Crystal form of macrocyclic derivative, preparation method therefor and use thereof

Abstract

The present invention relates to the field of chemical pharmaceuticals, relates to a crystal form of (3R,11R)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazapentacyclo[13.5.2.18,11.04,9.018,22]tricosan-1(21),4,6,8,15(22),16,19-heptaen-14-one and a preparation method therefor and a use thereof, and specifically relates to a crystal form C of a compound of formula I and a preparation method therefor, solving the problems of small particle size, poor flowability, poor stability, hygroscopicity and the like of the compound of formula I.

Description

Crystal form of macrocyclic derivatives, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of chemical pharmacy, and in particular to a macrocyclic derivative (3R, 11R)-6-fluoro-3, 11-dimethyl-10-oxa-2, 13, 17, 18, 21-pentazapentacyclic [13.5.2.1 8,11 .0 4,9 .0 18,22 ] New crystalline forms A, C, D, E, F, and G of tricosane-1(21),4,6,8,15(22),16,19-heptene-14-one and their preparation methods. Background Art

[0002] In November 2018, the US FDA approved the TRK inhibitor larotrectinib, a new oral drug for the treatment of patients with abnormal TRK mutations. Previous studies have shown that the NTRK gene encoding TRK can fuse with other genes, leading to cancer growth in multiple locations throughout the body. Larotrectinib selectively inhibits TRK. Other TRK kinase inhibitors are also under investigation, including LOXO-195 (Loxo Oncology Inc, Phase 2) and repotrectinib (TP Therapeutics Inc, Phase 2). A series of patent applications for TRK inhibitors have been published, including WO2015089139A1, WO2006082392A1, and WO2007123269A1. While some progress has been made in the research and application of TRK inhibitors, significant room for improvement remains, necessitating continued research and development of new TRK inhibitors.

[0003] WO2020233645A1 discloses a macrocyclic derivative having the structure of the following formula I, wherein the molecular formula is C 19 H 18 FN5O2, chemical name: (3R,11R)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazapentacyclo[13.5.2.1 8,11 .0 4,9 .0 18,22 ]Tricosane-1(21),4,6,8,15(22),16,19-hepten-14-one. WO2020233645A1 also discloses a preparation method of the compound of formula I and its use as an inhibitor of one or more protein kinases among TRK, ALK, and ROS1, indicating that the compound has a good inhibitory effect on one or more protein kinases among TRK, ALK, and ROS1.

[0004] However, the solid obtained by the preparation method of the compound of formula I disclosed in WO2020233645A1 is still not satisfactory in terms of stability, particle size, fluidity, hygroscopicity, etc.

[0005] Currently, there is no report in the prior art on other crystal forms of the compound of formula I. The present inventors have obtained other crystal forms of the compound of formula I through extensive experiments. Summary of the Invention

[0006] In view of the problems existing in the above-mentioned prior art, the present invention provides a compound of formula I with the following structure: (3R,11R)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazapentacyclic [13.5.2.1 8,11 .0 4,9 .0 18,22 ]Crystalline form of tricosane-1(21),4,6,8,15(22),16,19-hepten-14-one and its preparation method.

[0007] In a first aspect, the present invention provides Form C of the compound of Formula I (hereinafter referred to as "Form C").

[0008] The crystalline form C has an X-ray powder diffraction pattern using Cu-Kα radiation, and 2θ expressed in degrees has characteristic peaks at 8.2±0.2°, 9.8±0.2°, 11.7±0.2°, 13.3±0.2°, 17.0±0.2°, 17.4±0.2°, 19.7±0.2°, 20.0±0.2°, 20.6±0.2°, 22.9±0.2°, and 23.9±0.2°.

[0009] Preferably, the crystalline form C has an X-ray powder diffraction pattern using Cu-Kα radiation, and 2θ expressed in degrees is 8.2±0.2°, 9.8±0.2°, 11.7±0.2°, 12.5±0.2°, 13.3±0.2°, 14.3±0.2°, 15.7±0.2°, 15.9±0.2°, 16.5±0.2°, 17.0±0.2°, 17.4±0.2°, 17.8±0.2°. There are characteristic peaks at 18.0±0.2°, 19.4±0.2°, 19.7±0.2°, 20.0±0.2°, 20.6±0.2°, 21.5±0.2°, 21.9±0.2°, 22.9±0.2°, 23.9±0.2°, 24.6±0.2°, 25.7±0.2°, 27.3±0.2°, 28.7±0.2°, 29.5±0.2°, and 30.3±0.2°.

[0010] More preferably, the crystalline form C, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic peaks and relative intensities in 2θ expressed in degrees at the following positions:

[0011] Table 1

[0012] More preferably, the X-ray powder diffraction pattern of the crystalline form C is substantially as shown in FIG1 .

[0013] Furthermore, the differential scanning calorimetry (DSC) spectrum of the crystalline form C has endothermic peaks at 87-117°C and 293-299°C, and an inverted peak at 250°C. The DSC spectrum is substantially as shown in FIG2 .

[0014] Furthermore, the crystal form C is a dihydrate, and its water content is measured to be 8.95%.

[0015] Accordingly, the present invention provides a method for preparing Form C, comprising:

[0016] The compound of formula I is dissolved in a solvent to obtain a solution, wherein the solvent is methanol, ethanol, n-propanol, isopropanol, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a mixture thereof, water is added or the above solution is added to water, a solid is precipitated, the solid is separated, and vacuum dried to obtain Form C.

