Crystalline form of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-B]pyridazine-6-amine and its salts

Abstract

This provides a specific crystalline form of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine that has excellent physical properties (e.g., physical and chemical stability). [Solution] Provided are 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine having the following chemical structure, specific crystalline forms of its salts, and methods for preparing and using such crystalline forms. JPEG2026062769000017.jpg40153

Description

[Technical Field]

[0001] Technical field This disclosure relates to 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl The present invention relates to the crystalline forms of ethyl[1,2-b]pyridazine-6-amine and its salts, as well as to methods for preparing and using such crystalline forms. [Background technology]

[0002] background 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. It is an inhibitor and a neurotrophic tyrosine receptor kinase (NTRK) inhibitor, with the following chemical structure: [ka] It has.

[0003] The ROS1 gene encodes a receptor tyrosine kinase, which was discovered as a human ortholog of v-ros, an oncogene product of the aerosarcoma virus UR2 (University of Rochester oncovirus 2). The ROS1 fusion gene, obtained through chromosomal rearrangement involving the ROS1 gene and subsequent fusion of the ROS1 gene with another gene, was discovered in the glioblastoma cell line U118MG. In U118MG cells, the gene encoding the Golgi protein FIG (fused in glioblastoma) fuses with the ROS1 gene to form a gene encoding the FIG-ROS1 fusion protein. The fusion between FIG and ROS1 constitutively activates the ROS1 kinase enzyme activity. By undergoing structural changes, the FIG-ROS1 fusion protein possesses cell transformation and tumorigenic activity mediated by the activation of the ROS1 signaling pathway, including STAT3, ERK, and SHP2.

[0004] Chromosomal translocations of the ROS1 gene were also observed in the non-small cell lung cancer cell line HCC78 and in clinical lung cancer specimens. Identified. The fusion gene of the SLC34A2 gene and the ROS1 gene has been reported in HCC78 cells, and the transmembrane protein coding CD74-ROS1 fusion gene of the CD74 gene and the ROS1 gene. This gene has been reported in specimens from non-small cell lung cancer patients. It is a fusion gene of the FIG gene and the ROS1 gene. The gene was found in two of the 23 patient samples from bile duct cancer patients.

[0005] Large-scale screening of patient samples using FISH (fluorescence in situ hybridization) identified fusion genes of the ROS1 gene containing SDC, CD74, EZR, SLC34A2, LRIG3, or TPM3. One of the ROS1 fusion genes, SDC-ROS1, CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, LRIG3-ROS1, or TPM3-ROS1, was detected in 13 out of 1476 non-small cell lung cancer patient samples.

[0006] Similarly, a large-scale screening of non-small cell lung cancer patient samples using FISH revealed the ROS1 fusion gene in 18 out of 1073 cases. Furthermore, analysis of patient samples showed that the ROS1 gene is highly expressed in brain tumors.

[0007] ROS1 has been shown to be activated 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 ROS1 pathways that contribute to tumor growth and tumor cell survival, namely STAT3, ERK, and SHP2. For this reason, 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 enzyme activity.

[0008] Neurotrophic tyrosine receptor kinases, also known as tropomyosin-related kinases (Trk), These are high-affinity receptors activated by soluble growth factors called neurotrophins (NTs). The NTRK receptor family has three members: NTRK1 (also known as TrkA), NTRK2 (also known as TrkB), and NTRK3 (also known as TrkC).

[0009] NT includes several proteins such as: nerve growth factor (NGF) which activates NTRK1, and NTRK2 Examples include brain-derived neurotrophic factor (BDNF) and NT-4 / 5, which activate NTRK, and NT3, which activates NTRK3. Each NTRK receptor contains an extracellular domain (ligand-binding site), a transmembrane domain, and an intracellular domain (including a kinase domain). Upon binding to a ligand, each kinase catalyzes autophosphorylation, which then activates downstream signaling pathways.

[0010] NTRKs are widely expressed in nerve tissue during their developmental stages and play a crucial role in the maintenance and survival of these cells. Previous studies have shown that NTRKs play an important role in both the development and function of the nervous system.

[0011] Many references state that NTRK signaling is associated with cancer. For example, NTRK is present at low levels in non-nervous regions of adult humans, and NTRK expression is increased in the later stages of prostate cancer. In normal prostate tissue and early-stage androgen-dependent prostate tumors, NTRK1 is expressed only at low or undetectable levels, while neither NTRK2 nor NTRK3 are expressed. However, in later-stage androgen-independent prostate tumors... In cancer, all isoforms of the NTRK receptor and their ligands are overexpressed. Evidence indicates that these late-stage prostate cancer cells depend on NTRK for their tumor survival. Therefore, NTRK inhibitors may induce apoptosis in androgen-independent prostate cancer. Recent references also show that NTRK overexpression, activation, 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.

[0012] CEP-751, CEP-701, indolocarbazole compounds, oxindo Selective NTRK tyrosine kinase inhibitors have been reported, including tetramine compounds, pyrazolyl condensed ring compounds, isothiazole compounds, and various other compounds. [Overview of the Initiative]

[0013] overview This disclosure is based on the unexpected discovery that certain crystalline forms of compound 1 or its salts possess superior physical properties (e.g., physical and chemical stability).

[0014] In one aspect, the present disclosure shows that the crystal form A has a tetragonal crystal system and the space group is P41212. Furthermore, the unit cell parameters are a=b=9.63 (1) Å, c=61.14 (2) Å, α=β=γ=90° and V= 5666 (5) Å 33-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluoro phenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (Compound 1) adipate crystal form characterized by Form A.

[0015] In another aspect, the present disclosure features a method for preparing crystalline Form A of Compound 1 adipate. The method includes the step of mixing an amorphous form of Compound 1 adipate with a solvent; and adding an anti-solvent to the mixture to obtain crystalline Form A of Compound 1 adipate.

[0016] In another aspect, the present disclosure features crystalline Form B of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (Compound 1) adipate, which exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one 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° obtained using CuKα irradiation.

[0017] In another aspect, the present disclosure features a method for preparing crystalline Form B of Compound 1 adipate. The method includes the step of dissolving an amorphous form of Compound 1 adipate in a solvent comprising dichloromethane and methanol to form a solution; and evaporating the solvent to obtain crystalline Form B of Compound 1 adipate.

[0018] In another aspect, the present disclosure features crystalline form C of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (Compound 1) adipate, which exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one 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° obtained using CuKα irradiation.

[0019] In another aspect, the present disclosure features a method for preparing crystalline form C of Compound 1 adipate. The method comprises the steps of dissolving an amorphous form of Compound 1 adipate in ethanol to form a solution; adding acetone to the solution; and removing ethanol and acetone by evaporation to obtain crystalline form C of Compound 1 adipate. forming a solution; adding acetone to the solution; and removing ethanol and acetone by evaporation to obtain crystalline form C of Compound 1 adipate.

[0020] In another aspect, the present disclosure features crystalline form D of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine (Compound 1) adipate, which exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one 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° obtained using CuKα irradiation.

[0021] In another aspect, the present disclosure features a method for preparing crystalline form D of Compound 1 adipate. The method comprises the steps of dissolving an amorphous form of Compound 1 adipate in dimethylacetamide to form a solution; adding acetone to the solution; and removing dimethylacetamide and acetone by evaporation to obtain crystalline form D of Compound 1 adipate.

[0022] In another aspect, the present disclosure features a crystal morphology A of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) free base, wherein crystal morphology A exhibits an X-ray powder diffraction (XRPD) pattern including at least one 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° obtained using CuKα irradiation.

[0023] In another aspect, this disclosure features a method for preparing crystalline form A of compound 1 free base. The method involves mixing a base with a solution containing water and a compound 1 hydrochloride salt in an alcohol, The process includes obtaining crystalline form A of compound 1 free base.

[0024] In another aspect, the present disclosure relates to a crystal morphology B having at least one diffraction angle 2θ selected from the group consisting of 6.1±0.2°, 9.4±0.2°, and 21.3±0.2° obtained using CuKα irradiation. It is characterized by crystalline form B of the free base of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1), which exhibits an X-ray powder diffraction (XRPD) pattern containing 1 diffraction peak.

[0025] In another aspect, the present disclosure is characterized by a method for preparing crystalline form B of compound 1 free base. The method involves dispersing crystalline form A of compound 1 free base 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 form compound 1 free base. The process includes obtaining crystalline form B of the exobase.

[0026] In another aspect, this disclosure relates to a crystal morphology C obtained using CuKα irradiation of 18.6±0.2° , having a diffraction angle 2θ selected from the group consisting of 20.2±0.2° and 21.1±0.2° The X-ray powder diffraction (XRPD) pattern shows another diffraction peak, 3-{4-[(2R)-2-aminopro The free base of [poxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) is characterized by the crystalline form C.

