WO2021190623A1 - Fgfr4抑制剂的盐型、晶型及其用途 - Google Patents

Fgfr4抑制剂的盐型、晶型及其用途 Download PDF

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WO2021190623A1
WO2021190623A1 PCT/CN2021/083204 CN2021083204W WO2021190623A1 WO 2021190623 A1 WO2021190623 A1 WO 2021190623A1 CN 2021083204 W CN2021083204 W CN 2021083204W WO 2021190623 A1 WO2021190623 A1 WO 2021190623A1
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cancer
crystal form
salt
ray powder
diffraction pattern
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PCT/CN2021/083204
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English (en)
French (fr)
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高金恒
徐晓峰
陈亮
孙中心
张赟
刘湘永
丁列明
王家炳
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贝达药业股份有限公司
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Priority to EP21777116.1A priority Critical patent/EP4130004A4/en
Priority to JP2022558575A priority patent/JP2023519011A/ja
Priority to CN202180021447.5A priority patent/CN115397827B/zh
Priority to KR1020227037683A priority patent/KR20220159457A/ko
Publication of WO2021190623A1 publication Critical patent/WO2021190623A1/zh

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07C55/14—Adipic 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
    • C07C59/255—Tartaric 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-methyl-5,6-dihydropyrimidine And [5,4-c][1,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide new crystal form, salt form and crystal of said salt form form.
  • the present invention also relates to a pharmaceutical composition comprising the crystal form or salt form, the use of the salt form, crystal form and pharmaceutical composition as an FGFR4 inhibitor, and a method for treating FGFR4 mediated diseases.
  • Fibroblast growth factor receptor belongs to the receptor-type tyrosine protein kinase (Receptor Tyrosine Kinase, RTK) superfamily. FGFR binds to fibroblast growth factor (FGF) to Different tissues regulate cell proliferation, differentiation and migration through complex signal transmission pathways (Jouanneau J et al. Oncogene, 1999, 18:327-333). FGFR is a single-chain glycoprotein consisting of an extracellular domain, a single transmembrane domain, and a tyrosine kinase domain in the cytoplasm. The extracellular domain is composed of a leader peptide and three immunoglobulin domains.
  • FGF fibroblast growth factor
  • the FGFR tyrosine kinase family includes FGFR1, FGFR2, FGFR3 and FGFR4.
  • the FGFR4 gene is located on chromosome 5q35.1, its length is about 11.3kb, and there are 18 exons (Kostrzewa M. Mammalian gene, 1998, 9(2): 131-135).
  • FGFR4 protein belongs to an important member of the FGFR tyrosine kinase family, and its 388th amino acid is located in the highly conserved transmembrane region of RTK structure. The changes in the pathophysiological function of FGFR4 protein caused by this structural change can enhance the activity of tyrosine kinases. .
  • FGFR4 protein is a type of transmembrane tyrosine kinase receptor with autophosphorylation activity, which plays an important role in embryonic development, tissue repair and angiogenesis (Eswarakumar VPet al. Cytokine Growth Factor Rev, 2005 , 16(2):139-149).
  • the signal pathway of FGFR4 when the ligand is mediated by heparin or heparin, it binds to FGFR4, causing the FGFR4 monomer to dimerize, following the tyrosine phosphorylation of the C-terminus, the kinase insertion region and the proximal membrane region in the cytoplasm Later, the A loop (activation loop, A loop) kinase region is phosphorylated to activate FGFR4 (Schlessinger J et al. Mol Cell, 2000, 6:743-750).
  • the activated FGFR4 mainly has two intracellular agents: phospholipase C and FGF receptor substrate 2 (FRS2) (Dailey L et al. Cytokine Growth Factor Rev, 2005, 16: 233-247).
  • the Src homology region 2 (SH2) domain of phospholipase C binds to its activated C-terminal tyrosine, so that PLC is phosphorylated and binds to the C-terminal tyrosine site.
  • the activated PLC hydrolyzes its substrate 4,5-diphosphate phosphatidylinositol (PIP 2 ) to form diacylglycerol (DAG) and inositol triphosphate (IP 3 ).
  • DAG diacylglycerol
  • IP 3 inositol triphosphate
  • IP3 binds to specific receptors in cells to stimulate the intracellular calcium pool to release Ca 2+
  • Ca 2+ binds to calmodulin to activate Ca 2+ /calmodulin-dependent protein kinase.
  • both Ca 2+ and diacylglycerol can activate members of the protein kinase C family.
  • the secondary signals generated by PIP2 hydrolysis can also activate a
  • the SOS protein binds to the Src homology region 3 (SH3) domain of growth factor receptor binding 2 (Grb2) to form a Grb2/SOS complex, which can be linked to FGFR4 or FGF receptor Substrate 2 ⁇ (FGFR substrate 2 ⁇ , FRS2 ⁇ ) binds, in which FRS2 ⁇ is connected to the transmembrane protein-phosphotyrosine binding domain (PTB) to promote the exchange of guanosine on Ras and make Ras become Ras-GTP.
  • PTB transmembrane protein-phosphotyrosine binding domain
  • the autophosphorylation of FGFR4 activates the JAK family factor (JAK), and the activated JAK phosphorylates the specific signal protein adsorption site on FGFR4, which can act as a signal transducer and activator of transcription, STAT) and other berthing sites for signaling molecules.
  • JAK JAK family factor
  • STAT signal transducer and activator of transcription
  • Small molecule FGFR4 inhibitors inhibit the proliferation signal mediated by FGFR4 by blocking the binding of extracellular ligand molecules to receptors or the transmission of intracellular kinase signals.
  • FGFR4 inhibitors There are many types of FGFR4 inhibitors currently under development. AstraZeneca has developed FGFR4 selective inhibitor AZ709. Its in vitro experiments have shown a good inhibitory effect on cells expressing high levels of FGF19 or FGFR4, but in vivo experiments have not been significant. effect.
  • Novartis's FGFR4 selective inhibitor FGF401 can specifically target FGFR4 and treat malignant tumors such as liver cancer that it overexpresses.
  • H3 Biomedicine's FGFR4 specific inhibitor H3B6527 has strong anti-tumor activity on FGF19 gene-amplified cells, and there are no bile acid-related adverse reactions in mouse and monkey animal models.
  • Blueprint Medicine has developed and reported a FGFR4 specific inhibitor BLU554 to treat liver cancer and cholangiocarcinoma with overexpression of FGFR4.
  • the salt forms and/or polymorphs of specific organic pharmaceutical compounds have distinct physical properties, such as morphology, melting point, solubility, hygroscopicity and stability, etc., due to their unique structures. It exhibits different behaviors in terms of formulation, therapeutic activity, and chemical and physical stability.
  • the present invention relates to a compound represented by structural formula I N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-methyl-5, Salt forms and crystal forms of 6-dihydropyrimido[5,4-c][1,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide.
  • the present invention provides the crystal form A of the compound represented by structural formula I, and the maleate, phosphate, adipate and L-tartrate salts of the compound represented by structural formula I.
  • the preferred salts of the compound represented by structural formula I are maleate and phosphate.
  • the present invention provides the maleate, L-tartrate, adipate and phosphate crystal forms of the compound represented by structural formula I.
  • the present invention provides crystal form A of the compound represented by structural formula I.
  • the X-ray powder diffraction pattern of crystal form A has diffraction angles 2 ⁇ : 7.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.3° ⁇ 0.2 °, 15.1° ⁇ 0.2° characteristic peak.
  • the X-ray powder diffraction pattern of the crystal form A has diffraction angles 2 ⁇ of 7.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.3° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.1° ⁇ 0.2°, 20.9 ° ⁇ 0.2°, 25.2° ⁇ 0.2° characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form A has diffraction angles 2 ⁇ of 7.5° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.3° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.1° ⁇ 0.2°, 20.9 ° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 30.2 ⁇ 0.2° characteristic peaks.
  • the crystal form A has an X-ray powder diffraction pattern approximately as shown in FIG. 1.
  • the crystal form A also has a thermogravimetric analysis (TGA) profile as shown in FIG. 2 and a differential scanning calorimetry (DSC) profile as shown in FIG. 3.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the present invention provides the maleate salt crystal form 1 of the compound represented by structural formula I.
  • the X-ray powder diffraction pattern of the crystal form has diffraction angles 2 ⁇ of 3.7° ⁇ 0.2°, 9.9° ⁇ 0.2°, 11.0 ° ⁇ 0.2°, 16.2° ⁇ 0.2° characteristic peaks.
  • the X-ray powder diffraction pattern of the maleate salt crystal form 1 has diffraction angles 2 ⁇ of 3.7° ⁇ 0.2°, 9.9° ⁇ 0.2°, 11.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.2° ⁇ 0.2°, 20.6° ⁇ 0.2° characteristic peaks.
