Solid form of compound

Abstract

A solid form of a compound of formula (I) or a salt thereof, or a solvate thereof, or a solvate of a salt thereof, or a mixture thereof is provided.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. In particular, the present invention relates to a solid form of a compound. Background Art

[0002] FAK, also known as protein tyrosine kinase 2 (PTK2), is a non-receptor tyrosine kinase and a key component of the focal adhesion complex. FAK plays an important role in mediating integrin and growth factor signals to regulate the invasion, proliferation and survival of tumor cells. FAK is widely expressed and evolutionarily conserved. Studies over the past two decades have shown that FAK is overexpressed in a variety of solid tumors, and the expression level is negatively correlated with tumor prognosis. Recent studies have also shown that FAK plays an important role in regulating the tumor microenvironment, suggesting that FAK plays an important role in adaptive resistance to immunotherapy and anti-tumor therapy.

[0003] The compound of formula (I) is a FAK inhibitor, which exhibits anti-tumor activity in CDX (human tumor cell line transplanted mice) models of multiple tumor types. In order to prepare the expected drug substance, we urgently need to find a solid form to improve the drugability of the compound, especially with beneficial properties 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) or a salt thereof, or a solvate thereof, or a solvate of a salt thereof, or a mixture thereof in solid form:

[0005]

[0006] Optionally, the salt is a pharmaceutically acceptable salt.

[0007] Optionally, the solid form is a crystalline form.

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

[0009] Optionally, the solid form is Form A of the free base of the compound of formula (I).

[0010] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 10.979, 19.26, 21.581 and 24.801 degrees 2Θ.

[0011] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 4.781, 10.979, 19.26, 21.581, 22.26 and 24.801 degrees 2Θ.

[0012] Optionally, it has an 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.

[0013] Optionally, it has an X-ray powder diffraction (XRPD) including peaks at 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 degrees 2Θ.

[0014] Optionally, it has an X-ray powder diffraction (XRPD) pattern including chromatograms at 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, 23.2 2, 23.521, 24.217, 24.801, 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, 44.279. Optionally, it has substantially Figure 1 XRPD spectrum shown.

[0015] Optionally, it exhibits an endothermic event as characterized by DSC, having an onset temperature at about 212.95°C and / or a peak temperature at about 214.24°C.

[0016] Optionally, the solid form is Form I of the tartrate salt of formula (I).

[0017] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 10.34, 17.981, 18.281 and 21.901 degrees 2Θ.

[0018] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees 2Θ.

[0019] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 4.627, 10.34, 13.019, 17.981, 18.281, 21.2, 21.901, 23.121, 27.299, 27.541 and 29.879 degrees 2Θ.

[0020] Optionally, it has an 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.

[0021] Optionally, it has an X-ray powder diffraction (XRPD) pattern including chromatograms at 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, 26.8 one or more of 6.179, 27.299, 27.541, 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, 44.403.

[0022] Optionally, it has substantially Figure 3 XRPD spectrum shown.

[0023] Optionally, it exhibits an endothermic event as characterized by DSC, having an onset temperature at about 235.42°C and / or a peak temperature at about 235.89°C.

[0024] Optionally, the solid form is Form III of the tartrate salt of formula (I).

[0025] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 13.2, 13.519, 15.181, 21.901, 22.521, 23.121 and 24.9 degrees 2Θ.

[0026] Optionally, it has an X-ray powder diffraction (XRPD) including peaks at 13.2, 13.519, 15.181, 18.539, 21.901, 22.521, 23.121, 23.219, 24.9, 26.419 and 26.62 degrees 2Θ.

[0027] Optionally, it has an X-ray powder diffraction (XRPD) including peaks at 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 2Θ.

[0028] Optionally, it has an X-ray powder diffraction (XRPD) including 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, one or more of 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.

[0029] Optionally, it has substantially Figure 5 XRPD spectrum shown.

[0030] Optionally, it exhibits an endothermic event as characterized by DSC, having an onset temperature at about 235.42°C and / or a peak temperature at about 235.89°C.

[0031] Optionally, it is a phosphate salt of the compound of formula (I).

[0032] Optionally, it is phosphate crystal form I of the compound of formula (I).

[0033] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 13.76, 19.08, 20.581 and 22.319 degrees 2Θ.

[0034] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 13.76, 15.941, 19.08, 20.581, 22.319 and 24.642 degrees 2Θ.

[0035] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 13.76, 14.52, 15.941, 19.08, 20.581, 22.319, 23.381, 23.818, 24.642 and 28.219 degrees 2Θ.

[0036] Optionally, it has an 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.

[0037] Optionally, it has substantially Fig.10 XRPD spectrum shown.

[0038] Optionally, it is a maleate salt of the compound of formula (I).

[0039] Optionally, it is maleate crystalline form I of the compound of formula (I).

[0040] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 18.459, 20.237, 22.185 and 24.12 degrees 2Θ.

[0041] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 10.32, 15.998, 18.459, 20.237, 22.185 and 24.12 degrees 2Θ.

[0042] Optionally, it has an X-ray powder diffraction (XRPD) comprising 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.

[0043] Optionally, it has an 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.

[0044] Optionally, it has substantially Fig.12 XRPD spectrum shown.

[0045] Optionally, it is a benzoate salt of the compound of formula (I).

[0046] Optionally, it is benzoate crystal form I of the compound of formula (I).

[0047] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 6.639, 8.461, 20.16 and 21.699 degrees 2Θ.

[0048] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 6.639, 8.461, 12.119, 14.52, 20.16 and 21.699 degrees 2Θ.

