WO2022089648A1 - Crystalline forms of salts of fgfr4 inhibitor - Google Patents

Crystalline forms of salts of fgfr4 inhibitor Download PDF

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Publication number
WO2022089648A1
WO2022089648A1 PCT/CN2021/128025 CN2021128025W WO2022089648A1 WO 2022089648 A1 WO2022089648 A1 WO 2022089648A1 CN 2021128025 W CN2021128025 W CN 2021128025W WO 2022089648 A1 WO2022089648 A1 WO 2022089648A1
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cancer
compound
crystalline form
fgfr4
disease
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PCT/CN2021/128025
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French (fr)
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Hongwei Yang
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Jacobio Pharmaceuticals Co., Ltd.
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Priority to CN202180074237.2A priority Critical patent/CN116528866A/en
Publication of WO2022089648A1 publication Critical patent/WO2022089648A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C07C55/07—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the inhibitor of FGFR4 is a hot research direction in the field of worldwide liver cancer therapeutic research, and the biopharmaceutical companies around the world are competing in the field of FGFR4 inhibitors.
  • no one drug of FGFR4 inhibitor has been marketed currently due to the limitation of experimental methods and the period of the research and so on. China has the highest incidence of liver cancer and the most patients with liver cancer in the world, thus the breakthrough in this direction of FGFR inhibitors will have strong significance to clinical application.
  • the present invention is aimed to provide a variety of new pharmaceutically acceptable salts of the compound I and the crystalline forms of those salts which can exhibit such excel-lent properties as good solubility and stability, low hygroscopicity, improved bioavailability and the like.
  • a crystalline form I of compound I phosphate is provided herein.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I L-malate according to any one of items 1-7; or the pharmaceutical composition according to item 10.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I phosphate according to item 18; or the pharmaceutical composition according to item 21.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I hydrochloride according to item 29; or the pharmaceutical composition according to item 32.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • X-ray powder diffraction pattern comprising characteristic peaks at 2 ⁇ val-ues of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, and 17.6 ⁇ 0.2°.
  • the crystalline Form I of Compound I maleate according to item 40 wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2 ⁇ value (s) selected from 11.6 ⁇ 0.2°, 12.1 ⁇ 0.2°, and 25.7 ⁇ 0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, 11.6 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.6 ⁇ 0.2°, and 25.7 ⁇ 0.2°.
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I maleate according to any one of items 40-45, and at least one pharmaceutically acceptable excipient.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I maleate according to item 40-45; or the pharmaceutical composition according to item 48.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a process of preparing the crystalline Form I of Compound I citrate according to item 56 comprising cooling a hot solution containing compound I and citric acid in acetone, and stirred for crystallization to obtain the crystalline Form I of Compound I citrate.
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I citrate according to item 56, and at least one pharmaceuti-cally acceptable excipient.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I citrate according to item 56; or the pharma-ceutical composition according to item 59.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • X-ray powder diffraction pattern comprising characteristic peaks at 2 ⁇ val-ues of 6.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, and 18.0 ⁇ 0.2°.
  • the crystalline Form I of Compound I tosilate according to item 67 wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2 ⁇ value (s) selected from 3.5 ⁇ 0.2°, 9.2 ⁇ 0.2°, and 23.7 ⁇ 0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2 ⁇ values of 3.5 ⁇ 0.2°, 6.9 ⁇ 0.2°, 9.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 18.0 ⁇ 0.2°, and 23.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2 ⁇ value (s) selected from 15.2 ⁇ 0.2°, 16.2 ⁇ 0.2°, and 18.7 ⁇ 0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2 ⁇ values of 3.5 ⁇ 0.2°, 6.9 ⁇ 0.2°, 9.2 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.2 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.7 ⁇ 0.2°, and 23.7 ⁇ 0.2°.
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I tosilate according to any one of items 67-73, and at least one pharmaceutically acceptable excipient.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I tosilate according to item 67-73; or the pharmaceutical composition according to item 76.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • X-ray powder diffraction pattern comprising characteristic peaks at 2 ⁇ val-ues of 7.2 ⁇ 0.2°, 14.9 ⁇ 0.2°, 18.1 ⁇ 0.2°, and 24.7 ⁇ 0.2°.
  • the crystalline Form I of Compound I besylate according to item 84, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2 ⁇ value (s) selected from 3.8 ⁇ 0.2°, 9.7 ⁇ 0.2°, and 11.9 ⁇ 0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2 ⁇ values of 3.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 14.9 ⁇ 0.2°, 18.1 ⁇ 0.2°, and 24.7 ⁇ 0.2°.
  • the crystalline Form I of Compound I besylate according to item 84 or 85, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2 ⁇ value (s) selected from 13.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, and 21.0 ⁇ 0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2 ⁇ values of 3.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.9 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, and 24.7 ⁇ 0.2°.
  • the crystalline Form I of Compound I besylate according to any one of items 84-86, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2 ⁇ value (s) selected from 19.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, and 22.8 ⁇ 0.2°.
  • the crystalline Form I of Compound I besylate according to any one of items 84-87, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2 ⁇ values of 3.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.9 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, and 24.7 ⁇ 0.2°.
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I besylate according to any one of items 84-89, and at least one pharmaceutically acceptable excipient.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I besylate according to item 84-89; or the pharmaceutical composition according to item 92.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the crystalline Form I of Compound I besylate according to item 84-89; or the pharmaceutical composition according to item 92 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  • a process of preparing the crystalline Form I of Compound I succinate according to item 100 comprising cooling a hot solution containing compound I and succinic acid in ace-tone, and stirred for crystallization to obtain the crystalline Form I of Compound I succinate.
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I succinate according to item 102, and at least one pharma-ceutically acceptable excipient.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I succinate according to item 102; or the pharmaceutical composition according to item 103.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a process of preparing the crystalline Form I of Compound I fumarate according to item 111 comprising cooling a hot solution containing compound I and fumaric acid in ace-tone, and stirred for crystallization to obtain the crystalline Form I of Compound I fumarate.
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I fumarate according to item 111, and at least one pharma- ceutically acceptable excipient.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I fumarate according to item 111; or the pharmaceutical composition according to item 114.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a process of preparing the crystalline Form I of Compound I oxalate according to item 122 comprising cooling a hot solution containing compound I and oxalic acid in acetone, and stirred for crystallization to obtain the crystalline Form I of Compound I oxalate.
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I oxalate according to item 122, and at least one pharmaceu-tically acceptable excipient.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I oxalate according to item 122; or the phar-maceutical composition according to item 125.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • Figure 1 The XRPD pattern for Crystalline Form I of Compound I phosphate.
  • FIG. 3 The TGA graph for Crystalline Form I of Compound I phosphate.
  • Figure 4 The XRPD pattern for Crystalline Form I of Compound I hydrochloride.
  • FIG. 6 The TGA graph for Crystalline Form I of Compound I hydrochloride.
  • Figure 8 The DSC thermogram for Crystalline Form I of Compound I maleate.
  • FIG. 12 The TGA graph for Crystalline Form I of Compound I citrate.
  • Figure 15 The HPLC graph for Crystalline Form I of Compound I L-malate.
  • Figure 22 The XRPD pattern for Crystalline Form I of Compound I L-malate of example 11.
  • Figure 30 The DSC thermogram for Crystalline Form I of Compound I oxalate.
  • degree 2 ⁇ allow appropriate error margins in the pre-sent invention.
  • the error margins are represented by “ ⁇ ” .
  • the degree 2 ⁇ of about “6.7 ⁇ 0.3” denotes a range from about 6.7+0.3, i.e., about 7.0, to about 6.7-0.3, i.e., about 6.4.
  • treat refers in some embodiments, to amelioration of the dis-ease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • treating refers to alleviation or amelioration of at least one physical parameter including those which may not be discernible by the patient.
  • %w/v %weight/volume
  • %w/v value refers to the amount of the particular component or ingredient in the formulation. It is commonly understood that equivalent concentrations can be expressed in different units. For example, a concentration of 0.1%w/v can also be expressed as a 1 mg/ml solution.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°and 9.4 ⁇ 0.2°, and further comprises optionally one or more characteristic peak (s) at 2 ⁇ val-ue (s) selected from 11.8 ⁇ 0.2° and 25.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.8 ⁇ 0.2° and 25.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.8 ⁇ 0.2° and 25.6 ⁇ 0.2°, and further comprises optionally one or more characteris-tic peak (s) at 2 ⁇ value (s) selected from 20.9 ⁇ 0.2° and 24.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.8 ⁇ 0.2°, 20.9 ⁇ 0.2°, 24.2 ⁇ 0.2°, and 25.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.8 ⁇ 0.2°, 13.5 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.7 ⁇ 0.2°, 24.2 ⁇ 0.2°, 25.6 ⁇ 0.2°, and 28.0 ⁇ 0.2°.
  • a process of preparing the crystalline Form I of Compound I L-malate comprising cooling a hot solution containing compound I and L-malic acid in acetone (for example cooling the hot solution to about 5°C to 30°C such as 5°C, 10°C, 15°C, 20°C, 25 °C, 30 °C, etc. ) , to crystallize compound I L-malate as crystalline Form I.
  • the amount of L-malic acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of com-pound I.
  • the L-malic acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30°C to 56°C(such as 30°C, 35°C, 40°C, 45°C, 50°C or 56°C) to obtain a hot solution, then cooling the hot solution to 10 to 30°C (such as 10°C, 15°C, 20°C, 25°C or 30°C) to crystallize compound I L-malate as crystalline Form I.
  • the crystalline Form I of Compound I L-malate of the present invention is the pharmaceutical composition containing the crystalline Form I of Compound I L-malate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4.
  • the disease or condi-tion related to FGFR4 is cancer.
  • the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I phosphate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I phosphate of the present invention.
  • the disease or con-dition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the X-ray powder diffraction pattern is substantially the same as Figure 4.
  • a process of preparing the crystalline Form I of Compound I hydrochloride comprising combining the compound I and hydrochloric acid in ethyl acetate at 10 to 30°C, to crystallize the Compound I hydrochloride as crystalline form I.
  • the amount of hydrochloric acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I.
  • the hydrochloric acid was added into a container containing Compound I dissolved in ethyl acetate dropwise at 10 to 30°C (such as 10°C, 15°C, 20°C, 25°C or 30°C) to crystallize the Compound I hydrochloride as crystalline form I.
  • crys-talline Form I of Compound I hydrochloride of the present invention in another aspect, provided herein is a pharmaceutical composition
  • a pharmaceutical composition comprising the crys-talline Form I of Compound I hydrochloride of the present invention and a pharmaceutical acceptable carrier, diluent or excipient.
  • a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I hydro-chloride of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I hydrochloride of the present invention.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the crystalline Form I of Compound I hydrochloride of the present invention is the pharmaceutical composition containing the crystalline Form I of Compound I hydrochloride of the present invention for use in treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • crystalline Form I of the compound I maleate (herein also referred to as crystalline Form I of formula I-3) having the structure of formula I-3 characterized by X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, and 17.6 ⁇ 0.2°:
  • the X-ray pow-der diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, 11.6 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.6 ⁇ 0.2°, and 25.7 ⁇ 0.2°, and further comprises optionally one or more characteristic peak (s) at 2 ⁇ value (s) selected from 9.5 ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.5 ⁇ 0.2°, and 22.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, 9.5 ⁇ 0.2°, 11.6 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.6 ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.5 ⁇ 0.2°, 22.8 ⁇ 0.2°, and 25.7 ⁇ 0.2°.
  • the X-ray pow-der diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.7 ⁇ 0.2°, 8.2 ⁇ 0.2°, 9.5 ⁇ 0.2°, 11.6 ⁇ 0.2°, 12.1 ⁇ 0.2°, 17.6 ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.5 ⁇ 0.2°, 22.8 ⁇ 0.2°, and 25.7 ⁇ 0.2°, and further comprises optionally one or more characteristic peak (s) at 2 ⁇ value (s) selected from 13.5 ⁇ 0.2°, 16.0 ⁇ 0.2°, 18.2 ⁇ 0.2°, and 18.6 ⁇ 0.2°.
  • the X-ray pow-der diffraction pattern is substantially the same as Figure 7.
  • a process of preparing the crystalline Form I of Compound I maleate comprising combining the compound I and maleic acid in ethyl acetate at 10 to 30°C, to crystallize Form I of Compound I maleate.
  • the amount of maleic acid is 1.0 to 1.5 equivalent (such as 1.0 equivalent, 1.1 equiv-alent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gas-tric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • crystalline Form I of the compound I citrate (herein also referred to as crystalline Form I of formula I-4) having the structure of formula I-4:
  • composition comprising the crys-talline Form I of Compound I citrate of the present invention and a pharmaceutical acceptable carrier, diluent or excipient.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I citrate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I citrate of the present invention.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the crystalline Form I of Compound I citrate of the present invention is the pharmaceutical composition containing the crystalline Form I of Compound I citrate of the present invention for use in treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • crystalline Form I of the compound I tosilate (herein also referred to as crystalline Form I of formula I-5) having the structure of formula I-5 characterized by X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 2 ⁇ values of 6.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, and 18.0 ⁇ 0.2°:
  • the X-ray pow-der diffraction pattern comprises characteristic peaks at 2 ⁇ values of 6.9 ⁇ 0.2°, 14.6 ⁇ 0.2°, and 18.0 ⁇ 0.2°, and further comprises optionally one or more characteristic peak (s) at 2 ⁇ value (s) selected from 3.5 ⁇ 0.2°, 9.2 ⁇ 0.2°, and 23.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 3.5 ⁇ 0.2°, 6.9 ⁇ 0.2°, 9.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 18.0 ⁇ 0.2°, and 23.7 ⁇ 0.2°.
  • the X-ray pow-der diffraction pattern comprises characteristic peaks at 2 ⁇ values of 3.5 ⁇ 0.2°, 6.9 ⁇ 0.2°, 9.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 18.0 ⁇ 0.2°, and 23.7 ⁇ 0.2°, and further comprises optionally one or more characteristic peak (s) at 2 ⁇ value (s) selected from 11.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, and 13.2 ⁇ 0.2°.
  • the X-ray powder dif-fraction pattern comprises characteristic peaks at 2 ⁇ values of 3.5 ⁇ 0.2°, 6.9 ⁇ 0.2°, 9.2 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 18.0 ⁇ 0.2°, and 23.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern further comprises characteristic peaks at 2 ⁇ val-ues of 3.5 ⁇ 0.2°, 6.9 ⁇ 0.2°, 9.2 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.2 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.7 ⁇ 0.2°, and 23.7 ⁇ 0.2°.
  • the X-ray pow-der diffraction pattern comprises characteristic peaks at 2 ⁇ values of 3.5 ⁇ 0.2°, 6.9 ⁇ 0.2°, 9.2 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.2 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.7 ⁇ 0.2°, and 23.7 ⁇ 0.2°, and further comprises optionally one or more characteristic peak (s) at 2 ⁇ value (s) selected from 19.6 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.5 ⁇ 0.2°, and 27.0 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 3.5 ⁇ 0.2°, 6.9 ⁇ 0.2°, 9.2 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.2 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.3 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.5 ⁇ 0.2°, and 27.0 ⁇ 0.2°.
  • the X-ray pow-der diffraction pattern is substantially the same as Figure 13.
  • a process of preparing the crystalline Form I of Compound I tosilate comprising combining the compound I and p-toluenesulfonic acid in THF at 10 to 30°C, to crystallize the Compound I tosilate as crystalline form I.
  • the amount of p-toluenesulfonic acid is 1.0 to 1.3 equivalent (such as 1.0 equivalent, 1.1 equivalent, 1.2 equivalent or 1.3 equivalent) of compound I.
  • crys-talline Form I of Compound I tosilate of the present invention in another aspect, provided herein is a pharmaceutical composition
  • a pharmaceutical composition comprising the crys-talline Form I of Compound I tosilate of the present invention and a pharmaceutical accepta-ble carrier, diluent or excipient.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I tosilate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I tosilate of the present invention.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the crystalline Form I of Compound I tosilate of the present invention is the pharmaceutical composition containing the crystalline Form I of Compound I tosilate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4.
  • the disease or condi- tion related to FGFR4 is cancer.
  • the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • crystalline Form I of the compound I besylate (herein also referred to as crystalline Form I of formula I-6) having the structure of formula I-6 characterized by X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 2 ⁇ values of 7.2 ⁇ 0.2°, 14.9 ⁇ 0.2°, 18.1 ⁇ 0.2°, and 24.7 ⁇ 0.2°:
  • the X-ray pow-der diffraction pattern comprises characteristic peaks at 2 ⁇ values of 7.2 ⁇ 0.2°, 14.9 ⁇ 0.2°, 18.1 ⁇ 0.2°, and 24.7 ⁇ 0.2° and further comprises optionally one or more characteristic peak (s) at 2 ⁇ value (s) selected from 3.8 ⁇ 0.2°, 9.7 ⁇ 0.2°, and 11.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 3.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 14.9 ⁇ 0.2°, 18.1 ⁇ 0.2°, and 24.7 ⁇ 0.2°.
  • the X-ray pow-der diffraction pattern comprises characteristic peaks at 2 ⁇ values of 3.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 14.9 ⁇ 0.2°, 18.1 ⁇ 0.2°, and 24.7 ⁇ 0.2°, and further comprises optionally one or more characteristic peak (s) at 2 ⁇ value (s) selected from 13.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, and 21.0 ⁇ 0.2°.
  • the X-ray powder diffraction pattern comprises characteristic peaks at 2 ⁇ values of 3.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.9 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, and 24.7 ⁇ 0.2°.
  • the X-ray pow-der diffraction pattern comprises characteristic peaks at 2 ⁇ values of 3.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.9 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, and 24.7 ⁇ 0.2°, further comprises optionally one or more characteristic peak (s) at 2 ⁇ value (s) selected from 19.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, and 22.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern further comprises characteristic peaks at 2 ⁇ values of 3.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.9 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, and 24.7 ⁇ 0.2°.
  • the X-ray pow-der diffraction pattern is substantially the same as Figure 14.
  • a process of preparing the crystalline Form I of Compound I besylate comprising combining the compound I and benzenesulfonic acid in ethyl acetate at 10 to 30°C, to crystallize the Compound I besylate as crystalline form I.
  • the amount of benzenesulfonic acid is 1.0 to 1.3 equivalent (such as 1.0 equivalent, 1.1 equivalent, 1.2 equivalent or 1.3 equivalent) of compound I.
  • the benzenesulfonic acid was added into a container con-taining Compound I dissolved in ethyl acetate dropwise at 10 to 30°C (such as 10°C, 15°C, 20°C, 25°C or 30°C) to crystallize the Compound I besylate as crystalline form I.