[0017] Preferably, the weight-to-volume ratio of the compound of formula I to the solvent is 1:10-1:20, and the weight-to-volume ratio of the compound of formula I to water is 1:20-1:80, and the unit is g / mL.

[0018] Preferably, the vacuum drying temperature is 20-60° C. and the time is 8-24 h.

[0019] In another aspect, the present invention provides a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of Form C. Preferably, in the pharmaceutical composition, Form C can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients and prepared into a galenic formulation.

[0020] In another aspect, the present invention provides the use of Form C or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by one or more protein kinases among TRK, ALK, and ROS1, preferably, the disease mediated by one or more protein kinases among TRK, ALK, and ROS1 is pain, cancer, inflammation, neurodegenerative disease or trypanosome infection, more preferably, the cancer is neuroblastoma, ovarian cancer, breast cancer, prostate cancer, gastric cancer, digestive tract tumor, liver cancer, bile duct cancer, pancreatic cancer, multiple myeloma, astrocytoma, medulloblastoma, glioma, melanoma, thyroid cancer, lung cancer, large cell neuroendocrine tumor, colorectal cancer, breast cancer, sarcoma, head and neck tumor and renal cancer.

[0021] In another aspect, the present invention provides use of Form C or a pharmaceutical composition thereof in the preparation of one or more protein kinase inhibitors selected from the group consisting of TRK, ALK, and ROS1.

[0022] In addition, the present invention also provides a method for treating a disease mediated by one or more protein kinases among TRK, ALK, and ROS1, the method comprising administering a therapeutically effective amount of Form C to an individual in need thereof, wherein the disease mediated by one or more protein kinases among TRK, ALK, and ROS1 is preferably pain, cancer, inflammation, neurodegenerative disease or trypanosome infection, wherein the cancer is preferably neuroblastoma, ovarian cancer, breast cancer, prostate cancer, gastric cancer, digestive tract tumor, liver cancer, bile duct cancer, pancreatic cancer, multiple myeloma, astrocytoma, medulloblastoma, glioma, melanoma, thyroid cancer, lung cancer, large cell neuroendocrine tumor, colorectal cancer, breast cancer, sarcoma, head and neck tumor and renal cancer.

[0023] The present invention also provides a method for inhibiting one or more protein kinases among TRK, ALK, and ROS1, which comprises contacting Form C or a pharmaceutical composition thereof with one or more protein kinases among TRK, ALK, and ROS1.

[0024] In another aspect, the present invention provides Form A of the compound of Formula I (hereinafter referred to as "Form A").

[0025] The crystalline form A has an X-ray powder diffraction pattern using Cu-Kα radiation, and 2θ expressed in degrees has characteristic peaks at 6.7±0.2°, 7.7±0.2°, 10.4±0.2°, 13.4±0.2°, 16.5±0.2°, 19.7±0.2°, 20.2±0.2°, 21.4±0.2°, and 23.3±0.2°.

[0026] Preferably, the crystalline form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern with 2θ expressed in degrees at 6.7±0.2°, 7.7±0.2°, 8.2±0.2°, 9.8±0.2°, 10.4±0.2°, 11.8±0.2°, 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 15.1 There are characteristic peaks at ±0.2°, 15.4±0.2°, 16.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.8±0.2°, 19.7±0.2°, 20.2±0.2°, 21.4±0.2°, 23.3±0.2°, 24.7±0.2°, 25.4±0.2°, and 32.4±0.2°.

[0027] More preferably, the crystalline form A, using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic peaks and relative intensities in 2θ expressed in degrees at the following positions:

[0028] Table 2

[0029] More preferably, the X-ray powder diffraction pattern of the crystalline form A is substantially as shown in FIG3 .

[0030] Furthermore, the differential scanning calorimetry (DSC) spectrum of the crystalline form A has endothermic peaks at 121-146°C and 297-302°C, and an inverted peak at 233°C. The DSC spectrum is substantially as shown in FIG4 .

[0031] Accordingly, the present invention provides a method for preparing Form A, comprising:

[0032] The compound of formula I was added to dichloromethane and dissolved, the solvent was evaporated, the solid was separated, and vacuum dried to obtain Form A.

[0033] Preferably, the weight-to-volume ratio of the compound of formula I to dichloromethane is 1:50-1:100, and the unit is g / mL.

[0034] Preferably, the vacuum drying temperature is 20-60° C. and the time is 8-24 h.

[0035] In another aspect, the present invention provides Form D of the compound of Formula I (hereinafter referred to as "Form D").

[0036] The crystalline form D uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic peaks at 9.3±0.2°, 10.6±0.2°, 12.3±0.2°, 13.3±0.2°, 15.7±0.2°, 16.9±0.2°, 19.4±0.2°, 21.1±0.2°, 22.8±0.2°, and 26.9±0.2°, with 2θ expressed in degrees.

[0037] Preferably, the crystalline form D uses Cu-Kα radiation, and its X-ray powder diffraction pattern, expressed in degrees, has characteristic peaks at 9.3±0.2°, 10.6±0.2°, 12.3±0.2°, 13.3±0.2°, 15.7±0.2°, 16.9±0.2°, 19.4±0.2°, 21.1±0.2°, 22.8±0.2°, 24.2±0.2°, 24.9±0.2°, 25.5±0.2°, 26.9±0.2°, 27.9±0.2°, 32.3±0.2°, and 33.4±0.2°.