[0049] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 3.981, 6.639, 8.461, 12.119, 14.52, 15.441, 20.16, 20.639, 21.699 and 24.659 degrees 2Θ.

[0050] Optionally, it has an X-ray powder diffraction (XRPD) including peaks at 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 2Θ.

[0051] Optionally, it has substantially Fig.18 XRPD spectrum shown.

[0052] In another aspect, the present invention provides a tartrate salt of a compound of formula (I),

[0053]

[0054] Optionally, it is tartrate crystal form I of the compound of formula (I).

[0055] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 10.34, 17.981, 18.281 and 21.901 degrees 2Θ.

[0056] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees 2Θ.

[0057] Optionally, it has an X-ray powder diffraction (XRPD) comprising peaks at 4.627, 10.34, 13.019, 17.981, 18.281, 21.2, 21.901, 23.121, 27.299, 27.541 and 29.879 degrees 2Θ.

[0058] Optionally, it has an 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.

[0059] Optionally, it has an X-ray powder diffraction (XRPD) pattern including chromatograms at 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, 26.8 one or more of 6.179, 27.299, 27.541, 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, 44.403.

[0060] Optionally, it has substantially Figure 3 XRPD spectrum shown.

[0061] In another aspect, the present invention provides a method for preparing a solid form of a compound of formula (I), comprising:

[0062] The non-solid form of the compound of formula (I) is exposed to one or more solvents, stirred for a period of time under heating conditions to dissolve it, and then cooled to room temperature to obtain a solid form. The compound of formula (I) is

[0063]

[0064] Optionally, the solvent is anhydrous ethanol.

[0065] In another aspect, the present invention provides a method for preparing a solid salt form of a compound of formula (I), comprising:

[0066] The non-solid form of the compound of formula (I) and the acid radical are exposed to one or more solvents, stirred for a period of time under heating conditions to dissolve, and then cooled to room temperature to obtain a solid form of the compound salt, wherein the compound of formula (I) is

[0067]

[0068] In another aspect, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a solid form of the compound of formula (I) of the present invention and a pharmaceutically acceptable excipient, in particular, an effective amount of the solid form of the compound of formula (I).

[0069] In another aspect, the present invention provides a use of a solid form and a pharmaceutical composition of a compound of formula (I) according to the present invention as a FAK inhibitor.

[0070] On the other hand, the present invention provides a solid form of the compound of formula (I) according to the present invention and a pharmaceutical composition for use in the preparation of a pharmaceutical composition for treating the following diseases: Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, liver cancer, bile duct cancer, 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, gastroesophageal cancer Cancer of the junction, thymus, pancreas, uterus, testis, melanoma, skin, mesothelioma, thymoma, germ cell, glioblastoma, nasopharynx, oropharynx, or larynx; in particular 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, melanoma, mesothelioma, ovary, prostate, kidney, sarcoma, thyroid cancer, testis, thymoma, or uterus. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 The X-ray powder diffraction (XRPD) pattern of the free base form A of the compound of formula (I).

[0072] Figure 2a Thermogravimetric analysis (TGA) of the free base form A of the compound of formula (I) is shown; Figure 2b The results of differential scanning calorimetry (DSC) analysis of the free base form A of the compound of formula (I) are shown.

[0073] Figure 3 The X-ray powder diffraction (XRPD) pattern of the tartrate form I of the compound of formula (I).

[0074] Figure 4a Thermogravimetric analysis (TGA) of the tartrate crystalline form I of the compound of formula (I) is shown; Figure 4b The differential scanning calorimetry (DSC) analysis results of the tartrate salt form I of the compound of formula (I) are shown; Figure 4c The tartrate salt form I of the compound of formula (I) is shown 1 H NMR (DMSO-d6) pattern; Figure 4d The dynamic vapour sorption (DVS) isotherm diagram of the tartrate salt form I of the compound of formula (I) is shown.

[0075] Figure 5 The X-ray powder diffraction (XRPD) pattern of the tartrate crystal form III of the compound of formula (I). Figure 5a Thermogravimetric analysis (TGA) of the tartrate crystal form III of the compound of formula (I) is shown; Figure 5b The differential scanning calorimetry (DSC) analysis results of the tartrate salt form III of the compound of formula (I) are shown; Figure 5c The tartrate salt form III of the compound of formula (I) is shown 1 H NMR (DMSO-d6) pattern; Figure 5d The dynamic vapour sorption (DVS) isotherm diagram of the tartrate salt form III of the compound of formula (I) is shown.

[0076] Figure 6 The XRPD pattern of Form B of the free base of the compound of formula (I) is shown.

[0077] Figure 7 The XRPD pattern of Form C of the free base of the compound of formula (I) is shown.

[0078] Figure 8 The XRPD pattern of the free base form D of the compound of formula (I) is shown.

[0079] Fig. 9 The XRPD pattern of the sulfate crystal form I of the compound of formula (I) is shown.

[0080] Fig.10 The XRPD pattern of the phosphate crystal form I of the compound of formula (I) is shown.

[0081] Fig.11The XRPD pattern of the phosphate crystal form II of the compound of formula (I) is shown.

[0082] Fig.12 The XRPD pattern of maleate salt form I of the compound of formula (I) is shown.

[0083] Fig.13 The XRPD pattern of maleate salt form II of the compound of formula (I) is shown.

[0084] Fig.14 The XRPD pattern of Form I of the citrate salt of the compound of formula (I) is shown.