  • the X-ray powder diffraction pattern of the maleate salt crystal form 1 has diffraction angles 2 ⁇ of 3.7° ⁇ 0.2°, 9.9° ⁇ 0.2°, 11.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 16.2° ⁇
  • the characteristic peaks are 0.2°, 17.2° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.6° ⁇ 0.2°, 22.6° ⁇ 0.2°, 24.4° ⁇ 0.2°.
  • the maleate salt crystal form 1 has an X-ray powder diffraction pattern approximately as shown in FIG. 4.
  • the maleate salt crystal form 1 also has a thermogravimetric analysis (TGA) pattern as shown in FIG. 5 and a differential scanning calorimetry (DSC) pattern as shown in FIG. 6.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the stoichiometric ratio of the maleate to the compound represented by structural formula I is 1:1.
  • the present invention provides the maleate salt crystal form 2 of the compound represented by structural formula I.
  • the X-ray powder diffraction pattern of the crystal form has diffraction angles 2 ⁇ of 5.6° ⁇ 0.2°, 7.0° ⁇ 0.2°, 19.9 ° ⁇ 0.2°, characteristic peak.
  • the X-ray powder diffraction pattern of the maleate salt crystal form 2 has a diffraction angle 2 ⁇ of 5.6° ⁇ 0.2°, 7.0° ⁇ 0.2°, 9.9° ⁇ 0.2°, 14.5° ⁇ 0.2°, 19.9° ⁇ A characteristic peak of 0.2°.
  • the maleate salt crystal form 2 has an X-ray powder diffraction pattern approximately as shown in FIG. 7.
  • the maleate salt crystal form 2 has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 8.
  • DSC differential scanning calorimetry
  • the present invention provides the phosphate of the compound represented by structural formula I, wherein the stoichiometric ratio of the phosphate to the compound represented by structural formula I is 1.5:1, which can be represented by formula II:
  • the present invention provides crystal form 1 of formula II, which is called phosphate crystal form 1 for convenience.
  • the X-ray powder diffraction pattern of this crystal form has diffraction angles 2 ⁇ of 4.9° ⁇ 0.2°, 10.7° ⁇ 0.2°, 16.8° ⁇ 0.2 °, 21.3° ⁇ 0.2° characteristic peak.
  • the X-ray powder diffraction pattern of the phosphate crystal form 1 has diffraction angles 2 ⁇ of 4.9° ⁇ 0.2°, 8.3° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.8 ⁇ 0.2°, The characteristic peaks are 16.8° ⁇ 0.2°, 21.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystal form 1 has diffraction angles 2 ⁇ of 4.9° ⁇ 0.2°, 8.3° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.8 ⁇ 0.2°,
  • the characteristic peaks are 16.8° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.3° ⁇ 0.2°, 28.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystal form 1 has diffraction angles 2 ⁇ of 4.9° ⁇ 0.2°, 8.3° ⁇ 0.2°, 10.7° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.8 ⁇ 0.2°,
  • the characteristic peaks are 16.8° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.3° ⁇ 0.2°, 24.7° ⁇ 0.2°, 28.5° ⁇ 0.2°.
  • the phosphate crystal form 1 has an X-ray powder diffraction pattern approximately as shown in FIG. 9 or FIG. 10.
  • the phosphate crystal form 1 also has a TGA spectrum as shown in FIG. 11 and a DSC spectrum as shown in FIG. 12 basically.
  • the present invention provides the L-tartrate salt crystal form 1 of the compound represented by structural formula I.
  • the X-ray powder diffraction pattern of the crystal form has diffraction angles 2 ⁇ of 5.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.7 ° ⁇ 0.2°, 20.7° ⁇ 0.2° characteristic peaks.
  • the X-ray powder diffraction pattern of the L-tartrate salt crystal form 1 has diffraction angles 2 ⁇ of 5.4° ⁇ 0.2°, 12.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.7° ⁇ 0.2° characteristic peaks.
  • the X-ray powder diffraction pattern of the L-tartrate salt crystal form 1 has diffraction angles 2 ⁇ of 5.4° ⁇ 0.2°, 12.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.7° ⁇ 0.2°, 22.2° ⁇ 0.2°, 26.4° ⁇ 0.2° characteristic peaks.
  • the L-tartrate salt crystal form 1 has an X-ray powder diffraction pattern approximately as shown in FIG. 13.
  • the L-tartrate salt crystal form 1 has a TGA spectrum approximately as shown in FIG. 14.
  • the L-tartrate salt crystal form 1 has a DSC spectrum approximately as shown in FIG. 15.
  • the present invention provides the adipate salt crystal form 1 of the compound represented by structural formula I.
  • the X-ray powder diffraction pattern of the crystal form has diffraction angles 2 ⁇ of 5.8° ⁇ 0.2°, 8.4° ⁇ 0.2°, 12.3 ° ⁇ 0.2°, 22.9° ⁇ 0.2° characteristic peaks.
  • the X-ray powder diffraction pattern of the adipate crystal form 1 has diffraction angles 2 ⁇ of 5.8° ⁇ 0.2°, 8.4° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.3° ⁇ 0.2°, 17.5° ⁇ 0.2°, 22.9° ⁇ 0.2° characteristic peaks.
  • the X-ray powder diffraction pattern of the adipate crystal form 1 has diffraction angles 2 ⁇ of 5.8° ⁇ 0.2°, 8.4° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.3° ⁇
  • the characteristic peaks are 0.2°, 17.5° ⁇ 0.2°, 22.9° ⁇ 0.2°, 25.4° ⁇ 0.2°, 25.9° ⁇ 0.2°.
  • the adipate salt crystal form 1 has an X-ray powder diffraction pattern approximately as shown in FIG. 16.
  • the adipate salt crystal form 1 has a TGA spectrum approximately as shown in FIG. 17 and a DSC spectrum approximately as shown in FIG. 18.
  • the compound represented by structural formula I has low amorphous solubility, poor stability, and high hygroscopicity.
  • the research of the present invention found that the crystal form A and phosphate crystal form 1 of the compound represented by structural formula I have better stability and lower hygroscopicity; the adipate crystal form 1 and maleate crystal form 1 have better stability. Excellent stability, therefore, these salts and crystal forms are beneficial to the production of drugs, and their chemical stability and safety.
  • the most surprising thing is phosphate crystal form 1, which has a stable preparation process, low cost, and at the same time has low hygroscopicity, high stability and better pharmacokinetic properties.
  • the X-ray powder diffraction patterns are all measured using the K ⁇ line of the Cu target.
  • the experimental temperature of the present invention is room temperature.
  • the present invention further provides the preparation of the compound represented by structural formula I and its crystal form A, maleate crystal form 1, maleate crystal form 2, phosphate crystal form 1, adipate crystal form 1, and L-tartaric acid Method of salt crystal form 1.
  • the compound represented by structural formula I can be prepared by the following route:
  • reaction conditions of the preparation route of the compound represented by structural formula I are described in the specific examples. It should be understood that the reaction solvents and conditions used in the preparation route are not limited to the solvents and conditions used in the specific examples. Other reaction conditions can also be applied to the preparation of the compound represented by the structural formula I.
  • the present invention further provides a pharmaceutical composition, which contains a therapeutically effective amount of the salt or crystal form of the present invention, and pharmaceutically acceptable excipients, adjuvants or carriers.
  • the present invention also provides preferred embodiments of the above-mentioned pharmaceutical composition.
  • the above-mentioned pharmaceutical composition contains a therapeutically effective amount of the salt form or crystal form of the present invention, in combination with at least one other active ingredient.
  • the pharmaceutical composition is for oral administration.
  • the pharmaceutical composition is used in tablets or capsules.
  • the pharmaceutical composition contains 0.01% to 99% by weight of the crystal form of the present invention.
  • the pharmaceutical composition contains 10% to 70% by weight of the crystal form of the present invention.
  • the pharmaceutical composition contains 20-50% by weight of the crystal form of the present invention.
  • the present invention further provides the application of the crystal form or the pharmaceutical composition in the preparation of medicines.
  • the application is to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis.
  • the application is the preparation of drugs for the treatment of diseases mediated by FGFR4.
  • the disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, intracranial tumor, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, Lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
  • the application is as an FGFR4 inhibitor.
  • the present invention also provides a method for administering a therapeutically effective amount of at least any one crystal form or pharmaceutical composition to a subject to treat and/or prevent diseases mediated by FGFR4.
  • the FGFR4-mediated disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer , Ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, intracranial tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xu Wangshi cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any one crystal form or a pharmaceutical composition thereof to a subject, the cancer being breast cancer, multiple myeloma, bladder cancer, intrauterine cancer Membrane cancer, stomach cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, intracranial tumors , Hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer , Testicular cancer or liposarcoma.
  • the cancer being breast cancer, multiple myeloma, bladder cancer,
  • the subject to be treated is a human being.
  • an acid and the compound represented by structural formula I form a corresponding salt, and these salt-type compounds may exist in various physical forms. For example, it may be in the form of a solution, suspension or solid.