[0038] More preferably, the crystalline form D uses Cu-Kα radiation, and its X-ray powder diffraction pattern, expressed in degrees, has characteristic peaks and relative intensities at the following positions:

[0039] Table 3

[0040] More preferably, the X-ray powder diffraction pattern of the crystalline form D is substantially as shown in FIG5 .

[0041] Furthermore, the differential scanning calorimetry (DSC) spectrum of the crystalline form D has an endothermic peak at 290-296° C., and the DSC spectrum is substantially as shown in FIG6 .

[0042] Accordingly, the present invention provides a method for preparing Form D, comprising:

[0043] The compound of formula I is dissolved in a solvent, wherein the solvent is ethanol, n-propanol, isopropanol, acetone, 2-butanone or a mixture thereof, and n-heptane is added or the above solution is added to n-heptane, solid is precipitated, the solid is separated, and vacuum dried to obtain Form D.

[0044] Preferably, the weight-to-volume ratio of the compound of formula I to the solvent is 1:10-1:20, and the weight-to-volume ratio of the compound of formula I to n-heptane is 1:30-1:80, and the unit is g / mL.

[0045] Preferably, the vacuum drying temperature is 20-60° C. and the time is 8-24 h.

[0046] In another aspect, the present invention provides Form E of the compound of Formula I (hereinafter referred to as "Form E").

[0047] The crystalline form E uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic peaks at 8.1±0.2°, 9.2±0.2°, 9.7±0.2°, 11.7±0.2°, 12.2±0.2°, 13.2±0.2°, 15.6±0.2°, 16.8±0.2°, 17.4±0.2°, 19.3±0.2°, 20.0±0.2°, 21.0±0.2°, 22.8±0.2°, and 26.8±0.2°, with 2θ expressed in degrees.

[0048] Preferably, the crystalline form E uses Cu-Kα radiation, and its X-ray powder diffraction pattern, 2θ expressed in degrees, is 8.1±0.2°, 9.2±0.2°, 9.7±0.2°, 10.5±0.2°, 11.7±0.2°, 12.2±0.2°, 13.2±0.2°, 14.4±0.2°, 15.6±0.2°, 16.8±0.2°, 17.4 There are characteristic peaks at ±0.2°, 18.1±0.2°, 19.3±0.2°, 19.7±0.2°, 20.0±0.2°, 20.6±0.2°, 21.0±0.2°, 22.8±0.2°, 23.8±0.2°, 24.8±0.2°, 25.5±0.2°, 26.8±0.2°, 27.8±0.2°, and 33.3±0.2°.

[0049] More preferably, the crystalline form E uses Cu-Kα radiation, and its X-ray powder diffraction pattern, expressed in degrees, has characteristic peaks and relative intensities at the following positions:

[0050] Table 4

[0051] More preferably, the X-ray powder diffraction pattern of the crystalline form E is substantially as shown in FIG7 .

[0052] Furthermore, the differential scanning calorimetry (DSC) spectrum of the crystalline form E has endothermic peaks at 75-115° C. and 294-297° C., and the DSC spectrum is substantially as shown in FIG8 .

[0053] Accordingly, the present invention provides a method for preparing Form E, comprising:

[0054] The compound of formula I was added to acetone, stirred at room temperature to dissolve, and then the solvent was naturally evaporated. The solid was separated and dried in vacuo to obtain Form E.

[0055] Preferably, the weight-to-volume ratio of the compound of formula I to acetone is 1:10-1:20, and the unit is g / mL.

[0056] Preferably, the vacuum drying temperature is 20-60° C. and the time is 8-24 h.

[0057] In another aspect, the present invention provides Form F of the compound of Formula I (hereinafter referred to as "Form F").

[0058] The crystalline form F uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic peaks at 6.5±0.2°, 9.7±0.2°, 10.8±0.2°, 12.1±0.2°, 17.5±0.2°, 18.6±0.2°, 19.9±0.2°, 21.3±0.2°, 23.3±0.2°, 23.7±0.2°, 24.8±0.2°, and 29.1±0.2°, with 2θ expressed in degrees.

[0059] Preferably, the crystalline form F has an X-ray powder diffraction pattern using Cu-Kα radiation, and 2θ expressed in degrees is 6.5±0.2°, 9.0±0.2°, 9.7±0.2°, 10.3±0.2°, 10.8±0.2°, 11.5±0.2°, 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 14.6±0.2°, 15.5±0.2°, 17.1±0.2°. There are characteristic peaks at 17.5±0.2°, 18.1±0.2°, 18.6±0.2°, 19.9±0.2°, 20.3±0.2°, 21.0±0.2°, 21.3±0.2°, 22.8±0.2°, 23.3±0.2°, 23.7±0.2°, 24.5±0.2°, 24.8±0.2°, 27.6±0.2°, 29.1±0.2°, and 30.0±0.2°.

[0060] More preferably, the crystalline form F has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks and relative intensities of 2θ expressed in degrees at the following positions:

[0061] Table 5

[0062] More preferably, the X-ray powder diffraction pattern of the crystalline form F is substantially as shown in FIG9 .

[0063] Furthermore, the differential scanning calorimetry (DSC) spectrum of the crystalline form F has an endothermic peak at 153-167° C. and an endothermic peak at 294-297° C. The DSC spectrum is substantially as shown in FIG10 .

[0064] Accordingly, the present invention provides a method for preparing Form F, comprising:

[0065] The crystal form B of the compound of formula I is added to methyl isobutyl ketone, suspended and stirred, stirred at 20-40° C. for 2-24 hours, and then the solid is separated and vacuum dried to obtain the crystal form F.