[0085] Fig.15 The XRPD pattern of the lactate crystalline form I of the compound of formula (I) is shown.

[0086] Fig.16 The XRPD pattern of benzenesulfonate crystalline form I of the compound of formula (I) is shown.

[0087] Fig.17 The XRPD pattern of Form I of 2-hydroxyethanesulfonate salt of the compound of formula (I) is shown.

[0088] Fig.18 The XRPD pattern of Form I of the benzoate salt of the compound of formula (I) is shown.

[0089] Fig.19 The XRPD pattern of the p-toluenesulfonate crystalline form I of the compound of formula (I) is shown.

[0090] Fig. 20 The XRPD pattern of the hydrobromide salt form I of the compound of formula (I) is shown.

[0091] Fig.21 This is a stability analysis of the free base form A.

[0092] Fig. 22 This is the stability analysis of tartrate crystal form I.

[0093] Fig.23 This is a stability analysis of the tartrate crystal form III.

[0094] Fig.24 This is the XRPD diagram of the pressure stability of free base form A.

[0095] Fig.25 This is the XRPD diagram of the pressure stability of tartrate salt form I.

[0096] Fig.26 This is the XRPD diagram of the pressure stability of tartrate salt form III.

[0097] Fig. 27This is the XRPD diagram of the grinding condition stability of the free base form A.

[0098] Fig.28 This is the XRPD diagram of the grinding condition stability of tartrate salt form I.

[0099] Fig.29 This is the XRPD diagram of the grinding condition stability of the tartrate salt form III.

[0100] Fig.30 Suspension competition assay analysis of tartrate I and tartrate III at room temperature.

[0101] Fig.31 Suspension competition assay analysis of tartrate I and tartrate III at 50°C. Example

[0102] The following examples are provided to further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0103] The experimental methods in the following examples without specifying specific conditions can be carried out according to conventional conditions of such reactions or according to the conditions recommended by the manufacturers.

[0104] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0105] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0106] The term "about" or "approximately" as used herein, when used in combination with a numerical value or a numerical range, means that the value or numerical range may deviate from a range that is considered reasonable by a person of ordinary skill in the art, such as within experimental variation (or within statistical experimental error), so the value or numerical range 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% of the value or numerical range. The case disclosed herein where the term "about" is before a numerical value or numerical range also includes embodiments of the given value. For example, "about 3°C" discloses an embodiment where the temperature is "3°C". Throughout the specification, the terms "about" and "approximately" are used completely interchangeably. The term "between..." includes the endpoint numbers at both ends of the atmospheric limit, for example, the range described in "between 3 and 5" includes the numbers "3" and "5". The wavy line (i.e., "~") before the numerical value or numerical range used herein means "about" or "approximately".

[0107] The term "mixing" as used herein refers to causing one or more chemical entities to mix with another one or more chemical entities. Mixing includes the process (e.g., bond formation or cleavage; salt formation, solvate formation, chelation, or other changes in non-bonded associations) of adding one or more compounds to a solid, liquid, or gaseous mixture, or a liquid solution or multiphase liquid mixture of one or more compounds (the same or other chemical entities). The effect of mixing can include changing one or more compounds, such as by isomerization (e.g., interconversion, resolution of one isomer with another, or racemization).

[0108] As used herein, the term "pharmaceutically acceptable" means non-toxic, biologically tolerable, and suitable for administration to a subject.

[0109] The term "pharmaceutically acceptable salt" as used herein refers to a non-toxic, biologically tolerable salt suitable for administration to a subject, and the pharmaceutically acceptable salt of the compound refers to a non-toxic, biologically tolerable acid addition salt suitable for administration to a subject, including but not limited to: acid addition salts formed by the compound with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by the compound with organic acids, 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 0-4), etc. In addition, if the compound of the present invention is obtained from an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, then a pharmaceutically acceptable salt can be prepared by the conventional method of preparing an acid addition salt from a free base compound, by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare a pharmaceutically acceptable salt. In some embodiments, the salt is a tartrate, a hydrochloride, a succinate, a salicylate or a fumarate. In some embodiments, the salt is a tartrate.

[0110] The term "solvate" as used herein refers to a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. For example, when the solvent is water, the solvate is a "hydrate". The solvate can be a channel solvate. It should be understood that the term "solvate" as used herein includes compounds and solvates of compounds, as well as mixtures thereof.

[0111] Unless otherwise specified, the terms "solvent", "organic solvent" and "inert solvent" as used herein each refer to an inert organic solvent under the reaction conditions described in conjunction therewith, including but not limited to benzene, toluene, acetonitrile (MeCN), ethyl acetate (EtOAc), isopropyl acetate (IPAc), hexane, heptane, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), ether, methanol (MeOH), ethanol, isopropanol, butanol, methyl tert-butyl ether (MTBE or TBME), dioxane, acetone, 2-butanone (MEK), N-methylpyrrolidone (NMP), pyridine, etc. In some embodiments, including but not limited to ethyl acetate (EtOAc), tetrahydrofuran (THF), methanol (MeOH), 75% ethanol, dioxane, methyl tert-butyl ether, acetone, etc. Unless otherwise specified, the solvent used in the reactions described herein is an inert organic solvent.

[0112] The term "subject" as used herein refers to mammals and non-mammals. Mammals refer to any member of the class mammals, including but not limited to: humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, and pigs; livestock, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" does not limit a particular age or sex. In some embodiments, the subject is a human.