  • the salt-type compound is in solid form. When in solid form, the compound may be amorphous, crystalline, eutectic or a mixture thereof.
  • salt or “salt type” can be defined as an amorphous or crystalline material in which the free base API and acid are ionized, or in which the two components of free base API and acid utilize significant intermolecular Interactions, such as hydrogen bonds, to combine to produce uniform crystalline materials are called eutectics. It should be understood that the salt in the present invention may also be partially ionized and partially eutectic.
  • substantially pure means that the content of the crystal form is not less than 85% by weight, preferably not less than 95%, and more preferably not less than 98%.
  • the precise positions of the peaks in the drawings should not be interpreted as absolute values.
  • Those skilled in the art know that the 2 ⁇ values of X-ray powder diffraction patterns may have errors due to different measurement conditions (such as equipment and instruments used) and different samples (such as different batches of samples).
  • the measurement error of the diffraction angle of the graph is 5% or less, and usually, a difference of ⁇ 0.2° of a given value is considered appropriate.
  • the relative intensity of the peaks may fluctuate with experimental conditions and sample preparation such as the preferred orientation of the particles in the sample.
  • sample preparation such as the preferred orientation of the particles in the sample.
  • the use of automatic or fixed diverging slits will also affect the calculation of relative strength.
  • the intensity shown in the XRD curve included here is only exemplary and cannot be used as an absolute comparison.
  • terapéuticaally effective amount refers to a compound that is sufficient to affect the treatment of a disease, disorder, or symptom when it is administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition. quantity.
  • the “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the patient being treated, and/or the Changes in the weight of the patient. In any particular case, an appropriate amount may be obvious to those skilled in the art, or it may be determined by routine experimentation.
  • therapeuticically effective amount refers to the total amount of subjects in the combination that are effective in treating a disease, disorder, or condition.
  • the salt form or crystal form of the present invention can be used in combination as an active component, and mixed with a pharmaceutical carrier to form a pharmaceutical composition.
  • the pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration. Such as capsules, cachets or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion.
  • the salt or crystal form of the present invention can also be administered by a controlled release method and/or delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier constituting one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. In addition, the product can be easily prepared into the desired appearance.
  • “Pharmaceutically acceptable carrier” refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical preparation, for example: diluents and excipients such as water, various organic solvents, etc.; such as starch, pregelatinized starch, sucrose, Fillers such as dextrin, mannitol, lactose, spray-dried lactose, microcrystalline cellulose, silicified microcrystalline cellulose, inorganic salts, etc.; such as starch syrup, dextrin, powdered sugar, syrup, mucilage, polyethylene glycol , Cellulose derivatives, alginate, gelatin, hydroxypropyl cellulose, copovidone and polyvinylpyrrolidone (PVP); wetting agents such as distilled water, ethanol and glycerin; such as dry starch, low substitution Disintegrants of hydroxypropyl cellulose, hydroxypropyl starch, agar, calcium carbonate, sodium bicarbonate, crospovidone, croscarmel
  • absorption enhancers such as sodium cetyl sulfate, sodium stearyl sulfate, dioctyl sulfate Sodium sulfosuccinate, sodium dodecyl sulfonate, benzalkonium bromide, benzalkonium chloride, domefen, lecithin, cetyl alcohol, sodium lauryl sulfate, tween and spaan, etc.
  • Surfactants such as polyethylene glycol, carbomer, cellulose derivatives, glycerin gelatin, polyvinyl alcohol, cocoa butter, synthetic or fully synthetic fatty acid glycerides, polyvinyl alcohol 40 stearate, petrolatum, solid Paraffin wax, liquid paraffin, simethicone, lanolin, beeswax and dolphin, etc.; absorption carriers such as kaolin and bentonite; such as talc, micronized silica gel, silicon dioxide, hydrogenated vegetable oil, dodecyl Lubricants such as magnesium sulfate, sodium lauryl sulfate, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate and polyethylene glycol.
  • Surfactants such as polyethylene glycol, carbomer, cellulose derivatives, glycerin gelatin, polyvinyl alcohol, cocoa butter, synthetic or fully synthetic fatty acid glycerides, polyvinyl alcohol 40 stearate,
  • excipients can be added to the pharmaceutical composition, such as antioxidants, coloring agents, preservatives, pH regulators, hardeners, emulsifiers, propellants, dispersants, stabilizers, thickeners , Complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners and dyes.
  • excipients suitable for the desired dosage form and desired mode of administration are used.
  • disease or “disorder” or “condition” refers to any disease, discomfort, disease, symptom, or indication.
  • Figure 1 X-ray powder diffraction pattern of crystal form A of the compound represented by structural formula I.
  • FIG. 1 The thermogravimetric analysis (TGA) spectrum of the crystal form A of the compound represented by structural formula I.
  • FIG. 1 Differential scanning calorimetry (DSC) spectrum of the crystal form A of the compound represented by structural formula I.
  • Figure 4 X-ray powder diffraction pattern of the maleate salt crystal form 1 of the compound represented by structural formula I.
  • Figure 7 X-ray powder diffraction pattern of the maleate salt crystal form 2 of the compound represented by structural formula I.
  • Figure 8 DSC chart of the maleate salt form 2 of the compound represented by structural formula I.
  • Figure 9 X-ray powder diffraction pattern of phosphate crystal form 1 of the compound represented by structural formula I.
  • Figure 10 X-ray powder diffraction pattern of phosphate crystal form 1 of the compound represented by structural formula I.
  • FIG. 11 TGA spectrum of phosphate crystal form 1 of the compound represented by structural formula I.
  • Figure 12 DSC spectrum of phosphate crystal form 1 of the compound represented by structural formula I.
  • Figure 13 X-ray powder diffraction pattern of compound L-tartrate salt crystal form 1 represented by structural formula I.
  • FIG. 14 TGA spectrum of compound L-tartrate salt crystal form 1 represented by structural formula I.
  • Figure 15 DSC spectrum of compound L-tartrate salt crystal form 1 represented by structural formula I.
  • Figure 16 X-ray powder diffraction pattern of the adipate salt crystal form 1 of the compound represented by structural formula I.
  • Figure 17 TGA spectrum of crystalline form 1 of the adipate salt of the compound represented by structural formula I.
  • Figure 18 The DSC spectrum of the adipate salt crystal form 1 of the compound represented by structural formula I.
  • Figure 19 Amorphous dynamic moisture adsorption curve of the compound represented by structural formula I.
  • Figure 20 The dynamic water adsorption curve of the crystal form A of the compound represented by structural formula I.
  • Figure 21 The dynamic water adsorption curve of the maleate salt form 2 of the compound represented by structural formula I.
  • Figure 23 The dynamic water adsorption curve of the phosphate crystal form 1 of the compound represented by structural formula I.
  • the detection instrument information and detection method parameters used in the present invention are as follows:
  • DSC Differential Scanning Calorimeter
  • TGA Thermogravimetric Analyzer
  • Phosphoric acid content detection method ion chromatography
  • Preparation of reference substance solution Take about 25mg of anhydrous sodium dihydrogen phosphate reference substance, accurately weigh it, place it in a 100ml measuring flask, dissolve and dilute to the mark with water, shake well, accurately measure 1ml and place it in a 10ml measuring flask with water Dilute to scale, shake well, and get ready.
  • test solution Take about 20mg of this product, accurately weigh it, and place it in a 200ml brown volumetric flask, add an appropriate amount of diluent, dissolve it by ultrasound, and dilute it to the mark with diluent, shake well, and get it.
  • Determination method Precisely measure 10 ⁇ l each of the reference solution and the test solution, respectively inject them into the ion chromatograph, and record the chromatogram. Calculate the peak area according to the external standard method.
  • Use BRUKER D8 VENTURE collect single crystal data at 150K, Cu K ⁇ radiation; use the direct method (Shelxs97) to analyze the crystal structure, use the least square method to modify the structural parameters and distinguish the atom types, and use the geometric calculation method and the difference Fourier method to obtain all hydrogen Atomic position.
  • the technique or method is a conventional technique or method in the art.
  • the compounds represented by the structural formula I used as starting materials in the following Examples 2-10 are all the compounds represented by the structural formula I obtained by referring to the preparation method of Example 1.
  • the raw materials and reagents are obtained through commercial purchase; the percentages, ratios, ratios, or parts are calculated by weight.
  • API API
  • mCPBA m-chloroperoxybenzoic acid
  • Pd(PPh 3 ) 4 Tetrakis (triphenylphosphine) palladium
  • K 2 CO 3 potassium carbonate
  • PdCl 2 (dppf)CH 2 Cl 2 [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex;
  • Xant-phos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • RH relative humidity
  • RRT relative retention time
  • TEA triethylamine
  • XRD/XRPD X-ray powder diffraction
  • DSC Differential scanning calorimetry
  • DVS Dynamic moisture adsorption
  • Step 8 Preparation of the compound represented by structural formula I (free base FB)
  • the crystalline salt of the compound represented by structural formula I was screened, and experiments were carried out by feeding the compound represented by structural formula I and the counter ion in different solvent systems, as shown in Table 7 for details.
