Solid form of compounds

Abstract

The present invention relates to solid forms of compounds of formula (I), salts thereof, solvates thereof, solvates of salts thereof or mixtures thereof. JPEG2023536491000024.jpg49170

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to solid forms of compounds.

Background Art

[0002] FAK, also known as protein tyrosine kinase 2 (PTK2), is a non-receptor tyrosine kinase and an important component of the focal adhesion complex. FAK plays an important role in regulating tumor cell invasion, proliferation, and survival by mediating integrin and growth factor signals. FAK is widely expressed and evolutionarily conserved. According to studies over the past 20 years, FAK has been shown to be overexpressed in multiple solid tumors, and the expression level is negatively correlated with tumor prognosis. According to recent studies, it has been shown that FAK plays an important role in regulating the tumor microenvironment, suggesting that FAK plays an important role in the adaptability and drug resistance in immunotherapy and antitumor treatment.

[0003] The compound of formula (I) is a FAK inhibitor and exhibits antitumor activity in CDX (human-derived tumor cell line transplanted mice) models of multiple tumor types. In order to produce a desired drug substance, it is necessary to quickly find a solid form that improves the drug ability of the compound and has beneficial properties especially in terms of crystallinity, stability, hygroscopicity, and solubility.

Summary of the Invention

[0004] In one aspect, the present invention provides a compound of formula (I) in solid form, its salt, its solvate, the solvent of its salt, or a mixture thereof.

Chemical Formula

[0005] Preferably, the salt is a pharmaceutically acceptable salt.

[0006] Preferably, the solid form is a crystalline form.

[0007] Preferably, the solid form is a free base of the compound of formula (I).

[0008] Preferably, the solid form is the crystalline form A of the free base of the compound of formula (I).

[0009] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ of 10.979, 19.26, 21.581, and 24.801 degrees.

[0010] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 4.781, 10.979, 19.26, 21.581, 22.26, and 24.801 degrees 2θ.

[0011] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 4.781, 9.58, 10.979, 11.459, 14.678, 17.402, 19.26, 21.581, 22.26, 22.54, 24.801 and 29.219 degrees 2θ.

[0012] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees 4.781, 7.361, 7.619, 9.58, 10.54, 10.979, 11.459, 12.34, 12.96, 13.278, 14.678, 17.402, 18.54, 19.26, 19.918, 21.581, 22.26, 22.54, 23.521, 24.217, 24.801, 25.181 and 29.219.

[0013] Preferably, the solid form is 4.781, 5.255, 6.395, 7.361, 7.619, 8.818, 9.58, 10.54, 10.979, 11.459, 12.34, 12.96, 13.278, 14.678, 15.58, 16.377, 17.402, 18.54, 19.26, 19.918, 20.819, 21.581, 22.26, 22.54, 23.22, 23.521, 24.217, 24.8 The solid form has an X-ray powder diffraction (XRPD) pattern that includes one or more peaks located at 01, 25.181, 26.101, 26.439, 27.38, 28.543, 29.219, 29.721, 31.4, 31.717, 32.621, 33.118, 33.118, 33.458, 34.462, 35.178, 35.658, 36.556, 36.999, 39.335, 39.836, 43.02, and 44.279. Preferably, the solid form has an XRPD pattern substantially as shown in Figure 1.

[0014] Preferably, the solid state exhibits an endothermic phenomenon characterized by DSC, having an onset temperature of approximately 212.95°C and / or a peak temperature of approximately 214.24°C.

[0015] Preferably, the solid form is crystalline form I of the tartrate of formula (I).

[0016] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees of 10.34, 17.981, 18.281, and 21.901 degrees.

[0017] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees 2θ.

[0018] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ of 4.627, 10.34, 13.019, 17.981, 18.281, 21.2, 21.901, 23.121, 27.299, 27.541 and 29.879 degrees.

[0019] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 4.627, 10.34, 13.019, 15.76, 16.54, 17.159, 17.981, 18.281, 20.538, 21.2, 21.901, 23.121, 24.721, 25.659, 27.299, 27.541, 29.879, 32.277 and 41.821 degrees 2θ.

[0020] Preferably, the solid form is 4.637, 9.143, 10.34, 11.56, 13.019, 13.7, 14.039, 14.838, 15.76, 16.54, 17.159, 17.981, 18.281, 19.14, 19.795, 20.538, 21.2, 21.901, 23.121, 23.879, 24.721, 25.659, 26.179, 27.299, 27.541, The X-ray powder diffraction (XRPD) results include one or more peaks located at 28.22, 29.879, 30.459, 31.723, 32.277, 33.479, 33.941, 34.802, 35.401, 36.234, 36.536, 37, 37.666, 38.296, 38.777, 39.602, 39.94, 40.877, 41.821, 42.981, and 44.403.

[0021] Preferably, the solid form has substantially the XRPD pattern shown in Figure 3.

[0022] Preferably, the solid state exhibits an endothermic phenomenon characterized by DSC, having an onset temperature of approximately 235.42°C and / or a peak temperature of approximately 235.89°C.

[0023] Preferably, the solid form is crystalline form III of the tartrate of formula (I).

[0024] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees 13.2, 13.519, 15.181, 21.901, 22.521, 23.121 and 24.9 degrees.

[0025] Preferably, the solid form has an X-ray powder diffraction (XRPD) including peaks at 2θ of 13.2, 13.519, 15.181, 18.539, 21.901, 22.521, 23.121, 23.219, 24.9, 26.419 and 26.62 degrees.

[0026] Preferably, the solid form has an X-ray powder diffraction (XRPD) including peaks at 2θ of 8.939, 11.199, 13.2, 13.519, 14.02, 15.181, 18.539, 20.921, 21.901, 22.521, 23.121, 23.219, 24.9, 26.419 and 26.62 degrees.

[0027] Preferably, the solid form has an X-ray powder diffraction (XRPD) including one or more peaks among the peaks at 6.159, 7.339, 8.939, 10.179, 11.199, 11.481, 13.2, 13.519, 14.02, 14.719, 15.181, 16.461, 17.64, 17.999, 18.539, 19.22, 19.479, 20.019, 20.442, 20.921, 21.619, 22.521, 23.219, 23.518, 24.019, 24.9, 25.281, 25.9, 26.419, 26.62, 28.198, 28.978, 28.978, 29.703, 30.779, 31.202, 32.357, 33.117, 33.819, 34.183, 35.116, 36.059, 36.519, 37.219, 38.061, 39.161, 40.659, 41.654, 41.903, 43.139.

[0028] Preferably, the solid form has substantially the XRPD pattern shown in FIG. 5.

[0029] Preferably, the solid form exhibits an endothermic phenomenon characterized by DSC having an onset temperature at about 235.42 °C and / or a peak temperature at about 235.89 °C.

[0030] Preferably, the solid form is a phosphate of the compound of formula (I).

