WO2023083356A1 - Nitrogen fused-heterocyclic amide compound in solid form and use thereof - Google Patents

Abstract

Provided are a compound represented by formula (A) in a solid form, a compound represented by formula (A) in a crystalline form, a specific crystal form thereof, a pharmaceutical composition containing same, and the use thereof. The compound represented by formula (A) in the crystalline form and the specific crystal form thereof have a good crystallinity and stability, and the in-vivo and in-vitro drug efficacies show that the compound represented by formula (A) has a good inhibition effect on wild type and mutant kinases, cells and in-vivo tumors, and also has a good drug formation potential.

Description

Aza-condensed cyclic amides in solid form and uses thereof

This application claims to enjoy the patent of the previous application submitted by the applicant to the State Intellectual Property Office of China on November 15, 2021, the patent application number is 202111345026.6, and the invention title is "Aza-condensed cyclic amides in solid form and their uses". priority. The entirety of this prior application is incorporated by reference into the present application.

technical field

The present application relates to the field of medicine, in particular to aza-condensed cyclic amide compounds in solid form, aza-fused cyclic amide compounds in crystalline form and their specific crystal forms, pharmaceutical compositions containing them and their preparation as preventive and/or Use in medicine for treating diseases mediated by one or more of TRK, ROS1, and ALK.

Background technique

Tropomyosin-related kinase or Tropomyosin receptor kinase (TRK) is a kind of nerve growth factor receptor, and its family consists of three highly homologous TRKA, TRKB and TRKC isoforms, encoded by the neurotrophic receptor tyrosine kinase 1 (NTRK1), NTRK2, and NTRK3 genes, respectively. When the TRK receptor protein binds to the corresponding ligand, it can activate downstream signaling pathways, such as RAS/MAPK pathway, PLCγ pathway and PI3K pathway, to achieve different physiological functions. TRK family proteins are mainly expressed in nerve tissue under normal conditions, 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.

TRK kinases are activated in malignancies through multiple mechanisms, mainly structural rearrangements and changes in expression. For example, NTRK, the encoding gene of TRK kinase, is rearranged with other genes to produce a fusion oncogene, which leads to changes in the structure and expression of TRK kinase, which is no longer regulated and controlled by nerve growth factor ligands, and constitutively activated to promote Tumors develop. In addition, gene sequencing results also show that TRK kinase is closely related to the occurrence, metastasis and deterioration of various tumors, and is expressed in many tumors, such as non-small cell lung cancer, colorectal cancer, melanoma, gallbladder cancer, thyroid cancer carcinoma, malignant glioma, etc.

Currently, the first-generation TRK inhibitors Larotrectinib (LOXO-101) and Entrectinib (RXDX-101) were approved by the US Food and Drug Administration (FDA) in 2018 and 2019, respectively. Larotrectinib is a potent, oral, and selective tropomyosin receptor kinase inhibitor. Its efficacy data have been announced as early as the ASCO meeting in June 2017. In Phase I and Phase II clinical trials, a total of Of the 55 subjects, 46 of them were evaluable with 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 phase I clinical trials, the ORR of 24 evaluable patients was 79%.

Similar to other targeted drugs, TRK inhibitors also face the problem of drug resistance. Mutations in the kinase domain of NTRK can cause changes in the conformation of the kinase domain of TRK family proteins or changes in their binding affinity with ATP, thereby affecting the binding of TRK inhibitors to targets. The types of mutations include G595R, G639R, G667C, etc. In order to solve the drug resistance problem of the first-generation TRK inhibitors, the second-generation TRK inhibitors such as LOXO-195 and TPX-005 have been studied.

Contents of the invention

In one aspect, the present application provides a compound represented by formula (A) in solid form.

In some schemes of the present application, the above-mentioned compound represented by formula (A) in solid form can be measured by infrared spectroscopy by tablet method, and its infrared spectrum includes characteristic peaks (±4cm ^-1 ) at the following positions: 3429, 1643, 1488, 1453, 1232, 1027.

In some schemes of the present application, the compound represented by the formula (A) in solid form has an infrared spectrum substantially as shown in FIG. 12 .

In some schemes of the present application, the above-mentioned compound represented by formula (A) in solid form can be tested by X-ray powder diffraction method.

In some schemes of the present application, the compound represented by formula (A) in the above solid form has a chemical purity of ≥95%; preferably, it has a chemical purity of ≥97%; further preferably, it has a chemical purity of ≥98%. chemical purity.

In some schemes of the present application, the compound represented by the formula (A) in solid form above is amorphous, and it has an infrared spectrum substantially as shown in FIG. 12 by using Cu-Kα radiation.

In another aspect, the present application provides a compound represented by formula (A) in crystalline form.

On the other hand, the application provides the crystal form I of the compound represented by formula (A), using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 9.2, 17.9, 18.5.

In some schemes of the present application, the above crystal form I uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.9, 9.2, 17.9, 18.5, 23.8.

In some schemes of the present application, the above crystal form I uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.9, 9.2, 10.1, 17.9, 18.5, 23.8, 28.0.

In some schemes of the present application, the above crystal form I uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.9, 9.2, 10.1, 16.1, 17.9, 18.5, 23.8, 27.0, 28.0.

In some schemes of the present application, the above crystal form I uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.9, 9.2, 10.1, 16.1, 16.6, 17.9, 18.5, 23.8, 27.0, 28.0.

In some solutions of the present application, the above-mentioned crystal form I, using Cu-Kα radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .

On the other hand, the application provides the crystal form II of the compound represented by formula (A), using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 9.1, 18.3, 20.6.

In some schemes of the present application, the above crystal form II, using Cu-Kα radiation, has characteristic diffraction peaks (±0.2°) in the following 2θ angles in its X-ray powder diffraction pattern: 6.4, 9.1, 18.3, 20.6.

In some schemes of the present application, the above crystal form II uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.4, 9.1, 18.3, 20.6, 27.7.

In some schemes of the present application, the above crystal form II uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.4, 9.1, 18.3, 18.9, 20.6, 27.7.

In some schemes of the present application, the above crystal form II uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.4, 9.1, 18.3, 18.9, 20.6, 22.4, 23.9, 27.7.

In some solutions of the present application, the above-mentioned crystal form II, using Cu-Kα radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 2 .

In some aspects of the present application, the differential scanning calorimetry curve of the above crystal form II has an endothermic peak at 155.27±5°C.

In some aspects of the present application, the differential scanning calorimetry curve of the above crystal form II has endothermic peaks at 58.39±5°C and 155.27±5°C.

In some solutions of the present application, the above-mentioned crystal form II has a DSC spectrum substantially as shown in FIG. 3 .

In some aspects of the present application, the thermogravimetric analysis curve of the above crystal form II has a weight loss of 0.1910%±0.2% between room temperature and 75±5°C.

In some solutions of the present application, the above-mentioned crystal form II has a TGA spectrum substantially as shown in FIG. 3 .

On the other hand, the application provides crystal form III of formula (A), using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 13.3, 15.8 , 18.4.

In some schemes of the present application, the above-mentioned crystal form III uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 13.3, 15.8, 18.4, 23.7.

In some schemes of the present application, the above crystal form III uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 10.9, 13.3, 15.8, 18.4, 19.0, 23.7.

