Crystalline form of 3-{4-[(2R)-2-aminopropoxy]phenyl}-n-[(1R)-1-(3-fluorophenyl) ethyl]imidazo[1,2-b]pyridazin-6-amine free base, pharmaceutical composition comprising the same, and use thereof

Abstract

This disclosure relates to the crystal forms of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine and its salts, as well as methods for preparing and using such crystal forms.

Description

[Technical Field]

[0001] Field of Invention

[0002] This disclosure relates to the crystal forms of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine and its salts, and methods for preparing and using such crystal forms. [Previous Technology]

[0003] Background of the Invention

[0004] 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]-imidazo[1,2-b]pyridazine-6-amine (compound 1) is a known ROS1 receptor tyrosine kinase inhibitor and neurotrophic tyrosine receptor kinase (NTRK) inhibitor, and has the following chemical structure: (compound 1).

[0005] The ROS1 gene has been found to encode a receptor tyrosine kinase that is the human ortholog of the oncogene product v-ros of avian sarcoma virus UR2 (University of Rochester Tumor Virus 2). ROS1 fusion genes, resulting from chromosomal rearrangements including the ROS1 gene and subsequent fusion of the ROS1 gene to another gene, have been found in the glioblastoma cell line U118MG. In U118MG cells, the gene encoding the Golgi protein FIG (fused to glioblastoma) is fused with the ROS1 gene to form a gene encoding the FIG-ROS1 fusion protein. The fusion between FIG and ROS1 results in a structural change that constitutively initiates the activity of the ROS1 kinase enzyme, and the FIG-ROS1 fusion protein possesses cell transformation and tumorigenic activities mediated by the initiation of ROS1 signaling pathways involving STAT3, ERK, and SHP2.

[0006] Chromosomal translocations of the ROS1 gene have also been identified in the non-small cell lung cancer cell line HCC78 and clinical samples of lung cancer. A fusion gene of the SLC34A2 and ROS1 genes has been reported in HCC78 cells, and the presence of a CD74-ROS1 fusion gene encoding a transmembrane protein has been reported in non-small cell lung cancer patient samples. A fusion gene of the FIG and ROS1 genes has been found in two out of 23 patient samples from cholangiocarcinoma.

[0007] Large-scale screening of patient samples using FISH (fluorescence in situ hybridization) has identified fusion genes of the ROS1 gene with SDC, CD74, EZR, SLC34A2, LRIG3, or TPM3. Random ROS1 fusion genes SDC-ROS1, CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, LRIG3-ROS1, and TPM3-ROS1 have been detected in 13 out of 1476 non-small cell lung cancer patient samples.

[0008] Similarly, large-scale screening of non-small cell lung cancer patient samples using FISH has identified the ROS1 fusion gene in 18 out of 1073 cases. Furthermore, analysis using patient samples has shown that the ROS1 gene is highly expressed in brain tumors.

[0009] ROS1 has been shown to be initiated in cancers expressing ROS1 fusion genes (e.g., non-small cell lung cancer, cholangiocarcinoma, or brain tumors). Therefore, drugs that inhibit ROS1 kinase activity can block downstream pathways of ROS1, namely STAT3, ERK, and SHP2, which contribute to tumor growth and tumor cell survival. Therefore, ROS1 kinase inhibitors are expected to be useful as therapeutic agents for cancer. Compounds such as crizotinib, TAE684, pyrazole derivatives, and aminopyrazine derivatives have been reported to have inhibitory effects on ROS1 kinase activity.

[0010] Neurotrophic tyrosine receptor kinase, also known as tropomyosin-associated kinase (Trk), is a high-affinity receptor activated by a soluble growth factor called neurotrophic factor (NT). The NTRK receptor family has three members: NTRK1 (also known as TrkA), NTRK2 (also known as TrkB), and NTRK3 (also known as TrkC).

[0011] NT includes several proteins, including nerve growth factor (NGF) which initiates NTRK1, brain-derived neurotrophic factor (BDNF) and NT-4 / 5 which initiate NTRK2, and NT3 which initiates NTRK3. Each NTRK receptor includes an extracellular domain (ligand binding site), a transmembrane domain, and an intracellular domain (containing a kinase domain). Upon binding to a ligand, each kinase catalyzes autophosphorylation, which then initiates downstream signal transduction pathways.

[0012] NTRKs are widely expressed in neural tissue during its development and play an important role in the maintenance and survival of these cells. Previous studies have shown that NTRKs play an important role in the development and function of the nervous system.

[0013] Numerous references document the association of NTRK signaling with cancer. For example, NTRKs are present at low expression levels in regions outside the nervous system in adults; however, NTRK expression increases in advanced prostate cancer. In normal prostate tissue and early androgen-dependent prostate tumors, NTRK1 is expressed at only low or undetectable levels, while neither NTRK2 nor NTRK3 is expressed. However, in advanced androgen-independent prostate cancer, all subtypes of the NTRK receptor and its ligands are overexpressed. Evidence suggests that these advanced prostate cancer cells are NTRK-dependent for their tumor survival. Therefore, NTRK inhibitors can induce apoptosis in androgen-independent prostate cancer. Furthermore, recent references have shown that NTRK overexpression, initiation, amplification, fusion gene formation, or mutation is associated with neuroblastoma, secretory breast cancer, colorectal cancer, ovarian cancer, head and neck cancer, pancreatic cancer, and melanoma.

[0014] Selective NTRK tyrosine kinase inhibitors have been reported, including CEP-751, CEP-701, indoxazosole compounds, hydroxyindole compounds, pyrazolyl fused ring compounds, isothiazole compounds, and various other compounds. [Summary of the Invention]

[0015] Summary of the Invention

[0016] This disclosure is based on the unexpected discovery that certain crystal forms of compound 1 or its salts possess excellent physical properties (e.g., physical and chemical stability).

[0017] In one aspect, the present disclosure is characterized by crystal form A of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) adipate, wherein crystal form A has a tetragonal crystal system, space group P41212, and cell parameters a=b=9.63 (1) Å, c=61.14 (2) Å, α=β=γ=90°, and V=5666 (5) Å3.

[0018] In another aspect, the present disclosure is characterized by a method for preparing crystal form A of compound 1 adipate. The method includes mixing an amorphous form of compound 1 adipate with a solvent; and adding an antisolvent to the mixture to obtain crystal form A of compound 1 adipate.

[0019] In another aspect, the present disclosure is characterized by crystal form B of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) adipate, wherein crystal form B exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one diffraction peak obtained by using CuKα rays, the diffraction peak having a diffraction angle 2θ selected from the group consisting of 5.2±0.2°, 7.2±0.2°, and 20.9±0.2°.

[0020] In another aspect, the present disclosure is characterized by a method for preparing crystal form B of compound 1 adipate. The method includes dissolving the amorphous form of compound 1 adipate in a solvent comprising dichloromethane and methanol to form a solution; and evaporating the solvent to obtain crystal form B of compound 1 adipate.

[0021] In another aspect, the present disclosure is characterized by crystal form C of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) adipate, wherein crystal form C exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one diffraction peak obtained by using CuKα radiation, the diffraction peak having a diffraction angle 2θ selected from the group consisting of 5.7±0.2°, 21.0±0.2°, and 23.2±0.2°.

[0022] In another aspect, the present disclosure is characterized by a method for preparing crystalline form C of compound 1 adipic acid salt. The method includes dissolving the amorphous form of compound 1 adipic acid salt in ethanol to form a solution; adding acetone to the solution; and removing the ethanol and acetone by evaporation to obtain crystalline form C of compound 1 adipic acid salt.

[0023] In another aspect, the present disclosure is characterized by crystal form D of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) adipate, wherein crystal form D is characterized by an X-ray powder diffraction (XRPD) pattern of at least one diffraction peak obtained by using CuKα rays, the diffraction peak having a diffraction angle 2θ selected from the group consisting of 4.9±0.2°, 19.4±0.2°, and 21.6±0.2°.

[0024] In another aspect, the present disclosure is characterized by a method for preparing crystal form D of compound 1 adipate. The method includes dissolving the amorphous form of compound 1 adipate in dimethylacetamide to form a solution; adding acetone to the solution; and removing the dimethylacetamide and acetone by evaporation to obtain crystal form D of compound 1 adipate.

[0025] In another aspect, the present disclosure is characterized by crystal form A of the free base of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (compound 1), wherein crystal form A exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one diffraction peak obtained by using CuKα radiation, the diffraction peak having a diffraction angle 2θ selected from the group consisting of 8.5±0.2°, 12.7±0.2°, and 19.1±0.2°.

[0026] In another aspect, this disclosure is characterized by a method for preparing crystal form A of the free base of compound 1. The method comprises mixing a base with an aqueous and alcoholic solution comprising the hydrochloride salt of compound 1 to obtain crystal form A of the free base of compound 1.

[0027] In another aspect, the present disclosure is characterized by crystal form B of the free base of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (compound 1), wherein crystal form B exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one diffraction peak obtained by using CuKα radiation, the diffraction peak having a diffraction angle 2θ selected from the group consisting of 6.1±0.2°, 9.4±0.2°, and 21.3±0.2°.

[0028] In another aspect, the present disclosure is characterized by a method for preparing crystal form B of the free base of compound 1. The method includes dispersing crystal form A of the free base of compound 1 in dichloromethane to form a dispersion; and stirring the dispersion at a temperature of about 45°C to about 55°C (e.g., about 50°C) to obtain crystal form B of the free base of compound 1.

