting of brain cancer, head and neck cancer, esophageal cancer, lung cancer, liver cancer, stomach cancer, kidney cancer, pancreatic cancer, prostate cancer, colorectal cancer, ovarian cancer, breast cancer, thyroid cancer, skin cancer, leukemia, myelodysplastic syndrome, sarcoma, osteosarcoma and rhabdomyosarcoma.

16. (canceled)

17. The method according to claim 18, wherein the inflammation is chronic obstructive pulmonary disease or asthma.

18. A method for treating a disease selected from cancer, inflammation, or an autoimmune disease, the method comprising: administering to a patient suffering from such disease the crystal form according to claim 1.

19. The method according to claim 18, wherein the autoimmune disease is selected from a group consisting of: rheumatoid arthritis, psoriasis, and systemic lupus erythematosus.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1A shows an X-ray diffraction pattern of crystal form I in the present disclosure.

[0035] FIG. 1B shows an X-ray diffraction peak data plot of crystal form I in the present disclosure.

[0036] FIG. 1C shows a DSC plot of crystal form I in the present disclosure.

[0037] FIG. 2A shows an X-ray diffraction pattern of crystal form II obtained in Example 7.

[0038] FIG. 2B shows an X-ray diffraction peak data plot of crystal form II obtained in Example 7.

[0039] FIG. 3A shows an X-ray diffraction pattern of crystal form III obtained in Example 9.

[0040] FIG. 3B shows an X-ray diffraction peak data plot of crystal form III obtained in Example 9.

[0041] FIG. 4A shows an X-ray diffraction pattern of crystal form V obtained in Example 10.

[0042] FIG. 4B shows an X-ray diffraction peak data plot of crystal form V obtained in Example 10.

[0043] FIG. 5A shows an X-ray diffraction pattern of crystal form IV in the present disclosure.

[0044] FIG. 5B shows an X-ray diffraction peak data plot of crystal form IV in the present disclosure.

[0045] FIG. 5C shows a DSC plot of crystal form IV in the present disclosure.

[0046] FIG. 6 shows an X-ray diffraction pattern of crystal form I obtained in Example 6.

[0047] FIG. 7 shows an X-ray diffraction pattern of crystal form II obtained in Example 8.

[0048] FIG. 8 shows an X-ray diffraction pattern of the amorphous form obtained in Example 11.

[0049] FIG. 9 shows an X-ray diffraction pattern of the amorphous form after a high humidity test for 5 days in Example 12.

[0050] FIG. 10 shows an X-ray diffraction pattern of crystal form IV after a high humidity test for 5 days in Example 12.

[0051] FIG. 11 shows an X-ray diffraction pattern of crystal form I after a high humidity test for 5 days in Example 12.

[0052] FIG. 12 shows an X-ray diffraction pattern of crystal form II after a high humidity test for 5 days in Example 12.

[0053] FIG. 13 shows an X-ray diffraction pattern of the amorphous form after a high temperature test for 5 days in Example 13.

[0054] FIG. 14 shows an X-ray diffraction pattern of crystal form IV after a high temperature test for 5 days in Example 13.

[0055] FIG. 15 shows an X-ray diffraction pattern of crystal form I after a high temperature test for 5 days in Example 13.

[0056] FIG. 16 shows an X-ray diffraction pattern of crystal form II after a high temperature test for 5 days in Example 13.

[0057] FIG. 17 shows an X-ray diffraction pattern of crystal form IV after an accelerated test for 30 days in Example 14.

[0058] FIG. 18 shows an X-ray diffraction pattern of crystal form I after an accelerated test for 30 days in Example 14.

[0059] FIG. 19 shows an X-ray diffraction pattern of crystal form II after an accelerated test for 30 days in Example 14.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0060] The present disclosure is further described below in connection with preferred embodiments for better understandings for the disclosure. It should be understood by those skilled in the art that the detailed description below is only illustrative and not limiting, while it should not be used to limit the protection scope of the present disclosure.

[0061] All numerical designations of the present disclosure (e.g., temperature, time, concentration, and weight, including ranges for each of these) may generally be approximated by varying (+) or (−) in appropriate increments of 0.1 or 1.0. All numerical designations are understood to be preceded by the term “about”.

