Salt of compound and crystal form thereof

Abstract

The invention relates to a salt of a compound and a crystal form thereof. More specifically, the invention belongs to the field of pharmacy, and provides pharmaceutically acceptable salts and crystal forms of a compound 4-chloro-3-(2-((4-((3S, 5R)-3, 5-dimethylpiperazine-1-yl) phenyl) amino) pyrimidine-5-yl) ethyl)-5-methoxy-N-methylbenzamide, and pharmaceutical compositions, preparation methods and applications of the pharmaceutically acceptable salts and the crystal forms.

Description

[0001] This application is a divisional application. The parent application is a Chinese patent application with an application date of October 13, 2020, an invention name of “Salts of compounds and their crystalline forms”, and an application number of 202080071856.1.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to Chinese Patent Application No. 201910973785.3 filed on October 14, 2019, which is incorporated herein in its entirety for all purposes. Technical Field

[0004] The present invention belongs to the field of pharmacy, 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 crystal forms thereof, as well as pharmaceutical compositions, preparation methods and applications thereof. Background Art

[0005] Fibroblast growth factor (FGF) has been recognized as an important regulator 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 factor (FGF) and its receptor (FGFR) play an important role in cell proliferation, cell differentiation, cell migration, cell survival, protein synthesis and angiogenesis. There are many evidences that FGF signaling is directly related to cancer. The dysregulation of FGFR signaling is involved in many cancers, including squamous non-small cell lung cancer (squamous NSCLC), small cell lung cancer (SCLC), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer and bladder cancer. For example, FGFR1 has been found to be amplified in 22% of squamous NSCLC, FGFR2 amplification has been reported in up to 10% of gastric cancer, and FGFR3 mutations have been found in about 50-60% of non-muscle invasive and 17% of highly malignant bladder cancers. Therefore, inhibition of FGFR activity can be used to treat proliferative diseases, such as cancer.

[0006] 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 its preparation method. The structure of the compound is as follows:

[0007]

[0008] Studies have shown that 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 can effectively inhibit FGFR activity and can therefore be used to prevent and treat diseases that respond to inhibition of FGFR activity, such as cancer.

[0009] Many compounds can exist in multiple crystalline forms or in amorphous forms. However, for a given compound, it is difficult to predict: (1) whether the compound has polymorphism; (2) how to obtain unknown crystalline forms; and (3) what the properties of these crystalline forms are, such as stability, solubility, flowability, pharmacokinetic parameters, and in vivo bioavailability, which may vary depending on the crystalline form. See J. Bernstein "Polymorphism in Molecular Crystals", Oxford University Press, (2002).

[0010] Salt formation does not change the biological activity of the compound itself, but it can change the physicochemical properties of the compound. For a given compound, it is difficult to predict which salts of the compound have better physicochemical properties than the free compound. Given the unpredictability of crystal formation and crystal properties, it is even more difficult to predict which salts can form crystalline forms with favorable properties.

[0011] Since the properties of solids depend on the compound itself and the microstructure of the solid, different solid forms of a compound often exhibit different physicochemical properties and different biopharmaceutical properties. The differences in physicochemical properties and biopharmaceutical properties can be determined by a variety of technical means and can ultimately be used to distinguish these different solid forms. For example, physical properties such as solubility, stability, etc. and biopharmaceutical properties such as C max 、T max , bioavailability, etc. are important when describing the solid form of a compound.

[0012] Therefore, in the development 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, it is necessary to study the salt and crystalline form of the compound. SUMMARY OF THE INVENTION

[0014] After extensive exploration and research, the inventors discovered that compound 4-chloro-3-(2-(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 this application) can be prepared into a variety of pharmaceutically acceptable salts, and its chemical structure is shown in Formula A, for example. Compared with the free form of Compound 78, the solubility of the salt of Formula A (e.g., the hemi-tartrate salt) is significantly increased, which is beneficial to improving the pharmacokinetic properties of Compound 78 and increasing the bioavailability of the compound in vivo. The inventors also discovered that the salt of Formula A can exist in different crystalline forms and can form solvates with certain solvents. The inventors have conducted extensive research on the polymorphic forms of the salt of Formula A, and determined and prepared crystalline forms that meet pharmaceutical requirements. Based on these studies, the present invention provides a pharmaceutically acceptable salt of compound 78 as shown in Formula A and its various crystalline forms, such as Form A-III, Form B-II, Form B-III and Form CI.

[0015] In one aspect, the present invention provides a pharmaceutically acceptable salt of 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide, which is shown in Formula A:

[0016]

[0017] wherein n is 0.5 or 1; and M is a pharmaceutically acceptable acid.

[0018] In one embodiment, the present invention provides a salt of formula A, wherein M is hydrochloric acid, tartaric acid or p-toluenesulfonic acid.

[0019] In another embodiment, the present invention provides a salt of formula A, wherein 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 hemi-tartrate of compound 78), or n is 1 and M is p-toluenesulfonic acid (also known as the p-toluenesulfonate of compound 78).

[0020] In another embodiment, the present invention provides a salt of formula A, wherein n is 1 and M is hydrochloric acid, and is Form A-III (also known as Form A-III of the monohydrochloride salt of Compound 78, abbreviated as Form A-III).

[0021] In another embodiment, the present invention provides a salt of formula A, wherein n is 0.5 and M is tartaric acid, and is Form B-II (also known as Form B-II of the hemi-tartrate salt of Compound 78, abbreviated as Form B-II).

[0022] In yet another embodiment, the present invention provides a salt of formula A, wherein n is 0.5 and M is tartaric acid, and is Form B-III (also known as Form B-III of the hemi-tartrate salt of Compound 78, abbreviated as Form B-III).

[0023] In yet another embodiment, the present invention provides a salt of formula A, wherein n is 1 and M is p-toluenesulfonic acid, and is Form CI (also known as Form CI of p-toluenesulfonic acid salt of Compound 78, abbreviated as Form CI).

[0024] On the other hand, the present invention provides methods for preparing salts of formula A and crystalline forms thereof (e.g., crystalline form A-III, crystalline form B-II, crystalline form B-III or crystalline form CI), which are repeatable and easy to operate.

[0025] On the other hand, the present invention provides a pharmaceutical composition comprising an effective amount of a salt of formula A and a crystalline form thereof (e.g., crystalline form A-III, crystalline form B-II, crystalline form B-III or crystalline form CI), and optionally comprising a pharmaceutically acceptable carrier.

[0026] On the other hand, the present invention also provides a method for preventing or treating a disease responsive to inhibition of FGFR activity, such as cancer, comprising administering to an individual in need thereof an effective amount of a salt of formula A and a crystalline form thereof, such as crystalline form A-III, crystalline form B-II, crystalline form B-III or crystalline form CI.

[0027] On the other hand, the present invention also provides the use of a salt of formula A and a crystalline form thereof (such as crystalline form A-III, crystalline form B-II, crystalline form B-III or crystalline form CI) in the preparation of a drug for treating a disease responsive to inhibition of FGFR activity, such as cancer.

[0028] In another aspect, the present invention provides a salt of formula A and a crystalline form thereof (eg, Form A-III, Form B-II, Form B-III or Form CI) for use in therapy.

[0029] In one embodiment, the present invention provides a salt of formula A and a crystalline form thereof (e.g., Form A-III, Form B-II, Form B-III or Form CI) for use in treating a disease responsive to inhibition of FGFR activity, such as cancer.

[0030] The cancers include, but are not limited to, lung cancer (such as 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, bile duct cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma and hematological tumors (such as myeloproliferative neoplasms). BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The X-ray powder diffraction pattern of the crystalline form A-III of the monohydrochloride salt of compound 78 is given, wherein the horizontal axis (X-axis) is the diffraction angle 2θ and the vertical axis (Y-axis) is the diffraction intensity.

[0032] Figure 2 The differential scanning calorimetry diagram of the crystalline form A-III of the monohydrochloride salt of compound 78 is shown, wherein the horizontal axis (X-axis) is temperature (°C) and the vertical axis (Y-axis) is heat flow (mW).

[0033] Figure 3 A thermogravimetric analysis chart of the crystalline form A-III of the monohydrochloride salt of compound 78 is given, wherein the horizontal axis (X-axis) is temperature (°C) and the vertical axis (Y-axis) is weight percentage (%).

[0034] Figure 4 The X-ray powder diffraction pattern of the crystalline form B-II of the hemi-tartrate salt of compound 78 is given, where the horizontal axis (X-axis) is the diffraction angle 2θ and the vertical axis (Y-axis) is the diffraction intensity.

[0035] Figure 5 A differential scanning calorimetry graph of Form B-II of the hemi-tartrate salt of Compound 78 is shown, with the horizontal axis (X-axis) being temperature (° C.) and the vertical axis (Y-axis) being heat flow (mW).

[0036] Figure 6 A thermogravimetric analysis diagram of the crystalline form B-II of the hemi-tartrate salt of compound 78 is given, wherein the horizontal axis (X-axis) is temperature (°C) and the vertical axis (Y-axis) is weight percentage (%).

[0037] Figure 7 The X-ray powder diffraction pattern of the crystalline form B-III of the hemi-tartrate salt of compound 78 is given, where the horizontal axis (X-axis) is the diffraction angle 2θ and the vertical axis (Y-axis) is the diffraction intensity.

[0038] Figure 8 A differential scanning calorimetry graph of Form B-III of the hemitartrate salt of Compound 78 is shown, with the horizontal axis (X-axis) being temperature (° C.) and the vertical axis (Y-axis) being heat flow (mW).

