Solid forms of azafused ring amide compounds and uses thereof

Abstract

The application provides a compound shown in formula (A) in a solid form, a compound shown in formula (A) in a crystalline form, specific crystal forms thereof, a pharmaceutical composition containing the same, and uses thereof. The compound shown in formula (A) in a crystalline form and the specific crystal forms thereof have good crystallinity and stability, and show good pharmacodynamic effects in vivo and in vitro. The compound shown in formula (A) has good inhibitory effects on wild-type and mutant kinases, cells and tumors in vivo, and has good drug development potential.

Description

[0001] This application claims priority to the prior application of the applicant filed with the China National Intellectual Property Office on November 15, 2021, with the patent application number 202111345026.6, and the invention name of "Solid Form of Aza-Fused Ring Amide Compound and Use Thereof". The prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application relates to the field of medicine, in particular to solid forms of aza-fused ring amide compounds, crystalline forms of aza-fused ring amide compounds and specific crystal forms thereof, pharmaceutical compositions containing the same and the use thereof in the preparation of a medicament for the prevention and / or treatment of diseases mediated by one or more of TRK, ROS1, ALK. BACKGROUND

[0003] Tropomyosin-related kinase or Tropomyosin receptor kinase (TRK) is a class of nerve growth factor receptors, which consists of three highly homologous subtypes of TRKA, TRKB and TRKC, respectively encoded by neurotrophic receptor tyrosine kinase 1 (NTRK1), NTRK2 and NTRK3 genes. When the TRK receptor protein binds to the corresponding ligand, it can realize different physiological functions by activating the downstream signal pathways, such as RAS / MAPK pathway, PLCγ pathway and PI3K pathway. TRK family proteins are mainly expressed in nerve tissues under normal circumstances, participate in the differentiation and survival of nerve cells, and the formation of axons and dendrites, and play an important role in embryonic development and the maintenance of normal functions of the nervous system.

[0004] TRK kinases are activated in malignant tumors through various mechanisms, mainly structural rearrangement and expression changes. For example, the rearrangement of the NTRK gene encoding TRK kinase with other genes produces a fusion oncogene, which causes changes in the structure and expression of TRK kinase, which is no longer regulated and controlled by nerve growth factor ligands, and is constitutively activated, promoting tumor occurrence and development. In addition, gene sequencing results also show that TRK kinases are closely related to the occurrence, metastasis and malignancy of various tumors, and are expressed in various tumors, such as non-small cell lung cancer, colorectal cancer, melanoma, gallbladder cancer, thyroid cancer, malignant glioma, etc.

[0005] Currently, the first generation of TRK inhibitors, Larotrectinib (LOXO-101) and Entrectinib (RXDX-101), were approved by the U.S. Food and Drug Administration (FDA) in 2018 and 2019, respectively. Larotrectinib is a potent, oral, selective tropomyosin receptor kinase inhibitor. The efficacy data was published as early as the ASCO conference in June 2017. In the phase I and II clinical trials, a total of 55 subjects were recruited, of which 46 evaluable patients had an overall response rate (ORR) of 78%. Entrectinib is a potent inhibitor of TRK, ROS1 and ALK proteins, and can pass through the blood-brain barrier. In the phase I clinical trial, the ORR of 24 evaluable patients was 79%.

[0006] Similar to other targeted drugs, TRK inhibitors also face the problem of drug resistance. Mutations in the NTRK kinase domain can cause changes in the conformation of the TRK family protein kinase domain or changes in ATP binding affinity, thereby affecting the binding of TRK inhibitors to the target. The mutation types include G595R, G639R, G667C, etc. To solve the problem of drug resistance of the first generation of TRK inhibitors, the second generation of TRK inhibitors such as LOXO-195, TPX-005, etc. are under research.

[0007] SUMMARY

[0008] In one aspect, the present application provides a compound of formula (A) in solid form.

[0009]

[0010] In some embodiments of the present application, the compound of formula (A) in solid form described above can be tested by infrared spectroscopy using a tablet pressing method, and the infrared spectrum thereof includes characteristic peaks (±4 cm-1) at the following positions: 3429, 1643, 1488, 1453, 1232, 1027. -1 ) 3429, 1643, 1488, 1453, 1232, 1027.

[0011] In some embodiments of the present application, the compound of formula (A) in solid form described above has an infrared spectrum substantially as shown in Figure Figure 12 .

[0012] In some embodiments of the present application, the compound of formula (A) in solid form described above can be tested by X-ray powder diffraction method.

[0013] In some embodiments of the present application, the compound of formula (A) in solid form described above has a chemical purity of ≥95%; preferably, it has a chemical purity of ≥97%; further preferably, it has a chemical purity of ≥98%.

[0014] In some embodiments of the application, the solid form of the compound of Formula (A) is amorphous, which has an infrared spectrum substantially as shown in Figure 12

[0015] In another aspect, the application provides a crystalline form of the compound of Formula (A).

[0016] In another aspect, the application provides Form I of the compound of Formula (A), which has an X-ray powder diffraction pattern with characteristic peaks (±0.2°) at the following 2-theta angles: 9.2, 17.9, 18.5, using Cu-Ka radiation.

[0017] In some embodiments of the application, Form I described above has an X-ray powder diffraction pattern with characteristic peaks (±0.2°) at the following 2-theta angles: 8.9, 9.2, 17.9, 18.5, 23.8, using Cu-Ka radiation.

[0018] In some embodiments of the application, Form I described above has an X-ray powder diffraction pattern with characteristic peaks (±0.2°) at the following 2-theta angles: 8.9, 9.2, 10.1, 17.9, 18.5, 23.8, 28.0, using Cu-Ka radiation.

[0019] In some embodiments of the application, Form I described above has an X-ray powder diffraction pattern with characteristic peaks (±0.2°) at the following 2-theta angles: 8.9, 9.2, 10.1, 16.1, 17.9, 18.5, 23.8, 27.0, 28.0, using Cu-Ka radiation.

[0020] In some embodiments of the application, Form I described above has an X-ray powder diffraction pattern with characteristic peaks (±0.2°) at the following 2-theta angles: 8.9, 9.2, 10.1, 16.1, 16.6, 17.9, 18.5, 23.8, 27.0, 28.0, using Cu-Ka radiation.

[0021] In some embodiments of the application, Form I described above has an X-ray powder diffraction pattern substantially as shown in Figure 1

[0022] In another aspect, the application provides Form II of the compound of Formula (A), which has an X-ray powder diffraction pattern with characteristic peaks (±0.2°) at the following 2-theta angles: 9.1, 18.3, 20.6, using Cu-Ka radiation.

[0023] ​​In some embodiments of the application, Form II has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0024] In some embodiments of the application, Form II has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0025] In some embodiments of the application, Form II has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0026] In some embodiments of the application, Form II has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0027] In some embodiments of the application, Form II has an X-ray powder diffraction pattern substantially as shown in Figure 2. Figure 2

[0028] In some embodiments of the application, Form II has a differential scanning calorimetry curve with an endothermic peak at 155.27 ± 5 °C.

[0029] In some embodiments of the application, Form II has a differential scanning calorimetry curve with endothermic peaks at 58.39 ± 5 °C and 155.27 ± 5 °C.

[0030] In some embodiments of the application, Form II has a differential scanning calorimetry curve substantially as shown in Figure 4. Figure 3

[0031] In some embodiments of the application, Form II has a thermogravimetric analysis curve with a weight loss of 0.1910% ± 0.2% between room temperature and 75 ± 5 °C.

[0032] In some embodiments of the application, Form II has a thermogravimetric analysis curve substantially as shown in Figure 6. Figure 3

[0033] In another aspect, the present application provides Form III of formula (A), which has an X-ray powder diffraction pattern substantially as shown in Figure 8. ​​​

[0034] In some embodiments of the application, Form III has an X-ray powder diffraction pattern substantially as shown in Figure 3.

[0035] In some embodiments of the application, Form III has an X-ray powder diffraction pattern substantially as shown in Figure 3.

[0036] In some embodiments of the application, Form III has an X-ray powder diffraction pattern substantially as shown in Figure 3.

[0037] In some embodiments of the application, Form III has an X-ray powder diffraction pattern substantially as shown in Figure 3.

[0038] In some embodiments of the application, Form III has an X-ray powder diffraction pattern substantially as shown in Figure 3.

[0039] In some embodiments of the application, Form III has an X-ray powder diffraction pattern substantially as shown in Figure 3. Figure 4

[0040] In some embodiments of the application, Form III has a differential scanning calorimetry curve with an endothermic peak at 182.29 ± 5 °C.

[0041] In some embodiments of the application, Form III has a differential scanning calorimetry curve substantially as shown in Figure 4. Figure 5

[0042] In another aspect, the present application provides Form IV of the compound of Formula (A), which has an X-ray powder diffraction pattern substantially as shown in Figure 5.

[0043] ​​In some embodiments of the application, Form IV has an X-ray powder diffraction pattern using Cu-Kalpharadiation with characteristic diffraction peaks (±0.2°) at the following 2 theta angles: 8.5, 10.0, 13.1, 17.2, 17.9, 25.0.

[0044] In some embodiments of the application, Form IV has an X-ray powder diffraction pattern using Cu-Kalpharadiation with characteristic diffraction peaks (±0.2°) at the following 2 theta angles: 8.5, 10.0, 13.1, 17.2, 17.9, 20.0, 25.0.