[0113] As used herein, the term "treat" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partial or substantial achievement of one or more of the following results: partial or total alleviation of the extent of a disease, disorder or syndrome; improvement of clinical symptoms or indicators associated with the disease; or delay, inhibition or reduction of the likelihood of progression of a disease, disorder or syndrome.

[0114] As used herein, the term "effective amount" refers to a solid form of a compound of formula (I) that is sufficient to reduce or improve the severity, duration, progression or onset of a disease or condition, delay or prevent the progression of a disease or condition, cause regression of a disease or condition or delay the recurrence or progression of symptoms, or enhance or improve the therapeutic effect of another therapy. The exact amount given to the subject will depend on various factors, such as a given drug or compound, a pharmaceutical formulation, a route of administration, a type of disease, a condition, the identity of the subject or host being treated, etc., but can still be routinely determined by a person skilled in the art. For example, determining the effective amount also depends on the degree, severity and type of cell proliferation. A technician will be able to determine a suitable dose based on these and other factors. When co-administered with other therapeutic agents, for example, when co-administered with an anticancer agent, the "effective amount" of any other therapeutic agent will depend on the type of drug used. Suitable doses are known for approved therapeutic agents and can be adjusted by a technician based on the subject's condition, the type of condition being treated, and the amount of the compound or a pharmaceutically acceptable salt thereof. In the absence of an explicit indication of an amount, some amount should be assumed. The effective dosage of the solid form of the compound of formula (I) may be 10 μg-2000 mg. This example is non-limiting.

[0115] The solid form of the compound of formula (I) may be administered by any suitable method of administration. Suitable methods include oral, intravenous, intramuscular or subcutaneous administration to a subject.

[0116] As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antimicrobial agents, isotonic agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known to those skilled in the art. Unless any conventional media or agents are incompatible with the active ingredient, they are contemplated for use in the compositions herein. Supplementary active ingredients may also be added to the pharmaceutical compositions.

[0117] Therefore, the solid form of the compound of formula (I) can be orally administered with a pharmaceutically acceptable carrier such as an inert diluent or an absorbable edible carrier. They can be encapsulated in hard or soft shell gelatin capsules, can be compressed into tablets, or can be directly mixed with the patient's food. For oral therapeutic administration, the compound or its pharmaceutically acceptable salt can be combined with one or more excipients and used in the form of ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups or wafers. These preparations contain an effective amount of the compound of formula (I) (or its pharmaceutically acceptable salt).

[0118] Tablets, lozenges, pills, capsules, etc. may further include: a binder such as tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; or a sweetener such as sucrose, fructose, lactose or aspartame; or a flavoring agent.

[0119] Solid forms of the compounds of formula (I) may also be administered intravenously or intraperitoneally by infusion or injection.

[0120] Exemplary pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In any event, the final dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

[0121] Sterile injectable solutions can be prepared by mixing the desired amount of the Fig.13 The solid form of the compound of the grinding conditions stability XRPD pattern of the tartrate salt form I is prepared by mixing with the various other ingredients mentioned above in an appropriate solvent and then filtering and sterilizing. For sterile powders for preparing sterile injection solutions, the preferred preparation method may be vacuum drying and freeze drying techniques, which can produce a powder of the active ingredient plus any other desired ingredients present after previous sterile filtration.

[0122] The amount of the solid form of the compound of formula (I) required for the treatment of can not only change with the selected specific salt, but also can change with the route of administration, the nature of the disease being treated and the age and condition of the patient, and can finally be determined by the attending physician or clinician. However, in general, dosage can be in the range of about 0.1 to about 50 mg / kg body weight per day.

[0123] The desired dose may conveniently be presented in a single dose or in divided doses administered at appropriate intervals.

[0124] As used herein, the term "solid form" and related terms refer to a physical form that is not predominantly liquid or gaseous. The solid form may be crystalline, non-crystalline, or a mixture thereof.

[0125] The term "crystal form" as used herein refers to a crystal form. It includes single-component crystal forms and multi-component crystal forms, and includes but is not limited to polymorphs, solvates, and other molecular complexes, and salts thereof, solvates of salts, other molecular complexes of salts, and polymorphs. In some embodiments, the crystal form of a substance may be substantially free of amorphous and / or other crystal forms. In some embodiments, the crystal form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight of one or more amorphous and / or other crystal forms. In some embodiments, the crystal form of a substance may be physically and / or chemically pure. In some embodiments, the crystal form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and / or chemically pure. In some embodiments, the crystalline forms described herein are substantially pure, i.e., substantially free of other crystalline forms and / or other compounds, containing 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.

[0126] Crystal forms can show different physical characteristic data, which are unique to specific crystal forms such as the crystal forms 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 can be used to identify specific crystal forms. Those skilled in the art can determine whether a crystal form is "consistent" with the reference data provided herein that are identified as being unique to a specific crystal form. Characteristic data that are "consistent" with the data of a reference crystal form are understood by those skilled in the art to be equivalent to the same crystal form as the reference crystal form. In the analysis of whether the data is "consistent", those skilled in the art will understand that, due to, for example, experimental error and routine sample-to-sample analysis, specific characteristic data points may vary to a reasonable degree and still describe a given crystal form.

[0127] As used herein, "amorphous" or "amorphous form" and related terms refer to a substance, component or product that is substantially not crystalline as determined by x-ray powder diffraction. In particular, the term "amorphous" describes a disordered solid form, i.e., a solid form that lacks a grown crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms. In some embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight of one or more other amorphous and / or crystalline forms. In some embodiments, an amorphous form of a substance may be physically and / or chemically pure. In some embodiments, an amorphous form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure.

