Crystal form of piperazine amide derivative, method for producing the same, and use thereof

Abstract

The present invention relates to crystal forms of piperazine amide derivatives, a method for producing the same, and uses thereof. Specifically, it relates to crystal forms A, B, C, D, and E of the compound represented by the following formula (I), a method for producing the same, a pharmaceutical composition thereof, and uses thereof, and belongs to the field of chemical pharmaceuticals. According to the present invention, the amorphous form of the compound represented by the following formula (I) has small particle size and can solve problems such as deterioration in fluidity and stability. The crystal forms prepared in the present invention and pharmaceutical compositions thereof can be used in the production of pharmaceuticals for treating diseases such as cancer. JPEG2025522142000018.jpg3981

Description

Technical Field

[0001] The present invention belongs to the field of chemical pharmaceuticals. Specifically, the present invention relates to novel crystal forms A, B, C, D, E of (6-(4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)(3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl ketone, a piperazine amide derivative, and a method for producing the same. Furthermore, the present invention relates to a pharmaceutical composition containing the above novel crystal form and its pharmaceutical use.

Background Art

[0002] The rearranged during transfection (RET) gene is an oncogene that encodes a receptor tyrosine kinase and regulates cell growth and survival. Activation of this gene requires dimer formation through interaction with receptors of the glial cell line-derived neurotrophic factor family and their α receptors, regulation of the signal pathway by phosphorylation, and the exertion of signal transduction and life activity regulation functions. Abnormal expression of the RET gene is associated with various cancer diseases. Since this gene can continuously maintain an activated state without ligand dependence through chromosomal rearrangement to fuse with other genes or through site-specific mutations, it leads to abnormal signal pathways, which may cause excessive cell proliferation and the onset of cancer.

[0003] In recent years, evidence has been increasing that RET gene fusions and mutations are the driving forces inducing some cancers, showing significant specificity without overlapping with other driver genes. RET gene fusions are often found in papillary thyroid cancer and non-small cell lung cancer. For example, 30% of sporadic papillary thyroid cancers, 70% of radiation-induced papillary thyroid cancers, and about 2% of non-small cell lung cancers are driven by RET gene fusions. RET gene mutations are often found in medullary thyroid cancer. For example, more than 50% of medullary thyroid cancers, almost all congenital medullary cancers, and multiple endocrine neoplasia are induced by site-specific mutations of the RET gene.

[0004] To treat cancer patients with RET gene fusions or mutations, currently, multi-target kinase inhibitors with RET kinase inhibitory activity are mainly used as the main treatment method. However, under this condition, due to off-target effects and drug toxicity, the drug dosage does not reach a level sufficient to inhibit the abnormal expression of the RET gene. Also, during cancer treatment, cancer cells may develop drug resistance due to mutations. Once drug resistance occurs, the treatment options for patients will be very limited. Therefore, currently, selective RET kinase inhibitors for treating cancer patients with RET gene fusions or mutations are highly needed.

[0005] International Patent Publication WO2020 / 207419A1 discloses a piperazine amide derivative having a structure represented by the following Formula I, with a molecular formula of C 23 H 24 FN 11 O, and a chemical name of (6-(4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)(3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl ketone. International Patent Publication WO2020 / 207419A1 further discloses a method for producing the compound represented by Formula I and its use as a RET kinase inhibitor, and it has been shown that the compound has a good RET kinase inhibitory effect.

Chemical Formula

[0006] However, the compound represented by the above formula I disclosed in International Patent Publication WO2020 / 207419A1 has an amorphous form of the solid prepared according to its production method, and is not sufficient in terms of stability, particle size, fluidity, hygroscopicity, etc. In particular, the amorphous particles disclosed in International Patent Publication WO2020 / 207419A1 have a small particle size and poor fluidity, and are not suitable for the forming process of solid preparations (such as tablets, capsules or granules).

[0007] Currently, in the prior art, a form of the compound represented by formula I that is suitable for pharmaceutical forming and has desirable stability has not yet been disclosed, and there has been no report on the crystal form of the compound represented by formula I. As a result of a large number of experiments by the present inventors, a crystal form of the compound represented by formula I was obtained.

Summary of the Invention

[0008] Therefore, in view of the problems existing in the above prior art, the present invention provides a crystal form of a compound having a structure represented by the following formula I (6-(4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)(3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl ketone and a method for producing the same.

Chemical Formula

[0009] In a first aspect, the present invention provides a crystal form A of the compound represented by formula I (hereinafter referred to as "crystal form A").

[0010] The crystalline form A has characteristic peaks at positions where 2θ represented in degrees in its powder X-ray diffraction pattern using Cu-Kα rays is 8.5 ± 0.2°, 11.4 ± 0.2°, 14.4 ± 0.2°, 15.7 ± 0.2°, 16.7 ± 0.2°, 17.8 ± 0.2°, 25.1 ± 0.2°, 28.1 ± 0.2°.

[0011] Preferably, the crystalline form A has characteristic peaks at positions where 2θ represented in degrees in its powder X-ray diffraction pattern using Cu-Kα rays is 7.0 ± 0.2°, 8.5 ± 0.2°, 11.4 ± 0.2°, 13.1 ± 0.2°, 14.4 ± 0.2°, 15.7 ± 0.2°, 16.7 ± 0.2°, 17.8 ± 0.2°, 20.2 ± 0.2°, 21.2 ± 0.2°, 22.0 ± 0.2°, 23.1 ± 0.2°, 24.3 ± 0.2°, 25.1 ± 0.2°, 26.2 ± 0.2°, 28.1 ± 0.2°.

[0012] More preferably, the crystalline form A has characteristic peaks and relative intensities at positions where 2θ represented in degrees in its powder X-ray diffraction pattern using Cu-Kα rays are as follows.

[0013]

Table 1

[0014] More preferably, the powder X-ray diffraction pattern of the crystalline form A is basically as shown in FIG. 1.

[0015] Furthermore, the crystalline form A has an endothermic peak at 247 to 253°C in its differential scanning calorimetry (DSC) curve. The DSC curve is basically as shown in FIG. 2.

[0016] Correspondingly, the present invention provides a method for producing crystalline form A, which comprises forming a suspension by adding an amorphous form of a compound represented by formula I to a solvent which is methanol, ethanol, n-propanol, isopropanol, acetone, methyl isobutyl ketone, 2-butanone or a mixture thereof, stirring the suspension as a crystal slurry at 5 to 50 °C for 1 to 7 days, separating the solid and drying it under vacuum to obtain crystalline form A.