[0045] In some embodiments of the application, Form IV has an X-ray powder diffraction pattern using Cu-Kalpharadiation with characteristic diffraction peaks (±0.2°) at the following 2 theta angles: 8.5, 10.0, 13.1, 15.7, 17.2, 17.9, 20.0, 25.0, 25.9.

[0046] In some embodiments of the application, Form IV has an X-ray powder diffraction pattern using Cu-Kalpharadiation with characteristic diffraction peaks (±0.2°) at the following 2 theta angles: 8.5, 10.0, 13.1, 15.7, 17.2, 17.9, 19.5, 20.0, 25.0, 25.9.

[0047] In some embodiments of the application, Form IV has an X-ray powder diffraction pattern using Cu-Kalpharadiation with characteristic diffraction peaks (±0.2°) at the following 2 theta angles: 5.5, 8.5, 10.0, 13.1, 14.0, 15.7, 17.2, 17.9, 19.5, 20.0, 25.0, 25.9.

[0048] In some embodiments of the application, Form IV has an X-ray powder diffraction pattern using Cu-Kalpharadiation with characteristic diffraction peaks (±0.2°) at the following 2 theta angles: 5.5, 8.5, 10.0, 13.1, 14.0, 15.7, 17.2, 17.9, 19.0, 19.5, 20.0, 25.0, 25.9, 26.4.

[0049] In some embodiments of the application, Form IV has an X-ray powder diffraction pattern using Cu-Kalpharadiation with characteristic diffraction peaks (±0.2°) at the following 2 theta angles: 5.5, 8.5, 10.0, 13.1, 14.0, 15.7, 16.5, 17.2, 17.9, 19.0, 19.5, 20.0, 22.9, 25.0, 25.9, 26.4.

[0050] In some embodiments of the application, Form IV has an X-ray powder diffraction pattern substantially in accordance with that set out in Figure 6.

[0051] In some embodiments of the application, Form IV has an X-ray powder diffraction pattern substantially in accordance with that set out in Figure 6. Figure 6 or Figure 8 In some embodiments of the application, Form IV has an X-ray powder diffraction pattern substantially in accordance with that set out in Figure 6.

[0052] In some embodiments of the application, Form IV has a differential scanning calorimetry curve with an endothermic peak at 192.07 ± 5 °C.

[0053] In some embodiments of the application, Form IV has a differential scanning calorimetry curve with endothermic peaks at 64.82 ± 5 °C and 192.07 ± 5 °C.

[0054] In some embodiments of the application, Form IV has a DSC pattern substantially in accordance with that set out in Figure 6. Figure 7

[0055] In some embodiments of the application, Form IV has a thermogravimetric analysis curve with a weight loss of 1.1526% ± 0.2% between room temperature and 75 ± 5 °C.

[0056] In some embodiments of the application, Form IV has a TGA pattern substantially in accordance with that set out in Figure 6. Figure 7

[0057] In another aspect, the present application provides Form V of the compound of Formula (A), which has an X-ray powder diffraction pattern substantially in accordance with that set out in Figure 7.

[0058] In some embodiments of the application, Form V has an X-ray powder diffraction pattern substantially in accordance with that set out in Figure 7.

[0059] In some embodiments of the application, Form V has an X-ray powder diffraction pattern substantially in accordance with that set out in Figure 7.

[0060] ​​In some embodiments of the application, Form V has an X-ray powder diffraction pattern substantially as shown in Figure 6 using Cu-Ka radiation.

[0061] In some embodiments of the application, Form V has an X-ray powder diffraction pattern substantially as shown in Figure 6 using Cu-Ka radiation.

[0062] In some embodiments of the application, Form V has an X-ray powder diffraction pattern substantially as shown in Figure 6 using Cu-Ka radiation.

[0063] In some embodiments of the application, Form V has an X-ray powder diffraction pattern substantially as shown in Figure 6 using Cu-Ka radiation.

[0064] In some embodiments of the application, Form V has an X-ray powder diffraction pattern substantially as shown in Figure 6 using Cu-Ka radiation.

[0065] In some embodiments of the application, Form V has an X-ray powder diffraction pattern substantially as shown in Figure 6 using Cu-Ka radiation. Figure 9

[0066] In another aspect, the present application provides Form VI of the compound of Formula (A), which has an X-ray powder diffraction pattern substantially as shown in Figure 7 using Cu-Ka radiation.

[0067] In some embodiments of the application, Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 7 using Cu-Ka radiation.

[0068] ​In some embodiments of the application, the Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0069] In some embodiments of the application, the Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0070] In some embodiments of the application, the Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0071] In some embodiments of the application, the Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0072] In some embodiments of the application, the Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0073] In some embodiments of the application, the Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 2. Figure 10

[0074] In some embodiments of the application, the Form VI has a differential scanning calorimetry curve with an endothermic peak at 184.47 ± 5 °C.

[0075] In some embodiments of the application, the Form VI has a differential scanning calorimetry curve with an endothermic peak at 184.47 ± 5 °C. Figure 11

[0076] In some embodiments of the application, the Form VI has a thermogravimetric analysis curve with a weight loss of 0.253% ± 0.2% between room temperature and 200 °C ± 5 °C.

[0077] In some embodiments of the application, the Form VI has a thermogravimetric analysis curve with a weight loss of 0.253% ± 0.2% between room temperature and 200 °C ± 5 °C.​​Figure 11 TGA pattern shown.

[0078] In another aspect, the present application provides a crystalline composition comprising one or more of Form I, Form II, Form III, Form IV, Form V, Form VI of the compound of Formula (A).

[0079] In some embodiments of the present application, the Form II accounts for 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more by weight of the crystalline composition.

[0080] In some embodiments of the present application, the Form III accounts for 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more by weight of the crystalline composition.

[0081] In some embodiments of the present application, the Form IV accounts for 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more by weight of the crystalline composition.

[0082] In some embodiments of the present application, the Form VI accounts for 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more by weight of the crystalline composition.

[0083] In another aspect, the present application provides a pharmaceutical composition comprising a solid form of the compound of Formula (A), a crystalline form of the compound of Formula (A), or the above-mentioned crystalline composition.

[0084] In some embodiments of the present application, the above-mentioned pharmaceutical composition comprises one or more of Form I, Form II, Form III, Form IV, Form V, Form VI of the compound of Formula (A).

[0085] In another aspect, the present application also provides a pharmaceutical composition comprising a solid form of the compound of Formula (A), a crystalline form of the compound of Formula (A), or the above-mentioned crystalline composition, and a pharmaceutically acceptable carrier.

[0086] In some embodiments of the present application, the above-mentioned pharmaceutical composition comprises one or more of Form I, Form II, Form III, Form IV, Form V, Form VI of the compound of Formula (A), and a pharmaceutically acceptable carrier.

[0087] In another aspect, the present application provides the above-mentioned solid form of the compound of Formula (A), the crystalline form of the compound of Formula (A), the above-mentioned crystalline composition, Form I, Form II, Form III, Form IV, Form V, or Form VI of the compound of Formula (A), or the above-mentioned pharmaceutical composition for use as a medicament or in the manufacture of a medicament.

[0088] In some embodiments of the application, the medicament is used for treating a pain disease, a cell proliferation disease, an inflammatory disease, a neurodegenerative disease or an infectious disease.

[0089] In some embodiments of the application, the medicament is used for preventing and / or treating a disease mediated by one or more of TRK, ROS1 or ALK.

[0090] In some embodiments of the application, the medicament is used for preventing and / or treating a tumor positive for NTRK gene rearrangement / fusion and / or drug resistance mutation, or a tumor positive for ROS1 gene rearrangement / fusion and / or drug resistance mutation; preferably, the tumor is a solid tumor or a hematological tumor; further preferably, the tumor is a solid tumor.

[0091] In some embodiments of the application, the NTRK drug resistance mutation is NTRK1-G595R, NTRK1-G667C, NTRK3-G623R or NTRK3-G696A; preferably, the NTRK drug resistance mutation is NTRK1-G595R, NTRK3-G623R or NTRK1-G667C; further preferably, the NTRK drug resistance mutation is NTRK1-G595R or NTRK1-G667C.

[0092] In another aspect, the application also provides the compound of formula (A) in a solid form, the compound of formula (A) in a crystalline form, the crystalline composition, the crystalline form I, the crystalline form II, the crystalline form III, the crystalline form IV, the crystalline form V or the crystalline form VI of the compound of formula (A) or the pharmaceutical composition as described above for use in preventing and / or treating a disease mediated by one or more of TRK, ROS1 or ALK.

[0093] In another aspect, the application also provides a method for preventing and / or treating a disease mediated by one or more of TRK, ROS1 or ALK, comprising: administering to a patient a therapeutically effective amount of the compound of formula (A) in a solid form, the compound of formula (A) in a crystalline form, the crystalline composition, the crystalline form I, the crystalline form II, the crystalline form III, the crystalline form IV, the crystalline form V or the crystalline form VI of the compound of formula (A) or the pharmaceutical composition as described above.

