Salts of compound and crystalline forms thereof

Abstract

To provide salts of a compound and crystalline forms thereof.SOLUTION: The present invention relates to salts of a compound and crystalline forms thereof. More specifically, the present invention belongs to the pharmaceutical field and provides pharmaceutically acceptable salts of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide and crystalline forms thereof, pharmaceutical compositions comprising the same, as well as methods for preparing the same and the use thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority from Chinese Patent Application No. 201910973785.3, filed on October 14, 2019, the entire contents of which are incorporated herein for all purposes.

[0003] The present invention belongs to the pharmaceutical field and provides pharmaceutically acceptable salts of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide and crystalline forms thereof, pharmaceutical compositions containing them, methods for preparing them, and uses thereof. [Background technology]

[0004] Fibroblast growth factors (FGFs) are recognized as important mediators in many physiological processes. The fibroblast growth factor receptor family of receptor tyrosine kinases consists of four members (FGFR1, FGFR2, FGFR3, and FGFR4). Fibroblast growth factors (FGFs) and their receptors (FGFRs) play important roles in cell proliferation, cell differentiation, cell migration, cell survival, protein synthesis, and angiogenesis. There is a growing body of evidence directly linking FGF signaling to cancer. Dysregulation of FGFR signaling has been implicated in many cancers, including squamous non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, and bladder cancer. For example, FGFR1 amplification is found in 22% of squamous NSCLCs, FGFR2 amplification has been reported in up to 10% of gastric cancers, and FGFR3 mutations are found in approximately 50-60% of non-muscle-invasive bladder cancers and 17% of high-grade bladder cancers. Therefore, inhibition of FGFR activity is useful for treating proliferative diseases such as cancer.

[0005] PCT patent application WO2014 / 139465A1 first disclosed the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (i.e., compound 78 in WO2014 / 139465A1) and a method for preparing the same. The structure of the compound is shown as follows:

[0006] [ka]

[0007] Studies have shown that the compound 4-chloro-3-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide can effectively inhibit FGFR activity. Therefore, it is useful for the prevention and treatment of diseases that respond to the inhibition of FGFR activity, such as cancer.

[0008] Many compounds can exist in various crystalline or amorphous forms. However, for a given compound, it is highly unpredictable (1) whether the compound exhibits polymorphism, (2) how to prepare such unknown crystalline forms, and (3) how the properties of such unknown crystalline forms, such as stability, solubility, flowability, pharmacokinetic parameters, and in vivo bioavailability, vary depending on the crystalline form. See J. Bernstein, "Polymorphism in Molecular Crystals," Oxford University Press, (2002).

[0009] Forming a salt of a compound does not change the biological activity of the compound itself, but may change the physicochemical properties of the compound.For a given compound, it is highly unpredictable which salt of the compound has better physicochemical properties than the free compound.Considering the unpredictability of crystal formation and crystal properties, it is even more unpredictable to predict which salt can form a crystalline form with good properties.

[0010] Because the properties of solid substances depend on the compound itself and the microstructure of the solid, different solid forms of a compound often exhibit different physicochemical and biopharmaceutical properties. Differences in physicochemical and biopharmaceutical properties can be determined by various technical means and may ultimately be used to distinguish these different solid forms from one another. For example, physical properties such as solubility, stability, and C max , T max Differences in biopharmaceutical properties such as bioavailability are also important in describing the solid state of a compound.

[0011] Therefore, in the development of the compound 4-chloro-3-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide, it is necessary to study the salts of the compound and its crystalline form. Summary of the Invention

[0012] After extensive research and investigation, the present inventors have found that the compound 4-chloro-3-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (also referred to as "Compound 78" in the context of the present invention) can be prepared into various pharmaceutically acceptable salts represented by formula A. Compared with Compound 78 in its free form, the salt of formula A (e.g., the hemitartrate salt) has significantly increased solubility, which is beneficial for improving the pharmacokinetic properties and in vivo bioavailability of Compound 78. The present inventors have also found that the salt of formula A can exist in different crystalline forms and can form solvates with certain solvents. The present inventors have extensively studied the polymorphism of the salt of formula A and finally prepared and determined a crystalline form that meets the requirements for pharmaceutical use. Based on these studies, the present invention provides pharmaceutically acceptable salts of compound 78 of formula A, and various crystalline forms thereof, e.g., Form A-III, Form B-II, Form B-III, and Form CI.

[0013] In one embodiment, the present invention provides a pharmaceutically acceptable salt of 4-chloro-3-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide, represented by Formula A: [ka] wherein n is 0.5 or 1, and M is a pharmaceutically acceptable acid.

[0014] In one embodiment, the invention provides a salt of Formula A, wherein M is hydrochloric acid, tartaric acid, or p-toluenesulfonic acid.

[0015] In another embodiment, the invention provides a salt of Formula A, where n is 1 and M is hydrochloric acid (also known as the monohydrochloride salt of compound 78), n is 0.5 and M is tartaric acid (also known as the hemitartrate salt of compound 78), or n is 1 and M is p-toluenesulfonic acid (also known as the mono-p-tosylate salt of compound 78).

[0016] In another embodiment, the present invention provides a salt of Formula A, wherein n is 1 and M is hydrochloric acid, and the salt is Form A-III (also referred to as Form A-III of the monohydrochloride salt of Compound 78, or simply referred to as Form A-III).

[0017] In another embodiment, the present invention provides a salt of Formula A where n is 0.5 and M is tartaric acid, and the salt is Form B-II (also referred to as Form B-II of the hemitartrate salt of Compound 78, or simply referred to as Form B-II).

[0018] In another embodiment, the present invention provides a salt of Formula A where n is 0.5 and M is tartaric acid, and the salt is Form B-III (also referred to as Form B-III of the hemitartrate salt of Compound 78, or simply referred to as Form B-III).

[0019] In another embodiment, the present invention provides a salt of Formula A where n is 1 and M is p-toluenesulfonic acid, wherein the salt is Form CI (also referred to as Form CI of the mono-p-tosylate salt of Compound 78, or simply referred to as Form CI).

[0020] In another aspect, the present invention provides methods for preparing the salt of formula A and its crystalline forms (e.g., Form A-III, Form B-II, Form B-III, Form CI), which methods are reproducible and easy to operate.

[0021] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a salt of Formula A and a crystalline form thereof (e.g., Form A-III, Form B-II, Form B-III, Form CI), and optionally a pharmaceutically acceptable carrier.

[0022] In another aspect, the present invention further provides a method for preventing or treating a disease responsive to inhibition of FGFR activity, e.g., cancer, said method comprising administering to a subject in need thereof an effective amount of a salt of Formula A and its crystalline forms (e.g., Form A-III, Form B-II, Form B-III, Form CI).

[0023] In another aspect, the present invention further provides the use of a salt of Formula A and its crystalline forms (e.g., Form A-III, Form B-II, Form B-III, Form CI) in the manufacture of a medicament for treating a disease responsive to inhibition of FGFR activity, such as cancer.

[0024] In another aspect, the present invention provides salts of Formula A and crystalline forms thereof (e.g., Form A-III, Form B-II, Form B-III, Form CI) for use in therapy.

[0025] In one embodiment, the invention provides a salt of Formula A and its crystalline forms (e.g., Form A-III, Form B-II, Form B-III, Form CI) for use in the treatment of a disease responsive to inhibition of FGFR activity, such as cancer.

[0026] Such cancers include, but are not limited to, lung cancer (e.g., squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, biliary tract cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma, and hematological malignancies (e.g., myeloproliferative disorders). [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of Form A-III of the monohydrochloride salt of Compound 78, where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 2]Figure 2 shows the differential scanning calorimetry (DSC) curve of Form A-III of the monohydrochloride salt of compound 78, where the horizontal axis (X-axis) plots temperature (°C) and the vertical axis (Y-axis) plots heat flow (mW). [Figure 3] FIG. 3 shows the thermogravimetric (TG) curve of Form A-III of the monohydrochloride salt of compound 78, where the horizontal axis (X-axis) plots temperature (°C) and the vertical axis (Y-axis) plots weight percent (%). [Figure 4] FIG. 4 shows the X-ray powder diffraction pattern of Form B-II of the hemitartrate salt of Compound 78, where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 5] Figure 5 shows the differential scanning calorimetry (DSC) curve of Form B-II of the hemitartrate salt of compound 78, where the horizontal axis (X-axis) plots temperature (°C) and the vertical axis (Y-axis) plots heat flow (mW). [Figure 6] Figure 6 shows the thermogravimetric (TG) curve of Form B-II of the hemitartrate salt of compound 78, where the horizontal axis (X-axis) plots temperature (°C) and the vertical axis (Y-axis) plots weight percent (%). [Figure 7] FIG. 7 shows the X-ray powder diffraction pattern of Form B-III of the hemitartrate salt of Compound 78, where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 8] Figure 8 shows the differential scanning calorimetry (DSC) curve of Form B-III of the hemitartrate salt of compound 78, where the horizontal axis (X-axis) plots temperature (°C) and the vertical axis (Y-axis) plots heat flow (mW). [Figure 9] FIG. 9 shows the thermogravimetric (TG) curve of Form B-III of the hemitartrate salt of Compound 78, where the horizontal axis (X-axis) plots temperature (°C) and the vertical axis (Y-axis) plots weight percent (%). [Figure 10]FIG. 10 shows a dynamic vapor sorption (DVS) isotherm plot of Form B-III of the hemitartrate salt of Compound 78, where the horizontal axis (X-axis) plots relative humidity (%) and the vertical axis (Y-axis) plots weight change (%). [Figure 11] FIG. 11 shows a dynamic vapor sorption (DVS) isotherm plot of Form B-II of the hemitartrate salt of Compound 78, where the horizontal axis (X-axis) plots relative humidity (%) and the vertical axis (Y-axis) plots weight change (%). [Figure 12] FIG. 12 shows the X-ray powder diffraction pattern of Form CI of the mono-p-tosylate salt of Compound 78, where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 13] FIG. 13 shows the differential scanning calorimetry (DSC) curve of the mono-p-tosylate salt form CI of compound 78, where the horizontal axis (X-axis) plots temperature (°C) and the vertical axis (Y-axis) plots heat flow (mW). [Figure 14] FIG. 14 shows the thermogravimetric (TG) curve of the mono-p-tosylate salt form CI of compound 78, where the horizontal axis (X-axis) plots temperature (°C) and the vertical axis (Y-axis) plots weight percent (%). [Figure 15] FIG. 15 shows the X-ray powder diffraction pattern of Form A-III of the monohydrochloride salt of Compound 78 after 5 days under humid conditions (25° C., 92.5%±5% relative humidity), where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 16] FIG. 16 shows the X-ray powder diffraction pattern of Form A-III of the monohydrochloride salt of Compound 78 after 10 days under humid conditions (25° C., 92.5%±5% relative humidity), where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 17] FIG. 17 shows the X-ray powder diffraction pattern of Form B-II of the hemitartrate salt of Compound 78 after 3 days under humid conditions (25° C., 92.5%±5% relative humidity), where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 18] FIG. 18 shows the X-ray powder diffraction pattern of Form B-II of the hemitartrate salt of Compound 78 after being slurried in water for 2 days, where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 19] FIG. 19 shows the X-ray powder diffraction pattern of Form B-II of the hemitartrate salt of Compound 78 after being slurried in water for 4 days, where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 20] FIG. 20 shows the X-ray powder diffraction pattern of Form B-III of the hemitartrate salt of Compound 78 after being slurried in water for 2 days, where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 21] FIG. 21 shows the X-ray powder diffraction pattern of Form B-III of the hemitartrate salt of Compound 78 after being slurried in water for 4 days, where the horizontal axis (X-axis) plots the diffraction angle 2θ and the vertical axis (Y-axis) plots the diffraction intensity. [Figure 22] FIG. 22 shows a micrograph of the free form of compound 78, prepared according to Example 9 of WO2014 / 139465A1, showing that it is a needle-like crystal. [Figure 23] FIG. 23 shows a micrograph of Form B-III of the hemitartaric acid of Compound 78, showing that it is a tabular crystal. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition Unless otherwise indicated, the following terms used in this application (including the specification and claims) have the meanings indicated below. It should be noted that the singular forms "a," "an," and "the" in the specification and claims include plural references unless the context clearly dictates otherwise.

[0029] As used herein, the terms "salt(s) of the invention," "pharmaceutically acceptable salt(s) of 4-chloro-3-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide," "salt(s) of 4-chloro-3-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide," "salt(s) of Compound 78," and "salt(s) of Formula A" can be used interchangeably and all refer to a salt of Formula A described herein, i.e., an acid addition salt formed by Compound 78 and a "pharmaceutically acceptable acid" described herein.

[0030] As used herein, the term "crystalline forms of the present invention" refers to Form A-III of the monohydrochloride salt of Compound 78, Form B-II of the hemitartrate salt of Compound 78, Form B-III of the hemitartrate salt of Compound 78, or Form CI of the mono-p-tosylate salt of Compound 78, as well as mixtures thereof in any ratio.

[0031] As used herein, the terms "form," "crystal form," "crystalline form," and "polymorph" can be used interchangeably.

[0032] The term "pharmaceutically acceptable acid," as used herein, refers to an acid that is capable of forming an acid addition salt of compound 78 and that does not have undesirable properties for animal or human applications, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, phosphorous acid, sulfuric acid, sulfurous acid, nitric acid, and the like; and organic acids such as malic acid, maleic acid, mandelic acid, fumaric acid, tartaric acid, succinic acid, citric acid, aspartic acid, glutamic acid, 2-hydroxy-2-phenylpropionic acid, gluconic acid, lactic acid, camphorsulfonic acid, methanesulfonic acid, ethylsulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, β-hydroxybutyric acid, benzoic acid, salicylic acid, acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, stearic acid, HOOC-(CH) n -COOH (wherein n is 0 to 4) and the like.