[0031] Preferably, the solid form is crystalline form I of the phosphate of the compound of formula (I).

[0032] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees 13.76, 19.08, 20.581, and 22.319.

[0033] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ of 13.76, 15.941, 19.08, 20.581, 22.319 and 24.642 degrees.

[0034] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees 13.76, 14.52, 15.941, 19.08, 20.581, 22.319, 23.381, 23.818, 24.642 and 28.219.

[0035] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 9.121, 10.082, 12.6, 13.76, 14.52, 15.941, 18.581, 19.08, 19.781, 20.581, 22.319, 23.381, 23.818, 24.642, 25.66, 26.537, 28.219, 29.419 and 33.98 degrees 2θ.

[0036] Preferably, the solid form has substantially the XRPD pattern shown in Figure 10.

[0037] Preferably, the solid form is a maleate of the compound of formula (I).

[0038] Preferably, the solid form is crystalline form I of the maleate of the compound of formula (I).

[0039] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees of 18.459, 20.237, 22.185, and 24.12 degrees.

[0040] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 10.32, 15.998, 18.459, 20.237, 22.185 and 24.12 degrees 2θ.

[0041] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 6.801, 10.32, 15.998, 18.459, 19.761, 20.237, 22.185, 24.12, 25.599 and 35.258 degrees 2θ.

[0042] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 6.801, 9.575, 10.32, 13.258, 13.662, 15.041, 15.998, 18.459, 19.761, 20.237, 20.781, 21.498, 21.78, 22.185, 24.12, 25.599, 27.062, 28.203 and 35.258 degrees 2θ.

[0043] Preferably, the solid form has substantially the XRPD pattern shown in Figure 12.

[0044] Preferably, the solid form is a benzoate salt of the compound of formula (I).

[0045] Preferably, the solid form is crystalline form I of the benzoate of the compound of formula (I).

[0046] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees of 6.639, 8.461, 20.16, and 21.699.

[0047] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees 6.639, 8.461, 12.119, 14.52, 20.16, and 21.699.

[0048] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees 3.981, 6.639, 8.461, 12.119, 14.52, 15.441, 20.16, 20.639, 21.699 and 24.659.

[0049] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees of 3.981, 6.639, 8.461, 9.6, 12.119, 12.602, 14.52, 15.441, 16.882, 18.12, 18.941, 20.16, 20.639, 21.699, 23.378, 23.719, 24.659, 28.418 and 29.259 degrees.

[0050] Preferably, the solid form has substantially the XRPD pattern shown in Figure 18.

[0051] In another embodiment, the present invention provides tartrate salts of compounds of formula (I). [ka]

[0052] Preferably, the solid form is crystalline form I of the tartrate salt of the compound of formula (I).

[0053] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ degrees of 10.34, 17.981, 18.281, and 21.901 degrees.

[0054] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees 2θ.

[0055] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 2θ of 4.627, 10.34, 13.019, 17.981, 18.281, 21.2, 21.901, 23.121, 27.299, 27.541 and 29.879 degrees.

[0056] Preferably, the solid form has X-ray powder diffraction (XRPD) including peaks at 4.627, 10.34, 13.019, 15.76, 16.54, 17.159, 17.981, 18.281, 20.538, 21.2, 21.901, 23.121, 24.721, 25.659, 27.299, 27.541, 29.879, 32.277 and 41.821 degrees 2θ.

[0057] Preferably, the solid form is 4.637, 9.143, 10.34, 11.56, 13.019, 13.7, 14.039, 14.838, 15.76, 16.54, 17.159, 17.981, 18.281, 19.14, 19.795, 20.538, 21.2, 21.901, 23.121, 23.879, 24.721, 25.659, 26.179, 27.299, 27.541, The X-ray powder diffraction (XRPD) results include one or more peaks located at 28.22, 29.879, 30.459, 31.723, 32.277, 33.479, 33.941, 34.802, 35.401, 36.234, 36.536, 37, 37.666, 38.296, 38.777, 39.602, 39.94, 40.877, 41.821, 42.981, and 44.403.

[0058] Preferably, the solid form has substantially the XRPD pattern shown in Figure 3.

[0059] In another embodiment, the present invention provides a method for producing a solid form of a compound of formula (I), comprising the steps of exposing a non-solid form of the compound of formula (I) to one or more solvents, stirring under heating conditions for a certain period of time to dissolve it, and then cooling it to room temperature to obtain a solid form, wherein the compound of formula (I) is as shown in the following chemical formula 3. [ka]

[0060] Preferably, the solvent is anhydrous ethanol.

[0061] In another embodiment, the present invention provides a method for producing a salt solid form of a compound of formula (I), comprising the steps of exposing the non-solid form and acid group of the compound of formula (I) to one or more solvents, stirring under heating conditions for a certain period of time to dissolve them, and then cooling to room temperature to obtain a salt solid form of the compound, wherein the compound of formula (I) is as shown in the following chemical formula 4. [ka]

[0062] In another embodiment, the present invention provides a pharmaceutical composition characterized by comprising a solid form of the compound of formula (I) described in the present invention and a pharmaceutically acceptable excipient. In particular, an effective amount of the solid form of the compound of formula (I).

[0063] In another aspect, the present invention provides a solid form of the compound of formula (I) described in the present invention and uses for a pharmaceutical composition as a FAK inhibitor.

[0064] In another embodiment, the present invention relates to Hodgkin lymphoma, non-Hodgkin lymphoma, lung cancer, liver cancer, cholangiocarcinoma, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, esophagogastric junction adenocarcinoma, thymic carcinoma, pancreatic cancer, uterine cancer, testicular cancer, malignant melanoma, skin cancer, mesothelioma, thymoma, germ cell carcinoma, and glioma. The present invention provides for the use of a solid form and pharmaceutical composition of a compound of formula (I) described in the present invention in the manufacture of a drug for treating blastoma, nasopharyngeal cancer, oropharyngeal cancer or laryngeal cancer, particularly non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, leukemia, bladder cancer, cervical cancer, bile duct cancer, esophageal cancer, gastric cancer, glioblastoma, liver cancer, malignant melanoma, mesothelioma, ovarian cancer, prostate cancer, kidney cancer, sarcoma, thyroid cancer, testicular cancer, thymoma, or uterine cancer. [Brief explanation of the drawing]