  • crys-talline Form I of Compound I besylate of the present invention in another aspect, provided herein is a pharmaceutical composition
  • a pharmaceutical composition comprising the crys-talline Form I of Compound I besylate of the present invention and a pharmaceutical accepta-ble carrier, diluent or excipient.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gas-tric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or pre-caution of a subject having a disease or condition related to FGFR4 comprising administering to the subject a therapeutically effective amount of crystalline Form I of Com-pound I besylate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I besylate of the present invention.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is se-lected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the crystalline Form I of Compound I besylate of the present invention is the pharmaceutical composition containing the crystalline Form I of Compound I besylate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4.
  • the disease or condi-tion related to FGFR4 is cancer.
  • the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • crystalline Form I of the compound I succinate (herein also referred to as crystalline Form I of formula I-8) having the structure of formula I-8:
  • the X-ray powder diffraction pattern is substantially the same as Figure 23.
  • a process of preparing the crystalline Form I of Compound I succinate comprising cooling a hot solution containing compound I and succinic acid in acetone (for example cooling the hot solution to about 5°C to 30°C such as 5°C, 10°C, 15°C, 20 °C, 25 °C, 30 °C , etc. ) , to crystallize the Compound I succinate as crystalline form I.
  • the amount of succinic acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I.
  • the succinic acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30°C to 56°C(such as 30°C, 35°C, 40°C, 45°C, 50°C or 56°C) to obtain a hot solution, then cooling the hot solution to 10 to 30°C (such as 10°C, 15°C, 20°C, 25°C or 30°C) to crystallize the Compound I succinate as crystalline form I.
  • composition comprising the crys-talline Form I of Compound I succinate of the present invention and a pharmaceutical ac-ceptable carrier, diluent or excipient.
  • a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I succinate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I succinate of the present invention.
  • the disease or con-dition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the crystalline Form I of Compound I succinate of the present invention is the pharmaceutical composition containing the crystalline Form I of Compound I succinate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4.
  • the disease or condi-tion related to FGFR4 is cancer.
  • the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • crystalline Form I of the compound I fumarate (herein also referred to as crystalline Form I of formula I-9) having the structure of formula I-9:
  • the X-ray powder diffraction pattern is substantially the same as Figure 26.
  • a process of preparing the crystalline Form I of Compound I fumarate comprising cooling a hot solution containing compound I and fumaric acid in acetone (for example cooling the hot solution to about 5°C to 30°C such as 5°C, 10°C, 15°C, 20 °C, 25 °C, 30 °C, etc. ) , to crystallize the Compound I fumarate as crystalline form I.
  • the amount of fumaric acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of com-pound I.
  • the fumaric acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30°C to 56°C(such as 30°C, 35°C, 40°C, 45°C, 50°C or 56°C) to obtain a hot solution, then cooling the hot solution to 10 to 30°C (such as 10°C, 15°C, 20°C, 25°C or 30°C) to crystallize the Compound I fumarate as crystalline form I.
  • a pharmaceutical composition comprising the crys-talline Form I of Compound I fumarate of the present invention and a pharmaceutical ac-ceptable carrier, diluent or excipient.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal can-cer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or pre- caution of a disease or condition related to FGFR4 in a subject comprising ad-ministering to the subject a therapeutically effective amount of crystalline Form I of Com-pound I fumarate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I fumarate of the present invention.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is se-lected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the crystalline Form I of Compound I fumarate of the present invention is the pharmaceutical composition containing the crystalline Form I of Compound I fumarate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4.
  • the disease or condi-tion related to FGFR4 is cancer.
  • the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the X-ray pow-der diffraction pattern is substantially the same as Figure 29.
  • a process of preparing the crystalline Form I of Compound I oxalate comprising cooling a hot solution containing compound I and oxalic acid in acetone (for example cooling the hot solution to about 5°C to 30°C such as 5°C, 10°C, 15°C, 20 °C, 25 °C, 30 °C, etc. ) , to crystallize the Compound I oxalate as crystalline form I.
  • the amount of oxalic acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I.
  • the oxalic acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30°C to 56°C (such as 30°C, 35°C, 40°C, 45°C, 50°C or 56°C) to obtain a hot solution, then cooling the hot solution to 10 to 30°C (such as 10°C, 15°C, 20°C, 25°C or 30°C) to crystallize the Compound I oxa-late as crystalline form I.
  • 30°C to 56°C such as 30°C, 35°C, 40°C, 45°C, 50°C or 56°C
  • 10 to 30°C such as 10°C, 15°C, 20°C, 25°C or 30°C
  • a pharmaceutical composition comprising the crys-talline Form I of Compound I oxalate of the present invention and a pharmaceutical accepta-ble carrier, diluent or excipient.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I oxalate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I oxalate of the present invention.
  • the disease or condition related to FGFR4 is cancer.
  • the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the crystalline Form I of Compound I oxalate of the present invention is the pharmaceutical composition containing the crystalline Form I of Compound I oxalate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4.
  • the disease or condi-tion related to FGFR4 is cancer.
  • the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  • the XRPD pattern data in the present invention were collected according to the follow-ing general protocol.
  • the XRPD was conducted for each sample using a Bruker D8 Advance Diffractometer (Instrument ID: LY-01-034, ⁇ -2 ⁇ goniometer, Momonochromator, Lynxeye detector) .
  • the X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively.
  • Data was col-lected using Collection Software (Diffrac Plus XRD Commander) at the Cu K ⁇ radiation with a wavelength of from 3.0 to 40 degrees (2 ⁇ ) using a step size of 0.02° (2 ⁇ ) degrees and a step time of 0.2 seconds.
  • Collection Software Diffrac Plus XRD Commander
  • a typical error associated with measurement can occur as a result of a variety of factors . Therefore peaks are considered to have a typical associated error of ⁇ 0.2° 2 ⁇ .
  • the model of the zero background sample holder is 24.6 mm diameter x1.0 mm thick-ness, manufactured by MTI corporation. Unless indicated otherwise, the sample hasn’t been ground before testing.
  • the XRPD patterns collected were imported into MDI Jade.
  • the measured XRPD pat-tern was aligned to a pattern of a sample with an internal reference to determine the absolute peak positions of the sample.
  • the internal reference used was corundum and the absolute peak position for corundum was calculated based on the corundum cell parameters. All peaks of the sample were extracted in a table with the accurate peak position together with the rela-tive peak intensities. A typical error for 2 ⁇ in this data is ⁇ 0.2°.
  • the minor error associated with this measurement can occur as a result of a variety of factors including:
  • sample preparation e.g., sample height
  • peaks are considered to have a typical associated error of ⁇ 0.2° 2 ⁇ .
  • the 2 ⁇ difference value between two adjacent characteristic peaks is less or more than 0.2° 2 ⁇ , one or two of the two characteristic peaks should be optionally selected.
  • the higher intensive peak has been preferably selected as the characteristic peak, and the lower intensive shoulder peak has not been selected as the characteristic peak.
  • DSC analyses were carried out with a TA Instruments Q200 DSC (Instrument ID: LY-01-002) .
  • the sample pan is aluminium covered without a hole.
  • the sample weight is 0.5 mg to 5 mg.
  • the samples were analyzed from the equilibrated temperature 25°C to the highest test temperature 250°C at a heating rate of 10°C/min under 50 mL/min nitrogen flow.
  • TGA measurements were performed using a TA Instruments Q500 TGA (Instrument ID: LY-01-003) using nitrogen purge gas at a rate of 40 ml/min (Hi-Res sensitivity 3.0; Ramp 10.00°C/min, res 5.0 to 150.00°C; Ramp 10.00°C/min to 300°C) .
  • the sample pan is a plati- num pan.
  • the sample weight is 1 mg to 10 mg.
  • Injection volume 10.00 ⁇ L
  • the mobile phase A H 2 O (10 mM K 2 HPO 4 ) ;
  • the XRPD pattern of the product shows that the solid form of the phosphate of Compound I is the crystalline form (referred to as crystalline Form I of Formula I-1 or crystalline Form I of compound I phosphate herein) .
  • the DSC thermogram shows that the crystalline of phosphate of compound I has a wide endothermic peak at 50 to 120°Cand a melting point at 154°C.
  • the TGA graph of the product shows that the crystal-line of phosphate of Compound I is anhydrous, and there is about 2.9%weight loss before 100°C and it has been decomposed at 154°C.
  • the XRPD pattern of the product shows that the solid form of the hydrochlo-ride of Compound I is the crystalline form (referred to as crystalline Form I of Formula I-2 or crystalline Form I of compound I hydrochloride herein) .
  • the DSC thermogram ( Figure 5) shows that the crystalline form of hydrochloride of compound I has a wide endothermic peak before 150°C, two continuous endothermic peaks at 150°C to 250°C, and has no obvious melting peak.
  • the TGA graph of the product shows that the crystalline form of hy-drochloride of compound I has about 6.3%weight loss before 100°C and it has been decom-posed at 174°C and 241°C.
  • the 1 H-NMR data of the product shows that the molar ratio of Compound I to maleic acid is 1: 1.
  • the XRPD pattern of the product ( Figure 7) shows that the solid form of the ma-leate of compound I is the crystalline form (referred to as crystalline Form I of Formula I-3 or crystalline Form I of compound I maleate herein) and the main peaks and their relative inten-sity in the Figure 7 are shown in the following Table 3.
  • the DSC thermogram of the product Figure 8) shows that the crystalline form of maleate of compound I has a melting point at 181°C and is accompanied by decomposition.
  • the TGA graph of the product ( Figure 9) shows that the crystalline form of maleate of compound I is anhydrous and it has been decomposed at 174°C.
  • the 1 H-NMR data of the product shows that the molar ratio of compound I to citric acid is 1: 1.
  • the XRPD pattern of the product ( Figure 10) shows that the solid form of the citrate of compound I is the crystalline form (referred to as crystalline Form I of Formula I-4 or crystal-line Form I of compound citrate herein) .
  • the DSC thermogram of the product ( Figure 11) shows that the crystalline form of citrate of compound I has a melting point at 160°C and is accompanied by decomposition.
  • the TGA graph of the product shows that the crystalline form of citrate of compound I is anhydrous and decomposes at 143°C.
  • the 1 H-NMR data of the product shows that the molar ratio of Compound I to p-toluenesulfonic acid is 1: 1.
  • the XRPD pattern of the product shows that the solid form of the tosilate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-5 or crystalline Form I of compound I tosilate herein) and the main peaks and their relative intensity in the Figure 13 are shown in the following Table 4.
  • the 1 H-NMR data of the product shows that the molar ratio of Compound I to benzene-sulfonic acid is 1: 1.
  • the XRPD pattern of the product shows that the solid form of the besylate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-6 or crystalline Form I of compound I besylate herein) and the main peaks and their relative intensity in the Figure 14 are shown in the following Table 5.
  • the 1 H-NMR data of the product shows that the molar ratio of Compound I to L-malic acid is 1: 1.
  • the purity of the product was 99%, which was analyzed by HPLC ( Figure 15) .
  • the XRPD pattern of the product shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crystal-line Forma I of compound I L-malate herein) .
  • the DSC thermogram of the product ( Figure 17) shows that the crystalline form of L-malate of compound I has a melting point at 169°C and is accompanied by decomposition.
  • the TGA graph ( Figure 18) shows that the product is anhy-drous and decomposes at 166°C.
  • the XRPD pattern of the product shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crys-talline Forma I of compound I L-malate herein) and the main peaks and their relative intensity in the Figure 19 are shown in the following Table 6.
  • the XRPD pattern of the product shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crys-talline Forma I of compound I L-malate herein) and the main peaks and their relative intensity in the Figure 20 are shown in the following Table 7.
  • the XRPD pattern of the product shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crys-talline Forma I of compound I L-malate herein) and the main peaks and their relative intensity in the Figure 21 are shown in the following Table 8.
  • the XRPD pattern of the product shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crys-talline Forma I of compound I L-malate herein) and the main peaks and their relative intensity in the Figure 22 are shown in the following Table 9.
  • the 1 H-NMR spectrum of the product shows that the molar ratio of Compound I to suc-cinic acid is 2: 1.
  • the XRPD pattern of the product ( Figure 23) shows that the solid form of the succinate of Compound I is a crystalline form (referred to as crystalline Form I of Formu-la I-8 or crystalline Form I of compound I succinate herein) .
  • the DSC thermogram of the product ( Figure 24) shows that the crystalline form of succinate of Compound I has a weak endothermic peak at 100 to 140°C, a melting point at 160°C and is accompanied by decompo-sition.
  • the TGA graph of the product ( Figure 25) shows that the crystalline form of succinate of compound I is anhydrous and decomposes at 130°C.
  • the 1 H-NMR spectrum of the product shows that the molar ratio of Compound I to fu-maric acid is 2: 1.
  • the XRPD pattern of the product ( Figure 26) shows that the solid form of the fumarate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-9 or crystalline Form I of compound I fumarate herein) .
  • the DSC thermogram of the prod-uct ( Figure 27) shows that the crystalline form of fumarate of Compound I has a weak endo-thermic peak 150 to 170°C, a melting point at 160°C and was accompanied by decomposition.
  • the TGA graph of the product ( Figure 28) shows that the crystalline form of fumarate of compound I is anhydrous and decomposes at 171°C.
  • the 1 H-NMR spectrum of the product shows that the molar ratio of Compound I to ox-alic acid is 2: 1.
  • the XRPD pattern of the product ( Figure 29) shows that the solid form of the oxalate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-8 or crystalline Form I of compound I oxalate herein) .
  • the DSC thermogram of the product ( Figure 30) shows that the crystalline form of oxalate of compound I has a melting point at 180°C and was accompanied by decomposition.
  • the TGA graph of the product shows that the crystalline form of oxalate of compound I is anhydrous and decomposes at 174°C.
  • the 1 H-NMR spectrum of the product has no characteristic peak of hydrogen atom of L-malic acid, it indicated that the solid form of the product was no longer the crystalline Form I of compound I L-malate.
  • the XRPD patterns were compared to observe whether the crystalline form of the sam-ple had changed after storing at 25°C/85%RH for 24h. It can be seen from the XRPD pat-terns that the crystalline form of Compound I phosphate and hydrochloride clearly had changed ( Figure 32 and Figure 33) , while other crystalline forms had not changed compared to their original crystalline forms respectively. Additionally, the color of the Compound I phosphate had changed from off-white to pink powder and the solid form of the Compound I hydrochloride had changed from crystalline to amorphous brown viscous solid.
  • the hygroscopicity of the sample was characterized by dynamic vapor sorption (DVS) using the above DVS instrument and method. The results were shown in the Table 11:
  • Healthy SD rats aged 6 ⁇ 8 weeks were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.
  • IVC individually ventilated cage
  • the tested sample such as crystalline Form I of compound I maleate, crystalline Form I of compound I tosilate or crystalline Form I of compound I L-malate
  • Tween 80 Tween 80
  • the mixture was smashed until no obvious particles, then the 0.5 wt%methyl cellulose water solution was added, sonicated for 15 to 20 mins, to obtain the suspension of tested sample at a concentration of 1 mg/mL.
  • Blood samples were taken from the rat’s orbit at 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 5 h, 7 h, 10 h, 24 h respectively after oral administration by gavage.
  • the blood samples were placed in cen-trifuge tube with ethylenediamine tetracetic acid (EDTA) as the anticoagulant. After centrifu-gation at 5000rpm/min for 10mins, 100 ⁇ L plasma was measured and stored at -80°C.
  • EDTA ethylenediamine tetracetic acid
  • V ACN : V H2O 1: 1
  • Injection volume 0.2 ⁇ L
  • the model of the chromatographic column Phenomenex Kinetex 5 ⁇ m C18 (100A (2.1*50) mm) chromatographic column;
  • Ion source electrospray ionization (ESI) ; Ionization mode: positive ion mode; Curtain Gas (CUR) : 30.00 Psi; Ion Source Gas1 (GS1) : 50.00 Psi; Ion Source Gas2 (GS2) : 50.00 Psi; IonSpray Voltage (IS) : 5500V; Temperature (TEM) : 600°C; Collision Gas (CAD) : 8.00 Psi; Interface Heater (ihe) condition: on;
  • the tested sample (such as the suspension of crystalline Form I of compound I maleate, the suspension of crystalline Form I of Compound I tosilate, or the solution of crystalline Form I of com- pound I besylate ) was administered to each rat in each group by oral gavage at a dosage of 10 mg/kg.
  • the result of PK study 1 as shown in Table 14 was obtained by the above-mentioned preparation of blood sample, analysis and detection.
  • Light exposure condition 25 ⁇ 5°C, the total illuminance is not less than 1.2x10 6 Lux ⁇ hr, the energy near ultraviolet is not less than 200 w ⁇ hr/m 2 , opened) ; or
  • Oxidation condition (opened) .
  • Accelerated condition (40°C/75%RH, opened and dark; 40°C/75%RH, sealed and dark) .
  • Light exposure condition (5000 Lux, 90 ⁇ w/cm 2 , opened) .
  • the crystalline Form I of Compound I L-malate of the present invention is much more stable than compound I (free base) under all the above three types of experimental conditions.
  • the percent of the total impu-rities in the compound I (free base) under high temperature condition is 11.67%at day 5, which is almost 292 times of the percent of total impurities in the compound I (free base) at day 0 (0.04%)
  • the percent of the total impurities in the crystalline Form I of Com-pound I L-malate of the present invention under high temperature condition is only 0.27%at day 5, which is only 4.5 times of the percent of total impurities in the crystalline Form I of Compound I L-malate at day 0 (0.06%)
  • the crystalline Form I of Compound I L-malate of the present invention is almost 55 times more stable than compound I (free base) .
  • the crystalline Form I of Compound I L-malate of the present invention possesses various excellent properties, such as physical and chemical stabil-ity and hygroscopicity, which can ensure that the medicine containing the Compound I as an active ingredient has a good industrial quality stability and quality uniformity for a long time when storing, for example, the crystalline form will not be influenced by humidity, tempera-ture and light etc. More importantly, it can be demonstrated by the highest AUC that the crys-talline Form I of Compound I L-malate has an enhanced bioavailability as compared to other crystalline forms, which renders it much more suitable for therapeutic use.
  • the crystalline Form I of Compound I L-malate of the present invention exhibits more excellent properties, including but not limited to physical and chemical stability, solubility, PK characteristics, hygroscopicity, and the like.

Abstract

Providing crystalline forms of salts of (R) -N-(5-cyano-4- ((1- (methylthio) propan-2-yl) amino) pyridin-2-yl) -7-formyl-6-((4-methyl-2-oxopiperazin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1(2H) -carboxamide, preparation process thereof, pharmaceutical composition containing such crystalline forms and use thereof.

Description

[Title established by the ISA under Rule 37.2] CRYSTALLINE FORMS OF SALTS OF FGFR4 INHIBITOR TECHNICAL FIELD
The present invention relates to crystalline forms of salts of FGFR4 inhibitors, in particular, to crystalline forms of salts of (R) -N- (5-cyano-4- ( (1- (methylthio) propan-2-yl) amino) pyridin-2-yl) -7-formyl-6- ( (4-methyl-2-oxopiperazin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide, preparation process thereof and use thereof.