[0027] In another aspect, the present disclosure features a method for preparing crystalline form C of compound 1 free base. The method includes the steps of: dissolving crystalline form A of compound 1 free base in dichloromethane to form a solution; and removing the dichloromethane by evaporation to obtain crystalline form C of compound 1 free base.

[0028] In another aspect, the present disclosure features a crystal morphology D of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound I) free base, wherein the crystal morphology D exhibits an X-ray powder diffraction (XRPD) pattern including at least one 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° obtained using CuKα irradiation.

[0029] In another aspect, the present disclosure is characterized by a method for preparing crystalline form D of free base compound 1. The method comprises the steps of: dissolving crystalline form A of free base compound 1 in methanol to form a solution; adding methyl tert-butyl ether to the solution; and evaporating the methanol. The process includes removing methyl tert-butyl ether to obtain the crystalline form D of compound 1 free base. nothing.

[0030] In another context, this disclosure relates to at least one crystalline form described herein; and The pharmaceutical composition is characterized by containing a pharmaceutically acceptable carrier.

[0031] In yet another aspect, the present disclosure features a method for treating cancer. The method includes administering a therapeutically effective amount of one of the pharmaceutical compositions described herein to a subject in need of treatment for cancer.

[0032] The embodiments described herein may have one or more of the following advantages:

[0033] In some embodiments, certain crystalline forms described herein have relatively low hygroscopicity. For example, the weight increase of crystalline forms A and D of compound 1-adipate at 80% RH is These are 0.235% and 0.34%, respectively. As another example, the weight increases of crystalline forms A, B, and C of compound 1 free base at 80% RH are 0.1%, 0.005%, and 0.107%, respectively. Hygroscopicity is the same as that of the drug. Hygroscopicity affects the stability of the substance, as well as its flowability and uniformity during the formulation process, thus impacting the quality of the drug product. Hygroscopicity also affects the preparation, storage, and subsequent handling of the drug. Crystalline forms with low hygroscopicity do not require specific storage conditions, reducing the costs of storage and quality control.

[0034] In some embodiments, the specific crystalline forms described herein have excellent physical stability. For example, crystalline form A of compound 1 adipate remains crystallinely unchanged for at least two weeks when stored in air under conditions of 40°C / 75%RH. Excellent physical stability The properties of the drug product are extremely important in drug discovery. During the manufacture of the drug product, (storage, transport and formulation) There are many processes (including those involved in storage and transportation). These processes often involve storage and transportation. The drug is subjected to stress conditions that can be caused by collisions between drug substances, the wet granulation process in drug manufacturing, seasonal and local climatic differences, and weather factors. High temperature and high humidity are the most common stress conditions. Changes in crystal morphology during these processes can cause changes in drug absorption or lead to toxicity and side effects. Compound 1 Crystallized form A of adipine salts ensures consistent and controllable quality of drug substances and drug products. Indeed, it possesses excellent physical stability that minimizes toxicity caused by crystallization and ensures the therapeutic effect of the drug.

[0035] In some embodiments, the specific crystalline forms described herein have excellent chemical stability. For example, when stored in air for two weeks under conditions of 40°C / 75%RH, the purity of crystalline form A of compound 1-adipate remains essentially unchanged. Chemical purity is important for drug efficacy and stability. Ensuring integrity and preventing adverse effects is extremely important. If a drug contains impurities above the limit, the physicochemical properties and appearance of the drug may change, and its stability may be affected. Increased impurities also lead to a decrease in the active ingredient content, a reduction in drug activity, and / or an increase in the toxicity and side effects of the drug product. The crystalline form A of compound 1 adipate shows little change in purity after storage and is non-degradable, which is Effectively minimize the potential risks of reduced drug purity, decreased drug efficacy, and increased toxicity.

[0036] In some embodiments, the specific crystalline forms described herein (e.g., crystalline forms A-C of compound 1 adipate and crystalline forms A-C of compound 1 free base) contain little to no residual organic solvent. Generally, if the residual organic solvent in a compound exceeds relevant standards, the compound cannot be used as a drug substance, as many organic solvents are harmful to humans and the environment. Therefore, it is necessary to minimize the residual organic solvent in drug substances to ensure drug safety and product quality.

[0037] Other features, purposes, and advantages are evident from the specification and claims. [Brief explanation of the drawing]

[0038] Description of the drawing [Figure 1]Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline form A of compound 1-adipate. [Figure 2] Figure 2 shows the TGA curve for crystalline form A of compound 1-adipate. [Figure 3] Figure 3 shows the DSC curve for crystalline form A of compound 1-adipate. [Figure 4] Figure 4 shows the DVS curve for crystalline form A of compound 1-adipate. [Figure 5] Figure 5 shows the XRPD pattern of crystalline form B of compound 1-adipate. [Figure 6] Figure 6 shows the TGA curve for crystalline form B of compound 1-adipate. [Figure 7] Figure 7 shows the DSC curve for crystalline form B of compound 1-adipate. [Figure 8] Figure 8 shows the DVS curve for crystalline form B of compound 1-adipate. [Figure 9] Figure 9 shows the XRPD pattern of crystalline form C of compound 1-adipate. [Figure 10] Figure 10 shows the TGA curve for crystalline form C of compound 1-adipate. [Figure 11] Figure 11 shows the DSC curve of crystalline form C of compound 1-adipinate. [Figure 12] Figure 12 shows the DVS curve for crystalline form C of compound 1-adipate. [Figure 13] Figure 13 shows the XRPD pattern of crystalline morphology D of compound 1-adipate. [Figure 14] Figure 14 shows the TGA curve for crystalline form D of compound 1-adipate. [Figure 15] Figure 15 shows the DSC curve for crystalline form D of compound 1-adipate. [Figure 16] Figure 16 shows the DVS curve for crystalline form D of compound 1-adipate. [Figure 17] Figure 17 shows the XRPD pattern of crystalline form A of compound 1 free base. [Figure 18]Figure 18 shows the TGA curve for crystalline form A of compound 1 free base. [Figure 19] Figure 19 shows the DSC curve of crystalline form A of compound 1 free base. [Figure 20] Figure 20 shows the DVS curve for crystalline form A of compound 1 free base. [Figure 21] Figure 21 shows the XRPD pattern of crystalline form B of compound 1 free base. [Figure 22] Figure 22 shows the TGA curve for crystalline form B of compound 1 free base. [Figure 23] Figure 23 shows the DSC curve of crystalline form B of compound 1 free base. [Figure 24] Figure 24 shows the DVS curve for crystalline form B of compound 1 free base. [Figure 25] Figure 25 shows the XRPD pattern of the crystalline form C of compound 1 free base. [Figure 26] Figure 26 shows the TGA curve for the crystalline form C of compound 1 free base. [Figure 27] Figure 27 shows the DSC curve of the crystalline form C of compound 1 free base. [Figure 28] Figure 28 shows the DVS curve for the crystal morphology C of compound 1 free base. [Figure 29] Figure 29 shows the XRPD pattern of crystalline form D of compound 1 free base. [Figure 30] Figure 30 shows the TGA curve for crystalline form D of compound 1 free base. [Figure 31] Figure 31 shows the DSC curve of crystalline form D of compound 1 free base. [Figure 32] Figure 32 shows the DVS curve for crystalline form D of compound 1 free base. [Modes for carrying out the invention]

[0039] Similar reference symbols in various drawings indicate the same elements.

[0040] Detailed explanation This disclosure generally refers to 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluor The present invention relates to the crystalline form of lophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) and its salt, as well as to methods for preparing and using such crystalline forms.

[0041] Crystal morphology and preparation method Crystal morphology of compound 1 adipine salt A In some embodiments, the disclosure features crystalline form A of compound 1-adipate. Generally, crystalline form A of compound 1-adipate can be characterized by relevant crystal system and relevant unit cell parameters. In some embodiments, crystalline form A is tetragonal It has a crystal system, its space group is P41212, and its unit cell parameter is a=b=9.63 (1) Å c=61.14 (2) Å, α=β=γ=90° and V=5666 (5) Å 3 Therefore, the crystalline form A of compound 1, adipine salt, is considered to be an anhydrous form.

[0042] In some embodiments, crystalline form A of compound 1 adipate is obtained using CuKα irradiation. The diffraction angle 2θ is selected from the group consisting of 5.8±0.2°, 21.1±0.2°, and 23.3±0.2°. The XRPD pattern shows at least one (e.g., two or three) diffraction peaks having the following characteristics. In one embodiment, the XRPD pattern of crystalline form A of compound 1 adipate is further CuKα Select from the group consisting of 18.5±0.2°, 19.4±0.2°, and 29.2±0.2° obtained using irradiation. The XRPD pattern of crystalline form A of compound 1 adipate is further irradiated with CuKα. Selected from the group consisting of 11.7±0.2°, 13.7±0.2°, and 20.7±0.2° obtained using [the specified method]. It includes at least one (e.g., 2 or 3) diffraction peaks with a diffraction angle of 2θ. In this case, the XRPD pattern of crystalline form A of compound 1 adipate is as shown in Table 3 below. At least one of the folding peaks (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15 or (All) are included. In some embodiments, the XRPD pattern of crystalline form A of compound 1 adipate The details are essentially as shown in Figure 1.