[0029] In another aspect, the present disclosure is characterized by crystal form C of the free base of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (compound 1), wherein crystal form C exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one diffraction peak obtained by using CuKα rays, the diffraction peak having a diffraction angle 2θ selected from the group consisting of 18.6±0.2°, 20.2±0.2°, and 21.1±0.2°.

[0030] In another aspect, the present disclosure is characterized by a method for preparing crystal form C of the free base of compound 1. The method includes dissolving crystal form A of the free base of compound 1 in dichloromethane to form a solution; and removing the dichloromethane by evaporation to obtain crystal form C of the free base of compound 1.

[0031] In another aspect, the present disclosure is characterized by crystal form D of the free base of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (compound I), wherein crystal form D exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one diffraction peak obtained by using CuKα radiation, the diffraction peak having a diffraction angle 2θ selected from the group consisting of 8.6±0.2°, 18.4±0.2°, and 20.9±0.2°.

[0032] In another aspect, the present disclosure is characterized by a method for preparing crystal form D of the free base of compound 1. The method includes dissolving crystal form A of the free base of compound 1 in methanol to form a solution; adding methyl tributyl ether to the solution; and removing methanol and methyl tributyl ether by evaporation to obtain crystal form D of the free base of compound 1.

[0033] In another aspect, the present disclosure is characterized by pharmaceutical compositions comprising at least one crystal form described herein and a pharmaceutically acceptable carrier.

[0034] In another aspect, this disclosure is characterized by a method for treating cancer. The method includes administering a therapeutically effective amount of the pharmaceutical composition described herein to a subject in need.

[0035] The implementation scheme described herein may have one or more of the following advantages.

[0036] In some embodiments, certain crystal forms described herein have relatively low hygroscopicity. For example, the weight increases of crystal forms A and D of Compound 1 adipate at 80% RH are 0.235% and 0.34%, respectively. As another example, the weight increases of crystal forms A, B, and C of Compound 1 free base at 80% RH are 0.1%, 0.005%, and 0.107%, respectively. Hygroscopicity affects the stability of the drug substance, its flowability and homogeneity during formulation, thereby affecting the quality of the finished drug product. Hygroscopicity also affects the preparation, storage, and post-processing of the drug. Crystal forms with low hygroscopicity have no requirements for storage conditions, which reduces storage and quality control costs.

[0037] In some embodiments, certain crystal forms described herein exhibit excellent physical stability. For example, when stored in air at 40°C / 75%RH, crystal form A of compound 1 adipate remains crystalline for at least two weeks. Excellent physical stability is crucial for drug development. Numerous processes (including storage, transportation, and formulation) occur during the manufacture of finished pharmaceutical products. These processes are typically subjected to stress conditions caused by: impacts to the active pharmaceutical ingredient during storage and transportation, wet granulation processes in drug production, seasonal and regional climate variations, and weather factors. High temperature and high humidity are the most common stress conditions. Crystal form transformations during these processes can lead to alterations in drug absorption or to toxicity and side effects. The excellent physical stability of crystal form A of compound 1 adipate ensures consistent and controllable quality of the active pharmaceutical ingredient and the finished drug product, minimizes toxicity caused by crystal transformation, and ensures the therapeutic efficacy of the drug.

[0038] In some embodiments, certain crystal forms described herein exhibit excellent chemical stability. For example, when stored in air at 40°C / 75%RH for two weeks, the purity of crystal form A of compound 1 adipate remains substantially unchanged. Chemical purity is crucial for ensuring drug efficacy and safety, and for preventing adverse reactions. If a drug contains impurities exceeding limits, its physicochemical properties and appearance can be altered, and stability can be affected. Increased impurities can also lead to reduced content of the active ingredient, decreased drug activity, and / or increased toxicity and side effects of the finished drug. The minimal change in purity of crystal form A of compound 1 adipate after storage and its non-degradability effectively minimize the potential risks of reduced drug purity, reduced drug efficacy, and increased toxicity.

[0039] In some embodiments, certain crystal forms described herein (e.g., crystal form AC of compound 1 adipate and crystal form AC of compound 1 free base) have virtually no residual organic solvents. Generally, if the residual organic solvents in a compound exceed relevant standards, the compound cannot be used as a pharmaceutical ingredient because many organic solvents are harmful to humans and the environment. Therefore, to ensure drug safety and product quality, the residual organic solvents in pharmaceutical ingredients must be minimized.

[0040] Other features, objectives, and advantages will be apparent from the specification and the claims.

Implementation Method

[0074] Detailed Description of Preferred Embodiments

[0075] This disclosure generally relates to the crystal forms of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (compound 1) and its salts, and methods for preparing and using such crystal forms. Crystal forms and preparation methods: Crystal form A of compound 1 adipate

[0076] In some embodiments, the present disclosure is characterized by crystal form A of compound 1 adipic acid salt. Typically, crystal form A of compound 1 adipic acid salt can be characterized by the relevant crystal system and relevant cell parameters. In some embodiments, crystal form A has a tetragonal crystal system, space group P41212, and cell parameters a=b=9.63 (1) Å, c=61.14 (2) Å, α=β=γ=90°, and V=5666 (5) Å3. Crystal form A of compound 1 adipic acid salt is considered to be an anhydrous compound.

[0077] In some embodiments, the crystal form A of compound 1 adipate comprises an XRPD pattern of at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 5.8 ± 0.2°, 21.1 ± 0.2°, and 23.3 ± 0.2°. In some embodiments, the XRPD pattern of crystal form A of compound 1 adipate also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 18.5 ± 0.2°, 19.4 ± 0.2°, and 29.2 ± 0.2°. In some embodiments, the XRPD pattern of crystal form A of compound 1 adipic acid salt also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, said diffraction peaks having a diffraction angle 2θ selected from the group consisting of 11.7 ± 0.2°, 13.7 ± 0.2°, and 20.7 ± 0.2°. In some embodiments, the XRPD pattern of crystal form A of compound 1 adipic acid salt includes at least one (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, or all) diffraction peaks from Table 3 below. In some embodiments, the XRPD pattern of crystal form A of compound 1 adipic acid salt is substantially as depicted in Figure 1.

[0078] In some embodiments, crystalline form A of compound 1 adipate may have relatively high solubility in a buffered aqueous solution at pH 1.0 or in simulated gastric juice (SGF), indicating that it readily dissolves in gastric juice in the stomach. For example, crystalline form A of compound 1 adipate may have a solubility of at least about 10 mg / mL (e.g., at least about 12 mg / mL, at least about 14 mg / mL, or at least about 15 mg / mL) to at most about 25 mg / mL (e.g., at most about 24 mg / mL, at most about 22 mg / mL, or at most about 20 mg / mL) in a buffered aqueous solution at pH 1.0 or in SGF.

[0079] Typically, the crystal form A of compound 1 adipate has excellent physical and / or chemical stability (e.g., at elevated temperatures such as 40°C, in environments with relatively high humidity such as at least 60% RH, and / or when exposed to light). For example, the crystal form A of compound 1 adipate is stable at room temperature for at least 36 months in a sealed container.

[0080] Typically, crystalline form A of compound 1 adipic acid salt has excellent solubility. For example, crystalline form A of compound 1 adipic acid salt may have a solubility of at least about 15 mg / mL (e.g., at least about 17 mg / mL) in simulated gastric juice or in a buffer solution at pH 1. Typically, crystalline form A of compound 1 adipic acid salt has very low or almost no hygroscopicity.

[0081] In some embodiments, crystalline form A of compound 1 adipic acid salt can be prepared by a method comprising the steps of: (1) mixing an amorphous form of compound 1 adipic acid salt with a solvent; and (2) adding an antisolvent to the mixture to obtain crystalline form A of compound 1 adipic acid salt. Typically, when an antisolvent is added to the mixture, white crystals appear within about 5 minutes to about 12 hours. In some embodiments, when no crystals appear when an antisolvent is added to the mixture, crystalline form A of compound 1 adipic acid salt can be obtained by removing the solvent and antisolvent through evaporation (e.g., by blow drying).

[0082] In some embodiments, the solvent suitable for preparing crystal form A of compound 1 adipate may include alcohol (e.g., ethanol or isopropanol), sulfoxide (e.g., dimethyl sulfoxide (DMSO)), or acetamide (dimethylformamide (DMF) or dimethylacetamide (DMAc)).

[0083] In some embodiments, the solvent suitable for preparing crystal form A of compound 1 adipate may include a hydrocarbon (e.g., heptane or toluene), an ether (e.g., tetrahydrofuran (THF) or methyl tributyl ether), a nitrile (e.g., acetonitrile), a ketone (e.g., acetone), an ester (e.g., ethyl acetate), or water. Crystal form B of compound 1 adipate

[0084] In some embodiments, the present disclosure is characterized by crystal form B of compound 1 adipic acid salt. In some embodiments, crystal form B of compound 1 adipic acid salt exhibits an XRPD pattern comprising at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 5.2 ± 0.2°, 7.2 ± 0.2°, and 20.9 ± 0.2°. In some embodiments, the XRPD pattern of crystal form B of compound 1 adipic acid salt further comprises at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 17.3 ± 0.2°, 20.5 ± 0.2°, and 22.2 ± 0.2°. In some embodiments, the XRPD pattern of crystal form B of compound 1 adipic acid salt also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, said diffraction peaks having a diffraction angle 2θ selected from the group consisting of 14.5 ± 0.2°, 25.7 ± 0.2°, and 26.2 ± 0.2°. In some embodiments, the XRPD pattern of crystal form B of compound 1 adipic acid salt includes at least one (e.g., two, three, four, five, six, seven, nine, ten, or all) diffraction peaks from Table 6 below. In some embodiments, the XRPD pattern of crystal form B of compound 1 adipic acid salt is substantially as depicted in Figure 5. Crystal form B of compound 1 adipic acid salt is considered to be a hydrate and comprises about 3.6 moles of water per mole of compound 1 adipic acid salt.

