Solid forms of a compound

Abstract

This invention relates to compounds of formula (I) or their salts, solvates thereof, solvents of their salts, or mixtures thereof in solid form: .

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more particularly to the solid form of a compound. Prior Technology

[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 a crucial role in mediating integrin and growth factor signaling to regulate tumor cell invasion, proliferation, and survival. FAK is widely expressed and evolutionarily conserved. Studies over the past two decades have shown that FAK is overexpressed in various solid tumors, and its expression level is negatively correlated with tumor prognosis. Recent research also indicates that FAK plays an important role in regulating the tumor microenvironment, suggesting its significant role in adaptive resistance to immunotherapy and antitumor therapies.

[0003] Compound (I) is a FAK inhibitor that has shown antitumor activity in CDX (human tumor cell line transplanted to mice) models of multiple tumor types. To prepare the desired drug substance, we urgently need to find a solid form that improves the drug-likeness of the compound, especially by exhibiting beneficial properties in terms of crystallinity, stability, hygroscopicity, and solubility. Summary of the Invention

[0004] On the one hand, the present invention provides compounds of formula (I) in solid form, or salts thereof, or solvates thereof, or solvates thereof, or mixtures thereof: (I).

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

[0006] Optionally, the solid form is crystalline.

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

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

[0009] Optionally, it has X-ray powder diffraction (XRPD) peaks at 2θ at 10.979, 19.26, 21.581 and 24.801 degrees.

[0010] Optionally, it has X-ray powder diffraction (XRPD) peaks at 4.781, 10.979, 19.26, 21.581, 22.26 and 24.801 degrees 2θ.

[0011] Optionally, it has X-ray powder diffraction (XRPD) 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] Optionally, it has X-ray powder diffraction (XRPD) 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.

[0013] Optionally, it features X-ray powder diffraction (XRPD) 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, and 23.2. 2. One or more peaks from 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, and 44.279. Optionally, it has an XRPD spectrum substantially as shown in Figure 1.

[0014] Optionally, it exhibits endothermic events as characterized by DSC, with a start temperature of about 212.95 °C and / or a peak temperature of about 214.24 °C.

[0015] Optionally, the solid form is crystal form I of tartrate of formula (I).

[0016] Optionally, it has X-ray powder diffraction (XRPD) peaks at 10.34, 17.981, 18.281 and 21.901 degrees 2θ.

[0017] Optionally, it has X-ray powder diffraction (XRPD) peaks at 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees 2θ.

[0018] Optionally, it has X-ray powder diffraction (XRPD) 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.

[0019] Optionally, it has X-ray powder diffraction (XRPD) peaks at 2θ degrees located 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.

[0020] Optionally, it features X-ray powder diffraction (XRPD) including 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, 2 One or more peaks from 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.

[0021] Optionally, it has an XRPD spectrum that is essentially as shown in Figure 3.

[0022] Optionally, it exhibits endothermic events as characterized by DSC, with a start temperature at approximately 235.42 °C and / or a peak temperature at approximately 235.89 °C.

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

[0024] Optionally, it has X-ray powder diffraction (XRPD) peaks at 13.2, 13.519, 15.181, 21.901, 22.521, 23.121 and 24.9 degrees 2θ.

[0025] Optionally, it has X-ray powder diffraction (XRPD) 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.

[0026] Optionally, it has X-ray powder diffraction (XRPD) peaks at 2θ degrees located 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.

[0027] Optionally, it features X-ray powder diffraction (XRPD) 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, One or more peaks from 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] Optionally, it has an XRPD spectrum that is essentially as shown in Figure 5.

[0029] Optionally, it exhibits endothermic events as characterized by DSC, with a start temperature at approximately 235.42 °C and / or a peak temperature at approximately 235.89 °C.

[0030] Optionally, it is a phosphate of compound (I).

[0031] Optionally, it is the phosphate crystal form I of compound (I).

[0032] Optionally, it has X-ray powder diffraction (XRPD) peaks at 13.76, 19.08, 20.581, and 22.319 degrees 2θ.

[0033] Optionally, it has X-ray powder diffraction (XRPD) peaks at 13.76, 15.941, 19.08, 20.581, 22.319 and 24.642 degrees 2θ.

[0034] Optionally, it has X-ray powder diffraction (XRPD) peaks at 2θ degrees located at 13.76, 14.52, 15.941, 19.08, 20.581, 22.319, 23.381, 23.818, 24.642, and 28.219 degrees.

[0035] Optionally, it has X-ray powder diffraction (XRPD) 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] Optionally, it has an XRPD spectrum that is essentially as shown in Figure 10.

[0037] Optionally, it is a maleate of formula (I).

[0038] Optionally, it is maleate crystal form I of compound (I).

[0039] Optionally, it has X-ray powder diffraction (XRPD) peaks at 18.459, 20.237, 22.185, and 24.12 degrees 2θ.

[0040] Optionally, it has X-ray powder diffraction (XRPD) peaks at 10.32, 15.998, 18.459, 20.237, 22.185 and 24.12 degrees 2θ.

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

[0042] Optionally, it has X-ray powder diffraction (XRPD) peaks at 2θ degrees located 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.

[0043] Optionally, it has an XRPD spectrum that is essentially as shown in Figure 12.

[0044] Optionally, it is a benzoate of formula (I).

[0045] Optionally, it is benzoate crystal form I of compound (I).

[0046] Optionally, it has X-ray powder diffraction (XRPD) peaks at 2θ at 6.639, 8.461, 20.16, and 21.699 degrees.

[0047] Optionally, it has X-ray powder diffraction (XRPD) peaks at 6.639, 8.461, 12.119, 14.52, 20.16 and 21.699 degrees 2θ.

[0048] Optionally, it has X-ray powder diffraction (XRPD) 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.

[0049] Optionally, it has X-ray powder diffraction (XRPD) 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.

[0050] Optionally, it has an XRPD spectrum that is essentially as shown in Figure 18.

[0051] On the other hand, the present invention provides tartrate salts of compounds of formula (I), (I).