[0043] In some embodiments, crystalline form A of compound 1 adipinate is aqueous with a pH of 1.0. It may have relatively high solubility in buffer solutions or pseudo-gastric juice (SGF), and its crystalline form is similar to that of the stomach. It is suggested that it can be readily dissolved in gastric juice. 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 an aqueous buffer solution or SGF having a pH of 1.0.

[0044] Generally, crystalline form A of compound 1-adipate is physically and / or chemically stable. Having properties (for example, high temperatures such as 40°C and relatively high humidity such as at least 60% RH) (In the environment and / or under exposure to light). For example, crystalline form A of compound 1-adipate can be stable at room temperature for at least 36 months in a sealed container.

[0045] Generally, crystalline form A of compound 1 adipate has excellent solubility. For example, compound 1 Crystal form A of adipinate may have a solubility of at least about 15 mg / mL (e.g., at least about 17 mg / mL) in a simulated gastric juice or a buffer solution with a pH of 1. Generally, compound 1 adipinate Crystal morphology A of the phosphate salt has very low hygroscopicity or almost no hygroscopicity.

[0046] In some embodiments, the crystalline form A of compound 1 adipate is obtained by the following steps: (1) compound It can be prepared by a method comprising (2) mixing the amorphous form of compound 1-adipate with a solvent, and (3) adding a reverse solvent to the mixture to obtain crystalline form A of compound 1-adipate. Generally, when the reverse solvent is added to the mixture, white crystals can be seen in about 5 minutes to about 12 hours. In the case where no crystals are observed when the reverse solvent is added to the mixture, the solvent and reverse solvent can be removed by evaporation (e.g., by blow drying) to obtain crystalline form A of compound 1 adipate.

[0047] In some embodiments, suitable solvents for preparing crystalline form A of compound 1 adipinate include alcohols (e.g., ethanol or isopropanol) and sulfoxides (e.g., dimethyl (e.g., dimethylformamide (DMF) or dimethyl sulfoxide (DMSO)) or amide (e.g., dimethylformamide (DMF) or dimethyl sulfoxide) Luacetamide (DMAc) is one example.

[0048] In some embodiments, suitable solvents for preparing crystalline form A of compound 1 adipine salt include hydrocarbons (e.g., heptane or toluene), ethers (e.g., tetrahydrofuran (THF) or methyl tert-butyl ether), nitriles (e.g., acetonitrile), and ketones (e.g., Examples include acetone, esters (e.g., ethyl acetate), or water.

[0049] Crystal form B of compound 1 adipine salt In some embodiments, the present disclosure features crystalline form B of compound 1 adipate. In some embodiments, crystalline form B of compound 1 adipate is obtained using CuKα irradiation. The XRPD pattern shows at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ selected from the group consisting of 5.2±0.2°, 7.2±0.2°, and 20.9±0.2°. In this embodiment, the XRPD pattern of crystalline form B of compound 1 adipate is further determined by CuKα irradiation. Selected from the group consisting of 17.3±0.2°, 20.5±0.2°, and 22.2±0.2° obtained using [the specified method]. It includes at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ. In some embodiments, the XRPD pattern of crystalline form B of compound 1 adipate is further obtained by CuKα irradiation. The number of times selected from the group consisting of 14.5±0.2°, 25.7±0.2°, and 26.2±0.2° obtained It includes at least one (e.g., 2 or 3) diffraction peaks with angle 2θ. In some embodiments, the XRPD pattern of crystalline form B of compound 1 adipate is the diffraction peaks shown in Table 6 below. It includes at least one of the steps (e.g., 2, 3, 4, 5, 6, 7, 9, 10 or all of them). In some embodiments, the XRPD pattern of crystalline form B of compound 1 adipate is substantially shown in Figure 5. As stated above, the crystalline form B of compound 1 adipate is a hydrate, and the compound 1 Molar It is estimated that one unit of adipinate contains approximately 3.6 molars of water.

[0050] In some embodiments, the crystalline form B of compound 1 adipate is obtained by the following steps: (1) compound The amorphous form of substance 1, adipinate, is dissolved in a solvent containing dichloromethane and methanol. (1) A step of forming a solution; and (2) Evaporating the solvent to obtain crystalline form B of compound 1 adipate. It can be prepared by a method that includes the step of using The volume ratio of dichloromethane to methanol in the solvent may be in the range of about 2:1 to about 1:2 (e.g., about 1:1). In some embodiments, the evaporation in step (2) is (e.g., by heating) Alternatively, this can be done by exposing the solution to air at room temperature (without using rotary evaporation). It is possible.

[0051] Crystal form of compound 1 adipine salt C In some embodiments, the present disclosure features a crystalline form C of compound 1-adipate. In some embodiments, the crystalline form C of compound 1-adipate is obtained using CuKα irradiation. The diffraction angle 2θ is selected from the group consisting of 5.7±0.2°, 21.0±0.2°, and 23.2±0.2°. The XRPD pattern shows that it has at least one (e.g., two or three) diffraction peaks. In that embodiment, the XRPD pattern of the crystalline form C of compound 1 adipate is further expressed as CuKα-illuminated. The XRPD pattern of the crystalline form C of compound 1 adipate is further obtained using CuKα irradiation, and includes at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ selected from the group consisting of 5.4±0.2°, 13.6±0.2°, and 29.2±0.2°. The number of times selected from the group consisting of 18.4±0.2°, 20.6±0.2°, and 21.7±0.2° obtained by this process It includes at least one diffraction peak (e.g., 2 or 3) with an angle of 2θ. In some embodiments, the XRPD pattern of the crystalline form C of compound 1 adipate is the diffraction peak shown in Table 7 below. It includes at least one of the steps (e.g., 2, 3, 4, 5, 6, 7, 9, 10 or all of them). In some embodiments, the XRPD pattern of the crystalline form C of compound 1 adipate is substantially shown in Figure 9. As stated above, the crystalline form C of compound 1-adipic acid is a hydrate, and it is thought that each molar of compound 1-adipic acid contains approximately 13 molars of water. Generally, compound 1-adipic acid Salt crystal form C has low hygroscopicity.

[0052] In some embodiments, the crystalline form C of compound 1 adipate is obtained by the following steps: (1) compound (1) Dissolve the amorphous form of substance 1 adipinate in ethanol to form a solution; (2) Add acetone to the solution; and (3) Remove the ethanol and acetone by evaporation to form a solution. It may be prepared by a method that includes the step of obtaining the crystalline form C of compound 1-adipate. In some embodiments, the above method further involves stirring the solution for an extended period after step (2), for example, at least 1 hour (e.g., at least 5 hours, at least 10 hours, at least 24 hours). This may include the following. In some embodiments, the evaporation in step (3) involves blow-drying the solution using nitrogen at room temperature (without using, for example, heating or rotary evaporation). This can be implemented by [method].

[0053] Crystal morphology D of compound 1 adipinate In some embodiments, the present disclosure features crystalline form D of compound 1 adipate. In some embodiments, crystalline form D of compound 1 adipate is obtained using CuKα irradiation. The diffraction angle 2θ is selected from the group consisting of 4.9±0.2°, 19.4±0.2°, and 21.6±0.2°. The XRPD pattern shows that it has at least one (e.g., two or three) diffraction peaks. In that embodiment, the XRPD pattern of crystalline form D of compound 1 adipate is further CuKα-illuminated. Selected from the group consisting of 13.5±0.2°, 21.3±0.2°, and 24.3±0.2° obtained using the ray. It includes at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ. In some embodiments, the XRPD pattern of the crystalline form D of compound 1 adipate is further irradiated with CuKα. Select from the group consisting of 10.3±0.2°, 16.4±0.2°, and 20.5±0.2° obtained using the method. It includes at least one (e.g., 2 or 3) diffraction peaks with a diffraction angle of 2θ. In some embodiments, the XRPD pattern of crystalline form D of compound 1 adipate is the diffraction pattern shown in Table 8 below. It contains at least one peak (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, or all of them). In some embodiments, the XRPD pattern of crystalline form D of compound 1-adipate is substantially as shown in Figure 13. Crystalline form D of compound 1-adipate is a DMAc solvate and is thought to contain about 1.3 molars of DMAc per molar of compound 1-adipate. Generally, crystalline form D of compound 1-adipate salt has low hygroscopicity.