[0085] In some embodiments, the crystalline form B of compound 1 adipate can be prepared by a method comprising the steps of: (1) dissolving the amorphous form of compound 1 adipate in a solvent containing dichloromethane and methanol to form a solution; and (2) evaporating the solvent to obtain the crystalline form B of compound 1 adipate. In some embodiments, the volume ratio of dichloromethane to methanol in the solvent used in step (1) can be about 2:1 to about 1:2 (e.g., about 1:1). In some embodiments, the evaporation in step (2) can be performed by exposing the solution to air at room temperature (e.g., without heating or using rotary evaporation). Crystalline form C of compound 1 adipate

[0086] In some embodiments, the present disclosure is characterized by crystal form C of compound 1 adipic acid salt. In some embodiments, crystal form C of compound 1 adipic acid salt exhibits an XRPD pattern comprising at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 5.7 ± 0.2°, 21.0 ± 0.2°, and 23.2 ± 0.2°. In some embodiments, the XRPD pattern of crystal form C of compound 1 adipic acid salt further comprises at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 5.4 ± 0.2°, 13.6 ± 0.2°, and 29.2 ± 0.2°. In some embodiments, the XRPD pattern of crystal form C of compound 1 adipic acid salt also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, said diffraction peaks having a diffraction angle 2θ selected from the group consisting of 18.4 ± 0.2°, 20.6 ± 0.2°, and 21.7 ± 0.2°. In some embodiments, the XRPD pattern of crystal form C of compound 1 adipic acid salt includes at least one (e.g., two, three, four, five, six, seven, nine, ten, or all) diffraction peaks from Table 7 below. In some embodiments, the XRPD pattern of crystal form C of compound 1 adipic acid salt is substantially as depicted in Figure 9. Crystal form C of compound 1 adipic acid salt is considered to be a hydrate and comprises about 13 moles of water per mole of compound 1 adipic acid salt. Typically, crystal form C of compound 1 adipic acid salt has low hygroscopicity.

[0087] In some embodiments, the crystalline form C of compound 1 adipate can be prepared by a method comprising the following steps: (1) dissolving the amorphous form of compound 1 adipate in ethanol to form a solution; (2) adding acetone to the solution; and (3) removing the ethanol and acetone by evaporation to obtain the crystalline form C of compound 1 adipate. In some embodiments, the above method may further include stirring the solution for a longer period of time after step (2), for example, at least one hour (e.g., at least 5 hours, at least 10 hours, at least 24 hours). In some embodiments, the evaporation in step (3) can be carried out by drying the solution with nitrogen at room temperature (e.g., without heating or using rotary evaporation). Crystalline form D of compound 1 adipate

[0088] In some embodiments, the present disclosure is characterized by crystal form D of compound 1 adipic acid salt. In some embodiments, crystal form D of compound 1 adipic acid salt is represented by an XRPD pattern of at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 4.9 ± 0.2°, 19.4 ± 0.2°, and 21.6 ± 0.2°. In some embodiments, the XRPD pattern of crystal form D of compound 1 adipic acid salt also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 13.5 ± 0.2°, 21.3 ± 0.2°, and 24.3 ± 0.2°. In some embodiments, the XRPD pattern of crystal form D of compound 1 adipic acid salt also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, said diffraction peaks having a diffraction angle 2θ selected from the group consisting of 10.3 ± 0.2°, 16.4 ± 0.2°, and 20.5 ± 0.2°. In some embodiments, the XRPD pattern of crystal form D of compound 1 adipic acid salt includes at least one (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, or all) diffraction peaks from Table 8 below. In some embodiments, the XRPD pattern of crystal form D of compound 1 adipic acid salt is substantially as depicted in Figure 13. Crystal form D of compound 1 adipic acid salt is considered to be a DMAc solvate and comprises about 1.3 moles of DMAc per mole of compound 1 adipic acid salt. Typically, crystal form D of compound 1 adipic acid salt has low hygroscopicity.

[0089] In some embodiments, the crystal form D of compound 1 adipate can be prepared by a method comprising the following steps: (1) dissolving the amorphous form of compound 1 adipate in dimethylacetamide to form a solution; (2) adding acetone to the solution; and (3) removing the dimethylacetamide and acetone by evaporation to obtain the crystal form D of compound 1 adipate. In some embodiments, the above method may further include stirring the solution for a longer period of time after step (2), for example, at least one hour (e.g., at least 5 hours, at least 10 hours, at least 24 hours). In some embodiments, the evaporation in step (3) can be carried out by drying the solution with nitrogen at room temperature (e.g., without heating or using rotary evaporation). Crystal form A of the free base of compound 1

[0090] In some embodiments, the present disclosure is characterized by crystal form A of the free base of compound 1. In some embodiments, crystal form A of the free base of compound 1 is characterized by an XRPD pattern of at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 8.5 ± 0.2°, 12.7 ± 0.2°, and 19.1 ± 0.2°. In some embodiments, the XRPD pattern of crystal form A of the free base of compound 1 also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 16.9 ± 0.2°, 17.9 ± 0.2°, and 20.0 ± 0.2°. In some embodiments, the XRPD pattern of crystal form A of the free base of compound 1 also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, said diffraction peaks having a diffraction angle 2θ selected from the group consisting of 21.3 ± 0.2°, 25.6 ± 0.2°, and 34.1 ± 0.2°. In some embodiments, the XRPD pattern of crystal form A of the free base of compound 1 includes at least one (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, or all) diffraction peaks from Table 10 below. In some embodiments, the XRPD pattern of crystal form A of the free base of compound 1 is substantially as depicted in Figure 17. Crystal form A of the free base of compound 1 is considered to be a hydrate and comprises about 1 mole of water per mole of free base of compound 1.

[0091] Generally, crystal form A of the free base of Compound 1 exhibits excellent physical and / or chemical stability. For example, crystal form A of the free base of Compound 1 is stable for at least 36 months in a sealed container at room temperature. Furthermore, crystal form A of the free base of Compound 1 has very low or almost no hygroscopicity.

[0092] In some embodiments, crystal form A of the free base of Compound 1 can be prepared by a method comprising the following steps: mixing a base (e.g., an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide) with a solution of water and an alcohol (e.g., ethanol or isopropanol) comprising the hydrochloride salt of Compound 1 to obtain crystal form A of the free base of Compound 1. In some embodiments, the mixing step can be carried out at an elevated temperature (e.g., 60-70°C). In some embodiments, when no crystals form after mixing the base with the hydrochloride salt solution of Compound 1, the above method may further comprise adding seed crystals to the mixture to induce crystallization. In some embodiments, the method may further comprise cooling the mixture to a suitable temperature (e.g., -5-5°C) after the mixing step to promote crystallization. Crystal form B of the free base of Compound 1

[0093] In some embodiments, the present disclosure is characterized by crystal form B of the free base of compound 1. In some embodiments, crystal form B of the free base of compound 1 is characterized by an XRPD pattern of at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 6.1 ± 0.2°, 9.4 ± 0.2°, and 21.3 ± 0.2°. In some embodiments, the XRPD pattern of crystal form B of the free base of compound 1 also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 13.8 ± 0.2°, 18.8 ± 0.2°, and 20.7 ± 0.2°. In some embodiments, the XRPD pattern of crystal form B of the free base of compound 1 further includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, said diffraction peaks having a diffraction angle 2θ selected from the group consisting of 9.7 ± 0.2°, 11.0 ± 0.2°, and 11.9 ± 0.2°. In some embodiments, the XRPD pattern of crystal form B of the free base of compound 1 includes at least one (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, or all) diffraction peaks from Table 11 below. In some embodiments, the XRPD pattern of crystal form B of the free base of compound 1 is substantially as depicted in Figure 21. Crystal form B of the free base of compound 1 is considered to be an anhydrous compound.

[0094] In some embodiments, crystal form B of the free base of compound 1 can be prepared by a method comprising the following steps: (1) dispersing crystal form A of the free base of compound 1 in dichloromethane to form a dispersion (i.e., the crystals are not completely soluble in dichloromethane); and (2) stirring the dispersion at a temperature of about 45°C to about 55°C (e.g., about 50°C) to obtain crystal form B of the free base of compound 1. In some embodiments, the stirring step may be performed for at least 3 days (e.g., at least 7 days) and / or up to 10 days. In some embodiments, the above method may further comprise filtering the dispersion to obtain crystal form B of the free base of compound 1. Crystal form C of the free base of compound 1

[0095] In some embodiments, the present disclosure is characterized by crystal form C of the free base of compound 1. In some embodiments, crystal form C of the free base of compound 1 is characterized by an XRPD pattern of at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 18.6 ± 0.2°, 20.2 ± 0.2°, and 21.1 ± 0.2°. In some embodiments, the XRPD pattern of crystal form C of the free base of compound 1 also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 8.8 ± 0.2°, 16.2 ± 0.2°, and 20.6 ± 0.2°. In some embodiments, the XRPD pattern of crystal form C of the free base of compound 1 also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, said diffraction peaks having a diffraction angle 2θ selected from the group consisting of 15.6 ± 0.2°, 15.9 ± 0.2°, and 25.9 ± 0.2°. In some embodiments, the XRPD pattern of crystal form C of the free base of compound 1 includes at least one (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, or all) diffraction peaks from Table 12 below. In some embodiments, the XRPD pattern of crystal form C of the free base of compound 1 is substantially as depicted in Figure 25. Crystal form C of the free base of compound 1 is considered to be an anhydrous compound. Generally, crystal form C of the free base of compound 1 exhibits excellent physical stability.