[0128] In one aspect, the present invention provides a solid form comprising a compound of formula (I) or a salt thereof, or a solvate thereof, or a solvate of a salt thereof, or a mixture thereof:

[0129]

[0130] In some embodiments, the solid form comprising the compound of formula (I) can be a crystalline form, a partially crystalline form, or a mixture of a crystalline form and an amorphous form. In some embodiments, the solid form can include a crystalline form of a compound of formula (I), or a salt thereof, or a solvate thereof, or a solvate of a salt thereof, or a mixture thereof. In some embodiments, the solid form further includes a coformer. In some embodiments, a co-crystal comprising a solid form of a compound of formula (I) and a coformer. In some embodiments, the solid form is an amorphous form. In some embodiments, the solid form is substantially pure.

[0131] In some embodiments, the solid form includes the solid form of the free alkali of the compound of formula (I) or its solvate. In some embodiments, the solid form includes the solid form of the anhydrous free alkali of the compound of formula (I). In some embodiments, the solid form includes the solid form of the solvate of the free alkali of the compound of formula (I). The compound of formula (I), or its salt, or its solvate, or the solvate of its salt, or its mixture can exist in a variety of solid forms. Such solid forms include crystalline forms, amorphous solids, or a mixture of crystalline forms and amorphous forms. In some embodiments, the solid form is substantially crystalline. In some embodiments, the solid form is crystalline.

[0132] In some embodiments, the molar ratio of the compound of formula (I) in the solid form to the solvent / water ranges from about 10:1 to about 1:10. In some embodiments, the molar ratio of the compound of formula (I) in the solid form to the solvent / water ranges from about 5:1 to about 1:5. The molar ratio of the compound of formula (I) in the solid form to the solvent / water ranges from about 3:1 to about 1:3. The molar ratio of the compound of formula (I) in the solid form to the solvent / water ranges from about 2:1 to about 1:2. In some embodiments, the molar ratio is about 1:2 (i.e., a disolvate). In some embodiments, the molar ratio is about 1:1 (i.e., a monosolvate). In some embodiments, the molar ratio is about 2:1 (i.e., a hemisolvate).

[0133] In some embodiments, the solid form is a crystalline form A of the free base of the compound of formula (I). In some embodiments, the crystalline form A of the free base is substantially free of amorphous forms. In some embodiments, the crystalline form A of the free base is substantially free of other crystalline forms. In some embodiments, the crystalline form A of the free base is substantially free of salts of the compound of formula (I). In some embodiments, the crystalline form A of the free base is substantially pure crystalline form A.

[0134] In some embodiments, the crystalline Form A of the free base has an x-ray powder diffraction (XRPD) pattern including 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 embodiments, the crystalline Form A of the free base has substantially Figure 1 XRPD spectrum shown.

[0135] In some embodiments, Form A of the free base exhibits a weight loss of about 0.46% when heated from about 25°C to about 172°C. In some embodiments, Form A of the free base has substantially Figure 2a The TGA spectrum is shown in Figure 2. From TGA analysis, the free base of the compound of formula (I) is a non-solvate in form A.

[0136] In some embodiments, the crystalline Form A of the free base exhibits an endothermic event as characterized by DSC with an onset temperature at about 212.95° C. and / or a peak temperature at about 214.24° C. In some embodiments, the crystalline Form A of the free base has substantially Figure 2b DSC spectrum shown.

[0137] In some embodiments, the solid form is a salt of a compound of formula (I). The compound of formula (I) forms a salt with an acid. The ratio of the compound of formula (I) to the acid can be stoichiometric or non-stoichiometric. In some embodiments, the ratio of the compound of formula (I) to the acid ranges from about 5:1 to about 1:5. In some embodiments, the ratio of the compound of formula (I) to the acid ranges from 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 ratio of the compound of formula (I) to the acid ranges from about 1:1. In some embodiments, the acid is one or more of: tartaric acid, hydrochloric acid, succinic 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 hydrobromide. In some embodiments, the acid is one or more of: tartaric acid, hydrochloric acid, succinic acid, salicylic acid and fumaric acid.

[0138] In some embodiments, the solid form is a crystalline form of a tartrate salt of a compound of formula (I). In some embodiments, the solid form is a crystalline form I of a tartrate salt of a 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 a compound of formula (I) is about 1:1. In some embodiments, it has an x-ray powder diffraction (XRPD) pattern including peaks at 10.3, 13.0, 18.0, 18.3, 21.2, 21.9, 23.1, 25.7, 27.3, and 30.0 degrees 2θ. In some embodiments, it has substantially Figure 3 XRPD spectrum shown.

[0139] In some embodiments, the crystalline Form I of the tartrate salt of the compound of formula (I) exhibits a weight loss of about 0.87% when heated from about 25°C to about 158°C. In some embodiments, it has substantially Figure 4a The TGA spectrum shown is shown in Figure 2. From TGA analysis, the crystalline form I of the tartrate salt of the compound of formula (I) is an unsolvated form.

[0140] In some embodiments, the crystalline Form I of the tartrate salt of the compound of formula (I) exhibits an endothermic event as characterized by DSC, with an onset temperature at about 235.42° C. and / or a peak temperature at about 235.89° C. In some embodiments, it has substantially Figure 4b DSC spectrum shown.

[0141] In some embodiments, the crystalline Form I of the tartrate salt of the compound of formula (I) exhibits a weight gain of about 1% when subjected to an increase in relative humidity from about 0 to about 95% relative humidity. Figure 4c DVS spectrum shown.