[0017] Preferably, the weight-to-volume ratio of the compound represented by formula I to the solvent is 1:10 to 1:50 in the unit of g / mL.

[0018] Preferably, the vacuum drying is carried out at a temperature of 20 to 60 °C for 8 to 24 hours.

[0019] In another aspect, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of crystalline form A as an active ingredient. Preferably, in the pharmaceutical composition, crystalline form A can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients to prepare a galenical preparation.

[0020] In yet another aspect, the present invention provides the use of crystalline form A or its pharmaceutical composition in the manufacture of a medicament for treating a disease associated with the fusion or mutation of the RET gene, wherein the disease is cancer, and preferably the cancer is breast cancer, non-small cell lung cancer, or rectal cancer.

[0021] In yet another aspect, the present invention provides the use of crystalline form A or its pharmaceutical composition in the manufacture of a RET kinase inhibitor.

[0022] Furthermore, the present invention further provides a method for treating a disease associated with the fusion or mutation of the RET gene, which comprises administering a therapeutically effective amount of crystalline form A to an individual in need thereof, wherein the disease is cancer, and preferably the cancer is breast cancer, non-small cell lung cancer, or rectal cancer.

[0023] The present invention further provides a method for inhibiting RET kinase, which includes contacting crystalline form A or a pharmaceutical composition thereof with RET kinase.

[0024] In another aspect, the present invention provides crystalline form B of the compound represented by formula I (hereinafter referred to as "crystalline form B").

[0025] The crystalline form B has characteristic peaks at positions where 2θ represented in degrees is 5.9±0.2°, 11.8±0.2°, 13.4±0.2°, 17.7±0.2°, 23.6±0.2°, 26.9±0.2° in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0026] Preferably, the crystalline form B has characteristic peaks at positions where 2θ represented in degrees is 5.9±0.2°, 9.0±0.2°, 9.9±0.2°, 11.8±0.2°, 13.4±0.2°, 17.7±0.2°, 21.9±0.2°, 23.6±0.2°, 24.5±0.2°, 26.9±0.2°, 29.9±0.2° in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0027] More preferably, the crystalline form B has characteristic peaks and relative intensities at positions where 2θ represented in degrees is as follows in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0028] [Table 2]

[0029] More preferably, the powder X-ray diffraction pattern of the crystalline form B is basically as shown in Figure 3.

[0030] Furthermore, the crystalline form B has endothermic peaks at 133~158°C and 243~251°C in the differential scanning calorimetry (DSC) curve. The DSC curve is basically as shown in Figure 4.

[0031] Correspondingly, the present invention provides a method for producing crystalline form B, which comprises adding an amorphous form of the compound represented by formula I to dichloromethane to form a suspension, stirring this suspension as a crystal slurry at 5 to 35 °C for 1 to 7 days, separating the solid and drying it under vacuum to obtain crystalline form B.

[0032] Preferably, the weight-volume ratio of the compound represented by formula I to dichloromethane is 1:10 to 1:50 in the unit of g / mL.

[0033] Preferably, the vacuum drying is carried out at 20 to 60 °C for 8 to 24 hours.

[0034] In another aspect, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of crystalline form B as an active ingredient. Preferably, in the pharmaceutical composition, crystalline form B can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients to prepare a galenical preparation.

[0035] In yet another aspect, the present invention provides the use of crystalline form B or its pharmaceutical composition in the manufacture of a medicament for treating a disease related to the fusion or mutation of the RET gene, wherein the disease is cancer, and the cancer is preferably breast cancer, non-small cell lung cancer, or rectal cancer.

[0036] In yet another aspect, the present invention provides the use of crystalline form B or its pharmaceutical composition in the manufacture of a RET kinase inhibitor.

[0037] The present invention further provides a method for treating a disease related to the fusion or mutation of the RET gene, which comprises administering a therapeutically effective amount of crystalline form B to a subject in need thereof, wherein the disease is cancer, and the cancer is preferably breast cancer, non-small cell lung cancer, or rectal cancer.

[0038] The present invention further provides a method for inhibiting RET kinase, which comprises contacting crystalline form B or its pharmaceutical composition with RET kinase.

[0039] In another aspect, the present invention provides a crystalline form C of the compound represented by formula I (hereinafter referred to as "crystalline form C").

[0040] The crystalline form C has characteristic peaks at positions where 2θ represented in degrees in its powder X-ray diffraction pattern using Cu-Kα radiation is 6.9 ± 0.2°, 8.6 ± 0.2°, 11.5 ± 0.2°, 13.9 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 18.4 ± 0.2°, 20.3 ± 0.2°, 23.8 ± 0.2°, 26.9 ± 0.2°.

[0041] Preferably, the crystalline form C has characteristic peaks at positions where 2θ represented in degrees in its powder X-ray diffraction pattern using Cu-Kα radiation is 6.9 ± 0.2°, 8.6 ± 0.2°, 9.3 ± 0.2°, 9.7 ± 0.2°, 11.5 ± 0.2°, 13.9 ± 0.2°, 14.9 ± 0.2°, 15.8 ± 0.2°, 16.3 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 18.4 ± 0.2°, 20.3 ± 0.2°, 23.2 ± 0.2°, 23.8 ± 0.2°, 24.4 ± 0.2°, 25.3 ± 0.2°, 26.9 ± 0.2°, 28.2 ± 0.2°.

[0042] More preferably, the crystalline form C has characteristic peaks and relative intensities at positions where 2θ represented in degrees in its powder X-ray diffraction pattern using Cu-Kα radiation are as follows.

[0043] [Table 3]

[0044] More preferably, the powder X-ray diffraction pattern of the crystalline form C is substantially as shown in FIG. 5.

[0045] Furthermore, the crystalline form C has a negative peak at 172 to 195°C and an endothermic peak at 246 to 252°C in its differential scanning calorimetry (DSC) curve. The DSC curve is substantially as shown in FIG. 6.

[0046] Correspondingly, the present invention provides a method for producing crystalline form C, which includes adding an amorphous form of a compound represented by formula I to a solvent that is methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate or a mixture thereof to form a suspension, making it into a crystal slurry at 5 to 50 °C and stirring for 1 to 7 days, then separating the solid and drying it under vacuum to obtain crystalline form C.

[0047] Preferably, the weight-to-volume ratio of the compound represented by formula I to the solvent is 1:10 to 1:50 in the unit of g / mL.