[0052] Optionally, it is the tartrate crystal form I of compound (I).

[0053] Optionally, it has X-ray powder diffraction (XRPD) peaks at 10.34, 17.981, 18.281 and 21.901 degrees 2θ.

[0054] Optionally, it has X-ray powder diffraction (XRPD) peaks at 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees 2θ.

[0055] Optionally, it has X-ray powder diffraction (XRPD) 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.

[0056] Optionally, it has X-ray powder diffraction (XRPD) peaks at 2θ degrees located 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.

[0057] Optionally, it features X-ray powder diffraction (XRPD) including 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, 2 One or more peaks from 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.

[0058] Optionally, it has an XRPD spectrum that is essentially as shown in Figure 3.

[0059] On the other hand, the present invention provides a method for preparing a compound of formula (I) in solid form, comprising the steps of: The non-solid form of the compound of formula (I) is exposed to one or more solvents, stirred under heating conditions for a period of time to dissolve it, and then cooled to room temperature to obtain the solid form. The compound of formula (I) is... (I).

[0060] Optionally, the solvent is anhydrous ethanol.

[0061] On the other hand, the present invention provides a method for preparing a solid form of a compound salt of formula (I), the steps of which include:

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

[0063] On the other hand, the present invention provides a pharmaceutical composition characterized in that the pharmaceutical composition comprises 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 compound of formula (I) in solid form.

[0064] On the other hand, the present invention provides a solid form of the compound of formula (I) described herein and the use of the pharmaceutical composition in use as a FAK inhibitor.

[0065] On the other hand, the present invention provides the use of a solid form of the compound of formula (I) and a pharmaceutical composition thereof in the preparation for the treatment of the following diseases: 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, and gastroesophageal cancer. Cancer of the junction, thymic cancer, pancreatic cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma, thymoma, germ cell cancer, glioblastoma, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer; especially 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. Simple Explanation of the Diagram

[0066] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of the free alkali crystal form A of compound (I). Figure 2a shows the thermogravimetric analysis (TGA) of the free alkali crystal form A of compound (I); Figure 2b shows the differential scanning calorimetry (DSC) analysis results of the free alkali crystal form A of compound (I). Figure 3 shows the X-ray powder diffraction (XRPD) pattern of tartrate crystal form I of compound (I). Figure 4a shows the thermogravimetric analysis (TGA) of tartrate crystal form I of compound (I); Figure 4b shows the differential scanning calorimetry (DSC) analysis results of tartrate crystal form I of compound (I); Figure 4c shows the 1H NMR (DMSO-d6) chromatogram of tartrate crystal form I of compound (I); Figure 4d shows the dynamic vapor adsorption (DVS) isotherm of tartrate crystal form I of compound (I). Figure 5 shows the X-ray powder diffraction (XRPD) pattern of tartrate crystal form III of compound (I). Figure 5a shows the thermogravimetric analysis (TGA) of tartrate crystal form III of compound (I); Figure 5b shows the differential scanning calorimetry (DSC) analysis results of tartrate crystal form III of compound (I); Figure 5c shows the 1H NMR (DMSO-d6) pattern of tartrate crystal form III of compound (I); Figure 5d shows the dynamic vapor adsorption (DVS) isotherm of tartrate crystal form III of compound (I). Figure 6 shows the XRPD diagram of the free alkali crystal form B of compound (I). Figure 7 shows the XRPD diagram of the free alkali crystal form C of compound (I). Figure 8 shows the XRPD diagram of the free alkali crystal form D of compound (I). Figure 9 shows the XRPD diagram of sulfate crystal form I of compound (I). Figure 10 shows the XRPD diagram of phosphate crystal form I of compound (I). Figure 11 shows the XRPD diagram of phosphate crystal form II of compound (I). Figure 12 shows the XRPD diagram of maleate crystal form I of compound (I). Figure 13 shows the XRPD diagram of maleate crystal form II of compound (I). Figure 14 shows the XRPD diagram of citrate form I of compound (I). Figure 15 shows the XRPD diagram of lactate crystal form I of compound (I). Figure 16 shows the XRPD diagram of benzenesulfonate crystal form I of compound (I). Figure 17 shows the XRPD diagram of crystal form I of compound (I) 2-hydroxyethanesulfonate. Figure 18 shows the XRPD diagram of benzoate I of compound (I). Figure 19 shows the XRPD diagram of p-toluenesulfonate crystal form I of compound (I). Figure 20 shows the XRPD diagram of hydrobromide crystal form I of compound (I). Figure 21 shows the stability analysis of free alkali crystal form A. Figure 22 shows the stability analysis of tartrate crystal form I. Figure 23 shows the stability analysis of tartrate crystal form III. Figure 24 shows the XRPD diagram of the pressure-condition stability of free alkali crystal form A. Figure 25 shows the XRPD diagram of the pressure-condition stability of tartrate crystal form I. Figure 26 shows the XRPD diagram of the pressure-condition stability of tartrate crystal form III. Figure 27 shows the XRPD diagram of the stability of free alkali crystal form A under grinding conditions. Figure 28 shows the XRPD diagram of the stability of tartrate crystal form I under grinding conditions. Figure 29 shows the XRPD diagram of the stability of tartrate crystal form III under grinding conditions. Figure 30 shows the suspension competition experiment analysis of tartrate I and tartrate III at room temperature. Figure 31 shows the suspension competition experiment analysis of tartrate I and tartrate III at 50℃. Implementation

[0067] The following embodiments are provided to further illustrate the invention. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0068] Unless otherwise specified, the experimental methods described in the following examples can be performed under the standard conditions for such reactions or under the conditions recommended by the manufacturer.