[0096] In some embodiments, the crystal form C of the free base of compound 1 can be prepared by a method comprising the following steps: (1) dissolving the crystal form A of the free base of compound 1 in dichloromethane to form a solution (i.e., the crystals are completely dissolved in dichloromethane); and (2) removing the dichloromethane by evaporation to obtain the crystal form C of the free base of compound 1. In some embodiments, the evaporation can be carried out at elevated temperatures, such as about 45°C to about 55°C (e.g., about 50°C). Crystal form D of the free base of compound 1

[0097] In some embodiments, the present disclosure is characterized by crystal form D of the free base of compound 1. In some embodiments, crystal form D of the free base of compound 1 is represented by an XRPD pattern of at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 8.6 ± 0.2°, 18.4 ± 0.2°, and 20.9 ± 0.2°. In some embodiments, the XRPD pattern of crystal form D of the free base of compound 1 also includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, the diffraction peaks having diffraction angles 2θ selected from the group consisting of 15.5 ± 0.2°, 18.0 ± 0.2°, and 20.1 ± 0.2°. In some embodiments, the XRPD pattern of crystal form D of the free base of compound 1 further includes at least one (e.g., two or three) diffraction peaks obtained by using CuKα radiation, said diffraction peaks having a diffraction angle 2θ selected from the group consisting of 11.3 ± 0.2°, 15.7 ± 0.2°, and 16.0 ± 0.2°. In some embodiments, the XRPD pattern of crystal form D of the free base of compound 1 includes at least one (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, or all) diffraction peaks from Table 13 below. In some embodiments, the XRPD pattern of crystal form D of the free base of compound 1 is substantially as depicted in Figure 29. Crystal form D of the free base of compound 1 is considered to be a solvate / hydrate mixture.

[0098] In some embodiments, the crystal form D of the free base of compound 1 can be prepared by a method comprising the steps of: (1) dissolving the crystal form A of the free base of compound 1 in methanol to form a solution; (2) adding methyl tributyl ether to the solution; and (3) removing methanol and methyl tributyl ether by evaporation to obtain the crystal form D of the free base of compound 1. In some embodiments, evaporation can be performed using a rotary evaporator at an elevated temperature (e.g., about 40-45°C). Pharmaceutical Composition

[0099] This disclosure is further characterized by a pharmaceutical composition comprising a therapeutically effective amount of at least one (e.g., two or more) crystal form of compound 1 or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) as an active ingredient, and at least one pharmaceutically acceptable carrier (e.g., an adjuvant or diluent). Examples of pharmaceutically acceptable salts include acid addition salts, such as salts formed by the reaction of compound 1 with: hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), inorganic acids (e.g., sulfuric acid, phosphoric acid, and nitric acid), and aliphatic, alicyclic, aromatic, or heterocyclic sulfonic acids or carboxylic acids (e.g., formic acid, acetic acid, propionic acid, succinic acid, adipic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halobenzenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, and naphthalenesulfonic acid).

[0100] The carrier in the pharmaceutical composition must be "acceptable" (and preferably, capable of stabilizing the active ingredient) in relation to its compatibility with the active ingredient of the composition, and harmless to the subject to be treated. One or more solubilizers may be used as pharmaceutical carriers for delivering the crystalline form of compound 1 or its salts described herein. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium dodecyl sulfate, and D&C Yellow #10.

[0101] The pharmaceutical compositions described herein may optionally include at least one other additive selected from disintegrants, binders, lubricants, flavoring agents, preservatives, colorants, and any mixtures thereof. Examples of these and other additives can be found in "Handbook of Pharmaceutical Excipients"; edited by AH Kibbe, 3rd edition, American Pharmaceutical Association, USA and Pharmaceutical Press UK, 2000.

[0102] The pharmaceutical compositions described herein may be used for parenteral, oral, topical, nasal, rectal, buccal, or sublingual administration, or for administration via the respiratory tract, for example, in the form of aerosols or fine powders suspended in the air. As used herein, the term “parenteral” means subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intraperitoneal, intraocular, intraauricular, or intracranial injection, as well as any suitable infusion technique. In some embodiments, the composition may be in the form of tablets, capsules, powders, microparticles, granules, syrups, suspensions, solutions, nasal sprays, transdermal patches, injectable solutions, or suppositories.

[0103] The sterile injectable composition may be a solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable carriers and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils are commonly used as solvents or suspension media (e.g., synthetic mono- or diglycerides of glycerol). Fatty acids such as oleic acid and their glyceride derivatives may be used in the preparation of injectables because they are natural, pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethyleneized form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, hydroxymethyl cellulose, or similar dispersants. Other commonly used surfactants or other similar emulsifiers or bioavailability enhancers, such as Tweens or Spans, which are commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for formulation purposes.

[0104] Compositions for oral administration may be in any orally acceptable dosage form, including capsules, tablets, emulsions, aqueous suspensions, dispersants, and solutions. In the case of tablets, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are often added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When oral administration is in the form of an aqueous suspension or emulsion, the active ingredient may be suspended or dissolved in an oil phase in combination with an emulsifier or suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may be added.

[0105] Nasal aerosols or inhalation compositions may be prepared according to techniques known in the pharmaceutical formulation field. For example, such compositions may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0106] Compositions having one or more crystal forms of compound 1 or its salts can also be administered in the form of suppositories for rectal use. Treatment methods

[0107] Furthermore, this disclosure is characterized by methods for treating cancer or preparing medicaments for such treatments using crystalline forms of compound 1 as listed above or its salts. The method may include administering the pharmaceutical composition described herein to a subject in need (e.g., a patient) in an amount that is therapeutically effective for treating cancer (e.g., a solid tumor). In some embodiments, the cancer may have a ROS1 fusion mutation (e.g., in ROS1-positive cancer) or an NTRK fusion mutation, such as a fusion mutation in NTRK1, NTRK2, and / or NTRK3 (e.g., in NTRK-positive cancer). In some embodiments, the cancer may have a detectable increase in the expression level of the ROS1 gene and / or a detectable increase in the expression level of the NTRK gene. In some embodiments, the cancer may have detectable expression of the ROS1 fusion gene and / or detectable expression of the NTRK fusion gene. In some embodiments, the cancer may be treated by inhibiting ROS1 kinase activity and / or inhibiting NTRK kinase activity. Specific examples of such cancers (e.g., malignant cancers) include lung cancer (e.g., non-small cell lung cancer), thyroid cancer, colorectal cancer, leukemia, lymphoma, multiple myeloma, brain tumors, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumors, liver cancer, mesothelioma, kidney cancer, prostate cancer, neuroendocrine tumors, melanoma, breast cancer, endometrial cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma, sarcoma, bladder cancer, or testicular cancer, glioblastoma, and non-Hodgkin's lymphoma (e.g., anaplastic large cell lymphoma). In some embodiments, the cancer that can be treated by the crystal form described herein may be a systemic cancer, a recurrent cancer, or a refractory cancer. "Therapeutic effective amount" refers to the amount of pharmaceutical composition required to impart a therapeutic effect to a treated subject.

[0108] As used herein, the terms "treatment (treatment, treat, and treating)" refer to reversing, alleviating, or delaying the onset of cancer or one or more symptoms thereof, or inhibiting the progression of cancer or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In another embodiment, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., given a history of symptoms and / or given genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, thereby preventing or delaying their recurrence.

[0109] Typical doses of the crystalline form of compound 1 or its salts described herein may vary over a wide range and will depend on various factors, such as the type of disease being treated, individual patient needs, route of administration, excipient use, and the possibility of co-administration with other treatments. Exemplary daily doses may be at least about 0.1 mg (e.g., at least about 0.5 mg, at least about 1 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 50 mg, or at least about 100 mg) and / or up to about 800 mg (e.g., up to about 700 mg, up to about 600 mg, up to about 500 mg, up to about 400 mg, up to about 300 mg, up to about 200 mg, up to about 100 mg, up to about 75 mg, up to about 50 mg, up to about 20 mg, or up to about 15 mg). Those skilled in the art or physicians may consider variations in the dosage range and actual implementation to suit the situation being treated.

[0110] In some embodiments, the pharmaceutical composition described herein may be administered once daily. In some embodiments, the pharmaceutical composition may be administered more than once daily (e.g., twice daily, three times daily, or four times daily).

[0111] This disclosure is further characterized by a method for inhibiting the activity of ROS1 and / or NTRK kinases in cells (e.g., in a patient or in a tissue sample obtained from a patient). The method comprises contacting cells with a crystal form of the compound 1 described herein or a salt thereof in an amount sufficient to inhibit the activity of ROS1 and / or NTRK kinases in the cells.