[0062] A crystal form of a fused ring compound and a preparation method thereof and uses thereof, wherein the fused ring compound has a structure of the following formula:

##STR00002##

[0063] Crystal form I, having characteristic diffraction peaks at 2θ angles of about 11.3°, 17.2°, 21.1° using X-ray diffraction; crystal form II, having characteristic diffraction peaks at 2θ angles of about 25.1°, 21.2°, 14.1° using X-ray diffraction; crystal form III, having characteristic diffraction peaks at 2θ angles of about 6.6°, 13.4° and 8.0° using X-ray diffraction; crystal form IV, having characteristic diffraction peaks at 2θ angles of about 11.8°, 13.3° and 16.7° using X-ray diffraction; or crystal form V, having characteristic diffraction peaks at 2θ angles of about 6.5°, 13.3° and 20.0° using X-ray diffraction; wherein the error in the 2θ angles is ±0.5°.

[0064] Further, crystal form I further has characteristic diffraction peaks at 2θ angles of about 11.3°, 17.2°, 21.1°, 22.7°, 18.5°, 13.8° using X-ray diffraction; crystal form II further has characteristic diffraction peaks at 2θ angles of about 25.1°, 21.2°, 14.1°, 16.0°, 7.0°, 18.4° using X-ray diffraction; crystal form III further has characteristic diffraction peaks at 2θ angles of about 6.6°, 13.4°, 8.0°, 20.0°, 21.1°, 10.5° using X-ray diffraction; crystal form IV further has characteristic diffraction peaks at 2θ angles of about 11.8°, 13.3°, 16.7°, 17.8°, 21.8°, 24.4° using X-ray diffraction; crystal form V further has characteristic diffraction peaks at 2θ angles of about 6.5°, 13.3°, 20.0°, 10.4°, 24.0°, 24.8° using X-ray diffraction; wherein the error in the 2θ angles is ±0.5°.

Example 1

[0065] Preparation of crystal form I:

[0066] 10 g of the fused ring compound prepared in Example 11 and 30 g of dichloromethane were added to a reaction flask, heated to dissolve, and further added with 90 g of ethanol, concentrated to a remaining weight of about 100 g, followed by stirring for crystallization at 20° C. for 4 hours, then filtered, and dried at 100° C. to obtain crystal form I.

[0067] The crystal form I prepared by the above process had a melting point of 207-209° C. The X-ray diffraction pattern showed characteristic diffraction peaks at 2θ angles of 11.3°, 13.8°, 17.2°, 18.5°, 20.2°, 21.1°, 22.7°, 25.2°, 28.0°, 29.6°, 31.2°, and 33.2° (see FIGS. 1A and 1B). FIG. 1C showed thermal analysis plot of crystal form I. TGA showed that crystal form I started to lose weight at about 145° C., while DSC plot shows an absorption peak at about 209° C.

Example 2

[0068] The solubilities (μg/mL) of crystal form I in different environments are shown in

[0069] Table 1.

TABLE-US-00001 TABLE 1 Solvent Ultrasonic R.T. (25° C.) 37° C. 75° C. Stability Water 4.63 3.84 3.87 2.24 Stable within 24 hours pH 1.2 hydrochloric 294.60 275.20 404.30 867.60 Stable within acid solution 24 hours pH 4.5 acetic acid-sodium 1.56 1.29 1.67 1.55 Stable within acetate solution 24 hours pH 6.8 PBS solution 2.79 3.58 1.51 1.41 Stable within 24 hours Simulated gastric 119.65 99.81 167.38 431.94 Stable within fluid (SGF) 24 hours Simulated fasting 4.76 2.07 2.87 8.64 Stable within intestinal fluid (FaSSIF) 24 hours Simulated postprandial 9.46 8.09 11.35 18.92 Stable within intestinal fluid (FeSSIF) 24 hours

Example 3

[0070] Preparation of crystal form IV:

[0071] 10 g of the fused ring compound prepared in Example 11 and 300 g of acetonitrile were added to a reaction flask, heated to dissolve, followed by stirring for crystallization at 25° C. for 4 hours, then filtered, and dried at 80° C. for 10 hours to obtain crystal form IV.

[0072] The crystal form IV prepared by the above process had a melting point of 185-188° C. The X-ray diffraction pattern showed characteristic diffraction peaks at 2θ angles of 6.6°, 8.2°, 9.7°, 11.8°, 13.3°, 15.0°, 16.7°, 17.8°, 20.2°, 21.8°, 24.4°, 27.9°, 29.1°, 30.4° (see FIGS. 5A and 5B). FIG. 5C showed a thermal analysis plot of crystal form IV. TGA showed that crystal form IV started to lose weight at about 250° C., while DSC plot shows an absorption peak at about 188° C.

Example 4

[0073] Preparation of crystal form IV:

[0074] 10 g of the fused ring compound prepared in Example 11 and 200 g of acetonitrile were added to a reaction flask, heated to dissolve, then added with 50 g of water, followed by stirring for crystallization at 5° C. for 2θ hours, and then filtered, and dried at 120° C. for 2 hours to obtain crystal form IV.