[0069] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0070] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0071] As used herein, the terms "about" or "approximately" when used in conjunction with a numerical value or range of values ​​indicate that the value or range of values ​​may deviate from a range that is reasonable to a person skilled in the art, for example, within experimental variation (or within statistical experimental error). Therefore, the numerical value or range of values ​​may vary, for example, between 1% and 15%, 1% and 10%, 1% and 5%, 0.5% and 5%, and 0.5% and 1% of the numerical value or range of values ​​disclosed herein. The use of the term "about" preceding a numerical value or range of values ​​also includes embodiments with a given value. For example, "about 3°C" discloses an embodiment with a temperature of "3°C". Throughout the specification, the terms "about" and "approximately" are used interchangeably. The term "between" includes the endpoints of an atmospheric limit; for example, the range described as "between 3 and 5" includes the digits "3" and "5". The tilde (~) before the numerical value or range used in this article indicates "approximately" or "about".

[0072] As used herein, the term "mixing" refers to the formation of a mixture of one or more chemical entities with another one or more chemical entities. Mixing includes the process of adding one or more compounds to a mixture of solids, liquids, or gases, or a liquid solution or multiphase liquid mixture of one or more compounds (the same or other chemical entities) (e.g., bond formation or cleavage; salt formation, solvate formation, chelation, or other alteration of nonbonded association). The effects of mixing can include altering one or more compounds, such as through isomerization (e.g., tautomerism, separation of one isomer from another, or racemization).

[0073] The term "pharmaceutically acceptable" as used in this article refers to something that is non-toxic, biologically tolerable, and suitable for administration to subjects.

[0074] As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic, biologically tolerable salt suitable for administration to a subject. 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, hydrobromic acids, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by the compound with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates, and salts formed with alkyl dicarboxylic acids of the formula HOOC-(CH2)n-COOH (where n is 0-4), etc. Furthermore, if the compound of the present invention is obtained from an acid addition salt, a free base can be obtained by alkalizing a solution of an acidic salt. Conversely, if the product is a free base, a pharmaceutically acceptable salt can be prepared using conventional methods for preparing acid addition salts from free base compounds, by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable salts. In some embodiments, the salt is a tartrate, hydrochloride, succinate, salicylate, or fumarate. In some embodiments, the salt is a tartrate.

[0075] As used herein, the term "solvent" refers to a compound that is stoichiometric or non-stoichiometric in solvent bound by non-covalent intermolecular forces. For example, when the solvent is water, the solvate is a "hydrate". A solvate can be a channel solvate. It should be understood that the term "solvent" as used herein includes compounds and solvates of compounds, as well as mixtures thereof.

[0076] Unless otherwise stated, the terms "solvent," "organic solvent," and "inert solvent" as used herein each refer to an inert organic solvent under the reaction conditions described herein, including but not limited to benzene, toluene, acetonitrile (MeCN), ethyl acetate (EtOAc), isopropyl acetate (IPAc), hexane, heptane, dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), diethyl ether, methanol (MeOH), ethanol, isopropanol, butanol, methyl tributyl 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 tributyl ether, acetone, etc. Unless otherwise specified, the solvents used in the reactions described herein are inert organic solvents.

[0077] As used herein, the term "subject" refers to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as chimpanzees and other ape 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 so on. 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 implementations, the subject is a human.

[0078] The term "therapeutic" as used herein refers to achieving the desired pharmacological and / or physiological effect. This effect may be therapeutic and may include partially or substantially achieving one or more of the following results: partial or complete reduction of the severity of the disease, symptom, or syndrome; improvement of disease-related clinical symptoms or indicators; or delay, inhibit, or reduce the likelihood of progression of the disease, symptom, or syndrome.

[0079] As used herein, the term "effective amount" refers to the solid form of a compound of formula (I) 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 the remission of a disease or condition or delay the recurrence or progression of symptoms, or enhance or improve the therapeutic effect of another therapy. The precise amount given to a subject will depend on various factors, such as the given drug or compound, the drug formulation, the route of administration, the type of disease, the condition, the identity of the subject or host being treated, etc., but can still be routinely determined by those 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 the appropriate 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. Appropriate 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 its pharmaceutically acceptable salt. Where no amount is explicitly stated, some amount should be assumed. The effective dose of the compound of formula (I) in solid form can be 10 μg to 2000 mg. This example is non-limiting.

[0080] 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 the subject.

[0081] As used herein, "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable carrier" includes any and all solvents, dispersion media, coatings, antimicrobial agents, isotonic agents, absorption delay agents, etc. The use of such media and reagents for pharmaceutical active substances is well known to those skilled in the art. Unless any conventional media or reagent is incompatible with the active ingredient, its use in the compositions herein is contemplated. Additional active ingredients may also be incorporated into the pharmaceutical composition.

[0082] Therefore, the solid form of the compounds of formula (I) can be administered orally with pharmaceutically acceptable carriers such as inert diluents or absorbable edible carriers. They can be encapsulated in hard-shell or soft-shell gelatin capsules, compressed into tablets, or mixed directly with the patient's food. For oral therapeutic administration, the compounds or pharmaceutically acceptable salts thereof can be combined with one or more excipients and used in the form of ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, or rice paper capsules. These formulations contain an effective amount of the compound of formula (I) (or a pharmaceutically acceptable salt thereof).

[0083] Tablets, lozenges, pills, capsules, etc., may further include: binders, such as astragalus gum, gum arabic, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; or sweeteners, such as sucrose, fructose, lactose or aspartame; or flavoring agents.

[0084] The solid form of the compound of formula (I) can also be administered intravenously or intraperitoneally by infusion or injection.

[0085] Exemplary drug dosage forms for injection or infusion include: sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient, which are suitable for ad hoc preparation of sterile injectable or infusion solutions or dispersions. In any case, the final dosage form should be sterile, flowable, and stable under both manufacturing and storage conditions.

[0086] Sterile injectable solutions can be prepared by incorporating the desired amount of the compound in solid form, as shown in the XRPD graph of the milling conditions of tartrate crystal form I of Figure 13, with various other desired components described above into a suitable solvent, followed by filtration and sterilization. For sterile powders used to prepare sterile injectable solutions, preferred preparation methods include vacuum drying and freeze-drying techniques, which can produce powders containing the active ingredient plus any other desired components present after previous sterile filtration.