[0112] All publications cited herein (e.g., patents, patent application publications, and articles) are incorporated herein by reference in their entirety.

[0113] The following examples are illustrative and not intended to be limiting. Examples: Instruments and Analytical Methods

[0114] The following instruments and measurement methods are used in the examples described below: X-ray powder diffraction

[0115] X-ray powder diffraction (XRPD) patterns were obtained using a Bruker D8 focusing X-ray powder diffractometer employing CuKα rays at 1.54056 Å at a voltage of 40 kV and a current of 40 mA. For each step, XRPD analysis was performed by measuring at the 2θ angle within a scan range of 3° to 42° with a scan step size of 0.02° and a scan time of 0.2 seconds. During the measurement, an appropriate amount of sample was placed on the sample plate of the diffractometer and flattened using a spatula or glass slide. Thermogravimetric analysis

[0116] Thermogravimetric analysis (TGA) was performed using a TA Instruments TGA Discovery 550. The sample was placed in an aluminum pan and weighed by the instrument. The sample was evaluated at a predetermined temperature using a linear heat ramp of 10°C / min under N2 (50 ml / min). Differential scanning calorimetry (DSC)

[0117] Differential scanning calorimetry (DSC) was performed using a TA Instruments Discovery DSC 25. The sample was weighed and placed in a covered aluminum pan. The sample was evaluated under N2 (50 ml / min) by linear heating at 10°C / min to the predetermined temperature. Dynamic vapor adsorption method.

[0118] Dynamic vapor adsorption (DVS) was performed using Intrinsic DVS (Surface Measurement Systems, UK). Samples were weighed in amounts of 20-30 mg and placed in the sample chamber. Measurements were performed in DMDT mode while maintaining the sample chamber temperature at 25 ± 1°C. Polarized light microscopy was also used.

[0119] Polarized light microscopy (PLM) was performed using a DM750P polarized light microscope. The magnification range was adjusted to obtain the morphology and microstructure of the sample. High-performance liquid chromatography (HPLC) was then used.

[0120] High-performance liquid chromatography (HPLC) was performed using the instruments and parameters summarized in Table 1. Table 1 HPLC Agilent 1260 (DAD detector) column Waters ACQUITY BEH C18, 2.1×75mm, 1.7µm mobile phase A: 10mM phosphate buffer (Ph=7.2):ACN:MeOH=34:3:3 (v / v / v) B: 10mM phosphate buffer (Ph=7.2):ACN:MeOH=6:17:17 (v / v / v) gradient Time (min) % B 0.0 14 0.5 14 15.5 86 15.51 14 19.0 14 speed 0.5 mL / min Injection volume 2µL Column temperature 50°C Sample plate temperature 10°C diluent Acetonitrile: H2O with 10mM NaOH = 50:50 (v / v) Example 1: Preparation and characterization of crystal form A of compound 1 adipate

[0121] A suitable amount of the amorphous form of compound 1 adipate was dissolved in 0.5 mL of solvent to form a solution. An antisolvent was added to the resulting solution to obtain a solid, confirming that the solid was crystalline form A of compound 1 adipate. If no solid was formed after adding the antisolvent, the solvent and antisolvent were removed by blowing dry to obtain a solid. Various solvents and antisolvents were used in the above experiments and are summarized in Table 2 below. Table 2 No. solvent Concentration (mg / mL) antisolvent Volume (mL) XRPD 1 EtOH 20.5 THF 5 amorphous 2 ACN 5 Crystal form A 3 water 5 Crystal form A 4 acetone 5 Crystal form C 5 EA 2 Crystal form A 6 heptane 5 Crystal form A 7 MTBE 5 Crystal form A 8 Toluene 5 Crystal form A 9 IPA 21.46 THF 5 amorphous 10 ACN 5 Crystal form A 11 water 5 Crystal form A 12 acetone 5 Crystal form A 13 EA 5 Crystal form A 14 heptane 1 Crystal form A 15 MTBE 3.5 Crystal form A 16 Toluene 5 Crystal form A 17 DMSO 60.82 THF 5 N / A 18 ACN 5 Crystal form A 19 water 5 Crystal form A 20 acetone 5 Crystal form A twenty one EA 5 Crystal form A twenty two Toluene 5 Crystal form A twenty three MTBE 1 Crystal form A twenty four DCM 5 Crystal form A 25 DMF 60.87 THF 5 Crystal form A 26 ACN 1.5 Crystal form A 27 water 5 Crystal form A 28 acetone 5 Crystal form A 29 EA 5 Crystal form A 30 Toluene 3 Crystal form A 31 MTBE 1.5 Crystal form A 32 DCM 5 Crystal form A 33 DMAc 59.88 THF 5 Crystal form A 34 ACN 4 Crystal form A 35 water 5 Crystal form A 36 acetone 5 Crystal form D 37 EA 5 Crystal form A 38 Toluene 5 Crystal form A 39 MTBE 2 Crystal form A 40 DCM 5 Crystal form A

[0122] As shown in Table 2, most solvent / antisolvent combinations form the crystal form A of compound 1 adipic acid salt, except for some solvent / antisolvent combinations that form the amorphous form, or crystal form C or D of compound 1 adipic acid salt.

[0123] The NMR data for crystal form A of compound 1 adipic acid salt are as follows: ¹H NMR (500 MHz, DMSO) δ 1.13-1.14 (d, J=5.0 Hz, 3H), 1.47-1.48 (d, J=5.0 Hz, 7H), 2.15-2.18 (t, J=5.0 Hz, J=10.0 Hz, 4H), 3.25-3.29 (m, 1H), 3.79-3.83 (m, 2H), 4.80-4.85 (m, 1H), 6.76-6.77 (d, J=5.0 Hz, 1H), 6.92-6.94 (d, J=10.0 Hz, 2H), 7.01-7.05 (t, J=10.0 Hz, 1H), 7.23-7.28(m, 2H), 7.37-7.42(m, 1H), 7.64-7.65(d, J=5.0 Hz, 1H), 7.72-7.76(t, J=10.0 Hz, 4H).

[0124] The IR data of crystal form A of compound 1 adipate are as follows: IR (cm-1): 1701, 1628, 1612, 1586, 1463, 1333, 1246, 1110, 829, 821.

[0125] A representative XRPD diagram of crystal form A obtained from compound 1 adipate is shown in Figure 1, and the XRPD data are listed in Table 3 below. Table 3

[0126] The TGA curve of crystal form A of compound 1 adipate is shown in Figure 2. As shown in Figure 2, crystal form A of compound 1 adipate exhibits a weight loss of 0.072% when heated to 150°C.

[0127] The DSC curve of crystal form A of compound 1 adipate is shown in Figure 3. As shown in Figure 3, crystal form A of compound 1 adipate exhibits an endothermic peak at 181.41°C.

[0128] The DVS curve of crystal form A obtained from compound 1 adipate is shown in Figure 4. As shown in Figure 4, crystal form A of compound 1 adipate exhibits a 0.235% weight increase at 80% RH, indicating low hygroscopicity. Furthermore, XRPD shows that the crystal form of the sample does not change before and after the DVS test.

[0129] The above results indicate that the crystal form A of compound 1 (adipate) is an anhydrous compound. Solubility

[0130] The solubility of compound 1 adipate crystal form A was evaluated using the following procedure. Specifically, 50 mg of compound 1 adipate crystal form A was mixed with 2 mL of the following media: (1) KCl / HCl buffer at pH 1.0, (2) potassium hydrogen phthalate buffer at pH 3.0, (3) sodium acetate trihydrate buffer at pH 4.5, (4) potassium dihydrogen phosphate buffer at pH 6.0, (5) potassium dihydrogen phosphate buffer at pH 7.5, (6) SGF (simulated gastric juice), (7) FaSSIF (simulated gastric juice under fasting conditions, pH = 6.5), (8) FeSSIF (simulated gastric juice under eating conditions, pH = 5.0), and (9) water. The mixtures were then stirred in a water bath at 37°C. After equilibration for 2 hours and 24 hours, the concentration of crystals (mg / mL) in the mixtures was measured by HPLC, and the undissolved solids were evaluated by XRPD. The results are summarized in Table 4 below. Table 4 No. medium pH after 24 hours XRPD Solubility at 2 hours (mg / mL) Solubility at 24 hours (mg / mL) 1 pH 1.0 3.746 Change 20.431 17.820 2 pH 3.0 4.418 Change 1.348 0.852 3 pH 4.5 4.541 Type A 2.839 2.885 4 pH 6.0 5.055 Type A 2.337 1.703 5 pH 7.5 5.570 Change 0.597 0.419 6 SGF 5.281 Change 15.611 15.990 7 FaSSIF 5.008 Change 0.331 0.225 8 FeSSIF 4.205 Type A 0.493 0.143 9 water 5.115 Type A 1.606 1.413

[0131] As shown in Table 4, the crystal form A of compound 1 adipic acid salt exhibits excellent solubility in buffer solution at pH 1.0 and in SGF. Stability

[0132] A predetermined amount of compound 1 adipate in crystal form A was stored under the following conditions: (1) exposure to air at 25°C / 60% RH for one or two weeks, (2) exposure to air at 40°C / 75% RH for one or two weeks, (3) exposure to air at 80°C for one day, and (4) exposure to light for 10 days. Crystal form and chemical impurities were examined by XRPD and HPLC, respectively. The results are summarized in Table 5. Table 5 No. condition time XRPD purity(%) 1 Starting materials Crystal form A 99.86 2 25°C / 60% RH 1 week Crystal form A 99.81 3 2 weeks Crystal form A 99.79 4 40°C / 75% RH 1 week Crystal form A 99.84 5 2 weeks Crystal form A 99.81 6 80°C 1 day Crystal form A 99.68 7 Exposure to light (1.2 million lux h) 10 days Crystal form A 99.79 8 Exposure to light (1.2 million lux h) 10 days Crystal form A 99.81

[0133] In Table 5, sample 1 is the starting material for crystal form A before any test; samples 2 and 3 were subjected to the above conditions (1); samples 4 and 5 were subjected to the above conditions (2); sample 6 was subjected to the above conditions (3); and samples 7 and 8 were subjected to the above conditions (4), with sample 7 being uncovered and sample 8 being completely covered with tin foil as a comparison. As shown in Table 5, crystal form A of compound 1 adipate exhibits excellent physical and chemical stability under stress conditions.