In some schemes of the present application, the above crystal form III uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 10.9, 11.3, 13.3, 15.8, 17.1, 18.4, 19.0, 23.7.

In some schemes of the present application, the above crystal form III uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 10.9, 11.3, 13.3, 15.8, 17.1, 18.4, 19.0, 19.9, 23.7.

In some schemes of the present application, the above crystal form III uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 7.4, 10.9, 11.3, 13.3, 15.8, 17.1, 18.4, 19.0, 19.9, 23.7.

In some solutions of the present application, the above-mentioned crystal form III, using Cu-Kα radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .

In some aspects of the present application, the differential scanning calorimetry curve of the above crystal form III has an endothermic peak at 182.29±5°C.

In some solutions of the present application, the above-mentioned crystal form III has a DSC spectrum substantially as shown in FIG. 5 .

On the other hand, the application provides the crystal form IV of the compound represented by formula (A), using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.5, 10.0, 17.2, 17.9.

In some schemes of the present application, the above crystal form IV uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.5, 10.0, 13.1, 17.2, 17.9, 25.0.

In some schemes of the present application, the above crystal form IV uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.5, 10.0, 13.1, 17.2, 17.9, 20.0, 25.0.

In some schemes of the present application, the above crystal form IV uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.5, 10.0, 13.1, 15.7, 17.2, 17.9, 20.0, 25.0, 25.9.

In some schemes of the present application, the above crystal form IV uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.5, 10.0, 13.1, 15.7, 17.2, 17.9, 19.5, 20.0, 25.0, 25.9.

In some schemes of the present application, the above crystal form IV uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ 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.

In some schemes of the present application, the above crystal form IV uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ 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.

In some schemes of the present application, the above crystal form IV uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ 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.

In some schemes of the present application, the above crystal form IV uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ 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, 23.4, 23.7, 25.0, 25.9, 26.4.

In some solutions of the present application, the above crystal form IV, using Cu-Kα radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 6 or FIG. 8 .

In some aspects of the present application, the differential scanning calorimetry curve of the above crystal form IV has an endothermic peak at 192.07±5°C.

In some aspects of the present application, the differential scanning calorimetry curve of the above crystal form IV has endothermic peaks at 64.82±5°C and 192.07±5°C.

In some solutions of the present application, the above crystal form IV has a DSC spectrum substantially as shown in FIG. 7 .

In some aspects of the present application, the thermogravimetric analysis curve of the above crystal form IV has a weight loss of 1.1526%±0.2% between room temperature and 75±5°C.

In some solutions of the present application, the above crystal form IV has a TGA spectrum substantially as shown in FIG. 7 .

On the other hand, the application provides the crystal form V of the compound represented by formula (A), using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 12.7, 18.2.

In some schemes of the present application, the above crystal form V uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 12.7, 18.2, 23.4.

In some schemes of the present application, the above crystal form V uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 12.7, 16.7, 18.2, 23.4.

In some schemes of the present application, the above crystal form V uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 12.7, 16.7, 18.2, 23.4, 25.4, 28.1.

In some schemes of the present application, the above crystal form V uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 7.0, 12.7, 14.2, 16.7, 18.2, 23.4, 25.4, 28.1.

In some schemes of the present application, the above crystal form V uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 7.0, 12.7, 14.2, 16.7, 18.2, 23.4, 24.5, 25.4, 28.1.

In some schemes of the present application, the above crystal form V uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 7.0, 12.1, 12.7, 14.2, 16.7, 17.6, 18.2, 23.4, 24.5, 25.4, 28.1.

In some schemes of the present application, the above crystal form V uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 7.0, 12.1, 12.7, 14.2, 16.7, 17.6, 18.2, 20.2, 23.4, 24.5, 25.4, 28.1, 28.8.

In some solutions of the present application, the above-mentioned crystal form V, using Cu-Kα radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .

On the other hand, the application provides the crystal form VI of the compound represented by formula (A), using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 16.9, 22.3.

In some schemes of the present application, the above crystal form VI uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 16.9, 18.6, 22.3.

In some schemes of the present application, the above crystal form VI uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 7.4, 11.5, 16.9, 18.6, 22.3.

In some schemes of the present application, the above crystal form VI uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 7.4, 11.5, 16.9, 18.6, 19.4, 22.3, 25.3.

In some schemes of the present application, the above crystal form VI uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 7.4, 11.5, 16.9, 18.6, 19.4, 20.1, 22.3, 25.3, 28.6.

In some schemes of the present application, the above crystal form VI uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 7.4, 11.5, 16.9, 18.6, 19.4, 20.1, 22.3, 22.8, 23.2, 25.3, 28.6.

In some schemes of the present application, the above crystal form VI uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 7.4, 11.5, 16.9, 18.6, 19.4, 20.1, 22.3, 22.8, 23.2, 25.3, 26.7, 28.6.

In some solutions of the present application, the above crystal form VI, using Cu-Kα radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .

In some aspects of the present application, the differential scanning calorimetry curve of the above crystal form VI has an endothermic peak at 184.47±5°C.

In some solutions of the present application, the above crystal form VI has a DSC spectrum substantially as shown in FIG. 11 .

In some aspects of the present application, the thermogravimetric analysis curve of the above crystal form VI has a weight loss of 0.253%±0.2% between room temperature and 200°C±5°C.

In some solutions of the present application, the above crystal form VI has a TGA spectrum substantially as shown in FIG. 11 .

In another aspect, the present application provides a crystalline composition, comprising one or more of the crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI of the compound of formula (A) kind.

In some embodiments of the present application, the crystal form II accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% of the weight of the crystalline composition.

In some solutions of the present application, the crystal form III accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% of the weight of the crystalline composition.

In some embodiments of the present application, the crystal form IV accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% of the weight of the crystalline composition.

In some embodiments of the present application, the crystal form VI accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% of the weight of the crystalline composition.

In another aspect, the present application provides a pharmaceutical composition, comprising the compound represented by formula (A) in solid form, the compound represented by formula (A) in crystalline form or the above crystalline composition.

In some schemes of the present application, the above-mentioned pharmaceutical composition comprises one or more of the crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI of the compound represented by formula (A). kind.

On the other hand, the present application also provides a pharmaceutical composition, comprising the compound represented by formula (A) in solid form, the compound represented by formula (A) in crystalline form or the above crystalline composition, and a pharmaceutically acceptable carrier .

In some schemes of the present application, the above-mentioned pharmaceutical composition comprises one or more of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI of the compound of formula (A), and a pharmaceutically acceptable carrier.

On the other hand, the present application provides the compound represented by formula (A) in the above solid form, the compound represented by formula (A) in crystalline form, the above crystal composition, crystal form I and crystal form of the compound represented by formula (A) Application of II, crystal form III, crystal form IV, crystal form V or crystal form VI or the above-mentioned pharmaceutical composition as a medicine or in the preparation of a medicine.

In some aspects of the present application, the drug is used to treat pain diseases, cell proliferation diseases, inflammatory diseases, neurodegenerative diseases or infectious diseases.

In some aspects of the present application, the drug is used to prevent and/or treat diseases mediated by one or more of TRK, ROS1 or ALK.

In some schemes of the present application, the drug is used to prevent and/or treat NTRK gene rearrangement/fusion and/or drug-resistant mutation-positive tumors, or ROS1 gene rearrangement/fusion and/or drug-resistant mutation-positive tumors; Preferably, the tumor is a solid tumor or a blood tumor; further preferably, the tumor is a solid tumor.