[0094] In some embodiments of the application, the disease is a tumor positive for NTRK gene rearrangement / fusion and / or drug resistance mutation, or a tumor positive for ROS1 gene rearrangement / fusion and / or drug resistance mutation; preferably, the tumor is a solid tumor or a hematological tumor; further preferably, the tumor is a solid tumor.

[0095] In some embodiments of the application, the NTRK resistance mutation is NTRK1-G595R, NTRK1-G667C, NTRK3-G623R, or NTRK3-G696A; preferably, the NTRK resistance mutation is NTRK1-G595R, NTRK3-G623R, or NTRK1-G667C; further preferably, the NTRK resistance mutation is NTRK1-G595R or NTRK1-G667C.

[0096] In some embodiments of the application, the disease is selected from a pain disease, a cell proliferative disease, an inflammatory disease, a neurodegenerative disease, or an infectious disease.

[0097] In one embodiment, the TRK-mediated disease is selected from a disease mediated by one, two, or three of TRKA, TRKB, or TRKC.

[0098] In one embodiment, the disease involves a dysregulation in the expression, activity, or level of a NTRK gene, a TRK protein, or the like; preferably, a NTRK gene fusion, amplification, rearrangement, mutation, or overexpression; further preferably, a NTRK gene rearrangement / fusion or mutation.

[0099] In some embodiments of the application, the NTRK mutation is NTRK1-G595R, NTRK1-G667C, NTRK3-G623R, or NTRK3-G696A; preferably, the NTRK resistance mutation is NTRK1-G595R, NTRK3-G623R, or NTRK1-G667C; further preferably, the NTRK resistance mutation is NTRK1-G595R or NTRK1-G667C.

[0100] In one embodiment, the disease involves a dysregulation in the expression, activity, or level of a ROS1 gene, a ROS1 protein, or the like; preferably, a ROS1 gene fusion, amplification, rearrangement, mutation, or overexpression; further preferably, a ROS1 gene rearrangement / fusion or mutation.

[0101] In one embodiment, the disease involves a dysregulation in the expression, activity, or level of one or more of a TRK, ALK, ROS1 gene, protein, or the like; preferably, a NTRK, ALK, ROS1 gene fusion, amplification, rearrangement, mutation, or overexpression; further preferably, a NTRK, ALK, ROS1 gene fusion or mutation.

[0102] In one embodiment, the cell proliferative disease is a tumor or a cancer.

[0103] In one embodiment, the above-mentioned tumor or cancer is a solid tumor and a hematological tumor; preferably a solid tumor; further preferably a solid tumor positive for NTRK gene rearrangement / fusion and / or drug resistance mutation, or a solid tumor positive for ROS1 gene rearrangement / fusion and / or drug resistance mutation.

[0104] In some aspects of the application, the NTRK drug resistance mutation is NTRK1-G595R, NTRK1-G667C, NTRK3-G623R or NTRK3-G696A; preferably, the NTRK drug resistance mutation is NTRK1-G595R, NTRK3-G623R or NTRK1-G667C; further preferably, the NTRK drug resistance mutation is NTRK1-G595R or NTRK1-G667C.

[0105] In one embodiment, the above-mentioned tumor or cancer is a malignant hematopathy, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma, colorectal cancer, melanoma, cancer of the head and neck, gallbladder cancer, thyroid cancer, malignant glioma, gastric cancer, neuroblastoma or salivary gland cancer; preferably, the lung cancer is non-small cell lung cancer.

[0106] Definitions and Descriptions

[0107] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed in isolation, but rather should be construed in the context of the entire patent application. Reference to a "compound of Formula (A) in solid form" means a compound of Formula (A) in a solid state.

[0108] Reference to a "compound of Formula (A) in crystalline form" means a compound of Formula (A) in a crystalline state, including anhydrous and unsolvated forms, hydrate forms and solvate forms of a compound of Formula (A).

[0109] The term "solvate" or "solvates" refers to an association including stoichiometric or non-stoichiometric amounts of solvent molecules with a compound of Formula (A) of the application, including associations containing water molecules and one or more other solvent molecules, and associations containing only one or more other solvent molecules.

[0110] The term "hydrate" refers to an association including stoichiometric or non-stoichiometric amounts of water molecules with a compound of Formula (A) of the application.

[0111] The "anhydrous and unsolvated form" means that no water molecules or solvent molecules are present, or that water molecules or solvent molecules are present in an intermolecularly bound manner with the compound of Formula (A), for example in an adsorbed manner.

[0112] In the context of the present application, the 2-theta values in the characteristic diffraction peaks, diffraction peaks and / or X-ray powder diffraction patterns are given in degrees (°).

[0113] The term "crystalline composition" refers to a solid form comprising one, two or more of crystalline Form I, crystalline Form II, crystalline Form III, crystalline Form IV, crystalline Form V, or crystalline Form VI referred to in the present application. Furthermore, the crystalline composition can optionally comprise other crystalline forms or other amorphous forms of the compound of Formula (A) or salts thereof in addition to the crystalline forms of the present application, or impurities in addition to these substances. It will be understood by those skilled in the art that the sum of the amounts of the components in the crystalline composition should be 100%.

[0114] The term "room temperature" is intended to mean room temperature in the conventional sense in the art, typically 10-30 °C, preferably 25 °C ± 5 °C.

[0115] The term "substantially" or "substantially as shown in the figure" in the context of X-ray powder diffraction patterns means that a substantially pure form of a certain crystalline form has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in its powder X-ray diffraction pattern appearing in the given pattern. Further, as the amount of a certain crystalline form in a product is gradually reduced, some of the diffraction peaks attributed to that crystalline form in the X-ray powder diffraction pattern can be lost due to the sensitivity of the instrument. In addition, for any given crystalline form, there can be slight errors in the position of the peaks, which are also known in the art of crystallography. For example, due to changes in temperature, sample movement or calibration of the instrument during analysis of the sample, the position of the peaks can shift, and the error in the measurement of the 2-theta values is sometimes about ± 0.3°, and typically about ± 0.2°. Therefore, when determining the structure of each crystalline form, this error should be taken into account, and the term "substantially" or "substantially as shown in the figure" is intended to encompass such differences in the position of the diffraction peaks to ± 0.3°, preferably ± 0.2°.

[0116] The term "substantially" or "substantially as shown in the figure" in the context of DSC or TGA patterns means that for the same crystalline form of the same compound, the error in the onset temperature of thermal transition, the peak temperature of endotherm, the peak temperature of exotherm, the melting point, the onset temperature of weight loss or the end temperature of weight loss, etc. is typically within about 5 °C, and typically within about 3 °C in successive analyses. When a certain compound is described as having a given onset temperature of thermal transition, peak temperature of endotherm, peak temperature of exotherm, melting point, onset temperature of weight loss or end temperature of weight loss, etc., this means the temperature ± 5 °C.

[0117] The term "cell proliferative disorder" as used herein refers to a condition in which a population of cells is growing at a rate that is less than or greater than the expected rate under given physiological conditions.

[0118] The term "tumor" includes benign, malignant, and borderline tumors, with malignant tumors collectively referred to as cancer.

[0119] The term "prevent" as used herein refers to the reduction in the frequency of, or delay in the onset of, symptoms of a medical condition in a subject when a compound or drug (e.g., a combination product claimed herein) is administered to a subject as compared to a subject to which the compound or drug is not administered.

[0120] The term "treat" as used herein refers to alleviating, relieving, or ameliorating a symptom of a disease or condition, ameliorating an underlying metabolic cause of a symptom, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.

[0121] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means those carriers or excipients that do not cause an undesirable physiological effect(s) when administered to an organism, and do not abrogate the biological activity and properties of the active compound.

[0122] The intermediate compounds of the present application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by a combination of the specific embodiments listed below with other chemical synthetic methods known to those skilled in the art, and equivalents thereof known to those skilled in the art, preferred embodiments include, but are not limited to, the examples of the present application.

[0123] The chemical reactions of the specific embodiments of the present application are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In some instances, the solvent can be changed after a given reaction to facilitate the further reactions and / or to facilitate purification. In some instances, it is desirable to remove the protecting groups used in the synthesis of the compounds of the present application.

[0124] The present application will now be described in detail by examples, which are not intended to limit the present application in any manner.

[0125] All solvents used in the present application are commercially available and used without further purification.

[0126] Technical Effects

[0127] The solid forms of the compound of Formula (A), the crystalline forms of the compound of Formula (A), and the specific crystalline forms provided herein have one or more of the following beneficial effects:

[0128] (1) The compound of formula (A) in solid form has good properties, and is easy to weigh, transfer, separate, purify and store.

[0129] (2) The compound of formula (A) in crystalline form and the specific crystal form have good crystallinity;

[0130] (3) The compound of formula (A) in crystalline form and the specific crystal form are easy to purify, filter and separate, especially the crystal form IV, and are easy to prepare and have high yield;

[0131] (4) The preferred crystal form has good physical and chemical stability, and has good prospects for pharmaceutical use;

[0132] (5) The in vitro kinase activity inhibition test shows that the compound of formula (A) has excellent inhibitory activity on various kinases (e.g., TRK, ALK, ROS1) and their mutants, especially on TRK and its mutant forms;

[0133] (5) The in vitro cell inhibition activity test shows that the compound of formula (A) has strong inhibitory effect on various NTRK mutant cells, and has IC 50 below 10 nM, preferably below 5 nM, and further preferably below 1 nM;

[0134] (6) The in vivo tumor inhibition test results show that the compound of formula (A) has better in vivo anti-tumor effect, better tolerance and higher possibility of drug development compared with the control compound;

[0135] (7) The in vivo mechanism research test shows that the compound of formula (A) can inhibit the phosphorylation of TRK in tumor tissue, thereby effectively inhibiting the phosphorylation of PLCγ1 and AKT, and inhibiting the growth of tumor tissue. BRIEF DESCRIPTION OF DRAWINGS

[0136] Figure 1 : X-ray powder diffraction pattern of crystal form I of Example 1.