[0039] Fig. 9 A thermogravimetric analysis graph of the crystalline form B-III of the hemi-tartrate salt of compound 78 is given, wherein the horizontal axis (X-axis) is temperature (°C) and the vertical axis (Y-axis) is weight percentage (%).

[0040] Fig.10 The dynamic gas adsorption isotherm of the crystalline form B-III of the hemi-tartrate salt of compound 78 is given, wherein the horizontal axis (X-axis) is the relative humidity (%) and the vertical axis (Y-axis) is the weight change percentage (%).

[0041] Fig.11 The dynamic gas adsorption isotherm of the crystalline form B-II of the hemi-tartrate salt of compound 78 is given, wherein the horizontal axis (X-axis) is the relative humidity (%) and the vertical axis (Y-axis) is the weight change percentage (%).

[0042] Fig.12 The X-ray powder diffraction pattern of the crystalline form CI of the p-toluenesulfonate salt of Compound 78 is given, where the horizontal axis (X-axis) is the diffraction angle 2θ and the vertical axis (Y-axis) is the diffraction intensity.

[0043] Fig.13 A differential scanning calorimetry graph of Form CI of p-toluenesulfonate salt of Compound 78 is shown, wherein the horizontal axis (X-axis) is temperature (° C.) and the vertical axis (Y-axis) is heat flow (mW).

[0044] Fig.14 A thermogravimetric analysis chart of the crystalline form CI of the p-toluenesulfonate salt of compound 78 is shown, wherein the horizontal axis (X-axis) is temperature (° C.) and the vertical axis (Y-axis) is weight percentage (%).

[0045] Fig.15 The X-ray powder diffraction pattern of the hydrochloride form A-III of compound 78 after being placed under high humidity conditions (25°C, relative humidity of 92.5%±5%) for 5 days is given. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0046] Fig.16 The X-ray powder diffraction pattern of the hydrochloride form A-III of compound 78 after being placed under high humidity conditions (25°C, relative humidity of 92.5%±5%) for 10 days is given. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0047] Fig.17 The X-ray powder diffraction pattern of the hemi-tartrate form B-II of compound 78 after being placed under high humidity conditions (25°C, relative humidity of 92.5%±5%) for 3 days is given, where the horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0048] Fig.18 The X-ray powder diffraction pattern of the crystalline form B-II of the hemi-tartrate salt of compound 78 after slurrying in water for 2 days is given, where the horizontal axis (X-axis) is the diffraction angle 2θ and the vertical axis (Y-axis) is the diffraction intensity.

[0049] Fig.19The X-ray powder diffraction pattern of the crystalline form B-II of the hemi-tartrate salt of compound 78 after slurrying in water for 4 days is given, where the horizontal axis (X-axis) is the diffraction angle 2θ and the vertical axis (Y-axis) is the diffraction intensity.

[0050] Fig. 20 The X-ray powder diffraction pattern of the crystalline form B-III of the hemi-tartrate salt of compound 78 after slurrying in water for 2 days is given, where the horizontal axis (X-axis) is the diffraction angle 2θ and the vertical axis (Y-axis) is the diffraction intensity.

[0051] Fig.21 The X-ray powder diffraction pattern of the crystalline form B-III of the hemi-tartrate salt of compound 78 after slurrying in water for 4 days is given, where the horizontal axis (X-axis) is the diffraction angle 2θ and the vertical axis (Y-axis) is the diffraction intensity.

[0052] Fig. 22 A microscopic photograph of the free form of Compound 78 prepared according to Example 9 of WO 2014 / 139465 A1 is given, showing that it is needle-shaped crystals.

[0053] Fig.23 A microscopic photograph of the crystalline form B-III of the hemi-tartrate salt of compound 78 is given, showing that it is a plate-like crystal. DETAILED DESCRIPTION OF THE INVENTION

[0055] definition

[0056] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below. It should be noted that the singular forms used in this specification and the appended claims also include the plural forms, unless the context clearly indicates otherwise.

[0057] As used herein, the terms "salt of the present invention", "pharmaceutically acceptable salt of 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide", "salt of 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide", "salt of Compound 78", "pharmaceutically acceptable salt of Compound 78" and "salt of Formula A" can be used interchangeably and all refer to the salt of Formula A described herein, that is, the acid addition salt formed by Compound 78 and the "pharmaceutically acceptable acid" described herein.

[0058] The term "crystalline form of the present invention" used herein refers to the crystalline form A-III of the monohydrochloride salt of compound 78, the crystalline form B-II of the hemi-tartrate salt of compound 78, the crystalline form B-III of the hemi-tartrate salt of compound 78 or the crystalline form CI of the p-toluenesulfonate salt of compound 78, or a mixture thereof in any proportion.

[0059] As used herein, the terms "crystalline form," "crystal form," "crystalline form," and "polymorph" are used interchangeably.

[0060] The term "pharmaceutically acceptable acid" as used herein refers to an acid that can form an acid addition salt with Compound 78 and does not have undesirable properties for animal or human use, including but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, phosphorous acid, sulfuric acid, sulfurous acid, nitric acid, etc.; 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, ethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, β-hydroxybutyric acid, benzoic acid, salicylic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, stearic acid, HOOC-(CH2) n -COOH (wherein n is 0-4) and the like.

[0061] As used herein, "an organic acid ester having no more than eight carbon atoms" refers to R1COOR2, wherein R1 and R2 are independently saturated or unsaturated, linear or branched hydrocarbon groups, and the total number of carbon atoms in R1 and R2 is less than or equal to 7. Preferably, wherein R1 and R2 are independently saturated, linear or branched 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 no more than eight carbon atoms include, but are not limited to, methyl acetate, ethyl acetate, and n-propyl acetate.

[0062] As used herein, the term "about" when used in conjunction with a numerical value means adjusting the given numerical value to 10% above or below the numerical value. For example, about 50% means a range of 45% to 55%.

[0063] The term "substantially pure" as used herein means that the purity of the crystalline form is at least 50%, at least 60%, at least 70%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, for example, the purity of the crystalline form is 95%, 96%, 97%, 98%, 99% or 100% by weight.

[0064] The term "substantially free of other crystalline forms" as used herein means that the content of the other crystalline forms is less than 50% by weight of the total weight of the crystalline forms, preferably less than 40%, preferably less than 30%, preferably less than 20%, preferably less than 10%, preferably less than 5%, preferably less than 1%.

[0065] As used herein, the term "solution" refers to a homogeneous mixture of one or more solutes in one or more solvents.

[0066] The term "dissolving solvent" as used herein refers to an organic solvent in which a substance can be partially or completely dissolved under appropriate conditions. The term "anti-dissolving solvent" as used herein refers to any appropriate organic solvent in which the solubility of the substance is less than that in the dissolving solvent.

[0067] The term "water-miscible organic solvent" as used herein refers to an organic solvent that is miscible with water in any proportion. Examples thereof include, but are not limited to, C 1-6 Alkyl alcohol, acetone, tetrahydrofuran, acetonitrile, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.

[0068] The term "C 1-6 "Alkyl alcohol" 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, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, n-hexanol, etc.

[0069] The term "effective amount" as used herein refers to the amount of the salt of the present invention or the crystalline form of the present invention that can effectively inhibit FGFR activity in vitro or can effectively prevent or treat a disease that responds to the inhibition of FGFR activity after being administered to an individual. The effective amount of the salt of the present invention or the crystalline form of the present invention will vary with a variety of factors such as the specific salt type used, the disease to be treated and its severity, the age and relevant health conditions of the individual, the route and form of administration, the judgment of the attending physician or veterinary practitioner, etc.

[0070] The term "disease responsive to inhibition of FGFR activity" as used herein refers to a disease that can be prevented or treated by inhibiting FGFR activity, such as cancer, including but not limited to lung cancer (such as squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial carcinoma, esophageal cancer, bile duct cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma and blood tumors (such as myeloproliferative neoplasms), etc.

[0071] As used herein, "individual" means mammals and non-mammals. Mammals mean any member of the class mammals, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats and pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; etc. Examples of non-mammals include but are not limited to birds, etc. The term "individual" does not indicate a particular age or sex.

[0072] The term "treat" as used herein refers to the alleviation of an undesirable physiological change or disorder, such as the formation or spread of cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, relief of symptoms, reduction in the extent of the disease, maintenance of disease stability, and slowing of disease progression. "Treatment" also means that survival is prolonged compared to an individual who is not receiving treatment.

[0073] As used herein, the term "prevention" refers to preventing or delaying the onset of a disease in an individual at risk of developing the disease.

[0074] Implementation

[0075] Embodiment 1. Salt of formula A:

[0076]

[0077] Where n is 0.5 or 1; and

[0078] M is a pharmaceutically acceptable acid.

[0079] Embodiment 2. The salt of formula A according to embodiment 1, wherein M is hydrochloric acid, tartaric acid or p-toluenesulfonic acid.

[0080] Embodiment 3. The 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.

[0081] Embodiment 4. The salt of formula A according to embodiment 3, wherein n is 1 and M is hydrochloric acid, and is in 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°;

[0082] Preferably, the crystalline form A-III has characteristic X-ray powder 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°;

[0083] More preferably, the crystalline 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°:

[0084] Further preferably, the crystalline form A-III has characteristic 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°, 17.1±0.2°, 18.8±0.2°, 19. 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°:

[0085] Most preferably, the crystalline form A-III has Figure 1 The X-ray powder diffraction spectrum is shown.

[0086] Embodiment 5. The salt of formula A according to embodiment 4, wherein the differential scanning calorimetry curve of the crystalline form A-III has an endothermic peak at about 290.2-295.4°C.