In some schemes of the present 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.

On the other hand, the present application also provides the compound represented by the formula (A) in solid form, the compound represented by the formula (A) in crystal form, the above crystal composition, the crystal form I and crystal form of the compound represented by the formula (A). Form II, crystalline form III, crystalline form IV, crystalline form V or crystalline form VI or the above pharmaceutical composition is used for preventing and/or treating diseases mediated by one or more of TRK, ROS1 or ALK.

On the other hand, the present application also provides a method for preventing and/or treating diseases mediated by one or more of TRK, ROS1 or ALK, comprising: administering to a patient a therapeutically effective amount of the above solid form of formula ( The compound shown in A), the compound shown in formula (A) in crystalline form, the above-mentioned crystalline composition, the crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V or crystal form of the compound shown in formula (A) Crystal form VI or the above pharmaceutical composition.

In some schemes of the present application, the above-mentioned 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 blood tumor; further preferably, the tumor is a solid tumor.

In some schemes of the present 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.

In some aspects of the present application, the above diseases are selected from pain diseases, cell proliferative diseases, inflammatory diseases, neurodegenerative diseases or infectious diseases.

In one embodiment, the above TRK-mediated disease is selected from diseases mediated by one, two or three of TRKA, TRKB or TRKC.

In one embodiment, the above-mentioned disease involves NTRK gene, TRK protein, or their expression, activity or level disorder; preferably, involves NTRK gene fusion, amplification, rearrangement, mutation or high expression; further preferably, involves NTRK Gene rearrangement/fusion or mutation.

In some schemes of the present application, the NTRK 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.

In one embodiment, the above-mentioned disease involves ROS1 gene, ROS1 protein, or their expression, activity or level imbalance; preferably, involves ROS1 gene fusion, amplification, rearrangement, mutation or high expression; more preferably, involves ROS1 Gene rearrangement/fusion or mutation.

In one embodiment, the above-mentioned disease involves one or more genes, proteins, or their expression, activity or level of TRK, ALK, ROS1; preferably involves one or more genes in NTRK, ALK, ROS1 Fusion, amplification, rearrangement, mutation or high expression; further preferably gene fusion or mutation involving one or more of NTRK, ALK and ROS1.

In one embodiment, the aforementioned cell proliferative disease is a tumor or cancer.

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 ROS1 gene rearrangement/fusion and / or solid tumors positive for drug resistance mutations.

In some schemes of the present 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.

In one embodiment, the aforementioned tumor or cancer is a hematological malignancy, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma, colorectal cancer, melanoma, cancer of the head and neck, gallbladder cancer , thyroid cancer, malignant glioma, gastric cancer, neurocytoma or salivary gland cancer; preferably, the lung cancer is non-small cell lung cancer.

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific phrase or term should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning.

The "compound represented by formula (A) in solid form" mentioned in the present application refers to the compound represented by formula (A) in solid form.

The "compound represented by formula (A) in crystalline form" mentioned in this application refers to the compound represented by formula (A) in crystalline form, including the anhydrous and solvent-free form and hydrate form of the compound represented by formula (A) and solvated forms.

The term "solvate" or "solvate" refers to an association formed between a stoichiometric or non-stoichiometric solvent molecule and a compound represented by formula (A) of the present application, including water molecules and a or more other solvent molecules, and only one or more other solvent molecules.

The term "hydrate" refers to an association formed between water molecules in a stoichiometric or non-stoichiometric ratio and the compound represented by formula (A) of the present application.

The "anhydrous and solvent-free form" refers to the absence of water molecules or solvent molecules, or the coexistence of water molecules or solvent molecules with the compound represented by formula (A) in a non-intermolecular combination, such as adsorption.

In the context of the present application, said characteristic diffraction peaks, diffraction peaks and/or 2θ angle values in X-ray powder diffraction patterns are all in degrees (°).

The term "crystalline composition" refers to a solid form comprising one of the crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, or crystalline form VI mentioned in this application, Two or more. Moreover, in addition to the crystal form of the present application, the crystalline composition may optionally contain other crystal forms or other amorphous forms of the compound represented by formula (A) or its salt, or impurities other than these substances. Those skilled in the art should understand that the sum of the contents of each component in the crystalline composition should be 100%.

The "room temperature" is the room temperature in the conventional sense in the field, generally 10-30°C, preferably 25°C±5°C.

In X-ray powder diffraction pattern, the terms "substantially" or "substantially as shown" refer to a crystal form that is substantially pure, with at least 50% of the powder X-ray diffraction pattern, 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 appear in a given spectrum. Furthermore, when the content of a certain crystalline form in the product gradually decreases, some diffraction peaks in the X-ray powder diffraction pattern attributed to the crystalline form may decrease due to the detection sensitivity of the instrument. Furthermore, for any given crystalline form, there may be slight errors in the position of the peaks, as is well known in the art of crystallography. For example, due to temperature changes, sample movement or instrument calibration when analyzing samples, the position of the peak can move, and the measurement error of the 2θ value is sometimes about ±0.3°, usually about ±0.2°. Therefore, when determining the structure of each crystal form, this error should be taken into account, and the term "substantially" or "substantially as shown in the drawings" is also intended to cover such differences in the diffraction peak positions, meaning ± 0.3°, preferably ±0.2°.

In the DSC spectrum or TGA spectrum, the term "substantially" or "substantially as shown" refers to the same crystal form of the same compound, in continuous analysis, the thermal transition onset temperature, endothermic peak peak value Temperature, exothermic peak-to-peak temperature, melting point, weight loss onset temperature or weight loss end temperature etc. are typically within about 5°C, usually within about 3°C. When describing that a certain compound has a given thermal transition start temperature, endothermic peak peak temperature, exothermic peak peak temperature, melting point, weight loss start temperature or weight loss end temperature, etc., it refers to the temperature ± 5°C.

As used herein, the term "cell proliferative disorder" refers to a disorder in which a population of cells grows at a rate that is either slower or higher than expected for a given physiological state and conditions.

The term "tumor" includes benign tumors, malignant tumors and borderline tumors, where malignant tumors are collectively referred to as cancer.

As used herein, the term "prevention" means that, when used for a disease or disorder (such as cancer), the compound or drug (such as the combination product claimed in this application) is compared to a subject who is not administered the compound or drug (such as the combination product claimed herein). The medicament is capable of reducing the frequency or delaying the onset of symptoms of a medical condition in a subject.

As used herein, the term "treating" means alleviating, alleviating or ameliorating the symptoms of a disease or disorder, ameliorating an underlying metabolically caused symptom, inhibiting a disease or symptom, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, causing a disease Regression of a disease or disorder, alleviation of a condition caused by a disease or disorder, or arrest of symptoms of a disease or disorder.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to those carriers or excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound.

The intermediate compound 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, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred implementations include but are not limited to the examples of the present application.

The chemical reactions in the specific embodiments of the present application are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.

The present application will be specifically described through examples below, and these examples do not imply any limitation to the present application.

All solvents used in this application were commercially available and used without further purification.

technical effect

The compound represented by formula (A) in solid form, the compound represented by formula (A) in crystalline form, and the specific crystal form provided by the application have one or more of the following beneficial effects:

(1) The compound represented by formula (A) in solid form has good properties and is convenient for weighing, transferring, separating, purifying and storing.