[0048] Preferably, the vacuum drying is carried out at a temperature of 20 to 60 °C for 8 to 24 hours.

[0049] In another aspect, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of crystalline form C as an active ingredient. Preferably, in the said pharmaceutical composition, crystalline form C can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients to prepare a galenical preparation.

[0050] In yet another aspect, the present invention provides the use of crystalline form C or its pharmaceutical composition in the manufacture of a medicament for treating a disease associated with the fusion or mutation of the RET gene, wherein the disease is cancer, and the cancer is preferably breast cancer, non-small cell lung cancer, or rectal cancer.

[0051] In yet another aspect, the present invention provides the use of crystalline form C or its pharmaceutical composition in the manufacture of a RET kinase inhibitor.

[0052] Also, the present invention further provides a method for treating a disease associated with the fusion or mutation of the RET gene, which includes administering a therapeutically effective amount of crystalline form C to an individual in need thereof, wherein the disease is cancer, and the cancer is preferably breast cancer, non-small cell lung cancer, or rectal cancer.

[0053] The present invention further provides a method for inhibiting RET kinase, which includes contacting crystalline form C or its pharmaceutical composition with RET kinase.

[0054] In another aspect, the present invention provides crystalline form D of the compound represented by formula I (hereinafter referred to as "crystalline form D").

[0055] The crystalline form D has characteristic peaks at positions where 2θ represented in degrees is 6.1 ± 0.2°, 6.9 ± 0.2°, 9.3 ± 0.2°, 12.2 ± 0.2°, 14.0 ± 0.2°, 18.7 ± 0.2°, 25.6 ± 0.2° in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0056] Preferably, the crystalline form D has characteristic peaks at positions where 2θ represented in degrees is 6.1 ± 0.2°, 6.9 ± 0.2°, 9.3 ± 0.2°, 12.2 ± 0.2°, 12.7 ± 0.2°, 13.2 ± 0.2°, 14.0 ± 0.2°, 15.3 ± 0.2°, 18.7 ± 0.2°, 21.1 ± 0.2°, 25.6 ± 0.2°, 27.2 ± 0.2° in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0057] More preferably, the crystalline form D has characteristic peaks and relative intensities at positions where 2θ represented in degrees is as follows in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0058] [Table 4]

[0059] More preferably, the powder X-ray diffraction pattern of the crystalline form D is basically as shown in FIG. 7.

[0060] Furthermore, the crystalline form D has a negative peak at 200 to 235°C and an endothermic peak at 247 to 254°C in the differential scanning calorimetry (DSC) curve. The DSC curve is basically as shown in FIG. 8.

[0061] Correspondingly, the present invention provides a method for producing crystalline form D, which comprises dissolving the compound represented by formula I in N,N-dimethylacetamide and stirring at 10-50 °C until clear, adding water to precipitate crystals, separating the solid and drying it under vacuum to obtain crystalline form D.

[0062] Preferably, the weight-to-volume ratio of the compound represented by formula I to N,N-dimethylacetamide is 1:20 to 1:50 in units of g / mL.

[0063] Preferably, the volume ratio of N,N-dimethylacetamide to water is 1:1 to 1:4.

[0064] Preferably, the vacuum drying is carried out at a temperature of 20-60 °C for 8-24 hours.

[0065] In another aspect, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of crystalline form D as an active ingredient. Preferably, in the pharmaceutical composition, crystalline form D can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients to prepare a galenical preparation.

[0066] In yet another aspect, the present invention provides the use of crystalline form D or its pharmaceutical composition in the manufacture of a medicament for treating a disease associated with a fusion or mutation of the RET gene, wherein the disease is cancer, and the cancer is preferably breast cancer, non-small cell lung cancer, or rectal cancer.

[0067] In yet another aspect, the present invention provides the use of crystalline form D or its pharmaceutical composition in the manufacture of a RET kinase inhibitor.

[0068] Furthermore, the present invention further provides a method for treating a disease associated with a fusion or mutation of the RET gene, which comprises administering a therapeutically effective amount of crystalline form D to an individual in need thereof, wherein the disease is cancer, and the cancer is preferably breast cancer, non-small cell lung cancer, or rectal cancer.

[0069] The present invention further provides a method for inhibiting RET kinase, which includes contacting crystalline form D or a pharmaceutical composition thereof with RET kinase.

[0070] In another aspect, the present invention provides crystalline form E of the compound represented by formula I (hereinafter referred to as "crystalline form E").

[0071] The crystalline form E has characteristic peaks at positions where 2θ represented in degrees is 6.3 ± 0.2°, 12.7 ± 0.2°, 13.3 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 23.4 ± 0.2°, 27.0 ± 0.2° in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0072] Preferably, the crystalline form E has characteristic peaks at positions where 2θ represented in degrees is 6.3 ± 0.2°, 8.6 ± 0.2°, 12.7 ± 0.2°, 13.3 ± 0.2°, 14.9 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 19.1 ± 0.2°, 21.2 ± 0.2°, 21.9 ± 0.2°, 23.4 ± 0.2°, 27.0 ± 0.2°, 27.7 ± 0.2° in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0073] More preferably, the crystalline form E has characteristic peaks and relative intensities at the following 2θ positions represented in degrees in the powder X-ray diffraction pattern using its Cu-Kα ray.

[0074]

Table 5

[0075] More preferably, the powder X-ray diffraction pattern of the crystalline form E is basically as shown in FIG. 9.

[0076] Furthermore, the crystalline form E has an endothermic peak at 146 - 156°C in the differential scanning calorimetry (DSC) curve. The DSC curve is basically as shown in FIG. 10.

[0077] Correspondingly, the present invention provides a method for producing crystalline form E, which includes adding a compound represented by formula I to dimethyl sulfoxide, heating to 70-80 °C, stirring for 10-30 hours until dissolved clearly, then cooling to 0-20 °C to precipitate crystals, separating the solid and drying it under vacuum to obtain crystalline form E.

[0078] Preferably, the weight-to-volume ratio of the compound represented by formula I to dimethyl sulfoxide is 1:5 to 1:10 in the unit of g / mL.

[0079] Preferably, the vacuum drying is carried out at a temperature of 20-60 °C for 8-24 hours.

[0080] In another aspect, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of crystalline form E as an active ingredient. Preferably, in the pharmaceutical composition, crystalline form E can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients to prepare a galenical preparation.

[0081] In yet another aspect, the present invention provides the use of crystalline form E or its pharmaceutical composition in the manufacture of a medicament for treating a disease associated with the fusion or mutation of the RET gene, wherein the disease is cancer, and the cancer is preferably breast cancer, non-small cell lung cancer, or rectal cancer.