[0137] Figure 2 : X-ray powder diffraction pattern of crystal form II of Example 2.

[0138] Figure 3 : DSC-TGA pattern of crystal form II of Example 2.

[0139] Figure 4 : X-ray powder diffraction pattern of crystal form III of Example 3.

[0140] Figure 5 : DSC-TGA pattern of crystal form III of Example 3.

[0141] Figure 6 X-ray powder diffraction pattern of crystalline Form IV of Example 4.

[0142] Figure 7 DSC-TGA pattern of crystalline Form IV of Example 4.

[0143] Figure 8 X-ray powder diffraction pattern of crystalline Form IV of Example 5.

[0144] Figure 9 X-ray powder diffraction pattern of crystalline Form V of Example 7.

[0145] Figure 10 X-ray powder diffraction pattern of crystalline Form VI of Example 8.

[0146] Figure 11 DSC-TGA pattern of crystalline Form VI of Example 8.

[0147] Figure 12 IR pattern of solid obtained from Example 0.

[0148] Figure 13 Resulting graph of Test Example 4. DETAILED DESCRIPTION

[0149] 1. X-ray powder diffractometer (XRPD)

[0150] (1) Instrument model: Bruker D8 Advance X-ray powder diffractometer

[0151] Test method: About 5-20 mg of sample (Examples 1-4, Examples 6-8) was used for XRPD testing

[0152] Detailed XRPD parameters are as follows:

[0153] X-ray generator: Cu, Kα,

[0154] Light tube voltage: 40 kV, light tube current: 40 mA

[0155] Scan range: 3°-40° (2θ)

[0156] Scan step: 0.02°

[0157] Sample plate: Zero background sample plate.

[0158] (2) Instrument model: D2 PHASER benchtop X-ray diffractometer

[0159] Test Method: Approximately 100-200 mg of sample (Example 0, Example 5) was used for XRPD testing

[0160] Detailed XRPD parameters are as follows:

[0161] X-ray generator: Cu, K a,

[0162] Beam voltage: 30 kV, beam current: 10 mA

[0163] Scan range: 3-60° (2 theta)

[0164] Scan step size: 0.02°

[0165] Sample holder: Zero background sample holder.

[0166] 2. Differential Scanning Calorimeter (DSC)

[0167] Instrument model: TA Discovery 250 Differential Scanning Calorimeter

[0168] Test Method: The sample was placed in a pierced aluminum crucible and equilibrated at 25 °C before heating to the final temperature at a rate of 10 °C / min.

[0169] Sample size: 1-3 mg

[0170] Gas type: Nitrogen

[0171] Flow rate: 50 mL / min

[0172] Heating start temperature: 25 °C.

[0173] 3. Thermal Gravimetric Analyzer (TGA)

[0174] Instrument model: TA Discovery 55 Thermal Gravimetric Analyzer (TA, US)

[0175] Test Method: The sample was placed in a pre-tared aluminum crucible and the sample mass was automatically weighed in the TGA furnace before heating the sample to the final temperature at a rate of 10 °C / min.

[0176] Sample size: 1-5 mg

[0177] Gas type: Nitrogen

[0178] Sample chamber gas flow rate: 60 mL / min

[0179] Heating start temperature: Room temperature

[0180] Termination temperature: 250 / 300 °C.

[0181] 4. Dynamic water sorption-desorption analysis (DVS)

[0182] Instrument model: DVS Intrinsic Dynamic Vapor Sorption (SMS)

[0183] Test method: Place sufficient sample (10-20 mg) into a pre-tared sample chamber and automatically weigh. Dry the sample at 40 °C (for anhydrous only, for hydrates start at 25 °C) until dm / dt is less than 0.002%. Cool to 25 °C and start the test using the operating parameters in the table below.

[0184] Stage time 60 minutes Drying / test temperature 40℃ / 25℃ Cycle Whole cycle Each RH equilibration time 1 hour Data storage rate 5 seconds Total gas flow 200 sccm Total gas flow rate after experiment 200 sccm

[0185] 5. High performance liquid chromatography (HPLC)

[0186] Instrument model: Agilent 1260 series (Waters, US)

[0187] Column: Express C18 4.6 x 100 mm, 2.7 pm

[0188] Test conditions: Wavelength 248 nm; column temperature 40 °C

[0189] Flow rate: 1.0 mL / min

[0190] Injection volume: 5 pL.

[0191] 6. Nuclear Magnetic Resonance Spectroscopy (NMRS)

[0192] Instrument model: Bruker AVANCE III 400 (Bruker, GER)

[0193] Content and test solvent: 1 H-NMR, test solvent DMSO-d6.

[0194] 7. Infrared Spectroscopy (IR)

[0195] Detection instrument: PerkinElmer Spectrum 100 FT-IR infrared spectrometer

[0196] Test method: Weigh 3 mg of sample, dilute with KBr and press into a tablet, test at room temperature, specific parameters: detection range: 4000-400 cm-1 Wavenumber, resolution: 4cm -1 .

[0197] Abbreviations: DCM: dichloromethane; DIPEA: diisopropylethylamine; DMF: N,N-dimethylformamide; EA: ethyl acetate; PE: petroleum ether; DMSO: dimethyl sulfoxide; TBTU: O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid; BOP: benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; ATP: 5'-adenosine triphosphate; DTT: 1,4-dithiothreitol; MTT: 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyltetrazolium bromide thiazole blue.

[0198] To better understand the content of this application, further explanation is provided below with reference to specific embodiments. However, the specific implementation methods are not intended to limit the content of this application. For test methods not specified in the following preparation examples, examples, comparative examples, test examples, or experimental examples, conventional methods and conditions should be followed, or the methods should be selected according to the product instructions.

[0199] Preparation Example 1: Preparation of Compound (A)

[0200]

[0201] Step a: A mixed solution of (2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine (5.826 g, 28.958 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (6.534 g, 28.958 mmol), n-butanol (50 mL), and diisopropylamine (8.790 g, 86.874 mmol) was reacted at 100 °C for 4 h. The solution was concentrated under reduced pressure to obtain crude ethyl 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (B1). This crude product was used directly in the next reaction without purification. (ES, m / z): 391.05 [M+H] + .

[0202] Step b: The crude ethyl 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate was dissolved in absolute ethanol (50 mL) and stirred at 75 °C until the system was clear and transparent, then an aqueous solution of LiOH (4.86 g, 115.832 mmol) (50 mL) was added and stirred at 75 °C for 5 h. After cooling to room temperature, the absolute ethanol was removed by reduced pressure concentration. The pH was adjusted to 3-4 by slowly adding 1 N aqueous HC1 solution, and a large amount of white solid was precipitated. After stirring at room temperature for 30 min, the mixture was filtered, and the filter cake was washed with a small amount of purified water. The filter cake was collected and dried to obtain white powder 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxylic acid (9.9 g). The filtrate was extracted with EA (2 x 50 mL), and the combined organic phase was washed with water (2 x 50 mL) and saturated aqueous NaCl solution (50 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 4:1 to 2:1, v / v) was performed, and the product was collected and concentrated under reduced pressure to obtain white powder 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxylic acid (386 mg). A total of 5-((2R,4S)-2-(2,5-difluorophenyl)-4- fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (B2, 10.286 g, 98%) was obtained. (ES, m / z): 363.04 [M+H] + .

[0203] Step c: 1-Boc-4-(4-aminophenyl)piperazine (918 mg, 3.312 mmol) was added to a solution of 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxylic acid (intermediate B2, 1000 mg, 2.76 mmol) and TBTU (1063 mg, 3.312 mmol) in anhydrous DMF (10 mL), then DIPEA (1284 mg, 9.936 mmol) was added dropwise at 0 °C, and the reaction was stirred at room temperature overnight. The reaction solution was mixed with water (50 mL) and stirred, and a solid precipitated. The filter cake was obtained by reduced pressure suction filtration and dried in a vacuum drying oven to obtain tert-butyl 4-(4-(5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)piperazine-1-carboxylate (B3, 1320 mg, 77%). (ES, m / z): 622.09 [M+H] + .

[0204] Step d: To tert-butyl 4-(4-(5-((2R,4S)-2-(2,5-difluorophenyl)-4- fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)piperazine-1- carboxylate (1.320 g, 2.125 mmol) was added DCM and CF3COOH (12 mL, 3 / 1, v / v), stirred at room temperature for 4 h, the reaction was concentrated under reduced pressure, to the residue was added water (80 mL) and EA (10 mL), adjusted to alkaline with ammonia (pH = 9), stirred to have solid precipitate, the filter cake was obtained by reduced pressure suction filtration, the filter cake was washed with a small amount of water, and dried after airing to obtain 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-(4-(piperazin-1- yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (B4, 907 mg, 82%), (ES, m / z): 522.09 [M+H] + .