(2) The compound represented by the formula (A) in crystalline form and the specific crystal form have good crystallinity;

(3) The compound represented by the formula (A) in crystalline form and the specific crystal form are easy to purify, filter and separate, especially the crystal form IV, which is easy to prepare and has a high yield;

(4) The preferred crystal form has good physical and chemical stability, and has good medicinal prospects;

(5) The in vitro kinase activity inhibition test shows that the compound shown in formula (A) has excellent inhibitory activity on various kinases (for example, TRK, ALK, ROS1) and mutants thereof, especially TRK and mutant forms thereof;

(5) The in vitro cell inhibitory activity test shows that the compound shown in formula (A) has a strong inhibitory effect on cells with multiple NTRK mutations, and the inhibitory activity on 6 kinds of cells has an IC below _10nM , preferably below 5nM, Further preferably below 1nM;

(6) In vivo anti-tumor test results show that: compared with the control compound, the compound represented by formula (A) has better in vivo anti-tumor effect, better tolerance, and higher possibility of becoming a drug;

(7) Research on the mechanism of action in vivo Experiments show that the compound represented by 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.

Description of drawings

Figure 1: X-ray powder diffraction pattern of Form I of Example 1.

Figure 2: X-ray powder diffraction pattern of Form II of Example 2.

Figure 3: DSC-TGA spectrum of Form II of Example 2.

Figure 4: X-ray powder diffraction pattern of Form III of Example 3.

Figure 5: DSC-TGA spectrum of Form III of Example 3.

Figure 6: X-ray powder diffraction pattern of Form IV of Example 4.

Figure 7: DSC-TGA spectrum of Form IV of Example 4.

Figure 8: X-ray powder diffraction pattern of Form IV of Example 5.

Figure 9: X-ray powder diffraction pattern of Form V of Example 7.

Figure 10: X-ray powder diffraction pattern of Form VI of Example 8.

Figure 11 : DSC-TGA spectrum of Form VI of Example 8.

Figure 12: IR spectrum of the solid obtained in Example 0.

Figure 13: Graph of the results of Test Example 4.

Detailed ways

1. X-ray powder diffractometer (XRPD)

(1) Instrument model: Bruker D8Advance X-ray powder diffractometer

Test method: about 5-20 mg samples (Example 1-4, Example 6-8) are used for XRPD detection

The detailed XRPD parameters are as follows:

X-ray generator: Cu, Kα,

Phototube voltage: 40kV, phototube current: 40mA

Scanning range: 3°-40°(2θ)

Scan step: 0.02°

Sample tray: Zero background sample tray.

(2) Instrument model: D2 PHASER desktop X-ray diffractometer

Test method: about 100～200mg samples (Example 0, Example 5) are used for XRPD detection

The detailed XRPD parameters are as follows:

X-ray generator: Cu, Kα,

Phototube voltage: 30kV, phototube current: 10mA

Scanning range: 3°-60°(2θ)

Scan step: 0.02°

Sample tray: Zero background sample tray.

2. Differential Scanning Calorimeter (DSC)

Instrument Model: TA Discovery 250 Differential Scanning Calorimeter

Test method: Take the sample and place it in a perforated aluminum crucible, equilibrate the sample at 25°C and heat it to the final temperature at a heating rate of 10°C/min.

Sample size: 1~3mg

Gas flow type: nitrogen

Flow rate: 50mL/min

Heating start temperature: 25°C.

3. Thermal Gravimetric Analyzer (TGA)

Instrument model: TA Discovery 55 thermogravimetric analyzer (TA, US)

Test method: Place the sample in an aluminum crucible that has been peeled in advance. After the sample quality is automatically weighed in the TGA heating furnace, the sample is heated to the final temperature at a rate of 10°C/min.

Sample size: 1~5mg

Gas flow type: nitrogen

Sample chamber air flow rate: 60mL/min

Heating start temperature: room temperature

Termination temperature: 250/300°C.

4. Dynamic moisture adsorption and desorption analysis (DVS)

Instrument model: DVS Intrinsic dynamic water vapor adsorption instrument (SMS)

Test method: A sufficient amount of sample (10-20 mg) is placed in the pre-tared sample chamber and weighed automatically. Samples were dried at 40°C (for anhydrates only, starting at 25°C for hydrates) until dm/dt was less than 0.002%. Cool to 25°C and start the test using the operating parameters in the table below.

stage time	60 minutes
Drying/testing temperature	40℃/25℃
cycle	the whole cycle
Equilibration time per RH	1 hour
data storage rate	5 seconds
total airflow	200 sccm
Total gas flow after experiment	200 sccm

5. High performance liquid chromatography (HPLC)

Instrument model: Agilent 1260series (Waters, US)

Column:

Express C18 4.6x 100mm, 2.7μm

Test conditions: wavelength 248nm; column temperature 40°C

Flow rate: 1.0mL/min

Injection volume: 5 μL.

6. Nuclear Magnetic Resonance Spectroscopy (NMRS)

Instrument model: Bruker AVANCE III 400 (Bruker, GER)

Contents and test solvent: ¹ H-NMR, the test solvent is DMSO-d6.

7. Infrared Spectroscopy (IR)

Testing instrument: PerkinElmer Spectrum 100FT-IR infrared spectrometer

Test method: weigh 3 mg of the sample, dilute it with KBr, press it into tablets, and test at room temperature. The specific parameters are: detection range: 4000-400cm ^{- 1} wave number, resolution: 4cm ^-1 .

Abbreviations: DCM: dichloromethane; DIPEA: diisopropylethylamine; DMF: N,N-dimethylformamide; EA: ethyl acetate; PE: petroleum ether; DMSO: dimethylsulfoxide; TBTU: O-Benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid; BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro Phosphate; ATP: 5'-adenosine triphosphate; DTT: 1,4-dithiothreitol; MTT: 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyltetrabromide Azothiazolium blue.

In order to better understand the content of the present application, further description will be made below in conjunction with specific examples, but the specific implementation manners are not intended to limit the content of the present application. For the test methods that do not indicate specific conditions in the following preparation examples, examples, comparative examples, test examples or test examples, select according to conventional methods and conditions, or according to the product description.

Preparation Example 1: Preparation of Formula (A) Compound

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

Step b: 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- Crude ethyl carboxylate was dissolved in absolute ethanol (50 mL), stirred at 75°C until the system was clear and transparent, then LiOH (4.86g, 115.832mmol) aqueous solution (50mL) was added, stirred at 75°C for 5h. After cooling to room temperature, it was concentrated under reduced pressure to remove absolute ethanol. Slowly add 1N HCl aqueous solution dropwise to adjust the pH to 3-4, a large amount of white solid precipitates out, stir at room temperature for 30 min, then filter with suction, and wash the filter cake with a small amount of purified water. The filter cake was collected, dried and weighed to obtain a white powdery solid 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), the combined organic phases were washed with water (2 x 50 mL) and saturated aqueous NaCl (50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. Purified by column chromatography (PE:EA=4:1～2:1, v/v), collected product points, concentrated under reduced pressure, and obtained white powdery solid 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 was obtained Pure product (B2, 10.286g, 98%), (ES, m/z): 363.04[M+H] ⁺ .