[0087] Embodiment 6. The salt of formula A according to embodiment 3, wherein n is 0.5 and M is tartaric acid, and is in crystalline 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°;

[0088] Preferably, the crystalline form B-II has characteristic X-ray powder 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°;

[0089] More preferably, the crystalline form B-II has 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° by X-ray powder diffraction;

[0090] Further preferably, the crystalline 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°;

[0091] Most preferably, the crystalline form B-II has Figure 4 The X-ray powder diffraction spectrum is shown.

[0092] Embodiment 7. The salt of formula A according to Embodiment 6, wherein the differential scanning calorimetry curve of the crystalline 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.

[0093] Embodiment 8. The salt of formula A according to any one of embodiments 6 to 7, wherein the crystalline form B-II has Figure 6 Thermogravimetric analysis curve is shown, which shows about 4.3% weight loss in the range of 30-100°C.

[0094] Embodiment 9. The salt of formula A according to embodiment 3, wherein n is 0.5 and M is tartaric acid, and is in crystalline 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°;

[0095] Preferably, the crystalline form B-III has characteristic diffraction angles (2θ) of X-ray powder diffraction 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°;

[0096] More preferably, the crystalline 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°;

[0097] Further preferably, the crystalline form B-III has 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°, 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°;

[0098] Most preferably, the crystalline form B-III has Figure 7 The X-ray powder diffraction spectrum is shown.

[0099] Embodiment 10. The salt of formula A according to Embodiment 9, wherein the differential scanning calorimetry curve of the crystalline form B-III has an endothermic peak at about 269.2-271.3°C.

[0100] Embodiment 11. The salt of formula A according to any one of embodiments 9 to 10, wherein the crystalline form B-III has Fig. 9 Thermogravimetric analysis curve shown.

[0101] Embodiment 12. The salt of formula A according to embodiment 3, wherein n is 1 and M is p-toluenesulfonic acid, and is crystalline 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°;

[0102] Preferably, the crystalline form CI has 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° by X-ray powder diffraction;

[0103] More preferably, the crystalline form CI has 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° by X-ray powder diffraction;

[0104] Further preferably, the crystal form CI has characteristic X-ray powder 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°, 17.9±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°;

[0105] Most preferably, the crystalline form CI has Fig.12 The X-ray powder diffraction spectrum is shown.

[0106] Embodiment 13. The salt of formula A according to embodiment 12, wherein the differential scanning calorimetry curve of the crystalline form CI has an endothermic peak at about 289.77-291.04°C.

[0107] Embodiment 14. The salt of formula A according to any one of embodiments 12 to 13, wherein the crystalline form CI has Fig.14 Thermogravimetric analysis curve shown.

[0108] Embodiment 15. A pharmaceutical composition comprising an effective amount of a salt of formula A according to any one of Embodiments 1 to 14, and optionally comprising a pharmaceutically acceptable carrier.

[0109] Embodiment 16. A method for preventing or treating a disease responsive to inhibition of FGFR activity, comprising administering an effective amount of a salt of formula A according to any one of Embodiments 1 to 14 to a subject in need thereof.

[0110] Embodiment 17. Use of a salt of formula A according to any one of Embodiments 1 to 14 for the preparation of a medicament for preventing or treating a disease responsive to inhibition of FGFR activity, such as cancer.

[0111] Embodiment 18. The use according to embodiment 17, wherein the cancer is selected from lung cancer (such as squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial carcinoma, esophageal cancer, bile duct cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma and blood tumors (such as myeloproliferative neoplasms).

[0112] Embodiment 19. A salt of formula A according to any one of embodiments 1 to 14 for use in therapy.

[0113] Embodiment 20. A salt of formula A according to any one of embodiments 1 to 14 for use in treating a disease responsive to inhibition of FGFR activity, such as cancer.

[0114] Embodiment 21. The salt of formula A according to embodiment 20, wherein the cancer is selected from lung cancer (such as 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, bile duct cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma and blood tumors (such as myeloproliferative neoplasms).

[0115] Embodiment 22. A method for preparing a salt of formula A according to any one of embodiments 4 to 5, comprising:

[0116] (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 hydrochloric acid in a dissolving solvent or in a mixed solvent consisting of a water-miscible organic solvent and water under heating and stirring to react and form a salt;

[0117] (2) cooling the reaction product obtained in step (1) to allow solid to fully precipitate;

[0118] (3) The separated solid is Form A-III;

[0119] (4) Optionally, drying the solid obtained in step (3).

[0120] Embodiment 23. The method according to embodiment 22, wherein the hydrochloric acid is concentrated hydrochloric acid with a concentration of 36%-38% by weight.

[0121] Embodiment 24. A method according to any one of Embodiments 22 to 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 not less than about 1:1, for example, about 1:1 or 1.2:1.

[0122] Embodiment 25. A method according to any one of Embodiments 22 to 24, wherein the ratio of the volume 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 not less than about 10 ml / g, for example, about 20 ml / g or about 60 ml / g.

[0123] Embodiment 26. The method according to any one of embodiments 22 to 25, wherein the dissolving solvent is selected from C 1-6 Alkyl alcohol, preferably, the dissolving solvent is selected from methanol, ethanol, isopropanol, tert-butanol and a mixture thereof, more preferably, the dissolving solvent is ethanol.

[0124] Embodiment 27. The method according to any one of embodiments 22 to 26, wherein the water-miscible organic solvent is selected from C 1-6 Alkyl alcohol, preferably, the water-miscible organic solvent is selected from methanol, ethanol, isopropanol, tert-butanol and a mixture thereof, more preferably, the water-miscible organic solvent is selected from ethanol, isopropanol and a mixture thereof.

[0125] Embodiment 28. A method according to any one of Embodiments 22 to 27, wherein the volume percentage of the water-miscible organic solvent in the mixed solvent is not greater than about 95%, preferably, the volume percentage of the water-miscible organic solvent in the mixed solvent is 95%, 90% or 80%.

[0126] Embodiment 29. The method according to any one of Embodiments 22 to 28, wherein in the optional step (4), the drying temperature is 50-80°C.

[0127] Embodiment 30. A method for preparing a salt of formula A according to any one of embodiments 6 to 8, comprising:

[0128] (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 and L-tartaric acid in ethanol under heating and stirring to react and form a salt;

[0129] (2) cooling the reaction product obtained in step (1) to allow solid to fully precipitate;

[0130] (3) The separated solid is Form B-II;

[0131] (4) Optionally, drying the solid obtained in step (3).

[0132] Embodiment 31. A method according to 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 not less than about 1:2, preferably, about 4:5 or about 3.4:1.

[0133] Embodiment 32. A method according to any one of embodiments 30 to 31, wherein the ratio of the volume 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 not less than about 10 ml / g, for example, about 72 ml / g or about 75 ml / g.

[0134] Embodiment 33. The method according to any one of embodiments 30 to 32, wherein in the optional step (4), the drying temperature is 50-85°C.

[0135] Embodiment 34. A method for preparing a salt of formula A according to any one of embodiments 9 to 11, comprising:

[0136] (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 and 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 react to form a salt, thereby obtaining a first solution; provided that the dissolving solvent is not a single solvent ethanol;

[0137] (2) optionally, adding an anti-dissolving solvent to the first solution to obtain a second solution;

[0138] (3) cooling the first solution or the second solution to allow solid to fully precipitate;

[0139] (4) The separated solid is Form B-III;

[0140] (5) Optionally, drying the solid obtained in step (4).

[0141] Embodiment 35. A method according to 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 not less than about 1:1, preferably, the molar ratio is about 1:1 or about 1.5:1.

[0142] Embodiment 36. A method according to any one of embodiments 34 to 35, wherein the ratio of the volume of the dissolving solvent, water or a 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 not less than about 10 ml / g, 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.

[0143] Embodiment 37. The method according to any one of embodiments 34 to 36, wherein the dissolving solvent is selected from C 1-6 Alkyl alcohol, acetone, toluene, organic acid esters of not more than eight carbon atoms and mixtures thereof, preferably, the dissolving solvent is selected from methanol, ethanol, isopropanol, tert-butanol, n-butanol, acetone, toluene, n-propyl acetate, ethyl acetate and mixtures thereof, more preferably, the dissolving solvent is selected from methanol, ethanol, isopropanol, acetone, toluene, n-propyl acetate, ethyl acetate and mixtures thereof.

[0144] Embodiment 38. A method according to Embodiment 37, wherein the dissolving solvent is selected from a mixed solvent consisting of two solvents selected from 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).

[0145] Embodiment 39. The method according to any one of embodiments 34 to 38, wherein the water-miscible organic solvent is selected from C 1-6 Alkyl alcohol, acetone and mixtures thereof, preferably, the water-miscible organic solvent is selected from methanol, ethanol, isopropanol, tert-butanol, acetone and mixtures thereof, more preferably, the water-miscible organic solvent is selected from ethanol, isopropanol, acetone and mixtures thereof.

[0146] Embodiment 40. A method according to any one of Embodiments 34 to 39, wherein the volume percentage of the water-miscible organic solvent in the mixed solvent is not greater than about 95%, such as 95%, 90%, or 80%.

[0147] Embodiment 41. A method according to any one of embodiments 34 to 40, wherein the anti-dissolution solvent is selected from toluene, organic acid esters of not more than eight carbon atoms and mixtures thereof, preferably, the anti-dissolution solvent is selected from toluene, ethyl acetate, n-propyl acetate and mixtures thereof, more preferably, the anti-dissolution solvent is selected from toluene, ethyl acetate and mixtures thereof.

[0148] Embodiment 42. A method according to any one of embodiments 34 to 41, wherein in step (3), the cooling is natural cooling or temperature-controlled cooling.