[0075] The crystal form IV prepared by the above process had a melting point of 185-187° C. The X-ray diffraction pattern showed characteristic diffraction peaks at 2θ angles of 6.6°, 8.2°, 9.7°, 11.8°, 13.2°, 15.0°, 16.7°, 17.8°, 20.2°, 21.8°, 24.4°, 27.9°, 29.1°, and 30.4°.

Example 5

[0076] The solubilities (μg/mL) of crystal form IV in different environments are shown in Table 2.

TABLE-US-00002 TABLE 2 Solvent Ultrasonic R.T. (25° C.) 37° C. 75° C. Stability Water 2.96 2.68 2.39 2.98 Stable within 24 hours pH 1.2 hydrochloric 1289.40 1283.50 1431.40 1516.50 Stable within acid solution 24 hours pH 4.5 acetic acid-sodium 3.04 2.75 3.04 3.45 Stable within acetate solution 24 hours pH 6.8 PBS solution 2.48 2.12 2.18 2.62 Stable within 24 hours Simulated gastric 570.49 533.36 655.37 766.58 Stable within fluid (SGF) 24 hours Simulated fasting 5.43 6.05 4.70 5.12 Stable within intestinal fluid (FaSSIF) 24 hours Simulated postprandial 29.70 31.70 26.02 28.48 Stable within intestinal fluid (FeSSIF) 24 hours

Example 6

[0077] Preparation of crystal form I: 1.0g of the fused ring compound prepared in Example 11 was added to a flask, which is further added with 30 mL of ethanol as a solvent, heated at an oil bath temperature of 85° C., stirred and dissolved to clear, then left to stand at room temperature, cooled for crystallization, and then filtered and collected for solids, and dried under vacuum at room temperature.

[0078] The X-ray diffraction pattern of crystal form I prepared by the above process showed characteristic diffraction peaks at 2θ angles of 10.4°, 11.3°, 13.9°, 17.3°, 18.0°, 18.6°, 20.3°, 20.8°, 21.3°, 22.8°, 25.3°, 28.0°, 29.7°, and 31.3° (see FIG. 6).

Example 7

[0079] Preparation of crystal form II:

[0080] 4.0g of the fused ring compound prepared in Example 11 was added with 12.0 g of dichloromethane, heated to dissolve, then added with 36.0 g of anhydrous methanol, stirred for 16 hours at 15° C. and filtered. The filter cake was washed with a small amount of methanol, dried at 60° C. under reduced pressure, and baked to obtain 3.90 g of a light yellow solid.

[0081] The characterization data of crystal form II prepared by the above process were shown in FIGS. 2A and 2B. The X-ray diffraction patterns showed characteristic diffraction peaks at 2θ angles of 5.7°, 7.0°, 9.9°, 11.5°, 12.2°, 14.1°, 16.0°, 17.3°, 18.4°, 21.2°, 22.9°, 25.1°, and 31.7° (see FIG. 2A).

Example 8

[0082] Preparation of crystal form II:

[0083] 1.0 g of the fused ring compound prepared in Example 11 was added to a flask, which is further added with 45 mL of solvent (EA:MeOH=1:1), heated at oil bath temperature of 70° C., stirred and dissolved to clear, then left to stand at room temperature, cooled for crystallization, then filtered and collected for solids, and dried under vacuum at room temperature.

[0084] The X-ray diffraction patterns of crystal form II prepared by the above process showed characteristic diffraction peaks at 2θ angles of 5.7°, 7.0°, 9.9°, 11.5°, 12.2°, 14.2°, 15.9°, 17.2°, 18.3°, 21.2°, 23.0°, 25.1°, and 31.5° (see FIG. 7).

Example 9

[0085] Preparation of crystal form III:

[0086] 4.0 g of the fused ring compound prepared in Example 11 was added with 200 mL of ethyl acetate, heated to reflux until the solid dissolved, cooled down for crystallization, stirred at 15° C. for 16 hours and filtered. The filter cake was dried at 60° C. under reduced pressure and dried to obtain 3.55 g of a light yellow solid.

[0087] The characterization data of crystal form III prepared by the above process were shown in FIGS. 3A and 3B. The X-ray diffraction patterns showed characteristic diffraction peaks at 2θ angles of 6.6°, 8.0°, 8.8°, 10.5°, 11.9°, 13.4°, 14.3°, 17.9°, 20.0°, 21.1°, and 22.8° (see FIG. 3A).