[0087] The amount of the solid form of the compound of formula (I) required for treatment can vary not only with the specific salt chosen, but also with the route of administration, the nature of the disease being treated, and the patient's age and condition, and can ultimately be determined by the attending physician or clinician. However, generally, the dosage can range from about 0.1 to about 50 mg / kg body weight per day.

[0088] The required dose can be conveniently available as a single dose or in fractions administered at appropriate intervals.

[0089] The term "solid form" and related terms used herein refer to physical forms that are not primarily liquid or gaseous. Solid forms can be crystalline, amorphous, or mixtures thereof.

[0090] The term "crystal form" as used herein refers to a crystalline form. This includes single-component and multi-component crystalline forms, and includes, but is not limited to, polymorphs, solvates, other molecular complexes, and their salts, 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 crystalline 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 crystalline 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 crystal form described herein is substantially pure, i.e., substantially free of other crystal 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 crystal forms and / or other compounds.

[0091] Crystal forms can exhibit different physical characteristics unique to a particular crystal form, such as the one described herein. These characteristics can be obtained using various techniques known to those skilled in the art, including, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), pyrolysis gravimetric analysis (TGA), and nuclear magnetic resonance spectroscopy (HNMR). The information provided by these techniques can be used to identify a specific crystal form. Those skilled in the art can determine whether a crystal form “matches” the reference data provided herein that is specific to a particular crystal form. Characteristics “matching” the 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 “matches”, those skilled in the art should understand that, due to factors such as experimental errors and routine inter-sample analysis, specific characteristic data points can vary to a reasonable extent while still describing a given crystal form.

[0092] As used herein, "amorphous" or "amorphous form" and related terms refer to substances, components, or products that are substantially non-crystalline when determined by X-ray powder diffraction. Specifically, the term "amorphous" describes a disordered solid form, i.e., a solid form lacking a grown crystal order. In some embodiments, the amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms. In some embodiments, the 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, the amorphous form of a substance may be physically and / or chemically pure. In some embodiments, the amorphous form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure.

[0093] On the one hand, the present invention provides a solid form comprising a compound of formula (I) or a salt thereof, a solvate thereof, a solvate of a salt thereof, or a mixture thereof: (I).

[0094] In some embodiments, the solid form comprising a compound of formula (I) may be a crystalline form, a partially crystalline form, or a mixture of crystalline and amorphous forms. In some embodiments, the solid form may comprise a crystalline form of a compound of formula (I), a salt thereof, a solvate thereof, a solvate of a salt thereof, or a mixture thereof. In some embodiments, the solid form further comprises a co-formation. In some embodiments, a eutectic solid comprising a 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.

[0095] In some embodiments, the solid form comprises the solid form of a free base of formula (I) or a solvation thereof. In some embodiments, the solid form comprises the solid form of an anhydrous free base of formula (I). In some embodiments, the solid form comprises the solid form of a solvation of a free base of formula (I). The compound of formula (I), or a salt thereof, or a solvation thereof, a solvent of a salt thereof, or a mixture thereof, may exist in a variety of solid forms. Such solid forms include crystalline, amorphous solids, or mixtures of crystalline and amorphous forms. In some embodiments, the solid form is substantially crystalline. In some embodiments, the solid form is crystalline.

[0096] In some embodiments, the molar ratio of the compound of formula (I) in solid form to solvent / water ranges from about 10:1 to about 1:10. In some embodiments, the molar ratio of the compound of formula (I) in solid form to solvent / water ranges from about 5:1 to about 1:5. The molar ratio of the compound of formula (I) in solid form to solvent / water ranges from about 3:1 to about 1:3. The molar ratio of the compound of formula (I) in solid form to solvent / water ranges from about 2:1 to about 1:2. In some embodiments, the molar ratio is about 1:2 (i.e., a dual solvate). In some embodiments, the molar ratio is about 1:1 (i.e., a single solvate). In some embodiments, the molar ratio is about 2:1 (i.e., a hemisolvate).

[0097] In some embodiments, the solid form is crystal form A of a free base of formula (I). In some embodiments, crystal form A of the free base is substantially free of amorphous forms. In some embodiments, crystal form A of the free base is substantially free of other crystal forms. In some embodiments, crystal form A of the free base is substantially free of salts of formula (I). In some embodiments, crystal form A of the free base is substantially pure crystal form A.

[0098] In some embodiments, crystal form A of the free base has X-ray powder diffraction (XRPD) 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, crystal form A of the free base has an XRPD spectrum substantially as shown in Figure 1.

[0099] In some embodiments, crystal form A of the free base shows a weight loss of about 0.46% when heated from about 25°C to about 172°C. In some embodiments, crystal form A of the free base has a TGA spectrum substantially as shown in Figure 2a. From TGA analysis, crystal form A of the free base of the compound of formula (I) is a solvate.

[0100] In some embodiments, crystal form A of the free base exhibits an endothermic event as characterized by DSC, with an onset temperature of about 212.95 °C and / or a peak temperature of about 214.24 °C. In some embodiments, crystal form A of the free base has a DSC spectrum substantially as shown in Figure 2b.

[0101] 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 the following: 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 the following: tartaric acid, hydrochloric acid, succinic acid, salicylic acid, and fumaric acid.

[0102] In some embodiments, the solid form is a crystal form of the tartrate salt of formula (I). In some embodiments, the solid form is crystal form I of the tartrate salt of formula (I). In crystal form I of the tartrate salt of formula (I), the molar ratio of formula (I) to tartaric acid is about 1:1. In some embodiments, it has X-ray powder diffraction (XRPD) 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 an XRPD spectrum substantially as shown in FIG3.

[0103] In some embodiments, the tartrate form I of the compound of formula (I) shows a weight loss of about 0.87% when heated from about 25°C to about 158°C. In some embodiments, it has a TGA spectrum substantially as shown in FIG4a. From TGA analysis, the tartrate form I of the compound of formula (I) is a solvate.

[0104] In some embodiments, the tartrate form I 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 a DSC spectrum substantially as shown in FIG4b.