  • the dichloromethane (16L) solution of the compound represented by structural formula I (1.5kg) was concentrated under reduced pressure, and the crystal form A of the compound represented by structural formula I was slowly added to the concentrated system as seed crystals (10.01g crystal form A was dispersed in 500mL ethyl acetate Suspension system). Concentration under reduced pressure was continued while slowly adding ethyl acetate (12L). After concentrating to the remaining solvent amount of about 6-7L, stop concentrating. The obtained concentration system was transferred to a 20L reactor, and stirring was continued for 12 hours. Filter, place the obtained solid in a vacuum drying oven, and vacuum dry at 50°C for 6 to 18 hours. Weighed to obtain 0.84 kg of crystal form A of the compound represented by structural formula I.
  • the phosphate content was detected by ion chromatography (the same sample was tested twice). Theoretical value of 1.5 phosphate content: 20.46%, ⁇ 10% range: 18.41%-22.50%. The test results are shown in Table 10.
  • the unit cell parameters of phosphate crystal form 1 are as follows:
  • the crystal belongs to the monoclinic system, and the space group is P2 1 ,
  • the number of asymmetric units in the unit cell Z 2.
  • the main data of the X-ray powder diffraction pattern of the adipate salt crystal form 1 is shown in Table 13.
  • the moisture absorption of the sample (the sample is a variety of crystal forms shown in Table 14) was measured using a dynamic moisture adsorption instrument (DVS), and the moisture absorption and weight gain of the sample was changed from 0%RH (relative humidity) to 80%RH.
  • the test results are shown in Figure 19-23, and the test results are shown in Table 14.
  • crystal form A, L-tartrate crystal form 1 and phosphate crystal form 1 of the compound represented by structural formula I are non-hygroscopic under the test conditions and have outstanding advantages.
  • Example 12 Determination of the stability of the crystal form of the compound represented by structural formula I
  • Sample and experimental preparation Take an appropriate amount of the amorphous compound shown in structural formula I, the crystal form A of the compound shown in structural formula I, the maleate crystal form 1, the maleate crystal form 2, the phosphate crystal form 1, and the adipic acid crystal. Type 1 was tested for stability. Samples were taken at different times for HPLC testing. The experimental conditions and testing results are shown in Table 15.
  • the packaging is all: polyester/aluminum/polyamide/polyethylene composite film and bag for medicine.
  • HPLC detection results show that the compound crystal form A, maleate crystal form 1, phosphate crystal form 1, and adipic acid crystal form 1 of structural formula I provided by the present invention have excellent stability.
  • the phosphate and maleate of the compound represented by structural formula I have unexpected significant advantages, such as high physical stability and chemical stability.
  • the formation of the crystalline salt of the compound represented by structural formula I was not observed in the presence of the following acids: benzenesulfonic acid, sulfuric acid, p-toluenesulfonic acid, aspartic acid, citric acid, L-malic acid, Fumaric acid and oxalic acid.
  • the stable crystal form A, maleate crystal form 1 and phosphate crystal form 1 of the compound represented by structural formula I have surprising advantages.
  • FB crystal form A, maleate crystal form 1 and phosphate crystal form 1 have low hygroscopicity, and are not easy to change the crystal form due to changes in environmental temperature and humidity.
  • the maleate salt crystal form 2 and the amorphous form of the compound represented by structural formula I are hygroscopic under relative humidity conditions, and the stability is also poor, which easily leads to weight change and/or phase change.
  • composition Weigh maleate crystal form 1, phosphate crystal form 1, and adipate crystal form 1, and all are mixed into 0.5% CMC-Na solution to prepare a suspension solution to be tested. The final concentration of each compound is 5 mg /mL.
  • mice were randomly divided into three groups, each group included 3 male rats, named maleate group, phosphate group, and adipate group.
  • An in vitro kinase detection experiment was used to evaluate the effect of the compound represented by structural formula I of the present invention on the activity of tyrosine kinase FGFR4.
  • the method used in the experiment is the Mobility shift assay method.
  • the substrate used in the experiment is a fluorescently labeled peptide. Under the action of the enzyme in the reaction system, the substrate is transformed into a product, and the charge on it is also corresponding. Change, this method can use the difference in charge of the substrate and the product to separate the two and detect them separately.
  • a 300 ⁇ M compound DMSO solution was diluted in a 384-well plate into a 100-fold final concentration of DMSO solution, and a 3-fold gradient dilution was used to transfer 250nL of a 100-fold final concentration of the compound to the target plate OptiPlate-384F using a dispenser Echo 550.
  • the final concentration of the compound is 3000nM, 1000nM, 333.3nM, 111.1nM, 37.04nM, 12.35nM, 4.115nM, 1.372nM, 0.4572nM, 0.1524nM, the compound and enzyme pre-incubation time is 60mins;
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min is the average value of the negative control well, representing the conversion rate reading of the wells without enzyme activity
  • Conversion%_max is the average value of the positive control well ratio, representing the conversion rate reading of the wells without compound inhibition .
  • 1BLU554 is the No. 40 compound disclosed by Blueprint Medicines Corporation in WO2015061572.
  • the compound of the present invention has an inhibitory effect on FGFR4 kinase, and the inhibitory effect of the compound on FGFR4 is much stronger than that on FGFR1, and has very good selectivity.
  • CCG CELL TITER-GLO
  • ATP participates in a variety of enzymatic reactions in organisms and is an indicator of living cell metabolism, its content directly reflects the number and cell state of cells.
  • CellTiter-Glo TM reagent was added to the cell culture medium to measure the luminescence value. The value is directly proportional to the amount of ATP, and ATP is positively related to the number of living cells, so cell viability can be inspected by detecting ATP content.
  • the 600 ⁇ M test substance dissolved in DMSO was diluted with DMSO in a 1:3 ratio to a 200-fold final concentration solution, then the cell culture medium was diluted 20 times (10 ⁇ ), and 20 ⁇ L of the compound solution was added to the 96 wells containing cells In the plate, the final compound concentration from high to low is 3000nM, 1000nM, 333.3nM, 111.1nM, 37.04nM, 12.35nM, 4.115nM, 1.372nM, 0.4572nM, and the well plates are placed in a 37°C, 5% CO2 incubator. 96hrs;
  • Inhibition rate% (blank group value-administration group value) / (blank group value-zero adjustment group value) * 100
  • the compound represented by the structural formula I of the present invention has a good inhibitory effect on the proliferation of Hep3B cells.
  • Example C Xenograft tumor model
  • mice were inoculated subcutaneously at the right anterior scapula of 5 ⁇ 10 6 human hepatoma cells Hep3B, and the volume ratio of cell suspension to matrigel was 1:1 (0.2/mL/mouse).
  • the treatment group is given a test compound solution prepared with an appropriate solvent, and the solvent control group is given a blank solvent.
  • the tumor volume was measured twice a week, and the tumor weight was measured after the last administration to determine the activity of the compound.
  • the tumor growth inhibition rate (%, TGI) was calculated.
  • Body weight measurement is used as a routine measure of toxicity, and the frequency is the same as that of tumor volume measurement.
  • the compound represented by the structural formula I of the present invention shows good anti-tumor activity.
  • the inhibitory rate of the compound represented by structural formula I on Hep3B tumor volume growth is 73.02%, 86.26% and 90.26%, respectively.
  • the growth inhibition rates were 84.76%, 92.27%, and 98.15%, respectively, indicating that the compound represented by structural formula I showed a dose-dependent effect in inhibiting tumor volume and weight.
  • the animals administered with the compound represented by structural formula I did not experience significant weight loss, suggesting that the two compounds were well tolerated under the conditions of the dose.