[0033] As used herein, the term "organic acid ester of 8 or less carbon atoms" refers to an organic acid ester represented by R1COOR2, where R1 and R2 are independently saturated or unsaturated, straight or branched chain hydrocarbon groups, and the total number of carbon atoms in R1 and R2 is 7 or less; Preferably, R1 and R2 are independently saturated, straight or branched chain hydrocarbon groups, and the total number of carbon atoms in R1 and R2 is 1, 2, 3, 4, 5, 6, or 7. Examples of organic acid esters having 8 or less carbon atoms include, but are not limited to, methyl acetate, ethyl acetate, and n-propyl acetate.

[0034] As used herein, the term "about" when used in conjunction with a numerical value refers to the stated numerical value above or below the stated value by a variance of 10%. For example, about 50% means a range of 45% to 55%.

[0035] As used herein, the term "substantially pure" means that the form is at least 50%, at least 60%, at least 70%, preferably at least 80%, more preferably at least 90%, and even more preferably at least 95% by weight pure. For example, the form is 95%, 96%, 97%, 98%, 99%, or 100% pure by weight.

[0036] As used herein, the term "substantially free of other forms" means that the content of said other forms is less than 50% by weight, preferably less than 40% by weight, preferably less than 30% by weight, preferably less than 20% by weight, preferably less than 10% by weight, preferably less than 5% by weight, preferably less than 1% by weight, based on the total weight of said forms.

[0037] As used herein, the term "solution" means a homogeneous mixture of one or more solutes in one or more solvents.

[0038] As used herein, the term "dissolving solvent" refers to an organic solvent that can fully or partially dissolve a substance under appropriate conditions. As used herein, the term "dissolution-preventing solvent" refers to any suitable organic solvent in which the substance has a lower solubility than in the dissolving solvent.

[0039] As used herein, the term "water-miscible organic solvent" refers to an organic solvent that can be mixed with water in any proportion. Examples include, but are not limited to, C 1-6 Examples thereof include alkanols, acetone, tetrahydrofuran, acetonitrile, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0040] As used herein, "C 1-6The term "alkanol" refers to a fully saturated, straight or branched chain alkyl alcohol having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples include, but are not limited to, methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, t-butanol, n-pentanol, i-pentanol, n-hexanol, and the like.

[0041] As used herein, the term "effective amount" refers to an amount of a salt of the present invention, or a crystalline form of the present invention, that is effective to inhibit FGFR activity in vitro or that is effective to prevent or treat a disease responsive to inhibition of FGFR activity after administration to a subject. The effective amount of a salt of the present invention, or a crystalline form of the present invention, will vary depending on various factors, including the particular salt used, the disease being treated and its severity, the age and health of the subject, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.

[0042] As used herein, the term "disease responsive to inhibition of FGFR activity" refers to diseases that can be prevented or treated by inhibiting FGFR activity, such as cancers including, but not limited to, lung cancer (e.g., squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, biliary tract cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma, and hematological malignancies (e.g., myeloproliferative disorders).

[0043] As used herein, the term "subject" refers to 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 cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds. The term "subject" does not denote a particular age or sex.

[0044] As used herein, the terms "treat," "treating," or "treatment" refer to the alleviation of an undesirable physiological change or disorder, such as the onset or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, amelioration of symptoms, reduction in disease severity, stabilization of disease, and delay in disease progression. The terms "treat," "treating," or "treatment" also refer to longer survival compared to a subject not receiving treatment.

[0045] As used herein, the terms "prevent," "preventing," or "prevention" refer to preventing or postponing the onset of a disease in a subject at risk of contracting the disease.

[0046] Embodiment

[0047] Embodiment 1. A salt of Formula A: [ka] wherein n is 0.5 or 1, and M is a pharmaceutically acceptable acid.

[0048] Embodiment 2. The salt of Formula A of embodiment 1, wherein M is hydrochloric acid, tartaric acid, or p-toluenesulfonic acid.

[0049] Embodiment 3. A salt of Formula A according to embodiment 2, wherein n is 1 and M is hydrochloric acid; n is 0.5 and M is tartaric acid; or n is 1 and M is p-toluenesulfonic acid.

[0050] Embodiment 4. n is 1 and M is hydrochloric acid, and the salt is Form A-III having X-ray powder diffraction characteristic diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 12.3±0.2°, 13.3±0.2°, 23.1±0.2°, and 24.1±0.2°; Preferably, said Form A-III has X-ray powder diffraction characteristic diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 16.2±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, and 26.4±0.2°; More preferably, said Form A-III has X-ray powder diffraction characteristic diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 15.8±0.2°, 16.2±0.2°, 18.3±0.2°, 18.5±0.2°, 20.2±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, 26.4±0.2°, 27.1±0.2°, and 27.8±0.2°; More preferably, said Form A-III has a lateral flexion angle of 5.8±0.2°, 6.2±0.2°, 7.9±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, 17.4±0.2°, 18.3±0. X-ray powder diffraction characteristics with diffraction angles (2θ) of 2°, 18.5±0.2°, 19.6±0.2°, 20.2±0.2°, 21.0±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, 24.8±0.2°, 26.4±0.2°, 27.1±0.2°, and 27.8±0.2°; Most preferably, the salt of Formula A according to embodiment 3, wherein Form A-III has the X-ray powder diffraction pattern shown in FIG.

[0051] Embodiment 5. The salt of Formula A of embodiment 4, wherein Form A-III has a differential scanning calorimetry (DSC) curve with an endothermic peak at about 290.2 to 295.4°C.

[0052] Embodiment 6. n is 0.5, and M is tartaric acid, and the salt is Form B-II having X-ray powder diffraction characteristic diffraction angles (2θ) of 7.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.1±0.2°, 18.0±0.2°, and 20.6±0.2°; Preferably, said Form B-II has X-ray powder diffraction characteristic diffraction angles (2θ) of 3.8±0.2°, 7.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.7±0.2°, and 23.0±0.2°; More preferably, said Form B-II has X-ray powder diffraction characteristic diffraction angles (2θ) of 3.8±0.2°, 7.5±0.2°, 10.1±0.2°, 11.3±0.2°, 13.4±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.7±0.2°, 23.0±0.2°, 25.1±0.2°, and 27.8±0.2°; More preferably, said Form B-II has X-ray powder diffraction characteristic diffraction angles (2θ) of 3.8±0.2°, 7.5±0.2°, 10.1±0.2°, 11.3±0.2°, 11.8±0.2°, 13.1±0.2°, 13.4±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.1±0.2°, 21.7±0.2°, 23.0±0.2°, 25.1±0.2°, and 27.8±0.2°; Most preferably, the salt of Formula A according to embodiment 3, wherein Form B-II has the X-ray powder diffraction pattern shown in FIG.

[0053] Embodiment 7. The salt of Formula A of embodiment 6, wherein Form B-II has a differential scanning calorimetry (DSC) curve with endothermic peaks at about 54.8-92.2°C, 166.9-174.4°C, and 263.3-265.3°C, and an exothermic peak at about 194.2-202.7°C.

[0054] Embodiment 8. The salt of Formula A of either embodiment 6 or 7, wherein Form B-II has the thermogravimetric analysis (TGA) curve shown in FIG. 6, exhibiting a weight loss of about 4.3% in the temperature range of 30°C to 100°C.

[0055] Embodiment 9. n is 0.5, and M is tartaric acid, and the salt is Form B-III having X-ray powder diffraction characteristic diffraction angles (2θ) of 13.1±0.2°, 14.6±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, and 26.3±0.2°; Preferably, said Form B-III has X-ray powder diffraction characteristic diffraction angles (2θ) of 12.4±0.2°, 13.1±0.2°, 13.7±0.2°, 14.6±0.2°, 16.5±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, and 26.3±0.2°; More preferably, said Form B-III has X-ray powder diffraction characteristic diffraction angles (2θ) of 7.6±0.2°, 8.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.4±0.2°, 13.1±0.2°, 13.4±0.2°, 13.7±0.2°, 14.6±0.2°, 15.9±0.2°, 16.5±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, and 26.3±0.2°; More preferably, said Form B-III has a lateral flexion angle of 7.6±0.2°, 8.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.4±0.2°, 13.1±0.2°, 13.4±0.2°, 13.7±0.2°, 14.6±0.2°, 15.9±0.2°, 16.5±0.2°, 17.2±0. X-ray powder diffraction characteristics with diffraction angles (2θ) of 2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 19.6±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, 24.6±0.2°, 26.3±0.2°, 27.6±0.2°, and 29.2±0.2°; Most preferably, the salt of Formula A according to embodiment 3, wherein Form B-III has the X-ray powder diffraction pattern shown in FIG.

[0056] Embodiment 10. The salt of Formula A of embodiment 9, wherein Form B-III has a differential scanning calorimetry (DSC) curve with an endothermic peak at about 269.2 to 271.3°C.

[0057] Embodiment 11. The salt of Formula A of either embodiment 9 or 10, wherein said Form B-III has the thermogravimetric analysis (TGA) curve shown in FIG.

[0058] Embodiment 12. n is 1 and M is p-toluenesulfonic acid, and the salt is Form CI having X-ray powder diffraction characteristic diffraction angles (2θ) of 7.8±0.2°, 11.1±0.2°, 11.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, and 24.0±0.2°; Preferably, Form CI has X-ray powder diffraction characteristic diffraction angles (2θ) of 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 13.8±0.2°, 14.3±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, 22.2±0.2°, 24.0±0.2°, and 26.1±0.2°; More preferably, said Form CI has X-ray powder diffraction characteristic diffraction angles (2θ) of 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 13.5±0.2°, 13.8±0.2°, 14.3±0.2°, 14.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 24.0±0.2°, 26.1±0.2°, and 27.4±0.2°; More preferably, the form CI is 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 12.2±0.2°, 12.9±0.2°, 13.5±0.2°, 13.8±0.2°, 14.3±0.2°, 14.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.9±0.2°, 19.9±0.2°, 20.9±0.2°, 21.9±0.2°, 22.9±0.2°, 23.9±0.2°, 24.3±0.2°, 24.7±0.2°, 25.9±0.2°, 26.9±0.2°, 27.9±0.2°, 28.9±0.2°, 29.9±0.2°, 30.9±0.2°, 31.9±0.2°, 32.9±0.2°, 33.9±0.2°, 34.9±0.2°, 35.9±0.2°, 36.9±0.2°, 37.9±0.2°, 38.9±0.2°, 39.9±0.2°, 40.9±0.2°, 41.9±0.2°, 42.9±0.2°, 43.9±0.2°, 44.9±0.2°, 45.9±0.2°, 46.9±0.2°, 47.9±0.2°, 48.9±0.2°, 49.9±0.2°, having X-ray powder diffraction characteristic diffraction angles (2θ) of 18.2±0.2°, 19.2±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 23.5±0.2°, 24.0±0.2°, 25.0±0.2°, 26.1±0.2°, 27.4±0.2°, and 32.8±0.2°; Most preferably, the salt of Formula A of embodiment 3, wherein Form CI has the X-ray powder diffraction pattern shown in FIG.

[0059] Embodiment 13. The salt of Formula A of embodiment 12, wherein Form CI has a differential scanning calorimetry (DSC) curve with an endothermic peak at about 289.77 to 291.04°C.

[0060] Embodiment 14. The salt of Formula A of either embodiment 12 or 13, wherein Form CI has a thermogravimetric analysis (TGA) curve as shown in Figure 14.

[0061] Embodiment 15. A pharmaceutical composition comprising an effective amount of a salt of Formula A as described in any one of Embodiments 1-14, and optionally a pharmaceutically acceptable carrier.

[0062] Embodiment 16. A method for preventing or treating a disease responsive to inhibition of FGFR activity, comprising administering to a subject in need thereof an effective amount of a salt of Formula A described in any one of Embodiments 1 to 14.

[0063] Embodiment 17. Use of a salt of Formula A as defined in any one of Embodiments 1 to 14 in the manufacture of a medicament for preventing or treating a disease responsive to inhibition of FGFR activity, such as cancer.

[0064] Embodiment 18. The use of embodiment 17, wherein the cancer is selected from lung cancer (e.g., squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, biliary tract cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma, and hematological malignancies (e.g., myeloproliferative disorders).

[0065] Embodiment 19. A salt of Formula A according to any one of Embodiments 1 to 14 for use in therapy.

[0066] Embodiment 20. A salt of Formula A as defined in any one of Embodiments 1 to 14 for use in treating a disease that responds to inhibition of FGFR activity, such as cancer.

[0067] Embodiment 21. The salt of Formula A of embodiment 20, wherein the cancer is selected from lung cancer (e.g., squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, biliary tract cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma, and hematological malignancies (e.g., myeloproliferative disorders).

[0068] Embodiment 22. A method for preparing a salt of Formula A according to any one of Embodiments 4 and 5, comprising: (1) a step of reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with hydrochloric acid in a dissolving solvent or in a mixed solvent of a water-miscible organic solvent and water under heating and stirring to form a salt; (2) a step of cooling the reaction product obtained in the step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form A-III; (4) optionally drying the solid obtained in step (3): The method comprising:

[0069] Embodiment 23 The method of embodiment 22, wherein the hydrochloric acid is concentrated hydrochloric acid having a concentration of 36 to 38% by weight.