[0105] In some embodiments, the tartrate crystal form I of the compound of formula (I) shows a weight increase of about 1% when subjected to an increase in relative humidity from about 0 to about 95%. In some embodiments, it has a DVS spectrum substantially as shown in FIG4c.

[0106] In some embodiments, the present invention provides a pharmaceutical composition characterized in that the pharmaceutical composition comprises a compound of formula (I) in solid form and a pharmaceutically acceptable excipient. In particular, an effective amount of the compound of formula (I) in solid form.

[0107] In some embodiments, the present invention provides the use of a solid form of a compound of formula (I) and a pharmaceutical composition thereof in the preparation of a treatment for the following diseases: 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, and stomach cancer. Cancer of the esophageal junction, thymic cancer, pancreatic cancer, uterine cancer, testicular cancer, melanoma, skin cancer, mesothelioma, thymoma, germ cell cancer, glioblastoma, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer; especially 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.

[0108] The meanings of the abbreviations used are as follows: mg ml TGA pyrolysis gravimetric analysis DSC Differential Scanning Calorimetry DVS gravimetric analysis vapor absorption isotherm

[0109] Determination methods

[0110] 1. Powder X-ray diffraction (XRPD) Instrument Model Rigaku Ultima IV diffraction lines CuKα(40Kv, 30mA) Scan rate 20∘ / min (2θ value) Scan range 3∘~45∘(2θ value)

[0111] 2. Thermogravimetric analysis (TGA) Instrument Model TA Q500 heating rate 10℃ / min

[0112] 3. Differential Scanning Calorimetry (DSC) Instrument Model TA Q2000 heating rate 10℃ / min

[0113] 4. Deuterated Vapor Absorption Isotherm (DVS) for Gravimetric Analysis Instrument Model SMS DVS Intrinsic temperature 25℃ Relative humidity (RH) change control process 40-95-0-95-0%

[0114] [Example] [1] [:Mode] [(I)] [Preparation of free base compounds]

[0115] Following the method disclosed in WO2010058032, the free base of compound (I) was prepared, (M+H)+ :589

[0116] [Example] [2] [:Mode] [(I)] [Screening of the free base crystal form of compounds]

[0117] The crystallinity and scale-up studies of the free base obtained above were conducted in different solvents. It was found that the free base has polymorphs. Four polymorphs were obtained within the crystal form screening range, but only crystal form A can be scaled up and reproduced. Therefore, crystal form A of the free base is the optimal crystal form of the free base of compound (I).

[0118] Table 1: Study on the crystallinity of free base compounds of formula (I) reagents Crystal form Floating Volatilization 75% ethanol B B 95% Isopropanol B B water B NA 2-Butanone C C Methyl tributyl ether A B acetone A A Ethyl acetate A A Isopropanol A Amorphous Acetonitrile A A methanol B B Tetrahydrofuran A A Dioxane D B

[0119] 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 removed by vacuum distillation until a solid precipitated. After standing, the solid was collected and dried to obtain the free base crystal form A.

[0120] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 12.5 Hz, 2H), 7.98 – 7.91 (m, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 7.05 (d, J = 6.4 Hz, 1H), 4.48 (s, 2H), 3.79 (s, 3H), 3.67 (s, 1H), 2.94 (s, 3H), 2.73 (d, J = 11.3 Hz, 2H), 2.16 (s, 3H), 1.94 (t, J = 11.2 Hz, 2H), 1.79 – 1.71 (m, 2H), 1.52 (qd, J = 11.9, 3.9 Hz, 2H).

[0121] XRPD characterization data of free base crystals A of compound (I): 2Ɵ spacing strength% 4.781 18.4684 27.4 5.255 16.8038 13 6.395 13.8099 6.4 7.361 11.9993 8 7.619 11.5939 7.9 8.818 10.02 2.1 9.58 9.2247 34.6 10.54 8.3863 18 10.979 8.0519 34.6 11.459 7.7157 22.8 12.34 7.167 11.1 12.96 6.8254 6.9 13.278 6.6626 7.7 14.678 6.0299 13.1 15.58 5.683 5.2 16.377 5.408 6.7 17.402 5.0918 23.9 18.54 4.7817 16.6 19.26 4.6045 100 19.918 4.4539 16.5 20.819 4.2631 10.8 21.581 4.1143 54.3 22.26 3.9903 33.7 22.54 3.9414 25.3 23.22 3.8275 5.9 23.521 3.7792 14.9 24.217 3.6721 18.6 24.801 3.587 53.6 25.181 3.5337 12.5 26.101 3.4112 4.8 26.439 3.3683 4.3 27.38 3.2547 10.5 28.543 3.1247 5 29.219 3.0538 17.8 29.721 3.0035 5.8 31.4 2.8466 4.1 31.717 2.8188 2.5 32.621 2.7428 6.1 33.118 2.7027 3.5 33.458 2.676 2.2 34.462 2.6003 2.8 35.178 2.549 1.9 35.658 2.5158 3.9 36.556 2.456 1.5 36.999 2.4276 3.5 39.335 2.2887 1.3 39.836 2.261 2.4 43.02 2.1008 2.6 44.279 2.0439 1.9

[0122] [Example] [3] [:Mode] [(I)] [Screening of crystalline salts of compounds]

[0123] [3.1] [Preparation of acid solutions]

[0124] Acid solutions were prepared according to the different solubilities of the acids, as follows: 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 1 mol / L; Aspartic acid, hippuric acid, and glutamic acid: aqueous solution, concentration 0.02 mol / L; 2-Naphthalenesulfonic acid: aqueous solution, concentration 0.01 mol / L.

[0125] 17.6 mg (approximately 0.03 mmol) of free alkali crystal form A was added to a 10 mL sample vial, along with an appropriate amount of reaction solvent. After stirring to dissolve, acid solution (reaction molar ratio 1:1) was added separately. The mixture was reacted at 50 °C for 3 h, then cooled to room temperature and stirred overnight. The samples were then placed in a 4 °C refrigerator and allowed to stand for 8 h. For samples without solid precipitation, the solid was volatilized at room temperature and then subjected to XRPD analysis. For samples with solid precipitation, the solvent was removed by centrifugation. The solid obtained from centrifugation and the solid obtained from the supernatant were dried separately and then subjected to XRPD analysis to determine whether salt formation had occurred. The results are shown in Table 2.