BACKGROUND OF THE INVENTION
Fibroblast Growth Factor Receptor (FGFR) belongs to the family of receptor protein tyrosine kinases. Many signaling pathways, including Ras-MAPK, AKT-PI3K, and phospholipase C, can be activated through the binding of FGFR and its corresponding ligands, and these pathways play an important role in cell growth, proliferation and survival.
Alterations in FGFRs are associated with many human cancers, and these alterations, including overexpression of FGF ligand, FGFR or activated FGFR mutations, can lead to tumor occurrence, development and resistance to traditional cancer treatments by activating the pathway. Large-scale DNA sequencing of thousands of tumor samples revealed that components of the FGFR pathway are the most common mutations in human cancers. FGFR4 is a tyrosine kinase receptor in the human body encoded by the gene FGFR4 and is highly conserved in evolution, and it works by combining with its specific ligand FGF19. The signaling pathway of FGFR is roughly shown as follows: activated FGFR4 causes phosphorylation of FRS2 and recruits GRB2, thus the signaling pathways of Ras-Raf-ERK1/2MAPK and PI3K-Akt are finally activated, which makes the cells proliferate and resist apoptosis. More and more researches have indic ated that FGFR activation and the overexpression of FGF19 play an important role in the occurrence and development of liver cancer, and the inhibition of FGFR4 can eff  ectively reduce the occurrence of liver cancer. FGFR4, ligand FGF19 and coreceptor KLB were highly expressed in about 1/3 of liver cancer patients. In addition, the changes of FGFR4-FGF19 signal axis are also related to the occurrence of colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer, and thyroid cancer.
According to preliminary studies, fibroblast growth factor receptor 4 (FGFR4) inhibitors have great potential for the treatment of liver cancer, and have better pertinence and effectiveness than the similar drugs. Liver cancer, the second only to lung cancer, is the most common malignant tumor and fatal disease, and china has the most liver cancer patients in the world. Sorafenib, as the only approved first-line drug for the treatment of patients with advanced liver cancer, only extends average three months survival time of the patient, and it has strong side effects because it is a multi-targeted tyrosine kinase inhibitor. Therefore, the development of more effective liver cancer drugs has become an urgent need in the world, and FGFR4 inhibitors provide a possibility for breakthroughs in this area.
At present, the inhibitor of FGFR4 is a hot research direction in the field of worldwide liver cancer therapeutic research, and the biopharmaceutical companies around the world are competing in the field of FGFR4 inhibitors. However, no one drug of FGFR4 inhibitor has been marketed currently due to the limitation of experimental methods and the period of the research and so on. China has the highest incidence of liver cancer and the most patients with liver cancer in the world, thus the breakthrough in this direction of FGFR inhibitors will have strong significance to clinical application.
WO2020020377A1 had disclosed that the compound (R) -N- (5-cyano-4- ( (1- (methylthio) propan-2-yl) amino) pyridin-2-yl) -7-formyl-6- ( (4-methyl-2-oxopiperazin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (herein referred to as Compound Ⅰ) having the following structure can be used as a FGFR4 inhibitor, and the synthesis process of the compound I was described in Example 4 of WO2020020377A1.
Figure PCTCN2021128025-appb-000001
However, it is well-known that different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms and solvates may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient.
Drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystalline forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability and so on, which may have different influences on storage transfer, application, stability and efficacy of the drug. In order to obtain an effective crystalline form conducive to drug production or drug formulation, it is necessary to comprehensively investigate the crystallization behavior of drugs to obtain the crystalline form that meets the requirements of production. Pharmaceutical active substances used to prepare pharmaceutical compositions should be as pure as possible and must ensure long-term stability in a variety of environmental conditions. Therefore, the chemical stability, solid stability, shelf life and material treatment properties of pharmaceutical active substances are very important factors.
Thus, there is a need for the development of new pharmaceutically acceptable salts of the compound Ⅰ and the crystalline forms of such salts that can have desirable pharmaceutical properties and are suitable for the therapeutic use and the manufacturing process.
BRIEF SUMMARY OF THE INVENTION
The present invention is aimed to provide a variety of new pharmaceutically acceptable salts of the compound I and the crystalline forms of those salts which can exhibit such excel-lent properties as good solubility and stability, low hygroscopicity, improved bioavailability and the like.
In one aspect, provided herein is a crystalline form I of compound Ⅰ L-malate.
In one aspect, provided herein is a crystalline form I of compound Ⅰ phosphate.
In one aspect, provided herein is a crystalline form I of compound Ⅰ hydrochloride.
In one aspect, provided herein is a crystalline form I of compound Ⅰ maleate.
In one aspect, provided herein is a crystalline form I of compound Ⅰ citrate.
In one aspect, provided herein is a crystalline form I of compound Ⅰ tosilate.
In one aspect, provided herein is a crystalline form I of compound Ⅰ besylate.
In one aspect, provided herein is a crystalline form I of compound Ⅰ succinate.
In one aspect, provided herein is a crystalline form I of compound Ⅰ fumarate.
In one aspect, provided herein is a crystalline form I of compound Ⅰ oxalate.
In another aspect, provided herein is a method of preparing any one of the above-mentioned crystalline forms of salts of compound Ⅰ.
In another aspect, provided herein is a pharmaceutical composition comprising any one of the above-mentioned crystalline forms of salts of compound Ⅰ.
In another aspect, provided herein is use of any one of the above-mentioned crystalline forms of salts of compound Ⅰ, or the pharmaceutical composition in the manufacture of a me-dicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4, such as cancer, for example, liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma  and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of any one of the above-mentioned crystalline forms of salts of compound Ⅰ, or the pharmaceutical composition, wherein the disease or con-dition related to FGFR4 is cancer, including but not limited to liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In a further aspect, there is provided:
1. A crystalline Form I of Compound I L-malate,
Figure PCTCN2021128025-appb-000002
characterized by X-ray powder diffraction pattern comprising characteristic peaks at 2θ val-ues of 6.7±0.2°, 8.2±0.2° and 9.4±0.2°.
2. The crystalline Form I of Compound I L-malate according to item 1, wherein the X-ray powder diffraction pattern further comprises one or two characteristic peak (s) at 2θvalue (s) selected from 11.8±0.2° and 25.6±0.2°; preferably, the X-ray powder diffraction pat-tern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°and 25.6±0.2°.
3. The crystalline Form I of Compound I L-malate according to item 1 or 2, wherein the X-ray powder diffraction pattern further comprises one or two characteristic peak (s) at 2θvalue (s) selected from 20.9±0.2° and 24.2±0.2°; preferably, the X-ray powder diffraction pat-tern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 20.9±0.2°, 24.2±0.2° and 25.6±0.2°.
4. The crystalline Form I of Compound I L-malate according to any one of items 1-3, wherein the X-ray powder diffraction pattern further comprises one or two characteristic  peak (s) at 2θ value (s) selected from 13.5±0.2° and 19.0±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 13.5±0.2°, 19.0±0.2°, 20.9±0.2°, 24.2±0.2° and 25.6±0.2°.
5. The crystalline Form I of Compound I L-malate according to any one of items 1-4, wherein the X-ray powder diffraction pattern further comprises one or two characteristic peak (s) at 2θ value (s) selected from 22.7±0.2° and 28.0±0.2°.
6. The crystalline Form I of Compound I L-malate according to any one of items 1-5, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 13.5±0.2°, 19.0±0.2°, 20.9±0.2°, 22.7±0.2°24.2±0.2°, 25.6±0.2° and 28.0±0.2°.
7. The crystalline Form I of Compound I L-malate according to any one of items 1-6, wherein the X-ray powder diffraction pattern is substantially the same as Figure 16, Figure 19, Figure 20, Figure 21 or Figure 22.
8. A process of preparing the crystalline Form I of Compound I L-malate according to any one of items 1 to 7, comprising cooling a hot solution containing compound I and L-malic acid in acetone, and stirred for crystallization to obtain the crystalline Form I of Compound I L-malate.
9. The process according to item 8, wherein the amount of the L-malic acid is 1.1 to 1.5 equivalent of the compound I.
10. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I L-malate according to any one of items 1-7, and at least one pharmaceutically acceptable excipient.
11. Use of the crystalline Form I of Compound I L-malate according to any one of items 1-7; or the pharmaceutical composition according to item 10 for the manufacture of a me-dicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
12. The use according to item 11, wherein the disease or condition related to FGFR4 is cancer.
13. The use according to item 12, wherein the cancer is selected from liver cancer, head  and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
14. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I L-malate according to any one of items 1-7; or the pharmaceutical composition according to item 10.
15. The method according to item 14, wherein the disease or condition related to FGFR4 is cancer.
16. The method according to item 15, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
17. The crystalline Form I of Compound I L-malate according to any one of items 1-7; or the pharmaceutical composition according to item 10 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
18. A crystalline Form I of Compound I phosphate,
Figure PCTCN2021128025-appb-000003
characterized by X-ray powder diffraction pattern substantially the same as Figure 1.
19. A process of preparing the crystalline Form I of Compound I phosphate according to item 18, comprising cooling a hot solution containing compound I and phosphoric acid in ac-etone, and stirred for crystallization to obtain the crystalline Form I of Compound I phos-phate.
20. The process according to item 19, wherein the amount of the phosphoric acid is 1.1 to 1.5 equivalent of the compound I.
21. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I phosphate according to item 18, and at least one pharma- ceutically acceptable excipient.
22. Use of the crystalline Form I of Compound I phosphate according to item 18; or the pharmaceutical composition according to item 21 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
23. The use according to item 22, wherein the disease or condition related to FGFR4 is cancer.
24. The use according to item 23, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
25. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I phosphate according to item 18; or the pharmaceutical composition according to item 21.
26. The method according to item 25, wherein the disease or condition related to FGFR4 is cancer.
27. The method according to item 26, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
28. The crystalline Form I of Compound I phosphate according to item 18; or the phar-maceutical composition according to item 21 for use in the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4.
29. A crystalline Form I of Compound I hydrochloride,
Figure PCTCN2021128025-appb-000004
characterized by X-ray powder diffraction pattern substantially the same as Figure 4.
30. A process of preparing the crystalline Form I of Compound I hydrochloride accord- ing to item 29, comprising cooling a hot solution containing compound I and hydrochloric acid in ethyl acetate, and stirred for crystallization to obtain the crystalline Form I of Com-pound I hydrochloride.
31. The process according to item 30, wherein the amount of the hydrochloric acid is 1.1 to 1.5 equivalent of the compound I.
32. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I hydrochloride according to item 29, and at least one phar-maceutically acceptable excipient.
33. Use of the crystalline Form I of Compound I hydrochloride according to item 29; or the pharmaceutical composition according to item 32 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
34. The use according to item 33, wherein the disease or condition related to FGFR4 is cancer.
35. The use according to item 34, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
36. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I hydrochloride according to item 29; or the pharmaceutical composition according to item 32.
37. The method according to item 36, wherein the disease or condition related to FGFR4 is cancer.
38. The method according to item 37, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
39. The crystalline Form I of Compound I hydrochloride according to item 29; or the pharmaceutical composition according to item 32 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
40. A crystalline Form I of Compound I maleate,
Figure PCTCN2021128025-appb-000005
characterized by X-ray powder diffraction pattern comprising characteristic peaks at 2θ val-ues of 6.7±0.2°, 8.2±0.2°, and 17.6±0.2°.
41. The crystalline Form I of Compound I maleate according to item 40, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 11.6±0.2°, 12.1±0.2°, and 25.7±0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 11.6±0.2°, 12.1±0.2°, 17.6±0.2°, and 25.7±0.2°.
42. The crystalline Form I of Compound I maleate according to item 40 or 41, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 9.5±0.2°, 19.1±0.2°, 19.5±0.2°, and 22.8±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.1±0.2°, 17.6±0.2°, 19.1±0.2°, 19.5±0.2°, 22.8±0.2°, and 25.7±0.2°.
43. The crystalline Form I of Compound I maleate according to any one of items 40-42, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 13.5±0.2°, 16.0±0.2°, 18.2±0.2°, and 18.6±0.2°.
44. The crystalline Form I of Compound I maleate according to any one of items 40-43, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.1±0.2°, 13.5±0.2°, 16.0±0.2°, 17.6±0.2°, 18.2±0.2°, 18.6±0.2°, 19.1±0.2°, 19.5±0.2°, 22.8±0.2°, and 25.7±0.2°.
45. The crystalline Form I of Compound I maleate according to any one of items 40-44, wherein the X-ray powder diffraction pattern is substantially the same as Figure 7.
46. A process of preparing the crystalline Form I of Compound I maleate according to any one of items 40 to 45, comprising cooling a hot solution containing compound I and ma- leic acid in ethyl acetate, and stirred for crystallization to obtain the crystalline Form I of Compound I maleate.
47. The process according to item 46, wherein the amount of the maleic acid is 1.0 to 1.5 equivalent of the compound I.
48. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I maleate according to any one of items 40-45, and at least one pharmaceutically acceptable excipient.
49. Use of the crystalline Form I of Compound I maleate according to item 40-45; or the pharmaceutical composition according to item 48 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
50. The use according to item 49, wherein the disease or condition related to FGFR4 is cancer.
51. The use according to item 50, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
52. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I maleate according to item 40-45; or the pharmaceutical composition according to item 48.
53. The method according to item 52, wherein the disease or condition related to FGFR4 is cancer.
54. The method according to item 53, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
55. The crystalline Form I of Compound I maleate according to item 40-45; or the phar-maceutical composition according to item 48 for use in the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4.
56. A crystalline Form I of Compound I citrate,
Figure PCTCN2021128025-appb-000006
characterized by X-ray powder diffraction pattern substantially the same as Figure 10.
57. A process of preparing the crystalline Form I of Compound I citrate according to item 56, comprising cooling a hot solution containing compound I and citric acid in acetone, and stirred for crystallization to obtain the crystalline Form I of Compound I citrate.
58. The process according to item 57, wherein the amount of the citric acid is 1.1 to 1.5 equivalent of the compound I.
59. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I citrate according to item 56, and at least one pharmaceuti-cally acceptable excipient.
60. Use of the crystalline Form I of Compound I citrate according to item 56; or the pharmaceutical composition according to item 59 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
61. The use according to item 60, wherein the disease or condition related to FGFR4 is cancer.
62. The use according to item 61, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
63. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I citrate according to item 56; or the pharma-ceutical composition according to item 59.
64. The method according to item 63, wherein the disease or condition related to FGFR4 is cancer.
65. The method according to item 64, wherein the cancer is selected from liver cancer,  head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
66. The crystalline Form I of Compound I citrate according to item 56; or the pharma-ceutical composition according to item 59 for use in the treatment, prevention and/or precau-tion of a disease or condition related to FGFR4.
67. A crystalline Form I of Compound I tosilate,
Figure PCTCN2021128025-appb-000007
characterized by X-ray powder diffraction pattern comprising characteristic peaks at 2θ val-ues of 6.9±0.2°, 14.6±0.2°, and 18.0±0.2°.
68. The crystalline Form I of Compound I tosilate according to item 67, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θvalue (s) selected from 3.5±0.2°, 9.2±0.2°, and 23.7±0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 14.6±0.2°, 18.0±0.2°, and 23.7±0.2°.
69. The crystalline Form I of Compound I tosilate according to item 67 or 68, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 11.4±0.2°, 12.0±0.2°, and 13.2±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 18.0±0.2°, and 23.7±0.2°.
70. The crystalline Form I of Compound I tosilate according to any one of items 67-69, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 15.2±0.2°, 16.2±0.2°, and 18.7±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 15.2±0.2°, 16.2±0.2°, 18.0±0.2°, 18.7±0.2°, and 23.7±0.2°.
71. The crystalline Form I of Compound I tosilate according to any one of items 67-70, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 19.6±0.2°, 20.9±0.2°, 21.5±0.2°, 22.3±0.2°, 24.5±0.2°, and 27.0±0.2°.
72. The crystalline Form I of Compound I tosilate according to any one of items 67-71, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 15.2±0.2°, 16.2±0.2°, 18.0±0.2°, 18.7±0.2°, 19.6±0.2°, 20.9±0.2°, 21.5±0.2°, 22.3±0.2°, 23.7±0.2°, 24.5±0.2°, and 27.0±0.2°.
73. The crystalline Form I of Compound I tosilate according to any one of items 67-72, wherein the X-ray powder diffraction pattern is substantially the same as Figure 13.
74. A process of preparing the crystalline Form I of Compound I tosilate according to any one of items 67 to 73, comprising cooling a hot solution containing compound I and p-toluenesulfonic acid in THF, and stirred for crystallization to obtain the crystalline Form I of Compound I tosilate.
75. The process according to item 74, wherein the amount of the p-toluenesulfonic acid is 1.0 to 1.3 equivalent of the compound I.
76. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I tosilate according to any one of items 67-73, and at least one pharmaceutically acceptable excipient.
77. Use of the crystalline Form I of Compound I tosilate according to item 67-73; or the pharmaceutical composition according to item 76 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
78. The use according to item 77, wherein the disease or condition related to FGFR4 is cancer.
79. The use according to item 78, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
80. A method for the treatment, prevention and/or precaution of a disease or condition  related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I tosilate according to item 67-73; or the pharmaceutical composition according to item 76.
81. The method according to item 80, wherein the disease or condition related to FGFR4 is cancer.
82. The method according to item 81, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
83. The crystalline Form I of Compound I tosilate according to item 67-73; or the phar-maceutical composition according to item 76 for use in the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4.
84. A crystalline Form I of Compound I besylate,
Figure PCTCN2021128025-appb-000008
characterized by X-ray powder diffraction pattern comprising characteristic peaks at 2θ val-ues of 7.2±0.2°, 14.9±0.2°, 18.1±0.2°, and 24.7±0.2°.
85. The crystalline Form I of Compound I besylate according to item 84, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θvalue (s) selected from 3.8±0.2°, 9.7±0.2°, and 11.9±0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 14.9±0.2°, 18.1±0.2°, and 24.7±0.2°.
86. The crystalline Form I of Compound I besylate according to item 84 or 85, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 13.8±0.2°, 16.4±0.2°, and 21.0±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 13.8±0.2°, 14.9±0.2°, 16.4±0.2°, 18.1±0.2°, 21.0±0.2°, and 24.7±0.2°.
87. The crystalline Form I of Compound I besylate according to any one of items 84-86, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 19.8±0.2°, 20.3±0.2°, and 22.8±0.2°.
88. The crystalline Form I of Compound I besylate according to any one of items 84-87, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 13.8±0.2°, 14.9±0.2°, 16.4±0.2°, 18.1±0.2°, 19.8±0.2°, 20.3±0.2°, 21.0±0.2°, 22.8±0.2°, and 24.7±0.2°.
89. The crystalline Form I of Compound I besylate according to any one of items 84-88, wherein the X-ray powder diffraction pattern is substantially the same as Figure 14.