[0065] [Figure 1] This figure shows the X-ray powder diffraction (XRPD) of crystalline form A of the free base of the compound of formula (I). [Figure 2a] The thermogravimetric (TGA) values ​​of the free base of compound (I) in crystalline form A are shown. [Figure 2b] The differential scanning calorimetry (DSC) analysis results for crystalline form A of the free base of the compound of formula (I) are shown. [Figure 3] This figure shows the X-ray powder diffraction (XRPD) of crystalline form I of the tartrate salt of the compound of formula (I). [Figure 4a] The thermogravimetric (TGA) values ​​of crystalline form I of the tartrate salt of the compound of formula (I) are shown. [Figure 4b] The differential scanning calorimetry (DSC) analysis results for crystalline form I of the tartrate salt of the compound of formula (I) are shown. [Figure 4c] This figure shows the ¹H NMR (DMSO-d6) of crystalline form I of the tartrate salt of the compound of formula (I). [Figure 4d] This figure shows the dynamic water vapor adsorption (DVS) isotherm of crystalline form I of the tartrate salt of the compound of formula (I). [Figure 5] This figure shows the X-ray powder diffraction (XRPD) of crystalline form III of the tartrate salt of the compound of formula (I). [Figure 5a] The thermogravimetric (TGA) values ​​of the tartrate salt of the compound of formula (I) in crystalline form III are shown. [Figure 5b] The differential scanning calorimetry (DSC) analysis results for crystalline form III of the tartrate salt of the compound of formula (I) are shown. [Figure 5c] This figure shows the 1H NMR (DMSO-d6) of crystalline form III of the tartrate salt of the compound of formula (I). [Figure 5d] This figure shows the dynamic water vapor adsorption (DVS) isotherm of crystalline form III of the tartrate salt of the compound of formula (I). [Figure 6] The XRPD diagram of the crystalline form B of the free base of the compound of formula (I) is shown. [Figure 7] The XRPD diagram of the crystalline form C of the free base of the compound of formula (I) is shown. [Figure 8]The XRPD diagram of the crystalline form D of the free base of the compound of formula (I) is shown. [Figure 9] The XRPD diagram of crystalline form I of the sulfate of the compound of formula (I) is shown. [Figure 10] The XRPD diagram of crystalline form I of the phosphate of the compound of formula (I) is shown. [Figure 11] The XRPD diagram of crystalline form II of the phosphate of the compound of formula (I) is shown. [Figure 12] The XRPD diagram of crystalline form I of the compound maleate of formula (I) is shown. [Figure 13] The XRPD diagram of crystalline form II of the maleate of the compound of formula (I) is shown. [Figure 14] The XRPD diagram of crystalline form I of the citrate of the compound of formula (I) is shown. [Figure 15] The XRPD diagram of crystalline form I of the lactate of the compound of formula (I) is shown. [Figure 16] The XRPD diagram of crystalline form I of the benzenesulfonate of the compound of formula (I) is shown. [Figure 17] The XRPD diagram of crystalline form I of the 2-isethionate salt of the compound of formula (I) is shown. [Figure 18] The XRPD diagram of crystalline form I of the benzoate of the compound of formula (I) is shown. [Figure 19] The XRPD diagram of crystalline form I of the p-toluenesulfonate of the compound of formula (I) is shown. [Figure 20] The XRPD diagram of crystalline form I of the hydrobromide salt of the compound of formula (I) is shown. [Figure 21] This is a stability analysis of crystalline form A of the free base. [Figure 22] This is a stability analysis of crystalline form I of tartrate salts. [Figure 23] This is a stability analysis of crystalline form III of tartrate salts. [Figure 24] This is an XRPD diagram showing the stability of crystalline form A of the free base under pressure conditions. [Figure 25] This is an XRPD diagram showing the stability of crystalline form I of tartrate under pressure conditions. [Figure 26]This is an XRPD diagram showing the stability of crystalline form III of tartrate under pressure conditions. [Figure 27] This is an XRPD diagram showing the stability of free base crystalline form A under polishing conditions. [Figure 28] This is an XRPD diagram showing the stability of crystalline form I of tartrate under polishing conditions. [Figure 29] This is an XRPD diagram showing the stability of crystalline form III of tartrate under polishing conditions. [Figure 30] This is an experimental analysis of the suspension competition between tartrate I and tartrate III at room temperature. [Figure 31] This is an experimental analysis of the suspension competition between tartrate I and tartrate III at 50°C. [Modes for carrying out the invention]

[0066] Examples The present invention will be further explained below with reference to examples. Please understand that these examples are for illustrative purposes only and do not limit the scope of the present invention.

[0067] In the following examples, experimental methods for which specific conditions are not explicitly stated are all carried out under general conditions for such reactions or conditions recommended by the manufacturer.

[0068] Unless otherwise specified, the experimental materials and reagents used in the following examples are all commercially available.

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art.

[0070] As used herein, the terms “about” or “approximately,” when used in conjunction with a number or range of numbers, mean that the value or range of numbers may deviate from a range that would be considered reasonable by those skilled in the art, for example, within experimental variability (or within statistical experimental error). Thus, the number or range of numbers may vary, for example, between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, and between 0.5% and 1%. Where the term “about” precedes a number or range of numbers disclosed herein, embodiments of the given value are further included. For example, “about 3°C” discloses embodiments where the temperature is “3°C.” Throughout this specification, the terms “about” and “approximately” are used interchangeably. The term “between…” includes the numbers that define both ends of the range; for example, the range described as “between 3 and 5” includes the numbers “3” and “5.” As used herein, a dashed line (i.e., “~”) preceding a number or range of numbers means “about” or “approximately.”

[0071] As used herein, the term “mixing” means mixing one or more chemical substances with one or more other chemical substances. Mixing includes steps that involve adding one or more compounds to a mixture of solid, liquid or gaseous, liquid solution or multiphase liquid mixture of one or more compounds (the same or other chemical substances) (e.g., formation or decomposition of bonds, formation of salts, formation of solvates, chelation or other associations that alter nonbonds). The role of mixing may also include the modification of one or more compounds by isomerization (e.g., interconversion, splitting of isomers into other isomers and racemicization).

[0072] As used herein, the term "pharmaceutically acceptable" means non-toxic, bioacceptable, and suitable for administration to a subject.

[0073] As used herein, the term "pharmaceutically acceptable salt" means a salt that is non-toxic, bioacidic, and suitable for administration to a subject, and a pharmaceutically acceptable salt of the above compound means an acid addition salt that is non-toxic, bioacidic, and suitable for administration to a subject, and includes, but is not limited to, acid addition salts formed with the above compound and an inorganic acid, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, and nitrate, and acid addition salts formed with the above compound and an organic acid, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts formed with alkanedicarboxylic acids of the formula HOOC-(CH2)n-COOH (wherein n is 0 to 4). Furthermore, if the compound of the present invention is obtained from an acid addition salt, a free base can be obtained by alkalizing the solution of the acid salt. Conversely, if the product is a free base, a pharmaceutically acceptable salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid, using conventional methods for producing acid addition salts from free base compounds. Those skilled in the art should be familiar with various synthesis methods for producing pharmaceutically acceptable salts. In some embodiments, the salt is a tartrate, hydrochloride, butanediate, salicylate, or fumarate. In some embodiments, the salt is a tartrate.