Step c: Add 1-Boc-4-(4-aminophenyl)piperazine (918mg, 3.312mmol) to 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 (1284mg, 9.936mmol) was added dropwise to the solution at 0°C, and reacted overnight at room temperature. Add water (50mL) to the reaction solution and mix and stir, solids are precipitated, and the filter cake is obtained by suction filtration under reduced pressure, and dried in a vacuum 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)phenylpiperazine-1-carboxylate (B3 , 1320 mg, 77%). (ES, m/z): 622.09 [M+H] ⁺ .

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)phenylpiperazine-1-carboxylate (1.320 g, 2.125 mmol) was added DCM and CF ₃ COOH (12 mL, 3/1, v/v), room temperature Stir for 4h, concentrate the reaction solution under reduced pressure, add water (80mL) and EA (10mL) to the residue, adjust the alkalinity (pH=9) with ammonia water, stir to precipitate solids, obtain a filter cake by suction filtration under reduced pressure, and use A small amount of water rinsed the filter cake, weighed after drying 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] ⁺ .

Step e: Add glycolic acid (306mg, 4.026mmol) to 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-( Anhydrous solution of 4-(piperazin-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate B4, 700mg, 1.342mmol) and BOP (712mg, 1.610mmol) DMF (10 mL) solution, 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 solution was mixed with water (80 mL), and the mixture was extracted with EA (55 mL×2), and the combined organic phase was washed with H ₂ O (80 mL), brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , Carry out elution with column chromatography silica gel column, use 1% (v/v) MeOH-DCM first, use 2% (v/v) MeOH-DCM elution behind, collect product spot and concentrate, 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] ⁺ . ¹ H NMR (600MHz,DMSO-d ₆ )δ9.810(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＝5.4Hz,1H),4.556-4.548(m,1H),4.318- 4.225(m,1H),4.150(d,J=5.4Hz,2H),3.637(s,2H),3.513(s,2H),3.124-3.106(m,4H),2.957-2.912(m,1H) .

Reference substance preparation example 1-5:

In addition: Refer to the preparation process route and operation in WO2019029629A1 and WO2012034095A1 patent documents to prepare compounds D1-D5.

Example 0: Preparation of Compound of Formula (A) in Solid Form

Take the sample of Preparation Example 1 (about 50 mg) and pump it with an oil pump under heating conditions (50° C.) for 3 hours to obtain an off-white solid with a purity of 98.6%. IR (KBr, cm-1): 3429.38, 1643.78, 1487.95, 1453.15, 1232.01, 1026.79. As shown in Figure 12, a sample was taken for X-ray powder diffraction, which showed that it was amorphous.

Embodiment 1: Preparation of formula (A) compound crystal form I

At room temperature, weigh the sample of Example 0 (about 20 mg) into a sample bottle, add tetrahydrofuran (0.2 mL) to obtain a clear solution, gradually add methanol (1.4 mL) dropwise, stir at room temperature for 1 day, and filter to obtain a solid . The sample was taken for X-ray powder diffraction, and it was shown as a crystalline solid (crystal form I) with good crystallinity. The spectrum is shown in FIG. 1 , and the XRPD diffraction peak data is shown in Table 1.

Table 1 Example 1 XRPD diffraction peak data table of Form I

Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%
8.863	34.0	16.580	8.7	24.096	16.8

9.172	39.3	17.455	6.2	26.985-	11.0
9.878	9.3	17.876	98.3	27.350	8.4
10.088	12.4	18.530	100.0	28.028	12.1
14.017	4.9	19.100	9.5	28.426	6.5
14.305	6.6	21.003	7.3	the	the
16.075	9.3	23.827	31.3	the	the

Note: Select peaks with relative peak intensity >4.0% to list in the table.

Embodiment 2: Preparation of formula (A) compound crystal form II

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

Table 2 XRPD diffraction peak data table of embodiment 2 crystal form II

Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%
6.447	16.8	15.811	8.1	24.357	4.9
9.111	39.1	18.323	100.0	25.619	5.7
10.305	5.6	18.875	19.9	27.657	10.5
12.666	3.4	20.612	13.0	29.261	2.5
14.487	3.9	22.400	7.1	the	the
14.814	8.8	23.897	8.6	the	the

Embodiment 3: Preparation of formula (A) compound crystal form III

At room temperature, weigh the sample of Example 0 (about 30 mg) into a sample bottle, add acetonitrile (0.3 mL) to prepare a solution, stir at room temperature for 3 days, filter to obtain a solid, and dry at 50°C for 3 hours. The sample was taken for X-ray powder diffraction, and it was shown as a crystalline solid (crystal form III) with good crystallinity. The spectrum is shown in FIG. The sample was taken for DSC-TGA test, and the DSC graph showed an endothermic peak at 182.29°C, as shown in Figure 5.

Table 3 Example 3 XRPD diffraction peak data table of Form III

Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%
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	the	the
13.284	25.5	18.983	9.2	the	the

Note: Select peaks with relative peak intensity >5.0% to list in the table.

Embodiment 4: Preparation of formula (A) compound crystal form IV

At room temperature, weigh the sample of Example 0 (about 20 mg) in a sample bottle, add tetrahydrofuran (0.2 mL) to prepare a clear solution, gradually add isopropanol (1.3 mL) dropwise, and stir at room temperature for 1 day , filtered to obtain a solid, and dried at 50° C. for 3 hours. A sample was taken for X-ray powder diffraction, which showed a crystalline solid (crystal form IV) with good crystallinity. The spectrum is shown in Figure 6, and the XRPD diffraction peak data is shown in Table 4. The sample was taken for DSC-TGA test. The DSC graph showed two endothermic peaks at 64.82°C and 192.07°C. The TGA graph showed that the sample had a weight loss of 1.1526% between room temperature and 75°C, as shown in Figure 7.

Table 4 Example 4 XRPD diffraction peak data table of Form IV

Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%
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	the	the
16.505	9.0	22.958	10.7	the	the

Note: Select peaks with relative peak intensity >3.5% to list in the table.

Embodiment 5-6: Preparation of formula (A) compound crystal form IV

Using the sample obtained in Example 0, under the conditions listed in Table 5, Form IV can also be obtained. Wherein, embodiment 5 refers to the preparation method of embodiment 4.

Experimental conditions and results of table 5 embodiment 5-6

Table 6 Example 5 XRPD diffraction peak data table of Form IV

Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%
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	the	the
16.457	8.4	22.493	5.7	the	the

Note: Select peaks with relative peak intensity >5% to list in the table.

Embodiment 7: Preparation of formula (A) compound crystal form V

At room temperature, the sample of Example 0 (about 34 mg) was weighed into a sample bottle, dissolved in acetone (0.5 mL), stirred at 5° C. for 1 day, and filtered to obtain a solid. The sample was taken for X-ray powder diffraction, and it was shown as a crystalline solid (crystal form V) with good crystallinity. The spectrum is shown in FIG. 9 , and the XRPD diffraction peak data are shown in Table 7.

Table 7 Example 7 XRPD diffraction peak data table of Form V

Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%	Peak position (2θ)°	Relative Strength%
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	the	the

Note: Select peaks with relative peak intensity >4.0% to list in the table.