[0134] Accelerated stability tests were conducted on the crystal form A of compound 1 adipic acid salt by storing the sample at 40°C ± 2°C / 75 ± 5% RH for 6 months. The results are summarized in Table 6 below. Table 6 Storage conditions: 40 °C ± 2 °C / 75 ± 5% RH Inspection items Acceptance Standards 0 M 1 M 2 M 3 M 6 M Appearance White to pale yellow powder White powder White powder White powder White powder White powder Moisture content (KF) Report results 0.2% 0.1% 0.1% 0.1% 0.1% Related substances (UPLC) deF-6051 ≤ 0.50% ND ND ND ND ND Unspecified individual impurities ≤ 0.10% RRT1.48: 0.05% 0.05% 0.05% 0.05% 0.05% Total impurities ≤ 1.00% 0.05% 0.05% 0.05% 0.05% 0.05% Stereoisomers (HPLC) SR form ≤ 0.10% ND ND ND ND ND RS format ≤ 0.10% ND ND ND ND ND SS format ≤ 0.10% ND ND ND ND ND test DS-6051a (HPLC) / (Anhydrous and solvent-free base) 97.0–102.0% 99.5% 100.1% 99.6% 99.5% 99.0% Fatty acid (potentiometric titration) 25.2–27.8% 26.2% 26.5% 26.4% 26.2% 26.2% Crystal form (XRPD) The crystal form of the sample is consistent with that of the reference standard. Consistent Consistent Consistent Consistent Consistent Microbial limits Total aerobic microbial count ≤ 10 3 CFU / g < 100 CFU / g / / / < 100 CFU / g Total yeast and mold count ≤ 10 2 CFU / g < 100 CFU / g < 100 CFU / g E. coli Not present in 1 gram Does not exist Does not exist

[0135] As shown in Table 6, the crystal form A of compound 1 adipate exhibits excellent stability under the above accelerated test conditions.

[0136] The long-term stability of compound 1 adipate (crystal form A) was tested by storing the sample at 25°C ± 2°C / 60 ± 5% RH for 3 years. The results are summarized in Table 7 below. Table 7 Storage conditions: 25 °C ± 2 °C / 60 ± 5% RH Inspection items Acceptance Standards 0M 3M 6M 9M 12M 18M 24M 36M Appearance White to pale yellow powder White powder White powder White powder White powder White powder White powder White powder White powder deF-6051 ≤ 1.00% 0.46 0.46 0.45 0.46 0.46 0.46 0.45 0.44 Some unspecified impurities ≤ 0.30% Maximum value: 0.09 Maximum value: 0.09 Maximum value: 0.09 Maximum value: 0.09 Maximum value: 0.09 Maximum value: 0.09 Maximum value: 0.09 Maximum value: 0.09 Total impurities ≤ 3.00% 0.61 0.61 0.54 0.60 0.55 0.55 0.54 0.53 Moisture content Report results (%) 0.07 0.08 0.11 0.08 0.09 0.06 0.07 0.06 test (Anhydrous and solvent-free base) 97.0–102.0% 100.0 100.0 100.0 99.9 100.2 100.2 99.7 100.0

[0137] As shown in Table 7, crystal form A of compound 1 adipic acid salt exhibits excellent stability under the above-mentioned long-term test conditions. Example 2: Preparation and characterization of crystal form B of compound 1 adipic acid salt

[0138] 12 mg of the amorphous form of compound 1 adipic acid salt was placed in a 30 mL beaker. 1 mL of a 1:1 volume ratio mixture of dichloromethane and methanol was added to the beaker to dissolve the amorphous form of compound 1 adipic acid salt. The solvent was allowed to evaporate slowly at room temperature. After complete evaporation of the solvent, a solid was obtained and confirmed to be crystalline form B of compound 1 adipic acid salt.

[0139] The NMR data of crystal form B of compound 1 adipic acid salt are as follows: ¹H NMR (500 MHz, DMSO) δ 1.15 (br, 3H), 1.48 (br, 7H), 2.17 (br, 4H), 3.28 (br, 1H), 3.85 (br, 2H), 4.823 (br, 1H), 6.77 (br, 1H), 6.94 (br, 2H), 7.03 (br, 1H), 7.26 (br, 2H), 7.40 (br, 1H), 7.65 (br, 1H), 7.74 (br, 4H).

[0140] The IR data of crystal form B of compound 1 adipate are as follows: IR (cm-1): 3274, 3058, 2972, 2937, 2868, 1700, 1612, 1574, 1333, 1245, 1111, 829, 821.

[0141] A representative XRPD diagram of crystal form B obtained from compound 1 adipate is shown in Figure 5, and the XRPD data are listed in Table 8 below. Table 8

[0142] The TGA curve of crystal form B obtained from compound 1 adipate is shown in Figure 6. As shown in Figure 6, crystal form B of compound 1 adipate exhibits a weight loss of approximately 9.7% when heated to 150°C.

[0143] The DSC curve of crystal form B of compound 1 adipate is shown in Figure 7. As shown in Figure 7, crystal form B of compound 1 adipate exhibits an endothermic peak at 178.20°C.

[0144] The DVS curve of crystal form B obtained from compound 1 adipate is shown in Figure 8. As shown in Figure 8, crystal form B of compound 1 adipate exhibits a weight increase of approximately 8.2% at 80% RH, indicating that it is hygroscopic.

[0145] After heating the sample to 150°C, its XRPD showed a change in the crystal form of the sample.

[0146] The above results indicate that crystal form B of compound 1 adipic acid salt is a hydrate. Furthermore, it is believed that crystal form B of compound 1 adipic acid salt comprises approximately 3.6 moles of water per mole of compound 1 adipic acid salt. Example 3: Preparation and characterization of crystal form C of compound 1 adipic acid salt

[0147] 10 mg of the amorphous form of compound 1 adipic acid salt was placed in a 30 mL beaker. 0.5 mL of ethanol was added to the beaker to dissolve the amorphous form of compound 1 adipic acid salt. After adding 5 mL of acetone to the beaker, the solution was stirred at room temperature for one day. Then, a solid was obtained by purging the solution with nitrogen to remove the solvent, confirming that the solid was crystalline form C of compound 1 adipic acid salt.

[0148] The NMR data for the crystal form C of compound 1-adipate is as follows: ¹H NMR (500 MHz, DMSO) δ 1.13-1.14 (d, J=5.0 Hz, 3H), 1.47-1.48 (d, J=5.0 Hz, 7H), 2.14-2.18 (t, J=5.0 Hz, J=10.0 Hz, 4H), 3.25-3.29 (m, 1H), 3.81-3.88 (m, 2H), 4.81-4.86 (m, 1H), 6.76-6.78 (d, J=10.0 Hz, 1H), 6.93-6.94 (d, J=5.0 Hz, 2H), 7.01-7.05 (t, J=10.0 Hz, 1H), 7.23-7.28(m, 2H), 7.37-7.42(m, 1H), 7.64-7.65(d, J=5.0 Hz, 1H), 7.72-7.76(t, J=10.0 Hz, 4H).

[0149] The IR data of crystal form C of compound 1 adipate are as follows: IR (cm-1): 3275, 3057, 2974, 2939, 2868, 1700, 1612, 1583, 1333, 1245, 1110, 829, 821.

[0150] A representative XRPD diagram of crystal form C obtained from compound 1 adipate is shown in Figure 9, and the XRPD data are listed in Table 9 below. Table 9

[0151] The TGA curve of crystal form C obtained from compound 1 adipate is shown in Figure 10. As shown in Figure 10, crystal form C of compound 1 adipate exhibits a weight loss of approximately 38.1% when heated to 150°C.

[0152] The DSC curve of crystal form C of compound 1 adipate is shown in Figure 11. As shown in Figure 11, crystal form C of compound 1 adipate exhibits an endothermic peak at 179.67°C.

[0153] The DVS curve of crystal form C of compound 1 adipate is shown in Figure 12. As shown in Figure 12, crystal form C of compound 1 adipate shows a weight increase of about 1% at 80% RH, which indicates that it has low hygroscopicity.

[0154] After heating the sample to 160°C, its XRPD showed a change in crystal form.