[0070] Embodiment 24 The method of any one of embodiments 22 or 23, wherein the molar ratio of the hydrochloric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater, for example, about 1:1 or 1.2:1.

[0071] Embodiment 25. The method of any one of Embodiments 22 to 24, wherein the volume ratio of the dissolving solvent or the mixed solvent to the weight of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g or more, for example, about 20 ml / g or about 60 ml / g.

[0072] Embodiment 26. The dissolution medium is C 1-6 26. The method of any one of embodiments 22-25, wherein the dissolving solvent is selected from the group consisting of methanol, ethanol, i-propanol, t-butanol, and mixtures thereof; preferably, the dissolving solvent is selected from the group consisting of methanol, ethanol, i-propanol, t-butanol, and mixtures thereof; more preferably, the dissolving solvent is ethanol.

[0073] Embodiment 27. The water-miscible organic solvent is C 1-6 27. The method of any one of embodiments 22 to 26, wherein the water-miscible organic solvent is selected from methanol, ethanol, i-propanol, t-butanol, and mixtures thereof; preferably, the water-miscible organic solvent is selected from ethanol, i-propanol, and mixtures thereof.

[0074] Embodiment 28. The method of any one of embodiments 22 to 27, wherein the volume percentage of the water-miscible organic solvent in the mixed solvent is about 95% or less; preferably, the volume percentage of the water-miscible organic solvent in the mixed solvent is 95%, 90%, or 80%.

[0075] Embodiment 29. The method of any one of embodiments 22 to 28, wherein in optional step (4), the drying temperature is 50 to 80°C.

[0076] Embodiment 30. A method for preparing a salt of Formula A according to any one of Embodiments 6 to 8, comprising: (1) a step of reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with L-tartaric acid in ethanol under heating and stirring to form a salt; (2) a step of cooling the reaction product obtained in the step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form B-II; (4) optionally drying the solid obtained in step (3): The method comprising:

[0077] Embodiment 31. The method of embodiment 30, wherein the molar ratio of the L-tartaric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:2 or greater, preferably about 4:5 or about 3.4:1.

[0078] Embodiment 32 The method of any one of embodiments 30 or 31, wherein the volume ratio of ethanol to the weight of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g or more, for example, about 72 ml / g or about 75 ml / g.

[0079] Embodiment 33 The method according to any one of embodiments 30 to 32, wherein in optional step (4), the drying temperature is 50 to 85°C.

[0080] Embodiment 34. A method for preparing a salt of Formula A according to any one of Embodiments 9 to 11, comprising: (1) mixing and reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with L-tartaric acid in a dissolving solvent, in water, or in a mixed solvent consisting of a water-miscible organic solvent and water under heating and stirring to form a salt, thereby obtaining a first solution, provided that the dissolving solvent is not a single solvent of ethanol; (2) optionally adding a dissolution-preventing solvent to the first solution to obtain a second solution; (3) cooling the first solution or the second solution to sufficiently precipitate a solid; (4) isolating the precipitated solid as Form B-III; (5) optionally drying the solid obtained in step (4): The method comprising:

[0081] Embodiment 35. The method of embodiment 34, wherein the molar ratio of the L-tartaric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater, preferably about 1:1 or about 1.5:1.

[0082] Embodiment 36. The method of any one of embodiments 34 and 35, wherein the volume ratio of the dissolving solvent, the water, or the mixed solvent consisting of a water-miscible organic solvent and water to the weight of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g or more, for example, about 20 ml / g, about 30 ml / g, about 33 ml / g, about 50 ml / g, about 65 ml / g, about 98 ml / g, or about 286 ml / g.

[0083] Embodiment 37. The dissolution medium is C 1-6 37. The method of any one of embodiments 34 to 36, wherein the dissolving solvent is selected from alkanols, acetone, toluene, organic acid esters having 8 or less carbon atoms, and mixtures thereof; preferably, the dissolving solvent is selected from methanol, ethanol, i-propanol, t-butanol, n-butanol, acetone, toluene, n-propyl acetate, ethyl acetate, and mixtures thereof; more preferably, the dissolving solvent is selected from methanol, ethanol, i-propanol, acetone, toluene, n-propyl acetate, ethyl acetate, and mixtures thereof.

[0084] Embodiment 38. The method of embodiment 37, wherein the dissolution solvent is selected from a mixture of two of methanol, ethanol, toluene, n-propyl acetate, and ethyl acetate, such as n-propyl acetate / methanol (volume ratio of about 3:2), toluene / ethanol (volume ratio of about 1:1), or ethyl acetate / ethanol (volume ratio of about 11:15).

[0085] Embodiment 39. The water-miscible organic solvent is C 1-6 39. The method of any one of embodiments 34 to 38, wherein the water-miscible organic solvent is selected from methanol, ethanol, i-propanol, t-butanol, acetone, and mixtures thereof; preferably, the water-miscible organic solvent is selected from methanol, ethanol, i-propanol, t-butanol, acetone, and mixtures thereof; more preferably, the water-miscible organic solvent is selected from ethanol, i-propanol, acetone, and mixtures thereof.

[0086] Embodiment 40. The method of any one of embodiments 34 to 39, wherein the volume fraction of the water-miscible organic solvent in the mixed solvent is about 95% or less, e.g., 95%, 90%, or 80%.

[0087] Embodiment 41. The method of any one of embodiments 34-40, wherein the dissolution-preventing solvent is selected from toluene, organic acid esters having 8 or fewer carbon atoms, and mixtures thereof; preferably, the dissolution-preventing solvent is selected from toluene, ethyl acetate, n-propyl acetate, and mixtures thereof; more preferably, the dissolution-preventing solvent is selected from toluene, ethyl acetate, and mixtures thereof.

[0088] Embodiment 42 The method according to any one of embodiments 34 to 41, wherein in step (3), the cooling is natural cooling or controlled temperature cooling.

[0089] Embodiment 43. The method according to any one of embodiments 34 to 42, wherein in step (5), the drying temperature is 50 to 85°C.

[0090] Embodiment 44. A method for preparing a salt of Formula A according to any one of Embodiments 12 to 14, comprising: (1) a step of mixing and reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with p-toluenesulfonic acid monohydrate in a mixed solvent of a water-miscible organic solvent and water under heating and stirring to form a salt; (2) a step of cooling the reaction product obtained in the step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form CI; (4) optionally drying the solid obtained in step (3): The method comprising:

[0091] Embodiment 45. The method of embodiment 44, wherein the molar ratio of the p-toluenesulfonic acid monohydrate to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater, for example, about 1.5:1.

[0092] Embodiment 46. The method according to any one of embodiments 44 and 45, wherein the volume ratio of the mixed solvent consisting of a water-miscible organic solvent and water to the weight of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide in step (1) is about 10 ml / g or more, for example, about 36 ml / g or about 43 ml / g.

[0093] Embodiment 47. The water-miscible organic solvent is C 1-6 47. The method of any one of embodiments 44 to 46, wherein the water-miscible organic solvent is selected from an alkanol, acetone, and mixtures thereof; preferably, the water-miscible organic solvent is selected from i-propanol, acetone, and mixtures thereof.

[0094] Embodiment 48 The method of any one of embodiments 44 to 47, wherein the volume fraction of the water-miscible organic solvent in the mixed solvent is about 95% or less, for example, 80%.

[0095] Embodiment 49. The method of any one of embodiments 44-48, wherein a dissolution-preventing solvent (e.g., i-propanol) is added after the reaction in step (1) is complete and before step (2).

[0096] Embodiment 50 The method according to any one of embodiments 44 to 49, wherein in step (2), the cooling is natural cooling or controlled temperature cooling.

[0097] Embodiment 51. The method of any one of embodiments 44 to 50, wherein in optional step (4), the drying temperature is 50 to 60°C.

[0098] The salts of the present invention and the crystalline forms of the present invention have properties such as good crystallinity, high solubility, low hygroscopicity, and good stability. The salts of the present invention and the crystalline forms of the present invention have good reproducibility and are easy to scale up with the constant production of high-quality products that meet the quality requirements of drugs.

[0099] For example, the free form of Compound 78 prepared according to Example 9 of WO2014 / 139465A1 is a yellow solid needle-like crystal, while Form B-III of the present invention is a plate-like crystal with a smaller diameter length and better granularity than the needle-like crystal, and therefore has a smaller angle of repose, i.e., better flowability. These properties make Form B-III more advantageous for uniform mixing with excipients in the subsequent formulation procedure, allowing for simplification of the formulation process, improvement of production efficiency, and savings in production costs.

[0100] Furthermore, the salts of the present invention and the crystalline forms of the present invention have better dissolution properties.For example, compared with the free form of Compound 78, the salts of the present invention have a smaller solubility difference at different pH values, which makes the solubility of the salts of the present invention in body fluids with different pH values ​​more stable.In addition, Form B-III of the present invention has a higher solubility than the free form of Compound 78 and other salts under gastric acid conditions, which is beneficial for rapid dissolution in the stomach.On the other hand, the salts of the present invention and the crystalline forms of the present invention still have a high and stable solubility under the high pH conditions of the gastrointestinal tract, which is beneficial for sufficient absorption, thus resulting in higher bioavailability, and can also reduce the effect of food on in vivo drug absorption.

[0101] Form B-III of the present invention has low hygroscopicity and good stability, which makes Form B-III particularly convenient for use in manufacturing, storing, transporting formulations and treating diseases.

[0102] Furthermore, the crystalline forms of the present invention have high purity and low solvent residues, meeting quality requirements for drug substances such as ICH Q3A.

[0103] Those skilled in the art can verify the above advantages of the salts of the present invention and the crystalline forms of the present invention according to methods known in the art, such as the test methods disclosed in the pharmacopoeias of various countries or modifications thereof. For example, the crystalline forms of the present invention can be identified by X-ray powder diffraction, single crystal diffraction, Fourier infrared spectroscopy, differential scanning calorimetry, and / or thermogravimetric analysis.

[0104] It is known in the art that peak intensities and / or positions in X-ray powder diffraction patterns can vary depending on different experimental conditions. For example, measured 2θ values ​​may vary slightly due to different instruments, different test conditions, and / or preferred orientation. Furthermore, it is known that the relative intensity values ​​of peaks are more sensitive than peak positions to test sample characteristics, such as crystal size, crystal orientation effects, and the purity of the analyzed material. Therefore, the deviation in peak intensity may be up to about ±20% or more. However, despite experimental error, instrumental error, preferred orientation, etc., a person skilled in the art can obtain sufficient information to identify Forms A-III, B-II, B-III, and CI based on the major peaks of X-ray powder diffraction, even in combination with other characterization data.

[0105] Definition of Forms A-III

[0106] The present invention provides Form A-III.

[0107] In some embodiments, Form A-III can be identified by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction characteristic diffraction angles (2θ) of Form A-III include 5.8±0.2°, 6.2±0.2°, 12.3±0.2°, 13.3±0.2°, 23.1±0.2°, and 24.1±0.2°.

[0108] In some embodiments, X-ray powder diffraction characteristic diffraction angles (2θ) of Form A-III include 5.8±0.2°, 6.2±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 16.2±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, and 26.4±0.2°.

[0109] In some embodiments, X-ray powder diffraction characteristics of Form A-III include diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 15.8±0.2°, 16.2±0.2°, 18.3±0.2°, 18.5±0.2°, 20.2±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, 26.4±0.2°, 27.1±0.2°, and 27.8±0.2°.

[0110] In some embodiments, the X-ray powder diffraction characteristics of Form A-III include diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 7.9±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, These included 17.4±0.2°, 18.3±0.2°, 18.5±0.2°, 19.6±0.2°, 20.2±0.2°, 21.0±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, 24.8±0.2°, 26.4±0.2°, 27.1±0.2°, and 27.8±0.2°.

[0111] In some embodiments, the X-ray powder diffraction characteristics of Form A-III include diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 7.9±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, 17.4±0.2°, 18.3±0.2°, 18.5±0.2°, These include 19.6±0.2°, 20.2±0.2°, 21.0±0.2°, 21.4±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, 24.8±0.2°, 25.2±0.2°, 26.0±0.2°, 26.4±0.2°, 27.1±0.2°, 27.8±0.2°, 29.8±0.2°, 31.5±0.2°, and 32.7±0.2°.

[0112] In some embodiments, Form A-III has the X-ray powder diffraction pattern shown in FIG.

[0113] In some embodiments, Form A-III can be characterized by differential scanning calorimetry (DSC). In some embodiments, Form A-III has the DSC curve shown in Figure 2. In the DSC curve, the endothermic peak of Form A-III is between about 290.2 and 295.4°C.

[0114] In some embodiments, Form A-III may be characterized by thermogravimetric analysis (TGA). In some embodiments, Form A-III has the TGA curve shown in Figure 3, indicating that Form A-III is anhydrous or neat.

[0115] In some embodiments, the Form A-III is substantially pure.

[0116] In some embodiments, the Form A-III is substantially free of other forms, e.g., the Form A-III content by weight is at least 99%, at least 95%, at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0117] Preparation of Form A-III

[0118] The present invention provides a method for preparing Form A-III, comprising: (1) a step of reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with hydrochloric acid in a dissolving solvent or in a mixed solvent of a water-miscible organic solvent and water under heating and stirring to form a salt; (2) a step of cooling the reaction product obtained in the step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form A-III; (4) optionally drying the solid obtained in step (3).

[0119] In some embodiments, the hydrochloric acid is concentrated hydrochloric acid having a concentration of 36 to 38% by weight.