[0082] In yet another aspect, the present invention provides the use of crystalline form E or its pharmaceutical composition in the manufacture of a RET kinase inhibitor.

[0083] Also, the present invention further provides a method for treating a disease associated with the fusion or mutation of the RET gene, which includes administering a therapeutically effective amount of crystalline form E to a subject in need thereof, wherein the disease is cancer, and the cancer is preferably breast cancer, non-small cell lung cancer, or rectal cancer.

[0084] The present invention further provides a method for inhibiting RET kinase, which includes contacting crystalline form E or its pharmaceutical composition with RET kinase.

[0085] Compared with the prior art, the beneficial effects of the present invention are mainly as follows. The crystal form of the compound represented by formula (I) of the present invention has the advantages that the crystallization process is simple, easy to operate, less contaminated, and can realize industrial production. In addition, the crystalline pharmaceutical of the present invention has high product purity, excellent physical and chemical properties, good chemical and physical stability at high temperature / high humidity, excellent adaptability to processing (filtration, drying, elution and tableting), and reproducibility. Moreover, it has good dissolution rate, dissolution time and biological release property, small particle size, good hygroscopicity and fluidity, which contribute to the improvement of the pharmaceutical manufacturing process and formulation performance, and it is possible to expect market applications in many aspects.

Brief Description of the Drawings

[0086]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Best Mode for Carrying Out the Invention

[0087] General Definitions and Terms Unless otherwise specified, the scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art. In case of any conflict, the definitions provided in this application shall prevail. When representing an amount, concentration, other value, or parameter in the form of a range, a preferred range, or a preferred numerical upper limit and a preferred numerical lower limit, it should be understood that, whether or not the range is specifically disclosed, it is equivalent to specifically disclosing any range formed by combining any pair of a range upper limit or a preferred numerical value with any range lower limit or a preferred numerical value. Unless otherwise specified, the numerical ranges described in this specification are intended to include the endpoints of the range and all integers and fractions (decimals) within that range.

[0088] The terms "about" and "approximately" when used with a numerical variable generally mean that the numerical value of the variable and all numerical values of the variable are within the experimental error (e.g., within the 95% confidence interval of the average value), or within ±10% of a given numerical value, or within a wider range.

[0089] The expression "comprising" or similar expressions synonymous therewith such as "including", "containing", and "having" are open-ended and do not exclude other unrecited elements, steps, or components. The expression "consisting of" means excluding any unspecified element, step, or component. The expression "consisting essentially of" is limited to a range that includes, in addition to the specified elements, steps, or components, optionally existing elements, steps, or components that do not substantially affect the basic and novel features of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of".

[0090] As used herein, the terms "optional" or "optionally" mean that the events or circumstances described hereinafter may or may not occur. This expression includes the occurrence and non-occurrence of the said events or circumstances.

[0091] Unless otherwise specified, all percentages, parts by number, etc. used herein are by weight.

[0092] As used herein, the term "crystalline form" or "crystal" refers to any solid substance having three-dimensional order and, unlike an amorphous solid substance, gives rise to a characteristic powder X-ray diffraction pattern with well-defined boundary peaks.

[0093] As used herein, the term "amorphous" refers to any solid substance that does not have three-dimensional order.

[0094] As used herein, the term "X-ray powder diffraction (XRPD) pattern" refers to an experimentally observed diffraction pattern or parameters, data or numerical values derived therefrom. The XRPD pattern is usually characterized by peak position (abscissa) and / or peak intensity (ordinate).

[0095] As used herein, the term "2θ" refers to the peak position expressed in degrees (°) set in an X-ray diffraction experiment and is usually the unit of the horizontal axis in a diffraction pattern. When the incident beam makes an angle θ with a specific lattice plane and the reflection is diffracted, it is necessary to record the reflected beam at a 2θ angle in the experimental setup. It should be understood that the specific 2θ value of a specific crystal form referred to 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, Cu-Kα (where Kα1 is 1.5418 Å) is used as the radiation source. The XRPD pattern herein can be collected, for example, using a Rigaku MiniFlex-600 powder X-ray diffractometer. Exemplary test conditions are: scan speed: 10° / min, scan step width: 0.01°.

[0096] As used herein, the term "substantially" with respect to an X-ray diffraction peak means taking into account representative peak positions and intensity variations. For example, as understood by those skilled in the art, the peak position (2θ) may typically exhibit some variations on the order of 0.1 to 0.2 degrees (±0.1 to ±0.2 degrees), and some variations may also occur depending on the equipment used for the diffraction measurement. Also, as understood by those skilled in the art, the relative peak intensity may vary depending on differences between instruments, crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be regarded as only a qualitative measurement result.

[0097] As used herein, differential scanning calorimetry (DSC) measures the transition temperature when a crystal absorbs or releases heat due to a change in crystal structure or melting of the crystal. During continuous analysis of the same crystal form of the same compound, the error in the heat transition temperature and melting point is typically within about 5 °C. When it is described that a compound has a specific DSC peak or melting point, it means that it is the DSC peak or melting point ±5 °C. The term "essentially" also takes into account that temperature change. DSC is provided as an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified based on different transition temperature characteristics. Note that in the case of a mixture, its DSC peak or melting point can vary within a wider range. Also, since decomposition occurs with the melting of the substance, the melting temperature is related to the heating rate. The DSC curve can be measured, for example, with an instrument of model NETZSCH DSC214 Polyma. Exemplary test conditions are: heating rate: 10 °C / min, temperature range: 25 - 250 °C.

[0098] Pharmaceutical Compositions and Administration In one embodiment, according to the present invention, there is provided a pharmaceutical composition comprising a crystalline form of a compound represented by formula I and one or more pharmaceutically acceptable carriers.

[0099] As used herein, the term "pharmaceutically acceptable carrier" is a solid or liquid diluent, adjuvant, excipient or vehicle administered with a therapeutic agent, and is suitable for contact with human and / or other animal tissues within the scope of reasonable medical judgment, and does not cause excessive toxicity, irritation, allergic reaction, or other problems or complications corresponding to a reasonable benefit / risk.