[0205] Step e: Glycolic acid (306 mg, 4.026 mmol) was added to a solution of 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-(4-(piperazin-4-yl)phenyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide (intermediate B4, 700 mg, 1.342 mmol) and BOP (712 mg, 1.610 mmol) in anhydrous DMF (10 mL), then DIPEA (520 mg, 4.026 mmol) was added dropwise at 0 °C, and the reaction was stirred at room temperature for 4 h. The reaction was added to water (80 mL) and mixed, the mixture was extracted with EA (55 mL x 2), and the combined organic phase was washed with H2O (80 mL), brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was eluted on a silica gel column with 1% (v / v) MeOH-DCM first, and then 2% (v / v) MeOH-DCM, and the product was collected and concentrated to obtain 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-(4-(4-(2- hydroxyacetyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (A, 666 mg, 86%), (ES, m / z): 580.14 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 9.810 (s, 1H), 8.906-8.723 (m, 1H), 8.283-8.229 (m, 1H), 7.623 (s, 1H), 7.343 (s, 1H), 7.210 (s, 2H), 7.061-6.842 (m, 4H), 5.711-5.495 (m, 2H), 4.631 (t, J = 5.4 Hz, 1H), 4.556-4.548 (m, 1H), 4.318-4.225 (m, 1H), 4.150 (d, J = 5.4 Hz, 2H), 3.637 (s, 2H), 3.513 (s, 2H), 3.124-3.106 (m, 4H), 2.957-2.912 (m, 1H).

[0206] Reference Example 1-5:

[0207] Reference: Refer to the preparation process route and operation in WO2019029629A1 and WO2012034095A1 patent documents to prepare compounds D1-D5.

[0208]

[0209]

[0210] Example 0: Preparation of the compound of formula (A) in solid form

[0211] Take the sample of Reference Example 1 (about 50 mg), use an oil pump to extract under heating conditions (50°C) for 3 hours, and obtain a white solid with a purity of 98.6%. IR (KBr, cm-1): 3429.38, 1643.78, 1487.95, 1453.15, 1232.01, 1026.79. See Figure 12 , take the sample for X-ray powder diffraction, which shows amorphous.

[0212] Example 1: Preparation of the compound of formula (A) in crystalline form I

[0213] At room temperature, take the sample of Example 0 (about 20 mg) in a sample bottle, add tetrahydrofuran (0.2 mL) to obtain a clear solution, and gradually add methanol (1.4 mL) dropwise. Stir at room temperature for 1 day, and filter to obtain a solid. Take the sample for X-ray powder diffraction, which shows a crystalline solid (crystalline form I) with good crystallinity. See Figure 1 , and the XRPD diffraction peak data is shown in Table 1.

[0214] Table 1 XRPD diffraction peak data of Example 1 crystalline form I

[0215]

[0216]

[0217] Note: The peaks with relative intensity > 4.0% are listed in the table.

[0218] Example 2: Preparation of Form II of the compound of formula (A)

[0219] An appropriate amount of Form I obtained in Example 1 was dried at 50 °C for 3 hours to obtain a solid. The sample was subjected to X-ray powder diffraction, which showed that it was a crystalline solid (Form II) with good crystallinity, and the spectrum is shown in Figure 2. Figure 2 The XRPD diffraction peak data thereof are shown in Table 2. The sample was subjected to DSC-TGA test, the DSC graph showed that there was an endothermic peak at 58.39 °C and 155.27 °C, respectively, and the TGA graph showed that the sample had a weight loss of 0.1910% between room temperature and 75 °C, as shown in Figure 3. Figure 3 .

[0220] Table 2: XRPD diffraction peak data table of Form II of Example 2

[0221]

[0222] Example 3: Preparation of Form III of the compound of formula (A)

[0223] At room temperature, the sample (about 30 mg) of Example 0 was weighed into a sample bottle, acetonitrile (0.3 mL) was added to prepare a solution, which was stirred at room temperature for 3 days, and then filtered to obtain a solid, which was dried at 50 °C for 3 hours. The sample was subjected to X-ray powder diffraction, which showed that it was a crystalline solid (Form III) with good crystallinity, and the spectrum is shown in Figure 4. Figure 4 The XRPD diffraction peak data thereof are shown in Table 3. The sample was subjected to DSC-TGA test, the DSC graph showed that there was an endothermic peak at 182.29 °C, as shown in Figure 5. Figure 5 .

[0224] Table 3: XRPD diffraction peak data table of Form III of Example 3

[0225] Peak position (2 theta) ° Relative intensity % Peak position (2 theta) ° Relative intensity % Peak position (2 theta) ° Relative intensity % 5.618 100.0 15.802 47.2 19.901 6.7 7.431 5.5 16.272 5.6 23.688 9.9 10.937 8.8 17.053 5.9 23.845 5.4 11.319 8.4 18.428 13.2 13.284 25.5 18.983 9.2

[0226] Note: The peaks with relative intensity > 5.0% are listed in the table.

[0227] Example 4: Preparation of Form IV of the compound of formula (A)

[0228] At room temperature, the sample of Example 0 (about 20 mg) was weighed into a sample bottle, dissolved in tetrahydrofuran (0.2 mL), and isopropanol (1.3 mL) was added dropwise. The mixture was stirred at room temperature for 1 day, and a solid was obtained by filtration. The sample was dried at 50 °C for 3 hours. The sample was subjected to X-ray powder diffraction, and was shown to be a crystalline solid (Form IV) with good crystallinity. The XRPD pattern is shown in Figure 4. Figure 6 The sample was subjected to DSC-TGA tests. The DSC curve showed two endothermic peaks at 64.82 °C and 192.07 °C. The TGA curve showed that the sample lost 1.1526% of weight between room temperature and 75 °C. The DSC and TGA curves are shown in Figure 5. Figure 7 .

[0229] Table 4. XRPD peak data of Form IV of Example 4

[0230] Peak position (2 theta) ° Relative intensity % Peak position (2 theta) ° Relative intensity % Peak position (2 theta) ° Relative intensity % 5.390 11.4 17.184 100.0 23.371 15.2 8.527 97.1 17.897 45.7 24.172 8.7 10.046 59.4 18.994 11.8 25.017 27.2 13.117 16.6 19.463 14.1 25.893 24.3 14.091 3.8 19.958 19.0 26.453 15.6 15.258 7.0 21.259 9.7 29.194 5.4 15.731 20.1 22.052 6.8 16.505 9.0 22.958 10.7

[0231] Note: Peaks with relative intensity > 3.5% were selected for the table.

[0232] Example 5-6: Preparation of Form IV of the compound of Formula (A)

[0233] Using the sample of Example 0, Form IV was also obtained under the conditions listed in Table 5. In Example 5, the preparation method of Example 4 was used as a reference.

[0234] Table 5. Experimental conditions and results of Examples 5-6

[0235]

[0236] Table 6. XRPD peak data of Form IV of Example 5

[0237] Peak position (2 theta) ° Relative intensity % Peak position (2 theta) ° Relative intensity % Peak position (2 theta) ° Relative intensity % 5.479 9.6 17.202 74.6 22.932 11.6 8.573 100.0 17.468 18.6 23.369 13.6 10.066 55.4 17.928 32.2 23.737 14.3 11.527 5.8 18.612 5.3 24.219 8.2 13.129 23.9 19.015 11.3 25.023 34.6 13.999 10.0 19.469 15.4 25.358 20.6 14.229 6.5 19.982 24.8 25.841 22.6 15.144 5.1 21.321 5.5 26.421 11.6 15.692 19.8 22.032 7.0 16.457 8.4 22.493 5.7

[0238] Note: Peaks with relative intensity > 5% were selected for the table.

[0239] Example 7: Preparation of Form V of the compound of Formula (A)

[0240] At room temperature, the sample of Example 0 (about 34 mg) was weighed into a sample bottle, dissolved in acetone (0.5 mL), and stirred at 5 °C for 1 day. A solid was obtained by filtration. The sample was subjected to X-ray powder diffraction, and was shown to be a crystalline solid (Form V) with good crystallinity. The XRPD pattern is shown in Figure 6. Figure 9 The XRPD peak data of Form V of Example 7 is shown in Table 7.

[0241] Table 7. XRPD peak data of Form V of Example 7

[0242] Peak position (2 theta) ° Relative intensity % Peak position (2 theta) ° Relative intensity % Peak position (2 theta) ° Relative intensity % 6.003 100.0 17.582 8.1 23.448 52.5 7.048 12.4 18.190 45.0 23.986 4.1 10.203 4.1 18.526 4.3 24.451 9.9 11.571 4.3 20.247 8.7 25.395 18.4 12.113 7.2 20.578 6.6 26.628 4.3 12.729 42.2 20.783 8.9 28.120 19.5 14.225 9.6 20.954 6.1 28.793 7.1 16.727 27.7 23.228 18.3

[0243] Note: The peaks with relative intensity > 4.0% were selected and listed in the table.