Embodiment 8: Preparation of formula (A) compound crystal form VI

An appropriate amount of crystal form V obtained in Example 7 was weighed, and dried at a temperature of 50° C. for 3 hours to obtain a solid. The sample was taken for X-ray powder diffraction, and it was shown as a crystalline solid (form VI) with good crystallinity. The spectrum is shown in Figure 10, and the XRPD diffraction peak data is shown in Table 8. The sample was taken for DSC-TGA test. 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 11.

Table 8 Example 8 XRPD diffraction peak data table of Form VI

Note: Select peaks with relative peak intensity >3.0% to be listed in the table.

Comparative example 1-2

Weigh an appropriate amount of the sample of Example 0, dissolve it in tetrahydrofuran, and prepare a 10mg/0.3mL clear solution, divide the resulting solution evenly in centrifuge tubes, 0.3mL per tube, and then add 0.1mL of the following table to each tube Solvent 2 was shown, covered with a thin film and pierced, evaporated the solvent at room temperature.

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

comparative example	Solvent 2	result
Comparative example 1	Methanol	slime
Comparative example 2	acetone	slime

Test Example 1: Solid Stability Experiment of Different Crystal Forms of Compound of Formula (A)

Weigh an appropriate amount of formula (A) compound crystal form III (Example 3) in a vial, place it under high temperature (60°C, sealed) and accelerated (40°C/75%RH, open) conditions for 7 days, and take a sample The purity test and X-ray powder diffraction were carried out respectively to investigate the stability of the crystal form III (Example 3) of the compound of formula (A) under different conditions, and the results are shown in Table 10.

Weigh an appropriate amount of crystal form IV (Example 4) sample and place it in a vial, under high temperature (60°C, sealed), high humidity (25°C/92.5%RH, open) and acceleration (40°C/75%RH, open) Placed under the condition of (2) respectively for 7 days, the samples were taken for purity detection and X-ray powder diffraction respectively, to investigate the stability of formula (A) compound crystal form IV (embodiment 4) under different conditions, the results are shown in Table 11 .

The solid stability experiment result of table 10 crystal form III

The solid stability experiment result of table 11 crystal form IV

The data show that: the crystal form III of Example 3 can maintain chemical stability and crystal form stability under high temperature and accelerated conditions; the crystal form IV of Example 4 can maintain chemical stability and crystal form under high temperature, high humidity and accelerated conditions. Stablize.

Test example 2: DVS test of different crystal forms of the compound of formula (A)

Samples of the crystal form III of Example 3 and the crystal form IV of Example 4 were respectively placed in the DVS sample chamber for testing. The samples after DVS were taken for X-ray powder diffraction, and the results are shown in Table 12.

Table 12 DVS test results of different crystal forms

Embodiment and initial crystal form	After DVS crystal form
Example 3/Form III	Crystal form unchanged
Example 4/Form IV	Crystal form unchanged

The data show that the crystal forms of Form III and Form IV remain unchanged after DVS testing.

Test Example 1, TRK Kinase Inhibition Test

1. Operation steps:

1.1 Kinase reaction:

Add a certain concentration gradient of the test compound and enzyme solution to the compound plate in turn (add kinase buffer (1X kinase buffer (Cisbio, Cat#62EZBFDD), pH 7.5; 5mM MgCl ₂ , 1mM DTT) to the negative control well), and centrifuge at 1000rpm 30 seconds. Seal the plate and incubate the plate in a constant temperature incubator at 25°C for 30 minutes. Substrate solutions of TK-Sub-biotin (Cisbio, Cat#61TKOBL) and ATP (Sigma, Cat#R0441) were prepared, and the substrate mixed solution was added to a 384-well plate, and centrifuged at 1000rpm for 30 seconds. Seal the plate and incubate the plate in a constant temperature incubator at 25°C for 60 minutes.

1.2 Kinase detection:

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

Inhibition rate=(ratio _{negative control well-ratio compound well} )/(ratio _{negative control well} -ratio _{no enzyme control well} )×100%

1.3 Data Analysis and Curve Fitting

Data were fitted in XLFit excel plugin version 5.4.0.8 to obtain _IC50 values.

1.4 QC parameters

Reference compounds were included in each plate and their _IC50s were within 3-fold every time.

2. Test results: as shown in Table 13

The inhibitory activity of different compounds of table 13 to TRK kinase

Remarks: The above RXDX-101, LOXO-195, and LOXO-101 are all disclosed compounds, and marketed products (pharmaceutical or chemical grade products) are available on the market; the compound represented by formula (A): the sample of Preparation Example 1.

The results show that: the compound represented by formula (A) exhibits higher kinase inhibitory activity in various kinases, and the activity in TRKA, TRKB, TRKC and TRKC-G696A is better than that of RXDX-101, LOXO-195 and LOXO-101 or Comparable, but the inhibitory activity in multiple mutation-resistant kinases (G595R, G667C, G623R) was significantly better than that of RXDX-101, LOXO-195 and LOXO-101.

Test Example 2, ALK and ROS1 Kinase Inhibition Test

1. Operation steps:

1.1 Kinase reaction:

The compound was diluted to a certain concentration with DMSO, and diluted 4-fold. Add a certain concentration of compound, enzyme solution and DMSO to a 384-well plate, incubate at room temperature for 10 min; add fluorescein-labeled peptide, ATP (sigma, Cat.No.:A7699-1G, Lot No.:987-65-5) Incubate at ℃ for a certain period of time; add stop solution. reading.

The inhibition rate formula corresponding to a single concentration: inhibition rate = (OD _{negative control well} - OD _{compound well} ) / (OD _{negative control well} - OD _{no enzyme control well} ) × 100%

1.2 Data analysis and curve fitting

The data were fitted in XLFit excel plugin version 4.3.1 to obtain _IC50 values and the results are shown in Table 14.

Table 14 Different compounds have inhibitory activity on ALK and ROS1 kinases

Note: the compound shown in formula (A): the sample of Preparation Example 1.

The results show that: the compound shown in formula (A) shows strong inhibitory activity in ROS1 kinase, significantly better than RXDX-101 and LOXO-101, better than LOXO-195; it also has good inhibitory activity on ALK kinase, significantly Superior to LOXO-101 and LOXO-195.

Test example 3, in vitro cell inhibition test

1. Cell line

Source of 6 kinds of cell lines used in experiments: Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.

Cell type: mouse B cells

Medium: RPMI-1640+10% FBS

2. Test method

Cells in logarithmic growth phase were harvested and counted using a platelet counter. Pipette a certain density of cell suspension and inoculate it evenly in a 96-well plate, 100 μL per well, shake to make it evenly dispersed into the well; add 100 μL of a drug solution with a certain concentration gradient to each well, and set up three replicate wells for each drug concentration; Cultivate in a CO ₂ incubator at 37°C for 72 hours; add MTT working solution (5 mg/mL), 20 μL per well; act for 4 hours at 37°C; centrifuge at 1000 rpm/min for 5 min in a plate centrifuge, discard 180 μL of the medium, add 150 μL DMSO, micro The well shaker was shaken to mix well, the bottom of the plate was wiped clean, and the optical density value (OD) was detected at 550 nm with a microplate reader.

3. Data analysis

Inhibition rate=(control well OD-test well OD)/(control well OD-blank well OD)*100%. According to the inhibition rate of each concentration, use SPSS software to calculate the _IC50 value of the half inhibitory concentration.