[0142] In some embodiments, the present invention provides a pharmaceutical combination, characterized in that the pharmaceutical combination comprises a solid form of a compound of formula (I) and a pharmaceutically acceptable excipient, in particular, an effective amount of a solid form of a compound of formula (I).

[0143] In some embodiments, the present invention provides a solid form of the compound of formula (I) of the present invention and a pharmaceutical composition for use in the preparation of a pharmaceutical composition for treating the following diseases: Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, liver cancer, bile duct cancer, 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, gastric cancer Esophageal junction cancer, thymic cancer, pancreatic cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma, thymoma, germ cell cancer, glioblastoma, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer; in particular 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, melanoma, mesothelioma, ovarian cancer, prostate cancer, kidney cancer, sarcoma, thyroid cancer, testicular cancer, thymoma, or uterine cancer.

[0144] The abbreviations used have the following meanings:

[0145] mg milligram

[0146] ml milliliters

[0147] TGA Thermogravimetric analysis

[0148] DSC Differential Scanning Calorimetry

[0149] DVS Gravimetric Vapor Sorption Isotherm

[0150] Determination method

[0151] 1. Powder X-ray Diffraction (XRPD)

[0152]

[0153] 2. Thermogravimetric analysis (TGA)

[0154]

[0155] 3. Differential Scanning Calorimetry (DSC)

[0156]

[0157] 4. Gravimetric Vapor Sorption Isotherm (DVS)

[0158]

[0159] Example 1: Preparation of free base of compound of formula (I)

[0160] According to the method disclosed in WO2010058032, the free base of the compound of formula (I) was prepared, (M+H) + :589.

[0161] Example 2: Screening of free base crystalline forms of the compound of formula (I)

[0162] For the free base obtained above, crystallinity studies and scalability studies were carried out in different solvents. It was found that the free base existed in polymorphic forms. Four polymorphic forms were obtained within the crystal screening range, but only crystal form A could be scaled up and repeated. Therefore, free base crystal form A is the most preferred crystal form of the free base of the compound of formula (I).

[0163] Table 1: Crystallinity study of free base of compound of formula (I)

[0164]

[0165]

[0166] The free base (1.7 g) obtained above was dissolved in anhydrous ethanol (170 mL), stirred at 82-87° C. for 1-2 hours, cooled to room temperature, and partially distilled off under reduced pressure until solids precipitated. The mixture was allowed to stand, the solids were collected, and dried to obtain free base form A.

[0167] 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).

[0168] XRPD characterization data of free base crystal A of the compound of formula (I):

[0169]

[0170]

[0171] Example 3: Screening of crystalline salts of the compound of formula (I)

[0172] 3.1 Preparation of acid solution

[0173] According to the solubility of different acids, acid solutions are prepared separately, as follows:

[0174] 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, hydrobromic acid: methanol solution, concentration is 1 mol / L;

[0175] Aspartic acid, hippuric acid, glutamic acid: aqueous solution, concentration 0.02 mol / L;

[0176] 2-Naphthalenesulfonic acid: aqueous solution, concentration is 0.01 mol / L.

[0177] Free base form A 17.6mg (about 0.03mmol) was placed in a 10mL sample bottle, and an appropriate amount of reaction solvent was added. After stirring and dissolving, an acid solution (reaction molar ratio of 1:1) was added respectively. After reacting at 50°C for 3h, the temperature was lowered to room temperature, and stirring was continued overnight. Then, the mixture was placed in a 4°C refrigerator and allowed to stand for 8h. For samples without solid precipitation, the solid was evaporated at room temperature and then subjected to XRPD determination; for samples with solid precipitation, the solvent was removed by centrifugation, and the solid obtained by centrifugation and the solid obtained by evaporation of the clear liquid were dried and subjected to XRPD determination to determine whether the salt was formed. The results are shown in Table 2.

[0178] Table 2: Screening results of acid addition salts of compounds of formula (I)

[0179]

[0180] Note: I or II in the above table are different crystal forms of the corresponding acid after the corresponding acid radical is salified. For example, when the acid is sulfuric acid and the solvent is ethyl acetate, the precipitated crystal form I is the crystal form I of the sulfate. The same applies to other crystal forms. A, B and C are all crystal forms of the free base crystal form A compound. NA means no sample was obtained.

[0181] Figure 6 The XRPD pattern of Form B of the free base of the compound of formula (I) is shown.

[0182] Figure 7 The XRPD pattern of Form C of the free base of the compound of formula (I) is shown.

[0183] Figure 8 The XRPD pattern of the free base form D of the compound of formula (I) is shown.

[0184] Fig. 9 The XRPD pattern of the sulfate crystal form I of the compound of formula (I) is shown.

[0185] Fig.10 The XRPD pattern of the phosphate crystal form I of the compound of formula (I) is shown.

[0186] Fig.11 The XRPD pattern of the phosphate crystal form II of the compound of formula (I) is shown.

[0187] Fig.12 The XRPD pattern of maleate salt form I of the compound of formula (I) is shown.

[0188] Fig.13 The XRPD pattern of maleate salt form II of the compound of formula (I) is shown.

[0189] Fig.14 The XRPD pattern of Form I of the citrate salt of the compound of formula (I) is shown.

[0190] Fig.15 The XRPD pattern of the lactate crystalline form I of the compound of formula (I) is shown.

[0191] Fig.16 The XRPD pattern of benzenesulfonate crystalline form I of the compound of formula (I) is shown.