[0066] Preferably, the weight-to-volume ratio of the compound of formula I to methyl isobutyl ketone is 1:10-1:20, and the unit is g / mL.

[0067] Preferably, the vacuum drying temperature is 20-60° C. and the time is 8-24 h.

[0068] In another aspect, the present invention provides Form G of the compound of Formula I (hereinafter referred to as "Form G").

[0069] The crystalline form G uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic peaks at 6.5±0.2°, 8.2±0.2°, 9.8±0.2°, 11.0±0.2°, 17.4±0.2°, 19.0±0.2°, 20.0±0.2°, 21.6±0.2°, 23.8±0.2°, 28.0±0.2°, and 30.2±0.2°, with 2θ expressed in degrees.

[0070] Preferably, the X-ray powder diffraction pattern of the crystalline form G using Cu-Kα radiation is 6.5±0.2°, 8.2±0.2°, 9.1±0.2°, 9.8±0.2°, 10.5±0.2°, 11.0±0.2°, 11.7±0.2°, 12.3±0.2°, 13.8±0.2°, 14.3±0.2°, 15.7±0.2°, 17.4 There are characteristic peaks at ±0.2°, 17.7±0.2°, 18.1±0.2°, 18.6±0.2°, 19.0±0.2°, 19.7±0.2°, 20.0±0.2°, 21.6±0.2°, 23.1±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, 26.2±0.2°, 28.0±0.2°, and 30.2±0.2°.

[0071] More preferably, the X-ray powder diffraction pattern of the crystalline form G using Cu-Kα radiation has characteristic peaks and relative intensities at the following positions in 2θ expressed in degrees:

[0072] Table 5

[0073] More preferably, the X-ray powder diffraction pattern of the crystalline form G is substantially as shown in FIG11 .

[0074] Furthermore, the differential scanning calorimetry (DSC) spectrum of the crystalline form G has endothermic peaks at 85-134°C and 293-298°C, and an inverted peak at 207°C. The DSC spectrum is basically as shown in Figure 12.

[0075] Accordingly, the present invention provides a method for preparing Form G, comprising:

[0076] The compound of formula I was added to 2-butanone, stirred at room temperature until dissolved, and the solvent was naturally evaporated. The solid was separated and dried in vacuo to obtain Form G.

[0077] Preferably, the weight-to-volume ratio of the compound of formula I to 2-butanone is 1:10-1:20, and the unit is g / mL.

[0078] Preferably, the vacuum drying temperature is 20-60° C. and the time is 8-24 h.

[0079] On the other hand, the solid obtained by the preparation method of the compound of formula I disclosed in WO2020233645A1 is crystalline form B (hereinafter referred to as "crystalline form B").

[0080] The crystalline form B uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic peaks at 6.4±0.2°, 9.3±0.2°, 10.8±0.2°, 11.9±0.2°, 13.3±0.2°, 17.4±0.2°, 19.3±0.2°, 21.1±0.2°, 21.9±0.2°, 23.9±0.2°, and 26.8±0.2°, with 2θ expressed in degrees.

[0081] Preferably, the crystalline form B uses Cu-Kα radiation, and its X-ray powder diffraction pattern, expressed in degrees, has characteristic peaks at 6.4±0.2°, 7.2±0.2°, 9.3±0.2°, 10.0±0.2°, 10.8±0.2°, 11.9±0.2°, 13.3±0.2°, 14.8±0.2°, 16.2±0.2°, 17.4±0.2°, 18.5±0.2°, 19.3±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.2±0.2°, 23.9±0.2°, 25.6±0.2°, 26.8±0.2°, 27.8±0.2°, and 28.8±0.2°.

[0082] More preferably, the crystalline form B uses Cu-Kα radiation, and its X-ray powder diffraction pattern, expressed in degrees, has characteristic peaks and relative intensities at the following positions:

[0083] Table 5

[0084] More preferably, the X-ray powder diffraction pattern of the crystalline form B is substantially as shown in FIG13 .

[0085] Furthermore, the differential scanning calorimetry (DSC) spectrum of the crystalline form B has an endothermic peak at 294-298°C and an inverted peak at 240°C. The DSC spectrum is substantially as shown in FIG14 .

[0086] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0087] The crystallization process of the crystal form C of the compound of formula I of the present invention is simple, easy to operate, has low pollution, and can be industrially produced. In addition, the crystal form drug of the present invention has the advantages of high product purity, excellent physical and chemical properties, good high temperature / high humidity and chemical and physical stability, excellent adaptability and reproducibility in processing (filtration, drying, dissolution and tableting), and has a large particle size, good hygroscopicity and fluidity. It solves the problems of small particle size, poor fluidity, poor stability, and hygroscopicity existing in the compound of formula I, is conducive to the process processing of the drug and improves the drug performance, and has a good market application prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] FIG1 is an X-ray powder diffraction pattern of the crystalline form C prepared in Example 1.

[0089] FIG2 is a DSC spectrum of the crystalline form C prepared in Example 1.

[0090] FIG3 is an X-ray powder diffraction pattern of Form A prepared in Example 12.

[0091] FIG4 is a DSC spectrum of Form A prepared in Example 12.

[0092] FIG5 is an X-ray powder diffraction pattern of the crystalline form D prepared in Example 14.

[0093] FIG6 is a DSC spectrum of the crystalline form D prepared in Example 14.

[0094] Figure 7 is the X-ray powder diffraction pattern of Form E prepared in Example 22.

[0095] Figure 8 is the DSC spectrum of Form E prepared in Example 22.