4. Test results: The results are shown in Table 15:

The inhibitory activity of different compounds of table 15 to different cell lines

Note: the compound shown in formula (A): the sample of Preparation Example 1.

The inhibitory activity of table 16 reference compound to different cell lines

The results show that: the compound represented by the formula (A) of the present application exhibits better in vitro cell activity in various wild-type and mutant drug-resistant cell lines, which is significantly better than RXDX-101, LOXO-195, LOXO-101 and Prior Art Compounds D1-D5.

Test Example 4: Research on the In Vivo Mechanism of Compounds Shown in Formula (A)

1. Test method

1.1 Model preparation:

Take mutant drug-resistant cells Ba/F3LMNA-NTRK1-G595R in the logarithmic growth phase, collect them, resuspend them in serum-free medium, and make the cell concentration 6×10 ⁷ -10×10 ⁷ cells/mL, and suspend them into the cells An equal volume of Matrigel (Matrigel) was added to the solution so that the final concentration of cells was 3×10 ⁷ -5×10 ⁷ cells/mL. NuNu mice (Beijing Weitong Lihua, 4-6 weeks old, female) were subcutaneously inoculated with 0.1 mL of tumor cell suspension in the axils of the forelimbs, with an inoculation volume of 3×10 ⁶ -5×10 ⁶ cells/rat to prepare animal models.

1.2 Test grouping:

The maximum and minimum tumor diameters of transplanted tumors in nude mice were measured with vernier calipers, and the tumor volume was calculated: the formula for tumor volume (Tumor volume, TV) is: V=1/2×a×b ² , where a and b represent The largest and smallest diameters of the tumor mass. Nude mice with appropriate tumor volume were selected, and the animals were divided into 7 groups (200-300mm ³ ) in a balanced manner according to the tumor volume by random number method, with 3 animals in each group.

1.3 Administration

Carry out intragastric administration according to the animal's body weight, the administration volume is 10ml/kg, the compound represented by formula (A) is configured as "3%DMSO+96%HP-β-CD (0.5g/mL)+1%HCl" required dosing concentration.

There were three rats in the control group, and the tumor tissues were collected and frozen 4 hours after administration of vehicle. The other groups were given 100mg/kg of the compound represented by formula (A), and the tumor tissues were collected and frozen at 0.25h, 1h, 4h, 8h, 12h and 24h respectively.

1.4 Protein extraction and quantification

A certain amount of tumor tissue was taken and added to a corresponding volume of protein lysate (RIPA lysate (Thermo Fisher, product number 89900): protease inhibitor (cOmplete, Mini, EDTA-free, EASYpack; Roche, product number 04693159001): phosphatase inhibitor ( PhosStop, EASY pack; Roche, product number 04906837001) = 8:1:1), homogenate, lyse in ice bath for 30min. Centrifuge at low temperature and high speed, and take the supernatant for BCA protein quantification (operate according to the BCA protein quantification kit (Tiangen, catalog number: #PA115-01)). Finally, after the protein concentration was adjusted to a uniform concentration with the lysate, a loading buffer was added and boiled at 100°C for 10 min.

1.5 Western-blot

Use 4-20% 10-well precast gel; load 100μg; 140V electrophoresis for 1-1.5h; 300mA wet transfer for 1.5h-2h; 5% BSA blocking for 2-3h; primary antibody incubated overnight at 4°C (Trk 1:5000 , p-Trk, PLCγ1, p-PLCγ1, AKT, p-AKT, actin 1:1000); 4×5min 0.1% TBST washing; secondary antibody incubation at room temperature for 2h (1:5000), ECL light, exposure.

2. Test results: as shown in Figure 13.

From the test results, it can be seen that as time goes on, TRK, p-TRK, p-PLCγ1 and p-AKT in Figure 13 are all significantly reduced, which proves that the compound shown in formula (A) can significantly reduce the protein levels of TRK and p-TRK, Furthermore, it effectively inhibits the phosphorylation of p-PLCγ1/PLCγ1 and p-AKT/AKT to regulate cell growth and proliferation.

Test Example 5: In vivo drug efficacy experiment of compounds against NTRK mutation drug-resistant tumor models

experiment method

1.1 Model preparation

Cells in the logarithmic growth phase were collected, resuspended in serum-free medium, and the cell concentration was 6×10 ⁷ -10×10 ⁷ cells/mL, and an equal volume of Matrigel (Matrigel) was added to the cell suspension. ), so that the final concentration of cells is 3×10 ⁷ -5×10 ⁷ cells/mL. NuNu mice (Beijing Weitong Lihua, 4-6 weeks old, female) were subcutaneously inoculated with 0.1 mL of tumor cell suspension in the axils of the forelimbs, with an inoculation volume of 3×10 ⁶ -5×10 ⁶ cells/rat to prepare animal models.

1.2 Test grouping

The maximum and minimum tumor diameters of transplanted tumors in nude mice were measured with vernier calipers, and the tumor volume was calculated: the formula for tumor volume (Tumor volume, TV) is: V=1/2×a×b ² , where a and b represent The largest and smallest diameters of the tumor mass. Nude mice with appropriate tumor volume were selected, and the animals were divided into 7 groups (100-200 mm ³ ) in a balanced manner according to the tumor volume by random number method, with 6 animals in each group.

1.3 Observation indicators

On the day of grouping, intragastric administration was carried out according to the body weight of the animals. The administration volume was 10mL/kg. LOXO-195 was formulated into the required administration solution with 0.5% CMC-Na, and the compound represented by formula (A) was administered with "3% DMSO +96%HP-β-CD (0.5g/mL)+1%HCL" was configured as the required administration solution. Tumor diameter was measured twice a week, and tumor volume was calculated. The specific indicators are as follows:

Animal body weight: the animals are weighed before the administration in the morning, and the body weight loss greater than 20% is defined as drug toxicity (observed to the next day after the last administration);

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

Relative tumor proliferation rate T/C (%): T/C (%)=TRTV/CRTV×100% (TRTV: administration group RTV, CRTV: control group RTV);

Tumor growth inhibition rate (TGI)=[1-(Ti-T0)/(Vi-V0)]×100%. (wherein Ti represents the average tumor volume of a certain administration group on a certain day; T0 is the average tumor volume of this administration group at the beginning of administration; Vi is the average tumor volume of a vehicle control group on a certain day (the same day as Ti); V0 is mean tumor volume of the vehicle control group at the start of dosing);

Tumor inhibition rate: at the end of the experiment, the animals were killed by neck dislocation, 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 Weight x 100%.

test results

2.1Ba/F3LMNA-NTRK1-G667C model

2.1.1 The effect of drugs on the body weight of tumor-bearing mice

The body weight of each compound and each dose group has an upward trend, and the upward trend is more obvious than that of the control group. The body weight of each compound and each dose group increased significantly, which may be related to the compound, and it may also be due to the inhibition of tumor growth, which made the mice in better condition and increased their body weight significantly. The results are shown in Table 17.

2.1.2 Effects of drugs on tumor weight and tumor inhibition rate in tumor-bearing mice

The data results show that: at the same dosage (100mg/kg), compared with LOXO-195, the compound represented by formula (A) inhibits tumor growth more significantly; further, compared with the higher dosage of LOXO-195 Compared with the group (200mg/kg), the compound represented by the formula (A) (100mg/kg) also showed a better antitumor effect. The results are shown in Table 17.