[0120] In some embodiments, the molar ratio of the hydrochloric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater. In some embodiments, the molar ratio is about 1:1. In some embodiments, the molar ratio is 1.2:1.

[0121] In some embodiments, the ratio of the volume (ml) of the dissolving solvent or the mixed solvent to the weight (g) of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g or more, for example, about 20 ml / g or about 60 ml / g.

[0122] In some embodiments, the dissolution medium is C 1-6 In some embodiments, the dissolution solvent is selected from methanol, ethanol, i-propanol, t-butanol, and mixtures thereof. In some embodiments, the dissolution solvent is selected from ethanol.

[0123] In some embodiments, the water-miscible organic solvent is C 1-6 In some embodiments, the water-miscible organic solvent is selected from methanol, ethanol, i-propanol, t-butanol, and mixtures thereof. In some embodiments, the water-miscible organic solvent is selected from ethanol, i-propanol, and mixtures thereof.

[0124] In some embodiments, the volume percentage of the water-miscible organic solvent in the mixed solvent is about 95% or less, e.g., the volume percentage of the water-miscible organic solvent in the mixed solvent is 95%, 90%, 80%, etc.

[0125] In some embodiments, in step (1), the heating temperature should be below the boiling point of the solvent system, for example, 75 to 80°C, 75 to 85°C, and the like.

[0126] In some embodiments, in step (2), the cooling is natural or controlled, and the temperature is room temperature or below, for example, 20 to 25°C, 15 to 25°C, etc.

[0127] In some embodiments, in step (2), after cooling, the reaction mixture is stirred for 1 to 120 hours, for example, 2 hours, 20 hours, etc., to allow a solid to precipitate sufficiently.

[0128] In some embodiments, the drying temperature and drying time in step (4) may be routinely determined by one of ordinary skill in the art, so that the solid is sufficiently dried and maintains the desired crystalline form. In some embodiments, the drying temperature is 50 to 80°C, for example, 60°C. In some embodiments, the drying time is 1 to 24 hours, for example, 2 hours, 18 hours, etc.

[0129] Definition of Form B-II

[0130] The present invention provides Form B-II.

[0131] In some embodiments, Form B-II can be identified by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction characteristic diffraction angles (2θ) of Form B-II include 7.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.1±0.2°, 18.0±0.2°, and 20.6±0.2°.

[0132] In some embodiments, X-ray powder diffraction characteristic diffraction angles (2θ) of Form B-II include 3.8±0.2°, 7.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.7±0.2°, and 23.0±0.2°.

[0133] In some embodiments, X-ray powder diffraction characteristic diffraction angles (2θ) of Form B-II include 3.8±0.2°, 7.5±0.2°, 10.1±0.2°, 11.3±0.2°, 13.4±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.7±0.2°, 23.0±0.2°, 25.1±0.2°, and 27.8±0.2°.

[0134] In some embodiments, X-ray powder diffraction characteristic diffraction angles (2θ) of Form B-II include 3.8±0.2°, 7.5±0.2°, 10.1±0.2°, 11.3±0.2°, 11.8±0.2°, 13.1±0.2°, 13.4±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.1±0.2°, 21.7±0.2°, 23.0±0.2°, 25.1±0.2°, and 27.8±0.2°.

[0135] In some embodiments, the X-ray powder diffraction characteristics of Form B-II include diffraction angles (2θ) of 3.8±0.2°, 7.5±0.2°, 10.1±0.2°, 11.3±0.2°, 11.8±0.2°, 13.1±0.2°, 13.4±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 17.6±0.2°, 18.0±0.2°, 19.8±0.2°, 20.3±0.2°, 20.6±0.2°, 21.1±0.2°, 21.7±0.2°, 22.4±0.2°, 23.0±0.2°, 23.4±0.2°, 23.9±0.2°, 25.1±0.2°, and Including 27.8±0.2°.

[0136] In some embodiments, Form B-II has the X-ray powder diffraction pattern shown in FIG.

[0137] In some embodiments, Form B-II may be characterized by differential scanning calorimetry (DSC). In some embodiments, Form B-II has the DSC curve shown in Figure 5. In the DSC curve, Form B-II has endothermic peaks at about 54.8-92.2°C, 166.9-174.4°C, and 263.3-265.3°C, and an exothermic peak at about 194.2-202.7°C.

[0138] In some embodiments, Form B-II may be characterized by thermogravimetric analysis (TGA). In some embodiments, Form B-II has the TGA curve shown in Figure 6, which shows a weight loss of about 4.3% in the range of 30°C to 100°C, indicating that Form B-II contains significant adsorbed water. From Figure 6, combined with the DSC curve in Figure 5, Form B-II can be identified as a hygroscopic metastable form.

[0139] In some embodiments, the Form B-II is substantially pure.

[0140] In some embodiments, the Form B-II is substantially free of other forms, e.g., the Form B-II content by weight is at least 99%, at least 95%, at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0141] Preparation of Form B-II

[0142] The present invention provides a method for preparing Form B-II, comprising: (1) a step of reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with L-tartaric acid in ethanol under heating and stirring to form a salt; (2) a step of cooling the reaction product obtained in the step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form B-II; (4) optionally drying the solid obtained in step (3).

[0143] In some embodiments, the molar ratio of the L-tartaric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:2 or greater. In some embodiments, the molar ratio is about 4:5. In some embodiments, the molar ratio is about 3.4:1.

[0144] In some embodiments, the ratio of the volume (ml) of the ethanol to the weight (g) of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g (volume / weight ratio) or more, such as about 72 ml / g or about 75 ml / g.

[0145] In some embodiments, in step (1), the heating temperature should be below the boiling point of the solvent system, for example, 70 to 75°C.

[0146] In some embodiments, in step (2), the cooling is carried out naturally or at a controlled temperature, and the cooling is carried out at room temperature or a temperature below room temperature, for example, 20 to 25°C.

[0147] In some embodiments, in step (2), after cooling, the reaction mixture is stirred for 1 to 120 hours, for example, 18 hours, to allow a solid to precipitate sufficiently.

[0148] In some embodiments, the drying temperature and drying time in step (4) may be routinely determined by one of ordinary skill in the art so that the solid is sufficiently dried and the desired crystalline form is maintained. In some embodiments, the drying temperature is 50 to 85°C, e.g., 50°C, 65°C, 82°C, etc. In some embodiments, the drying time is 1 to 24 hours, e.g., 1 hour, 18 hours, 19 hours, etc.

[0149] Definition of Form B-III

[0150] The present invention provides Form B-III.

[0151] In some embodiments, Form B-III can be identified by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction characteristic diffraction angles (2θ) of Form B-III include 13.1±0.2°, 14.6±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, and 26.3±0.2°.

[0152] In some embodiments, X-ray powder diffraction characteristic diffraction angles (2θ) of Form B-III include 12.4±0.2°, 13.1±0.2°, 13.7±0.2°, 14.6±0.2°, 16.5±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, and 26.3±0.2°.

[0153] In some embodiments, X-ray powder diffraction characteristic diffraction angles (2θ) of Form B-III include 7.6±0.2°, 8.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.4±0.2°, 13.1±0.2°, 13.4±0.2°, 13.7±0.2°, 14.6±0.2°, 15.9±0.2°, 16.5±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, and 26.3±0.2°.

[0154] In some embodiments, the X-ray powder diffraction characteristics of Form B-III include diffraction angles (2θ) of 7.6±0.2°, 8.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.4±0.2°, 13.1±0.2°, 13.4±0.2°, 13.7±0.2°, 14.6±0.2°, 15.9±0.2°, These included 16.5±0.2°, 17.2±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 19.6±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, 24.6±0.2°, 26.3±0.2°, 27.6±0.2°, and 29.2±0.2°.

[0155] In some embodiments, the X-ray powder diffraction characteristics of Form B-III include diffraction angles (2θ) of 7.6±0.2°, 8.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.4±0.2°, 13.1±0.2°, 13.4±0.2°, 13.7±0.2°, 14.6±0.2°, 15.9±0.2°, 16.5±0.2°, 17.2±0.2°, 17.9±0.2°, 18.9±0.2°, 19.9±0.2°, 20.9±0.2°, 21.9±0.2°, 22.9±0.2°, 23.9±0.2°, 24.9±0.2°, 25.9±0.2°, 26.9±0.2°, 27.9±0.2°, 28.9±0.2°, 29.9±0.2°, 30.9±0.2°, 31.9±0.2°, 32.9±0.2°, 33.9±0.2°, 34.9±0.2°, 35.9±0.2°, 36.9±0.2°, 37.9±0.2°, 38.9±0.2°, 39.9±0.2°, 40.9±0.2°, 41.9±0.2°, 42.9±0.2°, 43.9±0.2°, 44.9±0.2°, 45.9±0.2°, 46.9±0.2°, 47.9±0.2°, 48.9±0.2°, 49.9 0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 19.6±0.2°, 20.8±0.2°, 21.4±0.2°, 22.6±0.2°, 23.2±0.2°, 23.7±0.2°, 24.6±0.2°, 26.3±0.2°, 27.1±0.2°, 27.6±0.2°, 27.8±0.2°, and 29.2±0.2°.

[0156] In some embodiments, Form B-III has the X-ray powder diffraction pattern shown in FIG.

[0157] In some embodiments, Form B-III may be characterized by differential scanning calorimetry (DSC). In some embodiments, Form B-III has the DSC curve shown in Figure 8. In the DSC curve, the endothermic peak for Form B-III is between about 269.2 and 271.3°C.

[0158] In some embodiments, Form B-III may be characterized by thermogravimetric analysis (TGA). In some embodiments, Form B-III has the TGA curve shown in Figure 9, indicating that Form B-III is anhydrous or pure.

[0159] In some embodiments, the Form B-III is substantially pure.

[0160] In some embodiments, the Form B-III is substantially free of other forms, e.g., the Form B-III content by weight is at least 99%, at least 95%, at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0161] Preparation of Form B-III

[0162] The present invention provides a method for preparing Form B-III, comprising: (1) mixing and reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with L-tartaric acid in a dissolving solvent, in water, or in a mixed solvent of a water-miscible organic solvent and water under heating and stirring to form a salt, thereby obtaining a first solution; provided that the dissolving solvent is not a single solvent of ethanol (i.e., it may be another dissolving solvent or a mixed solvent of ethanol and another dissolving solvent); (2) optionally adding a dissolution-preventing solvent to the first solution to obtain a second solution; (3) cooling the first solution or the second solution to sufficiently precipitate a solid; (4) isolating the precipitated solid as Form B-III; (5) optionally drying the solid obtained in step (4).

[0163] In some embodiments, the molar ratio of the L-tartaric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater. In some embodiments, the molar ratio is about 1:1. In some embodiments, the molar ratio is about 1.5:1.

[0164] In some embodiments, in step (1), the ratio of the volume (ml) of the dissolving solvent, the water, or the mixed solvent consisting of a water-miscible organic solvent and water to the weight (g) of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g (volume / weight ratio) or more, for example, about 20 ml / g, about 30 ml / g, about 33 ml / g, about 50 ml / g, about 65 ml / g, about 98 ml / g, or about 286 ml / g.

[0165] In some embodiments, the dissolution medium is C 1-6 The dissolving solvent is selected from alkanols, acetone, toluene, organic acid esters having 8 or fewer carbon atoms, and mixtures thereof. In some embodiments, the dissolving solvent is selected from methanol, ethanol, i-propanol, t-butanol, n-butanol, acetone, toluene, n-propyl acetate, ethyl acetate, and mixtures thereof. In some embodiments, the dissolving solvent is selected from methanol, ethanol, i-propanol, acetone, toluene, n-propyl acetate, ethyl acetate, and mixtures thereof.

[0166] In some embodiments, the dissolution solvent is selected from a mixture of two of methanol, ethanol, toluene, n-propyl acetate, and ethyl acetate, such as n-propyl acetate / methanol (volume ratio of about 3:2), toluene / ethanol (volume ratio of about 1:1), and ethyl acetate / ethanol (volume ratio of about 11:15).

[0167] In some embodiments, the water-miscible organic solvent is C 1-6 In some embodiments, the water-miscible organic solvent is selected from an alkanol, acetone, and mixtures thereof. In some embodiments, the water-miscible organic solvent is selected from methanol, ethanol, i-propanol, t-butanol, acetone, and mixtures thereof. In some embodiments, the water-miscible organic solvent is selected from ethanol, i-propanol, acetone, and mixtures thereof.

[0168] In some embodiments, the volume fraction of the water-miscible organic solvent in the mixed solvent is about 95% or less, e.g., 95%, 90%, 80%, etc.

[0169] In some embodiments, the dissolution preventing solvent is selected from toluene, organic acid esters having 8 or fewer carbon atoms, and mixtures thereof. In some embodiments, the dissolution preventing solvent is selected from toluene, ethyl acetate, n-propyl acetate, and mixtures thereof. In some embodiments, the dissolution preventing solvent is selected from toluene, ethyl acetate, and mixtures thereof.

[0170] In some embodiments, in step (1), the heating temperature should be below the boiling point of the solvent system, for example, 55-60°C, 70-72°C, 75-85°C, 90-95°C, and the like.

[0171] In some embodiments, in step (3), the cooling is natural or controlled, and the temperature is room temperature or below, for example, 20 to 25°C, 25 to 30°C, etc.

[0172] In some embodiments, in step (3), after cooling, the first solution or the second solution is stirred for 1 to 120 hours, for example, 2 hours, 16 hours, 17 hours, 18 hours, or 20 hours, to allow a solid to precipitate sufficiently.