[0149] Embodiment 43. The method according to any one of embodiments 34 to 42, wherein in step (5), the drying temperature is 50-85°C.

[0150] Embodiment 44. A method for preparing a salt of formula A according to any one of embodiments 12 to 14, comprising:

[0151] (1) mixing a 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 p-toluenesulfonic acid monohydrate in a mixed solvent consisting of a water-miscible organic solvent and water under heating and stirring to react and form a salt;

[0152] (2) cooling the reaction product obtained in step (1) to allow solid to fully precipitate;

[0153] (3) The separated solid is the crystal form CI;

[0154] (4) Optionally, drying the solid obtained in step (3).

[0155] Embodiment 45. A method according to 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 not less than about 1:1, for example, about 1.5:1.

[0156] Embodiment 46. A method according to any one of Embodiments 44 to 45, wherein the ratio of the volume of the mixed solvent consisting of a water-miscible organic solvent and water in step (1) 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 not less than about 10 ml / g, for example, about 36 ml / g or about 43 ml / g.

[0157] Embodiment 47. The method according to any one of embodiments 44 to 46, wherein the water-miscible organic solvent is selected from C 1-6 Alkyl alcohol, acetone and mixtures thereof. Preferably, the water-miscible organic solvent is selected from isopropanol, acetone and mixtures thereof.

[0158] Embodiment 48. The method according to any one of Embodiments 44 to 47, wherein the volume percentage of the water-miscible organic solvent in the mixed solvent is not greater than about 95%, for example, 80%.

[0159] Embodiment 49. A method according to any one of Embodiments 44 to 48, wherein an anti-dissolving solvent (such as isopropanol) is added after the reaction in step (1) is completed, and then step (2) is performed.

[0160] Embodiment 50. The method according to any one of embodiments 44 to 49, wherein in step (2), the cooling is natural cooling or temperature-controlled cooling.

[0161] Embodiment 51. The method according to any one of embodiments 44 to 50, wherein in the optional step (4), the drying temperature is 50-60°C.

[0162] The salt of the present invention and the crystal form of the present invention have the characteristics of good crystallinity, high solubility, low hygroscopicity and good stability. The salt of the present invention and the crystal form of the present invention have good production reproducibility, are easy to achieve scale-up production, and can continuously produce high-quality products to meet the quality requirements of drugs.

[0163] For example, the free form of compound 78 prepared according to Example 9 of WO2014 / 139465A1 is a yellow solid, which is a needle-shaped crystal, while the crystal form B-III of the present invention is a plate-shaped crystal, which has a smaller long diameter than the needle-shaped crystal and better granularity, and thus has a smaller angle of repose, that is, has better fluidity. These characteristics make the crystal form B-III more conducive to uniform mixing with auxiliary materials in subsequent preparation production, which can simplify the process flow of preparation production, improve production efficiency, and save production costs.

[0164] In addition, the salt of the present invention and the crystal form of the present invention have better solubility properties. For example, compared with the free form of compound 78, the salt of the present invention has a smaller difference in solubility at different pH values, which makes the solubility of the salt of the present invention in body fluids with different pH values ​​in the body more stable. In addition, the crystal 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 conducive to its rapid dissolution in the stomach. At the same time, under the higher pH conditions of the gastrointestinal tract, the salt of the present invention and the crystal form of the present invention still have a higher and more stable solubility, which is conducive to its full absorption, thereby producing a higher bioavailability and making the absorption of the drug in the body unaffected by eating.

[0165] The crystal form B-III of the present invention has low hygroscopicity and good stability, and is particularly convenient for the production, storage, transportation and use of the preparation in the treatment of diseases.

[0166] In addition, the crystal form of the present invention has high purity and little solvent residue, which meets the quality requirements of raw materials, such as the requirements of ICH Q3A.

[0167] Those skilled in the art can verify the above characteristics of the salt of the present invention and the crystal form of the present invention by methods known in the art, such as test methods disclosed in pharmacopoeias of various countries or their variations. For example, the crystal form of the present invention can be identified by X-ray powder diffraction, single crystal diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and / or thermogravimetric analysis.

[0168] Those skilled in the art know that the intensity and / or position of the X-ray powder diffraction peaks may vary due to different experimental conditions. For example, different instruments, different test conditions and / or preferred orientations, etc. may result in slightly different measured 2θ values. In addition, it is known that the relative intensity of the peaks is more easily affected by the sample being measured than the position of the peaks, such as the size of the crystals in the sample, the orientation of the crystals, and the purity of the material being analyzed, so the deviation of the peak intensity can be as high as about ±20% or more. Despite the presence of experimental errors, instrumental errors, and preferred orientations, etc., based on the main peaks of the X-ray powder diffraction, even further combined with other characterization data, those skilled in the art can obtain sufficient information to identify Form A-III, Form B-II, Form B-III, and Form CI.

[0169] Identification of Form A-III

[0170] The present invention provides crystal form A-III.

[0171] 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°.

[0172] 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°, 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°.

[0173] 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°, 10.3±0.2°, 12.3±0.2°, 13.3±0.2v, 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±0.2v, 26.4±0.2°, 27.1±0.2°, and 27.8±0.2°.

[0174] In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form A-III includes 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°, 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°.

[0175] In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form A-III includes 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°, 25.2±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°.

[0176] In some embodiments, Form A-III has Figure 1 The X-ray powder diffraction spectrum is shown.

[0177] In some embodiments, Form A-III can be identified by differential scanning calorimetry. In some embodiments, Form A-III has Figure 2 The differential scanning calorimetry analysis curve is shown in FIG. 1. In the DSC spectrum, the endothermic peak of Form A-III is at about 290.2-295.4°C.

[0178] In some embodiments, Form A-III can be identified by thermogravimetric analysis. In some embodiments, Form A-III has Figure 3 Thermogravimetric analysis curves are shown, which show that Form A-III is an anhydrate or pure crystal.

[0179] In some embodiments, the Form A-III is substantially pure.

[0180] In some embodiments, the crystalline form A-III is substantially free of other crystalline forms, for example, the content of the crystalline form A-III 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.

[0181] Preparation method of crystal form A-III

[0182] Provided herein is a method for preparing Form A-III, comprising:

[0183] (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 hydrochloric acid in a dissolving solvent or in a mixed solvent consisting of a water-miscible organic solvent and water under heating and stirring to react and form a salt;

[0184] (2) cooling the reaction product obtained in step (1) to allow solid to fully precipitate;

[0185] (3) separating and obtaining a solid, which is Form A-III;

[0186] (4) Optionally, drying the solid obtained in step (3).

[0187] In some embodiments, the hydrochloric acid is concentrated hydrochloric acid with a concentration of 36%-38% by weight.

[0188] In some embodiments, the molar ratio of hydrochloric acid to 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 no less than about 1:1. In some embodiments, the molar ratio is about 1:1. In some embodiments, the molar ratio is about 1.2:1.

[0189] 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 not less than about 10 ml / g, for example, about 20 ml / g, about 60 ml / g, etc.

[0190] In some embodiments, the dissolving solvent is selected from C 1-6 In some embodiments, the dissolving solvent is selected from methanol, ethanol, isopropanol, tert-butyl alcohol and mixtures thereof. In some embodiments, the dissolving solvent is selected from ethanol.

[0191] In some embodiments, the water-miscible organic solvent is selected from C 1-6 In some embodiments, the water miscible organic solvent is selected from methanol, ethanol, isopropanol, tert-butanol, and mixtures thereof. In some embodiments, the water miscible organic solvent is selected from ethanol, isopropanol, and mixtures thereof.

[0192] In some embodiments, the volume percentage of the water-miscible organic solvent in the mixed solvent is no more than about 95%, for example, the volume percentage of the water-miscible organic solvent in the mixed solvent is 95%, 90%, 80%, etc.

[0193] In some embodiments, in step (1), the heating temperature should be no higher than the boiling point of the solvent system, for example, 75-80°C, 75-85°C, etc.

[0194] In some embodiments, in step (2), the cooling is natural cooling or temperature-controlled cooling, cooling to room temperature or lower temperature, such as 20-25°C, 15-25°C, etc.

[0195] In some embodiments, in step (2), after cooling the reactants, the reactants are stirred for 1-120 hours, such as 2 hours, 20 hours, etc., to allow the solid to be fully precipitated.

[0196] In some embodiments, in the optional step (4), the drying temperature and drying time are routinely determined by those skilled in the art, which allows the solid to be fully dried and maintain the desired crystalline form. In some embodiments, the drying temperature is 50-80° C., such as 60° C. In some embodiments, the drying time is 1-24 hours, such as 2 hours, 18 hours, etc.

[0197] Identification of Form B-II

[0198] The present invention provides crystal form B-II.

[0199] In some embodiments, Form B-II can be identified by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form B-II includes 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°.

[0200] In some embodiments, the 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°.

[0201] In some embodiments, the 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°.

[0202] In some embodiments, the 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°.

[0203] In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form B-II includes 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 27.8±0.2°.

[0204] In some embodiments, Form B-II has Figure 4 The X-ray powder diffraction spectrum is shown.

[0205] In some embodiments, Form B-II can be identified by differential scanning calorimetry. In some embodiments, Form B-II has Figure 5 The differential scanning calorimetry analysis curve is shown in FIG. 1. In the DSC spectrum, the crystal 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.

[0206] In some embodiments, Form B-II can be identified by thermogravimetric analysis. In some embodiments, Form B-II has Figure 6 The thermogravimetric analysis curve shown in FIG. 1 shows that there is a weight loss of about 4.3% in the range of 30-100°C, indicating that the crystal form B-II contains more adsorbed water. Figure 5 From the differential scanning calorimetry analysis curve, it can be seen that the crystal form B-II is a hygroscopic metastable crystal form.