[0100] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, for example, sterile liquids such as water and oil, but are not limited thereto. For example, those derived from petroleum, animals, plants, and synthesis such as soybean oil, peanut oil, and mineral oil are also included. When the pharmaceutical composition is administered intravenously, an exemplary carrier is water. In particular, as the liquid carrier used in injection solutions, physiological saline, glucose, and aqueous glycerin solutions may be used. Suitable pharmaceutical excipients include glucose, starch, lactose, gelatin, maltose, sucrose, chalk, silica gel, glyceryl monostearate, sodium stearate, talc, sodium chloride, glycerin, propylene glycol, water, ethanol, and the like. The composition may optionally contain a small amount of wetting agent, emulsifying agent or pH buffer. Oral preparations may also contain standard carriers such as, for example, mannitol, lactose, starch, sodium stearate, cellulose, saccharin sodium, magnesium carbonate at the drug level. Examples of suitable pharmaceutically acceptable carriers are described, for example, in Remington’s Pharmaceutical Sciences (1990).

[0101] The compositions of the present invention can act systemically and / or locally. Therefore, the compositions of the present invention may be administered by suitable routes such as, for example, injection, intraarterial, subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal, or may be administered orally, nasally, buccally, transmucosally, topically, in the form of ophthalmic preparations, or by inhalation.

[0102] For these administration routes, the compositions of the present invention can be administered in suitable dosage forms. The dosage forms include, but are not limited to, tablets, dripping pills, capsules, tablets, hard candies, powders, sprays, creams, ointments, suppositories, gels, aqueous suspensions, injections, elixirs, and syrups.

[0103] The pharmaceutical composition of the present invention can be prepared by any method well-known in the art, such as mixing, dissolving, granulating, sugar coating, polishing, emulsifying, freeze-drying, etc. The term "therapeutically effective amount" as used herein refers to the amount of a compound that can, to some extent, alleviate one or more symptoms of a disease to be treated after administration.

[0104] The dosing regimen can be adjusted to provide the desired optimal response. For example, a single bolus may be administered, doses may be administered gradually in several divided doses, or the dose may be proportionally decreased or increased according to the urgency of the treatment situation. It should be noted that the dosage can vary depending on the type and severity of the condition to be alleviated and can include a single dose or multiple doses. Furthermore, it should be understood that the specific dosing regimen for a particular individual needs to be adjusted in a timely manner according to the individual's needs and the professional judgment of the employee administering or supervising the administration of the composition.

[0105] Unless otherwise specified, the term "treatment" as used herein means reversing, alleviating, inhibiting the progression of, or preventing the progression of a disease condition or disorder to which such term is applied, or one or more symptoms of such disease condition or disorder.

[0106] The term "individual" as used herein includes humans or non-human animals. Exemplary human individuals include individuals (referred to as patients) suffering from a disease (e.g., a disease described herein) or healthy individuals. The "non-human animals" in the present invention include all vertebrates, such as non-mammals like amphibians, reptiles, birds, and mammals such as non-human primates, domestic animals and / or animals that have been domesticated (dogs, cats, sheep, cows, pigs, etc.).

[0107] Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are only used when explaining the content of the present invention and do not limit the protection scope of the present invention. The technical scope of the present invention is determined based on the description of each claim.

[0108] Preparation and Characterization of Crystal Forms of Compounds Represented by Formula I [Preparation Example] The compound represented by formula I described in the examples of the present invention was prepared according to the method of Example 2 of International Publication WO2020 / 207419A1. That is, 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine hydrochloride (2c) (700 mg, 2.1 mmol), 6-(4-fluoro-1H-pyrazol-1-yl)pyridazine-3-carboxylic acid (2g) (390 mg, 1.9 mmol) and PyBOP (1.63 g, 3.1 mmol) were dissolved in 20 mL of DMF, cooled to 0 °C, DIPEA (810 mg, 6.3 mmol) was added, and the reaction was carried out for 30 minutes while maintaining at 0 °C. 10 mL of water was added to quench the reaction, 150 mL of ethyl acetate was added, washed three times with water (20 mL × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Then, it was isolated by silica gel column chromatography (the eluent was dichloromethane:methanol with a volume ratio of 20:1) to obtain a crude product. It was further isolated by a silica gel preparative plate (the developing solvent was dichloromethane:methanol with a volume ratio of 10:1), concentrated under reduced pressure, and then 400 mg of (6-(4-fluoro-1H-pyrazol-1-yl)pyridazin-3-yl)(3-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (I-13) was obtained in a yield of 43%. As a result detected by XRPD, the obtained solid was amorphous, and its powder X-ray diffraction pattern was as shown in Figure 11.

[0109] Information and Methods of Measuring Instruments As the X-ray powder diffractometer and measurement conditions in the present invention, an X-ray diffractometer (Rigaku D / max-2200 Cu target) was used, and the operation was carried out with a scanning speed of 10° / min and a scanning step width of 0.01°.

[0110] As the DSC measurement conditions in the present invention, a DSC detector (NETZSCH DSC214 Polyma) was used, and the operation was carried out with a heating rate of 10°C / min and a temperature range of 25 to 300°C.

[0111] As the measurement conditions of high performance liquid chromatography (HPLC) in the present invention, a liquid chromatograph (Agilent 1260) was used, and the operation was carried out with a column of Welch XB C-18 250 mm × 4.6 mm 3um, a detection wavelength of 260 nm, and a column temperature of 40°C.

Example

[0112] [Example 1] Preparation of Crystal Form A 0.1 g of the compound represented by Formula I and 4 mL of ethanol were mixed to obtain a suspension, which was stirred at 25°C for 1 day. Then, the solid was separated, and the filter cake was vacuum dried at 50°C for 24 hours to obtain 0.085 g of a solid in crystal form A. The powder X-ray diffraction pattern and DSC curve are as shown in Figures 1 to 2 respectively.

[0113] [Example 2] Preparation of Crystal Form A 0.1 g of the compound represented by Formula I and 1 mL of methanol were mixed to obtain a suspension, which was stirred at 5°C for 7 days. Then, the solid was separated, and the filter cake was vacuum dried at 50°C for 24 hours to obtain 0.088 g of a solid in crystal form A. The powder X-ray diffraction pattern and DSC curve are consistent with Figures 1 to 2 respectively.

[0114] [Example 3] Preparation of Crystal Form A 0.1 g of the compound represented by Formula I was mixed with 5 mL of n-propanol to obtain a suspension, which was stirred at 50 °C for 1 day. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.082 g of a solid in crystalline form A. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with those in Figures 1 to 2.

[0115] [Example 4] Preparation of Crystalline Form A 0.1 g of the compound represented by Formula I was mixed with 2 mL of isopropanol to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.086 g of a solid in crystalline form A. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with those in Figures 1 to 2.