Abstract

本发明涉及结构式I所示化合物的晶型和/或马来酸盐、磷酸盐、L-酒石酸盐、和己二酸盐，及各盐型的多种晶型，其制备方法及其应用。

Description

FGFR4抑制剂的盐型、晶型及其用途 技术领域
本发明涉及N-((3S,4S)-3-((6-(2,6-二氯-3,5-二甲氧基苯基)-9-甲基-5,6-二氢嘧啶并[5,4-c][1,8]萘啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰胺的新晶型、盐型及所述盐型的结晶形式。本发明还涉及包含所述晶型或盐型的药物组合物，所述盐型、晶型和药物组合物作为FGFR4抑制剂的用途，以及治疗FGFR4介导的疾病的方法。
背景技术
成纤维细胞生长因子受体(FGFR)属于受体型酪氨酸蛋白激酶(Receptor Tyrosine Kinase，RTK)超家族的一员，FGFR通过与成纤维细胞生长因子(fibroblast growth factor,FGF)结合，在不同组织中经过复杂的信号传递路径对细胞的增殖、分化和迁移进行调节(Jouanneau J et al.Oncogene,1999,18:327-333)。FGFR为单链糖蛋白，由胞外区、单次跨膜区及细胞质内的酪氨酸激酶区组成，其中胞外区由前导肽和3个免疫球蛋白结构域构成。FGFR酪氨酸激酶家族包括FGFR1、FGFR2、FGFR3和FGFR4。其中FGFR4基因位于染色体5q35.1上，其长度约为11.3kb，有18个外显子(Kostrzewa M.Mammalian genome,1998,9(2):131-135)。FGFR4蛋白属于FGFR酪氨酸激酶家族的重要成员，其第388位氨基酸位于RTK结构高度保守的跨膜区内，此结构改变所导致的FGFR4蛋白病理生理功能变化，可增强酪氨酸激酶的活性。FGFR4蛋白是一类具有自身磷酸化活性的跨膜酪氨酸激酶受体，在胚胎发育、组织修复和血管生成等进程中起着重要的作用(Eswarakumar V P et al.Cytokine Growth Factor Rev,2005,16(2):139-149)。
FGFR4的信号通路：当配体由肝素或类肝素介导后便与FGFR4结合，致使FGFR4单体发生二聚化，随着细胞质内C末端、激酶***区及近膜区的酪氨酸磷酸化后，A环(activation loop,A loop)激酶区经磷酸化使得FGFR4活化(Schlessinger J et al.Mol Cell,2000,6:743-750)。活化后的FGFR4主要有两个 胞内作用物：磷脂酶C和FGF受体底物2(FRS2)(Dailey L et al.Cytokine Growth Factor Rev,2005,16:233-247)。
FGFR4活化后，磷脂酶C的Src同源区2(SH2)结构域便与其活化的C末端酪氨酸结合，使PLC磷酸化后结合在C末端酪氨酸位点上。激活的PLC水解其底物4,5-二磷酸磷脂酰肌醇(PIP 2)形成二酰基甘油(DAG)和三磷酸肌醇(IP 3)。IP3与细胞内特异受体结合来刺激细胞内的钙池释放Ca 2+，Ca 2+与钙调蛋白结合以激活Ca 2+/钙调蛋白依赖性蛋白激酶。另外，Ca 2+与二酰基甘油都能激活蛋白激酶C家族中的成员。PIP2水解产生的二级信号除了能激活转录因子外，还能激活多种细胞内的反应。
SOS蛋白与生长因子受体结合蛋白2(growth factor receptor bound 2,Grb2)的Src同源区3(SH3)结构域结合形成Grb2/SOS复合物，该复合物可与FGFR4相连或与FGF受体底物2α(FGFR substrate 2α，FRS2α)结合，其中FRS2α与跨膜蛋白-磷酸酪氨酸结合域(phosphotyrosine binding domain,PTB)相连，促进鸟嘌呤核苷在Ras上面交换使Ras成为Ras-GTP，从而启动下游MAPK信号通路。
FGFR4的自身磷酸化使JAK家族因子(JAK)活化，活化的JAK使FGFR4上的特异性信号蛋白吸附位点磷酸化，此位点可以充当信号传导及转录激活蛋白(signal transducer and activator of transcription,STAT)及其他信号分子的停泊位点。STAT蛋白被FGFR4的停泊位点吸附后，其C端的酪氨酸残基被JAK磷酸化，随后便脱离受体形成稳定的同源或异源二聚体并转移到细胞核中与γ干扰素活化部位(gammainterferon activation site,GAS)增强子家族成员结合，激活靶基因的转录。
小分子FGFR4抑制剂是通过阻断胞外配体分子与受体的结合或胞内激酶信号的传递，以抑制FGFR4所介导的增殖信号。目前在开发的靶向FGFR4抑制剂有多种，阿斯利康研发了FGFR4选择性抑制剂AZ709，其体外实验对高水平表达FGF19或FGFR4的细胞显示出很好的抑制效果，但体内实验无明显作用。诺华公司的FGFR4选择性抑制剂FGF401能特异性靶向FGFR4，治疗其过表达的肝癌等恶性肿瘤。H3生物医药公司的FGFR4特异性抑制剂H3B6527对FGF19基因扩增的细胞具有强抗肿瘤活性，且在小鼠和猴的动物模型中没有胆汁酸相关 的不良反应。蓝图医药研发并报道了一个FGFR4特异性的抑制剂BLU554以治疗FGFR4过表达的肝癌和胆管癌。
随着科研人员对FGFR4结构和功能关系的深入了解以及其与其它基因相互作用的深入研究，特应性强、治疗效果好且不良反应低的FGFR4将会被设计开发出来，采用FGFR4分子靶向***将非常有意义。
鉴于活性成分的化学稳定性、固态稳定性和存储周期等性能对于药物来说都是非常重要的因素，因此探索可药用化合物的新盐型、新晶型或多晶型物提供了提高医药产品的整体性能的机会，同时扩大了制剂科学家设计时可用的材料品种。特定有机药物化合物的盐型和/或多晶型物，由于各自的独特的结构，而具有明显不同的物理性质，如形貌、熔点、溶解性、吸湿性及稳定性等，进而在药物制剂配制、治疗活性和化学、物理稳定性方面呈现出不同的行为。虽然技术人员有动机进行特定有机药物化合物的盐型和/或晶型的探究，但是应该注意到，通常无法单从分子结构预知化合物将发生何种成盐或结晶行为，无法预测特定有机药物化合物存在多少种晶体形式以及存在何种晶体形式，更不可能预测晶型本身的结构和性质。
发明内容
本发明涉及结构式I所示化合物N-((3S,4S)-3-((6-(2,6-二氯-3,5-二甲氧基苯基)-9-甲基-5,6-二氢嘧啶并[5,4-c][1,8]萘啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰胺的盐型及其晶型。
Figure PCTCN2021083204-appb-000001
本发明提供了结构式I所示化合物的晶型A，以及结构式I所示化合物的马来酸盐、磷酸盐、己二酸盐和L-酒石酸盐。
优选地，结构式I所示化合物的优选盐为马来酸盐和磷酸盐。
另一方面，本发明提供了结构式I所示化合物的马来酸盐、L-酒石酸盐、己二酸盐和磷酸盐的晶型。
在一些实施方案中，本发明提供结构式I所示化合物的晶型A，晶型A的X射线粉末衍射图具有衍射角2θ为：7.5°±0.2°、10.7°±0.2°、11.3°±0.2°、15.1°±0.2°的特征峰。
作为优选，所述晶型A的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°、10.7°±0.2°、11.3°±0.2°、13.1°±0.2°、15.1°±0.2°、20.9°±0.2°、25.2°±0.2°的特征峰。
作为优选，所述晶型A的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°、10.7°±0.2°、11.3°±0.2°、13.1°±0.2°、15.1°±0.2°、20.9°±0.2°、21.6°±0.2°、22.8±0.2°、23.5°±0.2°、25.2°±0.2°、30.2±0.2°的特征峰。
作为优选，所述晶型A具有约如图1所示的X射线粉末衍射图。
另一方面，所述晶型A还具有基本上如图2所示的热重分析(TGA)图谱和如图3所示的差示扫描量热(DSC)图谱。
在一些实施方案中，本发明提供了结构式I所示化合物的马来酸盐晶型1，该晶型X射线粉末衍射图具有衍射角2θ为3.7°±0.2°、9.9°±0.2°、11.0°±0.2°、16.2°±0.2°的特征峰。
作为优选，所述马来酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.7°±0.2°、9.9°±0.2°、11.0°±0.2°、13.4°±0.2°、16.2°±0.2°、17.2°±0.2°、20.6°±0.2°的特征峰。
作为优选，所述马来酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.7°±0.2°、9.9°±0.2°、11.0°±0.2°、13.4°±0.2°、16.2°±0.2°、17.2°±0.2°、18.7°±0.2°、19.4°±0.2°、20.6°±0.2°、22.6°±0.2°、24.4°±0.2°的特征峰。