Example 10

[0088] Preparation of crystal form V:

[0089] 1.0 g of the fused ring compound prepared in Example 11 was added with 6.0 g of tetrahydrofuran, heated to reflux until the solid dissolved, cool down for crystallization, stirred at 15° C. for 16 hours and filtered. The filter cake was dried at 60° C. under reduced pressure and dried to obtain 0.29 g of a light yellow solid.

[0090] The characterization data of crystal form V prepared by the above process were shown in FIGS. 4A and 4B. The X-ray diffraction patterns showed characteristic diffraction peaks at 2θ angles of 6.5°, 8.0°, 10.4°, 13.3°, 16.2°, 17.7°, 20.0°, 21.0°, 24.0°, 24.8°, 26.7°, and 29.1° (see FIG. 4A).

Example 11

[0091] Reference was made to the literature (CN 201610235304.5) for the preparation of the fused ring compound: (R)-N-(5 -(3-cyano-4-(3 -methylmorpholinyl)quinolin-6-yl )-2-methoxypyridin -3-yl)memethanesulfonamide.

##STR00003##

[0092] Step 1:

[0093] 6-bromo-4-chloro-quinoline-3-carbonitrile (1.605 g, 6.0 mmol) and (R)-3-methylmorpholine (1.821 g, 18.0 mmol, 3eq) were mixed in dioxane (30.0 mL) and stirred at 100° C. Upon the reaction was completed, the resultant was concentrated under vacuum, and the concentrate was diluted with water (60 mL) and extracted with ethyl acetate (60 mL×3).The organic layers were combined, washed sequentially with water (20 mL) and saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by fast column chromatography (silica gel, petroleum ether/ethyl acetate=3:1, v/v) to give a pale yellow solid of (R)-6-bromo-4-(3-methylmorpholinyl)quinoline-3-carbonitrile (1.566 g, 78.5% yield).

[0094] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.81 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 7.86 (dd, J=8.9, 2.2 Hz, 1H), 4.13-4.05 (m, 2H), 4.05-3.97 (m, 1H), 3.91-3.83 (m, 1H), 3.77(d, J=9.8 Hz, 1H), 3.66 (dd, J=11.9, 5.9 Hz, 1H), 3.33-3.26 (m, 1H), 1.14 (d, J=6.4 Hz, 3H).

[0095] Step 2:

[0096] A mixture of (R)-6-bromo-4-(3-methylmorpholinyl)quinoline-3-carbonitrile (1.0 g, 3 mmol), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (1.18 g, 3.6 mmol, 1.2 eq) and 2 N aqueous potassium carbonate solution (4.5 mL, 3.0 eq) in dioxane (20 mL) was degassed and then [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (110 mg, 0.15 mmol, 0.05 eq) was added. The resulting reaction mixture was degassed and back-charged with nitrogen (for three cycles) and then stirred for 5 hours at 100° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with (30 mL) water, and extracted with ethyl acetate (30 mL×3).The organic layers were combined and washed with saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by fast column chromatography (silica gel, dichloromethane/methanol=200:1, v/v) to give a white solid (1.056 g, 77.3% yield).

[0097] .sup.1H NMR (400 MHz, DMSO) δ9.47 (s, 1H), 8.86 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.29 (s, 1H), 8.19 (dd, J=8.8, 1.3 Hz, 1H), 8.10 (d, J=8.7 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 4.14-4.04 (m, 2H), 4.00 (s, 3H), 3.99-3.93 (m, 1H), 3.90-3.82 (m, 1H), 3.80-3.70 (m, 1H), 3.62 (dd, J=10.9, 3.6 Hz, 1H), 3.27 (d, J=13.6 Hz, 1H), 3.14 (s, 3H), 1.10 (d, J=6.2 Hz, 3H).

[0098] XRD of the resulting white solid is shown in FIG. 8, from which it can be seen that (R)-N-(5-(3-cyano-4-(3-methylmorpholinyl)quinolin-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide obtained using the preparation method of literature(CN 201610235304.5) was amorphous.

Example 12

[0099] Evaluation on effect of crystal form on stability—high humidity test for 5 days

[0100] The amorphous form obtained in Example 11, crystal form IV obtained in Example 3, crystal form I obtained in Example 6, and crystal form II obtained in Example 8 were each taken 30 mg, in triplicate, put into a penicillin bottle, which is transferred, without being sealed, at room temperature into a desiccator with saturated potassium nitrate at the bottom, and the samples were taken after 5 days and tested by XRD.

[0101] The XRD of the amorphous form after high humidity test for 5 days is shown in FIG. 9. Compared with that before the high humidity test (FIG. 8), there were obvious new peaks at 2θ angles of 7.2°, 10.3°, 11.3°, 16.9°, 17.3°, and 21.2°, with large changes in peak shape and peak intensity, indicating obvious crystal transformation in the amorphous form.