[0116] [Example 5] Preparation of Crystalline Form A 0.1 g of the compound represented by Formula I was mixed with 2 mL of acetone to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.083 g of a solid in crystalline form A. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with those in Figures 1 to 2.

[0117] [Example 6] Preparation of Crystalline Form A 0.1 g of the compound represented by Formula I was mixed with 2 mL of methyl isobutyl ketone to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.081 g of a solid in crystalline form A. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with those in Figures 1 to 2.

[0118] [Example 7] Preparation of Crystalline Form A 0.1 g of the compound represented by Formula I was mixed with 2 mL of 2-butanone to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.082 g of a solid in crystalline form A. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with those in Figures 1 to 2.

[0119] [Example 8] Preparation of Crystal Form A 0.1 g of the compound represented by formula I, 2 mL of ethanol and 2 mL of methanol were mixed to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.082 g of a solid in crystal form A. Its powder X-ray diffraction pattern and DSC curve are respectively in agreement with FIGS. 1-2.

[0120] [Example 9] Preparation of Crystal Form B 0.1 g of the compound represented by formula I and 2 mL of dichloromethane were mixed to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.078 g of a solid in crystal form B. Its powder X-ray diffraction pattern and DSC curve are as shown in FIGS. 3-4 respectively.

[0121] [Example 10] Preparation of Crystal Form B 0.1 g of the compound represented by formula I and 5 mL of dichloromethane were mixed to obtain a suspension, which was stirred at 5 °C for 7 days. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.075 g of a solid in crystal form B. Its powder X-ray diffraction pattern and DSC curve are respectively in agreement with FIGS. 3-4.

[0122] [Example 11] Preparation of Crystal Form B 0.1 g of the compound represented by formula I and 1 mL of dichloromethane were mixed to obtain a suspension, which was stirred at 35 °C for 1 day. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.076 g of a solid in crystal form B. Its powder X-ray diffraction pattern and DSC curve are respectively in agreement with FIGS. 3-4.

[0123] [Example 12] Preparation of Crystal Form C 0.1 g of the compound represented by formula I and 2 mL of methyl acetate were mixed to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was vacuum dried at 50 °C for 24 hours to obtain 0.082 g of a solid in crystal form C. Its powder X-ray diffraction pattern and DSC curve are as shown in FIGS. 5-6 respectively.

[0124] [Example 13] Preparation of Crystal Form C 0.1 g of the compound represented by formula I and 1 mL of methyl acetate were mixed to obtain a suspension, which was stirred at 5 °C for 7 days. Then, the solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.083 g of a solid in crystal form C. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with FIGS. 5 to 6.

[0125] [Example 14] Preparation of Crystal Form C 0.1 g of the compound represented by formula I and 5 mL of isopropyl acetate were mixed to obtain a suspension, which was stirred at 50 °C for 1 day. Then, the solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.082 g of a solid in crystal form C. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with FIGS. 5 to 6.

[0126] [Example 15] Preparation of Crystal Form C 0.1 g of the compound represented by formula I and 2 mL of butyl acetate were mixed to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.081 g of a solid in crystal form C. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with FIGS. 5 to 6.

[0127] [Example 16] Preparation of Crystal Form C 0.1 g of the compound represented by formula I and 2 mL of isobutyl acetate were mixed to obtain a suspension, which was stirred at 25 °C for 3 days. Then, the solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.082 g of a solid in crystal form C. Its powder X-ray diffraction pattern and DSC curve are respectively consistent with FIGS. 5 to 6.

[0128] [Example 17] Preparation of Crystal Form D 0.1 g of the compound represented by Formula I and 2 mL of N,N-dimethylacetamide were mixed to obtain a suspension. After stirring at 25 °C until it became clear, 2 mL of water was added to precipitate crystals. The solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.078 g of a solid in crystalline form D. Its powder X-ray diffraction pattern and DSC curve are as shown in FIGS. 7 to 8 respectively.

[0129] [Example 18] Preparation of Crystalline Form D 0.1 g of the compound represented by Formula I and 2 mL of N,N-dimethylacetamide were mixed to obtain a suspension. After stirring at 50 °C until it became clear, 5 mL of water was added to precipitate crystals. The solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.082 g of a solid in crystalline form D. Its powder X-ray diffraction pattern and DSC curve are in agreement with FIGS. 7 to 8 respectively.

[0130] [Example 19] Preparation of Crystalline Form D 0.1 g of the compound represented by Formula I and 5 mL of N,N-dimethylacetamide were mixed to obtain a suspension. After stirring at 10 °C until it became clear, 20 mL of water was added to precipitate crystals. The solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.084 g of a solid in crystalline form D. Its powder X-ray diffraction pattern and DSC curve are in agreement with FIGS. 7 to 8 respectively.

[0131] [Example 20] Preparation of Crystalline Form E 0.1 g of the compound represented by Formula I and 0.5 mL of dimethyl sulfoxide were mixed, heated to 80 °C, and stirred for 30 hours until it became clear. After cooling to 20 °C, crystals were precipitated. The solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.061 g of a solid in crystalline form E. Its powder X-ray diffraction pattern and DSC curve are as shown in FIGS. 9 to 10 respectively.

[0132] [Example 21] Preparation of Crystalline Form E 0.1 g of the compound represented by Formula I was mixed with 1 mL of dimethyl sulfoxide, heated to 70 °C, stirred for 10 hours until dissolved clearly, then cooled to 0 °C to precipitate crystals, the solid was separated, and the filter cake was dried under vacuum at 50 °C for 24 hours to obtain 0.049 g of a solid in crystalline form E. Its powder X-ray diffraction pattern and DSC curve are respectively in agreement with FIGS. 9 to 10.

[0133] Preparation of Amorphous Forms of Compounds Represented by Formula I According to Example 2 of International Patent Publication WO2020 / 207419A1, an amorphous form of the compound represented by Formula I was prepared.

[0134] Stability test The amorphous form of the compound represented by Formula I prepared in the above Preparation Example, the crystalline form A form of the compound represented by Formula I prepared in Example 1, the crystalline form B form of the compound represented by Formula I prepared in Example 9, the crystalline form C form of the compound represented by Formula I prepared in Example 12, the crystalline form D form of the compound represented by Formula I prepared in Example 17, and the crystalline form E form of the compound represented by Formula I prepared in Example 20 were each left standing for 10 days under environments of 75% RH, 92.5% RH, 40 °C, 60 °C, and light irradiation. The powder X-ray diffraction patterns and purities of the compounds of each crystalline form were measured, and the specific results are shown in Table 6 below.