[0074] As used herein, the term “solvate” further means a compound containing a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. For example, if the solvent is water, the solvate is a “hydrate.” The solvate may also be a channel solvate. It should be understood that as used herein, the term “solvate” includes compounds, solvates of compounds, and mixtures thereof.

[0075] Unless otherwise stated, the terms “solvent,” “organic solvent,” and “inert solvent” as used herein mean an organic solvent that is inert under the conditions of the reaction described herein, and include, but are not limited to, benzene, toluene, acetonitrile (MeCN), ethyl acetate (ƒ), isopropyl acetate (IPAc), hexane, heptane, dioxolane, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), ethyl ether, methanol (MeOH), ethanol, isopropyl alcohol, butanol, methyl-t-butyl ether (MTBE or TBME), dioxane, acetone, 2-butanone (MEK), N-methylpyrrolidone (NMP), pyridine, etc. In some examples, ethyl acetate (ƒ), tetrahydrofuran (THF), methanol (MeOH), 75% ethanol, dioxane, methyl-t-butyl ether, acetone, etc. Unless otherwise specified, the solvent used in the reactions described herein is an inert organic solvent.

[0076] As used herein, the term “subject” means mammals and non-mammals. Mammals mean any member of the mammalian species and include, but are not limited to, humans, non-human primates such as gorillas and other monkeys, farm animals such as cattle, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats and rodents such as rats, mice and guinea pigs, and laboratory animals. Examples of non-mammals include, but are not limited to, birds. The term “subject” is not limited to a specific age or sex. In some embodiments, the subject is human.

[0077] As used herein, the term “treatment” means obtaining a desired pharmacological and / or physiological effect. Such effect may be therapeutic and includes obtaining, in part or in principle, one or more of the following: partial or complete relief of a disease, illness or syndrome; improvement of clinical symptoms or indicators associated with the disease; or delay, suppression or reduction of the progression of a disease, illness or syndrome.

[0078] As used herein, the term “effective dose” means an amount of the compound of formula (I) in solid form that is sufficient to reduce or improve the severity, duration, progression, or attacks of a disease or illness, to delay or inhibit the progression of a disease or illness, to resolve a disease or illness, to delay the recurrence or progression of symptoms, or to enhance or improve the therapeutic effect of other therapies. The exact amount administered to a subject depends on a variety of factors, such as the drug or compound administered, the pharmaceutical formulation, the route of administration, the type of disease, the illness, and the status of the subject or host being treated, but is still generally determined by those skilled in the art. For example, the determination of the effective dose also depends on the degree, severity, and type of cell proliferation. Those skilled in the art can determine an appropriate dose based on these factors and other factors. When administered with other therapeutic agents, for example, with anticancer agents, the “effective dose” of any other therapeutic agent depends on the type of drug used. An appropriate dose is known for approved therapeutic agents and can be adjusted by those skilled in the art based on the subject’s condition, the type of condition being treated, and the amount of the compound or its pharmaceutically acceptable salt. If the quantity is not specified, it should be assumed that there are several quantities. The effective dose of the compound of formula (I) in solid form may be 10 μg to 2000 mg. This example is non-limiting.

[0079] The solid form of the compound of formula (I) can be administered by any suitable method of administration. Suitable methods include oral, intravenous, intramuscular, or subcutaneous administration to a subject.

[0080] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” include any and all solvents, dispersions, coatings, antimicrobial agents, isotonic agents, and absorption retarders. The use of such media and reagents with pharmaceutically active substances is well known to those skilled in the art. Any common media or reagent should be considered for use in the compositions herein, provided that it is not miscible with the active ingredient. The supplemented active ingredient may be added to the pharmaceutical composition.

[0081] Therefore, the solid form of the compound of formula (I) above may be administered orally with a pharmaceutically acceptable carrier, such as an inert diluent or an absorbable food carrier. They may be encapsulated in hard or soft gelatin capsules, compressed into tablets, or mixed directly with the patient's food. For therapeutic oral administration, the compound or a pharmaceutically acceptable salt thereof may be combined with one or more excipients and used in the form of ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, or cachets. These formulations contain an effective amount of the compound of formula (I) above (or a pharmaceutically acceptable salt thereof).

[0082] Tablets, lozenges, pills, capsules, etc. may further contain binders such as tragacanth gum, acacia gum, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; or sweeteners or flavorings such as sucrose, fructose, lactose, or aspartame.

[0083] The solid form of the compound of formula (I) above may be administered by intravenous infusion or intraperitoneal injection.

[0084] Exemplary drug dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient, the sterile powder being suitable for the immediate preparation of sterile injection or infusion solutions or dispersions. In any case, the final dosage form should be sterile, flowable, and stable under manufacturing and storage conditions.

[0085] A sterile injection solution may be prepared by compounding the required amount of the solid form of the compound shown in the XRPD diagram of the stability of crystalline form I of tartrate in Figure 13 above with the various other components as needed in a suitable solvent, and then sterilizing by filtration. In the case of a sterile powder for the preparation of a sterile injection solution, a preferred preparation method may be vacuum drying and freeze-drying techniques that yield a powder of the active ingredient + any other desired components present after prior sterile filtration.

[0086] The required amount of the compound of formula (I) used in treatment in solid form may vary depending not only on the specific salt selected, but also on the route of administration, the nature of the disease being treated, and the patient's age and condition, and ultimately may be determined by the attending physician or clinician. However, generally, the dosage may be within the range of approximately 0.1 to approximately 50 mg / kg body weight per day.

[0087] The required dosage can easily be found in a single dose or in divided doses administered at appropriate intervals.

[0088] As used herein, the term "solid form" and related terms primarily refer to a physical form that is not in a liquid or gaseous state. The solid form may be crystalline, amorphous, or a mixture thereof.

[0089] As used herein, the term “crystalline form” means crystalline form. Crystalline forms include unicomponent crystalline forms and multicomponent crystalline forms, and include, but are not limited to, polymorphs, solvates and other molecular complexes, as well as salts thereof, solvates of salts, other molecular complexes and crystalline polymorphs of salts. In some embodiments, the crystalline form of a substance may not substantially contain amorphous and / or other crystalline forms. In some embodiments, the crystalline form of a substance may contain one or more amorphous and / or other crystalline forms in amounts less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight. In some embodiments, the crystalline form of a substance may be physically and / or chemically pure. In some embodiments, the crystalline form of the substance may be physically and / or chemically pure of about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90%. In some embodiments, the crystalline forms described herein are substantially pure, i.e., substantially free of other crystalline forms and / or other compounds, and contain less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% by weight of one or more other crystalline forms and / or other compounds.

[0090] Crystal forms may exhibit different physical characteristic data specific to a particular crystal form, such as those described herein. These characteristic data can be obtained by various techniques known to those skilled in the art, including, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and nuclear magnetic resonance spectroscopy (HNMR). The data provided by these techniques may be used to identify a specific crystal form. Those skilled in the art can determine whether a crystal form "matches" the reference data identified herein as specific to a particular crystal form. A crystal form having characteristic data that "matches" the data of a reference crystal form is understood by those skilled in the art to correspond to the same crystal form as the reference crystal form. In the analysis of whether the data "matches," those skilled in the art should understand that specific characteristic data points may vary to a reasonable extent due to experimental error and analysis between typical samples, etc., but still be described as a given crystal form.