[0207] In some embodiments, the Form B-II is substantially pure.

[0208] In some embodiments, the crystalline form B-II is substantially free of other crystalline forms. For example, the content of crystalline form B-II 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.

[0209] Preparation method of crystal form B-II

[0210] Provided herein is a method for preparing Form B-II, comprising:

[0211] (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 and L-tartaric acid in ethanol under heating and stirring to react and form a salt;

[0212] (2) cooling the reaction product obtained in step (1) to allow solid to fully precipitate;

[0213] (3) The separated solid is Form B-II;

[0214] (4) Optionally, drying the solid obtained in step (3).

[0215] In some embodiments, the molar ratio of L-tartaric acid to 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 no less than about 1:2. In some embodiments, the molar ratio is about 4:5. In some embodiments, the molar ratio is about 3.4:1.

[0216] In some embodiments, the ratio of the volume (ml) of 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 not less than about 10 ml / g (volume-to-weight ratio), for example, about 72 ml / g, about 75 ml / g, etc.

[0217] In some embodiments, in step (1), the heating temperature should be no higher than the boiling point of the solvent system, for example, 70-75°C.

[0218] In some embodiments, in step (2), the cooling is natural cooling or temperature-controlled cooling, cooling to room temperature or lower temperature, such as 20-25°C.

[0219] In some embodiments, in step (2), the reactant is cooled and then stirred for 1-120 hours, for example, 18 hours, to allow the solid to be fully precipitated.

[0220] In some embodiments, in step (4), the drying temperature and drying time can be routinely determined by those skilled in the art, so that the solid is fully dried and the desired crystalline form is maintained. In some embodiments, the drying temperature is 50-85° C., such as 50° C., 65° C., 82° C., etc. In some embodiments, the drying time is 1-24 hours, such as 1 hour, 18 hours, 19 hours, etc.

[0221] Identification of Form B-III

[0222] The present invention provides crystal form B-III.

[0223] In some embodiments, Form B-III can be identified by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form B-III includes 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°.

[0224] In some embodiments, the 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°.

[0225] In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form B-III includes 7.6±0.2°, 8.9±0.2°, 10.0±o.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°.

[0226] In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form B-III includes 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°. 2°, 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°.

[0227] In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form B-III includes 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°, 21.4±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°.

[0228] In some embodiments, Form B-III has Figure 7 The X-ray powder diffraction spectrum is shown.

[0229] In some embodiments, Form B-III can be identified by differential scanning calorimetry. In some embodiments, Form B-III has Figure 8 The differential scanning calorimetry analysis curve is shown in FIG. 1. In the DSC spectrum, the endothermic peak of Form B-III is at about 269.2-271.3°C.

[0230] In some embodiments, Form B-III can be identified by thermogravimetric analysis. In some embodiments, Form B-III has Fig. 9 Thermogravimetric analysis curves shown show that the crystalline form B-III is an anhydrate or pure crystal.

[0231] In some embodiments, the Form B-III is substantially pure.

[0232] In some embodiments, the crystalline form B-III is substantially free of other crystalline forms. For example, the content of crystalline form B-III 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.

[0233] Preparation method of crystal form B-III

[0234] The present invention relates to a method for preparing Form B-III, which comprises:

[0235] (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 and 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, reacting to form a salt, and obtaining a first solution; provided that the dissolving solvent is not a single solvent ethanol (that is, it can be other dissolving solvents, or a mixed solvent consisting of ethanol and other dissolving solvents);

[0236] (2) optionally, adding an anti-dissolving solvent to the first solution to obtain a second solution;

[0237] (3) cooling the first solution or the second solution to allow solid to fully precipitate;

[0238] (4) The separated solid is Form B-III;

[0239] (5) Optionally, drying the solid obtained in step (4).

[0240] In some embodiments, the molar ratio of L-tartaric acid to 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 no less than about 1:1. In some embodiments, the molar ratio is about 1:1. In some embodiments, the molar ratio is about 1.5:1.

[0241] In some embodiments, in step (1), the ratio of the volume (ml) of the dissolving solvent, water or a 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 not less than about 10 ml / g (volume-to-weight ratio), 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, about 286 ml / g, etc.

[0242] In some embodiments, the dissolving solvent is selected from C 1-6 Alkyl alcohol, acetone, toluene, organic acid esters of not more than eight carbon atoms, and mixtures thereof. In some embodiments, the dissolving solvent is selected from methanol, ethanol, isopropanol, tert-butyl alcohol, n-butyl alcohol, acetone, toluene, n-propyl acetate, ethyl acetate, and mixtures thereof. In some embodiments, the dissolving solvent is selected from methanol, ethanol, isopropanol, acetone, toluene, n-propyl acetate, ethyl acetate, and mixtures thereof.

[0243] In some embodiments, the dissolving solvent is selected from a mixed solvent consisting of two solvents selected from 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), ethyl acetate / ethanol (volume ratio of about 11:15), etc.

[0244] In some embodiments, the water-miscible organic solvent is selected from C 1-6 In some embodiments, the water miscible organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butyl alcohol, acetone, and mixtures thereof. In some embodiments, the water miscible organic solvent is selected from the group consisting of ethanol, isopropanol, acetone, and mixtures thereof.

[0245] In some embodiments, the volume percentage of the water-miscible organic solvent in the mixed solvent is no greater than about 95%, such as 95%, 90%, 80%, etc.

[0246] In some embodiments, the anti-solvent is selected from toluene, organic acid esters of not more than eight carbon atoms, and mixtures thereof. In some embodiments, the anti-solvent is selected from toluene, ethyl acetate, n-propyl acetate, and mixtures thereof. In some embodiments, the anti-solvent is selected from toluene, ethyl acetate, and mixtures thereof.

[0247] In some embodiments, in step (1), the heating temperature should be no higher than the boiling point of the solvent system, for example, 55-60°C, 70-72°C, 75-85°C, 90-95°C, etc.

[0248] In some embodiments, in step (3), the cooling is natural cooling or temperature-controlled cooling, cooling to room temperature or lower temperature, such as 20-25°C, 25-30°C, etc.

[0249] In some embodiments, in step (3), the first solution or the second solution is cooled and then stirred for 1-120 hours, such as 2 hours, 16 hours, 17 hours, 18 hours, 20 hours, etc., to allow the solid to be fully precipitated.

[0250] In some embodiments, in step (5), the drying temperature and drying time can be routinely determined by those skilled in the art, which allows the solid to be fully dried and maintain the desired crystalline form. In some embodiments, the drying temperature is 50-85°C, such as 55°C, 60°C, 65°C, etc. In some embodiments, the drying time is 1-24 hours, such as 2 hours, 3 hours, 5 hours, 6 hours, 16 hours, etc.

[0251] Identification of Form CI

[0252] The present invention provides crystal form CI.

[0253] In some embodiments, Form CI can be identified by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form CI includes 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°.

[0254] In some embodiments, the 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°.

[0255] In some embodiments, the 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°.

[0256] In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form CI includes 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±0.20, 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°.

[0257] In some embodiments, the X-ray powder diffraction characteristic diffraction angle (2θ) of Form CI includes 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°, 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°.

[0258] In some embodiments, Form CI has Fig.12 The X-ray powder diffraction spectrum is shown.

[0259] In some embodiments, Form CI can be identified by differential scanning calorimetry. In some embodiments, Form CI salt has Fig.13 The differential scanning calorimetry analysis curve is shown in FIG. 1. In the DSC spectrum, the endothermic peak of Form CI is at about 289.77-291.04°C.

[0260] In some embodiments, Form CI can be identified by thermogravimetric analysis. In some embodiments, Form CI has Fig.14 Thermogravimetric analysis curves shown show that the crystal form CI is an anhydrate or pure crystal.

[0261] In some embodiments, the Form CI is substantially pure.

[0262] In some embodiments, the crystalline form CI is substantially free of other crystalline forms. For example, the content of crystalline 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.

[0263] Preparation method of crystal form CI

[0264] Provided herein is a method for preparing Form CI, comprising:

[0265] (1) mixing a 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 p-toluenesulfonic acid monohydrate in a mixed solvent consisting of a water-miscible organic solvent and water under heating and stirring to react and form a salt;

[0266] (2) cooling the reaction product obtained in step (1) to allow solid to fully precipitate;

[0267] (3) The separated solid is the crystal form CI;

[0268] (4) Optionally, drying the solid obtained in step (3).

[0269] In some embodiments, the molar ratio of p-toluenesulfonic acid monohydrate to 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 no less than about 1: 1. In some embodiments, the molar ratio is about 1.5:1.

[0270] In some embodiments, the ratio of the volume (ml) of the mixed solvent consisting of the water-miscible organic solvent and water in step (1) 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 not less than about 10 ml / g (volume / weight ratio), for example, about 36 ml / g, about 43 ml / g, etc.

[0271] In some embodiments, the water-miscible organic solvent is selected from C 1-6 Alkyl alcohols, acetone, and mixtures thereof. In some embodiments, the water miscible organic solvent is selected from isopropanol, acetone, and mixtures thereof.

[0272] In some embodiments, the volume percentage of the water-miscible organic solvent in the mixed solvent is no greater than about 95%, such as 80%.

[0273] In some embodiments, in step (1), the heating temperature should be no higher than the boiling point of the solvent system, for example, 55-60°C, 75-85°C, etc.

[0274] In some embodiments, optionally, after the reaction in step (1) is completed, at least one anti-solvent (such as isopropanol) is added, and then step (2) is performed.