[0173] In some embodiments, the drying temperature and drying time in step (5) may be routinely determined by one of ordinary skill in the art so that the solid is sufficiently dried and the desired crystalline form is maintained. In some embodiments, the drying temperature is 50 to 85°C, e.g., 55°C, 60°C, 65°C, etc. In some embodiments, the drying time is 1 to 24 hours, e.g., 2 hours, 3 hours, 5 hours, 6 hours, 16 hours, etc.

[0174] Definition of form CI

[0175] The present invention provides Form CI.

[0176] In some embodiments, Form CI can be identified by X-ray powder diffraction. In some embodiments, Form CI's X-ray powder diffraction characteristic diffraction angles (2θ) include 7.8±0.2°, 11.1±0.2°, 11.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, and 24.0±0.2°.

[0177] In some embodiments, X-ray powder diffraction characteristic diffraction angles (2θ) of Form CI include 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 13.8±0.2°, 14.3±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, 22.2±0.2°, 24.0±0.2°, and 26.1±0.2°.

[0178] In some embodiments, X-ray powder diffraction characteristic diffraction angles (2θ) of Form CI include 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 13.5±0.2°, 13.8±0.2°, 14.3±0.2°, 14.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 24.0±0.2°, 26.1±0.2°, and 27.4±0.2°.

[0179] In some embodiments, the X-ray powder diffraction characteristics of Form CI at diffraction angles (2θ) are 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 12.2±0.2°, 12.9±0.2°, 13.5±0.2°, 13.8±0.2°, 14.3±0.2°, 14.7±0.2°. 2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 23.5±0.2°, 24.0±0.2°, 25.0±0.2°, 26.1±0.2°, 27.4±0.2°, and 32.8±0.2°.

[0180] In some embodiments, the X-ray powder diffraction characteristics of Form CI include diffraction angles (2θ) of 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 12.2±0.2°, 12.9±0.2°, 13.5±0.2°, 13.8±0.2°, 14.3±0.2°, 14.7±0.2°, 16.6±0.2°, 17.6±0.2°, 18.6±0.2°, 19.6±0.2°, 20.6±0.2°, 21.6±0.2°, 22.6±0.2°, 23.6±0.2°, 24.6±0.2°, 25.6±0.2°, 26.6±0.2°, 27.6±0.2°, 28.6±0.2°, 29.6±0.2°, 30.6±0.2°, 31.6±0.2°, 32.6±0.2°, 33.6±0.2°, 34.6±0.2°, 35.6±0.2°, 36.6±0.2°, 37.6±0.2°, 38.6±0.2°, 39.6±0.2°, 40.6±0.2°, 41.6±0.2°, 42.6±0.2°, 43.6±0.2°, 44.6±0.2°, 45.6±0.2°, 46.6±0.2°, 47.6±0.2°, 48.6±0.2°, 49.6±0 0.9±0.2°, 18.2±0.2°, 19.2±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 22.7±0.2°, 23.5±0.2°, 24.0±0.2°, 24.4±0.2°, 26.1±0.2°, 27.4±0.2°, 28.8±0.2°, 32.8±0.2°, and 33.6±0.2°.

[0181] In some embodiments, Form CI has the X-ray powder diffraction pattern shown in FIG.

[0182] In some embodiments, Form CI can be characterized by differential scanning calorimetry (DSC). In some embodiments, Form CI has the DSC curve shown in Figure 13. In the DSC curve, Form CI has an endothermic peak between about 289.77 and 291.04°C.

[0183] In some embodiments, Form CI may be characterized by thermogravimetric analysis (TGA). In some embodiments, Form CI has the TGA curve shown in Figure 14, indicating that Form CI is anhydrous or neat.

[0184] In some embodiments, Form CI is substantially pure.

[0185] In some embodiments, Form CI is substantially free of other forms, e.g., Form CI is at least 99%, at least 95%, at least 90%, at least 80%, at least 70%, at least 60%, or at least 50% by weight.

[0186] Preparation of Form CI

[0187] The present invention provides a method for preparing Form CI, comprising: (1) a step of reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with p-toluenesulfonic acid monohydrate under heating and stirring in a mixed solvent of a water-miscible organic solvent and water to form a salt; (2) a step of cooling the reaction product obtained in the step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form CI; (4) optionally drying the solid obtained in step (3).

[0188] In some embodiments, the molar ratio of the p-toluenesulfonic acid monohydrate to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater. In some embodiments, the molar ratio is about 1.5:1.

[0189] In some embodiments, in step (1), the ratio of the volume (ml) of the mixed solvent consisting of a water-miscible organic solvent and water to the weight (g) of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g (mass / weight ratio) or more, for example, about 36 ml / g, about 43 ml / g, etc.

[0190] In some embodiments, the water-miscible organic solvent is C 1-6 In some embodiments, the water-miscible organic solvent is selected from an alkanol, acetone, and mixtures thereof. In some embodiments, the water-miscible organic solvent is selected from i-propanol, acetone, and mixtures thereof.

[0191] In some embodiments, the volume fraction of the water-miscible organic solvent in the mixed solvent is about 95% or less, such as 80%.

[0192] In some embodiments, in step (1), the heating temperature should be below the boiling point of the solvent system, for example, 55 to 60°C, 75 to 85°C, and the like.

[0193] In some embodiments, at least one dissolution-preventing solvent (eg, i-propanol) is added after the reaction in step (1) is complete and before step (2).

[0194] In some embodiments, in step (2), the cooling is natural or controlled, and the cooling is at room temperature or below.

[0195] In some embodiments, in step (2), after cooling, the reaction mixture is stirred for 1 to 120 hours, for example, 15 hours, to allow a solid to precipitate sufficiently.

[0196] In some embodiments, the drying temperature and drying time in step (4) may be routinely determined by one of ordinary skill in the art, so that the solid is sufficiently dried and the desired crystalline form is maintained. In some embodiments, the drying temperature is 50 to 60°C, such as 50°C. In some embodiments, the drying time is 1 to 24 hours, such as 4 hours or 20 hours.

[0197] The features of each embodiment described as a method for preparing the same crystalline form can be combined in any manner to produce new embodiments, and the new embodiments resulting from any such combination are within the scope of the present invention just as if those embodiments resulting from such combination were specifically and individually recited herein.

[0198] Pharmaceutical Compositions and Uses

[0199] The salts of the present invention and the crystalline forms of the present invention are useful in inhibiting FGFR activity in vivo and in vitro.

[0200] The salts of the present invention and the crystalline forms of the present invention are useful for preventing or treating diseases that respond to inhibition of FGFR activity. Accordingly, the present invention provides a method for preventing or treating diseases that respond to inhibition of FGFR activity, comprising administering to a subject in need of such prevention or treatment a salt of the present invention or a crystalline form of the present invention, and optionally one or more other active ingredients. Furthermore, the present invention also provides the use of the salts of the present invention and the crystalline forms of the present invention in the manufacture of a medicament for preventing or treating diseases that respond to inhibition of FGFR activity. The diseases that respond to inhibition of FGFR activity are, for example, cancers, including, but not limited to, lung cancer (e.g., squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, biliary tract cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma, and hematological malignancies (e.g., myeloproliferative disorders).

[0201] The salts of the invention and the crystalline forms of the invention may be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, intramuscular, intravenous, intraarterial, intraperitoneal, intrapulmonary, intradermal, subcutaneous, intrathecal, epidural and intranasal administration.

[0202] The dosage of the salts of the present invention and the crystalline forms of the present invention to achieve the desired physiological effect can depend on many factors, such as the disease to be treated, the route and mode of administration, and the clinical condition of the patient. The daily dose can be, for example, in the range of 0.01 mg / day to 3 g / day, e.g., 0.05 mg / day to 2 g / day, or 100 mg / day to 1 g / day, etc. The daily dose can be administered once or in divided doses (e.g., 2 to 4 divided doses).

[0203] For the prevention or treatment of the above-mentioned diseases, the salts of the present invention and the crystalline forms of the present invention may be administered as they are, but are typically administered in the form of a pharmaceutical composition formulated together with a pharmaceutically acceptable carrier.

[0204] The pharmaceutical compositions of the present invention may be in any convenient form for administration, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, and patches. Pharmaceutically acceptable carriers used in preparing pharmaceutical compositions may include conventional ingredients in the field of pharmaceutical formulations, such as diluents, disintegrants, lubricants, pH adjusters, flavoring agents, fillers, preservatives, osmotic pressure adjusters, coloring agents, emulsifiers, suspending agents, and surfactants. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the pharmaceutical composition and must not have adverse effects on the subject's health. The carrier may be solid or liquid, or both. The pharmaceutical composition may contain 0.05 to 95% by weight of the salt of the present invention and the crystalline form of the present invention.

[0205] The pharmaceutical composition can be prepared by mixing the salt of the present invention or the crystalline form of the present invention with a pharmaceutically acceptable carrier. Carriers suitable for each dosage form are known to those skilled in the art and are described in detail in, for example, the following documents: Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, R.C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

[0206] In some embodiments, the crystalline forms of the present invention are not converted into other forms when formulated with one or more pharmaceutically acceptable carriers. In other embodiments, the crystalline forms of the present invention may be completely or partially converted into one or more other forms when formulated with one or more pharmaceutically acceptable carriers. However, those skilled in the art can use known technical means to maintain the stability of the crystalline forms as needed. In some embodiments, the crystalline forms of the present invention may be dissolved when formulated into a pharmaceutical composition, and as a result, they are no longer present in their respective forms in the pharmaceutical composition.

[0207] The salts of the present invention and the crystalline forms of the present invention may be administered in combination with one or more other active ingredients to achieve additive or synergistic therapeutic effects or to reduce side effects. When administered in combination, the salts of the present invention and the crystalline forms of the present invention and the one or more other active ingredients may be formulated into separate dosage forms that are administered simultaneously or sequentially, via the same or different routes of administration, or may be administered simultaneously in the same unit dosage form.

[0208] Other active ingredients that may be administered in combination with the salts and crystalline forms of the present invention may be anti-neoplastic agents and / or anti-neoplastic therapies, including, but not limited to: radiation therapy, immunotherapy, chemotherapy, such as DNA damaging chemotherapy and cell replication interfering chemotherapy.

[0209] Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and their analogs or metabolites, and adriamycin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

[0210] Examples of cell replication-interfering chemotherapeutic agents include, but are not limited to, paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κB inhibitors, including inhibitors of IκB kinase; antibodies that bind to proteins that are overexpressed in cancer and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and inhibitors of other proteins or enzymes known to be upregulated, overexpressed, or activated in cancer, the inhibition of which may downregulate cell replication. [Example]

[0211] The following examples are used to illustrate the invention without limiting the scope thereof, which is defined in the claims.

[0212] Example The compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide used in the examples was prepared according to Example 9 of WO2014 / 139465A1, and is a needle-shaped crystalline yellow solid, with a micrograph shown in FIG. 22.

[0213] All reagents, except for intermediates, used in this disclosure are commercially available. The names of all compounds, except for reagents, were generated by ChemDraw Professional 16.0.

[0214] Unless otherwise noted, X-ray powder diffraction patterns were obtained using a Germany Bruker D8 ADVANCE X-ray diffractometer (target: Cu; voltage: 40 kV; current: 40 mA; scan rate: 4 degrees / min; step size: 0.02°; scan range: 3°–45°).

[0215] Unless otherwise noted, differential scanning calorimetry (DSC) was performed using a NETZSCH DSC 204F1 (Germany) (purge gas: nitrogen; flow rate: 20–60 mL min -1 The temperature was measured at a rate of 10°C / min and a temperature range of 30°C to 300 / 350°C. The samples were measured in aluminum oxide pans. Indium was used for temperature calibration.

[0216] Unless otherwise stated, thermogravimetry (TG) analysis was carried out using a Germany NETZSCH TGA 209F1 (purge gas: nitrogen; heating rate: 10°C / min).

[0217] Unless otherwise noted, photomicrographs were obtained using a Nikon Ci-L microscope.

[0218] Example 1 - Preparation of Form A-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (0.51 g, 1 mmol) was suspended in 10 mL of 95% ethanol (i.e., a 95:5 volumetric ratio mixture of ethanol and water) and heated to 75-85°C under stirring. 100 μL of hydrochloric acid (concentration: 36-38 wt%) was added to the suspension to obtain a clear solution. The solution was cooled to 15-25°C and stirred for 20 hours. The solid was filtered and dried under vacuum at 60°C for 2 hours to obtain a sample. The chloride ion content in the sample was determined to be 6.48%, and the resulting sample was determined to be the monohydrochloride salt (theoretical content: 6.69%).

[0219] 1 H NMR(400MHz, CD3OD) δ 8.11 (2H, s), 7.48-7.42(2H, m), 7.36(1H, d, J=2.0), 7.29(1H, d, J=2.0), 7.00(2H, dd, J=9.6, 2.8), 3.91(3H, s), 3.73(2H, dd, J=13.3, 2.4), 3.48(2H, ddd, J=9.9, 6.6, 3.2), 3.05(2H, t, J=7.5), 2.89(3H, s), 2.82(2H, t, J=7.5), 2.69(2H, dd, J=13.3, 11.3), 1.38(6H, d, J=6.6).