[0091] As used herein, “amorphous form” or “amorphous form” and related terms mean that the substance, component, or product described above is not substantially crystalline as measured by X-ray powder diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In some embodiments, the amorphous form of a substance may not substantially contain other amorphous and / or crystalline forms. In some embodiments, the amorphous form of a substance may contain one or more other amorphous and / or crystalline forms in amounts less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight. In some embodiments, the amorphous form of a substance may be physically and / or chemically pure. In some embodiments, the amorphous form of the substance may be physically and / or chemically pure of about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90%.

[0092] In one embodiment, the present invention provides a solid form comprising a compound of formula (I), a salt thereof, a solvate thereof, a solvent of a salt thereof, or a mixture thereof. [ka]

[0093] In some embodiments, the solid form containing the compound of formula (I) may be crystalline, partially crystalline, or a mixture of crystalline and amorphous forms. In some embodiments, the solid form may include the crystalline form of the compound of formula (I), its salt, its solvate, a solvent of its salt, or a mixture thereof. In some embodiments, the solid form further includes a co-formation. In some embodiments, it includes a cocrystal of the solid form of the compound of formula (I) and a co-formation. In some embodiments, the solid form is amorphous. In some embodiments, the solid form is substantially pure.

[0094] In some embodiments, the solid form includes the solid form of the free base of the compound of formula (I) or its solvate. In some embodiments, the solid form includes the solid form of the anhydrous free base of the compound of formula (I). In some embodiments, the solid form includes the solid form of the solvate of the free base of the compound of formula (I). The compound of formula (I), its salt, its solvate, its solvent, or mixtures thereof can exist in a variety of solid forms. Such solid forms include crystalline solids, amorphous solids, or mixtures of crystalline and amorphous solids. In some embodiments, the solid form is substantially crystalline. In some embodiments, the solid form is crystalline.

[0095] In some examples, the molar ratio of the compound of formula (I) to solvent / water in the solid form is in the range of approximately 10:1 to approximately 1:10. In some examples, the molar ratio of the compound of formula (I) to solvent / water in the solid form is in the range of approximately 5:1 to approximately 1:5. In some examples, the molar ratio of the compound of formula (I) to solvent / water in the solid form is in the range of approximately 3:1 to approximately 1:3. In some examples, the molar ratio of the compound of formula (I) to solvent / water in the solid form is in the range of approximately 2:1 to approximately 1:2. In some examples, the above molar ratio is approximately 1:2 (i.e., disolvate). In some examples, the above molar ratio is approximately 1:1 (i.e., monosolvate). In some examples, the above molar ratio is approximately 2:1 (i.e., hemisolvate).

[0096] In some examples, the solid form is crystalline form A of the free base of the compound of formula (I). In some examples, crystalline form A of the free base is substantially free of amorphous forms. In some examples, crystalline form A of the free base is substantially free of other crystalline forms. In some examples, crystalline form A of the free base is substantially free of salts of the compound of formula (I). In some examples, crystalline form A of the free base is substantially pure crystalline form A.

[0097] In some examples, crystalline form A of the free base has X-ray powder diffraction (XRPD) with peaks at 4.8, 9.6, 11.0, 11.5, 17.4, 19.3, 21.6, 22.3, 22.5, and 24.8 degrees 2θ. In some examples, crystalline form A of the free base has substantially the XRPD pattern shown in Figure 1.

[0098] In some examples, crystalline form A of the free base exhibits a weight loss of approximately 0.46% when heated from approximately 25°C to approximately 172°C. In some examples, crystalline form A of the free base has substantially the TGA pattern shown in Figure 2a. As can be seen from the TGA analysis, crystalline form A of the free base of the compound of formula (I) above is a non-solvate.

[0099] In some examples, crystalline form A of the free base exhibits an endothermic phenomenon characterized by DSC, with an onset temperature of approximately 212.95°C and / or a peak temperature of approximately 214.24°C. In some examples, crystalline form A of the free base has substantially the DSC pattern shown in Figure 2b.

[0100] In some embodiments, the solid form is a salt of the compound of formula (I). The compound of formula (I) and the acid form a salt. The ratio of the compound of formula (I) to the acid may be stoichiometric or non-stoichiometric. In some embodiments, the range of the ratio of the compound of formula (I) to the acid is about 5:1 to about 1:5. In some embodiments, the range of the ratio of the compound of formula (I) to the acid is about 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, or 1:5. In some embodiments, the range of the ratio of the compound of formula (I) to the acid is about 1:1. In some embodiments, the acid is one or more of tartaric acid, hydrochloric acid, butanediic acid, salicylic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, malic acid, lactic acid, gluconic acid, aspartic acid, hippuric acid, glutamic acid, adipic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, and hydrobromic acid. In some embodiments, the acid is one or more of tartaric acid, hydrochloric acid, butanediic acid, salicylic acid, and fumaric acid.

[0101] In some examples, the solid form is the crystalline form of the tartrate salt of the compound of formula (I). In some examples, the solid form is the crystalline form I of the tartrate salt of the compound of formula (I). The molar ratio of the compound of formula (I) to tartaric acid in the crystalline form I of the tartrate salt of the compound of formula (I) is about 1:1. In some examples, the crystalline form I of the tartrate salt of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern that includes peaks at 2θ degrees 10.3, 13.0, 18.0, 18.3, 21.2, 21.9, 23.1, 25.7, 27.3 and 30.0. In some examples, the crystalline form I of the tartrate salt of the compound of formula (I) has an XRPD pattern substantially as shown in Figure 3.

[0102] In some examples, crystalline form I of the tartrate of the compound of formula (I) exhibits a weight loss of approximately 0.87% when heated from approximately 25°C to approximately 158°C. In some examples, crystalline form I of the tartrate of the compound of formula (I) has substantially the TGA pattern shown in Figure 4a. As can be seen from the TGA analysis, crystalline form I of the tartrate of the compound of formula (I) is a non-solvate.

[0103] In some examples, crystalline form I of the tartrate of the compound of formula (I) exhibits an endothermic phenomenon characterized by DSC, with an onset temperature of approximately 235.42°C and / or a peak temperature of approximately 235.89°C. In some examples, crystalline form I of the tartrate of the compound of formula (I) has substantially the DSC pattern shown in Figure 4b.

[0104] In some embodiments, crystalline form I of the tartrate of the compound of formula (I) exhibits a weight increase of about 1% when the relative humidity increases from about 0% to about 95%. In some embodiments, crystalline form I of the tartrate of the compound of formula (I) has substantially the DVS pattern shown in Figure 4c.