[0275] In some embodiments, in step (2), the cooling is natural cooling or temperature-controlled cooling, cooling to room temperature or lower.

[0276] In some embodiments, in step (2), the mixture is stirred for 1-120 hours, such as 15 hours, after cooling, so that the solid is fully precipitated.

[0277] In some embodiments, in the optional step (4), the drying temperature and drying time can be routinely determined by those skilled in the art, which allows the solid to be fully dried and maintain the desired crystalline form. In some embodiments, the drying temperature is 50-60° C., such as 50° C., etc. In some embodiments, the drying time is 1-24 hours, such as 4 hours, 20 hours, etc.

[0278] The features in the various embodiments of the preparation method described above for the same crystal form can be combined arbitrarily to obtain new technical solutions, and the new technical solutions obtained by these combinations are also included in the scope of the present invention, just as these technical solutions are specifically and one by one listed in this article.

[0279] Pharmaceutical compositions and uses

[0280] The salts of the present invention and the crystalline forms of the present invention can be used to inhibit FGFR activity in vivo and in vitro.

[0281] The salt of the present invention and the crystal formation of the present invention can be used to prevent or treat diseases that respond to inhibiting FGFR activity. Accordingly, the present invention provides a method for preventing or treating a disease that responds to inhibiting FGFR activity, comprising administering the salt of the present invention and the crystal formation of the present invention to an individual in need, and optionally administering one or more other active ingredients. In addition, the present invention also provides the use of the salt of the present invention and the crystal formation of the present invention in the preparation of a drug for preventing or treating a disease that responds to inhibiting FGFR activity. The disease that responds to inhibiting FGFR activity is, for example, cancer, and the cancer includes but is not limited to lung cancer (such as squamous non-small cell lung cancer and small cell lung cancer), gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial carcinoma, esophageal cancer, bile duct cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma and blood tumors (such as myeloproliferative tumors).

[0282] The salts of the present invention and the crystalline forms of the present invention can 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, etc.

[0283] The dosage of the salt of the present invention and the crystalline form of the present invention to achieve the expected physiological effect depends on various factors, such as the disease to be treated, the route and mode of administration, and the clinical condition of the individual. The daily dose can be, for example, 0.01 mg to 3 g / day, such as 0.05 mg to 2 g / day or 100 mg to 1 g / day. The daily dose can be administered once or in multiple doses (e.g., 2-4 doses).

[0284] To achieve the above prevention or treatment purposes, the salts and crystal forms of the present invention can be administered in their own form, but are usually formulated with a pharmaceutically acceptable carrier into a pharmaceutical composition for use.

[0285] The pharmaceutical composition of the present invention can be in any convenient form for administration, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. The pharmaceutically acceptable carriers used to prepare the pharmaceutical composition can be conventional components in the field of pharmaceutical preparations, such as diluents, disintegrants, lubricants, pH regulators, flavoring agents, fillers, preservatives, osmotic pressure regulators, colorants, emulsifiers, suspending agents, surfactants, etc. The pharmaceutically acceptable carrier should be compatible with other ingredients in the pharmaceutical composition and will not endanger the health of the subject of administration. It can be solid or liquid, or both. The salt of the present invention and the crystal form of the present invention can account for 0.05% to 95% of the total weight of the pharmaceutical composition.

[0286] 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. Suitable carriers for each dosage form are well known to those skilled in the art, for example, as described in detail in 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; and Rowe, R. C. and book of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

[0287] In some examples, the crystal forms of the present invention will not be transformed when they are made into a preparation with a pharmaceutically acceptable carrier. In other examples, the crystal forms of the present invention may be transformed when they are made into a preparation with a pharmaceutically acceptable carrier, and may be transformed into one or more other forms in whole or in part, but those skilled in the art can use known technical means to maintain the stability of the crystal forms as needed. In some examples, the crystal forms of the present invention can be dissolved when they are made into a pharmaceutical composition, so that they no longer exist in their respective crystal forms in the pharmaceutical composition.

[0288] The salt of the present invention and the crystal formation of the present invention can be used in combination with one or more other active ingredients to achieve an additive or synergistic therapeutic effect, or to reduce side effects. When used in combination, the salt of the present invention or the crystal formation of the present invention and the one or more other active ingredients can be administered simultaneously or successively in different unit dosage forms by the same or different administration routes, or simultaneously in the same unit dosage form.

[0289] Other active ingredients that can be used in combination with the salts of the present invention and the crystalline forms of the present invention can be anti-tumor drugs and / or anti-tumor therapies. Examples include, but are not limited to, radiotherapy, immunotherapy preparations, chemotherapeutic agents such as DNA damaging chemotherapeutic agents and chemotherapeutic agents that interfere with cell replication.

[0290] Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogs or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, daunorubicin, and daunomycin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosocarbamide, lomustine, methyllomustine, streptozotocin, decarbamide, 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).

[0291] Non-limiting examples of chemotherapeutic agents that interfere with cell replication include: 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 IκB kinase inhibitors; antibodies that bind to proteins overexpressed in cancer and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab and bevacizumab); and other protein or enzyme inhibitors that are known to be upregulated, overexpressed or activated in cancer and whose inhibition can downregulate cell replication. Example

[0292] The following examples are intended to illustrate the present invention without limiting the scope defined in the claims.

[0293] Experimental Section

[0294] 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 example was prepared according to the method in Example 9 of WO2014 / 139465A1, and was yellow needle-shaped crystals. The microscopic photograph thereof is shown in FIG. Fig. 22 shown.

[0295] All reagents (except intermediates) used in the present invention are purchased from commercial markets. All compound names (except reagents) are generated by software ChemDraw Professional 16.0.

[0296] Unless otherwise noted, X-ray powder diffraction patterns were measured using a German Bruker D8 ADVANCE (target: Cu, voltage: 40 kV, current: 40 mA, scanning speed: 4 degrees / min, step size: 0.02 degrees, measurement range: 3-45 degrees).

[0297] Unless otherwise noted, differential scanning calorimetry was performed using a DSC 204F1 from NETZSCH (Germany) (purge gas: nitrogen, flow rate: 20-60 mL min -1 , heating rate: 10°C / min, measuring range: 30°C→300 / 350°C), a punched aluminum pan was used for sample measurement, and indium was used for temperature correction.

[0298] Unless otherwise noted, thermogravimetric analysis was performed using a TGA 209F1 (Netzsch, Germany) (purge gas: nitrogen, heating rate: 10°C / min).

[0299] Unless otherwise noted, micrographs were obtained using a Nikon Ci-L microscope.

[0300] Example 1 - Preparation of Form A-III

[0301] 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 mixture of ethanol and water in a volume ratio of 95:5), and heated to 75-85°C under stirring; 100 μl of hydrochloric acid (36%-38% by weight) was added to the suspension to obtain a clear solution; the solution was cooled to 15-25°C, stirred for 20 hours, the solid was filtered out, and vacuum dried at 60°C for 2 hours to obtain a sample. The chloride ion content of the sample was measured to be 6.48%, and it can be judged from the chloride ion content that the obtained sample is a hydrochloride salt (theoretical content 6.69%).

[0302] 1 H NMR (400MHz, CD3OD) δ8.11 (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).

[0303] The obtained powder sample is form A-III, and its X-ray powder diffraction pattern is as follows: Figure 1As shown, it includes diffraction peaks (2θ): 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°, 25. .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°, among which the characteristic peaks are 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 test results are as follows Figure 2 As shown, the endothermic peak of Form A-III is at about 290.2-295.4°C.

[0304] Example 2 - Preparation of Form A-III

[0305] 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 anhydrous ethanol and heated to 75-85° C. under stirring to dissolve; 100 μl of hydrochloric acid (36%-38% by weight) was added to the solution and continued to stir at 75-85° C. for 5 minutes; the solution was cooled to 15-25° C. and stirred for 2 hours; the solid was filtered out and vacuum dried at 60° C. for 18 hours to obtain a sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form A-III sample obtained in Example 1.

[0306] Example 3 - Preparation of Form A-III

[0307] 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 volume ratio isopropanol:water mixture, and heated to 75-80°C under stirring; 352 μl of hydrochloric acid (36%-38% by weight) was added to the suspension; the obtained mixture was cooled to 20-25°C and stirred for 2 hours; the solid was filtered out and vacuum dried at 60°C for 2 hours to obtain 1.6 g of sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form A-III sample obtained in Example 1.

[0308] Example 4 - Preparation of Form B-II

[0309] 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) was mixed with 60 ml of anhydrous ethanol and heated to 70-74°C to dissolve; a solution of L-tartaric acid (0.24 g, 1.6 mmol) in ethanol (12 ml) was added thereto, and a solid was immediately precipitated; the mixture was stirred at 70-74°C for 30 minutes; the mixture was cooled to 50-55°C and stirred for 1 hour; the mixture was cooled to 20-25°C and stirred for 18 hours; the solid was filtered out and vacuum dried at 60°C for 2 hours, then at 65°C for 16 hours, and then at 82°C for 1 hour to obtain 1.15 g of the sample.

[0310] 1 H NMR (400MHz, DMSO) δ9.22 (1H, s), 8.48 (1H, q, J = 4.4), 8.22 (2H, s), 7.53 (2H, dd, J =9.7, 2.7), 7.43 (1H, d, J = 1.9), 7.40 (1H, d, J = 1.9), 6.88 (2H, dd, J = 9.7, 2.7), 3.8 8(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).