[0244] Example 8: Preparation of Form VI of the compound of formula (A)

[0245] An appropriate amount of Form V obtained in Example 7 was weighed and dried at 50 °C for 3 hours to obtain a solid. The sample was subjected to X-ray powder diffraction, which showed that it was a crystalline solid (Form VI) with good crystallinity, and the spectrum is shown in Figure 8. Figure 10 The XRPD diffraction peak data thereof are shown in Table 8. The sample was subjected to DSC-TGA testing, and the DSC graph showed an endothermic peak at 184.47 °C, and the TGA graph showed that the sample had a weight loss of 0.253% between room temperature and 200 °C, as shown in Figure 9. Figure 11 .

[0246] Table 8 XRPD diffraction peak data of Form VI of Example 8

[0247]

[0248] Note: The peaks with relative intensity > 3.0% were selected and listed in the table.

[0249] Comparative Example 1-2

[0250] An appropriate amount of the sample of Example 0 was weighed, dissolved in tetrahydrofuran to prepare a clear solution of 10 mg / 0.3 mL, and the resulting solution was equally divided into centrifuge tubes, 0.3 mL per tube. Then 0.1 mL of the solvent 2 shown in the table below was added to each tube, which was covered with a film and punctured, and the solvent was evaporated at room temperature.

[0251] Table 9 Experimental conditions and results of Comparative Example 1-2

[0252] Comparative example Solvent 2 Result Comparative example 1 Methanol Gummy Comparative example 2 Acetone Gummy

[0253] Test Example 1: Solid stability experiment of different crystal forms of the compound of formula (A)

[0254] An appropriate amount of Form III of the compound of formula (A) (Example 3) was weighed into a vial, and was placed at high temperature (60 °C, sealed) and accelerated (40 °C / 75% RH, open) for 7 days, respectively. The samples were subjected to purity testing and X-ray powder diffraction, respectively, to investigate the stability of Form III of the compound of formula (A) (Example 3) under different conditions, and the results are shown in Table 10.

[0255] A sample of crystalline Form IV (Example 4) was placed in a vial and subjected to high temperature (60°C, sealed), high humidity (25°C / 92.5% RH, open), and accelerated (40°C / 75% RH, open) conditions for 7 days. The samples were then tested for purity and subjected to X-ray powder diffraction to determine the stability of crystalline Form IV (Example 4) of the compound of Formula (A) under different conditions. The results are shown in Table 11.

[0256] Table 10. Results of solid stability experiments for crystalline Form III

[0257]

[0258] Table 11. Results of solid stability experiments for crystalline Form IV

[0259]

[0260] The data show that crystalline Form III of Example 3 is chemically and crystalline stable under high temperature and accelerated conditions, and that crystalline Form IV of Example 4 is chemically and crystalline stable under high temperature, high humidity, and accelerated conditions.

[0261] Test Example 2: DVS test of different crystalline forms of the compound of Formula (A)

[0262] A sample of crystalline Form III of Example 3 and a sample of crystalline Form IV of Example 4 were placed in a DVS sample chamber and tested. The samples were then subjected to X-ray powder diffraction after the DVS test. The results are shown in Table 12.

[0263] Table 12. Results of DVS tests of different crystalline forms

[0264] Example and initial crystal form Crystal form after DVS Example 3 / crystal form III Crystal form unchanged Example 4 / crystal form IV Crystal form unchanged

[0265] The data show that crystalline Form III and crystalline Form IV remain unchanged after the DVS test.

[0266] Test Example 1: TRK kinase inhibition test

[0267] 1. Procedure:

[0268] 1.1 Kinase reaction:

[0269] Add a gradient of concentrations of test compound, enzyme solution (add kinase buffer (1X kinase buffer (Cisbio, Cat#62EZBFDD), pH 7.5; 5mM MgCl2, 1 mM DTT) to negative control wells) to compound plate, centrifuge 1000 rpm for 30 seconds. Seal plate and incubate plate in a 25°C incubator for 30 minutes. Prepare substrate solution of TK-Sub-biotin (Cisbio, Cat#61TKOBL) and ATP (Sigma, Cat#R0441) and add substrate mix to 384 well plate, centrifuge 1000 rpm for 30 seconds. Seal plate and incubate plate in a 25°C incubator for 60 minutes.

[0270]

[0271]

[0272] 1.2 Kinase assay:

[0273] Dilute, mix and add TK antibody and XL665 to assay plate, centrifuge 1000 rpm for 30 seconds. Seal plate and incubate plate in a 25°C incubator for 60 minutes. Place assay plate on Envision machine for reading. (HTRF 665 / 615 ratio: 665 nm signal value / 615 nm signal value)

[0274] Inhibition = (Ratio 阴性对照孔 - Ratio 化合物孔 ) x 100% 阴性对照孔 无酶对照孔

[0275] 1.3 Data analysis and curve fitting

[0276] Fit data in XLFit excel add-in version 5.4.0.8 to obtain IC 50 values.

[0277] 1.4 QC parameters

[0278] Reference compounds are included in each plate and their IC 50 values are within 3-fold each time.

[0279] 2. Test results: as shown in Table 13

[0280] Table 13 Inhibition activity of different compounds on TRK kinase

[0281]

[0282] ​​Note: RXDX-101, LOXO-195, LOXO-101 are all disclosed compounds and commercially available products (drug or chemical grade products); the compound of formula (A): Preparation Example 1 sample.

[0283] The results show that the compound of formula (A) exhibits high kinase inhibition activity in a variety of kinases, and the activity in TRKA, TRKB, TRKC and TRKC-G696A is better than RXDX-101, LOXO-195 and LOXO-101 or comparable, and the inhibition activity in a variety of mutant drug-resistant kinases (G595R, G667C, G623R) is significantly better than RXDX-101, LOXO-195 and LOXO-101.

[0284] Test Example 2, ALK and ROS1 kinase inhibition test

[0285] 1. Operation steps:

[0286] 1.1 Kinase reaction:

[0287] The compound is diluted with DMSO to a certain concentration and 4-fold gradient dilution. Add a certain concentration of compound, enzyme solution and DMSO in a 384-well plate, incubate at room temperature for 10 min; add the fluorescein-labeled peptide, ATP (sigma, Cat. No.: A7699-1G, Lot No.: 987-65-5) and incubate at 28°C for a certain time; add the stop solution. Read.

[0288] The inhibition rate formula corresponding to a single concentration: inhibition rate = (OD 阴性对照孔 -OD 化合物孔 ) / (OD 阴性对照孔 -OD 无酶对照孔 )×100%

[0289]

[0290] 1.2 Data analysis and curve fitting

[0291] In XLFit excel plug-in version 4.3.1, the data is fitted to obtain IC 50 values, and the results are shown in Table 14.

[0292] Table 14 Inhibition activity of different compounds on ALK and ROS1 kinases

[0293]

[0294] Note: The compound of formula (A): Preparation Example 1 sample.

[0295] The results show that the compound represented by formula (A) has strong inhibitory activity in ROS1 kinase, is significantly better than RXDX-101 and LOXO-101, and is better than LOXO-195; has good inhibitory activity on ALK kinase, and is significantly better than LOXO-101 and LOXO-195.

[0296] Test Example 3, in vitro cell inhibition test

[0297] 1. Cell line

[0298] 6 test cell lines: Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.

[0299] Cell type: murine B cells

[0300] Culture medium: RPMI-1640 + 10% FBS

[0301] 2. Test method

[0302] Harvest cells in the logarithmic growth phase and count the cells using a platelet counter. A certain density of cell suspension is uniformly inoculated in a 96-well plate, 100 μL per well, shaken to uniformly disperse into the well; 100 μL of drug solution with a certain concentration gradient is added to each well, three replicate wells are set for each drug concentration; 37°C CO2 incubator for 72 hours; add MTT working solution (5 mg / mL), 20 μL per well; 37°C for 4 hours; plate centrifuge 1000 rpm / min for 5 min, aspirate 180 μL of culture medium, then add 150 μL of DMSO, shake well with a microplate shaker, wipe the bottom of the plate clean, and detect the optical density value (OD) at 550 nm with a microplate reader.

[0303] 3. Data analysis

[0304] Inhibition rate = (control well OD - test well OD) / (control well OD - blank well OD) * 100%, according to the inhibition rate of each concentration, the half inhibitory concentration IC value is calculated by SPSS software. 50

[0305] 4. Test results: the results are shown in Table 15:

[0306] Table 15 Inhibition activity of different compounds on different cell lines

[0307]

[0308]

[0309] Note: the compound represented by formula (A): preparation example 1 sample.

[0310] Table 16 Inhibition activity of control compounds on different cell lines​

[0311]

[0312] Results show that the compound represented by formula (A) in the present application has better in vitro cell activity in various wild type and mutant drug-resistant cell lines, and is significantly better than RXDX-101, LOXO-195, LOXO-101 and prior art compounds D1-D5.

[0313] Test Example 4: Study on the in vivo mechanism of the compound represented by formula (A)

[0314] 1. Test method

[0315] 1.1 Model preparation:

[0316] Take the mutant drug-resistant cells Ba / F3 LMNA-NTRK1-G595R in the logarithmic growth phase, collect and resuspend in serum-free medium to make the cell concentration 6x10 7 -10x10 7 individuals / mL, and add an equal volume of Matrigel to the cell suspension to make the final concentration of cells 3x10 7 -5x10 7 individuals / mL. Inoculate 0.1 mL of tumor cell suspension subcutaneously in the front limb armpit of NuNu mice (Beijing Weitong Lihua, 4-6 weeks, female) at an inoculation amount of 3x10 6 -5x10 6 individuals per mouse to prepare animal models.