[0105] In some embodiments, the present invention provides a pharmaceutical composition characterized by comprising a solid form of the compound of formula (I) and a pharmaceutically acceptable excipient. In particular, an effective amount of the solid form of the compound of formula (I).

[0106] In some embodiments, the present invention is used to treat Hodgkin lymphoma, non-Hodgkin lymphoma, lung cancer, liver cancer, cholangiocarcinoma, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, esophagogastric junction adenocarcinoma, thymic carcinoma, pancreatic cancer, uterine cancer, testicular cancer, malignant melanoma, skin cancer, mesothelioma, thymoma, and germ cell carcinoma. The present invention provides for the use of a solid form and pharmaceutical composition of a compound of formula (I) described in the present invention in the manufacture of a drug for treating glioblastoma, nasopharyngeal cancer, oropharyngeal cancer or laryngeal cancer, particularly non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, leukemia, bladder cancer, cervical cancer, bile duct cancer, esophageal cancer, gastric cancer, glioblastoma, liver cancer, malignant melanoma, mesothelioma, ovarian cancer, prostate cancer, kidney cancer, sarcoma, thyroid cancer, testicular cancer, thymoma, or uterine cancer.

[0107] The abbreviations used have the following meanings: mg milligrams ml (milliliter) TGA thermogravimetric analysis DSC (Differential Scanning Calorimetry) DVS gravimetric analysis water vapor adsorption isotherm

[0108] Measurement method 1. Powder X-ray diffraction (XRPD) [Table 1] 2, Thermogravimetric analysis (TGA) [Table 2] 3. Differential Scanning Calorimetry (DSC) [Table 3] 4. Gravimetric analysis water vapor adsorption isotherm (DVS) [Table 4]

[0109] Example 1: Preparation of the free base of the compound of formula (I) The free base of the compound of formula (I) was obtained by preparing it according to the method disclosed in WO2010058032. (M+H) + The value is 589.

[0110] Example 2: Screening of the crystalline form of the free base of the compound of formula (I). Crystallinity and scale-up studies were conducted on the free base obtained above in different solvents. The results showed that the free base has crystalline polymorphisms, and four types of crystalline polymorphisms were obtained within the crystalline polymorphism screening range. However, only crystalline polymorphism A could be scaled up and repeated. Therefore, it was found that crystalline polymorphism A of the free base is the most preferred crystalline form of the free base of the compound of formula (I).

[0111] Table 1, Crystallinity study of the free base of the compound of formula (I) [Table 5]

[0112] The free base obtained above (1.7 g) is dissolved in anhydrous ethanol (170 mL), stirred at 82-87°C for 1-2 hours, cooled to room temperature, and partially removed by vacuum distillation. The process is stopped until a solid precipitates, then allowed to stand, the solid is collected, and dried to obtain crystalline form A of the free base.

[0113] 1 H NMR(400MHz,DMSO-d6)δ8.78(d,J=12.5Hz,2H),7.98-7.91(m,1H),7.70(t,J=7.8H z,1H),7.57(d,J=7.6Hz,1H),7.31(d,J=7.9Hz,1H),7.16(s,1H),7.05(d,J=6.4Hz, 1H),4.48(s,2H),3.79(s,3H),3.67(s,1H),2.94(s,3H),2.73(d,J=11.3Hz,2H),2. 16(s,3H),1.94(t,J=11.2Hz,2H),1.79-1.71(m,2H),1.52(qd,J=11.9,3.9Hz,2H).

[0114] The XRPD feature data for crystal A of the free base of the compound of formula (I) is as follows: [Table 6A] [Table 6B]

[0115] Example 3: Screening of crystalline salts of the compound of formula (I). 3.1 Preparation of acid solution Based on the solubility of different acids, acid solutions were prepared accordingly, specifically as follows:

[0116] For sulfuric acid, phosphoric acid, acetic acid, maleic acid, tartaric acid, citric acid, malic acid, lactic acid, gluconic acid, adipic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, and hydrobromic acid, a methanol solution was used to a concentration of 1 mol / L. For aspartic acid, hippuric acid, and glutamic acid, an aqueous solution was prepared to a concentration of 0.02 mol / L. For 2-naphthalenesulfonic acid, an aqueous solution is used to adjust the concentration to 0.01 mol / L.

[0117] 17.6 mg (approximately 0.03 mmol) Crystalline form A of free base The samples were placed in 10 mL sample bottles, an appropriate amount of reaction solvent was added, and the mixture was stirred to dissolve them. Then, acid solutions (with a reaction molar ratio of 1:1) were added to each sample, and the reaction was carried out at 50°C for 3 hours. After cooling to room temperature, the mixture was stirred overnight, and then left to stand in a refrigerator at 4°C for 8 hours. For samples in which no solid precipitated, the mixture was evaporated at room temperature to obtain a solid, and then XRPD measurements were performed. For samples in which a solid precipitated, the solvent was removed by centrifugation, and the solid obtained by centrifugation and the solid obtained by evaporating the supernatant were dried and then XRPD measurements were performed to determine whether or not a salt had formed. The results are shown in Table 2.

[0118] Table 2, Screening results of acid addition salts of the compound of formula (I) [Table 7] Note: The I or II listed in the table above are different crystalline forms of the corresponding acid after the corresponding acid group has formed a salt. For example, if the acid is sulfuric acid and the solvent is ethyl acetate, the precipitated crystalline form I is crystalline form I of the sulfate. Other crystalline forms can be inferred in the same way. A, B, and C above are all crystalline forms of the free base of the compound of crystalline form A of the free base. NA indicates that no sample was obtained.

[0119] Figure 6 shows the XRPD diagram of the crystalline form B of the free base of the compound of formula (I).

[0120] Figure 7 shows the XRPD diagram of the crystalline form C of the free base of the compound of formula (I).

[0121] Figure 8 shows the XRPD diagram of the crystalline form D of the free base of the compound of formula (I).

[0122] Figure 9 shows the XRPD diagram of crystalline form I of the sulfate of the compound of formula (I).

[0123] Figure 10 shows the XRPD diagram of crystalline form I of the phosphate of the compound of formula (I).

[0124] Figure 11 shows the XRPD diagram of crystalline form II of the phosphate of the compound of formula (I).

[0125] Figure 12 shows the XRPD diagram of crystalline form I of the maleate of the compound of formula (I).

[0126] Figure 13 shows the XRPD diagram of crystalline form II of the maleate of the compound of formula (I).

[0127] Figure 14 shows the XRPD diagram of crystalline form I of the citrate of the compound of formula (I).

[0128] Figure 15 shows the XRPD diagram of crystalline form I of the lactate of the compound of formula (I).

[0129] Figure 16 shows the XRPD diagram of crystalline form I of the benzenesulfonate of the compound of formula (I).

[0130] Figure 17 shows the XRPD diagram of crystalline form I of the 2-isethionate salt of the compound of formula (I).