90. A process of preparing the crystalline Form I of Compound I besylate according to any one of items 84 to 89, comprising cooling a hot solution containing compound I and ben-zenesulfonic acid in ethyl acetate, and stirred for crystallization to obtain the crystalline Form I of Compound I besylate.
91. The process according to item 90, wherein the amount of the benzenesulfonic acid is 1.0 to 1.3 equivalent of the compound I.
92. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I besylate according to any one of items 84-89, and at least one pharmaceutically acceptable excipient.
93. Use of the crystalline Form I of Compound I besylate according to item 84-89; or the pharmaceutical composition according to item 92 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
94. The use according to item 93, wherein the disease or condition related to FGFR4 is cancer.
95 The use according to item 94, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
96. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I besylate according to item 84-89; or the  pharmaceutical composition according to item 92.
97. The method according to item 96, wherein the disease or condition related to FGFR4 is cancer.
98. The method according to item 97, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
99. The crystalline Form I of Compound I besylate according to item 84-89; or the pharmaceutical composition according to item 92 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
100. A crystalline Form I of Compound I succinate,
Figure PCTCN2021128025-appb-000009
characterized by X-ray powder diffraction pattern substantially the same as Figure 23.
101. A process of preparing the crystalline Form I of Compound I succinate according to item 100, comprising cooling a hot solution containing compound I and succinic acid in ace-tone, and stirred for crystallization to obtain the crystalline Form I of Compound I succinate.
102. The process according to item 101, wherein the amount of the succinic acid is 1.1 to 1.5 equivalent of the compound I.
103. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I succinate according to item 102, and at least one pharma-ceutically acceptable excipient.
104. Use of the crystalline Form I of Compound I succinate according to item 102; or the pharmaceutical composition according to item 103 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
105. The use according to item 104, wherein the disease or condition related to FGFR4 is cancer.
106. The use according to item 105, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
107. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I succinate according to item 102; or the pharmaceutical composition according to item 103.
108. The method according to item 107, wherein the disease or condition related to FGFR4 is cancer.
109. The method according to item 108, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
110. The crystalline Form I of Compound I succinate according to item 100; or the pharmaceutical composition according to item 103 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
111. A crystalline Form I of Compound I fumarate,
Figure PCTCN2021128025-appb-000010
characterized by X-ray powder diffraction pattern substantially the same as Figure 26.
112. A process of preparing the crystalline Form I of Compound I fumarate according to item 111, comprising cooling a hot solution containing compound I and fumaric acid in ace-tone, and stirred for crystallization to obtain the crystalline Form I of Compound I fumarate.
113. The process according to item 112, wherein the amount of the fumaric acid is 1.1 to 1.5 equivalent of the compound I.
114. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I fumarate according to item 111, and at least one pharma- ceutically acceptable excipient.
115. Use of the crystalline Form I of Compound I fumarate according to item 111; or the pharmaceutical composition according to item 114 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
116. The use according to item 115, wherein the disease or condition related to FGFR4 is cancer.
117. The use according to item 116, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
118. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I fumarate according to item 111; or the pharmaceutical composition according to item 114.
119. The method according to item 118, wherein the disease or condition related to FGFR4 is cancer.
120. The method according to item 119, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
121. The crystalline Form I of Compound I fumarate according to item 111; or the phar-maceutical composition according to item 114 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
122. A crystalline Form I of Compound I oxalate,
Figure PCTCN2021128025-appb-000011
characterized by X-ray powder diffraction pattern substantially the same as Figure 29.
123. A process of preparing the crystalline Form I of Compound I oxalate according to  item 122, comprising cooling a hot solution containing compound I and oxalic acid in acetone, and stirred for crystallization to obtain the crystalline Form I of Compound I oxalate.
124. A process of preparing the crystalline Form I of Compound I oxalate according to item 123, wherein the amount of the oxalic acid is 1.1 to 1.5 equivalent of the compound I.
125. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I oxalate according to item 122, and at least one pharmaceu-tically acceptable excipient.
126. Use of the crystalline Form I of Compound I oxalate according to item 122; or the pharmaceutical composition according to item 125 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
127. The use according to item 126, wherein the disease or condition related to FGFR4 is cancer.
128. The use according to item 127, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
129. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I oxalate according to item 122; or the phar-maceutical composition according to item 125.
130. The method according to item 129, wherein the disease or condition related to FGFR4 is cancer.
131. The method according to item 130, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
132. The crystalline Form I of Compound I oxalate according to item 122; or the phar-maceutical composition according to item 125 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ phosphate.
Figure 2: The DSC thermogram for Crystalline Form Ⅰ of Compound Ⅰ phosphate.
Figure 3: The TGA graph for Crystalline Form Ⅰ of Compound Ⅰ phosphate.
Figure 4: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ hydrochloride.
Figure 5: The DSC thermogram for Crystalline Form Ⅰ of Compound Ⅰ hydrochloride.
Figure 6: The TGA graph for Crystalline Form Ⅰ of Compound Ⅰ hydrochloride.
Figure 7: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ maleate.
Figure 8: The DSC thermogram for Crystalline Form Ⅰ of Compound Ⅰ maleate.
Figure 9: The TGA graph for Crystalline Form Ⅰ of Compound Ⅰ maleate.
Figure 10: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ citrate.
Figure 11: The DSC thermogram for Crystalline Form Ⅰ of Compound Ⅰ citrate.
Figure 12: The TGA graph for Crystalline Form Ⅰ of Compound Ⅰ citrate.
Figure 13: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ tosilate.
Figure 14: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ besylate.
Figure 15: The HPLC graph for Crystalline Form Ⅰ of Compound Ⅰ L-malate.
Figure 16: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ L-malate of example 7.
Figure 17: The DSC thermogram for Crystalline Form Ⅰ of Compound Ⅰ L-malate.
Figure 18: The TGA graph for Crystalline Form Ⅰ of Compound Ⅰ L-malate.
Figure 19: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ L-malate of example 8.
Figure 20: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ L-malate of example 9.
Figure 21: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ L-malate of example 10.
Figure 22: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ L-malate of example 11.
Figure 23: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ succinate.
Figure 24: The DSC thermogram for Crystalline Form Ⅰ of Compound Ⅰ succinate.
Figure 25: The TGA graph for Crystalline Form Ⅰ of Compound Ⅰ succinate.
Figure 26: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ fumarate.
Figure 27: The DSC thermogram for Crystalline Form Ⅰ of Compound Ⅰ fumarate.
Figure 28: The TGA graph for Crystalline Form Ⅰ of Compound Ⅰ fumarate.
Figure 29: The XRPD pattern for Crystalline Form Ⅰ of Compound Ⅰ oxalate.
Figure 30: The DSC thermogram for Crystalline Form Ⅰ of Compound Ⅰ oxalate.
Figure 31: The TGA graph for Crystalline Form Ⅰ of Compound Ⅰ oxalate.
Figure 32: The XRPD Plots of the Crystalline Form Ⅰ of Compound Ⅰ Phosphate in the Hy-groscopicity experiment.
Figure 33: The XRPD Plots of the Crystalline Form Ⅰ of Compound Ⅰ Hydrochloride in the Hygroscopicity experiment.
Figure 34: The XRPD Plots of the Stability Evaluation of Crystalline Form Ⅰ of Compound ⅠL-malate (part 1) .
Figure 35: The XRPD Plots of the Stability Evaluation of Crystalline Form Ⅰ of Compound ⅠL-malate (part 2) .
Figure 36: The XRPD Plots of the Stability Study of Crystalline Form Ⅰ of Compound ⅠL-malate for 7 Days.
Figure 37: The XRPD Plots of the Stability Study of Crystalline Form Ⅰ of Compound ⅠL-malate for 17 Days.
DETAILED DESCRIPTION OF THE INVENTION
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details. The description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with em-bodiments illustrated under any other heading.
DEFINITIONS
The compound of the present invention is named according to IUPAC rules using ChemBioDraw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols.  By way of example, the compound may be named or identified with common names, system-atic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry include but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC) . Accordingly, the compound Ⅰ having the above structure may also be named or identified as (R) -N- (5-cyano-4- ( (1- (methylthio) propan-2-yl) amino) pyridin-2-yl) -7-formyl-6- ( (4-methyl-2-oxopiperazin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide according to ChemBioDraw Ultra.
Unless indicated otherwise, the word “comprise” and variations thereof, such as, “com-prises” and “comprising” used herein are to be construed as “including, but not limited to" in an opened, inclusive sense. In other words, the other element (s) not specifically disclosed or listed may also be included. The terms “comprising” includes “consisting essentially of” . The term “consisting essentially of” includes “consisting of” .
Unless indicated otherwise, the singular forms “a” , “an” and "the" used herein include plural references.
Unless indicated otherwise, the term “about” used herein means having a value falling within an accepted standard error of the specified value, when considered by one of ordinary skill in the art.
Reference throughout this specification to “one embodiment” or “an embodiment” or “embodiments” means that a particular feature, structure or characteristic described in con-nection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
Unless indicated otherwise, the term “room temperature” used herein means the temper-ature range of the external circumstances is 20-30℃.
Unless indicated otherwise, the term “substantially” when referring, for example, to  1H-NMR spectrum, an XRPD pattern, a DSC thermogram or TGA graph, includes a pattern,  thermogram or graph that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art. For instance, the term "essentially the same" means that variability typical for a particular method is taken into account. For example, with reference to X-ray diffraction peak positions, the term "essentially the same" means that typical variability in peak position and intensity are taken into account. One skilled in the art will appreciate that the peak positions (2θ) will show some variability, typically as much as ± 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as varia-bility due to degree of crystallinity, preferred orientation, prepared sample surface and other factors known to those skilled in the art and should be taken as qualitative measures only.
Unless indicated otherwise, the term “X-ray powder diffraction (XRPD) pattern” as used herein refers to a diffraction pattern observed by an experiment or a parameter derived there-from. The X-ray powder diffraction pattern is characterized by the peak position and/or the peak intensity. The characteristic peaks of a given XRPD can be selected according to the peak locations and their relative intensity to conveniently distinguish this crystalline structure from others. The XRPD pattern in the present invention is obtained using the Bruker D8 Ad-vance Diffractometer. Those skilled in the art recognize that the measurements of the XRPD peak locations and/or intensity for a given crystalline form of the same compound will vary within a margin of error. The values of degree 2θ allow appropriate error margins in the pre-sent invention. Typically, the error margins are represented by “±” . For example, the degree 2θ of about “6.7±0.3” denotes a range from about 6.7+0.3, i.e., about 7.0, to about 6.7-0.3, i.e., about 6.4.
Unless indicated otherwise, the term “Differential Scanning Calorimeter (DSC) thermo-gram” as used herein refers to a thermogram generated by the Differential Scanning Calorim-eter.
Unless indicated otherwise, the term “Thermogravimetric Analysis (TGA) thermogram” as used herein refers to a graph generated by the Thermogravimetric Analytical instrument.
Unless indicated otherwise, the term “anhydrous” as used herein, refers to a crystalline form containing less than about 1 % (w/w) of adsorbed moisture as determined by standard  methods, such as a Karl Fisher analysis.
Unless indicated otherwise, the term “effective amount” as used herein, refers to that amount of a therapeutic compound necessary or sufficient to perform its intended function within a mammal. The effective amount of a therapeutic compound can vary according to factors such as the amount of the causative agent already present in the mammal, the age, sex, and weight of the mammal.
Unless indicated otherwise, the term “treat” , “treating” or “treatment” as used herein in connection with a disease or disorder refers in some embodiments, to amelioration of the dis-ease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another embodiment “treat” , "treating" or "treatment" refers to alleviation or amelioration of at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat” , "treat-ing" or "treatment" refers to modulation of the disease or disorder, either physically, (e.g., sta-bilization of a discernible symptom) , physiologically, (e.g, stabilization of a physical parame-ter) , or both. In yet another embodiment, “treat” , “treating” or “treatment” refers to prevention or delay of the onset or development or progression of the disease or disorder or symptom thereof.
Unless indicated otherwise, the term “subject” or “patient” as used herein, refers to hu-man and non-human mammals, including but, not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cows. In particular embodiments, a subject or patient is a human. In some embodiments, the term “patient” or “subject” refers to a human being who is diseased with the condition (i.e., disease or disorder) described herein and who would benefit from the treatment. As used herein, a subject is “in need of’ a treatment if such subject (patient) would benefit biologically, medically or in quality of life from such treatment.
Unless indicated otherwise, the term “FGFR4 kinase” and “FGFR4” can be used inter-changeably herein.
Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced  by an atom having a selected atomic mass or mass number different from the most abundant atomic mass or mass number in the nature. Isotopes can be radioactive or non-radioactive isotopes. Examples of isotopes that can be incorporated into compounds of the present dis-closure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to  2H (deuterium, D) ,  3H (triti-um) ,  11C,  13C,  14C,  15N,  18F,  31P,  32P,  35S,  36Cl and  125I. Isotopically labeled compounds of the present disclosure are equivalent to those unlabeled, for example, deuterated compounds of the present disclosure are equivalent to those non-deuterated. Such isotopically labelled com-pounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
Unless indicated otherwise, the term “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or com-plication, commensurate with a reasonable benefit /risk ratio.
Unless indicated otherwise, all ingredient concentrations are presented in units of %weight/volume (%w/v) . As is commonly understood, the %w/v value refers to the amount of the particular component or ingredient in the formulation. It is commonly understood that equivalent concentrations can be expressed in different units. For example, a concentration of 0.1%w/v can also be expressed as a 1 mg/ml solution.
Unless otherwise specified, the weight or dosage referred to herein for the crystalline forms of salts of compound I is the weight or dosage of the compound I itself, not that of a salt thereof. The weight or dosage of a corresponding salt of a compound suitable for the methods, compositions, or combinations disclosed herein may be calculated based on the ratio of the molecular weights of the salt and compound itself.
In one aspect, provided herein is a crystalline Form I of the compound I L-malate (herein also referred to as crystalline Form I of formula I-7) having the structure of formula I-7  characterized by X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2° and 9.4±0.2°:
Figure PCTCN2021128025-appb-000012
In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°and 9.4±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ val-ue (s) selected from 11.8±0.2° and 25.6±0.2°. In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2° and 25.6±0.2°.
In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2° and 25.6±0.2°, and further comprises optionally one or more characteris-tic peak (s) at 2θ value (s) selected from 20.9±0.2° and 24.2±0.2°. In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 20.9±0.2°, 24.2±0.2°, and 25.6±0.2°.
In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 20.9±0.2°, 24.2±0.2°, and 25.6±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 13.5±0.2° and 19.0±0.2°. In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder dif-fraction pattern further comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 13.5±0.2°, 19.0±0.2°, 20.9±0.2°, 24.2±0.2°, and 25.6±0.2°.
In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 13.5±0.2°, 19.0±0.2°, 20.9±0.2°, 24.2±0.2°, and 25.6±0.2°, and further  comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 22.7±0.2°and 28.0±0.2°. In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 13.5±0.2°, 19.0±0.2°, 20.9±0.2°, 22.7±0.2°, 24.2±0.2°, 25.6±0.2°, and 28.0±0.2°.
In some embodiments of the crystalline Form I of Compound I L-malate, the X-ray powder diffraction pattern is substantially the same as Figure 16, Figure 19, Figure 20, Figure 21, or Figure 22.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I L-malate, comprising cooling a hot solution containing compound I and L-malic acid in acetone (for example cooling the hot solution to about 5℃ to 30℃ such as 5℃, 10℃, 15℃, 20℃, 25 ℃, 30 ℃, etc. ) , to crystallize compound I L-malate as crystalline Form I. In some embodiments of the process, the amount of L-malic acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of com-pound I. In some embodiments of the process, the L-malic acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30℃ to 56℃(such as 30℃, 35℃, 40℃, 45℃, 50℃ or 56℃) to obtain a hot solution, then cooling the hot solution to 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize compound I L-malate as crystalline Form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I L-malate of the present invention and a pharmaceutical ac-ceptable carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I L-malate of the present invention; or the pharmaceutical composition containing the crystal-line Form I of Compound I L-malate of the present invention for the manufacture of a me-dicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal can-cer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma  and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I L-malate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I L-malate of the present invention. In some embodiments, the disease or con-dition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I L-malate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I L-malate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4. In some embodiments, the disease or condi-tion related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I phosphate (herein also referred to as crystalline Form I of formula I-1) having the structure of formula I-1:
Figure PCTCN2021128025-appb-000013
In some embodiments of the crystalline Form I of Compound I phosphate, the X-ray powder diffraction pattern is substantially the same as Figure 1.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I phosphate, comprising cooling a hot solution containing compound I and phos-phoric acid in acetone (for example cooling the hot solution to about 5℃ to 30℃ such as 5℃,  10℃, 15℃, 20℃, 25℃, 30℃, etc. ) , to crystallize the Compound I phosphate as crystalline Form I. In some embodiments of the process, the amount of phosphoric acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equiv-alent) of compound I. In some embodiments of the process, the phosphoric acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30℃ to 56℃ (such as 30℃, 35℃, 40℃, 45℃, 50℃ or 56℃) to obtain a hot solution, then cooling the hot solution to 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize Compound I phosphate as crystalline Form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I phosphate of the present invention and a pharmaceutical ac-ceptable carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I phos-phate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I phosphate of the present invention for the manufacture of a medica-ment for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal can-cer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I phosphate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I phosphate of the present invention. In some embodiments, the disease or con-dition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I phosphate of the present invention; or the pharmaceutical composition containing the crystalline Form I of  Compound I phosphate of the present invention for use in treatment, prevention and/or pre-caution of a disease or condition related to FGFR4. In some embodiments, the disease or con-dition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I hydrochloride (herein also referred to as crystalline Form I of formula I-2) having the structure of formula I-2:
Figure PCTCN2021128025-appb-000014
In some embodiments of the crystalline Form I of Compound I hydrochloride, the X-ray powder diffraction pattern is substantially the same as Figure 4.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I hydrochloride, comprising combining the compound I and hydrochloric acid in ethyl acetate at 10 to 30℃, to crystallize the Compound I hydrochloride as crystalline form I. In some embodiments of the process, the amount of hydrochloric acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I. In some embodiments of the process, the hydrochloric acid was added into a container containing Compound I dissolved in ethyl acetate dropwise at 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize the Compound I hydrochloride as crystalline form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I hydrochloride of the present invention and a pharmaceutical acceptable carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I hy-drochloride of the present invention; or the pharmaceutical composition containing the crys- talline Form I of Compound I hydrochloride of the present invention for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophage-al cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdo-myoma and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I hydro-chloride of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I hydrochloride of the present invention. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I hydrochloride of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I hydrochloride of the present invention for use in treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I maleate (herein also referred to as crystalline Form I of formula I-3) having the structure of formula I-3 characterized by X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, and 17.6±0.2°:
Figure PCTCN2021128025-appb-000015
In some embodiments of the crystalline Form I of Compound I maleate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, and 17.6±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 11.6±0.2°, 12.1±0.2°, and 25.7±0.2°. In some embodiments of the crystalline Form I of Compound I maleate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 11.6±0.2°, 12.1±0.2°, 17.6±0.2°, and 25.7±0.2°.