[0126] Table 2: Screening results of acid addition salts of compounds of formula (I) acid solvent sulfuric acid Phosphoric acid acetic acid Maleic acid Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization 75% ethanol NA Amorphous NA Amorphous NA B NA Amorphous acetone NA Amorphous I NA NA B NA II Ethyl acetate I Amorphous II C NA C NA I acid solvent tartaric acid Citric acid lactic acid malic acid Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization 75% ethanol NA I NA Amorphous NA I NA Amorphous acetone I NA NA Amorphous NA Amorphous NA Amorphous Ethyl acetate I I I I NA I NA Amorphous acid solvent gluconic acid hippuric acid glutamic acid Aspartic acid Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization 75% ethanol NA Amorphous NA Amorphous NA Amorphous NA Amorphous acetone NA B NA Amorphous NA Amorphous NA Amorphous Ethyl acetate NA C NA Amorphous NA Amorphous NA Amorphous acid solvent adipic acid mesylate benzenesulfonic acid 2-Hydroxyethylsulfonic acid Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization 75% ethanol NA Amorphous NA Amorphous NA Amorphous NA Amorphous acetone NA Amorphous NA Amorphous NA I NA Amorphous Ethyl acetate NA Amorphous NA Amorphous Amorphous I I Amorphous acid solvent benzoic acid p-Toluenesulfonic acid 2-Naphthalenesulfonic acid hydrobromic acid Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization Precipitation Volatilization 75% ethanol NA I NA B B NA NA Amorphous acetone NA I NA I B NA NA Amorphous Ethyl acetate NA I NA B NA Amorphous I Amorphous

[0127] Note: In the table above, I or II refer to different crystal forms of the corresponding acid after the anion forms a salt. 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. Other crystal forms can be deduced similarly. A, B, and C refer to the crystal forms of the free base of compound A. NA indicates that no sample was obtained.

[0128] Figure 6 shows the XRPD diagram of the free alkali crystal form B of compound (I).

[0129] Figure 7 shows the XRPD diagram of the free alkali crystal form C of compound (I).

[0130] Figure 8 shows the XRPD diagram of the free alkali crystal form D of compound (I).

[0131] Figure 9 shows the XRPD diagram of sulfate crystal form I of compound (I).

[0132] Figure 10 shows the XRPD diagram of phosphate crystal form I of compound (I).

[0133] Figure 11 shows the XRPD diagram of phosphate crystal form II of compound (I).

[0134] Figure 12 shows the XRPD diagram of maleate crystal form I of compound (I).

[0135] Figure 13 shows the XRPD diagram of maleate crystal form II of compound (I).

[0136] Figure 14 shows the XRPD diagram of citrate form I of compound (I).

[0137] Figure 15 shows the XRPD diagram of lactate crystal form I of compound (I).

[0138] Figure 16 shows the XRPD diagram of benzenesulfonate crystal form I of compound (I).

[0139] Figure 17 shows the XRPD diagram of crystal form I of compound (I) 2-hydroxyethanesulfonate.

[0140] Figure 18 shows the XRPD diagram of benzoate I of compound (I).

[0141] Figure 19 shows the XRPD diagram of p-toluenesulfonate crystal form I of compound (I).

[0142] Figure 20 shows the XRPD diagram of hydrobromide crystal form I of compound (I).

[0143] [Example] [4] [:Mode] [(I)] [Tartrate crystal form] [I] [Preparation]

[0144] In addition to preparing crystal form I using the methods described in the acid addition salt screening results above, it can also be prepared as follows: The free base (2.5 g) and tartaric acid (0.65 g) obtained above were 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 until a solid precipitated. The solid was then allowed to stand, collected, and dried to obtain tartrate crystal form I. The molar ratio of compound (I) to tartaric acid in crystal form I of the tartrate of formula (I) is approximately 1:1.

[0145] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 15.1 Hz, 2H), 8.06 (d, J = 7.4 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 13.8 Hz, 1H), 7.06 (d, J = 6.5 Hz, 1H), 4.48 (s, 2H), 4.03 (s, 2H), 3.79 (s, 4H), 3.01 (d, J = 11.5 Hz, 2H), 2.94 (s, 3H), 2.41 (s, 3H), 1.86 (d, J = 12.3 Hz, 2H), 1.62 (q, J = 11.8 Hz, 2H).

[0146] XRPD characterization data of tartrate crystal form I: 2Ɵ spacing strength% 4.637 19.0415 17.9 9.143 9.6641 7.3 10.34 8.5481 66.3 11.56 7.6488 10.4 13.019 6.7945 61.7 13.7 6.4582 16.8 14.039 6.3028 7.6 14.838 5.9653 17 15.76 5.6184 30.5 16.54 5.3551 32.9 17.159 5.1633 23.2 17.981 4.9291 77.5 18.281 4.8488 97.4 19.14 4.6333 2.7 19.795 4.4812 5.6 20.538 4.321 34.8 21.2 4.1874 82.3 21.901 4.055 100 23.121 3.8437 55.9 23.879 3.7233 15 24.721 3.5984 13.8 25.659 3.4689 35 26.179 3.4012 7.6 27.299 3.2642 48.9 27.541 3.236 27.1 28.22 3.1597 17 29.879 2.9879 38.5 30.459 2.9323 11.6 31.723 2.8183 7.2 32.277 2.7712 13.9 33.479 2.6744 12.3 33.941 2.639 6.8 34.802 2.5757 6.7 35.401 2.5335 1.4 36.234 2.4771 3.9 36.536 2.4573 3.7 37 2.4276 4.4 37.666 2.3862 2.7 38.296 2.3484 3.5 38.777 2.3203 2.4 39.602 2.2739 4.7 39.94 2.2554 3.6 40.877 2.2059 2.6 41.821 2.1582 11.8 42.981 2.1026 3.5 44.403 2.0385 3.1

[0147] [Example] [5] [:Mode] [(I)] [Tartrate crystal form] [III] [Preparation]

[0148] In addition to preparing the crystal form III using the methods described in the acid addition salt screening results above, it can also be prepared as follows: The free base (2.95 g) obtained above was dissolved in ethyl acetate (188 mL), heated to 60-65 °C, and 5 mL of tartaric acid methanol solution was added dropwise. The mixture was stirred for 1-3 hours, cooled to room temperature, filtered, and dried to obtain tartrate crystal form III. In the tartrate crystal form III of the compound of formula (I), the molar ratio of compound (I) to tartaric acid is approximately 1:1.