[0311] The obtained powder sample is the crystal form B-II, and its X-ray powder diffraction pattern is as follows: Figure 4As shown, it includes diffraction peaks (2θ): 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°, 2 The DSC test results are as follows: 0.6±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 27.8±0.2°, among which the characteristic peaks are 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°. Figure 5 As shown, Form B-II exhibits 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.

[0312] Example 5 - Preparation of Form B-II

[0313] 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazine-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (1g, 1.96mmol) was mixed with 60ml of anhydrous ethanol, heated to 70-75°C, and a small amount of insoluble matter was removed by hot filtration; a solution of L-tartaric acid (1g, 6.66mmol) in ethanol (15ml) was added thereto, and solids precipitated during the addition; stirred at 70-75°C for 1 hour; cooled to 24°C, the solids were filtered out, vacuum dried at 50°C for 17 hours, and then vacuum dried at 82°C for 1 hour to obtain a sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form B-II sample obtained in Example 4.

[0314] Example 6 - Preparation of Form B-III

[0315] 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) was mixed with 15 ml of a 8:2 volume ratio isopropanol:water mixture and heated to 70°C to dissolve; a solution of L-tartaric acid (0.29 g, 1.93 mmol) in a 8:2 volume ratio isopropanol:water mixture (5 ml) was added thereto to obtain a clear reaction solution; the mixture was stirred at 70-72°C for 10 minutes to precipitate a solid and kept warm for 30 minutes; the mixture was then cooled to 50-55°C and stirred for 1 hour, cooled to 40-45°C and stirred for 1 hour, cooled to 20-25°C and stirred for 17 hours; the solid was filtered out and vacuum dried at 60°C for 30 minutes and then vacuum dried at 65°C for 16 hours to obtain 0.97 g of a sample.

[0316] 1 H NMR (400MHz, DMSO) δ9.22 (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 (2H, 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).

[0317] The obtained powder sample is form B-III, and its X-ray powder diffraction pattern is as follows: Figure 7As shown, it includes diffraction peaks (2θ): 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°. 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°, among which the characteristic peaks are 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 test results are as follows Figure 8 As shown, the endothermic peak of Form B-III is at about 269.2-271.3°C.

[0318] Microscopic examination shows that Form B-III is a plate-like crystal, as shown in the following microscopic photograph: Fig.23 shown.

[0319] Example 7 - Preparation of Form B-III

[0320] 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 acetone:water mixture with a volume ratio of 8:2 under heating reflux and stirring; a solution of L-tartaric acid (0.08 g, 0.53 mmol) in acetone:water mixture with a volume ratio of 8:2 (1.5 ml) was added thereto; the temperature was lowered to 40°C and stirred for 1 hour; the temperature was lowered to 25°C and stirred for 2 hours; the precipitated solid was filtered out and vacuum dried at 55°C for 2 hours to obtain 0.21 g of sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form B-III sample obtained in Example 6.

[0321] Example 8 - Preparation of Form B-III

[0322] 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 methanol at 55-60°C and filtered while hot; L-tartaric acid (23 mg, 0.15 mmol) was added to the filtrate, and stirring was continued at 55-60°C for 30 minutes, and then the reaction system was cooled to 20-25°C and stirred for 18 hours; the precipitated solid was filtered out and vacuum dried at 55°C for 5 hours to obtain a sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form B-III sample obtained in Example 6.

[0323] Example 9 - Preparation of Form B-III

[0324] 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 75-85°C; a methanol (1 ml) solution of L-tartaric acid (23 mg, 0.15 mmol) was added thereto; 1 ml of methanol was added and stirred at 75-85°C for 50 minutes; cooled to 25-30°C and stirred for 16 hours; the precipitated solid was filtered out and vacuum dried at 55°C for 6 hours to obtain a sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form B-III sample obtained in Example 6.

[0325] Example 10 - Preparation of Form B-III

[0326] 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 90-95°C; a solution of L-tartaric acid (9.3 mg, 0.062 mmol) in ethanol (0.5 ml) was added thereto, and 2.5 ml of ethanol was added, and stirred at 80-90°C for 30 minutes; cooled to 20-25°C, stirred for 18 hours; the precipitated solid was filtered out, and vacuum dried at 55°C for 2 hours to obtain a sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form B-III sample obtained in Example 6.

[0327] Example 11 - Preparation of Form B-III

[0328] 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 volume ratio ethanol:water mixture under heating reflux; a solution of L-tartaric acid (0.08 g, 0.53 mmol) in a 9:1 volume ratio ethanol:water mixture (1.5 ml) was added thereto, and solid precipitated after 5 minutes; heating was stopped, cooled to 25-30°C, and stirred for 20 hours; the precipitated solid was filtered out and vacuum dried at 55°C for 3 hours to obtain 0.27 grams of sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form B-III sample obtained in Example 6.

[0329] Example 12 - Preparation of Form B-III

[0330] 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 (ethanol / ethyl acetate, volume ratio 1:1) at 75-80°C; a solution of L-tartaric acid (0.08 g, 0.53 mmol) in ethanol (2 ml) was added thereto, and a solid was precipitated within two minutes; the mixture was stirred at 75-80°C for 1 hour; the heating was stopped, the mixture was cooled to 25-30°C, and stirred for 16 hours; the precipitated solid was filtered out, and vacuum dried at 55°C for 16 hours to obtain 0.30 g of a sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with that of the Form B-III sample obtained in Example 6.

[0331] Example 13 - Preparation of Form B-III

[0332] 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 volume ratio isopropanol:water mixture under heating reflux; a solution of L-tartaric acid (0.08 g, 0.53 mmol) in a 9:1 volume ratio isopropanol:water mixture (2 ml) was added thereto; the temperature was lowered to 25-30°C and stirred for 17 hours; the solid was filtered out and vacuum dried at 55°C for 6 hours to obtain 0.24 g of sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form B-III sample obtained in Example 6.

[0333] Example 14 - Preparation of Form B-III

[0334] 4-Chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide (0.26g, 0.51mmol) was suspended in 15ml of water and heated to 75-85°C without dissolving; L-tartaric acid (0.08g, 0.53mmol) in water (2ml) was added to the suspension to obtain a clear solution and then a solid was precipitated; stirred at 75-85°C for 2 hours; cooled to 25-30°C and stirred for 19-20 hours; the precipitated solid was filtered out and vacuum dried at 55°C for 3 hours to obtain 0.23g of sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form B-III sample obtained in Example 6.

[0335] Example 15 - Preparation of Form CI

[0336] 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 heating 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 thereto; a solid was precipitated after stirring for about 5 minutes; the reaction solution was cooled to room temperature and stirring was continued for about 15 hours; the solid was filtered out and dried in vacuo at 50°C for 4 hours to obtain a sample.

[0337] 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), 8.2 3 (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, 2H), 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).

[0338] The obtained powder sample is crystal form CI, and its X-ray powder diffraction pattern is as follows: Fig.12As shown, it includes diffraction peaks (2θ): 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°, 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 test results are as follows Fig.13 As shown, the endothermic peak of Form CI is at about 289.77-291.04°C.

[0339] Example 16 - Preparation of Form CI

[0340] 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 isopropanol and water in a volume ratio of 8:2 under heating and reflux, and the insoluble matter was removed by hot filtration; 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 thereto; 50 ml of isopropanol was added, and solids precipitated after stirring for about 5 minutes; the reaction solution was cooled to room temperature and continued to stir for about 15 hours; the solids were filtered out and dried in vacuo at 50°C for 20 hours to obtain a sample. After testing, the X-ray powder diffraction pattern of the obtained sample was consistent with that of the crystal form CI sample obtained in Example 15.

[0341] Example 17 - Stability of the salt of the present invention under high temperature, high humidity and light conditions

[0342] Determination method: The crystal form B-III of the hemi-tartrate salt of compound 78 and the crystal form A-III of the monohydrochloride salt of compound 78 were placed in culture dishes, with the openings exposed, in sealed clean containers, and placed at 60°C, at 25°C and a relative humidity of 92.5%±5%, and at an illumination of 45001x±5001x for 10 days; samples were taken from each test sample, and the purity and crystal form of the samples were determined. The results are shown in Table 1.

[0343] Table 1 Stability test results of Form B-III and Form A-III

[0344]

[0345]

[0346] It can be seen from the data in Table 1 that after the crystal form B-III of the hemi-tartrate salt of compound 78 and the crystal form A-III of the monohydrochloride salt of compound 78 were placed under high temperature, high humidity and light conditions for 10 days, the chemical purity did not change significantly; after the crystal form A-III was placed under high humidity conditions, the crystal form changed (such as Fig.15 , Fig.16 When placed under high temperature and light conditions, the crystal form did not change significantly; Crystal form B-III did not change significantly under all test conditions and had good stability.

[0347] Example 18 - Stability of Form B-II and Form B-III

[0348] Determination method 1: The crystal form B-II and crystal form B-III of the hemi-tartrate salt of compound 78 were placed in a culture dish, with the opening exposed, in a sealed clean container, and placed at 25°C and a relative humidity of 92.5%±5% for 3 days or 5 days to detect the crystal form. The results are shown in Table 2.

[0349] Determination method 2: The crystal forms B-II and B-III of the hemi-tartrate salt of compound 78 were suspended in water and stirred at room temperature. Samples were taken on the second and fourth days to detect the crystal forms. The results are shown in Table 2.

[0350] Table 2 Stability test results of the crystal form B-II and crystal form B-III of the hemi-tartrate salt of compound 78

[0351]

[0352] It can be seen from the data in Table 2 that the crystal form B-II of the hemi-tartrate salt of compound 78 is unstable under both test conditions. The presence of water induces the crystal form to change (e.g. Figure 17-19 In contrast, the crystalline form B-III of the hemi-tartrate salt of compound 78 remained unchanged when placed under high humidity conditions and slurried in water (as shown in FIG. Fig. 20 and 21 The stability is good.