[0220] The resulting powder sample was Form A-III and had the X-ray powder diffraction pattern shown in Figure 1. The diffraction pattern consisted of: 5.8±0.2°, 6.2±0.2°, 7.9±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, 17.4±0.2°, 18.3±0.2°, 18.5±0.2°, 19.6±0.2°, 20.2±0.2°, 21.0±0.2°, 21.4±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, 24.8±0.2°, 25. The diffraction peaks (2θ) were at 26.2 ± 0.2°, 26.0 ± 0.2°, 26.4 ± 0.2°, 27.1 ± 0.2°, 27.8 ± 0.2°, 29.8 ± 0.2°, 31.5 ± 0.2°, and 32.7 ± 0.2°, with characteristic peaks (2θ) at 5.8 ± 0.2°, 6.2 ± 0.2°, 10.3 ± 0.2°, 12.3 ± 0.2°, 13.3 ± 0.2°, 15.0 ± 0.2°, 16.2 ± 0.2°, 22.2 ± 0.2°, 23.1 ± 0.2°, 24.1 ± 0.2°, and 26.4 ± 0.2°. The DSC result for the sample is shown in Figure 2 and indicates that the endothermic peak for Form A-III is between approximately 290.2 and 295.4 °C.

[0221] Example 2 - Preparation of Form A-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (0.51 g, 1 mmol) was suspended in 30 mL of absolute ethanol and heated to 75-85°C under stirring to dissolve. 100 μL of hydrochloric acid (concentration 36-38 wt%) was added to the solution, and the stirring was continued at 75-85°C for 5 minutes. The solution was cooled to 15-25°C and stirred for 2 hours. The solid was filtered and dried under vacuum at 60°C for 18 hours to obtain a sample. Upon measurement, the X-ray powder diffraction pattern of the obtained sample was identical to that of the Form A-III sample obtained in Example 1.

[0222] Example 3 - Preparation of Form A-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (2.04 g, 4 mmol) was suspended in 40 mL of a 9:1 volumetric ratio mixture of i-propanol and water and heated to 75-80°C under stirring. 352 μL of hydrochloric acid (concentration 36-38 wt%) was added to the suspension. The resulting mixture was cooled to 20-25°C and stirred for 2 hours. The solid was filtered and dried under vacuum at 60°C for 2 hours to obtain a 1.6 g sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample was identical to that of the Form A-III sample obtained in Example 1.

[0223] Example 4 - Preparation of Form B-II 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (1 g, 1.96 mmol) and 60 mL of absolute ethanol were mixed and heated to 70-74 °C to dissolve. A solution of L-tartaric acid (0.24 g, 1.6 mmol) in 12 mL of ethanol was added, and the solid precipitated immediately. The mixture was stirred at 70-74 °C for 30 min; cooled to 50-55 °C and stirred for 1 h; and cooled to 20-25 °C and stirred for 18 h. The solid was filtered and dried under vacuum at 60 °C for 2 h, then at 65 °C for 16 h, and then at 82 °C for 1 h to obtain a 1.15 g sample.

[0224] 1H NMR (400MHz, DMSO) δ 9.22 (1H, s), 8.48 (1H, q, J=4.4), 8.22 (2H, s), 7.53 (2H, dd, J=9.7, 2.7), 7.4 3(1H, d, J=1.9), 7.40(1H, d, J=1.9), 6.88(2H, dd, J=9.7, 2.7), 3.88(3H, s), 3.83(1H, s), 3.53(2H, d, J=9.8), 3.09(2H, d, J=6.6), 2.97(2H, dd, J=9.1, 6. 5), 2.80-2.70 (5H, m, J=14.4, 5.7), 2.30 (2H, t, J=11.4), 1.12 (6H, d, J=6.4).

[0225] The resulting powder sample was Form B-II and had the X-ray powder diffraction pattern shown in Figure 4. The diffraction pattern was 3.8±0.2°, 7.5±0.2°, 10.1±0.2°, 11.3±0.2°, 11.8±0.2°, 13.1±0.2°, 13.4±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 17.6±0.2°, 18.0±0.2°, 19.8±0.2°, 20.3±0.2°, 20.6±0.2°, 21.1±0.2°. The diffraction peaks (2θ) were at 21.7±0.2°, 22.4±0.2°, 23.0±0.2°, 23.4±0.2°, 23.9±0.2°, 25.1±0.2°, and 27.8±0.2°, with characteristic peaks (2θ) at 7.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.1±0.2°, 18.0±0.2°, and 20.6±0.2°. The DSC results for the sample are shown in Figure 5 and show that Form B-II has endothermic peaks at approximately 54.8-92.2°C, 166.9-174.4°C, and 263.3-265.3°C, and an exothermic peak at approximately 194.2-202.7°C.

[0226] Example 5 - Preparation of Form B-II 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (1 g, 1.96 mmol) and 60 mL of absolute ethanol were mixed and heated to 70-75°C, and filtered while hot to remove a small amount of insoluble material. A solution of L-tartaric acid (1 g, 6.66 mmol) in ethanol (15 mL) was added. A solid precipitated during the addition. The mixture was stirred at 70-75°C for 1 hour and cooled to 24°C. The solid was filtered and dried under vacuum at 50°C for 17 hours, followed by drying under vacuum at 82°C for 1 hour to obtain a sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-II sample obtained in Example 4.

[0227] Example 6 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (1 g, 1.96 mmol) and 15 mL of a mixture of i-propanol and water (8:2 volume ratio) were mixed and heated to 70°C to dissolve. A solution of L-tartaric acid (0.29 g, 1.93 mmol) dissolved in 5 mL of a mixture of i-propanol and water (8:2 volume ratio) was added to obtain a clear reaction solution. The solution was stirred at 70-72°C for 10 minutes, and a solid precipitated. The mixture was then incubated for 30 minutes, cooled to 50-55°C and stirred for 1 hour, then cooled to 40-45°C and stirred for 1 hour, and then cooled to 20-25°C and stirred for 17 hours. The solid was then filtered and dried under vacuum at 60°C for 30 minutes, then under vacuum at 65°C for 16 hours to give a 0.97g sample.

[0228] 1H NMR (400MHz, DMSO) δ 9.22 (1H, s), 8.48 (1H, q, J=4.3), 8.22 (2H, s), 7.55-7.50(2H, m), 7.43(1H, d, J=1.9), 7.40(1H, d, J=1.9), 6.88(2H, dd, J=9.7, 2.7), 3.88(3H, s), 3.84(1H, s), 3.57-3.48(2 H, m), 3.09 (2H, dd, J=11.6, 4.9), 2.97 (2H, dd, J=9.1, 6.5), 2.82-2.69 (5H, m, J=14.6, 5.8), 2.30 (2H, t, J=11.4), 1.13 (6H, d, J=6.4).

[0229] The resulting powder sample is Form B-III and has the X-ray powder diffraction pattern shown in Figure 7. The diffraction pattern contains the following peaks: 7.6±0.2°, 8.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.4±0.2°, 13.1±0.2°, 13.4±0.2°, 13.7±0.2°, 14.6±0.2°, 15.9±0.2°, 16.5±0.2°, 17.2±0.2°, 17.9±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 19.6±0.2°, 20.8±0.2°, 21.0±0.2°, 22.0±0.2°, 23.0±0.2°, 24.0±0.2°, 25.0±0.2°, 26.0±0.2°, 27.0±0.2°, 28.0±0.2°, 29.0±0.2°, 30.0±0.2°, 31.0±0.2°, 32.0±0.2°, 33.0±0.2°, 34.0±0.2°, 35.0±0.2°, 36.0±0.2°, 37.0±0.2°, 38.0±0.2°, 39.0±0.2°, 40.0±0.2°, 41.0±0.2°, 42.0±0.2°, 43.0±0.2°, 44.0±0.2°, 45.0±0.2°, 46.0±0 The diffraction peaks (2θ) were at 22.4±0.2°, 22.6±0.2°, 23.2±0.2°, 23.7±0.2°, 24.6±0.2°, 26.3±0.2°, 27.1±0.2°, 27.6±0.2°, 27.8±0.2°, and 29.2±0.2°, with characteristic peaks (2θ) at 13.1±0.2°, 14.6±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, and 26.3±0.2°. The DSC result for the sample is shown in Figure 8 and indicates that the endothermic peak for Form B-III is between about 269.2 and 271.3°C.

[0230] Microscopic examination showed that Form B-III was a tabular crystal with a micrograph as shown in FIG.

[0231] Example 7 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (0.26 g, 0.51 mmol) was dissolved in 7 mL of a mixture of acetone and water in a volume ratio of 8:2 under reflux and stirred. A solution of L-tartaric acid (0.08 g, 0.53 mmol) in a mixture of acetone and water in a volume ratio of 8:2 (1.5 mL) was added. The mixture was cooled to 40°C and stirred for 1 hour; then cooled to 25°C and stirred for 2 hours. The precipitated solid was filtered and dried under vacuum at 55°C for 2 hours to obtain a 0.21 g sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-III sample obtained in Example 6.

[0232] Example 8 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (51 mg, 0.1 mmol) was dissolved in 1.5 mL of methanol at 55°C to 60°C and filtered while hot. L-Tartaric acid (23 mg, 0.15 mmol) was added to the filtrate and stirring was continued at 55°C to 60°C for 30 minutes. The reaction mixture was then cooled to 20°C to 25°C and stirred for 18 hours. The precipitated solid was filtered and dried under vacuum at 55°C for 5 hours to obtain a sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-III sample obtained in Example 6.

[0233] Example 9 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (51 mg, 0.1 mmol) was dissolved in 3 mL of n-propyl acetate at 75°C to 85°C. A solution of L-tartaric acid (23 mg, 0.1 mmol) in methanol (1 mL) was added, followed by 1 mL of additional methanol. The mixture was stirred at 75°C to 85°C for 50 minutes, cooled to 25°C to 30°C, and stirred for 16 hours. The precipitated solid was filtered and dried under vacuum at 55°C for 6 hours to obtain a sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-III sample obtained in Example 6.

[0234] Example 10 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (21 mg, 0.041 mmol) was dissolved in 3 mL of toluene at 90°C to 95°C. A solution of L-tartaric acid (9.3 mg, 0.062 mmol) in ethanol (0.5 mL) was added; then, 2.5 mL of additional methanol was added. The mixture was stirred at 80°C to 90°C for 30 minutes, cooled to 20°C to 25°C, and stirred for 18 hours. The precipitated solid was filtered and dried under vacuum at 55°C for 2 hours to obtain a sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-III sample obtained in Example 6.

[0235] Example 11 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (0.26 g, 0.51 mmol) was dissolved in 6 mL of a 9:1 volumetric mixture of ethanol and water under reflux. A solution of L-tartaric acid (0.08 g, 0.53 mmol) in 1.5 mL of a 9:1 volumetric mixture of ethanol and water was added, and the solid precipitated after 5 minutes. Heating was stopped, and the mixture was cooled to 25-30°C and stirred for 20 hours. The precipitated solid was filtered and dried under vacuum at 55°C for 3 hours to obtain a 0.27 g sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-III sample obtained in Example 6.

[0236] Example 12 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (0.26 g, 0.51 mmol) was dissolved in 11 mL of a mixed solvent (1:1 volume ratio of ethanol:ethyl acetate) at 75-80°C. A solution of L-tartaric acid (0.08 g, 0.53 mmol) in 2 mL of ethanol was added, and the solid precipitated within 2 minutes. The mixture was stirred at 75-80°C for 1 hour. Heating was stopped, and the mixture was cooled to 25-30°C and stirred for 16 hours. The precipitated solid was filtered and dried under vacuum at 55°C for 16 hours to obtain a 0.30 g sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-III sample obtained in Example 6.

[0237] Example 13 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (0.26 g, 0.51 mmol) was dissolved in 6 mL of a 9:1 volumetric ratio mixture of i-propanol and water under reflux. A solution of L-tartaric acid (0.08 g, 0.53 mmol) in 2 mL of a 9:1 volumetric ratio mixture of i-propanol and water was added. The mixture was cooled to 25-30°C and stirred for 17 hours. The solid was filtered and dried under vacuum at 55°C for 6 hours to obtain a 0.24 g sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-III sample obtained in Example 6.

[0238] Example 14 - Preparation of Form B-III 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (0.26 g, 0.51 mmol) was suspended in 15 mL of water, and the mixture was heated to 75-85°C without dissolving. A solution of L-tartaric acid (0.08 g, 0.53 mmol) in water (2 mL) was added to the suspension, resulting in a clear solution, after which a solid precipitated. The mixture was stirred at 75-85°C for 2 hours, then cooled to 25-30°C and stirred for 19-20 hours. The precipitated solid was filtered and dried under vacuum at 55°C for 3 hours to obtain a 0.23 g sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form B-III sample obtained in Example 6.

[0239] Example 15 - Preparation of Form CI 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (300 mg, 0.59 mmol) was dissolved in 12 mL of a mixture of acetone and water in a volume ratio of 8:2 under reflux. A solution of p-toluenesulfonic acid monohydrate (168 mg, 0.89 mmol) in a mixture of acetone and water in a volume ratio of 8:2 (1 mL) was added. After stirring for about 5 minutes, a solid precipitated. The reaction was cooled to room temperature and stirring was continued for about 15 hours. The solid was filtered and dried under vacuum at 50°C for 4 hours to obtain a sample.

[0240] 1 H NMR (400MHz, DMSO) δ:9.29(s, 1H), 8.90(d, J=9.7Hz, 1H), 8.49(q, J=4.3Hz, 1H), 8.34-8.24(m, 1H), 8.23(s, 2H), 7.57 (t, J=6.1Hz, 2H), 7.46(d, J=8.0Hz, 2H), 7.41(dd, J=13.0, 1.8Hz, 2H), 7.09(dd, J=7.9, 0.5Hz, 2H), 6.91(d, J=9.1Hz, 2H), 3.87(s, 3H), 3.69(d, J=10.9Hz, 2H), 3.38(d, J=6.5Hz, 2H), 3.00-2.92(m, 2 H), 2.74 (dd, J=11.5, 5.8Hz, 5H), 2.51 (dd, J=19.2, 7.7Hz, 2H), 2.26 (s, 3H), 1.23 (d, J=6.5Hz, 6H).