[0317] 1.2 Test grouping:

[0318] Measure the maximum tumor diameter and minimum tumor diameter of the transplanted tumor of the nude mice with a vernier caliper, and calculate the tumor volume: the calculation formula of the tumor volume (Tumor volume, TV) is: V=1 / 2x a x b 2 , where a and b represent the maximum diameter and minimum diameter of the tumor mass, respectively. Select nude mice with appropriate tumor volume, and evenly divide the animals into 7 groups (200-300 mm 3 ) according to the tumor volume by random number method, 3 mice per group.

[0319] 1.3 Drug administration

[0320] Gavage administration according to the body weight of the animals, the administration volume is 10 ml / kg, and the compound represented by formula (A) is configured into the required administration concentration using “3% DMSO+96% HP-β-CD (0.5 g / mL)+1% HCl”.

[0321] Control group, a total of three, 4h after administration of the solvent tumor tissue frozen. Other groups were given 100mg / kg of the compound shown in formula (A), respectively, in 0h, 1h, 4h, 8h, 12h and 24h tumor tissue frozen.

[0322] 1.4 Protein extraction and quantification

[0323] A certain mass of tumor tissue was added to the corresponding volume of protein lysis solution (RIPA lysis solution (ThermoFisher, item number 89900): protease inhibitor (cOmplete, Mini, EDTA-free, EASYpack; Roche, item number 04693159001): phosphatase inhibitor (PhosStop, EASY pack; Roche, item number 04906837001) = 8:1:1), homogenized, and lysed in an ice bath for 30 min. Low-temperature high-speed centrifugation, and the supernatant was subjected to BCA protein quantification (according to the BCA protein quantification kit (Tiangen, item number: #PA115-01) operation). Finally, the protein concentration was adjusted to a uniform concentration, and the loading buffer was added, and boiled at 100°C for 10 min.

[0324] 1.5 Western-blot

[0325] 4-20% 10-hole prefabricated gel was used; loading amount 100μg; 140V electrophoresis 1-1.5h; 300mA wet transfer 1.5h-2h; 5% BSA blocking 2-3h; primary antibody 4℃ incubation overnight (Trk 1:5000, p-Trk, PLCγ1, p-PLCγ1, AKT, p-AKT, actin 1:1000); 4x5min 0.1% TBST washing; secondary antibody incubation at room temperature for 2h (1:5000), ECL luminescence, exposure.

[0326]

[0327] 2. Test results: as shown in Figure 13 .

[0328] From the test results, with the extension of time, Figure 13 TRK, p-TRK, p-PLCγ1 and p-AKT were significantly reduced, which proved that the compound shown in formula (A) could significantly reduce the protein level of TRK and p-TRK, and then effectively inhibit the phosphorylation of p-PLCγ1 / PLCγ1 and p-AKT / AKT, to regulate cell growth and proliferation.

[0329] Test example 5: in vivo pharmacodynamic experiment of the compound on NTRK mutant drug-resistant tumor model

[0330] Test method

[0331] 1.1 Model preparation

[0332] Take the cells in the logarithmic growth phase, collect, resuspend in serum-free medium, make the cell concentration 6x10 7 -10x10 7 Individual, prepare animal models. 7 -5x10 7 Individual, prepare animal models. 6 -5x10 6 Individual, prepare animal models.

[0333] 1.2 Test grouping

[0334] The maximum tumor diameter and minimum tumor diameter of the nude mouse transplanted tumor were measured with a vernier caliper, and the tumor volume was calculated: the formula for calculating the tumor volume (Tumor volume, TV) was: V=1 / 2x a x b 2 , where a and b represent the maximum diameter and minimum diameter of the tumor mass, respectively. Select nude mice with appropriate tumor volume, and evenly divide the animals into 7 groups (100-200mm 3 ) according to tumor volume using random number method, 6 in each group.

[0335] 1.3 Observation index

[0336] Gavage administration according to animal body weight from the grouping day, the administration volume was 10mL / kg, LOXO-195 was configured into the required administration solution using 0.5% CMC-Na, and the compound shown in formula (A) was configured into the required administration solution using "3% DMSO+96% HP-β-CD (0.5g / mL)+1%HCl". Tumor diameter was measured twice a week, and tumor volume was calculated. The specific indexes are as follows:

[0337] Animal body weight: the animals were weighed before administration in the morning every day, and a body weight reduction of more than 20% was defined as a toxic reaction of the drug (observed until the day after the last administration);

[0338] Tumor volume (Tumor volume, TV) = V=1 / 2x a x b 2 , where a and b represent the maximum diameter and minimum diameter of the tumor mass, respectively (observed until the day after the last administration);

[0339] Relative tumor proliferation rate T / C (%): T / C (%) = TRTV / CRTV x 100% (TRTV: RTV of the administration group, CRTV: RTV of the control group);

[0340] Tumor growth inhibition rate (TGI) = [1-(Ti-T0) / (Vi-V0)]x100%. (wherein Ti represents the average tumor volume of a certain day in a certain administration group; T0 is the average tumor volume at the beginning of administration in this administration group; Vi is the average tumor volume of the solvent control group on a certain day (the same day as Ti); V0 is the average tumor volume of the solvent control group at the beginning of administration);

[0341] Tumor inhibition rate: at the end of the experiment, the animals were sacrificed by decapitation, the tumor mass was peeled off and weighed, photographed, and the tumor inhibition rate was calculated, tumor inhibition rate = (average tumor weight of the control group-average tumor weight of the administration group) / average tumor weight of the control group x 100%.

[0342] Test results

[0343] 2.1 Ba / F3 LMNA-NTRK1-G667C model

[0344] 2.1.1 Effect of drugs on the body weight of tumor-bearing mice

[0345] The body weight of each compound in each dose group had an upward trend, and the upward trend was more obvious than that of the control group. The body weight of each compound in each dose group increased significantly, which may be related to the compound, or due to the inhibition of tumor growth, the state of the mice was better, and the body weight increased significantly. The results are shown in Table 17.

[0346] 2.1.2 Effect of drugs on the tumor weight and tumor inhibition rate of tumor-bearing mice

[0347] The data results show that: compared with LOXO-195, the compound represented by formula (A) has more significant inhibition on tumor growth under the same administration dose (100 mg / kg); further, compared with the LOXO-195 group with a higher administration dose (200 mg / kg), the compound represented by formula (A) (100 mg / kg) also shows better tumor inhibition effect. The results are shown in Table 17.

[0348] Table 17 In vivo results of Ba / F3 LMNA-NTRK1-G667C model

[0349]

[0350]

[0351] 2.2 Ba / F3 LMNA-NTRK1-G595R model

[0352] 2.2.1 Effect of drugs on the body weight of tumor-bearing mice

[0353] The weight of each compound in each dose group had an upward trend, and the upward trend was more obvious than that of the control group. The weight of each compound in each dose group increased significantly, which may be related to the compound, or due to the inhibition of tumor growth, making the mice in better condition, and the weight gain was obvious. The results are shown in Table 17.

[0354] 2.2.2 Effect of drugs on tumor weight and tumor inhibition rate of tumor-bearing mice

[0355] The data results show that: compared with LOXO-195 (100 mg / kg), the compound represented by formula (A) can achieve significant inhibition of tumor tissue weight at a lower administration dose (50 mg / kg), and the tumor weight inhibition rate is > 90%. The results are shown in Table 18.

[0356] Table 18 Ba / F3 LMNA-NTRK1-G595R model in vivo results

[0357]

[0358] Although the foregoing application has been described in some detail for purposes of clarity and understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the teachings of the present application. Accordingly, the foregoing description is to be regarded as illustrative rather than restrictive.

Claims

1. A crystalline form I of a compound of formula (A), characterized in that The crystalline form I has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 8.9±0.2°, 9.2±0.2°, 10.1±0.2°, 17.9±0.2°, 18.5±0.2°, 23.8±0.2°, 28.0±0.2°.

2. The crystalline Form I of the compound of Formula (A) according to claim 1, characterized in that, The crystalline form I has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 8.9±0.2°, 9.2±0.2°, 10.1±0.2°, 16.1±0.2°, 17.9±0.2°, 18.5±0.2°, 23.8±0.2°, 27.0±0.2°, 28.0±0.2°.

3. The crystalline Form I of the compound of Formula (A) according to claim 1, characterized in that, The crystalline form I has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 8.9±0.2°, 9.2±0.2°, 10.1±0.2°, 16.1±0.2°, 16.6±0.2°, 17.9±0.2°, 18.5±0.2°, 23.8±0.2°, 27.0±0.2°, 28.0±0.2°.

4. The crystalline Form I of the compound of Formula (A) according to claim 1, characterized in that, The crystalline form I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

5. A crystalline form II of a compound of formula (A), characterized in that The crystalline form II has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 6.4±0.2°，9.1±0.2°，18.3±0.2°，18.9±0.2°，20.6±0.2°，22.4±0.2°，23.9±0.2°，27.7±0.2°。 6. The crystalline Form II of the compound of formula (A) according to claim 5, characterized in that, The crystalline form II has an X-ray powder diffraction pattern substantially as shown in Figure 2.