[0054] In some embodiments, the crystalline form D of compound 1 adipine salt is obtained by the following steps: (1) compound (1) A step of dissolving the amorphous form of substance 1 adipinate in dimethylacetamide to form a solution; (2) A step of adding acetone to the solution; and (3) Dimethylacetamide and acetone It can be prepared by a method that includes the step of removing by evaporation to obtain crystalline form D of compound 1 adipate. In some embodiments, the above method further includes an extended time after step (2). For example, at least 1 hour (for example, at least 5 hours, at least 10 hours, at least 24 hours) The step may include stirring the solution. In some embodiments, the evaporation in step (3) may be carried out by blow-drying the solution with nitrogen at room temperature (without using, for example, heating or rotary evaporation).

[0055] Crystal morphology of compound 1 free base A In some embodiments, the disclosure features a crystalline form A of compound 1 free base. In some embodiments, crystalline form A of compound 1 free base exhibits an XRPD pattern including at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ selected from the group consisting of 8.5±0.2°, 12.7±0.2°, and 19.1±0.2°, obtained using CuKα irradiation. Furthermore, the XRPD pattern of the crystalline form A of compound 1 free base was obtained using CuKα irradiation. It includes at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 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 the crystalline form A of compound 1 free base is further obtained using CuKα irradiation. 21.3 It includes at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ selected from the group consisting of ±0.2°, 25.6±0.2°, and 34.1±0.2°. In some embodiments, the XRPD pattern of crystalline form A of compound 1 free base includes at least one of the diffraction peaks in Table 10 below. For example, this includes 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15 or all of them). In some embodiments, the XRPD pattern of crystalline form A of compound 1 free base is substantially as shown in Figure 17. Crystalline form A of compound 1 free base is a hydrate and is thought to contain about 1 molar of water per molar of compound 1 free base.

[0056] Generally, the crystalline form A of compound 1 free base exhibits excellent physical and / or chemical stability. It possesses such properties. For example, crystalline form A of compound 1 free base can be stable at room temperature for at least 36 months in a sealed container. Furthermore, crystalline form A of compound 1 free base has very low hygroscopicity or almost no hygroscopicity.

[0057] In some embodiments, the crystalline form A of compound 1 free base is obtained by the following steps: base (e.g.) It can be prepared by a method comprising the step of mixing a solution containing the hydrochloride salt of compound 1 in water and alcohol (e.g., ethanol or isopropanol) with an alkali hydroxide (such as sodium hydroxide or potassium hydroxide) to obtain crystalline form A of compound 1 free base. In some embodiments, the mixing step may be carried out at a high temperature (e.g., 60-70°C). In some embodiments If crystals do not form after mixing the base and compound 1 hydrochloride solution, the above method further The method may include a step of adding a crystalline nuclide to the mixture to induce crystallization. In some embodiments, the method further involves cooling the mixture to a suitable temperature (e.g., -5 to 5°C) after the mixing step. This may include a step to facilitate crystallization.

[0058] Crystal morphology of compound 1 free base B In some embodiments, the disclosure features a crystalline form B of the free base of compound 1. In some embodiments, the crystalline form B of the free base of compound 1 has a small diffraction angle 2θ selected from the group consisting of 6.1±0.2°, 9.4±0.2°, and 21.3±0.2° obtained by CuKα irradiation. It exhibits an XRPD pattern containing at least one (e.g., two or three) diffraction peaks. In some embodiments, Furthermore, the XRPD pattern of the crystalline form B of compound 1 free base was obtained using CuKα irradiation. It includes at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 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 crystalline form B of compound 1 free base further includes at least one (e.g., 2 or 3) 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° obtained using CuKα irradiation. In some embodiments, the XRPD pattern of crystalline form B of compound 1 free base includes at least one of the diffraction peaks in Table 11 below (e.g., For example, this includes 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15 or all of them). In some embodiments, the XRPD pattern of crystalline form B of compound 1 free base is substantially as shown in Figure 21. Crystalline form B of compound 1 free base is considered to be anhydrous.

[0059] In some embodiments, crystalline form B of free compound 1 can be prepared by a method comprising the following steps: (1) dispersing crystalline form A of free compound 1 in dichloromethane to form a dispersion (i.e., the crystals are not completely dissolved in the dichloromethane); and (2) stirring the dispersion at a temperature of about 45°C to about 55°C (e.g., about 50°C) to obtain crystalline form B of free compound 1. In some embodiments, the stirring step is performed for at least 3 days (e.g., at least 7 The procedure may be carried out for several days and / or at most 10 days. In some embodiments, the above method may further include filtering the dispersion to obtain crystalline form B of compound 1 free base.

[0060] Crystal form of compound 1 free base C In some embodiments, the present disclosure is characterized by the crystalline form C of compound 1 free base. In some embodiments, the crystalline form C of compound 1 free base is obtained by CuKα irradiation. The XRPD pattern shows at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ selected from the group consisting of ±0.2°, 20.2±0.2°, and 21.1±0.2°. Several embodiments In this case, the XRPD pattern of the crystalline form C of compound 1 free base was further obtained using CuKα irradiation. The diffraction angle 2θ is selected from the group consisting of 8.8±0.2°, 16.2±0.2°, and 20.6±0.2°. It includes at least one (e.g., two or three) diffraction peaks having the following characteristics. In some embodiments Furthermore, the XRPD pattern of the crystalline form C of compound 1 free base has a diffraction angle 2θ selected from the group consisting of 15.6±0.2°, 15.9±0.2°, and 25.9±0.2° obtained using CuKα irradiation. It includes at least one (e.g., 2 or 3) diffraction peaks. In some embodiments, the XRPD pattern of the crystalline form C of compound 1 free base includes at least one (e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15 or all) of the diffraction peaks in Table 12 below. In this embodiment, the XRPD pattern of crystalline form C of compound 1 free base is substantially as shown in Figure 25. Crystallographic form C of compound 1 free base is considered to be an anhydrous form. In general, crystalline form C of compound 1 free base has excellent physical stability.

[0061] In some embodiments, crystalline form C of free compound 1 can be prepared by a method comprising the following steps: (1) dissolving crystalline form A of free 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 crystalline form C of free compound 1. In this case, evaporation can be carried out at high temperatures such as approximately 45°C to approximately 55°C (for example, approximately 50°C).

[0062] Crystal morphology of compound 1 free base D In some embodiments, the disclosure features a crystalline form D of compound 1 free base. In some embodiments, the crystalline form D of compound 1 free base exhibits an XRPD pattern containing at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ selected from the group consisting of 8.6±0.2°, 18.4±0.2°, and 20.9±0.2° obtained using CuKα irradiation. Furthermore, the XRPD pattern of the crystalline form D of compound 1 free base was obtained using CuKα irradiation. It includes at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 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 the crystalline form D of compound 1 free base is further obtained using CuKα irradiation. It includes at least one (e.g., 2 or 3) diffraction peaks having a diffraction angle 2θ selected from the group consisting of ±0.2°, 15.7±0.2°, and 16.0±0.2°. In some embodiments, the XRPD pattern of crystalline form D of compound 1 free base includes at least one of the diffraction peaks in Table 13 below. For example, including 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15 or all of them). In some embodiments, the XRPD pattern of crystalline form D of compound 1 free base is substantially as shown in Figure 29. Crystalline form D of compound 1 free base is considered to be a mixture of solvate / hydrate. It can be done.

[0063] In some embodiments, the crystalline form D of compound 1 free base is obtained by the following steps: (1) dissolving the crystalline form A of compound 1 free base in methanol to form a solution; (2) methyl tert-butyl The compound may be prepared by a method comprising the steps of (3) adding ether to a solution, and (4) removing methanol and methyl tert-butyl ether by evaporation to obtain crystalline form D of compound 1 free base. In some embodiments, evaporation may be carried out at a high temperature (e.g., about 40-45°C) using a rotary evaporator.

[0064] Pharmaceutical composition This disclosure also features a pharmaceutical composition comprising, as an active ingredient, at least one (e.g., two or more) crystalline forms of compound 1 or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) in a therapeutically effective amount, and at least one pharmaceutically acceptable carrier (e.g., an adjuvant or diluent). Examples of pharmaceutically acceptable salts include acid addition salts, e.g., compound 1 and hydrogen halides. 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, Formed by the reaction between 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. Salt is one example.

[0065] The carrier in the pharmaceutical composition is compatible with the active ingredients of the composition (and preferably has "Permitted" means that the active ingredient can be stabilized and is not harmful to the subject being treated. It must be "solubilizable". One or more solubilizers may be used as pharmaceutical carriers for the delivery of compound 1 or a salt thereof as described herein in crystalline form. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0066] The pharmaceutical compositions described herein may optionally include at least one further addition selected from disintegrants, binders, lubricants, flavoring and odor-correcting agents, preservatives, colorants, and any mixture thereof. It may contain an additive. Examples of such additives and other additives can be found in the "Handbook of Pharmaceuticals E "xcipients"; can be found in Ed. AH Kibbe, 3rd Ed., American Pharmaceutical Association, USA and Pharmaceutical Press UK, 2000.