[0353] Example 19 - Comparison of the solubility of the salt of Formula A and the free form of Compound 78 in different buffers

[0354] Determination method: Excessive amounts of the hemi-tartrate crystal form B-III of compound 78, the p-toluenesulfonate crystal form CI of compound 78, and the free form of compound 78 were suspended in different pH buffers and water, stirred at 37°C for 30 minutes, centrifuged, filtered, and the filtrate was taken to determine the solubility. The solubility results are all calculated in free form, and the results are shown in Table 3. The different pH buffers were prepared according to the United States Pharmacopoeia (USP40-NF35).

[0355] Table 3 Solubility of the salt and free form of compound 78 of formula A in different media

[0356]

[0357] It can be seen from the data in Table 3 that the crystalline form B-III of the hemi-tartrate salt of compound 78 has good solubility in a medium at pH 1.2 and also has good solubility in pure water, which is significantly higher than that of the crystalline form CI and the free form; the crystalline form CI of the p-toluenesulfonate salt of compound 78 has low solubility in all tested media, but is relatively stable; the solubility of the free form of compound 78 varies greatly in different media, with a solubility of up to 12.6 mg / ml in a buffer solution at pH 4.5, but low solubility in other media and pure water.

[0358] This shows that the salt of the present invention and the crystal form of the present invention have better solubility properties. On the one hand, compared with the free form of compound 78, the difference in solubility of the salt of the present invention at different pH values ​​is smaller, which makes the solubility of the salt of the present invention in body fluids with different pH values ​​in the body more stable. On the other hand, under the higher pH conditions of the gastrointestinal tract, the salt of the present invention and the crystal form of the present invention still have higher and more stable solubility, which is conducive to their full absorption, thereby producing higher bioavailability, and making the absorption of the drug in the body unaffected by eating.

[0359] Example 20 - Hygroscopicity of the Salt of Formula A

[0360] Determination method: The crystal forms B-III and B-II of the hemi-tartrate of compound 78 were placed in the sample dish of the dynamic moisture sorption instrument (DVS-INTRINSIC) and the moisture absorption and weight gain of the samples were tested at 25°C in the relative humidity range of 0-95%. Fig.10 and Fig.11 .

[0361] Depend on Fig.10 It can be seen from the curve that the crystalline form B-III of the hemi-tartrate salt of compound 78 is not hygroscopic when the ambient humidity is lower than 85% RH; and is slightly hygroscopic when the ambient humidity is higher than 85% RH.

[0362] Depend on Fig.11 It can be seen from the curve that the crystalline form B-II of the hemi-tartrate salt of compound 78 continuously absorbs moisture at 0 to 80% RH, and the hygroscopicity further increases when the ambient humidity is higher than 85% RH; after the sample absorbs moisture, the absorbed water has a hysteresis phenomenon in the desorption process.

[0363] Example 21 - Pharmacokinetic study of the salt of formula A in dogs

[0364] Preparation of drug delivery preparations

[0365] Intravenous formulation: 71.48 mg of the crystalline form B-III of the hemi-tartrate of compound 78 was dissolved in a mixture of 10% polyethylene glycol-15 hydroxystearate (Solutol), 10% ethanol and 80% saline (60.7 ml) to obtain a clear solution for intravenous administration.

[0366] Oral administration preparation (0.5 mg / ml, concentration calculated as free form): 71.54 mg of the crystalline form B-III of the hemi-tartrate salt of compound 78 was suspended in 121.5 ml of deionized water to obtain a suspension for oral administration to dogs in the 1 mg / kg dose group.

[0367] Drug administration and sampling

[0368] The experimental design is shown in Table 4 below.

[0369]

[0370] The blood sampling time points are shown in Table 5 below:

[0371]

[0372] Biological sample analysis methods

[0373] The concentration of free form of compound 78 in dog plasma was determined by liquid chromatography-mass spectrometry (LC-MS / MS).

[0374] Data processing

[0375] The non-compartmental statistical moment method was used to analyze the data and calculate the pharmacokinetic parameters of each dose group using the pharmacokinetic software Phoenix (version 6.2.1.51). max and T max The absolute bioavailability (F%) is calculated according to the following formula:

[0376] (AUC 0-∞，PO × Dosage IV ) / (AUC 0-∞，Iv × Dosage PO )

[0377] Where AUC 0-∞，PO The exposure of the free form of compound 78 in dogs after oral administration (AUC 0-∞ ), AUC 0-∞，IV The exposure of the free form of compound 78 in dogs after intravenous administration (AUC 0-∞ ),dose IV Refers to the dose administered intravenously. Po Refers to the dose for oral administration.

[0378] Results and Discussion

[0379] The average values ​​of the main pharmacokinetic parameters of the hemi-tartrate form B-III of compound 78 in dogs are shown in Tables 6 and 7.

[0380] The overall mean exposure (AUC) of the hemitartrate of Compound 78 in dogs after intravenous administration of Form B-III (containing 1.0 mg / kg of free Compound 78) was 0-∞ ) was 1880±349h·ng / ml; the overall mean clearance (CL) was 9.09±1.51ml / min / kg; the overall mean plasma elimination half-life (t 1 / 2 ) was 5.90±0.645h; the overall average steady-state distribution volume (Vss) was 2.95±0.399L / kg.

[0381] After oral administration of the crystalline form B-III of the hemi-tartrate salt of compound 78 (containing 1.0 mg / kg of compound 78 in free form, fasting), the overall mean time to peak plasma concentration (T max ) was 0.792±0.459h; the overall maximum average concentration (C max ) was 141±68.8ng / ml; the overall mean exposure (AUC0-∞) was 665±276h·ng / ml; the overall mean plasma elimination half-life (t 1 / 2 ) was 5.36±1.69h; the overall average absolute bioavailability (F%) was 35.4%.

[0382]

[0383]

[0384] in conclusion

[0385] After a single oral administration of 1 mg / kg of the crystal form B-III of the hemi-tartrate of compound 78 to beagles, good oral absorption was shown in the dog, with an absolute oral bioavailability of about 35.4%. The crystal form B-III of the hemi-tartrate of compound 78 was absorbed rapidly in the dog, with a peak time of about 1 hour. After a single intravenous injection of the crystal form B-III of the hemi-tartrate of compound 78 at a dose of 1 mg / kg, the clearance rate in the dog was 9.09±1.51 ml / min / kg, which is a low-clearance drug. The steady-state apparent distribution volume was 2.95±0.40 L / kg, indicating a wide distribution. In summary, the crystal form B-III of the hemi-tartrate of compound 78 showed good pharmacokinetic characteristics in dogs.

[0386] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and the disclosure of this application has prompted those skilled in the art to make various feasible improvements or modifications to the technical solutions of the present invention, which are all included in the subject matter and scope of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety and for all purposes.

Claims

1. Salts of formula A: wherein n is 0.5 and M is tartaric acid, and the salt of formula A is a crystalline 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, the crystalline form B-III has characteristic diffraction angles (2θ) of X-ray powder diffraction 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, the crystalline 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°; Further preferably, the crystalline form B-III has 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°, 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°; Most preferably, the crystalline form B-III has an X-ray powder diffraction spectrum as shown in FIG. 7 .

2. The salt of formula A according to claim 1, wherein the differential scanning calorimetry curve of the crystalline form B-III has an endothermic peak at about 269.2-271.3°C.

3. The salt of formula A according to any one of claims 1 to 2, wherein the crystalline form B-III has a thermogravimetric analysis curve as shown in Figure 9.

4. A pharmaceutical composition comprising an effective amount of the salt of formula A according to any one of claims 1 to 3, and optionally comprising a pharmaceutically acceptable carrier.

5. Use of a salt of formula A according to any one of claims 1 to 3 in the preparation of a medicament for preventing or treating a disease responsive to inhibition of FGFR activity, wherein the disease is cancer.

6. The method of claim 5, wherein the cancer is selected from the group consisting of lung cancer, gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, bile duct cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma and blood tumors.

7. The use according to claim 6, wherein the lung cancer is selected from squamous non-small cell lung cancer and small cell lung cancer.

8. The use according to claim 6, wherein the hematological tumor is a myeloproliferative neoplasm.

9. A combination product comprising a salt of formula A as claimed in any one of claims 1 to 3 and one or more other active ingredients.

10. The combination product according to claim 9, wherein the other active ingredient is selected from antineoplastic drugs.

11. The combination product according to claim 10, wherein the anti-tumor drug is selected from the group consisting of immunotherapy agents, DNA damaging chemotherapeutic agents and chemotherapeutic agents that interfere with cell replication.

12. A combination product according to any one of claims 9 to 11, wherein the salt of formula A and one or more other active ingredients can be administered simultaneously or sequentially in different unit dosage forms by the same or different administration routes, or simultaneously in the same unit dosage form.

13. Use of a combination product according to any one of claims 9 to 12 in the preparation of a medicament for preventing or treating a disease responsive to inhibition of FGFR activity, said disease being cancer.

14. The method of claim 13, wherein the cancer is selected from the group consisting of lung cancer, gastric cancer, liver cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, urothelial cancer, esophageal cancer, bile duct cancer, colon cancer, rectal cancer, head and neck cancer, cervical cancer, pancreatic cancer, adrenal cancer, glioma, mesothelioma and hematological tumors.

15. The use according to claim 14, wherein the lung cancer is selected from squamous non-small cell lung cancer and small cell lung cancer.

16. The use according to claim 14, wherein the hematological tumor is a myeloproliferative neoplasm.

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