[0102] The XRD of crystal form IV after high humidity test for 5 days is shown in FIG. 10, which indicates barely no change for crystal form IV as compared to that before the high humidity test (FIG. 5A).

[0103] The XRD of crystal form I after high humidity test for 5 days is shown in FIG. 11, which indicates barely no change for crystal form I compared to that before the high humidity test (FIG. 6).

[0104] The XRD of crystal form II after high humidity test for 5 days is shown in FIG. 12, which indicates barely no change for crystal form II as compared to that before the high humidity test (FIG. 7).

Example 13

[0105] Evaluation on effect of crystal form on stability—high temperature test for 5 days

[0106] The amorphous form obtained in Example 11, crystal form IV obtained in Example 3, crystal form I obtained in Example 6, and crystal form II obtained in Example 8 were each taken 30 mg, in triplicate, put into a penicillin bottle, which is transferred, without being sealed, to QG 2003 ba incubation and drying oven, of which the temperature was adjusted to 60° C. The samples were taken after 5 days and tested by XRD.

[0107] The XRD of the amorphous form after high temperature test for 5 days is shown in FIG. 13. Compared with that before the high temperature test (FIG. 8), there were obvious new peaks at 2θ angles of 11.3°, 17.2°, 18.5°, 20.2°, 21.1°, 22.7°, 25.3°, with large changes in peak shape and peak intensity, indicating obvious crystal transformation in the amorphous form.

[0108] The XRD of crystal form IV after high temperature test for 5 days is shown in FIG. 14, which indicates barely no change for crystal form IV as compared to that before the high temperature test (FIG. 5A).

[0109] The XRD of crystal form I after high temperature test for 5 days is shown in FIG. 15, which indicates barely no change for crystal form I as compared to that before the high temperature test (FIG. 6).

[0110] The XRD of crystal form II after high temperature test for 5 days is shown in FIG. 16, which indicates barely no change for crystal form II as compared to that before the high temperature test (FIG. 7).

Example 14

[0111] Evaluation for accelerated stability of crystal forms I, II and IV

[0112] Crystal form IV obtained in Example 3, crystal form I obtained in Example 6, and crystal form II obtained in Example 8 were each taken 30 mg, in triplicate, put into sealed bags, which is transferred into BPN-80CH CO.sub.2 incubator, of which the temperature was set at 40° C. The samples were taken after 30 days and tested by XRD.

[0113] The XRD of crystal form IV after the accelerated stability test for 30 days is shown in

[0114] FIG. 17, which indicates barely no change for crystal form IV as compared to that before the accelerated test (FIG. 5A).

[0115] The XRD of crystal form I after the accelerated stability test for 30 days is shown in FIG. 18, which indicates barely no change for crystal form I as compared to that before the accelerated test (FIG. 6).

[0116] The XRD of crystal form II after the accelerated stability test for 30 days is shown in FIG. 19, which indicates barely no change for crystal form II as compared to that before the accelerated test (FIG. 7).

[0117] In summary, (R)-N-(5-(3-cyano-4-(3-methylmorpholinyl)quinolin-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide in the literature (CN201610235304.5) was prepared as an amorphous form, which showed significant crystal transformation under high humidity test and high temperature test for 5 days, and thus was not suitable for development as a drug crystal form. In contrast, crystal forms I, II, III, IV and V of the present application all have obvious characteristic crystalline diffraction peaks, thus they can overcome the technical defect of amorphous form with no regular crystal structure. Crystal form I, crystal form II and crystal form IV of the present disclosure were stable under the conditions of high humidity test and high temperature test for 5 days, and crystal form I, crystal form II and crystal form IV were stable in accelerated test for 30 days. Therefore, the stability of crystal form I, crystal form II and crystal form IV of the present disclosure was significantly better than that of the amorphous form in the literature (CN 201610235304.5). Crystal form I and crystal form IV in the present disclosure can be used to prepare a variety of drugs. In addition, based on the solubility of crystal form I and crystal form IV in different environments and their stability within 24 hours, it is known that the drugs prepared by the polymorphic crystals in the present disclosure are easy to be absorbed by human body and possess excellent effects in the treatment of diseases.

[0118] Obviously, the above embodiments of the present disclosure are only examples to clearly illustrate the disclosure, and not to limit the implementation of the disclosure. The ordinary skilled person in the art, on the basis of the above description, can also make other different forms of changes or variations. It is not possible to exhaust all the embodiments herein, where all obvious variations or changes derived from the technical solutions of the present disclosure are still within the protection scope of the present disclosure.