[0131] Figure 18 shows the XRPD diagram of crystalline form I of the benzoate of the compound of formula (I).

[0132] Figure 19 shows the XRPD diagram of crystalline form I of the p-toluenesulfonate of the compound of formula (I).

[0133] Figure 20 shows the XRPD diagram of crystalline form I of the hydrobromide salt of the compound of formula (I).

[0134] Example 4: Preparation of crystalline form I of the tartrate salt of the compound of formula (I) In addition to producing the above-mentioned crystalline form I using the method described in the screening results of the acid addition salt, it may also be produced more specifically as follows.

[0135] The free base (2.5 g) and tartaric acid (0.65 g) obtained above are dissolved in 75% ethanol (180 mL), stirred at 55-65°C for 1-3 hours, cooled to room temperature, and partially removed by vacuum distillation. The process is stopped until a solid precipitates, then allowed to stand, the solid is collected, and dried to obtain crystalline form I of the tartrate. The molar ratio of the compound of formula (I) to tartaric acid in crystalline form I of the tartrate of the compound of formula (I) is approximately 1:1.

[0136] 1H NMR(400MHz,DMSO-d6)δ8.78(d,J=15.1Hz,2H),8.06(d,J=7.4Hz,1H),7.70(t,J =7.8Hz,1H),7.57(d,J=7.6Hz,1H),7.31(d,J=7.9Hz,1H),7.18(d,J=13.8Hz,1H) ,7.06(d,J=6.5Hz,1H),4.48(s,2H),4.03(s,2H),3.79(s,4H),3.01(d,J=11.5H z,2H),2.94(s,3H),2.41(s,3H),1.86(d,J=12.3Hz,2H),1.62(q,J=11.8Hz,2H).

[0137] The XRPD feature data for crystalline form I of tartrate salts are as follows: [Table 8A] [Table 8B]

[0138] Example 5: Preparation of crystalline form III of the tartrate salt of compound (I). In addition to producing the above-mentioned crystalline form III by the method used in the screening results of the acid addition salts, it may also be produced more specifically as follows.

[0139] The free base obtained above (2.95 g) is dissolved in ethyl acetate (188 mL), heated to 60-65°C, 5 ml of methanol tartaric acid solution is added dropwise, the mixture is stirred for 1-3 hours, cooled to room temperature, filtered, and dried to obtain crystalline form III of the tartrate. The molar ratio of the compound of formula (I) to tartaric acid in crystalline form III of the tartrate of the compound of formula (I) is approximately 1:1.

[0140] 1H NMR(400MHz,DMSO-d6)δ8.78(d,J=12.9Hz,2H),8.03(d,J=7.6Hz,1H),7.70(t,J=7.8Hz,1H),7.57(d,J=7.6Hz,1H),7.31(d,J=8.0Hz,1H),7.1 8(s,1H),7.06(d,J=6.5Hz,1H),4.48(s,2H),3.97(s,2H),2.95(d,J=12 .4Hz,5H),2.36(s,5H),1.84(d,J=12.7Hz,2H),1.61(d,J=11.3Hz,2H).

[0141] The XRPD characteristic data for crystalline form III of tartrate salts are as follows: [Table 9A] [Table 9B]

[0142] Example 6, Measurement of Solubility Crystal form A of the free base, crystal form I of the tartrate, and crystal form III of tartaric acid of the compound of formula (I) were weighed to a constant mass and placed in 5 mL sample bottles. 2 mL each of deionized water, pH 2.0 glycine-hydrochloride buffer, pH 4.5 Na2HPO4-citrate buffer, and pH 6.8 Na2HPO4-citrate buffer were added to each bottle, and the bottles were shaken in a 25°C shaker for 24 hours. After filtration, the solubility of the filtrate was measured using HPLC, and whether or not a crystal form change occurred in the solid was detected by XRPD.

[0143] The chromatography conditions are as follows: Chromatography column: Unitary C18 (5 μm, 100 A, 4.6 × 250 mm) Mobile phase: Phase A is ammonium acetate with pH=6.2, and Phase B is acetonitrile, with an A:B ratio of 10:90. Detection wavelength: 230nm, Column temperature: 35℃ Sample injection volume: 20 μL.

[0144] The solubility measurement results are shown in Table 3.

[0145] Table 3, Solubility of free base and salt of compound (I) (25°C, mg / mL) [Table 10]

[0146] Solubility measurements showed that crystalline form A of the free base exhibited significantly improved solubility in a pH 6.8 buffer solution compared to the free base amorphous form. Crystalline form I of tartaric acid showed significantly improved solubility in both deionized water and a pH 6.8 buffer solution. Crystalline form III of the tartrate salt exhibited very good solubility in all solvent systems. The improved solubility in deionized water significantly reduced the difficulty of formulation, and the improved solubility in a pH 6.8 buffer solution significantly improved the oral bioavailability of the drug. XRPD detection showed that crystalline form A of the free base did not undergo crystal form change in a pH 6.8 buffer solution or deionized water, and crystalline form I of tartaric acid did not undergo crystal form change in deionized water.

[0147] Example 7, Accelerated Stability Test Evaluation According to the "Guiding Principles for Testing the Stability of Raw Materials and Formulations" in Part 4 of the 2015 edition of the "Chinese Pharmacopoeia," testing the stability of raw materials requires consideration of factors influencing the crystalline form and accelerated testing.

[0148] High-temperature test (T): The powder was placed in a suitable sealed glass bottle and left at 60°C for 10 days. Samples were taken on the 5th and 10th days, and the XRPD of the solid was measured.

[0149] High humidity test (H): The powder was opened and placed in a constant temperature and humidity chamber, left for 10 days under conditions of 25°C and 90%±5%RH. Samples were taken on the 5th and 10th days, and the XRPD of the solid was measured. Hygroscopicity and deliquescence were investigated.

[0150] High-intensity light irradiation test (L): The powder was opened and placed in a stable light irradiation box equipped with a fluorescent lamp. It was left for 10 days under conditions of an illuminance of 4500 ± 500 lx. Samples were taken on the 5th and 10th days, and the XRPD of the solid was measured.

[0151] Accelerated test (A): The powder was opened and placed in a constant temperature and humidity chamber, left for 10 days under conditions of 40°C and 75%±5%RH. Samples were taken on the 5th and 10th days, and the XRPD of the solid was measured.

[0152] The stability test results are shown in Figure 4, and for details of the spectrum, please refer to Figures 21-23.

[0153] Table 4, Experimental results on crystal structure stability [Table 11]

[0154] Stability results indicate that crystalline form A of the free base, crystalline form I of tartaric acid, and crystalline form III of the tartrate are all stable under each experimental condition, showing no crystalline form transition. However, the crystallinity of crystalline form III of the tartrate decreases in high-humidity environments. This suggests that attention should be paid to environmental humidity when storing crystalline form III, as there is a potential for it to transition to the amorphous state otherwise.