[0067] The pharmaceutical compositions described herein may be adapted for parenteral, oral, topical, nasal, rectal, cheek, or sublingual administration or administration via the airway, for example, in the form of aerosols or air-suspended fine powders. The term “parenteral” as used herein means subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-bursal, intrasternal, intra-shear, intra-lesional, intraperitoneal, intraocular, intra-aural or intracranial injection and any appropriate infusion technique. In some embodiments, the compositions may be in the form of tablets, capsules, powders, microparticles, granules, syrups, suspensions, solutions, nasal sprays, transdermal patches, injectable solutions or suppositories.

[0068] The sterile injection composition may be a solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, a fixing oil may be used as a solvent or suspension medium, as has been conventionally done (e.g., synthetic monoxide). (Non- or diglyceride). Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable preparations, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, carboxymethylcellulose or similar dispersants, and other commonly used surfactants such as Tween or Span. Other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms may also be used for formulation purposes.

[0069] Compositions for oral administration may be any orally acceptable dosage form, such as capsules, tablets, emulsions and aqueous suspensions, dispersants and solutions. For tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent. Specific sweeteners, flavoring agents, or colorants may be added if desired.

[0070] Nasal aerosols or inhalation compositions can be prepared according to techniques well known in the field of pharmaceutical formulation. For example, such compositions may contain benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and / or other technical components. It can be prepared as a solution in saline solution using other solubilizers or dispersants known in the field.

[0071] Compositions having one or more compounds or salts thereof in crystalline form may also be administered in the form of suppositories for rectal administration.

[0072] Treatment method Furthermore, this disclosure features a method for using a crystalline form of compound 1 or a salt thereof outlined above for the treatment of cancer or for the manufacture of a medicament for such treatment. The procedure may include administering to a subject (e.g., a patient) in need of treatment for cancer (e.g., a solid tumor) a therapeutically effective amount of the pharmaceutical composition described herein 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, e.g., in NTRK1, NTRK2 and / or NTRK3 (e.g., in NTRK-positive cancer). In some embodiments, the cancer may have a ROS1 gene expression level detection It may have a detectable increase and / or a detectable increase in the expression level of the NTRK gene. In some aspects, cancer is characterized by the detectable expression of ROS1 fusion genes and / or NTRK fusion genes. The gene may have detectable expression. In some embodiments, cancer may be treatable by inhibiting ROS1 kinase enzyme activity and / or NTRK kinase enzyme activity. Specific examples of cancer (e.g., malignant cancer) include lung cancer (e.g., non-small cell lung cancer), thyroid cancer, colorectal cancer, leukemia, lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendiceal cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumor, liver cancer, mesothelioma, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, uterine cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma, myasthenia masculinoma, bladder cancer, or testicular cancer, gliablastoma, and non-Hodgkin lymphoma (for example) Examples include anaplastic large cell lymphoma. In some embodiments, as described herein Cancers that can be treated by this crystalline form may be systemic cancers, recurrent cancers, or treatment-resistant cancers. "Therapeutic dose" refers to the amount of pharmaceutical composition necessary to impart a therapeutic effect to the subject being treated.

[0073] As used herein, the terms “treatment,” “treat,” and “treating” mean cancer or one or more of its symptoms, as described herein. This refers to reversing, mitigating, delaying, or inhibiting the onset of a condition. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment Treatment may be administered in the absence of symptoms. For example, treatment may be administered (for example, in light of the medical history of symptoms). Treatment may be administered to susceptible individuals before the onset of symptoms (in light of genetic or other factors of susceptibility). Treatment may also be continued after symptoms have subsided, for example, to prevent or delay their recurrence.

[0074] Typical doses of compound 1 or its salt in crystalline form as described herein are within a wide range. The dosage may vary and depends on various factors such as the type of disease being treated, the individual needs of each patient, the route of administration, the use of excipients, and the possibility of co-use with other therapeutic measures. An exemplary daily dose is 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 at most about 800 mg (e.g., For example, at most about 700mg, at most about 600mg, at most about 500mg, at most about 400mg, at most about 300mg, at most about 200mg, at most about 100mg, at most about 75mg, at most about 50mg, It may be approximately 20 mg or at most approximately 15 mg. Those skilled in the art or physicians should take the situation into consideration. To that end, relevant variations in this dose range and actual implementation may be considered.

[0075] In some embodiments, the pharmaceutical compositions described herein may be administered once daily. In some embodiments, the pharmaceutical compositions may be administered more than once daily (e.g., twice daily, three times daily). It may be administered once or four times a day.

[0076] This disclosure also features a method for inhibiting ROS1 and / or NTRK kinase enzyme activity in cells (e.g., in a patient's body or in a tissue sample obtained from a patient). The method involves cells and The process includes contacting a crystalline form of compound 1 or a salt of the compound described herein in an amount sufficient to inhibit ROS1 and / or NTRK kinase enzyme activity in cells.

[0077] All publications cited herein (e.g., patents, patent application publications, and articles) are incorporated herein by reference in their entirety.

[0078] The following examples are illustrative and not intended to be limiting. [Examples]

[0079] Examples Instruments and analytical methods The following instruments and measurement methods were used in the examples described below:

[0080] X-ray powder diffraction The X-ray powder diffraction (XRPD) pattern was obtained by irradiating CuKα at 1.54056 Å with a voltage of 40 kV and a current of 40 mA. The XRPD fraction was obtained using a Bruker D8 Focus X-ray powder diffractometer. The analysis was performed by measuring at an angle of 2θ within a scanning range of 3° to 42°, using a scanning step of 0.02° and a scan time of 0.2 seconds for each step. During the measurement, an appropriate amount The sample was placed on a diffractometer sample plate and flattened using a spatula or glass slide.

[0081] thermogravimetric analysis Thermogravimetric analysis (TGA) was performed using a TA Instruments TGA Discovery 550. The sample was then... The weight was measured using an instrument after placing it in an aluminum pan. A linear thermal gradient of 10°C / min was applied to the specified temperature. The samples were evaluated under N2 (50 ml / min) conditions using this method.

[0082] Differential scanning calorimetry Differential scanning calorimetry (DSC) was performed using a TA Instruments Discovery DSC 25. The sample was weighed and placed in a covered aluminum pan. A linear thermal gradient of 10°C / min was used to raise the sample to the target temperature. The samples were evaluated under N2 (50 ml / min) conditions using a skewer.

[0083] Dynamic water vapor adsorption Dynamic water vapor adsorption (DVS) was performed using DVS (Surface Measurement Systems, UK). Samples were weighed in quantities of 20-30 mg and placed in the sample chamber. Measurements were performed in DMDT mode when the sample chamber temperature was maintained at 25±1°C.

[0084] Polarized light microscopy Polarized light microscopy (PLM) was performed using a DM750P polarized light microscope. The morphology and microscopic details of the sample were examined. The magnification range was adjusted to obtain the desired structure.

[0085] High-pressure liquid chromatography High-pressure liquid chromatography (HPLC) uses the equipment and parameters summarized in Table 1. They used it. [Table 1]

[0086] Example 1: Preparation and characterization of crystalline form A of compound 1 adipate. An appropriate amount of compound 1-adipinate in amorphous form was dissolved in 0.5 mL of solvent to form a solution. A reverse solvent was added to the resulting solution to obtain a solid, which is the compound 1-adipinate. It was confirmed that the crystal form was A. If no solid was formed after the addition of the reverse solvent, The solvent and reverse solvent were removed by drying to obtain a solid. Several solvents and reverse solvents used in the above experiments are summarized in Table 2 below. [Table 2]

[0087] As shown in Table 2, certain solvent / reverse solvent combinations result in amorphous form or compound 1 azipi Except for the formation of crystalline form C or D of the phosphate salt, most solvent / reverse solvent combinations are chemical. The compound 1 adipinate formed crystalline form A.

[0088] The NMR data for crystalline form A of compound 1-adipate 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).

[0089] The IR data for crystalline form A of compound 1 adipate is as follows: IR (cm -1 ): 1701, 1628, 1612, 1586, 1463, 1333, 1246, 1110, 829, 821.

[0090] A representative XRPD pattern obtained from crystalline form A of compound 1 adipate is shown in Figure 1, and the XRPD data is listed in Table 3 below. [Table 3]

[0091] Figure 2 shows the TGA curve obtained from crystalline form A of compound 1 adipate. The crystalline form A of compound 1-adipate shows a 0.072% weight loss when heated to 150°C. This was shown.

[0092] Figure 3 shows the DSC curve obtained from crystalline form A of compound 1 adipate. The crystalline form A of compound 1 adipinate showed an endothermic peak at 181.41°C.