In some embodiments of the crystalline Form I of Compound I maleate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 11.6±0.2°, 12.1±0.2°, 17.6±0.2°, and 25.7±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 9.5±0.2°, 19.1±0.2°, 19.5±0.2°, and 22.8±0.2°. In some embodiments of the crystalline Form I of Compound I maleate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.1±0.2°, 17.6±0.2°, 19.1±0.2°, 19.5±0.2°, 22.8±0.2°, and 25.7±0.2°.
In some embodiments of the crystalline Form I of Compound I maleate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.1±0.2°, 17.6±0.2°, 19.1±0.2°, 19.5±0.2°, 22.8±0.2°, and 25.7±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 13.5±0.2°, 16.0±0.2°, 18.2±0.2°, and 18.6±0.2°. In some embodiments of the crystalline Form I of Compound I maleate, the X-ray powder diffraction pattern further comprises char-acteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.1±0.2°, 13.5±0.2°, 16.0±0.2°, 17.6±0.2°, 18.2±0.2°, 18.6±0.2°, 19.1±0.2°, 19.5±0.2°, 22.8±0.2°, and 25.7±0.2°.
In some embodiments of the crystalline Form I of Compound I maleate, the X-ray pow-der diffraction pattern is substantially the same as Figure 7.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I maleate, comprising combining the compound I and maleic acid in ethyl acetate at 10 to 30℃, to crystallize Form I of Compound I maleate. In some embodiments of the process, the amount of maleic acid is 1.0 to 1.5 equivalent (such as 1.0 equivalent, 1.1 equiv-alent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I. In some embodiments of the process, the maleic acid was added into a container containing Com- pound I dissolved in ethyl acetate dropwise at 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize the Compound I maleate as crystalline form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I maleate of the present invention and a pharmaceutical accepta-ble carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I male-ate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I maleate of the present invention for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodi-ments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gas-tric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I maleate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I maleate of the present invention. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I maleate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I maleate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4. In some embodiments, the disease or condi-tion related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I citrate (herein  also referred to as crystalline Form I of formula I-4) having the structure of formula I-4:
Figure PCTCN2021128025-appb-000016
In some embodiments of the crystalline Form I of Compound I citrate, the X-ray powder diffraction pattern is substantially the same as Figure 10.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I citrate, comprising cooling a hot solution containing compound I and citric acid in acetone (for example cooling the hot solution to about 5℃ to 30℃ such as 5℃, 10℃, 15℃, 20 ℃, 25 ℃, 30 ℃, etc. ) , to crystallize the Compound I citrate as crystalline form I. In some embodiments of the process, the amount of citric acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I. In some embodiments of the process, the citric acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30℃ to 56℃ (such as 30℃, 35℃, 40℃, 45℃, 50℃ or 56℃) to obtain a hot solution, then cooling the hot solution to 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize the Compound I citrate as crystalline form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I citrate of the present invention and a pharmaceutical acceptable carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I citrate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I citrate of the present invention for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal  cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I citrate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I citrate of the present invention. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I citrate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I citrate of the present invention for use in treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I tosilate (herein also referred to as crystalline Form I of formula I-5) having the structure of formula I-5 characterized by X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 2θ values of 6.9±0.2°, 14.6±0.2°, and 18.0±0.2°:
Figure PCTCN2021128025-appb-000017
In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 6.9±0.2°, 14.6±0.2°, and 18.0±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 3.5±0.2°, 9.2±0.2°, and 23.7±0.2°. In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray powder diffraction pattern comprises characteristic  peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 14.6±0.2°, 18.0±0.2°, and 23.7±0.2°.
In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 14.6±0.2°, 18.0±0.2°, and 23.7±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 11.4±0.2°, 12.0±0.2°, and 13.2±0.2°. In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray powder dif-fraction pattern comprises characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 18.0±0.2°, and 23.7±0.2°.
In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 18.0±0.2°, and 23.7±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 15.2±0.2°, 16.2±0.2°, and 18.7±0.2°. In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray powder diffraction pattern further comprises characteristic peaks at 2θ val-ues of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 15.2±0.2°, 16.2±0.2°, 18.0±0.2°, 18.7±0.2°, and 23.7±0.2°.
In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 15.2±0.2°, 16.2±0.2°, 18.0±0.2°, 18.7±0.2°, and 23.7±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 19.6±0.2°, 20.9±0.2°, 21.5±0.2°, 22.3±0.2°, 24.5±0.2°, and 27.0±0.2°. In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 15.2±0.2°, 16.2±0.2°, 18.0±0.2°, 18.7±0.2°, 19.6±0.2°, 20.9±0.2°, 21.5±0.2°, 22.3±0.2°, 23.7±0.2°, 24.5±0.2°, and 27.0±0.2°.
In some embodiments of the crystalline Form I of Compound I tosilate, the X-ray pow-der diffraction pattern is substantially the same as Figure 13.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I tosilate, comprising combining the compound I and p-toluenesulfonic acid in  THF at 10 to 30℃, to crystallize the Compound I tosilate as crystalline form I. In some em-bodiments of the process, the amount of p-toluenesulfonic acid is 1.0 to 1.3 equivalent (such as 1.0 equivalent, 1.1 equivalent, 1.2 equivalent or 1.3 equivalent) of compound I. In some embodiments of the process, the p-toluenesulfonic acid was added into a container containing Compound I dissolved in THF dropwise at 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize the Compound I tosilate as crystalline form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I tosilate of the present invention and a pharmaceutical accepta-ble carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I tosilate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I tosilate of the present invention for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I tosilate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I tosilate of the present invention. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I tosilate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I tosilate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4. In some embodiments, the disease or condi- tion related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I besylate (herein also referred to as crystalline Form I of formula I-6) having the structure of formula I-6 characterized by X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 2θ values of 7.2±0.2°, 14.9±0.2°, 18.1±0.2°, and 24.7±0.2°:
Figure PCTCN2021128025-appb-000018
In some embodiments of the crystalline Form I of Compound I besylate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 7.2±0.2°, 14.9±0.2°, 18.1±0.2°, and 24.7±0.2° and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 3.8±0.2°, 9.7±0.2°, and 11.9±0.2°. In some embodiments of the crystalline Form I of Compound I besylate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 14.9±0.2°, 18.1±0.2°, and 24.7±0.2°.
In some embodiments of the crystalline Form I of Compound I besylate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 14.9±0.2°, 18.1±0.2°, and 24.7±0.2°, and further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from 13.8±0.2°, 16.4±0.2°, and 21.0±0.2°. In some embodiments of the crystalline Form I of Compound I besylate, the X-ray powder diffraction pattern comprises characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 13.8±0.2°, 14.9±0.2°, 16.4±0.2°, 18.1±0.2°, 21.0±0.2°, and 24.7±0.2°.
In some embodiments of the crystalline Form I of Compound I besylate, the X-ray pow-der diffraction pattern comprises characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 13.8±0.2°, 14.9±0.2°, 16.4±0.2°, 18.1±0.2°, 21.0±0.2°, and 24.7±0.2°, further comprises optionally one or more characteristic peak (s) at 2θ value (s) selected from  19.8±0.2°, 20.3±0.2°, and 22.8±0.2°. In some embodiments of the crystalline Form I of Compound I besylate, the X-ray powder diffraction pattern further comprises characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 13.8±0.2°, 14.9±0.2°, 16.4±0.2°, 18.1±0.2°, 19.8±0.2°, 20.3±0.2°, 21.0±0.2°, 22.8±0.2°, and 24.7±0.2°.
In some embodiments of the crystalline Form I of Compound I besylate, the X-ray pow-der diffraction pattern is substantially the same as Figure 14.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I besylate, comprising combining the compound I and benzenesulfonic acid in ethyl acetate at 10 to 30℃, to crystallize the Compound I besylate as crystalline form I. In some embodiments of the process, the amount of benzenesulfonic acid is 1.0 to 1.3 equivalent (such as 1.0 equivalent, 1.1 equivalent, 1.2 equivalent or 1.3 equivalent) of compound I. In some embodiments of the process, the benzenesulfonic acid was added into a container con-taining Compound I dissolved in ethyl acetate dropwise at 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize the Compound I besylate as crystalline form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I besylate of the present invention and a pharmaceutical accepta-ble carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I besyl-ate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I besylate of the present invention for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodi-ments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gas-tric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a subject having a disease or condition related to FGFR4, said method comprising administering to the subject a therapeutically effective amount of crystalline Form I of Com-pound I besylate of the present invention; or the pharmaceutical composition containing the  crystalline Form I of Compound I besylate of the present invention. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is se-lected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I besylate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I besylate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4. In some embodiments, the disease or condi-tion related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I succinate (herein also referred to as crystalline Form I of formula I-8) having the structure of formula I-8:
Figure PCTCN2021128025-appb-000019
In some embodiments of the crystalline Form I of Compound I succinate, the X-ray powder diffraction pattern is substantially the same as Figure 23.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I succinate, comprising cooling a hot solution containing compound I and succinic acid in acetone (for example cooling the hot solution to about 5℃ to 30℃ such as 5℃, 10℃, 15℃, 20 ℃, 25 ℃, 30 ℃ , etc. ) , to crystallize the Compound I succinate as crystalline form I. In some embodiments of the process, the amount of succinic acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I. In some embodiments of the process, the succinic acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30℃ to 56℃(such as 30℃, 35℃, 40℃, 45℃, 50℃ or 56℃) to obtain a hot solution, then cooling the hot solution to 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize the Compound  I succinate as crystalline form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I succinate of the present invention and a pharmaceutical ac-ceptable carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I suc-cinate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I succinate of the present invention for the manufacture of a medica-ment for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal can-cer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I succinate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I succinate of the present invention. In some embodiments, the disease or con-dition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I succinate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I succinate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4. In some embodiments, the disease or condi-tion related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I fumarate (herein also referred to as crystalline Form I of formula I-9) having the structure of formula I-9:
Figure PCTCN2021128025-appb-000020
In some embodiments of the crystalline Form I of Compound I fumarate, the X-ray powder diffraction pattern is substantially the same as Figure 26.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I fumarate, comprising cooling a hot solution containing compound I and fumaric acid in acetone (for example cooling the hot solution to about 5℃ to 30℃ such as 5℃, 10℃, 15℃, 20 ℃, 25 ℃, 30 ℃, etc. ) , to crystallize the Compound I fumarate as crystalline form I. In some embodiments of the process, the amount of fumaric acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of com-pound I. In some embodiments of the process, the fumaric acid dissolved in acetone was added into a container containing Compound I dissolved in acetone dropwise at 30℃ to 56℃(such as 30℃, 35℃, 40℃, 45℃, 50℃ or 56℃) to obtain a hot solution, then cooling the hot solution to 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize the Compound I fumarate as crystalline form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I fumarate of the present invention and a pharmaceutical ac-ceptable carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I fumarate of the present invention; or the pharmaceutical composition containing the crystal-line Form I of Compound I fumarate of the present invention for the manufacture of a me-dicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal can-cer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre- caution of a disease or condition related to FGFR4 in a subject, said method comprising ad-ministering to the subject a therapeutically effective amount of crystalline Form I of Com-pound I fumarate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I fumarate of the present invention. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is se-lected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I fumarate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I fumarate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4. In some embodiments, the disease or condi-tion related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In one aspect, provided herein is a crystalline Form I of the compound I oxalate (herein also referred to as crystalline Form I of formula I-10) having the structure of formula I-10:
Figure PCTCN2021128025-appb-000021
In some embodiments of the crystalline Form I of Compound I oxalate, the X-ray pow-der diffraction pattern is substantially the same as Figure 29.
In another aspect, provided herein is a process of preparing the crystalline Form I of Compound I oxalate, comprising cooling a hot solution containing compound I and oxalic acid in acetone (for example cooling the hot solution to about 5℃ to 30℃ such as 5℃, 10℃, 15℃, 20 ℃, 25 ℃, 30 ℃, etc. ) , to crystallize the Compound I oxalate as crystalline form I. In some embodiments of the process, the amount of oxalic acid is 1.1 to 1.5 equivalent (such as 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent or 1.5 equivalent) of compound I. In some embodiments of the process, the oxalic acid dissolved in acetone was added into a  container containing Compound I dissolved in acetone dropwise at 30℃ to 56℃ (such as 30℃, 35℃, 40℃, 45℃, 50℃ or 56℃) to obtain a hot solution, then cooling the hot solution to 10 to 30℃ (such as 10℃, 15℃, 20℃, 25℃ or 30℃) to crystallize the Compound I oxa-late as crystalline form I.
In another aspect, provided herein is a pharmaceutical composition comprising the crys-talline Form I of Compound I oxalate of the present invention and a pharmaceutical accepta-ble carrier, diluent or excipient.
In another aspect, provided herein is use of the crystalline Form I of Compound I oxalate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I oxalate of the present invention for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is a method for the treatment, prevention and/or pre-caution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I of Compound I oxalate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I oxalate of the present invention. In some embodiments, the disease or condition related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
In another aspect, provided herein is the crystalline Form I of Compound I oxalate of the present invention; or the pharmaceutical composition containing the crystalline Form I of Compound I oxalate of the present invention for use in treatment, prevention and/or precau-tion of a disease or condition related to FGFR4. In some embodiments, the disease or condi-tion related to FGFR4 is cancer. In some embodiments, the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer,  lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
METHODS
The following Examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples:
Figure PCTCN2021128025-appb-000022
General Method 1: X-ray Powder Diffraction (XRPD)
The XRPD pattern data in the present invention were collected according to the follow-ing general protocol.
Instrument, parameters and method:
The XRPD was conducted for each sample using a Bruker D8 Advance Diffractometer (Instrument ID: LY-01-034, θ-2θ goniometer, Momonochromator, Lynxeye detector) . The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was col-lected using Collection Software (Diffrac Plus XRD Commander) at the Cu Kα radiation with a wavelength of
Figure PCTCN2021128025-appb-000023
from 3.0 to 40 degrees (2θ) using a step size of 0.02° (2θ) degrees and a step time of 0.2 seconds. A typical error associated with measurement can occur as a result of a variety of factors . Therefore peaks are considered to have a typical associated error of ±0.2° 2θ.
The model of the zero background sample holder is 24.6 mm diameter x1.0 mm thick-ness, manufactured by MTI corporation. Unless indicated otherwise, the sample hasn’t been  ground before testing.
Peak selection method:
The XRPD patterns collected were imported into MDI Jade. The measured XRPD pat-tern was aligned to a pattern of a sample with an internal reference to determine the absolute peak positions of the sample. The internal reference used was corundum and the absolute peak position for corundum was calculated based on the corundum cell parameters. All peaks of the sample were extracted in a table with the accurate peak position together with the rela-tive peak intensities. A typical error for 2θ in this data is ± 0.2°. The minor error associated with this measurement can occur as a result of a variety of factors including:
(a) sample preparation (e.g., sample height) ;
(b) instrument;
(c) calibration;
(d) operator (including those errors present when determining the peak locations) , and
(e) the nature of the material (e.g. preferred orientation and transparency errors) .
Therefore peaks are considered to have a typical associated error of ± 0.2° 2θ. No matter the 2θ difference value between two adjacent characteristic peaks is less or more than 0.2° 2θ, one or two of the two characteristic peaks should be optionally selected. Preferably when a higher intensive peak has a shoulder peak, no matter the 2θ difference value between the higher intensive peak and the shoulder peak are less or more than 0.2° 2θ, the higher intensive peak has been preferably selected as the characteristic peak, and the lower intensive shoulder peak has not been selected as the characteristic peak.
General Method 2: Differential Scanning Calorimetry (DSC)
DSC analyses were carried out with a TA Instruments Q200 DSC (Instrument ID: LY-01-002) . The sample pan is aluminium covered without a hole. The sample weight is 0.5 mg to 5 mg. The samples were analyzed from the equilibrated temperature 25℃ to the highest test temperature 250℃ at a heating rate of 10℃/min under 50 mL/min nitrogen flow.
General Method 3: The thermogravimetric analysis (TGA)
TGA measurements were performed using a TA Instruments Q500 TGA (Instrument ID: LY-01-003) using nitrogen purge gas at a rate of 40 ml/min (Hi-Res sensitivity 3.0; Ramp 10.00℃/min, res 5.0 to 150.00℃; Ramp 10.00℃/min to 300℃) . The sample pan is a plati- num pan. The sample weight is 1 mg to 10 mg.
General Method 4: Dynamic vapor sorption (DVS)
DVS were performed using following instrument and parameters:
Table 1. The parameters of the DVS
Figure PCTCN2021128025-appb-000024
General Method 5: High Performance Liquid Chromatography (HPLC)
The model of the HPLC system: Thermo DIONEX U3000;
The model of the chromatographic column: CERI L-Column3 C18 4.6×250mm, 5μm column;
Temperature of the column: 30℃;
Injection volume: 10.00 μL;
The mobile phase A: H 2O (10 mM K 2HPO 4) ;
The mobile phase B: ACN-THF (v/v=90: 10) ;
Flow rate: (1.0) mL/min;
Flow time: 52 mins.
The elution gradient is shown in the Table 2:
Table 2. The elution gradient of the HPLC
Time (min) mobile phase A (%) mobile phase B (%)
0 80 20
10 60 40
30 45 55
42 20 80
47 20 80
47.01 80 20
52 80 20
Example 1. Preparation of crystalline Form Ⅰ of Compound Ⅰ phosphate
Figure PCTCN2021128025-appb-000025
Compound I (26.8 mg) was dissolved in a flask with acetone (1.34 ml) , the mixture was stirred at 40℃ and phosphoric acid (6.9 mg, 1.2 equivalents of compound I) which was dis-solved in acetone (0.10ml) was added dropwise, precipitation occurred immediately. Then the mixture was cooled to room temperature and stirred overnight. The solid was collected by centrifugation and dried under nitrogen gas to obtain the product (the phosphate of compound I, Formula I-1) .
The XRPD pattern of the product (Figure 1) shows that the solid form of the phosphate of Compound I is the crystalline form (referred to as crystalline Form I of Formula I-1 or crystalline Form I of compound I phosphate herein) . The DSC thermogram (Figure 2) shows that the crystalline of phosphate of compound I has a wide endothermic peak at 50 to 120℃and a melting point at 154℃. The TGA graph of the product (Figure 3) shows that the crystal-line of phosphate of Compound I is anhydrous, and there is about 2.9%weight loss before 100℃ and it has been decomposed at 154℃.