[0241] The resulting powder sample was Form CI and had the X-ray powder diffraction pattern shown in Figure 12. The diffraction pattern consisted of 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 12.2±0.2°, 12.9±0.2°, 13.5±0.2°, 13.8±0.2°, 14.3±0.2°, 14.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2° The diffraction peaks (2θ) for Form CI are 19.2±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 22.7±0.2°, 23.5±0.2°, 24.0±0.2°, 24.4±0.2°, 26.1±0.2°, 27.4±0.2°, 28.8±0.2°, 32.8±0.2°, and 33.6±0.2°. The DSC results for this sample are shown in Figure 13 and indicate that the endothermic peak for Form CI is between approximately 289.77 and 291.04°C.

[0242] Example 16 - Preparation of Form CI 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (4.3 g, 8.44 mmol) was dissolved in 155 mL of a mixture of i-propanol and water (8:2 volume ratio) under reflux and filtered while hot to remove insoluble material. The filtrate was heated to reflux again, and a solution of p-toluenesulfonic acid monohydrate (2.4 g, 12.67 mmol) in water (2 mL) was added, followed by 50 mL of i-propanol. After stirring for approximately 5 minutes, a solid precipitated. The reaction mixture was cooled to room temperature and stirring was continued for approximately 15 hours. The solid was filtered and dried under vacuum at 50°C for 20 hours to obtain a sample. Upon measurement, the X-ray powder diffraction pattern of the resulting sample matched that of the Form CI sample obtained in Example 15.

[0243] Example 17 - Stability of salts of the present invention under high temperature, humidity, and light Quantitative analysis: Test samples of Compound 78 hemitartrate Form B-III and Compound 78 monohydrochloride Form A-III were placed on culture plates, then removed and placed in sealed, clean containers. The containers were then stored at 60°C, 25°C, 92.5% ± 5% relative humidity, and 4500 lx ± 500 lx for 10 days. Test samples were then collected, and the purity and crystalline form of the samples were determined. The results are shown in Table 1.

[0244] [Table 1]

[0245] The data in Table 1 show that the chemical purity of Form B-III of the hemitartrate salt of Compound 78 and Form A-III of the monohydrochloride salt of Compound 78 did not change significantly after being placed under high temperature, high humidity, or illumination for 10 days; the crystalline morphology of the Form A-III sample changed after being placed under high humidity conditions (as shown in Figures 15 and 16) but remained unchanged under high temperature and illumination conditions; whereas, Form B-III did not change significantly under all tested conditions and had better stability.

[0246] Example 18 - Stability of Form B-II and Form B-III Quantitative Method 1: Test samples of Form B-II and Form B-III of the hemitartrate salt of Compound 78 were placed on culture plates, respectively, and then placed in sealed, clean containers with the lids removed. The containers were then stored at 25°C and 92.5% ± 5% relative humidity for 3 or 5 days. The crystal forms of the test samples were then determined. The results are shown in Table 2.

[0247] Quantitative Method 2: Test samples of Form B-II and Form B-III of the hemitartrate salt of Compound 78 were suspended in water and stirred at room temperature. Test samples were collected on days 2 and 4, and the crystal forms were determined. The results are shown in Table 2.

[0248] [Table 2]

[0249] The data in Table 2 showed that Form B-II of the hemitartrate salt of Compound 78 was unstable under both test conditions, and the presence of moisture induced a change in crystalline form (as shown in Figures 17-19). In contrast, the crystalline form of Form B-III of the hemitartrate salt of Compound 78 remained unchanged when placed under humid conditions or slurried in water (as shown in Figures 20 and 21). Form B-III has high stability.

[0250] Example 19 - Comparison of the solubility of the salt of formula A of compound 78 and its free form in different buffers Quantitative method: Excessive samples of Compound 78 hemitartrate Form B-III, Compound 78 mono-p-tosylate Form CI, and the free form of Compound 78 were suspended in buffers of different pH and in water, respectively, stirred at a constant temperature of 37°C for 30 minutes, centrifuged, and filtered. The filtrates were used to determine the solubility of the samples. All solubility results were calculated based on the free form. The results are shown in Table 3. The buffers of different pH were prepared according to the United States Pharmacopoeia (USP40-NF35).

[0251] [Table 3]

[0252] The data in Table 3 show that Form B-III of the hemitartrate salt of Compound 78 has high solubility in pH 1.2 solvents, high solubility in purified water, and significantly higher solubility than Form CI and the free form. Form CI of the mono-p-tosylate salt of Compound 78 had low but stable solubility in all tested solvents. The free form of Compound 78 had very different solubilities in different media. More specifically, the free form of Compound 78 had a solubility of up to 12.6 mg / mL in a pH 4.5 buffer solution, but low solubility in other solvents and purified water.

[0253] These results indicated that the salts of the present invention and the crystalline forms of the present invention have better solubility profiles. In one aspect, compared with the free form of Compound 78, the salts of the present invention have a smaller difference in solubility at different pH values, making the solubility of the salts of the present invention more stable in body fluids with different pH values. In another aspect, the salts of the present invention and the crystalline forms of the present invention still have high and stable solubility even under high pH conditions in the gastrointestinal tract, which is beneficial for sufficient absorption, thus resulting in higher bioavailability and avoiding the effect of food on drug absorption in vivo.

[0254] Example 20 - Hygroscopicity of salts of formula A Quantitative analysis: Test samples of Forms B-III and B-II of the hemitartrate salt of Compound 78 were placed in the sample pans of a dynamic vapor sorption apparatus (DVS-INTRINSIC). The weight gain of the samples due to moisture absorption was then measured at 25°C and 0 to 95% relative humidity. The results are shown in Figures 10 and 11.

[0255] The curves in Figure 10 showed that Form B-III of the hemitartrate salt of compound 78 was non-hygroscopic when the ambient humidity was below 85% RH and slightly hygroscopic when the ambient humidity was above 85% RH.

[0256] The curves in Figure 11 show that the hemitartrate salt form B-II of compound 78 is continuously hygroscopic from 0 to 80% RH, and its hygroscopicity further increases when the ambient humidity is higher than 85% RH. After the sample absorbs moisture, the absorbed moisture generates hysteresis during the desorption process.

[0257] Example 21 - Pharmacokinetic study of the salt of formula A in dogs Preparation of formulations IV formulation: 71.48 mg of compound 78 hemitartrate salt form B-III was dissolved in a mixture (60.7 ml) of 10% macrogol-15 hydroxyl stearate (Solutol), 10% ethanol, and 80% saline to obtain a clear solution for IV administration. PO formulation (0.5 mg / ml based on free form concentration): 71.54 mg of Compound 78 hemitartrate salt Form B-III was suspended in 121.5 ml of deionized water to provide a suspension for PO administration to dogs in the 1 mg / kg dose group.

[0258] Medication and Sampling The experimental design is shown in Table 4 below:

[0259] [Table 4]

[0260] Sampling times are shown in Table 5 below:

[0261] [Table 5]

[0262] Biological sample analysis methods An LC-MS / MS method was used to determine the concentration of free form compound 78 in dog plasma.

[0263] Data analysis The data were analyzed using the non-compartmental statistical moment method and the pharmacokinetic software Phoenix (version 6.2.1.51), and the PK parameters for each group were calculated. max and T max The absolute bioavailability (F%) was calculated by the following formula:

[0264]

number

[0265] In the formula, AUC 0-∞,PO The exposure (AUC) of free form Compound 78 after oral administration in dogs 0-∞ ) and AUC 0-∞,IV The exposure (AUC) of free form Compound 78 after IV administration in dogs0-∞ ) and Dosage IV is the IV dose; PO is the oral dose.

[0266] Results and Discussion The mean values ​​of the main pharmacokinetic parameters of Form B-III of the hemitartrate salt of Compound 78 in dogs are shown in Tables 6 and 7.

[0267] After intravenous administration of Compound 78 hemitartrate Form B-III (containing 1.0 mg / kg of free Compound 78), the overall mean exposure (AUC 0-∞ ) was 1880 ± 349 h·ng / ml; the overall mean clearance (CL) was 9.09 ± 1.51 ml / min / kg; the overall mean blood elimination half-life (t 1 / 2 ) was 5.90 ± 0.645 h; the overall mean steady-state volume of distribution (V ss ) was 2.95±0.399L / kg.

[0268] After oral administration of Compound 78 hemitartrate Form B-III (containing 1.0 mg / kg of free Compound 78 in the fasted state), the mean time to peak plasma concentration (T max ) was 0.792 ± 0.459 hours. max The overall mean exposure (AUC 0-∞ The overall mean blood elimination half-life (t 1 / 2 The overall mean absolute bioavailability (F%) was 35.4%.

[0269] [Table 6]

[0270] [Table 7]

[0271] conclusion Good oral absorption in vivo was demonstrated in beagle dogs after administration of Compound 78 hemitartrate Form B-III at a single dose of 1 mg / kg by gavage, with an absolute oral bioavailability of approximately 35.4%. Compound 78 hemitartrate Form B-III exhibited a T of approximately 1 hour in dogs. max and had a rapid absorption effect. After intravenous administration of Form B-III of the hemitartrate salt of Compound 78 at a single dose of 1 mg / kg, the clearance (CL) in dogs was 9.09 ± 1.51 ml / min / kg, indicating that the salt was a low-clearance drug. ss was 2.95±0.40 L / kg, indicating a wide distribution. In summary, Form B-III of the hemitartrate salt of compound 78 exhibited good pharmacokinetic characteristics in dogs.

[0272] It is to be understood that the examples and embodiments described herein are for illustrative purposes only, and that various possible improvements or modifications in the embodiments of the invention will be suggested to those skilled in the art by the disclosure, and are within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference for all purposes.

Claims

1. A salt represented by formula A: 【Chemical Formula 1】 wherein n is 0.5 or 1, and M is a pharmaceutically acceptable acid.

2. 2. The salt of formula A according to claim 1, wherein M is hydrochloric acid, tartaric acid, or p-toluenesulfonic acid.

3. 3. The salt of formula A according to claim 2, wherein n is 1 and M is hydrochloric acid; n is 0.5 and M is tartaric acid; or n is 1 and M is paratoluenesulfonic acid.

4. n is 1 and M is hydrochloric acid, and the salt is Form A-III having X-ray powder diffraction characteristic diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 12.3±0.2°, 13.3±0.2°, 23.1±0.2°, and 24.1±0.2°; Preferably, said Form A-III has X-ray powder diffraction characteristic diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 16.2±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, and 26.4±0.2°; More preferably, said Form A-III has X-ray powder diffraction characteristic diffraction angles (2θ) of 5.8±0.2°, 6.2±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 15.8±0.2°, 16.2±0.2°, 18.3±0.2°, 18.5±0.2°, 20.2±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, 26.4±0.2°, 27.1±0.2°, and 27.8±0.2°; More preferably, said Form A-III has a lateral flexion angle of 5.8±0.2°, 6.2±0.2°, 7.9±0.2°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2°, 15.0±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, 17.4±0.2°, 18.3±0. having X-ray powder diffraction characteristic diffraction angles (2θ) of 2°, 18.5±0.2°, 19.6±0.2°, 20.2±0.2°, 21.0±0.2°, 22.2±0.2°, 23.1±0.2°, 24.1±0.2°, 24.8±0.2°, 26.4±0.2°, 27.1±0.2°, and 27.8±0.2°; Most preferably, the salt of formula A of claim 3, wherein said Form A-III has the X-ray powder diffraction pattern shown in Figure 1.

5. 5. The salt of Formula A of claim 4, wherein Form A-III has a differential scanning calorimetry (DSC) curve with an endothermic peak at about 290.2 to 295.4°C.

6. n is 0.5, and M is tartaric acid, and the salt is Form B-II having X-ray powder diffraction characteristic diffraction angles (2θ) of 7.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.1±0.2°, 18.0±0.2°, and 20.6±0.2°; Preferably, said Form B-II has X-ray powder diffraction characteristic diffraction angles (2θ) of 3.8±0.2°, 7.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.7±0.2°, and 23.0±0.2°; More preferably, said Form B-II has X-ray powder diffraction characteristic diffraction angles (2θ) of 3.8±0.2°, 7.5±0.2°, 10.1±0.2°, 11.3±0.2°, 13.4±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.7±0.2°, 23.0±0.2°, 25.1±0.2°, and 27.8±0.2°; More preferably, said Form B-II has X-ray powder diffraction characteristic diffraction angles (2θ) of 3.8±0.2°, 7.5±0.2°, 10.1±0.2°, 11.3±0.2°, 11.8±0.2°, 13.1±0.2°, 13.4±0.2°, 13.9±0.2°, 15.1±0.2°, 15.7±0.2°, 18.0±0.2°, 19.8±0.2°, 20.6±0.2°, 21.1±0.2°, 21.7±0.2°, 23.0±0.2°, 25.1±0.2°, and 27.8±0.2°; Most preferably, the salt of formula A according to claim 3, wherein said Form B-II has the X-ray powder diffraction pattern shown in Figure 4.

7. 7. The salt of Formula A of claim 6, wherein Form B-II has a differential scanning calorimetry (DSC) curve with endothermic peaks at about 54.8-92.2°C, 166.9-174.4°C, and 263.3-265.3°C, and an exothermic peak at about 194.2-202.7°C.