作为优选，所述马来酸盐晶型1具有约如图4所示的X射线粉末衍射图。
另一方面，所述马来酸盐晶型1还具有基本上如图5所示的热重分析(TGA)图谱和如图6所示的差示扫描量热(DSC)图谱。
在一些实施方案中，所述马来酸盐与结构式I所示化合物的化学计量比为1:1。
在一些实施方案中，本发明提供了结构式I所示化合物的马来酸盐晶型2，该晶型X射线粉末衍射图具有衍射角2θ为5.6°±0.2°、7.0°±0.2°、19.9°±0.2°、 的特征峰。
作为优选，所述马来酸盐晶型2的X射线粉末衍射图具有衍射角2θ为5.6°±0.2°、7.0°±0.2°、9.9°±0.2°、14.5°±0.2°、19.9°±0.2°的特征峰。
作为优选，所述马来酸盐晶型2具有约如图7所示的X射线粉末衍射图。
作为优选，所述马来酸盐晶型2具有基本上如图8所示的差示扫描量热(DSC)图谱。
在一些实施方案中，本发明提供了结构式I所示化合物的磷酸盐，其中磷酸盐与结构式I所示化合物的化学计量比为1.5:1，可以由式II表示：
Figure PCTCN2021083204-appb-000002
本发明提供了式II的晶型1，为了方便称为磷酸盐晶型1，该晶型X射线粉末衍射图具有衍射角2θ为4.9°±0.2°、10.7°±0.2°、16.8°±0.2°、21.3°±0.2°的特征峰。
作为优选，所述磷酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.9°±0.2°、8.3°±0.2°、10.7°±0.2°、11.6°±0.2°、12.8±0.2°、16.8°±0.2°、21.3°±0.2°的特征峰。
作为优选，所述磷酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.9°±0.2°、8.3°±0.2°、10.7°±0.2°、11.6°±0.2°、12.8±0.2°、16.8°±0.2°、20.1°±0.2°、21.3°±0.2°、28.5°±0.2°的特征峰。
作为优选，所述磷酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.9°±0.2°、8.3°±0.2°、10.7°±0.2°、11.6°±0.2°、12.8±0.2°、16.8°±0.2°、20.1°±0.2°、21.3°±0.2°、24.7°±0.2°、28.5°±0.2°的特征峰。
作为优选，所述磷酸盐晶型1具有约如图9或图10所示的X射线粉末衍射图。
另一方面，所述磷酸盐晶型1还具有基本上如图11所示的TGA图谱和如图12所示的DSC图谱。
在一些实施方案中，本发明提供了结构式I所示化合物的L-酒石酸盐晶型1，该晶型X射线粉末衍射图具有衍射角2θ为5.4°±0.2°、17.6°±0.2°、19.7°±0.2°、20.7°±0.2°的特征峰。
作为优选，所述L-酒石酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.4°±0.2°、12.9°±0.2°、16.5°±0.2°、17.6°±0.2°、19.7°±0.2°、20.7°±0.2°的特征峰。
作为优选，所述L-酒石酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.4°±0.2°、12.9°±0.2°、16.5°±0.2°、17.6°±0.2°、19.7°±0.2°、20.7°±0.2°、22.2°±0.2°、26.4°±0.2°的特征峰。
作为优选，所述L-酒石酸盐晶型1具有约如图13所示的X射线粉末衍射图。
作为优选，所述L-酒石酸盐晶型1具有约如图14所示的TGA谱图。
作为优选，所述L-酒石酸盐晶型1具有约如图15所示的DSC谱图。
在一些实施方案中，本发明提供了结构式I所示化合物的己二酸盐晶型1，该晶型X射线粉末衍射图具有衍射角2θ为5.8°±0.2°、8.4°±0.2°、12.3°±0.2°、22.9°±0.2°的特征峰。
作为优选，所述己二酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.8°±0.2°、8.4°±0.2°、10.0°±0.2°、10.4°±0.2°、12.3°±0.2°、17.5°±0.2°、22.9°±0.2°的特征峰。
作为优选，所述己二酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.8°±0.2°、8.4°±0.2°、10.0°±0.2°、10.4°±0.2°、12.3°±0.2°、17.5°±0.2°、22.9°±0.2°、25.4°±0.2°、25.9°±0.2°的特征峰。
作为优选，所述作为优选，所述己二酸盐晶型1具有约如图16所示的X射线粉末衍射图。
作为优选，所述己二酸盐晶型1具有约如图17所示的TGA谱图和约如图18所示的DSC谱图。
结构式I所示化合物的无定形溶解度较低、稳定性较差，且具有较高的引湿性。本发明研究发现，结构式I所示化合物的晶型A和磷酸盐晶型1具有较好的稳定性和更低的引湿性；己二酸盐晶型1和马来酸盐晶型1具有更优的稳定性，因此，这些盐和晶型对于药物的生产，及其化学稳定性和安全性是有益的。另外， 最令人惊奇的是磷酸盐晶型1，制备工艺稳定，成本低廉，且同时兼具低引湿性，高稳定性和更好药代动力学的性质。
如非特殊说明，所述X射线粉末衍射图均使用Cu靶的Kα谱线测得。
如非特殊说明，本发明的实验温度均为室温。
本发明进一步提供了制备结构式Ⅰ所示化合物及其晶型A、马来酸盐晶型1、马来酸盐晶型2、磷酸盐晶型1、己二酸盐晶型1和L-酒石酸盐晶型1的方法。
其中，结构式I所示化合物可通过下述路线制备：
Figure PCTCN2021083204-appb-000003
所述结构式I所示化合物制备路线的具体反应条件在具体实施例中进行描述，应当理解的是，所述制备路线所应用的反应溶剂和条件不仅限于是具体实施例中所应用的溶剂和条件，其他反应条件亦可适用于所述结构式I所示化合物的制备中。
本发明进一步提供了一种药物组合物，其含有治疗有效量的本发明所述盐型或晶型，和药学上可接受的辅料、辅助剂或载体。
其次，本发明还提供了上述药物组合物的优选实施方式。
作为优选，上述药物组合物含有治疗有效量的本发明的盐型或晶型，联用至少一种其他的活性成分。
作为优选，所述药物组合物用于口服给药。
作为优选，所述药物组合物用于片剂或胶囊。
作为优选，所述药物组合物含有0.01重量％-99重量％的本发明的晶型。
作为优选，所述药物组合物含有10重量％-70重量％的本发明的晶型。
作为优选，所述药物组合物含有20重量％-50重量％的本发明的晶型。
本发明进一步提供了所述晶型或药物组合物在制备药物中的应用。
本发明进一步提供了所述应用的优选技术方案：
作为优选，所述应用为治疗、预防、延迟或阻止癌症或癌症转移的发生或进展。
作为优选，所述应用为制备治疗由FGFR4介导的疾病的药物。
作为优选，所述疾病是癌症。
作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺式细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
作为优选，所述应用为用作FGFR4抑制剂。
本发明还提供了一种在治疗对象上施用治疗有效量的至少任意一种晶型或药物组合物治疗和/或预防由FGFR4介导的疾病的方法。
作为优选，在上述方法中，所述FGFR4介导的疾病是癌症。
作为优选，在上述方法中，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺式细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种晶型或其药物组合物，所述癌症是乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性 肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺式细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
作为优选，在上述方法中，所述的治疗对象为人类。
本发明的所有晶型都是基本上纯的。
在一些实施方案中，一种酸和结构式I所示化合物形成相应的盐，这些盐型化合物可以以各种物理形式存在。例如，可以是溶液、悬浮液或固体形式。在某些实施方式中，盐型化合物为固体形式。为固体形式时，所述化合物可以是无定形物，结晶物，共晶物或其混合物。
在本发明中，术语“盐”或“盐型”可以定义为游离碱API和酸被离子化的无定形或晶体材料，或者，其中游离碱API和酸这两种组分利用显著的分子间相互作用，诸如氢键来结合所产生的均匀的晶体材料，称为共晶。应当理解的是，本发明中的盐还可以是部分离子化的和部分共晶的。
本文所用的术语“基本上纯的”是指所述晶型的含量以重量计，不小于85％，优选不小于95％，更优选不小于98％。