7. The crystalline Form II of the compound of formula (A) according to claim 5, characterized in that, The crystalline form II has a differential scanning calorimetry curve with an endothermic peak at 155.27±5°C.

8. The crystalline Form II of the compound of Formula (A) according to claim 7, characterized in that, The crystalline form II has a DSC pattern substantially as shown in Figure 3.

9. A crystalline form III of a compound of formula (A), characterized in that The crystalline form III has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 5.6±0.2°，10.9±0.2°，13.3±0.2°，15.8±0.2°，18.4±0.2°，19.0±0.2°，23.7±0.2°。 10. The crystalline Form III of the compound of formula (A) according to claim 9, characterized in that, The crystalline form III has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 5.6±0.2°, 10.9±0.2°, 11.3±0.2°, 13.3±0.2°, 15.8±0.2°，17.1±0.2°，18.4±0.2°，19.0±0.2°，23.7±0.2°。 11. The crystalline Form III of the compound of formula (A) according to claim 9, characterized in that, The crystalline form III has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 5.6±0.2°, 10.9±0.2°, 11.3±0.2°, 13.3±0.2°, 15.8±0.2°，17.1±0.2°，18.4±0.2°，19.0±0.2°，19.9±0.2°，23.7±0.2°。 12. The crystalline Form III of the compound of formula (A) according to claim 9, characterized in that, The crystalline form III has an X-ray powder diffraction pattern substantially as shown in Figure 4.

13. The crystalline Form III of the compound of Formula (A) according to claim 9, characterized in that, The crystalline form III has a differential scanning calorimetry curve with an endothermic peak at 182.29±5°C.

14. The crystalline Form III of the compound of formula (A) according to claim 13, characterized in that, The crystalline form III has a DSC pattern substantially as shown in Figure 5.

15. A crystalline form IV of a compound of formula (A), characterized in that The crystalline form IV has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 8.5±0.2°，10.0±0.2°，13.1±0.2°，17.2±0.2°，17.9±0.2°，20.0±0.2°，25.0±0.2°。 16. The crystalline Form IV of the compound of Formula (A) according to claim 15, characterized in that, The crystal form IV has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 8.5±0.2°, 10.0±0.2°, 13.1±0.2°, 15.7±0.2°, 17.2±0.2°，17.9±0.2°，20.0±0.2°，25.0±0.2°，25.9±0.2°。 17. The crystalline Form IV of the compound of Formula (A) according to claim 15, characterized in that, The crystal form IV has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 8.5±0.2°, 10.0±0.2°, 13.1±0.2°, 15.7±0.2°, 17.2±0.2°，17.9±0.2°，19.5±0.2°，20.0±0.2°，25.0±0.2°，25.9±0.2°。 18. The crystalline Form IV of the compound of Formula (A) according to claim 15, characterized in that, The crystal form IV has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 5.5±0.2°, 8.5±0.2°, 10.0±0.2°, 13.1±0.2°, 14.0±0.2°，15.7±0.2°，17.2±0.2°，17.9±0.2°，19.5±0.2°，20.0±0.2°，25.0±0.2°，25.9±0.2°。 19. The crystalline Form IV of the compound of Formula (A) according to claim 15, characterized in that, The crystal form IV has an X-ray powder diffraction pattern substantially as shown in Figure 6 or Figure 8.

20. The crystalline Form IV of the compound of Formula (A) according to claim 15, characterized in that, The crystal form IV has a differential scanning calorimetry curve with an endothermic peak at 192.07±5 °C.

21. The crystalline Form IV of the compound of Formula (A) according to claim 20, characterized in that, The crystal form IV has a DSC pattern substantially as shown in Figure 7.

22. A crystal form V of the compound of formula (A), characterized in that The crystal form V has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 6.0±0.2°，12.7±0.2°，16.7±0.2°，18.2±0.2°，23.4±0.2°，25.4±0.2°，28.1±0.2°。 23. The crystalline Form V of the compound of Formula (A) according to claim 22, characterized in that, The crystal form V has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 6.0±0.2°, 7.0±0.2°, 12.7±0.2°, 14.2±0.2°, 16.7±0.2°，18.2±0.2°，23.4±0.2°，24.5±0.2°，25.4±0.2°，28.1±0.2°。 24. The crystalline Form V of the compound of Formula (A) according to claim 22, characterized in that, The crystal form V has an X-ray powder diffraction pattern substantially as shown in Figure 9.

25. A crystal form VI of the compound of formula (A), characterized in that, The crystal form VI has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 6.1±0.2°, 7.4±0.2°，11.5±0.2°，16.9±0.2°，18.6±0.2°，19.4±0.2°，22.3±0.2°，25.3±0.2°。 26. The crystalline Form VI of the compound of Formula (A) according to claim 25, characterized in that, The crystal form VI has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at the following 2Θ angles: 6.1±0.2°, 7.4±0.2°, 11.5±0.2°, 16.9±0.2°, 18.6±0.2°，19.4±0.2°，20.1±0.2°，22.3±0.2°，25.3±0.2°，28.6±0.2°。 27. The crystalline Form VI of the compound according to claim 25 of formula (A), which is characterized in that, The crystal form VI has an X-ray powder diffraction pattern substantially as shown in Figure 10.

28. A pharmaceutical composition comprising one or more of the crystal form I of any one of claims 1-4, the crystal form II of any one of claims 5-8, the crystal form III of any one of claims 9-14, the crystal form IV of any one of claims 15-21, the crystal form V of any one of claims 22-24, the crystal form VI of any one of claims 25-27.

29. The pharmaceutical composition of claim 28, further comprising a pharmaceutically acceptable carrier.

30. Use of the crystalline Form I of any one of claims 1-4, the crystalline Form II of any one of claims 5-8, the crystalline Form III of any one of claims 9-14, the crystalline Form IV of any one of claims 15-21, the crystalline Form V of any one of claims 22-24, the crystalline Form VI of any one of claims 25-27, or the pharmaceutical composition of claim 28 or 29 in the manufacture of a medicament for the prevention and / or treatment of a disease mediated by one or more of TRK, ROS1, or ALK, wherein, The disease is a tumor.

31. Use according to claim 30, characterized in that, The disease involves one or more of the genes, proteins, or their expression, activity or level of TRK, ALK, ROS1.

32. The use according to claim 30, characterized in that, The disease involves one or more of the gene fusion, amplification, rearrangement, mutation or overexpression of NTRK, ALK, ROS1.

33. The use according to claim 30, characterized in that, The disease involves one or more of the gene fusion or mutation of NTRK, ALK, ROS1.

34. The use according to claim 30, characterized in that, The TRK-mediated disease is a solid tumor.

35. Use according to claim 34, characterized in that, The solid tumor is lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioblastoma, colorectal cancer, melanoma, cancer of the head and neck, gallbladder cancer, thyroid cancer, malignant glioma, gastric cancer, neuroblastoma, or salivary gland cancer.

36. Use according to claim 35, characterized in that, The lung cancer is non-small cell lung cancer.

37. The use according to any one of claims 34-36, characterized in that, The TRK-mediated disease is selected from a disease mediated by one, two, or three of TRKA, TRKB, or TRKC.

38. The use according to any one of claims 34-36, characterized in that, The disease involves a dysregulation of a gene, a protein, or an expression, an activity, or a level of TRK.

39. The use according to any one of claims 34-36, characterized in that, The disease involves a gene fusion, amplification, rearrangement, mutation, or overexpression of NTRK.

40. The use according to any one of claims 34-36, characterized in that, The disease involves a gene fusion or mutation of NTRK.

41. Use according to claim 30 or 34, characterized in that, The TRK-mediated disease is a solid tumor that is positive for NTRK gene rearrangement / fusion and / or resistance mutation.

42. The use according to claim 41, characterized in that The NTRK resistance mutation is NTRK1-G595R, NTRK1-G667C, NTRK3 G623R, or NTRK3-G696A.

43. The use of claim 30, wherein, The ROS1-mediated disease is a solid tumor.

44. The use according to claim 43, characterized in that The solid tumor is lung cancer, colorectal cancer, thyroid cancer, malignant glioma, or ovarian cancer.

45. The use according to claim 44, characterized in that The lung cancer is non-small cell lung cancer.

46. The use according to any one of claims 43-45, characterized in that, The disease involves a dysregulation of a gene, a protein, or an expression, an activity, or a level of ROS1.

47. The use according to any one of claims 43-45, characterized in that, The disease involves a gene fusion, amplification, rearrangement, mutation, or overexpression of ROS1.

48. The use of claim 30 or 43, wherein, The ROS1-mediated disease is a solid tumor that is positive for ROS1 gene rearrangement / fusion and / or resistance mutation, and the solid tumor is non-small cell lung cancer.

49. The use of claim 30, wherein, The ALK-mediated disease is a solid tumor.

50. The use according to claim 49, characterized in that The disease is non-small cell lung cancer.

51. Use according to claim 49 or 50, characterized in that The disease involves a dysregulation of a gene, a protein, or an expression, an activity, or a level of ALK.

52. Use according to claim 49 or 50, characterized in that, The disease involves a gene fusion, amplification, rearrangement, mutation, or overexpression of ALK.

Images