[0155] The above results indicate that crystal form C of compound 1 adipic acid salt is a hydrate. Furthermore, it is believed that crystal form C of compound 1 adipic acid salt comprises approximately 13 moles of water per mole of compound 1 adipic acid salt. Example 4: Preparation and characterization of crystal form D of compound 1 adipic acid salt.

[0156] 30 mg of the amorphous form of compound 1 adipic acid salt was placed in a 30 mL beaker. 0.5 mL of dimethylacetamide (DMAc) was added to the beaker to dissolve the amorphous form of compound 1 adipic acid salt. After adding 5 mL of acetone to the beaker, the solution was stirred at room temperature for one day. Then, a solid was obtained by purging the solution with nitrogen to remove the solvent, confirming that the solid was crystalline form D of compound 1 adipic acid salt.

[0157] The NMR data for crystal form D of compound 1-adipate are as follows: ¹H NMR (500 MHz, DMSO) δ 1.10–1.12 (d, J=10.0 Hz, 3H), 1.47–1.49 (d, J=10.0 Hz, 7H), 1.96 (s, 3H), 2.17–2.20 (t, J=5.0 Hz, J=10.0 Hz, 4H), 2.78 (s, 3H), 2.94 (s, 3H), 3.21–3.24 (m, 1H), 3.83–3.86 (m, 2H), 4.82–4.85 (m, 1H), 6.76–6.78 (d, J=10.0 Hz, 1H). 6.93-6.94(d, J=5.0 Hz, 2H), 7.01-7.05(t, J=10.0 Hz, 1H), 7.23-7.28(m, 2H), 7.37-7.42(m, 1H), 7.63-7.64(d, J=5.0 Hz, 1H), 7.72-7.76(t, J=10.0 Hz, 4H).

[0158] The IR data of crystal form D of compound 1 adipate are as follows: IR (cm-1): 2937, 2873, 1628, 1613, 1583, 1457, 1333, 1242, 1110, 829, 821.

[0159] A representative XRPD diagram of crystal form D obtained from compound 1 adipate is shown in Figure 13, and the XRPD data are listed in Table 10 below. Table 10

[0160] The TGA curve of crystal form D obtained from compound 1 adipate is shown in Figure 14. As shown in Figure 14, crystal form D of compound 1 adipate exhibits a weight loss of approximately 14% when heated to 150°C.

[0161] The DSC curve of crystal form D of compound 1 adipate is shown in Figure 15. As shown in Figure 15, crystal form D of compound 1 adipate exhibits three endothermic peaks at 86.57°C, 96.33°C, and 175.11°C.

[0162] The DVS curve of crystal form D of compound 1 adipate is shown in Figure 16. As shown in Figure 16, crystal form D of compound 1 adipate shows a weight increase of about 0.34% at 80% RH, which indicates that it has low hygroscopicity.

[0163] The above results indicate that the crystal form D of compound 1 adipic acid salt is a DMAc solvate. Furthermore, it is believed that crystal form D of compound 1 adipic acid salt comprises approximately 1.3 moles of DMAc per mole of compound 1 adipic acid salt. Example 5: Preparation and characterization of crystal form A of the free base of compound 1.

[0164] Compound 1 HCl (75.5 g) (obtained, for example, by means of the method described in Example 5 of U.S. Patent Publication No. 2020 / 0062765) was dissolved in ethanol (604 mL) at 50°C. Sodium hydroxide (68.1 g) was added to the above solution. The mixture was cooled to 1°C over 1.5 hours and stirred for 18.5 hours. The mixture was then filtered, and the resulting solid was washed with a cooled mixture of ethanol (151 mL) and water (151 mL) and dried. The resulting solid was confirmed to be crystal form A of the free base of Compound 1.

[0165] The NMR data of crystal form A of the free base of compound 1 are as follows: ¹H NMR (500 MHz, DMSO) δ 1.09-1.10 (d, J=5.0 Hz, 3H), 1.48-1.49 (d, J=5.0 Hz, 3H), 3.16-3.20 (m, 1H), 3.75-3.79 (m, 2H), 4.82-4.86 (m, 1H), 6.76-6.78 (d, J=10.0 Hz, 1H), 6.92-6.94 (m, 2H), 7.01-7.05 (m, 1H), 7.23-7.28 (m, 2H), 7.37-7.42 (m, 1H), 7.62-7.63 (d, J=5.0 Hz, 3H), ... J=5.0 Hz, 1H), 7.72-7.75(m, 4H).

[0166] The IR data of crystal form A of the free base of compound 1 are as follows: IR (cm-1): 3350, 3247, 3055, 2961, 2923, 2864, 1611, 1586, 1349, 829, 819.

[0167] The representative XRPD of crystal form A obtained from the free base of compound 1 is illustrated in Figure 17, and the XRPD data are listed in Table 11 below. Table 11

[0168] The TGA curve of crystal form A obtained from the free base of compound 1 is shown in Figure 18. As shown in Figure 18, crystal form A of the free base of compound 1 exhibits a weight loss of approximately 4% when heated to 150°C.

[0169] The DSC curve of crystal form A of the free base of compound 1 is shown in Figure 19. As shown in Figure 19, crystal form A of the free base of compound 1 exhibits three endothermic peaks at 117.32°C, 168.67°C, and 178.29°C.

[0170] The DVS curve of crystal form A obtained from the free base of compound 1 is shown in Figure 20. As shown in Figure 20, crystal form A of the free base of compound 1 exhibits a weight increase of about 0.1% at 80% RH, indicating that it is almost non-hygroscopic.

[0171] XRPD showed that the crystal form of the sample did not change before and after the DVS test. On the other hand, XRPD showed that the crystal form changed after the sample was heated to 155°C.

[0172] The above results show that crystal form A of the free base of compound 1 is a hydrate. Furthermore, it is believed that crystal form A of the free base of compound 1 comprises approximately 1 mole of water per mole of the free base of compound 1. Example 6: Preparation and characterization of crystal form B of the free base of compound 1.

[0173] Approximately 50 mg of crystal form A of the free base of compound 1 was mixed with 1 mL of dichloromethane to form a dispersion. The resulting dispersion was stirred at 50°C for 3 or 7 days to obtain a solid, which was confirmed to be crystal form B of the free base of compound 1.

[0174] The NMR data of crystal form B of the free base of compound 1 are as follows: ¹H NMR (500 MHz, DMSO) δ 1.25-1.26 (d, J=4.0 Hz, 3H), 1.47-1.49 (d, J=8.0 Hz, 3H), 3.49-3.57 (m, 1H), 3.93-3.98 (m, 1H), 4.06-4.09 (m, 1H), 4.81-4.88 (m, 1H), 6.76-6.78 (d, J=8.0 Hz, 1H), 6.96-6.99 (m, 2H), 7.01-7.06 (m, 1H), 7.22-7.28 (m, 2H), 7.36-7.42 (m, 1H), 7.65-7.67(d, J=8.0 Hz, 1H), 7.74-7.80(m, 4H).

[0175] The IR data of crystal form B of the free base of compound 1 are as follows: IR (cm-1): 2960, 2910, 2846, 1624, 1611, 1586, 1335, 829.

[0176] The representative XRPD of crystal form B obtained from the free base of compound 1 is illustrated in Figure 21, and the XRPD data are listed in Table 12 below. Table 12

[0177] After removing the residual solvent, the TGA curve of crystal form B of the free base of compound 1 is shown in Figure 22. As shown in Figure 22, when heated to 150°C, crystal form B of the free base of compound 1 exhibits a weight loss of 0.005% (i.e., there is practically no weight loss).

[0178] The DSC curve of crystal form B obtained from the free base of compound 1 is shown in Figure 23. As shown in Figure 23, crystal form B of the free base of compound 1 exhibits an initial melting point of 143.10°C and a crystal transition peak at 184.68°C.

[0179] The DVS curve of crystal form B obtained from the free base of compound 1 is shown in Figure 24. As shown in Figure 24, crystal form B of the free base of compound 1 exhibits a 9.29% weight increase at 80% RH, indicating that it is hygroscopic.

[0180] XRPD showed that the crystal form of the sample did not change before and after the removal of residual solvent. On the other hand, XRPD showed that the crystal form of the sample changed before and after the DVS test.

[0181] The above results indicate that the crystal form B of the free base of compound 1 is an anhydrous compound. Example 7: Preparation and characterization of crystal form C of the free base of compound 1

[0182] Approximately 50 mg of crystal form A of the free base of compound 1 was mixed with 2 mL of dichloromethane. The mixture was heated to 50°C until the solid was completely dissolved. The solvent was evaporated at 50°C to obtain a solid, which was confirmed to be crystal form C of the free base of compound 1.

[0183] The NMR data of crystal form C of the free base of compound 1 are as follows: ¹H NMR (500 MHz, DMSO) δ 1.08-1.09 (d, J=5.0 Hz, 3H), 1.47-1.48 (d, J=5.0 Hz, 3H), 3.16-3.20 (m, 1H), 3.75-3.80 (m, 2H), 4.81-4.85 (m, 1H), 6.75-6.77 (d, J=10.0 Hz, 1H), 6.91-6.93 (m, 2H), 7.01-7.05 (m, 1H), 7.23-7.28 (m, 2H), 7.37-7.42 (m, 1H), 7.63-7.64 (d, J=5.0 Hz, 3H), ... J=5.0 Hz, 1H), 7.72-7.76(m, 4H).