[0155] Example 8: Stability study under mechanical stress 8.1 Stability under pressure conditions Appropriate amounts of free base crystalline form A, tartrate crystalline form I, and tartrate crystalline form III powders were placed at the bottom of the mold of a powder tablet press. The pressure conditions of the formulation process were simulated, and mechanical pressures of 2N, 4N, 6N, 8N, and 10N were applied to each. After maintaining the pressure for 5 minutes to ensure stability, samples were taken and the XRPD was measured to examine the stability of the crystalline forms under pressure conditions. For details of the spectra, please refer to Figures 24-26. Comparing the XRPD results shows that the crystalline forms of free base crystalline form A, tartrate crystalline form I, and tartrate crystalline form III are all stable under pressure conditions.

[0156] 8.2 Stability under polishing conditions Appropriate amounts of free base crystalline form A, tartrate crystalline form I, and tartrate crystalline form III powders were placed in an agate mortar, and agate beads were added. The polishing conditions of the formulation process were simulated, and the vibration frequency of the automatic ball mill was set to 25S-1. After polishing for 5 min, 10 min, 15 min, and 30 min, samples were taken and the XRPD was measured to consider the stability of the crystalline forms under the polishing conditions. For details of the spectra, please refer to Figures 27-29.

[0157] A comparison of XRPD results shows that under polishing conditions, crystal form A of the free base and crystal form III of the tartrate underwent a transformation to amorphous form, while crystal form I of the tartrate only experienced a decrease in crystallinity. Therefore, crystal form I of the tartrate is more stable under polishing conditions and more stable in the formulation process.

[0158] Example 9: Water vapor adsorption and desorption experiment of tartrate salt of compound (I) By examining adsorption and desorption experiments of crystalline forms I and III of tartaric acid at 25°C and within a relative humidity range of 0-95%, using a dynamic water vapor adsorption apparatus (DVS), the hygroscopic performance of various different crystalline forms was determined (see Figures 4d and 5d for details). The results showed that within a humidity range of 40-80% RH, crystalline form I absorbed 0.33% and crystalline form III absorbed 0.37%, indicating that crystalline form I is clearly more stable than crystalline form III under high humidity conditions (RH > 90%). Crystalline form III absorbed 18.1% at 90-95% RH, while crystalline form I of tartrate absorbed almost no moisture (0.08%).

[0159] Example 10: Study of the conversion relationship of the tartrate salt of the compound of formula (I) Suspension competition crystal transition studies were conducted for crystal forms I and III in different organic solvents to determine the crystal form that is stable under different conditions and to determine the mutual transition relationship between crystal forms I and III. 20 mg each of crystal form I and crystal form III were weighed out and placed in 2 mL or 10 mL glass bottles, and 0.5 mL or 1 mL of organic solvent was added to each based on solubility. The same type of solvent was divided into two batches, and each was suspended in a competitive state at room temperature and 50 °C for 24 hours. After centrifugation of the suspension (10000 rpm, 3 min), the solid powder was vacuum dried, and the PXRD was measured (see Figures 30 and 31 for details). The results of the suspension crystal transition tests are shown in Table 2. The results indicate that, with the exception of methyl-t-butyl ether and cyclohexane, at room temperature and 50 °C, physical mixtures of crystal forms I and III all transitioned to crystal form I after being suspended in and competing with common solvents such as 75% ethanol, anhydrous ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methanol, isopropyl alcohol, 2-butanone, toluene, and water. Under these conditions, it can be determined that crystal form I is a stable crystal form.

[0160] Table 5, Results of suspension crystal transition tests for crystalline forms I and III of the tartrate salt of compound (I). [Table 12]

[0161] Based on the above, stability evaluations and solubility studies of crystalline forms I and III of tartrate salts will further select the optimal crystalline form of tartrate salt suitable for development. Stability experimental results show that crystalline form I is superior to crystalline form III in terms of solvent-mediated crystal transition, polishing stability, and hygroscopic stability.

[0162] All references cited throughout this application (including documents, issued patents, published patent applications and concurrent patent applications) are expressly incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they would be commonly understood by those skilled in the art.

[0163] All features disclosed herein can be combined in any combination. Each feature disclosed herein may be replaced by an alternative feature that serves the same, equivalent, or similar purpose. Thus, unless otherwise explicitly stated, each disclosed feature is merely an example of a set of equivalent or similar features.

[0164] From the above description, those skilled in the art will readily recognize the essential features of the present invention and can adapt it to various uses and conditions by making various changes and modifications without departing from the spirit and scope of the invention. Therefore, other embodiments are also within the scope of the appended claims.

Claims

1. A solid form comprising a compound of formula (I), a salt thereof, a solvate thereof, a solvent of a salt thereof, or a mixture thereof, 【Chemistry 1】 This is crystalline form I of the tartrate salt of the compound of formula (I), and its properties are as follows: (a) A solid form characterized by having X-ray powder diffraction (XRPD) including peaks at 2θ degrees of 10.34, 17.981, 18.281 and 21.901 degrees.

2. The solid form according to claim 1, characterized by having X-ray powder diffraction (XRPD) including peaks at 2θ degrees of 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees.

3. The solid form according to claim 1, characterized by having X-ray powder diffraction (XRPD) including peaks at 2θ degrees of 4.627, 10.34, 13.019, 17.981, 18.281, 21.2, 21.901, 23.121, 27.299, 27.541 and 29.

879.

4. The solid form according to claim 1, characterized by having X-ray powder diffraction (XRPD) including peaks at 2θ of 4.627, 10.34, 13.019, 15.76, 16.54, 17.159, 17.981, 18.281, 20.538, 21.2, 21.901, 23.121, 24.721, 25.659, 27.299, 27.541, 29.879, 32.277 and 41.821 degrees.

5. A pharmaceutical composition comprising the solid form described in any one of claims 1 to 4.

6. A drug for use as a FAK inhibitor, comprising the solid form described in any one of claims 1 to 4 or the pharmaceutical composition described in claim 5.

7. A drug comprising a solid form according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the treatment of Hodgkin lymphoma, non-Hodgkin lymphoma, lung cancer, liver cancer, cholangiocarcinoma, myelodysplastic syndrome, leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, sarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, esophagogastric junction adenocarcinoma, thymic carcinoma, pancreatic cancer, uterine cancer, testicular cancer, malignant melanoma, skin cancer, mesothelioma, thymoma, germ cell carcinoma, glioblastoma, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer.

8. A drug comprising a solid form according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the treatment of non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, leukemia, bladder cancer, cervical cancer, bile duct cancer, esophageal cancer, gastric cancer, glioblastoma, liver cancer, malignant melanoma, mesothelioma, ovarian cancer, prostate cancer, kidney cancer, sarcoma, thyroid cancer, testicular cancer, thymoma, or uterine cancer.

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