[0192] Fig.17 The XRPD pattern of Form I of 2-hydroxyethanesulfonate salt of the compound of formula (I) is shown.

[0193] Fig.18 The XRPD pattern of Form I of the benzoate salt of the compound of formula (I) is shown.

[0194] Fig.19 The XRPD pattern of the p-toluenesulfonate crystalline form I of the compound of formula (I) is shown.

[0195] Fig. 20 The XRPD pattern of the hydrobromide salt form I of the compound of formula (I) is shown.

[0196] Example 4: Preparation of Tartrate Form I of the Compound of Formula (I)

[0197] In addition to preparing the crystalline form I by the method in the above acid addition salt screening results, it can also be prepared as follows:

[0198] 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 distilled to remove the solvent under reduced pressure until solids are precipitated. The mixture is allowed to stand, the solids are collected, and dried to obtain tartrate salt form I. In the tartrate salt form I of the compound of formula (I), the molar ratio of the compound of formula (I) to tartaric acid is about 1:1.

[0199] 1 H 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).

[0200] XRPD characterization data of tartrate salt form I:

[0201]

[0202]

[0203] Example 5: Preparation of tartrate salt form III of the compound of formula (I)

[0204] In addition to preparing the crystal form III by the method in the above acid addition salt screening results, it can also be prepared as follows: the free base (2.95 g) obtained above is dissolved in ethyl acetate (188 mL), heated to 60-65° C., 5 ml of tartaric acid methanol solution is added dropwise, stirred for 1-3 hours, cooled to room temperature, filtered, and dried to obtain the tartrate crystal form III. The molar ratio of the compound of formula (I) to tartaric acid in the crystal form III of the tartrate of the compound of formula (I) is about 1:1.

[0205] 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).

[0206] XRPD characterization data of tartrate salt form III:

[0207]

[0208]

[0209] Example 6: Solubility determination

[0210] A certain mass of free base crystal form A, tartrate crystal form I and tartaric acid crystal form III of the compound of formula (I) were weighed into a 5 mL sample bottle, and 2 mL of deionized water, pH 2.0 glycine-hydrochloric acid buffer, pH 4.5 Na2HPO4-citric acid buffer, and pH 6.8 Na2HPO4-citric acid buffer were added respectively. The mixture was shaken on a shaker at 25° C. for 24 hours and then filtered. The solubility of the filtrate was determined by HPLC; the solid was detected by XRPD to determine whether the crystal form had changed.

[0211] The chromatographic conditions were as follows:

[0212] Chromatographic column: Unitary C18 (5μm, 100A, 4.6×250mm)

[0213] Mobile phase: Phase A is ammonium acetate at pH = 6.2, phase B is acetonitrile, A:B = 10:90

[0214] Detection wavelength: 230nm Column temperature: 35℃

[0215] Injection volume: 20 μL

[0216] The solubility test results are shown in Table 3:

[0217] Table 3: Solubility of free base and salt of compound of formula (I) (25°C, mg / mL)

[0218] medium Free base amorphous Free base form A Tartrate Form I Tartrate Form III pH 2.0 >10 >10 >10 >10 pH 4.5 8.5 >10 5.2 >10 pH 6.8 0.05 1.06 >10 >10 Deionized water 1.07 0.033 2.59 >10

[0219] The solubility test results show that compared with the free base amorphous, the solubility of the free base form A in pH 6.8 buffered saline solution is significantly improved. The solubility of tartaric acid form I in deionized water and pH 6.8 buffered saline solution is significantly improved. Tartrate form III has very good solubility in all solvent systems. The improved solubility in deionized water greatly reduces the difficulty of formulation; the improved solubility in pH 6.8 buffered saline solution greatly improves the oral bioavailability of the drug. Through XRPD detection, the free base form A did not undergo a crystal form change in pH 6.8 buffered saline solution and deionized water; the tartaric acid form I did not undergo a crystal form change in deionized water.

[0220] Example 7: Accelerated stability test evaluation

[0221] According to the fourth part of the 2015 edition of the Chinese Pharmacopoeia, “Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Preparations”, the stability testing of active pharmaceutical ingredients requires testing of influencing factors and accelerated testing of the crystal form.

[0222] High temperature test (T): The powder was placed in a suitable sealed glass bottle at 60°C for 10 days, and samples were taken on the 5th and 10th days for solid XRPD testing.

[0223] High humidity test (H): Place the powder with its opening in a constant temperature and humidity chamber at 25°C and 90%±5%RH for 10 days, and take samples on the 5th and 10th days to test the solid XRPD to examine its hygroscopic deliquescent properties.

[0224] Strong light irradiation test (L): Place the powder opening in a light stabilization box equipped with a fluorescent lamp and place it at an illumination of 4500±500lx for 10 days. Samples are taken on the 5th and 10th days for solid XRPD testing.

[0225] Accelerated test (A): The powder opening was placed in a constant temperature and humidity chamber at 40°C and 75%±5%RH for 10 days, and samples were taken on the 5th and 10th days for solid XRPD testing.

[0226] The results of the stability test are shown in Table 4, and the spectrum is shown in the attached Figure 21-23 .

[0227] Table 4: Crystal stability test results

[0228]

[0229] The stability results show that free base crystal form A, tartaric acid crystal form I, and tartrate crystal form III are stable under all experimental conditions and will not undergo crystal form transformation. However, the crystallinity of tartrate crystal form III weakens under high humidity conditions, suggesting that attention should be paid to the ambient humidity when storing crystal form III, otherwise there is a potential possibility of transformation into an amorphous state.