[0093] Figure 4 shows the DVS curve obtained from crystalline form A of compound 1 adipate. The crystalline form A of compound 1 adipate showed a weight increase of 0.235% at 80% RH, which is low. It exhibited high hygroscopicity. Furthermore, XRPD showed no change in the crystal morphology of the sample before and after the DVS test. This indicates that.

[0094] The above results suggest that the crystalline form A of compound 1 adipine salt is an anhydrous form.

[0095] solubility The solubility of crystalline form A of compound 1-adipate was evaluated using the following procedure. Specifically, 50 mg of crystalline form A of compound 1-adipate was mixed with 2 mL of the following media: (1) KCl / HCl buffer solution with a pH of 1.0, (2) potassium hydrogen phthalate buffer solution with a pH of 3.0, (3) sodium acetate trihydrate buffer solution with a pH of 4.5, (4) potassium dihydrogen phosphate buffer solution with a pH of 6.0, (5) potassium dihydrogen phosphate buffer solution with a pH of 7.5, (6) SGF (simulated gastric juice), (7) FaSSIF (simulated intestinal fluid under fasting conditions, pH=6.5), (8) FeSSIF (simulated intestinal fluid under feeding conditions, pH=5.0), and (9) water. Each mixture was then stirred in a water bath at 37°C for 2 hours. After 24 hours of equilibration, the concentration of crystals in the mixture (mg / mL) was measured by HPLC, and the undissolved crystals were... The solids were evaluated using XRPD. The results are summarized in Table 4 below. [Table 4]

[0096] As shown in Table 4, crystalline form A of compound 1 adipate showed excellent solubility in a buffer and SGF with a pH of 1.0.

[0097] stability A predetermined amount of compound 1 adipate in crystalline form A is subjected to the following conditions: (1) exposed to air. The samples were stored (1) at 25°C / 60%RH for 1 or 2 weeks, (2) open to air, at 40°C / 75%RH for 1 or 2 weeks, (3) open to air, at 80°C for 1 day, and (4) exposed to light for 10 days. Crystal morphology and chemical impurities were checked by XRPD and HPLC, respectively. The results are summarized in Table 5. [Table 5]

[0098] In Table 5, sample number 1 is the material that started with crystalline morphology A before any of the tests; sample number Samples 2 and 3 were subjected to condition (1) above; samples 4 and 5 were subjected to condition (2) above; sample 6 was subjected to condition (3) above; and samples 7 and 8 were subjected to condition (4) above, where sample 7 was uncovered and sample 8 was completely covered with tin foil for comparison. As shown in Table 5, crystalline form A of compound 1 adipate showed excellent physical and chemical stability under stress conditions.

[0099] The samples were stored at 40°C ± 2°C / 75 ± 5% RH for 6 months, and accelerated stability testing was performed on crystalline form A of compound 1-adipate. The results are summarized in Table 6 below. [Table 6-1] [Table 6-2]

[0100] As shown in Table 6, the crystalline form A of compound 1 adipine salt was obtained under the accelerated test conditions above. It showed excellent stability below.

[0101] By storing the sample at 25°C ± 2°C / 60 ± 5% RH for 3 years, crystals of compound 1-adipate were obtained. A long-term stability test was conducted on form A. The results are summarized in Table 7 below. [Table 7]

[0102] As shown in Table 7, crystalline form A of compound 1 adipinate under the above long-term test conditions. It demonstrated excellent stability.

[0103] Example 2: Preparation and characterization of crystalline form B of compound 1 adipate 12 mg of the amorphous form of compound 1-adipinate 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-adipinate. The solvent was slowly evaporated at room temperature. After the solvent had completely evaporated, a solid was obtained, which was confirmed to be the crystalline form B of compound 1-adipinate.

[0104] The NMR data for crystalline form B of compound 1-adipate 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).

[0105] The IR data for crystalline form B of compound 1 adipate is as follows: IR (cm -1 ): 3274, 3058, 2972, 2937, 2868, 1700, 1612, 1574, 1333, 1245, 1111, 829, 821.

[0106] A representative XRPD pattern obtained from crystalline form B of compound 1 adipate is shown in Figure 5, and the XRPD data is listed in Table 8 below. [Table 8]

[0107] Figure 6 shows the TGA curve obtained from crystalline form B of compound 1 adipate. The crystalline form B of compound 1-adipate shows a weight loss of approximately 9.7% when heated to 150°C. I showed it.

[0108] Figure 7 shows the DSC curve obtained from crystalline form B of compound 1 adipate. The crystalline form B of compound 1 adipinate showed an endothermic peak at 178.20°C.

[0109] Figure 8 shows the DVS curve obtained from crystalline form B of compound 1 adipate. The crystalline form B of compound 1 adipine salt showed an increase in weight of approximately 8.2% at 80% RH, which is... This suggests that the crystalline form is hygroscopic.

[0110] After heating the sample to 150°C, its XRPD shows that the crystalline morphology of the sample has changed.

[0111] The results described above suggest that the crystalline form B of compound 1-adipate is a hydrate. Furthermore, the crystalline form B of compound 1-adipate is approximately 3.6 units per unit of compound 1-adipate. It is thought to contain water.

[0112] Example 3: Preparation and characterization of crystalline form C of compound 1 adipate 10 mg of compound 1-adipicate in amorphous form was placed in a 30 mL beaker. 0.5 mL of ethanol was added to the beaker to dissolve the amorphous compound 1-adipicate. After adding 5 mL of acetone to the beaker, the solution was stirred at room temperature for 1 day. Then, nitrogen was blown into the solution. The solvent was removed to obtain a solid, and it was confirmed that this was the crystalline form C of compound 1 adipate.

[0113] The NMR data for the crystal morphology C of compound 1-adipate 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), 2.14-2.18 (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).

[0114] The IR data for the crystalline form C of compound 1 adipate is as follows: IR (cm -1 ): 3275, 3057, 2974, 2939, 2868, 1700, 1612, 1583, 1333, 1245, 1110, 829, 821.

[0115] A representative XRPD pattern obtained from crystalline form C of compound 1 adipate is shown in Figure 9, and the XRPD data is listed in Table 9 below. [Table 9]

[0116] Figure 10 shows the TGA curve obtained from the crystal morphology C of compound 1-adipate. As shown above, the crystalline form C of compound 1-adipate showed a weight loss of approximately 38.1% when heated to 150°C.

[0117] Figure 11 shows the DSC curve obtained from the crystal morphology C of compound 1 adipate. As shown, the crystalline form C of compound 1 adipate showed an endothermic peak at 179.67°C.

[0118] Figure 12 shows the DVS curve obtained from the crystal morphology C of compound 1 adipate. Thus, the crystalline form C of compound 1 adipate shows an increase in weight of approximately 1% at 80% RH, which is... This suggests that the crystal morphology exhibits low hygroscopicity.

[0119] After heating the sample to 160°C, its XRPD shows that the crystalline morphology of the sample has changed.

[0120] The above results suggest that the crystalline form C of compound 1-adipate is a hydrate. Furthermore, it is thought that the crystalline form C of compound 1-adipate contains approximately 13 molars of water per molar of compound 1-adipate.

[0121] Example 4: Preparation and characterization of crystalline form D of compound 1 adipate 30 mg of compound 1-adipinate in amorphous form was placed in a 30 mL beaker. 0.5 mL of dimethylacetamide (DMAc) was added to the beaker to dissolve the amorphous compound 1-adipinate. 5 mL of acetone was added to the beaker, and the solution was stirred at room temperature for 1 day. Then nitrogen was added to the solution. By spraying with a solution, the solvent is removed to obtain a solid, which is the crystalline form of compound 1-adipate. It was confirmed that the state was D.

[0122] The NMR data for crystalline 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).

[0123] The IR data for the crystal morphology D of compound 1 adipinate is as follows: IR (cm -1 ): 2937, 2873, 1628, 1613, 1583, 1457, 1333, 1242, 1110, 829, 821.

[0124] A representative XRPD pattern obtained from crystalline form D of compound 1 adipate is shown in Figure 13, and the XRPD data is listed in Table 10 below. [Table 10]

[0125] Figure 14 shows the TGA curve obtained from the crystal morphology D of compound 1 adipate. As shown above, crystalline form D of compound 1 adipate showed a weight loss of approximately 14% when heated to 150°C.

[0126] Figure 15 shows the DSC curve obtained from the crystal morphology D of compound 1 adipate. Thus, the crystalline form D of compound 1 adipinate is found in three locations at 86.57°C, 96.33°C, and 175.11°C. It showed an endothermic peak.

[0127] Figure 16 shows the DVS curve obtained from the crystal morphology D of compound 1 adipate. Thus, crystalline form D of compound 1 adipate shows a weight increase of approximately 0.34% at 80% RH, which suggests that this crystalline form has low hygroscopicity.