Example 2. Preparation of crystalline Form Ⅰ of Compound Ⅰ hydrochloride
Figure PCTCN2021128025-appb-000026
Compound I (26.8 mg) was dissolved in a flask with ethyl acetate (5.4 ml) , the mixture was stirred at room temperature and hydrochloric acid (5.9 mg, 2.0 equivalents of Compound I) which was dissolved in methanol (0.10ml) was added dropwise, precipitation occurred im-mediately, then the mixture was stirred overnight. The solid was collected by centrifugation and dried under nitrogen gas to obtain the product (hydrochloride of compound I, Formula I-2) .
The XRPD pattern of the product (Figure 4) shows that the solid form of the hydrochlo-ride of Compound I is the crystalline form (referred to as crystalline Form I of Formula I-2 or crystalline Form I of compound I hydrochloride herein) . The DSC thermogram (Figure 5) shows that the crystalline form of hydrochloride of compound I has a wide endothermic peak before 150℃, two continuous endothermic peaks at 150℃ to 250℃, and has no obvious melting peak. The TGA graph of the product (Figure 6) shows that the crystalline form of hy-drochloride of compound I has about 6.3%weight loss before 100℃ and it has been decom-posed at 174℃ and 241℃.
Example 3. Preparation of crystalline Form Ⅰ of Compound Ⅰ maleate
Figure PCTCN2021128025-appb-000027
Compound I (309 mg) was dissolved in a flask with ethyl acetate (75 ml) , the mixture was stirred at room temperature and maleic acid (1.03 equivalents of Compound I) which was dissolved in ethyl acetate (0.2mol/ml, 3.0 ml) was added dropwise, precipitation occurred immediately, then the mixture was stirred overnight. The solid was collected by filtration and dried under vacuum at 35℃ to obtain the product (the maleate of compound I, Formula I-3) .
1H NMR (400 MHz, DMSO-d 6) δ 13.47 (s, 1H) , 10.07 (s, 1H) , 8.27 (s, 1H) , 7.60 (s, 1H) , 7.55 (s, 1H) , 6.78 (d, 1H) , 6.12 (s, 2H) , 4.93 (s, 2H) , 3.99 –3.91 (m, 2H) , 3.81 (dt, 1H) , 3.63 (s, 2H) , 3.44 (t, 2H) , 3.19 (s, 2H) , 2.93 (t, 2H) , 2.82 (dd, 1H) , 2.64 (t, 4H) , 2.14 (s, 3H) , 1.98 –1.88 (m, 2H) , 1.29 (d, 3H) .
The  1H-NMR data of the product shows that the molar ratio of Compound I to maleic acid is 1: 1. The XRPD pattern of the product (Figure 7) shows that the solid form of the ma-leate of compound I is the crystalline form (referred to as crystalline Form I of Formula I-3 or crystalline Form I of compound I maleate herein) and the main peaks and their relative inten-sity in the Figure 7 are shown in the following Table 3. The DSC thermogram of the product (Figure 8) shows that the crystalline form of maleate of compound I has a melting point at 181℃ and is accompanied by decomposition. The TGA graph of the product (Figure 9) shows that the crystalline form of maleate of compound I is anhydrous and it has been decomposed at 174℃.
Table 3. The main XRPD peaks and their relative intensity in the Figure 7
Peak position (°2θ) Relative intensity (%)
6.7 59.7
8.2 86.4
17.6 78.6
11.6 63.3
12.1 50.3
25.7 100.0
9.5 20.8
19.1 43.1
19.5 63.1
22.8 70.5
13.5 20.6
16.0 28.3
18.2 39.7
18.6 37.1
Example 4. Preparation of Crystalline Form Ⅰ of Compound I citrate
Figure PCTCN2021128025-appb-000028
Compound I (26.8 mg) was dissolved in a flask with acetone (1.34 ml) , the mixture was stirred at 40℃ and citric acid (11.5 mg, 1.2 equivalents of Compound I) which was dissolved in acetone (0.10ml) was added dropwise, precipitation occurred immediately. Then the mix- ture was cooled to room temperature and stirred overnight. The solid was collected by cen-trifugation and dried under nitrogen gas to obtain the product (the citrate of compound I, Formula I-4) .
1H NMR (400 MHz, DMSO-d 6) δ 13.46 (s, 1H) , 10.05 (s, 1H) , 8.25 (s, 1H) , 7.52 (d, 2H) , 6.75 (d, 1H) , 4.87 (s, 2H) , 4.02 –3.91 (m, 2H) , 3.85–3.74 (m, 1H) , 3.32 (d, 2H) , 3.15 (d, 2H) , 2.73 (d, 2H) , 2.69 (dd, , 1H) , 2.75 –2.65 (m, 7H) , 2.28 (s, 3H) , 2.12 (s, 3H) , 1.91 (d, 2H) , 1.30 (d, 3H) .
The  1H-NMR data of the product shows that the molar ratio of compound I to citric acid is 1: 1. The XRPD pattern of the product (Figure 10) shows that the solid form of the citrate of compound I is the crystalline form (referred to as crystalline Form I of Formula I-4 or crystal-line Form I of compound citrate herein) . The DSC thermogram of the product (Figure 11) shows that the crystalline form of citrate of compound I has a melting point at 160℃ and is accompanied by decomposition. The TGA graph of the product (Figure 12) shows that the crystalline form of citrate of compound I is anhydrous and decomposes at 143℃.
Example 5. Preparation of crystalline Form Ⅰ of Compound Ⅰ tosilate
Figure PCTCN2021128025-appb-000029
Compound I (1.04g) was dissolved in a flask with THF (20 ml) , the mixture was stirred at room temperature and p-toluenesulfonic acid which was dissolved in THF (0.2M, 10mL) was added dropwise, precipitation occurred after 10mins, then the mixture was stirred for 5 hrs. The solid was collected by filtration and dried in vacuum at 45℃ to obtain the product (the tosilate of compound I, Formula I-5) .
1H NMR (400 MHz, DMSO-d 6) δ 13.50 (s, 1H) , 10.06 (s, 1H) , 8.26 (s, 1H) , 7.66 (s, 1H) , 7.53 (s, 1H) , 7.48 (d, 2H) , 7.11 (d, 2H) , 6.81 (d, 1H) , 4.94 (s, 2H) , 4.01 (s, 2H) , 3.98 –3.91 (m, 2H) , 3.87 –3.75 (m, 1H) , 3.56 (s, 4H) , 2.91 (s, 4H) , 2.82 (dd, 1H) , 2.64 (dd, 1H) , 2.28 (s, 3H) , 2.13 (s, 3H) , 1.99 –1.86 (m, 2H) , 1.30 (d, 3H) .
The  1H-NMR data of the product shows that the molar ratio of Compound I to p-toluenesulfonic acid is 1: 1. The XRPD pattern of the product (Figure 13) shows that the solid form of the tosilate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-5 or crystalline Form I of compound I tosilate herein) and the main peaks and their relative intensity in the Figure 13 are shown in the following Table 4.
Table 4. The main XRPD peaks and their relative intensity in the Figure 13
Peak position (°2θ) Relative intensity (%)
6.9 100.0
14.6 64.5
18.0 72.9
3.5 33.3
9.2 23.9
23.7 99.6
11.4 29.9
12.0 31.7
13.2 34.7
15.2 42.1
16.2 29.9
18.7 30.9
19.6 48.9
20.9 47.1
21.5 33.7
22.3 30.8
24.5 27.5
27.0 44.5
Example 6. Preparation of crystalline Form Ⅰ of Compound Ⅰ besylate
Figure PCTCN2021128025-appb-000030
Compound I (1.0 g) was dissolved in a flask with ethyl acetate (160 ml) , the mixture was stirred at room temperature and benzenesulfonic acid which was dissolved in ethyl acetate (0.2M, 9.5mL) was added dropwise, precipitation occurred after 5 mins, then the mixture was stirred for 16 hrs. The solid was collected by filtration and dried in vacuum at 45℃ to obtain the product (the besylate of Compound Ⅰ, Formula I-6) .
1H NMR (400 MHz, DMSO-d 6) δ 13.57 (s, 1H) , 10.06 (s, 1H) , 8.27 (s, 1H) , 7.67 (s, 1H) , 7.64 –7.57 (m, 2H) , 7.51 (s, 1H) , 7.36 –7.29 (m, 3H) , 6.88 (d, 1H) , 4.95 (s, 2H) , 4.03 (s, 2H) , 3.99 –3.91 (m, 2H) , 3.88 –3.74 (m, 1H) , 3.70 –3.47 (m, 4H) , 3.00 –2.87 (m, 5H) , 2.82 (dd, 1H) , 2.65 (dd, 1H) , 2.13 (s, 3H) , 1.97 –1.84 (m, 2H) , 1.32 (t, 3H) .
The  1H-NMR data of the product shows that the molar ratio of Compound I to benzene-sulfonic acid is 1: 1. The XRPD pattern of the product (Figure 14) shows that the solid form of the besylate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-6 or crystalline Form I of compound I besylate herein) and the main peaks and their relative intensity in the Figure 14 are shown in the following Table 5.
Table 5. The main XRPD peaks and their relative intensity in the Figure 14
Peak position (°2θ) Relative intensity (%)
7.2 100.0
14.9 58.0
18.1 54.3
24.7 72.8
3.8 32.8
9.7 22.0
11.9 37.1
13.8 25.7
16.4 32.9
21.0 47.5
19.8 35.4
20.3 35.7
22.8 28.5
Example 7. Preparation of crystalline Form Ⅰ of Compound Ⅰ L-malate
Figure PCTCN2021128025-appb-000031
Compound I (26.8 mg) was dissolved in a flask with acetone (1.34 ml) , the mixture was stirred at 40℃ and L-malic acid (8.0 mg, 1.2 equivalents of Compound I) which was dis-solved in acetone (0.10 ml) was added dropwise. Then the mixture was cooled to room tem-perature and stirred for 40 mins, precipitation occurred. The solid was collected by centrifu- gation and dried with nitrogen gas to obtain the product (L-Malate of compound I, Formula I-7) .
1H NMR (400 MHz, DMSO-d 6) δ 13.48 (s, 1H) , 10.05 (s, 1H) , 8.23 (s, 1H) , 7.52 (s, 2H) , 6.75 (d, 1H) , 4.88 (s, 2H) , 4.25 (dd, 1H) , 3.99 –3.88 (m, 2H) , 3.80 (dt, 1H) , 3.29 (t, 2H) , 3.10 (s, 2H) , 2.92 (t, 2H) , 2.82 (dd, 1H) , 2.63 (m, 4H) , 2.44 (dd, 1H) , 2.27 (s, 3H) , 2.14 (s, 3H) , 1.97 –1.88 (m, 2H) , 1.30 (d, 3H) .
The  1H-NMR data of the product shows that the molar ratio of Compound I to L-malic acid is 1: 1. The purity of the product was 99%, which was analyzed by HPLC (Figure 15) . The XRPD pattern of the product (Figure 16) shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crystal-line Forma I of compound I L-malate herein) . The DSC thermogram of the product (Figure 17) shows that the crystalline form of L-malate of compound I has a melting point at 169℃ and is accompanied by decomposition. The TGA graph (Figure 18) shows that the product is anhy-drous and decomposes at 166℃.
In order to prepare the solid form of L-malate of Compound I, the molar ratio 1: 1.05 between Compound I and malic acid was used at the earlier exploring stage. However, there is no solid precipitating from the solution though the malic acid is enough. After trying some factors, the additional malic acid (about 0.15 equivalents of Compound I) was added, precipi-tation occurred unexpectedly.
Example 8. Preparation of crystalline Form Ⅰ of Compound Ⅰ L-malate
Compound Ⅰ L-malate (42.91 g) was dissolved in a flask with acetone (1.2 L) and water (0.1 L) at 40℃ to obtain the clear solution. The solution was stirred at 45℃ and L-malic acid (1.72 g) which was dissolved in acetone and water was added, cooled to room temperature and crystal seed (257 mg, 0.5%w/w of Compound I L-malate) which was mixed with acetone (5 ml) was added (the crystal seed was derived from Example 7) , stirred for 2h, precipitation occurred. Then the mixture cooled to -15℃ and stirred for 0.5h, centrifuged to collect the crude solid. The crude solid was washed with acetone by mixing and stirred with acetone. The solid was collected by centrifugation and dried with nitrogen gas to obtain the product (L-malate of compound I, Formula I-7) .
The XRPD pattern of the product (Figure 19) shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crys-talline Forma I of compound I L-malate herein) and the main peaks and their relative intensity in the Figure 19 are shown in the following Table 6.
Table 6. The main XRPD peaks and their relative intensity in the Figure 19
Peak position (°2θ) Relative intensity (%)
6.8 39.9
8.3 81.8
9.5 37.9
11.9 68.7
25.7 100.0
21.0 58.1
24.4 76.6
13.6 37.4
19.0 50.4
22.8 63.7
28.1 66.2
Example 9. Preparation of crystalline Form Ⅰ of Compound Ⅰ L-malate
Compound Ⅰ L-malate (81.28 g) was added in a flask with acetone (2.2 L) and water (0.2 L) , stirred at 50℃ and L-malic acid (3.27 g) which was dissolved in acetone (80 mL) was added, filtered to obtain the filtrate. The filtrate was stirred at 50℃, cooled to room tempera-ture and crystal seed (418 mg, 0.5%w/w of Compound I L-malate) which was mixed with acetone (8 ml) was added (the crystal seed was derived from Example 7) , stirred for 15 h, precipitation occurred. Then the mixture cooled to -10℃ and stirred for 3 h. The solid was collected by centrifugation and dried with nitrogen gas to obtain the product (L-Malate of compound I, Formula I-7) .
The XRPD pattern of the product (Figure 20) shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crys-talline Forma I of compound I L-malate herein) and the main peaks and their relative intensity in the Figure 20 are shown in the following Table 7.
Table 7. The main XRPD peaks and their relative intensity in the Figure 20
Peak position (°2θ) Relative intensity (%)
6.7 49.9
8.2 82.1
9.4 41.3
11.8 100.0
25.6 81.1
20.7 63.0
24.1 72.1
13.5 46.7
19.0 73.2
22.7 61.2
28.1 67.0
Example 10. Preparation of crystalline Form Ⅰ of Compound Ⅰ L-malate
Compound Ⅰ L-malate (110.99 g) was added in a flask with acetone (3.0 L) and water (0.3 L) , stirred at 47℃ and L-malic acid (4.41 g) which was dissolved in acetone (110 mL) was added, filtered to obtain the filtrate. The filtrate was stirred at 48℃, cooled to room tem-perature and crystal seed (0.55 g, 0.5%w/w of Compound I L-malate) which was mixed with acetone (22 ml) was added (the crystal seed was derived from Example 7) , stirred for 15 h, precipitation occurred. Then the mixture was cooled to -11℃ and stirred for 3 h. The solid was collected by centrifugation and dried with nitrogen gas to obtain the product (L-malate of compound I, Formula I-7) .
The XRPD pattern of the product (Figure 21) shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crys-talline Forma I of compound I L-malate herein) and the main peaks and their relative intensity in the Figure 21 are shown in the following Table 8.
Table 8. The main XRPD peaks and their relative intensity in the Figure 21
Peak position (°2θ) Relative intensity (%)
6.7 46.5
8.2 96.1
9.4 46.2
11.8 100.0
25.5 81.7
20.9 66.9
24.1 70.5
13.5 42.3
18.9 82.1
22.6 52.7
27.9 58.1
Example 11. Preparation of crystalline Form Ⅰ of Compound Ⅰ L-malate
Compound Ⅰ L-malate (412.54 g) was added in a flask with acetone (11.1 L) and water (1.2 L) , stirred at 51℃ and L-malic acid (16.52 g) which was dissolved in acetone was added, filtered to obtain the filtrate. The filtrate was stirred at 50℃, cooled to room temperature and crystal seed (2.07 g, 0.5%w/w of Compound I L-malate) which was mixed with acetone (41 ml) was added (the crystal seed was derived from Example 7) , stirred for 15 h, precipitation occurred. Then the mixture was cooled to -11℃ and stirred for 3 h. The solid was collected by centrifugation and dried with nitrogen gas to obtain the product (L-malate of compound I, Formula I-7) .
The XRPD pattern of the product (Figure 22) shows that the solid form of the L-malate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-7 or crys-talline Forma I of compound I L-malate herein) and the main peaks and their relative intensity in the Figure 22 are shown in the following Table 9.
Table 9. The main XRPD peaks and their relative intensity in the Figure 22
Peak position (°2θ) Relative intensity (%)
6.7 50.0
8.2 93.8
9.4 50.0
11.9 100.0
25.5 88.8
21.0 73.2
24.3 80.4
13.5 47.3
19.0 88.0
22.6 57.4
28.0 68.3
Example 12. Preparation of crystalline Form Ⅰ of Compound Ⅰ succinate
Figure PCTCN2021128025-appb-000032
Compound I (26.8 mg) was dissolved in a flask with acetone (1.34 ml) , the mixture was stirred at 40℃ and succinic acid (7.1 mg, 1.2 equivalents of Compound I) which was dis- solved in acetone (0.20ml) was added dropwise. Then the mixture was cooled to room tem-perature and stirred for 30mins, precipitation occurred, then the mixture was stirred overnight. The solid was collected by centrifugation and dried under nitrogen gas to obtain the product (succinate of Compound Ⅰ, Formula I-8) .
1H NMR (400 MHz, DMSO-d 6) δ 13.45 (s, 1H) , 12.13 (s, 0.5H) , 10.05 (s, 1H) , 8.24 (s, 1H) , 7.52 (d, 2H) , 6.74 (d, 1H) , 4.87 (s, 2H) , 3.95 –3.93 (m, 2H) , 3.82–3.77 (m, 1H) , 3.29–3.24 (m, 3H) , 3.04 (s, 2H) , 2.92 (dd, 2H) , 2.82 (dd, 1H) , 2.64–2.60 (m, 3H) , 2.40 (s, 1H) , 2.22 (s, 3H) , 2.12 (s, 3H) , 1.90 (d, 2H) , 1.30 (d, 3H) .
The  1H-NMR spectrum of the product shows that the molar ratio of Compound I to suc-cinic acid is 2: 1. The XRPD pattern of the product (Figure 23) shows that the solid form of the succinate of Compound I is a crystalline form (referred to as crystalline Form I of Formu-la I-8 or crystalline Form I of compound I succinate herein) . The DSC thermogram of the product (Figure 24) shows that the crystalline form of succinate of Compound Ⅰ has a weak endothermic peak at 100 to 140℃, a melting point at 160℃ and is accompanied by decompo-sition. The TGA graph of the product (Figure 25) shows that the crystalline form of succinate of compound I is anhydrous and decomposes at 130℃.
Example 13. Preparation of crystalline Form Ⅰ of Compound Ⅰ fumarate
Figure PCTCN2021128025-appb-000033
Compound Ⅰ (26.8 mg) was dissolved in a flask with acetone (1.34 ml) , the mixture was stirred at 40℃ and fumaric acid (7.0 mg, 1.2 equivalents of Compound I) which was dis-solved in acetone (0.10ml) was added dropwise. The mixture was cooled to room temperature and stirred for 20mins, precipitation occurred, then the mixture was stirred overnight. The solid was collected by centrifugation and dried with nitrogen gas to obtain the product (fumarate of Compound Ⅰ, Formula I-9) .