[0230] Example 8: Stability study under mechanical stress

[0231] 8.1 Stability of pressure conditions

[0232] Take appropriate amount of free base crystal form A, tartrate crystal form I and tartrate crystal form III powder and spread it on the bottom of the powder tablet press mold to simulate the pressure conditions in the preparation process. Apply mechanical pressures of 2, 4, 6, 8, and 10N respectively. After maintaining the pressure stable for 5 minutes, take samples for XRPD measurement to investigate the stability of the crystal form under pressure conditions. The spectrum is detailed in the attached Figure 24-26 Comparison of XRPD results showed that the free base form A, tartrate form I and tartrate form III were all stable under pressure conditions.

[0233] 8.2 Stability of grinding conditions

[0234] Take appropriate amounts of free base crystal form A, tartrate crystal form I and tartrate crystal form III powder and spread them in an agate mortar, add agate beads. Simulate the grinding conditions in the preparation process, set the vibration frequency of the automatic ball mill to 25S-1, grind for 5, 10, 15, and 30 minutes respectively, and then take samples for XRPD testing to investigate the crystal stability under the grinding conditions. See the attached spectrum for details. Figure 27-29 .

[0235] Comparison of XRPD results shows that under grinding conditions, free base crystal form A and tartrate crystal form III become amorphous, while tartrate crystal form I only has reduced crystallinity. Therefore, the grinding condition stability of tartrate crystal form I is better and more stable during the preparation process.

[0236] Example 9: Adsorption and desorption experiment of tartrate water of compound of formula (I)

[0237] The adsorption and desorption experiments of tartaric acid crystal forms I and III at 25°C and 0-95% relative humidity were carried out by using a dynamic water sorption instrument (DVS) to determine the hygroscopic properties of various crystal forms (see Appendix for details). Figure 4d , 5d). The results show that within the humidity range of 40-80% RH, the moisture absorption of Form I is 0.33%, and that of Form III is 0.37%. The stability of Form I under high humidity conditions (RH>90%) is significantly better than that of Form III. Form III absorbs 18.1% of RH from 90% to 95%, while Form I, the tartrate salt, has almost no moisture absorption (0.08%).

[0238] Example 10: Study on the conversion relationship of the tartrate salt of the compound of formula (I)

[0239] The suspension competition transformation of Form I and Form III was studied in different organic solvents to determine the stable crystal forms under different conditions and the mutual transformation relationship between Form I and Form III. Weigh 20 mg of Form I and Form III in a 2 mL or 10 mL glass bottle, and add 0.5 mL or 1 mL of organic solvent according to the solubility. Prepare two batches of the same solvent, place them at room temperature and 50 ° C for 24 hours of suspension competition, centrifuge the suspension (10000 rpm, 3 min), and vacuum dry the solid powder to test PXRD (see Appendix for details). Fig.30 , 31). The results of the suspension crystallization test are shown in Table 2. The results show that, except for methyl tert-butyl ether and cyclohexane, the physical mixture of Form I and Form III at room temperature and 50°C is transformed into Form I after suspension competition in common solvents such as 75% ethanol, anhydrous ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methanol, isopropanol, 2-butanone, toluene, water, etc. It can be judged that under these conditions, Form I is a stable form.

[0240] Table 5: Results of suspension crystallization test of tartrate forms I and III of compound of formula (I)

[0241]

[0242]

[0243] In summary, the stability evaluation and solubility study of tartrate crystal form I and crystal form III further optimized the tartrate crystal form suitable for development. The stability test results show that the solvent-mediated crystal transformation, grinding, and moisture absorption stability of crystal form I are better than those of crystal form III.

[0244] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications and concurrently pending patent applications) are hereby expressly incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly known to those of ordinary skill in the art.

[0245] All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature having the same, equivalent or similar purpose. Therefore, unless otherwise expressly stated, each feature disclosed is only an example of a series of equivalent or similar features.

[0246] According to the above description, those skilled in the art can easily determine the basic characteristics of the present invention, and without departing from the spirit and scope of the present invention, various changes and modifications can be made to the present invention to adapt it to various uses and conditions. Therefore, other embodiments are also within the scope of the appended claims.

Claims

1. Solid form of a compound of formula (I): It is a tartrate crystal form I of the compound of formula (I), characterized in that: It has an X-ray powder diffraction (XRPD) pattern including peaks at 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees 2Θ.

2. The solid form according to claim 1, characterized in that It has an X-ray powder diffraction (XRPD) including peaks at 4.627, 10.34, 13.019, 17.981, 18.281, 21.2, 21.901, 23.121, 27.299, 27.541 and 29.879 degrees 2Θ.

3. The solid form of claim 1, wherein It has an 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.

4. The solid form of claim 1, wherein It has an XRPD pattern substantially as shown in Figure 3.

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

6. Use of the solid form of any one of claims 1 to 4 or the pharmaceutical composition of claim 5 for the preparation of a medicament for use as a FAK inhibitor.

7. Use of the solid form of any one of claims 1 to 4 or the pharmaceutical composition of claim 5 in the preparation of a medicament for treating Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, liver cancer, bile duct cancer, 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, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma, thymoma, germ cell cancer, glioblastoma, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer.

8. Use of the solid form of any one of claims 1 to 4 or the pharmaceutical composition of claim 5 in the preparation of a medicament for treating the following diseases: 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, melanoma, mesothelioma, ovarian cancer, prostate cancer, kidney cancer, sarcoma, thyroid cancer, testicular cancer, thymoma, or uterine cancer.

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