[0184] The IR data of crystal form C of the free base of compound 1 are as follows: IR (cm-1): 1624, 1610, 1570, 1448, 1457, 1347, 829.

[0185] A representative XRPD diagram of crystal form C obtained from the free base of compound 1 is shown in Figure 25, and the XRPD data are listed in Table 13 below. Table 13

[0186] The TGA curve of crystal form C obtained from the free base of compound 1 is shown in Figure 26. As shown in Figure 26, crystal form C of the free base of compound 1 exhibits a weight loss of 0.107% when heated to 150°C.

[0187] The DSC curve of crystal form C of the free base of compound 1 is shown in Figure 27. As shown in Figure 27, crystal form C of the free base of compound 1 exhibits an endothermic peak at 167.45°C.

[0188] The DVS curve of crystal form C obtained from the free base of compound 1 is shown in Figure 28. As shown in Figure 28, crystal form C of the free base of compound 1 exhibits a weight increase of 5.468% at 80% RH, indicating that it is hygroscopic.

[0189] The XRPD of the samples was measured before and after the DVS test. The results showed no change in crystal form.

[0190] The above results indicate that the crystal form C of the free base of compound 1 is an anhydrous compound. Example 8: Preparation and characterization of crystal form D of the free base of compound 1.

[0191] 100 mg of crystal form A of the free base of compound 1 was mixed with 1 mL of methanol until the solid was completely dissolved. 10 mL of methyl tributyl ether (MTBE) was added to the above solution. The solvent in the resulting solution was removed by rotary evaporation at 40°C to obtain a solid, which was confirmed to be crystal form D of the free base of compound 1.

[0192] The NMR data for crystal form D of the free base of compound 1 are as follows: ¹H NMR (500 MHz, DMSO) δ 1.08-1.10 (d, J=8.0 Hz, 3H), 1.47-1.49 (d, J=8.0 Hz, 3H), 3.13-3.21 (m, 1H), 3.76-3.79 (m, 2H), 4.81-4.88 (m, 1H), 6.75-6.78 (d, J=12.0 Hz, 1H), 6.91-6.94 (m, 2H), 7.00-7.05 (m, 1H), 7.22-7.28 (m, 2H), 7.37-7.42 (m, 1H), 7.60-7.61 (d, J=8.0 Hz, 3H), ... J=4.0 Hz, 1H), 7.71-7.75(m, 4H).

[0193] The IR data of crystal form D of the free base of compound 1 are as follows: IR (cm-1): 1628, 1617, 1570, 1468, 1465, 1348, 1257, 1166, 830.

[0194] A representative XRPD diagram of crystal form D obtained from the free base of compound 1 is shown in Figure 29, and the XRPD data are listed in Table 14 below. Table 14

[0195] The TGA curve of crystal form D obtained from the free base of compound 1 is shown in Figure 30. As shown in Figure 30, crystal form D of the free base of compound 1 exhibits a weight loss of 1.263% when heated to 150°C.

[0196] The DSC curve of crystal form D of the free base of compound 1 is shown in Figure 31. As shown in Figure 31, crystal form D of the free base of compound 1 exhibits an endothermic peak at 177.64°C.

[0197] The DVS curve of crystal form D obtained from the free base of compound 1 is shown in Figure 32. As shown in Figure 32, crystal form D of the free base of compound 1 showed a weight increase of 2.896% at 80% RH, indicating that it has some hygroscopicity.

[0198] XRPD showed that the crystal form of the sample changed before and after the removal of residual solvent. On the other hand, XRPD showed that the crystal form of the sample did not change before and after the DVS test.

[0199] The above results indicate that the crystal form D of the free base of compound 1 is a mixture of solvate / hydrate.

[0200] Other embodiments are within the scope of the appended patent application. [Simplified Explanation of the Diagram]

[0041] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystal form A of compound 1 adipate.

[0042] Figure 2 shows the TGA curve of crystal form A of compound 1 adipate.

[0043] Figure 3 shows the DSC curve of crystal form A of compound 1 adipate.

[0044] Figure 4 shows the DVS curve of crystal form A of compound 1 adipate.

[0045] Figure 5 shows the XRPD diagram of crystal form B of compound 1 adipate.

[0046] Figure 6 shows the TGA curve of crystal form B of compound 1 adipate.

[0047] Figure 7 shows the DSC curve of crystal form B of compound 1 adipate.

[0048] Figure 8 shows the DVS curve of crystal form B of compound 1 adipate.

[0049] Figure 9 shows the XRPD diagram of crystal form C of compound 1 adipate.

[0050] Figure 10 shows the TGA curve of crystal form C of compound 1 adipate.

[0051] Figure 11 shows the DSC curve of crystal form C of compound 1 adipate.

[0052] Figure 12 shows the DVS curve of crystal form C of compound 1 adipate.

[0053] Figure 13 shows the XRPD diagram of crystal form D of compound 1 adipate.

[0054] Figure 14 shows the TGA curve of crystal form D of compound 1 adipate.

[0055] Figure 15 shows the DSC curve of crystal form D of compound 1 adipate.

[0056] Figure 16 shows the DVS curve of crystal form D of compound 1 adipate.

[0057] Figure 17 shows the XRPD diagram of crystal form A of the free base of compound 1.

[0058] Figure 18 shows the TGA curve of crystal form A of the free base of compound 1.

[0059] Figure 19 shows the DSC curve of crystal form A of the free base of compound 1.

[0060] Figure 20 shows the DVS curve of crystal form A of the free base of compound 1.

[0061] Figure 21 shows the XRPD diagram of crystal form B of the free base of compound 1.

[0062] Figure 22 shows the TGA curve of crystal form B of the free base of compound 1.

[0063] Figure 23 shows the DSC curve of crystal form B of the free base of compound 1.

[0064] Figure 24 shows the DVS curve of crystal form B of the free base of compound 1.

[0065] Figure 25 shows the XRPD diagram of crystal form C of the free base of compound 1.

[0066] Figure 26 shows the TGA curve of crystal form C of the free base of compound 1.

[0067] Figure 27 shows the DSC curve of crystal form C of the free base of compound 1.

[0068] Figure 28 shows the DVS curve of crystal form C of the free base of compound 1.

[0069] Figure 29 shows the XRPD diagram of crystal form D of the free base of compound 1.

[0070] Figure 30 shows the TGA curve of crystal form D of the free base of compound 1.

[0071] Figure 31 shows the DSC curve of crystal form D of the free base of compound 1.

[0072] Figure 32 shows the DVS curve of crystal form D of the free base of compound 1.

[0073] The same reference symbols in different figures represent the same elements.

Claims

1. A crystal form which is a free base of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (compound 1), wherein the crystal form exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks having diffraction angles of 2θ at 8.5 ± 0.2°, 12.7 ± 0.2°, and 19.1 ± 0.2° obtained by using CuKα rays.

2. The crystal form as claimed in claim 1, wherein the XRPD pattern further includes at least one peak having a diffraction angle 2θ of the group consisting of 16.9±0.2°, 17.9±0.2°, and 20.0±0.2° obtained by using CuKα rays.

3. The crystal form as claimed in claim 1, wherein the XRPD pattern further includes peaks with diffraction angles 2θ of 21.3±0.2°, 25.6±0.2°, and 34.1±0.2° obtained by using CuKα rays.

4. The crystal form as claimed in claim 1, wherein the XRPD pattern further comprises three diffraction peaks having diffraction angles 2θ of the group consisting of 16.9±0.2°, 17.9±0.2°, 20.0±0.2°, 21.3±0.2°, 25.6±0.2°, and 34.1±0.2° obtained by using CuKα rays.

5. The crystal form as claimed in claim 1, wherein the XRPD pattern further comprises diffraction peaks having diffraction angles 2θ of 16.9±0.2°, 17.9±0.2°, 20.0±0.2°, 21.3±0.2°, 25.6±0.2°, and 34.1±0.2° obtained by using CuKα rays.

6. The crystal form as described in claim 1, wherein the XRPD pattern further comprises three crystals selected at 11.2±0.2°, 12.4±0.2°, 14.4±0.2°, 15.6±0.2°, 16.9±0.2°, 17.9±0.2°, 20.0±0.2°, 21.3±0.2°, 21.8±0.2°, 22.1±0.2°, 24.1±0.2°, and 25.6±0.2°, obtained by using CuKα radiation. The diffraction peaks of the group consisting of diffraction angles 2θ, namely 27.2±0.2°, 27.7±0.2°, 28.7±0.2°, 29.4±0.2°, 30.1±0.2°, 31.3±0.2°, 32.4±0.2°, 33.3±0.2°, 33.9±0.2°, 34.1±0.2°, 35.1±0.2°, 36.2±0.2°, 37.3±0.2°, 40.2±0.2°, and 40.8±0.2°.

7. The crystal form as claimed in claim 1, wherein the crystal form of the free base of compound 1 is a hydrate.

8. A pharmaceutical composition comprising a crystal form as described in any one of claims 1-7 and a pharmaceutically acceptable carrier.

9. Use of a pharmaceutical composition as described in claim 8 for the preparation of a medicament for treating cancer.

10. The use as described in claim 9, wherein the cancer has a ROS1 fusion mutation.

11. The use as claimed in claim 9 or 10, wherein the cancer has a fusion mutation in NTRK1, NTRK2 or NTRK3.

12. The use as described in claim 9 or 10, wherein the cancer is non-small cell lung cancer.

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