[0096] Figure 9 is the X-ray powder diffraction pattern of the crystalline form F prepared in Example 24.

[0097] Figure 10 is the DSC spectrum of the crystalline form F prepared in Example 24.

[0098] Figure 11 is the X-ray powder diffraction pattern of the crystalline form G prepared in Example 26.

[0099] Figure 12 is the DSC spectrum of the crystalline form G prepared in Example 26.

[0100] FIG13 is an X-ray powder diffraction pattern of Form B prepared in Preparation Example.

[0101] FIG14 is a DSC spectrum of Form B prepared in Preparation Example. DETAILED DESCRIPTION

[0102] General Definitions and Terminology

[0103] Unless otherwise stated, the technology and scientific terms used herein have the same meaning as those skilled in the art to which the present invention pertains. If there is a contradiction, the definition provided herein shall prevail. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is equivalent to specifically disclosing any scope by combining any pair of upper range limits or preferred values ​​with any lower range limit or preferred values, without considering whether the scope is specifically disclosed. Unless otherwise stated, the numerical ranges listed herein are intended to include all integers and fractions (decimals) within the endpoints and range of the range.

[0104] The terms "about" and "approximately" when used in conjunction with a numerical variable generally refer to the value of that variable and all values ​​of that variable are within experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the stated value, or wider.

[0105] The expression "comprising" or its synonymous similar expressions "including", "containing" and "having" are open-ended and do not exclude additional unrecited elements, steps or ingredients. The expression "consisting of excludes any elements, steps or ingredients not specified. The expression "consisting essentially of" means that the scope is limited to the specified elements, steps or ingredients, plus the optional elements, steps or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of".

[0106] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0107] Unless otherwise indicated, percentages, parts, etc. herein are by weight.

[0108] As used herein, the term "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

[0109] As used herein, the term "amorphous" refers to any solid material that has no order in three dimensions.

[0110] As used herein, the term "X-ray powder diffraction (XRPD) pattern" refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0111] As used herein, the term "2θ" refers to the peak position expressed in degrees (°) based on the setup in the X-ray diffraction experiment, and is generally the unit of the abscissa in the diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires that the reflected beam be recorded at an angle of 2θ. It should be understood that the specific 2θ value of a specific crystalline form mentioned herein is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-Kα (Kα1 is ) as a radiation source. The XRPD patterns herein can be collected, for example, on a Rigaku MiniFlex-600 X-ray powder diffraction analyzer. Exemplary test conditions can be a scan speed of 10° / min and a scan step width of 0.01°.

[0112] As used herein, the term "substantially" with respect to X-ray diffraction peaks means that variations in representative peak positions and intensities are taken into account. For example, one skilled in the art will appreciate that peak positions (2θ) will exhibit some variation, typically as much as 0.1-0.2 degrees (±0.1 to ±0.2 degrees), and that the instrument used to measure diffraction will also introduce some variation. In addition, one skilled in the art will appreciate that relative peak intensities will vary due to instrument-to-instrument differences, as well as the degree of crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to one skilled in the art, and should be considered merely qualitative measurements.

[0113] As used herein, differential scanning calorimetry (DSC) measures the transition temperatures of a crystal when heat is absorbed or released due to changes in its crystal structure or melting. For the same crystalline form of the same compound, the thermal transition temperatures and melting points typically agree within approximately 5°C in consecutive analyses. When a compound is described as having a given DSC peak or melting point, this refers to ±5°C of that peak or melting point. The term "substantially" also takes into account such temperature variations. DSC provides an auxiliary method for distinguishing different crystalline forms. Different crystalline forms can be identified by their distinct transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. Furthermore, because decomposition occurs during melting, the melting temperature is dependent on the heating rate. DSC patterns can be measured, for example, on a NETZSCH DSC214 Polyma instrument. Exemplary testing conditions include a heating rate of 10°C / min and a temperature range of 25-300°C.

[0114] Pharmaceutical compositions and administration

[0115] In one embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of a compound of Formula I and one or more pharmaceutically acceptable carriers.

[0116] As used herein, the term "pharmaceutically acceptable carrier" refers to a solid or liquid diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0117] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as soybean oil, peanut oil, mineral oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include glucose, starch, lactose, gelatin, maltose, sucrose, chalk, silica gel, glyceryl monostearate, sodium stearate, talc, sodium chloride, glycerol, propylene glycol, water, ethanol, and the like. The composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, cellulose, sodium saccharin, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0118] The compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection, intra-arterial, subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal administration; or by oral, nasal, buccal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0119] For these routes of administration, the compositions of the present invention can be administered in suitable dosage forms, including but not limited to tablets, pills, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, aqueous suspensions, injections, elixirs, and syrups.

[0120] The pharmaceutical compositions of the present invention can be prepared by any method well known in the art, for example, by mixing, dissolving, granulating, sugar coating, grinding, emulsifying, lyophilizing, etc. As used herein, the term "therapeutically effective amount" refers to an amount of a compound that, after administration, will alleviate to some extent one or more symptoms of the condition being treated.

[0121] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0122] As used herein, unless otherwise indicated, the terms "treat," ...

[0123] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., amphibians, reptiles, birds) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., dogs, cats, sheep, cows, pigs, etc.).