[0135]

Table 6

[0136] From the results in Table 6 above, it became clear that crystalline forms A, B, C, D, and E showed better stability and higher purity compared to the amorphous form.

[0137] Particle size test The compounds of formula I in amorphous form prepared in the above Preparation Example, the compounds of formula I in crystalline form A prepared in Example 1, the compounds of formula I in crystalline form B prepared in Example 9, the compounds of formula I in crystalline form C prepared in Example 12, the compounds of formula I in crystalline form D prepared in Example 17, and the compounds of formula I in crystalline form E prepared in Example 20 were each measured for their particle size. The specific results are shown in Table 7 below.

[0138] [Table 7]

[0139] From the results in Table 7 above, it was revealed that the particle size of the amorphous compound was clearly small and significantly smaller compared to the particle sizes of crystalline forms A, B, C, D, and E (here, the D50 of the amorphous compound was 3.52 μm, which was 12% or less of the D50 of the crystalline forms of the present invention, and the D90 of the amorphous compound was 18.45 μm, which was 25% or less of the D90 of the crystalline forms of the present invention). Therefore, it was found that the present invention is suitable for the forming process of solid preparations (such as tablets, capsules, or granules).

[0140] Test of fluidity The compounds of formula I in amorphous form prepared in the above Preparation Example, the compounds of formula I in crystalline form A prepared in Example 1, the compounds of formula I in crystalline form B prepared in Example 9, the compounds of formula I in crystalline form C prepared in Example 12, the compounds of formula I in crystalline form D prepared in Example 17, and the compounds of formula I in crystalline form E prepared in Example 20 were each measured for their angle of repose. The specific results are shown in Table 8 below.

[0141] [Table 8]

[0142] From the above results, it was revealed that the amorphous form has a significantly larger angle of repose compared to crystalline forms A, B, C, D, and E. From this, it was found that crystalline forms A, B, C, D, and E are significantly superior to the amorphous form in terms of fluidity and are suitable for the forming process of solid preparations (such as tablets, capsules, or granules).

[0143] Hygroscopicity test The compound represented by formula I in amorphous form prepared in the above Preparation Example, the compound represented by formula I in crystalline form A prepared in Example 1, the compound represented by formula I in crystalline form B prepared in Example 9, the compound represented by formula I in crystalline form C prepared in Example 12, the compound represented by formula I in crystalline form D prepared in Example 17, and the compound represented by formula I in crystalline form E prepared in Example 20 were each left standing in an environment of 75% RH and 25 °C for 24 hours, their weights were weighed, and their hygroscopicity was determined. The specific results are shown in Table 9 below.

[0144]

Table 9

[0145] From the above results, it was revealed that the amorphous form has significantly higher hygroscopicity compared to crystalline forms A, B, C, D, and E. From this, it was found that crystalline forms A, B, C, D, and E are significantly superior to the amorphous form in terms of hygroscopicity.

[0146] In the technical solution of the present invention, numerical values or numerical endpoints are not limited by the meaning or the scope to be protected by the numerical values themselves, and may include allowable error ranges such as experimental errors, measurement errors, statistical errors, random errors, etc., widely recognized in the art. Also, those skilled in the art should understand that all of those error ranges are included in the technical scope of the present invention.

[0147] It will be apparent to those skilled in the art that many modifications and variations can be made without departing from the spirit and scope of the invention. The specific embodiments described herein are provided by way of example only and are not intended to be limiting in any way. The essential scope of the invention and its spirit are indicated by the appended claims, while the specification and examples are merely illustrative.

Claims

1. 【Fig. 1】 The crystalline form A of the compound represented by the above formula I is characterized in that the powder X-ray diffraction pattern using Cu-Kα line has characteristic peaks at positions where 2θ represented in degrees is 8.5 ± 0.2°, 11.4 ± 0.2°, 14.4 ± 0.2°, 15.7 ± 0.2°, 16.7 ± 0.2°, 17.8 ± 0.2°, 25.1 ± 0.2°, 28.1 ± 0.2°.

2. The crystalline form A according to Claim 1, wherein the powder X-ray diffraction pattern using Cu-Kα line has characteristic peaks at positions where 2θ represented in degrees is 7.0 ± 0.2°, 8.5 ± 0.2°, 11.4 ± 0.2°, 13.1 ± 0.2°, 14.4 ± 0.2°, 15.7 ± 0.2°, 16.7 ± 0.2°, 17.8 ± 0.2°, 20.2 ± 0.2°, 21.2 ± 0.2°, 22.0 ± 0.2°, 23.1 ± 0.2°, 24.3 ± 0.2°, 25.1 ± 0.2°, 26.2 ± 0.2°, 28.1 ± 0.2°.

3. The crystalline form A according to Claim 1 or 2, wherein the powder X-ray diffraction pattern is as shown in FIG.

1.

4. A method for producing the crystalline form A according to any one of Claims 1 to 3, characterized by including adding the amorphous form of the compound represented by formula I to a solvent which is methanol, ethanol, n-propanol, isopropanol, acetone, methyl isobutyl ketone, 2-butanone or a mixture thereof to form a suspension, turning this suspension into a crystal slurry at 5 to 50°C and stirring for 1 to 7 days, then separating the solid and drying it under vacuum to obtain the crystalline form A.

5. The method according to Claim 4, wherein the weight-to-volume ratio of the compound represented by the above formula I to the solvent is 1:10 to 1:50 in the unit of g / mL.

6. 【Fig. 2】 The crystalline form B of the compound represented by the above formula I is characterized in that the powder X-ray diffraction pattern using Cu-Kα line has characteristic peaks at positions where 2θ represented in degrees is 5.9 ± 0.2°, 11.8 ± 0.2°, 13.4 ± 0.2°, 17.7 ± 0.2°, 23.6 ± 0.2°, 26.9 ± 0.2°.

7. The crystalline form B according to claim 6, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at positions where 2θ, expressed in degrees, is 5.9 ± 0.2°, 9.0 ± 0.2°, 9.9 ± 0.2°, 11.8 ± 0.2°, 13.4 ± 0.2°, 17.7 ± 0.2°, 21.9 ± 0.2°, 23.6 ± 0.2°, 24.5 ± 0.2°, 26.9 ± 0.2°, 29.9 ± 0.2°.