[0128] The above results suggest that the crystalline form D of compound 1-adipate is a DMAc solvate. Furthermore, it is thought that the crystalline form D of compound 1-adipate contains approximately 1.3 molars of DMAc per molar of compound 1-adipate.

[0129] Example 5: Preparation and characterization of crystalline form A of free base compound 1. Compound 1 HCl (75.5g) (for example, as described in Example 5 of U.S. Patent Publication No. 2020 / 0062765) The substance obtained using the method 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 in 1.5 hours and stirred for 18.5 hours. Next The mixture was 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 then composed of compound 1 free base. It was confirmed that the crystal form is A.

[0130] The NMR data for crystalline form A of compound 1 free base is 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, 1H), 7.72-7.75 (m, 4H).

[0131] The IR data for crystalline form A of compound 1 free base is as follows: IR (cm -1 ): 3350, 3247, 3055, 2961, 2923, 2864, 1611, 1586, 1349, 829, 819.

[0132] A representative XRPD pattern obtained from crystalline form A of compound 1 free base is shown in Figure 17, and the XRPD data is listed in Table 11 below. [Table 11]

[0133] Figure 18 shows the TGA curve obtained from the crystal morphology A of compound 1 free base. Furthermore, the crystalline form A of compound 1 free base showed a weight loss of approximately 4% when heated to 150°C. .

[0134] Figure 19 shows the DSC curve obtained from the crystal morphology A of compound 1 free base. Furthermore, the crystalline form A of compound 1 free base exhibits three endothermic phases at 117.32°C, 168.67°C, and 178.29°C. He showed the mark.

[0135] Figure 20 shows the DVS curve obtained from the crystal morphology A of compound 1 free base. Furthermore, the crystalline form A of compound 1 free base showed a weight increase of approximately 0.1% at 80% RH, which is the crystalline form This suggests that the material has very little hygroscopic properties.

[0136] XRPD indicates that the crystal morphology of the sample did not change before and after the DVS test. After heating the sample to 155°C, its XRPD shows that the crystal morphology has changed.

[0137] The above results indicate that the crystalline form A of compound 1 free base is a hydrate. Furthermore, if the crystalline form A of compound 1 free base contains approximately 1 molar of water per molar of compound 1 free base, It's possible.

[0138] Example 6: Preparation and characterization of crystalline form B of compound 1 free base Approximately 50 mg of compound 1 free base in crystalline form A is mixed in 1 mL of dichloromethane to form a dispersion. The dispersion obtained in this way was stirred at 50°C for 3 or 7 days to obtain a solid, which was confirmed to be crystalline form B of compound 1 free base.

[0139] The NMR data for the crystal form B of compound 1 free base is 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).

[0140] The IR data for crystalline form B of compound 1 free base is as follows: IR (cm -1 ): 2960, 2910, 2846, 1624, 1611, 1586, 1335, 829.

[0141] A representative XRPD pattern obtained from crystalline form B of compound 1 free base is shown in Figure 21, and the XRPD data is listed in Table 12 below. [Table 12]

[0142] Figure 22 shows the TGA curve obtained from the crystal morphology B of compound 1 free base after removal of the residual solvent. As shown in Figure 22, the crystalline form B of compound 1 free base is obtained when heated to 150°C. It showed a weight loss of 0.005% (i.e., virtually no weight loss).

[0143] Figure 23 shows the DSC curve obtained from the crystal morphology B of compound 1 free base. Furthermore, the crystalline form B of compound 1 free base showed an initial melting point of 143.10°C and a crystal transition peak at 184.68°C.

[0144] Figure 24 shows the DVS curve obtained from the crystal morphology B of compound 1 free base. Furthermore, the crystalline form B of compound 1 free base showed a weight increase of 9.29% at 80% RH, which suggests that this crystalline form is hygroscopic.

[0145] XRPD indicates that the crystal morphology of the sample did not change before and after the removal of residual solvent. On the other hand, XRPD indicates that the crystal morphology of the sample changed before and after the DVS test.

[0146] The above results suggest that the crystal form B of compound 1 free base is an anhydrous form.

[0147] Example 7: Preparation and Characterization of Crystal Form C of Compound 1 Free Base Approximately 50 mg of crystal form A of compound 1 free base 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 compound 1 free base.

[0148] The NMR data for crystal form C of compound 1 free base 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, 1H), 7.72 - 7.76 (m, 4H).

[0149] The IR data for crystal form C of compound 1 free base are as follows: IR (cm -1 ): 1624, 1610, 1570, 1448, 1457, 1347, 829.

[0150] A representative XRPD pattern obtained from crystal form C of compound 1 free base is shown in Figure 25, and the XRPD data are listed in Table 13 below.

Table 13

[0151] The TGA curve obtained from crystal form C of compound 1 free base is shown in Figure 26. As shown in Figure 26 Form C of the free base of Compound 1 showed a weight loss of 0.107% when heated up to 150 °C. This was the case.

[0152] The DSC curve obtained from Form C of the free base of Compound 1 is shown in Figure 27. As shown in Figure 27, Form C of the free base of Compound 1 showed an endothermic peak at 167.45 °C.

[0153] The DVS curve obtained from Form C of the free base of Compound 1 is shown in Figure 28. As shown in Figure 28, Form C of the free base of Compound 1 showed a weight gain of 5.468% at 80% RH, suggesting that this crystal form has hygroscopicity.

[0154] XRPD of the sample was measured before and after the DVS test. The results show that there is no change in the crystal form. This indicates.

[0155] The above results suggest that Form C of the free base of Compound 1 is an anhydrate.

[0156] Example 8: Preparation and Characterization of Form D of the Free Base of Compound 1 100 mg of Form A of the free base of Compound 1 was mixed with 1 mL of methanol to completely dissolve the solid. Methyl tert-butyl ether (MTBE) (10 mL) was added to the above solution. The solvent in the solution thus obtained was removed by rotary evaporation at 40 °C to obtain a solid, which was confirmed to be [[ID=з4]]Form D of the free base of Compound 1.

[0157] The NMR data for 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 = 4.0 Hz, 1H), 7.71 - 7.75 (m, 4H).

[0158] The IR data for crystalline form D of the free base of Compound 1 are as follows: IR (cm -1 ): 1628, 1617, 1570, 1468, 1465, 1348, 1257, 1166, 830.

[0159] A representative XRPD pattern obtained from crystalline form D of the free base of Compound 1 is shown in Figure 29, and the XRPD data are listed in Table 14 below.

Table 14

[0160] The TGA curve obtained from crystalline form D of the free base of Compound 1 is shown in Figure 30. As shown in Figure 30 the crystalline form D of the free base of Compound 1 showed a weight loss of 1.263% when heated up to 150 °C .

[0161] The DSC curve obtained from crystalline form D of the free base of Compound 1 is shown in Figure 31. As shown in Figure 31 the crystalline form D of the free base of Compound 1 showed an endothermic peak at 177.64 °C.

[0162] The DVS curve obtained from crystalline form D of the free base of Compound 1 is shown in Figure 32. As shown in Figure 32 Furthermore, the crystalline form D of compound 1 free base showed a weight increase of 2.896% at 80% RH, which is the crystalline form This suggests that the material has some hygroscopic properties.

[0163] XRPD shows that the crystalline morphology of the sample changed before and after the removal of residual solvent. On the other hand, XRPD shows that the crystalline morphology of the sample did not change before and after the DVS test.

[0164] The above results indicate that the crystalline form D of compound 1 free base is a solvate / hydrate mixture. To instigate.