1H NMR (400 MHz, DMSO-d 6) δ 13.46 (s, 1H) , 10.06 (s, 1H) , 8.25 (s, 1H) , 7.51 (d, 2H) ,  6.75 (d, 1H) , 6.60 (s, 1H) , 4.87 (s, 2H) , 3.96 –3.93 (m, 2H) , 3.83–3.77 (m, 1H) , 3.29–3.24 (m, 3H) , 3.04 (s, 2H) , 2.92 (dd, 2H) , 2.82 (dd, 1H) , 2.64–2.59 (m, 3H) , 2.22 (s, 3H) , 2.11 (s, 3H) , 1.91 (d, 2H) , 1.30 (d, 3H) .
The  1H-NMR spectrum of the product shows that the molar ratio of Compound Ⅰ to fu-maric acid is 2: 1. The XRPD pattern of the product (Figure 26) shows that the solid form of the fumarate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-9 or crystalline Form I of compound I fumarate herein) . The DSC thermogram of the prod-uct (Figure 27) shows that the crystalline form of fumarate of Compound Ⅰ has a weak endo-thermic peak 150 to 170℃, a melting point at 160℃ and was accompanied by decomposition. The TGA graph of the product (Figure 28) shows that the crystalline form of fumarate of compound I is anhydrous and decomposes at 171℃.
Example 14. Preparation of crystalline Form Ⅰ of Compound Ⅰ oxalate
Figure PCTCN2021128025-appb-000034
Compound I (26.8 mg) was dissolved in a flask with acetone (1.34 ml) , the mixture was stirred at 40℃ and Dihydrate oxalic acid (7.6 mg, 1.2 equivalents of Compound I) which was dissolved in acetone (0.10ml) was added dropwise, precipitation occurred immediately. Then the mixture was cooled to room temperature and stirred overnight. The solid was collected by centrifugation and dried with nitrogen gas to obtain the product (the oxalate of Compound I, Formula I-10) .
1H NMR (400 MHz, DMSO-d 6) δ 13.49 (s, 1H) , 10.08 (s, 1H) , 8.28 (s, 1H) , 7.56 (d, 2H) , 6.79 (d, 1H) , 4.91 (s, 2H) , 4.02 –3.91 (t, 2H) , 3.88 –3.76 (m, 1H) , 3.35 (dd, 4H) , 2.92 (t, 4H) , 2.82 (dd, 1H) , 2.65 (dd, 1H) , 2.43 (s, 3H) , 2.14 (s, 3H) , 1.93 (d, 2H) , 1.30 (d, 3H) .
The  1H-NMR spectrum of the product shows that the molar ratio of Compound I to ox-alic acid is 2: 1. The XRPD pattern of the product (Figure 29) shows that the solid form of the oxalate of Compound I is a crystalline form (referred to as crystalline Form I of Formula I-8 or crystalline Form I of compound I oxalate herein) . The DSC thermogram of the product  (Figure 30) shows that the crystalline form of oxalate of compound I has a melting point at 180℃ and was accompanied by decomposition. The TGA graph of the product (Figure 31) shows that the crystalline form of oxalate of compound I is anhydrous and decomposes at 174℃.
Example 15.
The crystalline Form I of compound I L-malate (20 mg) was dissolved in acetone (1.5 ml) at 60℃, to obtain the clear solution. The solution was cooled to room temperature, and was slowly added into methyl tertbutyl ether (5 ml) , precipitation occurred. The mixture was stirred for 10-40 mins, and the solid was collected to obtain the product.
The  1H-NMR spectrum of the product has no characteristic peak of hydrogen atom of L-malic acid, it indicated that the solid form of the product was no longer the crystalline Form I of compound I L-malate.
Example 16.
The crystalline Form I of compound I L-malate (20 mg) was dissolved in THF (0.6 ml) at 60℃, to obtain the clear solution. The solution was cooled to room temperature, and was slowly added into isopropyl ether (5 ml) , precipitation occurred. The mixture was stirred for 10-40 mins, and the solid was collected to obtain the product.
The  1H-NMR spectrum of the product shows that the molar ratio of Compound I to the L-malate is 1: 0.58-0.82, it indicated that the crystalline Form I of compound I L-malate has been disintegrated.
Example 17 Water Solubility Study
The visual method was taken to measure the water solubility for the sample. Water was added gradually into a container with a known amount of the sample at 25℃. Then the mix-ture was stirred or treated ultrasonically in order to make the sample be dissolved to a clear solution. If the sample can be dissolved in water clearly, the amount of consumed water was recorded. If the solution was not clear at a 0.1 mg/ml, its solubility will be reported as “< 0.1” . If the solution was clear after adding lots of samples, its solubility will be reported as “>” the highest concentration. The results are shown in the following Table 10:
Table 10. Results of Water Solubility Study
Sample Water Solubility (mg/ml)
Crystalline Form I of Compound I maleate About 0.1
Crystalline Form I of Compound I citrate About 2.5
Crystalline Form I of Compound I L-malate About 0.1
Crystalline Form I of Compound I phosphate About 1.0
Crystalline Form I of Compound I succinate <0.1
Crystalline Form I of Compound I fumarate <0.1
Crystalline Form I of Compound I Hydrochloride >25
Crystalline From I of Compound I oxalate About 2.5
It can be seen from the above table that the water solubility of the Crystalline Form I of Compound I L-malate and Crystalline Form I of Compound I maleate is about 0.1, which in-dicates that Crystalline Form I of Compound I L-malate and Crystalline Form I of Compound I maleate are suitable for the manufacture of oral medicaments.
Example 18 Crystal Transformation Study
The XRPD patterns were compared to observe whether the crystalline form of the sam-ple had changed after storing at 25℃/85%RH for 24h. It can be seen from the XRPD pat-terns that the crystalline form of Compound Ⅰ phosphate and hydrochloride clearly had changed (Figure 32 and Figure 33) , while other crystalline forms had not changed compared to their original crystalline forms respectively. Additionally, the color of the Compound I phosphate had changed from off-white to pink powder and the solid form of the Compound I hydrochloride had changed from crystalline to amorphous brown viscous solid.
Example 19 Hygroscopicity Study
The hygroscopicity of the sample was characterized by dynamic vapor sorption (DVS) using the above DVS instrument and method. The results were shown in the Table 11:
Table 11 Results of Hygroscopicity Study
Figure PCTCN2021128025-appb-000035
It can be seen from the Table 11 that the crystalline Form I of Compound I Maleate is hygroscopic, the crystalline Form I of Compound I L-malate is slightly hygroscopic and the crystalline Form I of Compound I oxalate is also slightly hygroscopic.
Example 20 PK Study
Source of rats and feeding conditions:
Healthy SD rats aged 6～8 weeks were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.
SD rats were reared in each individually ventilated cage (IVC) and drank and ate freely. The conditions within the IVC: Temperature: 20～26℃; Humidity: 30～70%; Frequency of ventilation: 10-20 times/h; Diurnal rhythm: 12h/12h.
Preparation of the suspension of the tested sample
To the vortex mixer with steel balls were added the tested sample (such as crystalline Form I of compound I maleate, crystalline Form I of compound I tosilate or crystalline Form I of compound I L-malate) and Tween 80, the mixture was smashed until no obvious particles, then the 0.5 wt%methyl cellulose water solution was added, sonicated for 15 to 20 mins, to obtain the suspension of tested sample at a concentration of 1 mg/mL.
Preparation of the solution of the tested sample
To the vortex mixer were added the Polyoxyl 15 hydroxystearate (solutol) and the tested sample (such as crystalline Form I of compound I besylate or crystalline Form I of compound I oxalate) and DMSO, then saline was slowly added, the volume ratio of DMSO, solutol and saline was 1: 1: 8, and the mixture was stirred to obtain the solution of the tested sample at a concentration of 1 mg/mL.
Preparation of blood sample:
Blood samples were taken from the rat’s orbit at 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 5 h, 7 h, 10 h, 24 h respectively after oral administration by gavage. The blood samples were placed in cen-trifuge tube with ethylenediamine tetracetic acid (EDTA) as the anticoagulant. After centrifu-gation at 5000rpm/min for 10mins, 100μL plasma was measured and stored at -80℃. 50μL plasma and 5μL fluid infusion (V ACN: V H2O = 1: 1) and 200μL ACN containing verapamil as internal standard compound were mixed together, and then at 4℃ the supernatant was sepa-rated by centrifuging the mixture at 4600rpm/min. The supernatant and water were mixed together to obtain plasma homogenate sample, the volume ratio of supernatant and water was 1: 2.
Analysis and detection:
The reversed-phased liquid chromatography with tandem mass spectrometry (LCM S/MS) in positive ion mode equipped with UV detector was used to quantificationally analyze the compound I in SD rat’s plasma.
Injection volume: 0.2 μL;
The model of the chromatographic column: Phenomenex Kinetex 5μm C18 (100A (2.1*50) mm) chromatographic column;
The mobile phase A: V ACN: V H2O=5: 95, H 2O (0.1%HCOOH) ;
The mobile phase B: V ACN: V H2O=95: 5, H 2O (0.1%HCOOH) ;
Flow rate: 0.6 ml/min;
Flow time: 3.80 mins;
The elution gradient is shown in the Table 12:
Table 12 The elution gradient of the LCMS/MS
time (min) mobile phase A (%) mobile phase B (%)
0.00 100 0
0.30 100 0
2.20 5.00 95.0
3.00 5.00 95.0
3.01 100 0
3.80 100 0
The parameters of the mass spectrometer:
Ion source: electrospray ionization (ESI) ; Ionization mode: positive ion mode; Curtain Gas (CUR) : 30.00 Psi; Ion Source Gas1 (GS1) : 50.00 Psi; Ion Source Gas2 (GS2) : 50.00 Psi; IonSpray Voltage (IS) : 5500V; Temperature (TEM) : 600℃; Collision Gas (CAD) : 8.00 Psi; Interface Heater (ihe) condition: on;
The remaining parameters were described in the Table 13:
Table 13 The remaining parameters of the mass spectrometer
Figure PCTCN2021128025-appb-000036
(1) PK study 1
Nine healthy male SD rats were randomly divided equally into three groups. The tested sample (such as the suspension of crystalline Form I of compound I maleate, the suspension of crystalline Form I of Compound I tosilate, or the solution of crystalline Form I of com- pound I besylate ) was administered to each rat in each group by oral gavage at a dosage of 10 mg/kg. The result of PK study 1 as shown in Table 14 was obtained by the above-mentioned preparation of blood sample, analysis and detection.
Table 14 Results of PK Study 1
Figure PCTCN2021128025-appb-000037
It can be seen that the tested samples have essentially identical AUC last.
(2) PK study 2
Nine healthy male or female SD rats were divided randomly equally into three groups. Each group consisted of three female rats or three male rats. The tested sample (such as the suspension of crystalline Form I of compound I maleate, the suspension of crystalline Form I of Compound I L-malate or the solution of crystalline Form I of Compound I oxalate) was administered to each rat from each group by oral gavage at a dosage of 10 mg/kg. The results as shown in Table 15 were obtained by the above-mentioned preparation of blood sample, analysis and detection.
Table 15 Results of PK Study 2
Figure PCTCN2021128025-appb-000038
It can be seen from the above Table 15 that the AUC of the suspension of crystalline Form I of Compound I L-malate is higher than the suspension of crystalline Form I of Com-pound I maleate or the solution of crystalline Form I of Compound I oxalate in both male or female groups. This indicates that the absorption of the crystalline Form I of Compound I L-malate is better than the other sample, therefore, it is much more suitable for therapeutic use and suitable to manufacture a convenient oral formulation.
From the PK study 1 and PK study 2, it can be confirmed that the crystalline Form I of Compound I L-malate exhibits the best PK characteristics among many other crystalline  forms.
Example 21 Stability Evaluation of Crystalline Form I of Compound I L-malate
(1) Stability study 1
The crystalline Form I of Compound I L-malate was put into each of vials, then placed respectively under following experimental condition:
Room temperature condition (laboratorial bench, opened) ;
High temperature condition (drying oven, 60℃, opened) ;
Accelerated condition (40±2℃, 75±5%RH, opened) ;
Light exposure condition (25±5℃, the total illuminance is not less than 1.2x10 6 Lux·hr, the energy near ultraviolet is not less than 200 w·hr/m 2, opened) ; or
Oxidation condition (opened) .
The XRPD pattern for each sample under each condition as shown in Figure 34 or Figure 35 was obtained on day 5 and day 10. It can be seen from these XRPD patterns that the crys-talline Form I of Compound I L-malate remained unchanged under majority of conditions for 5 days and 10 days except under the oxidation condition.
(2) Stability study 2
The crystalline Form I of Compound I L-malate was put into each of vials, then placed respectively under following experimental condition:
Long-term condition (25℃/60%RH, opened and dark; 25℃/60%RH, sealed and dark) ; or
Accelerated condition (40℃/75%RH, opened and dark; 40℃/75%RH, sealed and dark) .
The XRPD pattern for each sample under each above-mentioned condition as shown in Figure 36 or Figure 37 was obtained on day 7 and day 17. It can be seen from these XRPD patterns that the crystalline Form I of Compound I L-malate remained unchanged under the long-term condition or the accelerated condition for 7 days and 17 days.
It can be confirmed from the stability study 1 and stability study 2 that the crystalline Form I of Compound I L-malate is stable under a variety of experimental conditions.
(3) Stability study 3
Each of the crystalline Form I of Compound I L-malate and Compound I (free base) was weighed into three weighing bottles, which were then placed under the following experi-mental conditions respectively:
High temperature condition (60℃, opened) ;
High humidity condition (92.5%RH, opened) ; and
Light exposure condition (5000 Lux, 90 μw/cm 2, opened) .
At day 0 and day 5, the total impurities in each of the crystalline Form I of Compound I L-malate and Compound I (free base) under the above experimental conditions were deter-mined respectively. The results were showed in the following table 16.
Table 16 Results of Stability Study 3
Figure PCTCN2021128025-appb-000039
It can be seen from the results in table 16 that the crystalline Form I of Compound I L-malate of the present invention is much more stable than compound I (free base) under all the above three types of experimental conditions. For example, the percent of the total impu-rities in the compound I (free base) under high temperature condition is 11.67%at day 5, which is almost 292 times of the percent of total impurities in the compound I (free base) at day 0 (0.04%) , whereas the percent of the total impurities in the crystalline Form I of Com-pound I L-malate of the present invention under high temperature condition is only 0.27%at day 5, which is only 4.5 times of the percent of total impurities in the crystalline Form I of  Compound I L-malate at day 0 (0.06%) , that is to say, the crystalline Form I of Compound I L-malate of the present invention is almost 55 times more stable than compound I (free base) .
Therefore, it can be concluded that the crystalline Form I of Compound I L-malate of the present invention exhibits unexpectedly better stability than compound I (free base) .
It can be seen from the above that the crystalline Form I of Compound I L-malate of the present invention possesses various excellent properties, such as physical and chemical stabil-ity and hygroscopicity, which can ensure that the medicine containing the Compound I as an active ingredient has a good industrial quality stability and quality uniformity for a long time when storing, for example, the crystalline form will not be influenced by humidity, tempera-ture and light etc. More importantly, it can be demonstrated by the highest AUC that the crys-talline Form I of Compound I L-malate has an enhanced bioavailability as compared to other crystalline forms, which renders it much more suitable for therapeutic use.
Furthermore, it will be appreciated by one skilled in the art that as compared to com-pound I (free base) , the crystalline Form I of Compound I L-malate of the present invention exhibits more excellent properties, including but not limited to physical and chemical stability, solubility, PK characteristics, hygroscopicity, and the like.
All references including patents, patent applications and publications cited in the present application are incorporated herein by reference in their entirety, as if each of them is indi-vidually incorporated. Further, it would be appreciated that one skilled in the art could make various changes or modifications to the invention without departing from the scope of the in-vention defined by the appended claims below. Accordingly, the present invention is not in-tended to be limited to the disclosed embodiments. Rather the present invention is intended to cover the disclosed embodiments as well as others falling within the scope and spirit of the invention to the fullest extent permitted in view of this disclosure and the inventions defined by the claims appended herein below.

Claims (132)

  1. A crystalline Form I of Compound I L-malate,
    Figure PCTCN2021128025-appb-100001
    characterized by X-ray powder diffraction pattern comprising characteristic peaks at 2θ val-ues of 6.7±0.2°, 8.2±0.2° and 9.4±0.2°.
  2. The crystalline Form I of Compound I L-malate according to claim 1, wherein the X-ray powder diffraction pattern further comprises one or two characteristic peak (s) at 2θ value (s) selected from 11.8±0.2° and 25.6±0.2°; preferably, the X-ray powder diffraction pat-tern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2° and 25.6±0.2°.
  3. The crystalline Form I of Compound I L-malate according to claim 1 or 2, wherein the X-ray powder diffraction pattern further comprises one or two characteristic peak (s) at 2θ value (s) selected from 20.9±0.2° and 24.2±0.2°; preferably, the X-ray powder diffraction pat-tern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 20.9±0.2°, 24.2±0.2° and 25.6±0.2°.
  4. The crystalline Form I of Compound I L-malate according to any one of claims 1-3, wherein the X-ray powder diffraction pattern further comprises one or two characteristic peak (s) at 2θ value (s) selected from 13.5±0.2° and 19.0±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 13.5±0.2°, 19.0±0.2°, 20.9±0.2°, 24.2±0.2° and 25.6±0.2°.
  5. The crystalline Form I of Compound I L-malate according to any one of claims 1-4, wherein the X-ray powder diffraction pattern further comprises one or two characteristic peak (s) at 2θ value (s) selected from 22.7±0.2° and 28.0±0.2°.
  6. The crystalline Form I of Compound I L-malate according to any one of claims 1-5, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values  of 6.7±0.2°, 8.2±0.2°, 9.4±0.2°, 11.8±0.2°, 13.5±0.2°, 19.0±0.2°, 20.9±0.2°, 22.7±0.2° 24.2±0.2°, 25.6±0.2° and 28.0±0.2°.
  7. The crystalline Form I of Compound I L-malate according to any one of claims 1-6, wherein the X-ray powder diffraction pattern is substantially the same as Figure 16, Figure 19, Figure 20, Figure 21 or Figure 22.
  8. A process of preparing the crystalline Form I of Compound I L-malate according to any one of claims 1 to 7, comprising cooling a hot solution containing compound I and L-malic acid in acetone, and stirred for crystallization to obtain the crystalline Form I of Compound I L-malate.
  9. The process according to claim 8, wherein the amount of the L-malic acid is 1.1 to 1.5 equivalent of the compound I.
  10. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I L-malate according to any one of claims 1-7, and at least one pharmaceutically acceptable excipient.