本发明中，“具有约如图1所示的X射线粉末衍射图”或“其X射线粉末衍射图基本上如图1所示”中所使用的术语“约”和“基本上”是表示附图中的峰的精确位置不应当被解释为绝对值。因为本领域技术人员可知，X射线粉末衍射图的2θ值可能会由于不同的测量条件(如所用的设备和仪器)和不同的样品(如不同批次的样品)而产生误差，X射线粉末衍射图的衍射角的测量误差为5％或更小，通常，给定的值的±0.2°的差别被认为是恰当的。还应理解，峰值的相对强度可能随实验条件和样品制备诸如颗粒在样品中的优选的取向而波动。自动或固定的发散狭缝的使用也将会影响相对强度的计算。在这里所包括的XRD曲线所示强度只是示例性的，不能被用作绝对比较。
本领域的技术人员将会理解，由于样品纯度、样品制备以及测量条件(例如加热速率)的变化，由DSC测量的数据可能会发生小的变化。应当理解，通过其它种类的仪器或通过使用不同于那些在下文中描述的条件，可能会给出可替换的熔点的读数。因此，本申请所引用的吸热图并不作为绝对值，且当解释DSC数 据时将考虑这样的测量误差。
本文所用术语“治疗有效量”是指一个化合物施用于治疗对象时对于治疗一种疾病、或一种疾病或病症的至少一种临床症状时，足以影响对疾病、病症或症状的这种治疗的量。“治疗有效量”可以随着化合物，疾病、病症和/或疾病或病症的症状，疾病、病症和/或疾病或病症的症状的严重程度，被治疗的患者的年龄，和/或被治疗的患者的体重等变化。在任意特定的情况下，一个合适的量对那些本领域的技术人员可以是显而易见的，也可以是用常规实验确定的。在联合治疗的情况下，“治疗有效量”是指有效治疗疾病、病症或病状的联用对象的总量。
本发明所述的盐型或晶型可以合并用药作为活性组分，与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式，取决于想采用的给药方式，例如，口服或注射(包括静脉注射)。因此，本发明的药物组合物可以采用适于口服给药的独立单位的形式。如包含预先确定剂量的活性组分的胶囊剂，扁囊剂或片剂。进一步地，本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液或油包水型乳液形式。另外，除上述提到的常见的剂型，本发明所述的盐型或晶型也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下，这种方法包括使活性组分和构成一个或多个必要组分的载体缔合的步骤。一般情况下，所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的密切混合制得。另外，该产品可以方便地制备成所需要的外观。
“药学上可接受的载体”是指适合于期望药物制剂的常规的药用载体，例如：诸如水、各种有机溶剂等的稀释剂、赋形剂；诸如淀粉、预胶化淀粉、蔗糖、糊精、甘露醇、乳糖、喷雾干燥乳糖、微晶纤维素、硅化微晶纤维素、无机盐类等的填充剂；诸如淀粉浆、糊精、糖粉、糖浆、胶浆、聚乙二醇、纤维素衍生物、藻酸盐、明胶、羟丙纤维素、共聚维酮和聚乙烯吡咯烷酮(PVP)等的粘合剂；诸如蒸馏水、乙醇和甘油等的湿润剂；诸如干淀粉、低取代羟丙纤维素、羟丙基淀粉、琼脂、碳酸钙、碳酸氢钠、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠等的崩解剂；诸如季铵化合物、氨基酸乙胺衍生物、乙酰醋酸酯类、β-二羧酸酯、芳香族酸性化合物、脂肪族酸性化合物等的吸收促进剂；诸如十六烷基 硫酸钠、十八烷基硫酸钠、二辛基琥珀酸磺酸钠、十二烷基磺酸钠、苯扎溴铵、苯扎氯铵、杜灭芬、卵磷脂、十六烷醇、十二烷基硫酸钠、吐温和司盘等的表面活性剂；诸如聚乙二醇、卡波姆、纤维素衍生物、甘油明胶、聚乙烯醇、可可豆酯、合成或全合成脂肪酸甘油酯、聚乙烯醇40硬脂酸酯、凡士林、固体石蜡、液体石蜡、二甲基硅油、羊毛脂、蜂蜡和豚酯等的载药基质；诸如高岭土和膨润土等的吸收载体；诸如滑石粉、微粉硅胶、二氧化硅、氢化植物油、十二烷基硫酸镁、十二烷基硫酸钠、硬脂酸、硬脂酸钙、硬脂酸镁、硬脂富马酸钠和聚乙二醇等的润滑剂。另外还可以在药物组合物中加入其它药学上可接受的辅料，如抗氧剂、着色剂、防腐剂、pH调节剂、硬化剂、乳化剂、抛射剂、分散剂、稳定剂、增稠剂、络合剂、缓冲剂、渗透促进剂、聚合物、芳香剂、甜味剂和染料。优选使用适合期望剂型和期望给药方式的辅料。
术语“疾病”或“病症”或“病状”是指任意的疾病、不适、病、症状或者适应症。
附图说明
图1：结构式I所示化合物晶型A的X射线粉末衍射图谱。
图2：结构式I所示化合物晶型A的热重分析(TGA)图谱。
图3：结构式I所示化合物晶型A的差示扫描量热(DSC)图谱。
图4：结构式I所示化合物马来酸盐晶型1的X射线粉末衍射图谱。
图5：结构式I所示化合物马来酸盐晶型1的热重分析(TGA)图谱。
图6：结构式I所示化合物马来酸盐晶型1的差示扫描量热(DSC)图谱。
图7：结构式I所示化合物马来酸盐晶型2的X射线粉末衍射图谱。
图8：结构式I所示化合物马来酸盐晶型2的DSC图。
图9：结构式I所示化合物磷酸盐晶型1的X射线粉末衍射图谱。
图10：结构式I所示化合物磷酸盐晶型1的X射线粉末衍射图谱。
图11：结构式I所示化合物磷酸盐晶型1的TGA图谱。
图12：结构式I所示化合物磷酸盐晶型1的DSC图谱。
图13：结构式I所示化合物L-酒石酸盐晶型1的X射线粉末衍射图谱。
图14：结构式I所示化合物L-酒石酸盐晶型1的TGA谱图谱。
图15：结构式I所示化合物L-酒石酸盐晶型1的DSC谱图谱。
图16：结构式I所示化合物己二酸盐晶型1的X射线粉末衍射图谱。
图17：结构式I所示化合物己二酸盐晶型1的TGA谱图谱。
图18：结构式I所示化合物己二酸盐晶型1的DSC谱图谱。
图19：结构式I所示化合物无定形的动态水分吸附曲线。
图20：结构式I所示化合物晶型A的动态水分吸附曲线。
图21：结构式I所示化合物马来酸盐晶型2的动态水分吸附曲线。
图22：结构式I所示化合物L-酒石酸盐晶型1的动态水分吸附曲线。
图23：结构式I所示化合物磷酸盐晶型1的动态水分吸附曲线。
除非另有说明，本发明所用到的检测仪器信息和检测方法参数如下：
表1
Figure PCTCN2021083204-appb-000004
表2
设备名称 差示扫描量热仪(DSC)
仪器 Discovery DSC 2500
样品盘 铝坩埚
保护气体 氮气
气体流速 50mL/min
常用检测方法 Ramp 10℃/min
表3
设备名称 热重分析仪(TGA)
仪器 Discovery TGA 550
样品盘 铂金坩埚+铝坩埚
保护气体 氮气
气体流速 40mL/min
检测方法 Ramp 10℃/min
表4
设备名称 动态水分吸附仪(DVS)
厂家 Surface Measurement Systems
仪器 DVS Resolution
样品盘 铝坩埚
保护气体 氮气
气体流速 200sccm
表5
Figure PCTCN2021083204-appb-000005
表6
设备名称 高效液相色谱仪(HPLC)
厂家 Waters
型号 H-Class
仪器 恒温恒湿箱
型号 宾得KBF720恒温恒湿箱
磷酸含量检测方法：离子色谱法
仪器：离子色谱仪
色谱柱：Dionex
Figure PCTCN2021083204-appb-000006
AS11-HC Analytical Column，4.0×250mm
保护柱:Dionex
Figure PCTCN2021083204-appb-000007
AG11-HC
流速：1.0ml/min
进样量：10μl
柱温：30℃
运行时间：约20分钟
淋洗液：25mmol/L氢氧化钾溶液
电流：62mA
稀释剂：乙腈-水(50∶50)
具体试验操作：于暗室红光下操作。
对照品溶液的配制：取无水磷酸二氢钠对照品约25mg，精密称定，置于100ml量瓶中，用水溶解并稀释至刻度，摇匀，精密量取1ml置10ml量瓶中，用水稀释至刻度，摇匀，即得。
供试品溶液的配制：取本品约20mg，精密称定，置200ml棕色量瓶中，加稀释剂适量，超声使溶解，并用稀释剂稀释至刻度，摇匀，即得。
测定法：精密量取对照品溶液及供试品溶液各10μl，分别注入离子色谱仪，记录色谱图。按外标法以峰面积计算。
计算公式：
Figure PCTCN2021083204-appb-000008
Figure PCTCN2021083204-appb-000009
单晶检测
使用BRUKER D8 VENTURE，在150K收集单晶数据，Cu Kα辐射；采用直接法(Shelxs97)解析晶体结构，使用最小二乘法修正结构参数和判别原子种类，使用几何计算法和差值Fourier法获得全部氢原子位置。
具体实施方式
下面通过给出的实施例对本发明作出进一步说明，但所述实施例并不对本发明要求保护的范围构成任何限制。在本发明的具体实施例中，除非特别说明，所述技术或方法为本领域的常规技术或方法等。如无特别说明，下述实施例2-10中作为起始物料的结构式I所示化合物均为参考实施例1制备方法获得的结构式I所示化合物。下面实施例中，除非另有说明，所述的原料、试剂通过市售购买获得；所述百分比、比例、比率或份数等按照重量计算。