8. 8. The salt of Formula A of claim 6 or 7, wherein Form B-II has a thermogravimetric analysis (TGA) curve as shown in Figure 6, exhibiting a weight loss of about 4.3% in the range of 30°C to 100°C.

9. n is 0.5, and M is tartaric acid, and the salt is Form B-III having X-ray powder diffraction characteristic diffraction angles (2θ) of 13.1±0.2°, 14.6±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, and 26.3±0.2°; Preferably, said Form B-III has X-ray powder diffraction characteristic diffraction angles (2θ) of 12.4±0.2°, 13.1±0.2°, 13.7±0.2°, 14.6±0.2°, 16.5±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, and 26.3±0.2°; More preferably, said Form B-III has X-ray powder diffraction characteristic diffraction angles (2θ) of 7.6±0.2°, 8.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.4±0.2°, 13.1±0.2°, 13.4±0.2°, 13.7±0.2°, 14.6±0.2°, 15.9±0.2°, 16.5±0.2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, and 26.3±0.2°; More preferably, said Form B-III has a lateral flexion angle of 7.6±0.2°, 8.9±0.2°, 10.0±0.2°, 11.0±0.2°, 12.4±0.2°, 13.1±0.2°, 13.4±0.2°, 13.7±0.2°, 14.6±0.2°, 15.9±0.2°, 16.5±0.2°, 17.2±0. having X-ray powder diffraction characteristic diffraction angles (2θ) of 2°, 18.3±0.2°, 18.9±0.2°, 19.4±0.2°, 19.6±0.2°, 21.4±0.2°, 22.6±0.2°, 23.7±0.2°, 24.6±0.2°, 26.3±0.2°, 27.6±0.2°, and 29.2±0.2°; Most preferably, the salt of formula A according to claim 3, wherein said Form B-III has the X-ray powder diffraction pattern shown in Figure 7.

10. 10. The salt of Formula A of claim 9, wherein Form B-III has a differential scanning calorimetry (DSC) curve with an endothermic peak at about 269.2-271.3°C.

11. 11. The salt of Formula A of claim 9 or 10, wherein Form B-III has the thermogravimetric analysis (TGA) curve shown in Figure 9.

12. n is 1 and M is p-toluenesulfonic acid, and the salt is Form CI having X-ray powder diffraction characteristic diffraction angles (2θ) of 7.8±0.2°, 11.1±0.2°, 11.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, and 24.0±0.2°; Preferably, Form CI has X-ray powder diffraction characteristic diffraction angles (2θ) of 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 13.8±0.2°, 14.3±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, 22.2±0.2°, 24.0±0.2°, and 26.1±0.2°; More preferably, Form CI has X-ray powder diffraction characteristic diffraction angles (2θ) of 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 13.5±0.2°, 13.8±0.2°, 14.3±0.2°, 14.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.2±0.2°, 19.2±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 24.0±0.2°, 26.1±0.2°, and 27.4±0.2°; More preferably, the form CI is 5.5±0.2°, 7.8±0.2°, 9.7±0.2°, 11.1±0.2°, 11.7±0.2°, 12.2±0.2°, 12.9±0.2°, 13.5±0.2°, 13.8±0.2°, 14.3±0.2°, 14.7±0.2°, 16.6±0.2°, 17.9±0.2°, 18.9±0.2°, 19.9±0.2°, 20.9±0.2°, 21.9±0.2°, 22.9±0.2°, 23.9±0.2°, 24.3±0.2°, 24.7±0.2°, 25.9±0.2°, 26.9±0.2°, 27.9±0.2°, 28.9±0.2°, 29.9±0.2°, 30.9±0.2°, 31.9±0.2°, 32.9±0.2°, 33.9±0.2°, 34.9±0.2°, 35.9±0.2°, 36.9±0.2°, 37.9±0.2°, 38.9±0.2°, 39.9±0.2°, 40.9±0.2°, 41.9±0.2°, 42.9±0.2°, 43.9±0.2°, 44.9±0.2°, 45.9±0.2°, 46.9±0.2°, 47.9±0.2°, 48.9±0.2°, 49.9±0.2°, having X-ray powder diffraction characteristic diffraction angles (2θ) of 18.2±0.2°, 19.2±0.2°, 20.0±0.2°, 20.6±0.2°, 22.2±0.2°, 23.5±0.2°, 24.0±0.2°, 25.0±0.2°, 26.1±0.2°, 27.4±0.2°, and 32.8±0.2°; Most preferably, the salt of Formula A according to claim 3, wherein Form CI has the X-ray powder diffraction pattern shown in Figure 12.

13. 13. The salt of Formula A of claim 12, wherein Form CI has a differential scanning calorimetry (DSC) curve with an endothermic peak at about 289.77 to 291.04°C.

14. 14. The salt of Formula A of claim 12 or 13, wherein Form CI has a thermogravimetric analysis (TGA) curve as shown in Figure 14.

15. A pharmaceutical composition comprising an effective amount of a salt of formula A according to any one of claims 1 to 14, and optionally a pharmaceutically acceptable carrier.

16. A method for preventing or treating a disease responsive to inhibition of FGFR activity, the method comprising administering to a subject in need of prevention or treatment an effective amount of a salt of formula A according to any one of claims 1 to 14.

17. Use of a salt of formula A according to any one of claims 1 to 14 in the manufacture of a medicament for preventing or treating a disease responsive to inhibition of FGFR activity, such as cancer.

18. 18. The use of claim 17, wherein the cancer is selected from lung cancer (e.g., squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, biliary tract cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma, and hematological malignancies (e.g., myeloproliferative disorders).

19. A salt of formula A according to any one of claims 1 to 14 for use in therapy.

20. A salt of formula A according to any one of claims 1 to 14 for use in the treatment of a disease responsive to inhibition of FGFR activity, such as cancer.

21. 21. The salt of formula A of claim 20, wherein the cancer is selected from lung cancer (e.g., squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, biliary tract cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma, and hematological malignancies (e.g., myeloproliferative disorders).

22. A method for preparing a salt of formula A according to any one of claims 4 to 5, comprising the steps of: (1) a step of reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with hydrochloric acid in a dissolving solvent or in a mixed solvent of a water-miscible organic solvent and water under heating and stirring to form a salt; (2) a step of cooling the reaction product obtained in step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form A-III; (4) optionally drying the solid obtained in step (3): The method comprising:

23. 23. The method of claim 22, wherein the hydrochloric acid is concentrated hydrochloric acid having a concentration of 36 to 38% by weight.

24. 24. The method of claim 22 or 23, wherein the molar ratio of the hydrochloric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater, such as about 1:1 or 1.2:

1.

25. The method according to any one of claims 22 to 24, wherein the volume ratio of the dissolving solvent or the mixed solvent to the weight of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g or more, for example, about 20 ml / g or about 60 ml / g.

26. The dissolving solvent is C 1-6 26. The method according to any one of claims 22 to 25, wherein the dissolving solvent is selected from the group consisting of methanol, ethanol, i-propanol, t-butanol, and mixtures thereof; preferably, the dissolving solvent is selected from the group consisting of methanol, ethanol, i-propanol, t-butanol, and mixtures thereof; more preferably, the dissolving solvent is ethanol.

27. The water-miscible organic solvent is C 1-6 27. The method of any one of claims 22 to 26, wherein the water-miscible organic solvent is selected from methanol, ethanol, i-propanol, t-butanol, and mixtures thereof; preferably, the water-miscible organic solvent is selected from ethanol, i-propanol, and mixtures thereof.

28. 28. The method according to claim 22, wherein the volume percentage of the water-miscible organic solvent in the mixed solvent is about 95% or less; preferably, the volume percentage of the water-miscible organic solvent in the mixed solvent is 95%, 90%, or 80%.

29. 29. The method according to any one of claims 22 to 28, wherein in the optional step (4), the drying temperature is 50 to 80°C.

30. A method for preparing a salt of formula A according to any one of claims 6 to 8, comprising the steps of: (1) mixing the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with L-tartaric acid in ethanol under heating and stirring to form a salt; (2) a step of cooling the reaction product obtained in step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form B-II; (4) optionally drying the solid obtained in step (3): The method comprising:

31. 31. The method of claim 30, wherein the molar ratio of the L-tartaric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:2 or more, preferably about 4:5, or about 3.4:

1.

32. 32. The method of claim 30, wherein the volume ratio of ethanol to the weight of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g or more, for example, about 72 ml / g or about 75 ml / g.

33. The method according to any one of claims 30 to 32, wherein in the optional step (4), the drying temperature is 50 to 85°C.

34. A method for preparing a salt of formula A according to any one of claims 9 to 11, comprising the steps of: (1) mixing and reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with L-tartaric acid in a dissolving solvent, in water, or in a mixed solvent consisting of a water-miscible organic solvent and water, under heating and stirring, to form a salt, thereby obtaining a first solution, provided that the dissolving solvent is not a single solvent of ethanol; (2) optionally adding a dissolution-preventing solvent to the first solution to obtain a second solution; (3) cooling the first solution or the second solution to sufficiently precipitate a solid; (4) isolating the precipitated solid as Form B-III; (5) optionally drying the solid obtained in step (4): The method comprising:

35. 35. The method of claim 34, wherein the molar ratio of the L-tartaric acid to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater, preferably the molar ratio is about 1:1 or about 1.5:

1.

36. 36. The method of claim 34, wherein the volume ratio of the dissolving solvent, the water, or the mixed solvent consisting of a water-miscible organic solvent and water to the weight of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 10 ml / g or more, for example, about 20 ml / g, about 30 ml / g, about 33 ml / g, about 50 ml / g, about 65 ml / g, about 98 ml / g, or about 286 ml / g.

37. The dissolving solvent is C 1-6 The method according to any one of claims 34 to 36, wherein the dissolving solvent is selected from alkanols, acetone, toluene, organic acid esters having 8 or less carbon atoms, and mixtures thereof; preferably, the dissolving solvent is selected from methanol, ethanol, i-propanol, t-butanol, n-butanol, acetone, toluene, n-propyl acetate, ethyl acetate, and mixtures thereof; more preferably, the dissolving solvent is selected from methanol, ethanol, i-propanol, acetone, toluene, n-propyl acetate, ethyl acetate, and mixtures thereof.

38. 38. The method of claim 37, wherein the dissolution solvent is selected from a mixture of two of methanol, ethanol, toluene, n-propyl acetate, and ethyl acetate, for example, n-propyl acetate / methanol (volume ratio of about 3:2), toluene / ethanol (volume ratio of about 1:1), or ethyl acetate / ethanol (volume ratio of about 11:15).

39. The water-miscible organic solvent is C 1-6 39. The method of any one of claims 34 to 38, wherein the water-miscible organic solvent is selected from an alkanol, acetone, and mixtures thereof; preferably, the water-miscible organic solvent is selected from methanol, ethanol, i-propanol, t-butanol, acetone, and mixtures thereof; more preferably, the water-miscible organic solvent is selected from ethanol, i-propanol, acetone, and mixtures thereof.

40. 40. The method according to any one of claims 34 to 39, wherein the volume fraction of the water-miscible organic solvent in the mixed solvent is about 95% or less, for example, 95%, 90%, or 80%.

41. 41. The method of any one of claims 34 to 40, wherein the dissolution preventing solvent is selected from toluene, an organic acid ester having 8 or less carbon atoms, and a mixture thereof; preferably, the dissolution preventing solvent is selected from toluene, ethyl acetate, n-propyl acetate, and a mixture thereof; more preferably, the dissolution preventing solvent is selected from toluene, ethyl acetate, and a mixture thereof.

42. The method according to any one of claims 34 to 41, wherein in step (3), the cooling is performed naturally or at a controlled temperature.

43. The method according to any one of claims 34 to 42, wherein in step (5), the drying temperature is 50 to 85°C.

44. A method for preparing a salt of formula A according to any one of claims 12 to 14, comprising the steps of: (1) a step of mixing and reacting the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide with p-toluenesulfonic acid monohydrate in a mixed solvent of a water-miscible organic solvent and water under heating and stirring to form a salt; (2) a step of cooling the reaction product obtained in step (1) to sufficiently precipitate a solid; (3) isolating the precipitated solid as Form CI; (4) optionally drying the solid obtained in step (3): The method comprising:

45. 45. The method of claim 44, wherein the molar ratio of the p-toluenesulfonic acid monohydrate to the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide is about 1:1 or greater, such as about 1.5:

1.

46. 46. ​​The method according to claim 44 or 45, wherein the volume ratio of the mixed solvent consisting of a water-miscible organic solvent and water to the weight of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide in step (1) is about 10 ml / g or more, for example, about 36 ml / g or about 43 ml / g.

47. The water-miscible organic solvent is C 1-6 47. The method according to any one of claims 44 to 46, wherein the water-miscible organic solvent is selected from an alkanol, acetone, and mixtures thereof; preferably, the water-miscible organic solvent is selected from i-propanol, acetone, and mixtures thereof.

48. 48. The method of any one of claims 44 to 47, wherein the volume fraction of the water-miscible organic solvent in the mixed solvent is about 95% or less, for example 80%.

49. 49. The method of any one of claims 44 to 48, wherein a dissolution-preventing solvent (e.g., i-propanol) is added after the reaction in step (1) is completed and before step (2).

50. The method according to any one of claims 44 to 49, wherein in step (2), the cooling is carried out naturally or at a controlled temperature.

51. 51. The method of any one of claims 44 to 50, wherein in the optional step (4), the drying temperature is 50 to 60°C.

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