  11. Use of the crystalline Form I of Compound I L-malate according to any one of claims 1-7; or the pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  12. The use according to claim 11, wherein the disease or condition related to FGFR4 is cancer.
  13. The use according to claim 12, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  14. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I L-malate according to any one of claims 1-7; or the pharmaceutical composition according to claim 10.
  15. The method according to claim 14, wherein the disease or condition related to FGFR4 is cancer.
  16. The method according to claim 15, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  17. The crystalline Form I of Compound I L-malate according to any one of claims 1-7; or the pharmaceutical composition according to claim 10 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  18. A crystalline Form I of Compound I phosphate,
    Figure PCTCN2021128025-appb-100002
    characterized by X-ray powder diffraction pattern substantially the same as Figure 1.
  19. A process of preparing the crystalline Form I of Compound I phosphate according to claim 18, comprising cooling a hot solution containing compound I and phosphoric acid in acetone, and stirred for crystallization to obtain the crystalline Form I of Compound I phos-phate.
  20. The process according to claim 19, wherein the amount of the phosphoric acid is 1.1 to 1.5 equivalent of the compound I.
  21. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I phosphate according to claim 18, and at least one pharma-ceutically acceptable excipient.
  22. Use of the crystalline Form I of Compound I phosphate according to claim 18; or the pharmaceutical composition according to claim 21 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  23. The use according to claim 22, wherein the disease or condition related to FGFR4 is cancer.
  24. The use according to claim 23, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung  cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  25. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I phosphate according to claim 18; or the pharmaceutical composition according to claim 21.
  26. The method according to claim 25, wherein the disease or condition related to FGFR4 is cancer.
  27. The method according to claim 26, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  28. The crystalline Form I of Compound I phosphate according to claim 18; or the phar-maceutical composition according to claim 21 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  29. A crystalline Form I of Compound I hydrochloride,
    Figure PCTCN2021128025-appb-100003
    characterized by X-ray powder diffraction pattern substantially the same as Figure 4.
  30. A process of preparing the crystalline Form I of Compound I hydrochloride accord-ing to claim 29, comprising cooling a hot solution containing compound I and hydrochloric acid in ethyl acetate, and stirred for crystallization to obtain the crystalline Form I of Com-pound I hydrochloride.
  31. The process according to claim 30, wherein the amount of the hydrochloric acid is 1.1 to 1.5 equivalent of the compound I.
  32. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I hydrochloride according to claim 29, and at least one pharmaceutically acceptable excipient.
  33. Use of the crystalline Form I of Compound I hydrochloride according to claim 29; or the pharmaceutical composition according to claim 32 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  34. The use according to claim 33, wherein the disease or condition related to FGFR4 is cancer.
  35. The use according to claim 34, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  36. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I hydrochloride according to claim 29; or the pharmaceutical composition according to claim 32.
  37. The method according to claim 36, wherein the disease or condition related to FGFR4 is cancer.
  38. The method according to claim 37, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  39. The crystalline Form I of Compound I hydrochloride according to claim 29; or the pharmaceutical composition according to claim 32 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  40. A crystalline Form I of Compound I maleate,
    Figure PCTCN2021128025-appb-100004
    characterized by X-ray powder diffraction pattern comprising characteristic peaks at 2θ val-ues of 6.7±0.2°, 8.2±0.2°, and 17.6±0.2°.
  41. The crystalline Form I of Compound I maleate according to claim 40, wherein the  X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 11.6±0.2°, 12.1±0.2°, and 25.7±0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 11.6±0.2°, 12.1±0.2°, 17.6±0.2°, and 25.7±0.2°.
  42. The crystalline Form I of Compound I maleate according to claim 40 or 41, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 9.5±0.2°, 19.1±0.2°, 19.5±0.2°, and 22.8±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.1±0.2°, 17.6±0.2°, 19.1±0.2°, 19.5±0.2°, 22.8±0.2°, and 25.7±0.2°.
  43. The crystalline Form I of Compound I maleate according to any one of claims 40-42, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 13.5±0.2°, 16.0±0.2°, 18.2±0.2°, and 18.6±0.2°.
  44. The crystalline Form I of Compound I maleate according to any one of claims 40-43, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 6.7±0.2°, 8.2±0.2°, 9.5±0.2°, 11.6±0.2°, 12.1±0.2°, 13.5±0.2°, 16.0±0.2°, 17.6±0.2°, 18.2±0.2°, 18.6±0.2°, 19.1±0.2°, 19.5±0.2°, 22.8±0.2°, and 25.7±0.2°.
  45. The crystalline Form I of Compound I maleate according to any one of claims 40-44, wherein the X-ray powder diffraction pattern is substantially the same as Figure 7.
  46. A process of preparing the crystalline Form I of Compound I maleate according to any one of claims 40 to 45, comprising cooling a hot solution containing compound I and maleic acid in ethyl acetate, and stirred for crystallization to obtain the crystalline Form I of Compound I maleate.
  47. The process according to claim 46, wherein the amount of the maleic acid is 1.0 to 1.5 equivalent of the compound I.
  48. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I maleate according to any one of claims 40-45, and at least one pharmaceutically acceptable excipient.
  49. Use of the crystalline Form I of Compound I maleate according to claim 40-45; or  the pharmaceutical composition according to claim 48 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  50. The use according to claim 49, wherein the disease or condition related to FGFR4 is cancer.
  51. The use according to claim 50, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  52. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I maleate according to any one of claims 40-45; or the pharmaceutical composition according to claim 48.
  53. The method according to claim 52, wherein the disease or condition related to FGFR4 is cancer.
  54. The method according to claim 53, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  55. The crystalline Form I of Compound I maleate according to claim 40-45; or the pharmaceutical composition according to claim 48 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  56. A crystalline Form I of Compound I citrate,
    Figure PCTCN2021128025-appb-100005
    characterized by X-ray powder diffraction pattern substantially the same as Figure 10.
  57. A process of preparing the crystalline Form I of Compound I citrate according to claim 56, comprising cooling a hot solution containing compound I and citric acid in acetone, and stirred for crystallization to obtain the crystalline Form I of Compound I citrate.
  58. The process according to claim 57, wherein the amount of the citric acid is 1.1 to 1.5 equivalent of the compound I.
  59. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I citrate according to claim 56, and at least one pharmaceu-tically acceptable excipient.
  60. Use of the crystalline Form I of Compound I citrate according to claim 56; or the pharmaceutical composition according to claim 59 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  61. The use according to claim 60, wherein the disease or condition related to FGFR4 is cancer.
  62. The use according to claim 61, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  63. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I citrate according to claim 56; or the phar-maceutical composition according to claim 59.
  64. The method according to claim 63, wherein the disease or condition related to FGFR4 is cancer.
  65. The method according to claim 64, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  66. The crystalline Form I of Compound I citrate according to claim 56; or the pharma-ceutical composition according to claim 59 for use in the treatment, prevention and/or precau-tion of a disease or condition related to FGFR4.
  67. A crystalline Form I of Compound I tosilate,
    Figure PCTCN2021128025-appb-100006
    characterized by X-ray powder diffraction pattern comprising characteristic peaks at 2θ val-ues of 6.9±0.2°, 14.6±0.2°, and 18.0±0.2°.
  68. The crystalline Form I of Compound I tosilate according to claim 67, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 3.5±0.2°, 9.2±0.2°, and 23.7±0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 14.6±0.2°, 18.0±0.2°, and 23.7±0.2°.
  69. The crystalline Form I of Compound I tosilate according to claim 67 or 68, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 11.4±0.2°, 12.0±0.2°, and 13.2±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 18.0±0.2°, and 23.7±0.2°.
  70. The crystalline Form I of Compound I tosilate according to any one of claims 67-69, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 15.2±0.2°, 16.2±0.2°, and 18.7±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 15.2±0.2°, 16.2±0.2°, 18.0±0.2°, 18.7±0.2°, and 23.7±0.2°.
  71. The crystalline Form I of Compound I tosilate according to any one of claims 67-70, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 19.6±0.2°, 20.9±0.2°, 21.5±0.2°, 22.3±0.2°, 24.5±0.2°, and 27.0±0.2°.
  72. The crystalline Form I of Compound I tosilate according to any one of claims 67-71, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values  of 3.5±0.2°, 6.9±0.2°, 9.2±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 14.6±0.2°, 15.2±0.2°, 16.2±0.2°, 18.0±0.2°, 18.7±0.2°, 19.6±0.2°, 20.9±0.2°, 21.5±0.2°, 22.3±0.2°, 23.7±0.2°, 24.5±0.2°, and 27.0±0.2°.
  73. The crystalline Form I of Compound I tosilate according to any one of claims 67-72, wherein the X-ray powder diffraction pattern is substantially the same as Figure 13.
  74. A process of preparing the crystalline Form I of Compound I tosilate according to any one of claims 67 to 73, comprising cooling a hot solution containing compound I and p-toluenesulfonic acid in THF, and stirred for crystallization to obtain the crystalline Form I of Compound I tosilate.
  75. The process according to claim 74, wherein the amount of the p-toluenesulfonic acid is 1.0 to 1.3 equivalent of the compound I.
  76. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I tosilate according to any one of claims 67-73, and at least one pharmaceutically acceptable excipient.
  77. Use of the crystalline Form I of Compound I tosilate according to any one of claims 67-73; or the pharmaceutical composition according to claim 76 for the manufacture of a me-dicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  78. The use according to claim 77, wherein the disease or condition related to FGFR4 is cancer.
  79. The use according to claim 78, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  80. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I tosilate according to any one of claims 67-73; or the pharmaceutical composition according to claim 76.
  81. The method according to claim 80, wherein the disease or condition related to FGFR4 is cancer.
  82. The method according to claim 81, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  83. The crystalline Form I of Compound I tosilate according to any one of claims 67-73; or the pharmaceutical composition according to claim 76 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  84. A crystalline Form I of Compound I besylate,
    Figure PCTCN2021128025-appb-100007
    characterized by X-ray powder diffraction pattern comprising characteristic peaks at 2θ val-ues of 7.2±0.2°, 14.9±0.2°, 18.1±0.2°, and 24.7±0.2°.
  85. The crystalline Form I of Compound I besylate according to claim 84, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 3.8±0.2°, 9.7±0.2°, and 11.9±0.2°; preferably, the X-ray powder dif-fraction pattern comprises the characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 14.9±0.2°, 18.1±0.2°, and 24.7±0.2°.
  86. The crystalline Form I of Compound I besylate according to claim 84 or 85, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 13.8±0.2°, 16.4±0.2°, and 21.0±0.2°; preferably, the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 13.8±0.2°, 14.9±0.2°, 16.4±0.2°, 18.1±0.2°, 21.0±0.2°, and 24.7±0.2°.
  87. The crystalline Form I of Compound I besylate according to any one of claims 84-86, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peak (s) at 2θ value (s) selected from 19.8±0.2°, 20.3±0.2°, and 22.8±0.2°.
  88. The crystalline Form I of Compound I besylate according to any one of claims 84-87, wherein the X-ray powder diffraction pattern comprises the characteristic peaks at 2θ values  of 3.8±0.2°, 7.2±0.2°, 9.7±0.2°, 11.9±0.2°, 13.8±0.2°, 14.9±0.2°, 16.4±0.2°, 18.1±0.2°, 19.8±0.2°, 20.3±0.2°, 21.0±0.2°, 22.8±0.2°, and 24.7±0.2°.
  89. The crystalline Form I of Compound I besylate according to any one of claims 84-88, wherein the X-ray powder diffraction pattern is substantially the same as Figure 14.
  90. A process of preparing the crystalline Form I of Compound I besylate according to any one of claims 84 to 89, comprising cooling a hot solution containing compound I and benzenesulfonic acid in ethyl acetate, and stirred for crystallization to obtain the crystalline Form I of Compound I besylate.
  91. The process according to claim 90, wherein the amount of the benzenesulfonic acid is 1.0 to 1.3 equivalent of the compound I.
  92. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I besylate according to any one of claims 84-89, and at least one pharmaceutically acceptable excipient.
  93. Use of the crystalline Form I of Compound I besylate according to any one of claims 84-89; or the pharmaceutical composition according to claim 92 for the manufacture of a me-dicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  94. The use according to claim 93, wherein the disease or condition related to FGFR4 is cancer.
  95. The use according to claim 94, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  96. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I besylate according to any one of claims 84-89; or the pharmaceutical composition according to claim 92.
  97. The method according to claim 96, wherein the disease or condition related to FGFR4 is cancer.
  98. The method according to claim 97, wherein the cancer is selected from liver cancer,  head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  99. The crystalline Form I of Compound I besylate according to any one of claims 84-89; or the pharmaceutical composition according to claim 92 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  100. A crystalline Form I of Compound I succinate,
    Figure PCTCN2021128025-appb-100008
    characterized by X-ray powder diffraction pattern substantially the same as Figure 23.
  101. A process of preparing the crystalline Form I of Compound I succinate according to claim 100, comprising cooling a hot solution containing compound I and succinic acid in ac-etone, and stirred for crystallization to obtain the crystalline Form I of Compound I succinate.
  102. The process according to claim 101, wherein the amount of the succinic acid is 1.1 to 1.5 equivalent of the compound I.
  103. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I succinate according to claim 102, and at least one pharma-ceutically acceptable excipient.
  104. Use of the crystalline Form I of Compound I succinate according to claim 102; or the pharmaceutical composition according to claim 103 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  105. The use according to claim 104, wherein the disease or condition related to FGFR4 is cancer.
  106. The use according to claim 105, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  107. A method for the treatment, prevention and/or precaution of a disease or condition  related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I succinate according to claim 102; or the pharmaceutical composition according to claim 103.
  108. The method according to claim 107, wherein the disease or condition related to FGFR4 is cancer.
  109. The method according to claim 108, wherein the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  110. The crystalline Form I of Compound I succinate according to claim 100; or the pharmaceutical composition according to claim 103 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  111. A crystalline Form I of Compound I fumarate,
    Figure PCTCN2021128025-appb-100009
    characterized by X-ray powder diffraction pattern substantially the same as Figure 26.
  112. A process of preparing the crystalline Form I of Compound I fumarate according to claim 111, comprising cooling a hot solution containing compound I and fumaric acid in ace-tone, and stirred for crystallization to obtain the crystalline Form I of Compound I fumarate.
  113. The process according to claim 112, wherein the amount of the fumaric acid is 1.1 to 1.5 equivalent of the compound I.
  114. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I fumarate according to claim 111, and at least one pharma-ceutically acceptable excipient.
  115. Use of the crystalline Form I of Compound I fumarate according to claim 111; or the pharmaceutical composition according to claim 114 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  116. The use according to claim 115, wherein the disease or condition related to FGFR4 is cancer.
  117. The use according to claim 116, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  118. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I fumarate according to claim 111; or the pharmaceutical composition according to claim 114.
  119. The method according to claim 118, wherein the disease or condition related to FGFR4 is cancer.
  120. The method according to claim 119, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  121. The crystalline Form I of Compound I fumarate according to claim 111; or the pharmaceutical composition according to claim 114 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  122. A crystalline Form I of Compound I oxalate,
    Figure PCTCN2021128025-appb-100010
    characterized by X-ray powder diffraction pattern substantially the same as Figure 29.
  123. A process of preparing the crystalline Form I of Compound I oxalate according to claim 122, comprising cooling a hot solution containing compound I and oxalic acid in ace-tone, and stirred for crystallization to obtain the crystalline Form I of Compound I oxalate.
  124. A process of preparing the crystalline Form I of Compound I oxalate according to claim 123, wherein the amount of the oxalic acid is 1.1 to 1.5 equivalent of the compound I.
  125. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form I of Compound I oxalate according to claim 122, and at least one pharma-ceutically acceptable excipient.
  126. Use of the crystalline Form I of Compound I oxalate according to claim 122; or the pharmaceutical composition according to claim 125 for the manufacture of a medicament for the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
  127. The use according to claim 126, wherein the disease or condition related to FGFR4 is cancer.
  128. The use according to claim 127, wherein the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  129. A method for the treatment, prevention and/or precaution of a disease or condition related to FGFR4 in a subject, comprising administering to the subject a therapeutically effec-tive amount of crystalline Form I of Compound I oxalate according to claim 122; or the pharmaceutical composition according to claim 125.
  130. The method according to claim 129, wherein the disease or condition related to FGFR4 is cancer.
  131. The method according to claim 130, wherein the cancer is selected from liver can-cer, head and neck cancer, esophageal cancer, gastric cancer, prostatic cancer, ovarian cancer, lung cancer, breast cancer, rhabdomyoma and/or colorectal cancer.
  132. The crystalline Form I of Compound I oxalate according to claim 122; or the phar-maceutical composition according to claim 125 for use in the treatment, prevention and/or precaution of a disease or condition related to FGFR4.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015059668A1 (en) * 2013-10-25 2015-04-30 Novartis Ag Ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors
CN107304210A (en) * 2016-04-25 2017-10-31 成都融科博海科技有限公司 A kind of selective FGFR4 kinase inhibitors
WO2017198149A1 (en) * 2016-05-20 2017-11-23 江苏豪森药业集团有限公司 Fgfr4 inhibitor, preparation method therefor, and applications thereof
WO2017202390A1 (en) * 2016-05-27 2017-11-30 杭州英创医药科技有限公司 Heterocyclic compound serving as fgfr4 inhibitor
WO2018028664A1 (en) * 2016-08-12 2018-02-15 江苏豪森药业集团有限公司 Fgfr4 inhibitor and preparation method and use thereof
CN108341815A (en) * 2017-01-25 2018-07-31 上海喆邺生物科技有限公司 A kind of inhibition kinases compound and application thereof
WO2020020377A1 (en) * 2018-07-27 2020-01-30 北京加科思新药研发有限公司 Fused ring derivative used as fgfr4 inhibitor

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015059668A1 (en) * 2013-10-25 2015-04-30 Novartis Ag Ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors
CN107304210A (en) * 2016-04-25 2017-10-31 成都融科博海科技有限公司 A kind of selective FGFR4 kinase inhibitors
CN107304211A (en) * 2016-04-25 2017-10-31 成都融科博海科技有限公司 A kind of selective FGFR4 kinase inhibitors
WO2017198149A1 (en) * 2016-05-20 2017-11-23 江苏豪森药业集团有限公司 Fgfr4 inhibitor, preparation method therefor, and applications thereof
WO2017202390A1 (en) * 2016-05-27 2017-11-30 杭州英创医药科技有限公司 Heterocyclic compound serving as fgfr4 inhibitor
WO2018028664A1 (en) * 2016-08-12 2018-02-15 江苏豪森药业集团有限公司 Fgfr4 inhibitor and preparation method and use thereof
CN108341815A (en) * 2017-01-25 2018-07-31 上海喆邺生物科技有限公司 A kind of inhibition kinases compound and application thereof
WO2020020377A1 (en) * 2018-07-27 2020-01-30 北京加科思新药研发有限公司 Fused ring derivative used as fgfr4 inhibitor

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