8. The crystalline form B according to claim 6 or 7, characterized in that the powder X-ray diffraction pattern is as shown in Figure 3.

9. A method for producing the crystalline form B according to any one of claims 6 to 8, characterized by adding the amorphous form of the compound represented by formula I to dichloromethane to form a suspension, stirring this suspension as a crystal slurry at 5 to 35°C for 1 to 7 days, then separating the solid and drying it under vacuum to obtain the crystalline form B.

10. The method according to claim 9, characterized in that the weight-to-volume ratio of the compound represented by formula I to dichloromethane is 1:10 to 1:50 in units of g / mL.

11. 【Chemical Formula 3】 The crystalline form C of the compound represented by the above formula I, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at positions where 2θ, expressed in degrees, is 6.9 ± 0.2°, 8.6 ± 0.2°, 11.5 ± 0.2°, 13.9 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 18.4 ± 0.2, 20.3 ± 0.2°, 23.8 ± 0.2°, 26.9 ± 0.

2.

12. The crystalline form C according to claim 11, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at positions where 2θ, expressed in degrees, is 6.9 ± 0.2°, 8.6 ± 0.2°, 9.3 ± 0.2°, 9.7 ± 0.2°, 11.5 ± 0.2°, 13.9 ± 0.2°, 14.9 ± 0.2°, 15.8 ± 0.2°, 16.3 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 18.4 ± 0.2°, 20.3 ± 0.2°, 23.2 ± 0.2°, 23.8 ± 0.2°, 24.4 ± 0.2°, 25.3 ± 0.2°, 26.9 ± 0.2°, 28.2 ± 0.2°.

13. The crystalline form C according to claim 11 or 12, characterized in that the powder X-ray diffraction pattern is as shown in Figure 5.

14. A method for producing the crystalline form C according to any one of claims 11 to 13, The method is characterized by including adding the amorphous form of the compound represented by formula I to a solvent which is methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate or a mixture thereof to form a suspension, making it into a crystal slurry at 5 to 50 °C and stirring for 1 to 7 days, then separating the solid and drying it under vacuum to obtain crystal form C.

15. The method according to claim 14, characterized in that the weight-to-volume ratio of the compound represented by formula I to the solvent is 1:10 to 1:50 in the unit of g / mL.

16. 【Chemical Formula 4】 The crystal form D of the compound represented by the above formula I, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at positions where 2θ represented in degrees is 6.1 ± 0.2°, 6.9 ± 0.2°, 9.3 ± 0.2°, 12.2 ± 0.2°, 14.0 ± 0.2°, 18.7 ± 0.2, 25.6 ± 0.2°.

17. The crystal form D according to claim 16, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at positions where 2θ represented in degrees is 6.1 ± 0.2°, 6.9 ± 0.2°, 9.3 ± 0.2°, 12.2 ± 0.2°, 12.7 ± 0.2°, 13.2 ± 0.2°, 14.0 ± 0.2°, 15.3 ± 0.2°, 18.7 ± 0.2°, 21.1 ± 0.2°, 25.6 ± 0.2°, 27.2 ± 0.2°.

18. The crystal form D according to claim 16 or 17, characterized in that the powder X-ray diffraction pattern is as shown in FIG.

7.

19. A method for producing the crystal form D according to any one of claims 16 to 18, comprising: adding the compound represented by formula I to N,N-dimethylacetamide, stirring at 10 to 50 °C until it dissolves to become clear, then adding water to precipitate crystals, separating the solid and drying it under vacuum to obtain crystal form D.

20. The method according to claim 19, characterized in that the weight-to-volume ratio of the compound represented by formula I to N,N-dimethylacetamide is 1:20 to 1:50 in the unit of g / mL.

21. The method according to claim 19 or 20, characterized in that the volume ratio of N,N-dimethylacetamide to water is 1:1 to 1:

4.

22. 【Fig. 5】 The crystalline form E of the compound represented by the above formula I is characterized in that the powder X-ray diffraction pattern using Cu-Kα line has characteristic peaks at positions where 2θ represented in degrees is 6.3 ± 0.2°, 12.7 ± 0.2°, 13.3 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 23.4 ± 0.2°, 27.0 ± 0.2°.

23. The crystalline form E according to claim 22, wherein the powder X-ray diffraction pattern using Cu-Kα line has characteristic peaks at positions where 2θ represented in degrees is 6.3 ± 0.2°, 8.6 ± 0.2°, 12.7 ± 0.2°, 13.3 ± 0.2°, 14.9 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 19.1 ± 0.2°, 21.2 ± 0.2°, 21.9 ± 0.2°, 23.4 ± 0.2°, 27.0 ± 0.2°, 27.7 ± 0.2°.

24. The crystalline form D according to claim 22 or 23, wherein the powder X-ray diffraction pattern is as shown in FIG.

9.

25. A method for producing the crystalline form E according to any one of claims 22 to 24, comprising adding the compound represented by formula I to dimethyl sulfoxide, heating to 70 - 80 °C, stirring for 10 - 30 hours until dissolved clearly, then cooling to 0 - 20 °C to precipitate crystals, separating the solid and drying in vacuum to obtain the crystalline form E.

26. The method according to claim 25, wherein the weight / volume ratio of the compound represented by the above formula I to dimethyl sulfoxide is 1:50 to 1:10 in the unit of g / mL.

27. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form A according to any one of claims 1 to 3, the crystalline form B according to any one of claims 6 to 8, the crystalline form C according to any one of claims 11 to 13, the crystalline form D according to any one of claims 16 to 18 or the crystalline form E according to any one of claims 22 to 24, and a pharmaceutically acceptable additive.

28. Use of the crystalline form A according to any one of claims 1 to 3, the crystalline form B according to any one of claims 6 to 8, the crystalline form C according to any one of claims 11 to 13, the crystalline form D according to any one of claims 16 to 18, the crystalline form E according to any one of claims 22 to 24 or the pharmaceutical composition according to claim 27 in the manufacture of a medicament for treating a disease associated with a fusion or mutation of the RET gene, wherein the disease is cancer, and preferably the cancer is breast cancer, non-small cell lung cancer or rectal cancer. **Claim 29** Use of the crystalline form A according to any one of claims 1 to 3, the crystalline form B according to any one of claims 6 to 8, the crystalline form C according to any one of claims 11 to 13, the crystalline form D according to any one of claims 16 to 18, the crystalline form E according to any one of claims 22 to 24 or the pharmaceutical composition according to claim 27 in the manufacture of a RET kinase inhibitor.

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