Table 17 Ba/F3LMNA-NTRK1-G667C model in vivo results

2.2Ba/F3LMNA-NTRK1-G595R model

2.2.1 The effect of drugs on the body weight of tumor-bearing mice

The body weight of each compound and each dose group has an upward trend, and the upward trend is more obvious than that of the control group. The body weight of each compound and each dose group increased significantly, which may be related to the compound, and it may also be due to the inhibition of tumor growth, which made the mice in better condition and increased their body weight significantly. The results are shown in Table 17.

2.2.2 Effects of drugs on tumor weight and tumor inhibition rate in tumor-bearing mice

The data results show that: compared with LOXO-195 (100mg/kg), at a lower dosage (50mg/kg), the compound represented by formula (A) can significantly inhibit the tumor tissue weight, and the tumor weight Inhibition rate>90%. The results are shown in Table 18.

Table 18 Ba/F3LMNA-NTRK1-G595R model in vivo results

While the foregoing invention has been described in some detail, by way of illustration and example, for purposes of clarity of understanding, it will be apparent from the teachings of this application that one of ordinary skill in the art can make further improvements without departing from the spirit or scope of the appended claims. It is subject to certain changes and modifications.

Claims (15)

1. A compound represented by formula (A) in solid form,

   
2. The compound represented by the formula (A) in solid form according to claim 1, characterized in that, the infrared spectrum measurement is carried out by tablet method, and its infrared spectrum includes characteristic peaks (±4 cm ⁻¹ ) at the following positions: 3429, 1643, 1488, 1453, 1232, 1027.
3. The compound represented by formula (A) in solid form according to claim 1 or 2, characterized in that it is a compound represented by formula (A) in crystal form.
4. The compound shown in the formula (A) of crystalline form according to claim 3, is characterized in that, it is the crystal form I of the compound shown in formula (A), uses Cu-Kα radiation, and its X-ray powder diffraction spectrum is in There are characteristic diffraction peaks at the following 2θ angles: (±0.2°): 9.2, 17.9, 18.5; or, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles (±0.2°) : 8.9, 9.2, 17.9, 18.5, 23.8;

   Its X-ray powder diffraction pattern has characteristic diffraction peak (± 0.2 °) at the following 2θ angles: 8.9, 9.2, 10.1, 17.9, 18.5, 23.8, 28.0; Or, it has X- X-ray powder diffraction pattern.
5. The compound shown in the formula (A) of crystalline form according to claim 3, is characterized in that, it is the crystal form II of the compound shown in formula (A), uses Cu-Kα radiation, and its X-ray powder diffraction pattern is in There are characteristic diffraction peaks (±0.2°) at the following 2θ angles: 9.1, 18.3, 20.6;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.4, 9.1, 18.3, 20.6;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: (±0.2°): 6.4, 9.1, 18.3, 20.6, 27.7;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.4, 9.1, 18.3, 18.9, 20.6, 27.7;

   Alternatively, it has an X-ray powder diffraction pattern substantially as shown in FIG. 2 .
6. According to claim 5, the compound represented by formula (A) in crystalline form has an endothermic peak at 155.27±5°C in its differential scanning calorimetry curve;

   Alternatively, it has a DSC profile substantially as shown in FIG. 3 .
7. The compound shown in the formula (A) of the crystalline form according to claim 3 is characterized in that it is the crystal form III of the compound shown in the formula (A), using Cu-Kα radiation, its X-ray powder diffraction spectrum is in There are characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 13.3, 15.8, 18.4;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 13.3, 15.8, 18.4, 23.7;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 10.9, 13.3, 15.8, 18.4, 19.0, 23.7;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 5.6, 10.9, 11.3, 13.3, 15.8, 17.1, 18.4, 19.0, 23.7;

   Alternatively, it has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
8. According to the compound represented by formula (A) in crystalline form according to claim 7, its differential scanning calorimetry curve has an endothermic peak at 182.29±5°C;

   Alternatively, it has a DSC profile substantially as shown in FIG. 5 .
9. The compound shown in the formula (A) of crystalline form according to claim 3, is characterized in that, it is the crystalline form IV of the compound shown in formula (A), uses Cu-Kα radiation, and its X-ray powder diffraction pattern is in There are characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.5, 10.0, 17.2, 17.9;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.5, 10.0, 13.1, 17.2, 17.9, 25.0;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.5, 10.0, 13.1, 17.2, 17.9, 20.0, 25.0;

   Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 8.5, 10.0, 13.1, 15.7, 17.2, 17.9, 20.0, 25.0, 25.9;

   Alternatively, it has an X-ray powder diffraction pattern substantially as shown in FIG. 6 or FIG. 8 .
10. According to the compound represented by formula (A) in crystalline form according to claim 9, its differential scanning calorimetry curve has an endothermic peak at 192.07±5°C;

    Alternatively, it has a DSC profile substantially as shown in FIG. 7 .
11. The compound shown in the formula (A) of the crystalline form according to claim 3 is characterized in that it is the crystal form V of the compound shown in the formula (A), using Cu-Kα radiation, its X-ray powder diffraction spectrum is in There are characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 12.7, 18.2;

    Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 12.7, 18.2, 23.4;

    Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 12.7, 16.7, 18.2, 23.4;

    Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.0, 12.7, 16.7, 18.2, 23.4, 25.4, 28.1;

    Alternatively, it has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .
12. The compound shown in the formula (A) of the crystalline form according to claim 3 is characterized in that it is the crystal form VI of the compound shown in the formula (A), using Cu-Kα radiation, its X-ray powder diffraction spectrum is in There are characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 16.9, 22.3;

    Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 16.9, 18.6, 22.3;

    Alternatively, its X-ray powder diffraction pattern has characteristic diffraction peaks (±0.2°) at the following 2θ angles: 6.1, 7.4, 11.5, 16.9, 18.6, 22.3;

    Alternatively, it has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .
13. A crystalline composition comprising the crystalline form I described in claim 4, the crystalline form II described in claim 5 or 6, the crystalline form III described in claim 7 or 8, and the crystalline form described in claim 9 or 10 One or more of Form IV, Form V of Claim 11, and Form VI of Claim 12.
14. A pharmaceutical composition comprising the compound of formula (A) in solid form according to claim 1 or 2, or the compound of formula (A) in crystalline form as claimed in claim 3, or the crystalline composition as claimed in claim 13 ;

    Preferably, the pharmaceutical composition comprises the crystalline form I described in claim 4, the crystalline form II described in claim 5 or 6, the crystalline form III described in claim 7 or 8, and the crystalline form described in claim 9 or 10. One or more of the crystalline form IV, the crystalline form V of claim 11, and the crystalline form VI of claim 12.
15. According to the compound shown in the formula (A) shown in the solid form according to claim 1 or 2, the compound shown in the formula (A) in the crystalline form described in any one of claims 3-12, the crystal described in claim 13 Composition, or the pharmaceutical composition described in claim 14 as medicine or the application in preparation medicine; Preferably, described medicine is used for preventing and/or treating one or more mediation in TRK, ROS or ALK diseases; further preferably, the diseases are selected from pain diseases, cell proliferative diseases, inflammatory diseases, neurodegenerative diseases or infectious diseases.

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