[0149] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 12.9 Hz, 2H), 8.03 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.31 (d, 1.84 (d, J = 12.7 Hz, 2H), 1.61 (d, J = 11.3 Hz, 2H).

[0150] XRPD characterization data of tartrate crystal form III: 2Ɵ spacing strength% 6.159 14.3388 2.2 7.339 12.0355 15.5 8.939 9.8841 25.5 10.179 8.6833 11.7 11.199 7.894 20.1 11.481 7.7011 5 13.2 6.7016 50.2 13.519 6.5444 29.1 14.02 6.3115 21.2 14.719 6.0132 9 15.181 5.8315 41.7 16.461 5.3809 10 17.64 5.0237 15.3 17.999 4.9242 16.9 18.539 4.7819 34.2 19.22 4.614 11.3 19.479 4.5533 11.2 20.019 4.4317 100 20.442 4.3409 6.7 20.921 4.2426 26.4 21.619 4.1071 16.5 22.521 3.9448 55.5 23.219 3.8276 39.4 23.518 3.7796 6.3 24.019 3.7019 4.8 24.9 3.5729 69.3 25.281 3.5199 4.4 25.9 3.4372 6.7 26.419 3.3708 13.1 26.62 3.3459 13.2 28.198 3.162 2.8 28.978 3.0787 8.1 29.703 3.0052 2.5 30.779 2.9025 9.1 31.202 2.8642 7.2 32.357 2.7645 3.4 33.117 2.7028 1.9 33.819 2.6483 2 34.183 2.6209 2.3 35.116 2.5534 2 36.059 2.4887 1.4 36.519 2.4584 3.5 37.219 2.4138 3.1 38.061 2.3623 3.7 39.161 2.2984 1.3 40.659 2.2172 1.5 41.654 2.1665 1.4 41.903 2.1542 1.5 43.139 2.0953 1.5

[0151] [Implementation Example] [6] [Solubility Measurement]

[0152] Weigh a certain mass of the free base crystal form A, tartrate crystal form I, and tartrate crystal form III of compound (I) into a 5 mL sample bottle, and add 2 mL of deionized water, 2 mL of glycine-hydrochloric acid buffer solution (pH 2.0), 2 mL of Na₂HPO₄-citric acid buffer solution (pH 4.5), and 2 mL of Na₂HPO₄-citric acid buffer solution (pH 6.8), respectively. After shaking on a shaker at 25°C for 24 hours, filter the solution. The solubility of the filtrate is determined by HPLC. The crystal form of the solid is detected by XRPD.

[0153] The chromatographic conditions are as follows: Column: Unitary C18 (5µm, 100A, 4.6×250 mm) Mobile phase: Phase A is ammonium acetate at pH 6.2, Phase B is acetonitrile, A:B = 10:90 Detection wavelength: 230nm; Column temperature: 35℃ Injection volume: 20 μL

[0154] The solubility test results are shown in Table 3:

[0155] Table 3: Solubility of free bases and salts of compounds of formula (I) (25℃, mg / mL) medium Free base amorphous Free alkali crystal type A Tartrate crystal form I Tartrate crystal 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

[0156] Solubility test results showed that, compared with the amorphous free base, free base crystal form A exhibited significantly improved solubility in pH 6.8 buffer solution. Tartaric acid crystal form I showed significantly improved solubility in both deionized water and pH 6.8 buffer solution. Tartrate crystal form III showed excellent solubility in all solvent systems. The improved solubility in deionized water greatly reduces formulation difficulty; the improved solubility in pH 6.8 buffer solution greatly improves the oral bioavailability of the drug. XRPD analysis showed that free base crystal form A did not undergo crystal form change in pH 6.8 buffer solution and deionized water; tartaric acid crystal form I also did not undergo crystal form change in deionized water.

[0157] [Example] [7] [Accelerated stability testing evaluation]

[0158] According to the "Guiding Principles for Stability Testing of Active Pharmaceutical Ingredients and Preparations" in Part IV of the 2015 edition of the Chinese Pharmacopoeia, the stability testing requirements for active pharmaceutical ingredients (APIs) require the investigation of influencing factors and accelerated testing to examine the crystal form.

[0159] High temperature test (T): The powder is placed in a suitable sealed glass bottle and placed at 60°C for 10 days. Samples are taken on the 5th and 10th days to test solid XRPD.

[0160] High humidity test (H): The powder was placed in a constant temperature and humidity chamber at 25℃ and 90% ± 5%RH for 10 days. Samples were taken on the 5th and 10th days to test the hygroscopic and deliquescent properties of the solid XRPD.

[0161] High light irradiation test (L): The powder opening was placed in a light stabilization chamber equipped with a fluorescent lamp and placed under an illuminance of 4500±500lx for 10 days. Samples were taken on the 5th and 10th days to test the solid XRPD.

[0162] Accelerated test (A): The powder opening was placed in a constant temperature and humidity chamber and placed at 40℃ and 75%±5%RH for 10 days. Samples were taken on the 5th and 10th days to test solid XRPD.

[0163] The results of the stability test are shown in Table 4, and the detailed spectra are shown in Figures 21 to 23.