[0124] The present invention is further described in the following examples. However, it is necessary to point out that the following examples are only used to describe the content of the invention and do not constitute a limitation on the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0125] Preparation and characterization of the crystalline form of the compound of formula I

[0126] Preparation Example

[0127] The compound of formula I described in the embodiment of the present invention is prepared according to the method in Example 8 of patent WO2020233645A1, that is, 5-(((1R)-1-((2R)-2-(aminomethyl)-5-fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 8h (797 mg), pentafluorophenyl diphenyl phosphate (1.08 g, 2.48 mmol) and N,N-diisopropylethylamine (2.14 g, 16.56 mmol) are dissolved in 12 mL of a mixed solution (dichloromethane:N,N-dimethylformamide=5:1), and the reaction is carried out at room temperature overnight. After the reaction was completed as monitored by LC-MS, 30 mL of saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product (3R,11R)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazapentacyclo[13.5.2.1]) was obtained by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN). 8,11 .0 4,9 .0 18,22 ]Tricosane-1(21),4,6,8,15(22),16,19-hepten-14-one (200 mg). XRPD detection showed that the obtained solid was Form B, and its X-ray powder diffraction pattern and DSC spectrum are shown in Figures 13-14 respectively.

[0128] Test instrument information and methods

[0129] The X-ray powder diffraction instrument and test conditions involved in the present invention are: X-ray diffraction instrument model Rigaku MiniFlex-600 Cu target; operation method: scanning speed 10° / min, scanning step width 0.01°.

[0130] The DSC test conditions involved in the present invention are: the DSC detector model is NETZSCH DSC214 Polyma; the operating method is: the heating rate is 10°C / min, and the temperature range is 25-350°C.

[0131] The high performance liquid chromatography (HPLC) test conditions involved in the present invention are: the liquid chromatograph model is Agilent 1260; the chromatographic column is Waters XBridge C18 4.6*150mm, 3.5μm or an equivalent column; the detection wavelength is 226nm; and the column temperature is 30°C.

[0132] Example 1 Preparation of Form C

[0133] 0.1 g of the compound of formula I was dissolved in 1 mL of ethanol, and 2 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum are shown in Figures 1-2, respectively.

[0134] Example 2 Preparation of Form C

[0135] 0.1 g of the compound of formula I was dissolved in 2 mL of ethanol, and 4 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0136] Example 3 Preparation of Form C

[0137] 0.05 g of the compound of formula I was dissolved in 1 mL of ethanol, and the solution was added dropwise to 4 mL of water to precipitate. The solid was separated and dried in vacuo at 50°C for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0138] Example 4 Preparation of Form C

[0139] 0.05 g of the compound of formula I was dissolved in 1 mL of methanol, and 2 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0140] Example 5 Preparation of Form C

[0141] 0.05 g of the compound of formula I was dissolved in 1 mL of n-propanol, and 4 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0142] Example 6 Preparation of Form C

[0143] 0.05 g of the compound of formula I was dissolved in 1 mL of isopropanol, and 4 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0144] Example 7 Preparation of Form C

[0145] 0.05 g of the compound of formula I was dissolved in 1 mL of acetone, and 4 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0146] Example 8 Preparation of Form C

[0147] 0.05 g of the compound of formula I was dissolved in 1 mL of N,N-dimethylformamide, and 4 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50°C for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0148] Example 9 Preparation of Form C

[0149] 0.05 g of the compound of formula I was dissolved in 1 mL of N,N-dimethylacetamide, and 4 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50°C for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0150] Example 10 Preparation of Form C

[0151] 0.05 g of the compound of formula I was dissolved in 1 mL of dimethyl sulfoxide, and 2 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0152] Example 11 Preparation of Form C

[0153] 0.05 g of the compound of formula I was dissolved in a mixed solvent of 0.5 mL of methanol and 0.5 mL of ethanol, and 4 mL of water was added dropwise to precipitate. The solid was separated and dried in vacuo at 50°C for 24 h. It was detected to be Form C, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 1-2, respectively.

[0154] Example 12 Preparation of Form A

[0155] 0.1 g of the compound of formula I was dissolved in 5 mL of dichloromethane, the solvent was evaporated, the precipitated solid was separated, and vacuum dried at 50° C. for 24 h. It was detected to be Form A, and its X-ray powder diffraction pattern and DSC spectrum are shown in Figures 3-4, respectively.

[0156] Example 13 Preparation of Form A

[0157] 0.1 g of the compound of formula I was dissolved in 10 mL of dichloromethane, the solvent was evaporated, the precipitated solid was separated, and vacuum dried at 50° C. for 24 h. It was detected to be Form A, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 3-4, respectively.

[0158] Example 14 Preparation of Form D

[0159] 0.1 g of the compound of formula I was dissolved in 1 mL of ethanol, and 3 mL of n-heptane was added dropwise to precipitate. The solid was separated and dried in vacuo at 50°C for 24 h. It was detected to be Form D, and its X-ray powder diffraction pattern and DSC spectrum are shown in Figures 5-6, respectively.

[0160] Example 15 Preparation of Form D

[0161] 0.05 g of the compound of formula I was dissolved in 1 mL of ethanol, and 4 mL of n-heptane was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form D, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 5-6, respectively.

[0162] Example 16 Preparation of Form D

[0163] 0.05 g of the compound of formula I was dissolved in 1 mL of ethanol, and the solution was added dropwise to 4 mL of n-heptane to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form D, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 5-6, respectively.

[0164] Example 17 Preparation of Form D

[0165] 0.05 g of the compound of formula I was dissolved in 1 mL of n-propanol, and 4 mL of n-heptane was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form D, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 5-6, respectively.