[0165] Other embodiments are within the scope of the following claims. The following are examples of aspects of the present invention. Item 1 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl] Crystal morphology A of imidazo[1,2-b]pyridazine-6-amine (compound 1) adipinate, wherein crystal morphology A has a tetragonal crystal system, a space group P41212, and unit cell parameters a=b=9.63 (1) Å, c=61.14 (2) Å, α=β=γ=90°, and V=5666 (5) Å3. Item 2 Crystal morphology A as described in item 1; and Pharmacologically acceptable carriers A pharmaceutical composition containing the following: Section 3 A step of mixing the amorphous form of compound 1 adipinate with a solvent; and The process involves adding a reverse solvent to the mixture to obtain crystalline form A of compound 1 adipate. A method for preparing the crystalline form A described in item 1, including the following. Section 4 The method according to item 3, wherein the solvent is an alcohol, sulfoxide, or amide, and the reverse solvent is a hydrocarbon, ether, nitrile, ketone, ester, or water. Section 5 An X-ray powder diffraction (XRPD) pattern comprising at least one 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° obtained using CuKα irradiation - of crystalline form B of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl ethyl]imidazo[1,2-b]pyridazin-6-amine (Compound 1) adipate. Item 6 The crystalline form B according to item 5, wherein the XRPD pattern further comprises at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 17.3 ± 0.2°, 20.5 ± 0.2° and 22.2 ± 0.2° obtained using CuKα irradiation. Item 7 The crystalline form B according to item 6, wherein the XRPD pattern further comprises at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 14.5 ± 0.2°, 25.7 ± 0.2° and 26.2 ± 0.2° obtained using CuKα irradiation. Item 8 The crystalline form B according to item 5, wherein the XRPD pattern is substantially as shown in FIG. 5. Item 9 Crystalline form B according to any one of items 5 to 8; and a pharmaceutically acceptable carrier A pharmaceutical composition comprising. Item 10 Dissolving the amorphous form of Compound 1 adipate in a solvent containing dichloromethane and methanol to form a solution; and Evaporating the solvent to obtain crystalline form B of Compound 1 adipate A method for preparing crystalline form B according to any one of items 5 to 8, comprising. Item 11 An X-ray powder diffraction (XRPD) pattern comprising at least one 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° obtained using CuKα irradiation - selected from the group consisting of - of crystalline form B of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl The turn is shown as 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl] Crystalline form C of [(nyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) adipate. Item 12 The XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 5.4±0.2°, 13.6±0.2°, and 29.2±0.2° obtained using CuKα irradiation. Hmm, the crystal form C described in item 11. Item 13 The XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 18.4±0.2°, 20.6±0.2°, and 21.7±0.2° obtained using CuKα irradiation. The crystal form C described in item 12. Item 14 Crystal morphology C as described in Section 11, the XRPD pattern is substantially as shown in Figure 9. Item 15 Crystal form C as described in any of items 11-14; and Pharmacologically acceptable carriers A pharmaceutical composition containing the following: Section 16 A step of dissolving the amorphous form of compound 1-adipine salt in ethanol to form a solution; The step of adding acetone to the solution; and The process of removing ethanol and acetone by evaporation to obtain the crystalline form C of compound 1-adipinate. A method for preparing the crystalline form C described in any of items 11 to 14, including the above. Item 17 The group consisting of 4.9±0.2°, 19.4±0.2°, and 21.6±0.2° obtained using CuKα irradiation. X-ray powder diffraction (XRPD) including at least one diffraction peak with a selected diffraction angle 2θ The turn is shown as 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl] Crystalline form D of [(nyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) adipate. Item 18 Crystal morphology D according to item 17, wherein the XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 13.5±0.2°, 21.3±0.2°, and 24.3±0.2° obtained using CuKα irradiation. Section 19 Crystal morphology D according to item 18, wherein the XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 10.3±0.2°, 16.4±0.2°, and 20.5±0.2° obtained using CuKα irradiation. Section 20 Crystal morphology D as described in Section 17, the XRPD pattern is substantially as shown in Figure 13. Section 21 Crystal morphology D as described in any of items 17-20; and Pharmacologically acceptable carriers A pharmaceutical composition containing the following: Section 22 The amorphous form of compound 1-adipine salt is dissolved in dimethylacetamide to form a solution. process; The step of adding acetone to the solution; and Dimethylacetamide and acetone are removed by evaporation to obtain the crystals of compound 1-adipine. Process to obtain morphology D A method for preparing crystalline form D as described in any of items 17 to 20, including the above. Section 23 The group consisting of 8.5±0.2°, 12.7±0.2°, and 19.1±0.2° obtained using CuKα irradiation. X-ray powder diffraction (XRPD) including at least one diffraction peak with a selected diffraction angle 2θ The turn is shown as 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl] Crystal form A of the free base of [(nyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1). Section 24 Crystal morphology A according to item 23, wherein the XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 16.9±0.2°, 17.9±0.2°, and 20.0±0.2° obtained using CuKα irradiation. Section 25 The XRPD patterns obtained using CuKα irradiation are 21.3±0.2°, 25.6±0.2° and 3 Crystal morphology A as described in item 24, comprising at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 4.1 ± 0.2°. Section 26 Crystal morphology A as described in Section 23, wherein the XRPD pattern is substantially as shown in Figure 17. Section 27 Crystal morphology A as described in any of items 23-26; and Pharmacologically acceptable carriers A pharmaceutical composition containing the following: Section 28 A step to obtain crystalline form A of free base compound 1 by mixing a base with a solution containing the hydrochloride salt of compound 1 in water and alcohol. A method for preparing crystalline form A as described in any of items 23 to 26, including the above. Section 29 The method described in item 28, wherein the base is sodium hydroxide. Item 30 X-ray powder diffraction (XRPD) patterns obtained using CuKα irradiation include at least one diffraction peak with a diffraction angle 2θ selected from the group consisting of 6.1±0.2°, 9.4±0.2°, and 21.3±0.2°. The expression shows 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl [ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) free base, crystalline form B. Section 31 Crystal morphology B according to item 30, wherein the XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 13.8±0.2°, 18.8±0.2°, and 20.7±0.2° obtained using CuKα irradiation. Section 32 The XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 9.7±0.2°, 11.0±0.2°, and 11.9±0.2° obtained using CuKα irradiation. M, the crystal form B described in item 31. Section 33 Crystal morphology B as described in section 30, wherein the XRPD pattern is substantially as shown in Figure 21. Section 34 Crystal morphology B as described in any of items 30-33; and Pharmacologically acceptable carriers A pharmaceutical composition containing the following: Section 35 A step of dispersing the crystalline form A of compound 1 free base in dichloromethane to form a dispersion; and The process involves stirring the dispersion at a temperature of approximately 45°C to 55°C to obtain crystalline form B of compound 1 free base. A method for preparing crystalline form B as described in any of items 30 to 33, including the above. Section 36 X-ray powder diffraction (XRPD) peaks containing at least one diffraction peak with a diffraction angle 2θ selected from the group consisting of 18.6±0.2°, 20.2±0.2°, and 21.1±0.2° obtained using CuKα irradiation. The turn is shown as 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl] [Nyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound 1) free base crystalline form C. Section 37 The XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 8.8±0.2°, 16.2±0.2°, and 20.6±0.2° obtained using CuKα irradiation. The crystal form C described in item 36. Section 38 The XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 15.6±0.2°, 15.9±0.2°, and 25.9±0.2° obtained using CuKα irradiation. Hmm, the crystal form C described in item 37. Section 39 Crystal morphology C as described in Section 36, the XRPD pattern is substantially as shown in Figure 25. Section 40 Crystal form C as described in any of items 36-39; and Pharmacologically acceptable carriers A pharmaceutical composition containing the following: Section 41 A step of dissolving crystalline form A of compound 1 free base in dichloromethane to form a solution; and a step of removing dichloromethane by evaporation to obtain crystalline form C of compound 1 free base. A method for preparing the crystalline form C described in any of sections 36 to 39, including the above. Section 42 The group consisting of 8.6±0.2°, 18.4±0.2°, and 20.9±0.2° obtained using CuKα irradiation. X-ray powder diffraction (XRPD) including at least one diffraction peak with a selected diffraction angle 2θ The turn is shown as 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl] Crystal morphology D of the free base of [(nyl)ethyl]imidazo[1,2-b]pyridazine-6-amine (compound I)). Section 43 Crystal morphology D according to item 42, wherein the XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 15.5±0.2°, 18.0±0.2°, and 20.1±0.2° obtained using CuKα irradiation. Section 44 Crystal morphology D according to item 43, wherein the XRPD pattern further includes at least one diffraction peak having a diffraction angle 2θ selected from the group consisting of 11.3±0.2°, 15.7±0.2°, and 16.0±0.2° obtained using CuKα irradiation. Section 45 Crystal morphology D as described in Section 42, the XRPD pattern is substantially as shown in Figure 29. Section 46 Crystal morphology D as described in any of items 42-45; and Pharmacologically acceptable carriers A pharmaceutical composition containing the following: Section 47 A step of dissolving the crystalline form A of compound 1 free base in methanol to form a solution; The step of adding methyl tert-butyl ether to the solution; and The process of removing methanol and methyl tert-butyl ether by evaporation to obtain the crystalline form D of compound 1 free base. A method for preparing crystalline form D as described in any of sections 42 to 45, including the above. Section 48 A method for treating cancer, comprising the step of administering to a subject in need of cancer treatment a therapeutically effective amount of the composition described in any one of claims 2, 9, 15, 21, 27, 34, 40, and 46. Section 49 The method described in item 48, wherein the cancer has a ROS1 fusion mutation. Section 50 The method according to item 48, wherein the cancer has a fusion mutation in NTRK1, NTRK2, or NTRK3. Section 51 If the cancer is non-small cell lung cancer, use one of the methods described in items 48-50. Section 52 If the cancer is thyroid cancer, describe it using one of the methods described in items 48-50.

Claims

[Claim 1] 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl] Imidazō[1,2-b]pyridazine-6-amine or a salt thereof.

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