[0164] Table 4: Experimental results of crystal form stability condition time Free alkali crystal type A Tartrate crystal form I Tartrate crystal form III high temperature (60℃) 5 days Consistent Consistent Consistent 10 days Consistent Consistent Consistent High humidity (92.5%RH) 5 days Consistent Consistent Consistent 10 days Consistent Consistent Consistent, crystallinity significantly reduced glare (4500lx) 5 days Consistent Consistent Consistent 10 days Consistent Consistent Consistent accelerate (40℃ / 75%) 5 days Consistent Consistent Consistent 10 days Consistent Consistent Consistent

[0165] Stability results showed that free alkali crystal form A, tartaric acid crystal form I, and tartrate crystal form III were stable under all experimental conditions and did not undergo crystal form transformation. However, the crystallinity of tartrate crystal form III weakened under high humidity, suggesting that attention should be paid to the ambient humidity during storage of crystal form III, otherwise there is a potential possibility of it transforming into an amorphous form.

[0166] [Example] [8] Stability Study under Mechanical Stress

[0167] [8.1] [Stability under pressure conditions]

[0168] Appropriate amounts of free alkali crystal form A, tartrate crystal form I, and tartrate crystal form III powder were evenly spread at the bottom of the mold of a powder tableting machine. Simulating the pressure conditions in the formulation process, mechanical pressures of 2, 4, 6, 8, and 10 N were applied respectively. After maintaining the pressure for 5 minutes, samples were taken to measure XRPD to examine the crystal form stability under pressure conditions. The XRPD results are detailed in Figures 24 to 26. Comparison of XRPD results shows that the free alkali crystal form A, tartrate crystal form I, and tartrate crystal form III are all stable under pressure conditions.

[0169] [8.2] [Stability of grinding conditions]

[0170] Appropriate amounts of free alkali crystal form A, tartrate crystal form I, and tartrate crystal form III powders were evenly spread in an agate mortar, and agate beads were added. The grinding conditions in the formulation process were simulated, with the vibration frequency of the automatic ball mill set to 25 s⁻¹. After grinding for 5, 10, 15, and 30 minutes respectively, samples were taken to test XRPD and examine the crystal form stability under the grinding conditions. Detailed spectra are shown in Figures 27 to 29.

[0171] XRPD results showed that under grinding conditions, free alkali crystal form A and tartrate crystal form III became amorphous, while tartrate crystal form I only experienced a decrease in crystallinity. Therefore, tartrate crystal form I exhibits better stability under grinding conditions and is more stable during formulation.

[0172] [Example] [9] [:Mode] [(I)] [Experiment on Adsorption and Desorption of Tartrate Compounds in Water]

[0173] Adsorption and desorption experiments of tartaric acid crystal forms I and III at 25℃ and 0–95% relative humidity were investigated using a dynamic water adsorption analyzer (DVS) to determine the hygroscopic properties of different crystal forms (see Figures 4d and 5d). The results showed that within the 40–80% RH humidity range, crystal form I had a moisture absorption of 0.33%, while crystal form III had a moisture absorption of 0.37%. Crystal form I exhibited significantly better stability than crystal form III under high humidity conditions (RH > 90%). Crystal form III absorbed 18.1% moisture from 90% to 95% RH, while tartrate crystal form I showed almost no moisture absorption (0.08%).

[0174] [Example]

[10] [:Mode] [(I)] [Study on the Conversion Relationship of Tartrate Compounds]

[0175] Suspension competition crystal transformation studies were conducted on crystal forms I and III in different organic solvents to determine the stable crystal forms under different conditions and the interconversion relationship between crystal forms I and III. 20 mg each of crystal form I and crystal form III were weighed into 2 mL or 10 mL glass bottles, and 0.5 mL or 1 mL of organic solvent was added according to the solubility. Two batches were prepared using the same solvent and suspended at room temperature and 50 °C for 24 h, respectively. After centrifugation (10000 rpm, 3 min), the solid powder was vacuum dried and PXRD was tested (see Figures 30 and 31). The results of the suspension crystal transformation experiments are shown in Table 2. The results show that, except for methyl tributyl ether and cyclohexane, the physical mixture of crystal forms I and III at room temperature and 50 °C all transformed into crystal form I after suspension competition in common solvents such as 75% ethanol, anhydrous ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, methanol, isopropanol, 2-butanone, toluene, and water. It can be determined that under these conditions, crystal form I is a stable crystal form.

[0176] Table 5: Results of suspension crystal transformation tests for tartrate crystal forms I and III of compound (I) serial number reagents room temperature 50℃ 1 75% ethanol I I 2 Anhydrous ethanol I I 3 Methyl tributyl ether mixture mixture 4 acetone I I 5 Ethyl acetate I I 6 Acetonitrile I I 7 Tetrahydrofuran I I 8 methanol I I 9 Isopropanol I I 10 2-Butanone I I 11 Cyclohexane mixture mixture 12 Toluene I I 13 water I I

[0177] In summary, the stability evaluation and solubility studies of tartrate crystal forms I and III have led to the selection of a suitable crystal form for development. Stability test results show that crystal form I exhibits superior solvent-mediated crystal transformation, grinding, and hygroscopic stability compared to crystal form III.

[0178] All references cited in this application (including bibliographic references, published patents, published patent applications, and concurrently pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly known to one of ordinary skill in the art.

[0179] All features disclosed in this specification can be combined in any combination. Each feature disclosed in this specification can be replaced by an alternative feature having the same, equivalent, or similar purpose. Therefore, unless otherwise expressly stated, each disclosed feature is merely an example of a series of equivalent or similar features.

[0180] Based on the above description, those skilled in the art can readily determine the basic features of the present invention, and various changes and modifications can be made to adapt the invention to various uses and conditions without departing from the spirit and scope of the invention. Therefore, other embodiments are also within the scope of the appended claims.

[0181] none

Claims

1. A solid form of a compound of formula (I), (I), which is tartrate crystal form I of compound (I), having X-ray powder diffraction (XRPD) peaks at 4.627, 10.34, 17.981, 18.281, 21.901 and 23.121 degrees 2θ.

2. A pharmaceutical composition comprising the solid form described in claim 1.

3. Use of the solid form of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating the following diseases: lung cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, esophageal cancer, gastroesophageal junction cancer, pancreatic cancer, and melanoma.

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