[0166] Example 18 Preparation of Form D

[0167] 0.05 g of the compound of formula I was dissolved in 1 mL of isopropanol, and 4 mL of n-heptane was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form D, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 5-6, respectively.

[0168] Example 19 Preparation of Form D

[0169] 0.05 g of the compound of formula I was dissolved in 1 mL of acetone, and 4 mL of n-heptane was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form D, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 5-6, respectively.

[0170] Example 20 Preparation of Form D

[0171] 0.05 g of the compound of formula I was dissolved in 1 mL of 2-butanone, and 4 mL of n-heptane was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form D, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 5-6, respectively.

[0172] Example 21 Preparation of Form D

[0173] 0.05 g of the compound of formula I was dissolved in a mixed solvent of 0.5 mL of ethanol and 0.5 mL of acetone, and 4 mL of n-heptane was added dropwise to precipitate. The solid was separated and dried in vacuo at 50° C. for 24 h. It was detected to be Form D, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 5-6, respectively.

[0174] Example 22 Preparation of Form E

[0175] 0.05 g of the compound of formula I was dissolved in 0.5 mL of acetone, the solvent was evaporated, the precipitate was separated, and the solid was dried in vacuo at 50° C. for 24 h. It was detected to be Form E, and its X-ray powder diffraction pattern and DSC spectrum are shown in Figures 7-8, respectively.

[0176] Example 23 Preparation of Form E

[0177] 0.05 g of the compound of formula I was dissolved in 1 mL of acetone, the solvent was evaporated, the precipitated solid was separated, and vacuum dried at 50° C. for 24 h. It was detected to be Form E, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 7-8, respectively.

[0178] Example 24 Preparation of Form F

[0179] 0.1 g of Form B of the compound of Formula I was added to 1 mL of methyl isobutyl ketone, suspended and stirred at 20°C for 24 h, the solid was separated, and vacuum dried at 50°C for 24 h. It was detected to be Form F, and its X-ray powder diffraction pattern and DSC spectrum are shown in Figures 9-10, respectively.

[0180] Example 25 Preparation of Form F

[0181] 0.05 g of Form B of the compound of Formula I was added to 1 mL of methyl isobutyl ketone, suspended and stirred at 40° C. for 2 h, the solid was separated, and vacuum dried at 50° C. for 24 h. It was detected to be Form F, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 9-10, respectively.

[0182] Example 26 Preparation of Form G

[0183] 0.05 g of the compound of formula I was dissolved in 0.5 mL of 2-butanone, the solvent was evaporated, the precipitated solid was separated, and vacuum dried at 50° C. for 24 h. It was detected to be Form G, and its X-ray powder diffraction pattern and DSC spectrum are shown in Figures 11-12, respectively.

[0184] Example 27 Preparation of Form G

[0185] 0.05 g of the compound of formula I was dissolved in 1 mL of 2-butanone, the solvent was evaporated, the precipitated solid was separated, and vacuum dried at 50° C. for 24 h. It was detected to be Form G, and its X-ray powder diffraction pattern and DSC spectrum were consistent with Figures 11-12, respectively.

[0186] Preparation of Form B of Formula I Compound

[0187] Form B of the compound of formula I prepared according to Example 8 of patent WO2020233645A1.

[0188] Stability test

[0189] The crystal form B of the compound of formula I prepared in the preparation example, the crystal form C of the compound of formula I prepared in Example 1, the crystal form A of the compound of formula I prepared in Example 12, the crystal form D of the compound of formula I prepared in Example 14, the crystal form E of the compound of formula I prepared in Example 22, the crystal form F of the compound of formula I prepared in Example 24, and the crystal form G of the compound of formula I prepared in Example 26 were placed in an environment of 75% RH40°C for 6 months and an environment of 60% RH25°C for 12 months, respectively, and the content of each crystal form was measured. The specific results are shown in Table 6.

[0190] Table 6

[0191] From the results in Table 6, it can be seen that compared with Form B, Form C has better stability and higher purity, and Form C has better stability than other forms.

[0192] Particle size experiment

[0193] The crystalline form B of the compound of formula I prepared in the preparation example, the crystalline form C of the compound of formula I prepared in Example 1, the crystalline form A of the compound of formula I prepared in Example 12, the crystalline form D of the compound of formula I prepared in Example 14, the crystalline form E of the compound of formula I prepared in Example 22, the crystalline form F of the compound of formula I prepared in Example 24, and the crystalline form G of the compound of formula I prepared in Example 26 were measured for their particle sizes. The specific results are shown in Table 7.

[0194] Table 7

[0195] As shown in Table 7, the particle size of Form B is significantly smaller, significantly smaller than that of Form C (wherein D50 is 28.62 μm, not more than 16% of the D50 of the present form; D90 is 55.11 μm, not more than 11% of the D90 of the present form), and the particle size of Form C is significantly larger than that of other forms. Therefore, the present invention is more suitable for the forming process of solid preparations (such as tablets, capsules or granules).

[0196] Liquidity experiment

[0197] The angles of repose of Form B of the compound of Formula I prepared in the Preparation Example, Form C of the compound of Formula I prepared in Example 1, Form A of the compound of Formula I prepared in Example 12, Form D of the compound of Formula I prepared in Example 14, Form E of the compound of Formula I prepared in Example 22, Form F of the compound of Formula I prepared in Example 24, and Form G of the compound of Formula I prepared in Example 26 were measured respectively. The specific results are shown in Table 8.

[0198] Table 8

[0199] The above results show that the angle of repose of Form B is significantly greater than that of Form C, indicating that Form C is significantly superior to Form B in terms of fluidity, and the angle of repose of Form C is significantly smaller than that of other forms. Therefore, the present invention is more suitable for the forming process of solid preparations (such as tablets, capsules or granules).

[0200] Hygroscopicity test

[0201] The crystal form B of the compound of formula I prepared in the preparation example, the crystal form C of the compound of formula I prepared in Example 1, the crystal form A of the compound of formula I prepared in Example 12, the crystal form D of the compound of formula I prepared in Example 14, the crystal form E of the compound of formula I prepared in Example 22, the crystal form F of the compound of formula I prepared in Example 24, and the crystal form G of the compound of formula I prepared in Example 26 were placed in an environment of 75% RH and 25°C for 24 hours, weighed, and the hygroscopicity was calculated. The specific results are shown in Table 9.

[0202] Table 9

[0203] The above results show that the hygroscopicity of Form B is significantly greater than that of Form C, and the hygroscopicity of Form C is significantly lower than that of other forms, indicating that Form C is significantly superior to Form B and other forms in terms of hygroscopicity.

[0204] Crystal transformation experiment

[0205] The crystalline form B of the compound of formula I prepared in the preparation example and the crystalline form D of the compound of formula I prepared in Example 14 were stirred in water at room temperature for 24 h, filtered and dried, and then tested by XRD. The specific results are shown in Table 10.

[0206] Table 10

[0207] The above results show that Form B and Form D are easily converted into Form C in water, indicating that Form C is more stable than Form B and Form D in an aqueous environment.

[0208] Those skilled in the art will understand that the meaning or intended scope of protection of the numerical values ​​or numerical endpoints involved in the technical solutions of the present invention are not limited to the numbers themselves. They include those allowable error ranges that have been widely accepted in the art, such as experimental errors, measurement errors, statistical errors and random errors, etc., and these error ranges are all included in the scope of the present invention.

[0209] It will be clear to those skilled in the art that many modifications and variations of the present invention may be made without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only and are not intended to be limiting in any way. The true scope and spirit of the present invention are shown by the appended claims, and the description and examples are merely exemplary.

Claims

1. Polymorph C of a compound of formula I, It is characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ in degrees of 8.2 ± 0.2°, 9.8 ± 0.2°, 11.7 ± 0.2°, 13.3 ± 0.2°, 17.0 ± 0.2°, 17.4 ± 0.2°, 19.7 ± 0.2°, 20.0 ± 0.2°, 20.6 ± 0.2°, 22.9 ± 0.2°, 23.9 ± 0.2°.

2. The crystalline form C according to claim 1, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ in degrees of 8.2 ± 0.2°, 9.8 ± 0.2°, 11.7 ± 0.2°, 12.5 ± 0.2°, 13.3 ± 0.2°, 14.3 ± 0.2°, 15.7 ± 0.2°, 15.9 ± 0.2°, 16.5 ± 0.2°, 17.0 ± 0.2°, 17.4 ± 0.2°, 17.8 ± 0.2°, 18.0 ± 0.2°, 19.4 ± 0.2°, 19.7 ± 0.2°, 20.0 ± 0.2°, 20.6 ± 0.2°, 21.5 ± 0.2°, 21.9 ± 0.2°, 22.9 ± 0.2°, 23.9 ± 0.2°, 24.6 ± 0.2°, 25.7 ± 0.2°, 27.3 ± 0.2°, 28.7 ± 0.2°, 29.5 ± 0.2°, 30.3 ± 0.2°.

3. The crystalline form C according to claim 1 or 2, characterized in that, Its X-ray powder diffraction pattern is shown in Figure 1.

4. The crystalline form C according to any one of claims 1-3, characterized in that, The crystalline form C is a dihydrate.

5. A method for preparing polymorph C as described in any one of claims 1-4, characterized in that, The method includes: dissolving the compound of formula I in a solvent to obtain a solution, the solvent being methanol, ethanol, n-propanol, isopropanol, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a mixture thereof, adding water or adding the above solution to water, precipitating a solid, separating the solid, and drying it under vacuum to obtain crystalline form C.

6. The method according to claim 5, wherein The weight-to-volume ratio of the compound of formula I to the solvent is 1:10 - 1:20, and the weight-to-volume ratio of the compound of formula I to water is 1:20 - 1:80, with the unit of g / mL.

7. A pharmaceutical composition, which comprises a therapeutically effective amount of crystalline form C as described in any one of claims 1 - 4 and a pharmaceutically acceptable excipient.

8. Use of the crystalline form C as described in any one of claims 1 - 4 or the pharmaceutical composition as claimed in claim 7 in the preparation of a drug for treating a disease mediated by one or more protein kinases of TRK, ALK, and ROS1. Preferably, the disease mediated by one or more protein kinases of TRK, ALK, and ROS1 is pain, cancer, inflammation, neurodegenerative disease, or trypanosome infection. More preferably, the cancer is neuroblastoma, ovarian cancer, breast cancer, prostate cancer, gastric cancer, gastrointestinal tumor, liver cancer, cholangiocarcinoma, pancreatic cancer, multiple myeloma, astrocytoma, medulloblastoma, glioma, melanoma, thyroid cancer, lung cancer, large cell neuroendocrine carcinoma, colorectal cancer, breast analogue secretory carcinoma, sarcoma, head and neck tumor, and kidney cancer.

9. Use of crystalline form C according to any one of claims 1-4 or the pharmaceutical composition according to claim 7 in the preparation of an inhibitor of one or more protein kinases among TRK, ALK, and ROS1.

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