缩略语：
API：原料药；
DCM：二氯甲烷；
DMF：N,N-二甲基甲酰胺；
EA：乙酸乙酯；
CH 3OH：甲醇；
Cs 2CO 3：碳酸铯；
hrs/h：小时；
HPLC：高效液相色谱；
LCMS/LC-MS：液相色谱-质谱联用；
lux：勒克斯；
min：分钟；
mCPBA:间氯过氧苯甲酸；
Pd(PPh 3) 4：四(三苯基膦)钯；
Pd(OAc):醋酸钯；
KOAc：乙酸钾；
K 2CO 3：碳酸钾；
Na 2CO 3：碳酸钠；
NaH：钠氢；
PdCl 2(dppf)CH 2Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物；
Xant-phos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；
RH：相对湿度；
RRT：相对保留时间；
TEA：三乙胺；
1H-NMR/HNMR：核磁共振氢谱；
XRD/XRPD：X-射线粉末衍射；
DSC：差示扫描量热；
TGA：热重分析；
DVS：动态水分吸附。
中间体1-S4的合成
Figure PCTCN2021083204-appb-000010
将3.57g 1-M1、6.2mL TEA和2.09g甲酸(含量88％)溶于100mL甲酸乙酯中，升温回流反应4hrs。LCMS检测反应完全。减压浓缩，残余物用乙酸乙酯溶解，有机层依次用少量水和饱和食盐水洗涤，浓缩，得到3.49g化合物1-S4，不必纯化直接用于下一步。
LC-MS[M+H +]171.08。
实施例1 结构式I所示化合物的合成
Figure PCTCN2021083204-appb-000011
步骤1：化合物1-A1的制备
将15.0g 1-B2、17.80g 1-S1、44.02g Cs 2CO 3、1.52g Pd(OAc) 2和5.86g Xant-phos溶于500mL甲苯中，氮气保护下115℃下反应8hrs。LCMS检测反应完全，减压浓缩，残余物用水溶解，DCM萃取。有机层依次用水和饱和食盐水洗涤，浓缩，残余物用柱层析分离纯化，洗脱剂为正己烷:二氯甲烷＝5:1，得到标题化合物。
LC-MS[M+H +]390.95。
步骤2：化合物1-A2的制备
将21.91g 1-A1、21.29g 1-S2、16.46g KOAc和3.66g PdCl 2(dppf)CH 2Cl 2溶于340mL 1,4-二氧六环中，氮气保护下100℃下反应8hrs。LCMS检测反应完全，减压浓缩，向残余物中加入水和EA的混合溶剂，搅拌分散，过滤，滤饼干燥，得到标题化合物。
LC-MS[M+H +]357.05。
步骤3：化合物1-A3的制备
将15.84g 1-A2、9.21g 1-S3、12.27g K 2CO 3和5.12g Pd(PPh 3) 4溶于350mL 1,4-二氧六环/40mL水中，氮气保护下90℃下反应6hrs。LCMS检测反应完全，减压浓缩，残余物用水溶解，DCM萃取。有机层依次用水和饱和食盐水洗涤，浓缩，残余物用柱层析分离纯化，洗脱剂为二氯甲烷:甲醇＝200:1，得到标题化合物。
LC-MS[M+H +]465.05。
步骤4：化合物1-01的制备
将8.50g 1-A3、1.65g冰醋酸和1.72g氰基硼氢化钠溶于100mL甲醇和150mL二氯甲烷混合液中，氮气保护下室温反应4hrs。LCMS检测反应完全，减压浓缩，残余物加入Na 2CO 3水溶液分散溶解，所得混合物用DCM萃取两次，合并有机相。有机相水洗后，干燥，过滤，滤液减压浓缩得到标题化合物。
LC-MS[M+H +]449.05。
步骤5：化合物1-02的制备
将7.17g 1-01溶于200mL DCM中，冰水浴条件下缓缓加入10.37g mCPBA(含量85％)，加毕，自然升至室温反应4hrs。LCMS检测反应完全。反应液中加入饱和碳酸氢钠水溶液洗涤两次，有机层依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残余物用柱层析分离纯化，洗脱剂为二氯甲烷，得到标题化合物。
LC-MS[M+H +]465.05。
步骤6：化合物1-03的制备
将2.83g 1-S4溶于20mL DMF中，降至0℃条件下缓缓加入0.77g氢化钠(含量60％)，此温度下反应40min。然后加入10mL化合物1-02(6.18g)的DMF溶液，搅拌40min，向反应液中加入DCM和水淬灭，分液，水层用DCM萃取两次。合并有机层依次用水和饱和食盐水洗涤，分离有机层，浓缩，残余物用柱层析分离纯化，洗脱剂为二氯甲烷:甲醇＝100:1，得到标题化合物。
LC-MS[M+H +]543.13。
步骤7：化合物1-04的制备
1.29g化合物1-03和0.52g 10％Pd/C溶于40mL/40mL的EA/CH 3OH混合溶剂中，H 2下，加热至30℃下反应2hrs。过滤，减压浓缩，残余物用柱层析分离纯化，洗脱剂为二氯甲烷:甲醇＝40:1，得到标题化合物。
LC-MS[M+H +]517.14。
步骤8：结构式I所示化合物的制备(游离碱FB)
将1.77g化合物1-04溶于40mL DCM中，加入1.90mL三乙胺，降温至-20℃，缓缓滴加0.31g丙烯酰氯，此温度下反应1h。LCMS检测反应完全，反应液用饱和NaHCO 3水溶液淬灭，有机层依次用水和饱和食盐水洗涤，减压浓缩，残余物用柱层析分离纯化，洗脱剂为DCM:MeOH＝80:1，得到标题结构式I所示化合物。
LC-MS[M+H +]571.15。
1H NMR(500MHz,DMSO-d 6):δ(ppm)8.15(s,1H),8.12(s,1H),8.00(d,J＝7.8Hz,1H),7.79(s,1H),6.96(s,1H),6.59(d,J＝7.5Hz,1H),6.20(br,1H),6.02-6.05(m,1H),5.49(br,1H),4.76(d,J＝14.0Hz,1H),4.71(d,J＝14.0Hz,1H),4.45(br,1H),4.24(br,1H),3.96(s,6H),3.81-3.87(m,2H),3.62-3.64(m,1H),3.51-3.64(m,1H),2.17(s,3H),1.92-1.99(m,1H),1.63-1.65(m,1H)。
实施例2 结构式I所示化合物结晶盐的筛选
对结构式I所示化合物的结晶盐进行筛选，以结构式I所示化合物和对离子在不同的溶剂体系中投料进行实验，详见表7。
表7盐型筛选实验数据汇总
Figure PCTCN2021083204-appb-000012
在实验条件下，在苯磺酸、硫酸、对甲苯磺酸、天冬氨酸、柠檬酸、L-苹果酸、富马酸和草酸存在下，未观察到结构式I所示化合物的结晶盐的形成。在甲磺酸、马来酸、酒石酸、磷酸的存在下，观察到结构式I所示化合物的结晶盐的形成，但其甲磺酸盐结晶显示弱晶态。
实施例3 结构式I所示化合物晶型A的制备方法
取8.3g结构式I所示化合物，加入80mL乙酸乙酯打浆15hrs，减压抽滤，滤饼于真空干燥箱50℃减压干燥6小时，得黄色固体7.10g即为结构式I所示化合物晶型A。
实施例4 结构式I所示化合物晶型A的制备方法
将结构式I所示化合物(1.5kg)的二氯甲烷(16L)溶液减压浓缩，向浓缩体系缓慢加入结构式I所示化合物晶型A做晶种(10.01g晶型A分散于500mL乙酸乙酯的混悬体系)。继续减压浓缩，同时缓慢加入乙酸乙酯(12L)。浓缩至剩余溶剂量约为6～7L时，停止浓缩。所得浓缩体系转入20L反应釜中，继续搅拌12小时。过滤，将所得固体置于真空干燥箱中，50℃真空干燥6至18小时。称重，得到0.84kg结构式I所示化合物晶型A。
1H NMR(500MHz,DMSO-d 6):δ(ppm)8.15(s,1H),8.12(s,1H),8.00(d,J＝7.8Hz,1H),7.79(s,1H),6.96(s,1H),6.59(d,J＝7.5Hz,1H),6.20(br,1H), 6.02-6.05(m,1H),5.49(br,1H),4.76(d,J＝14.0Hz,1H),4.71(d,J＝14.0Hz,1H),4.45(br,1H),4.24(br,1H),3.96(s,6H),3.81-3.87(m,2H),3.62-3.64(m,1H),3.51-3.64(m,1H),2.17(s,3H),1.92-1.99(m,1H),1.63-1.65(m,1H)。
结构式I所示化合物晶型A的X射线粉末衍射图主要数据如表8所示。
表8
Figure PCTCN2021083204-appb-000013
实施例5 结构式I所示化合物的磷酸盐晶型1的制备方法
将异丙醇(608mL)和结构式I所示化合物(34.20g)依次加入到四口瓶中，搅拌加热，升温至72℃后缓缓滴加20.70g磷酸水溶液(85％磷酸溶于86mL纯化水)，滴加完毕后，继续升温至81℃，体系完全溶清。过滤，滤液80℃搅拌20min后降至室温，搅拌过夜。然后向反应体系中滴加正庚烷(628mL)，继续搅拌6hrs。反应液过滤，滤饼抽干，于60℃真空干燥12hrs，得到41.49g结构式I所示化合物的磷酸盐晶型1，，XRPD图谱如图9所示。
实施例6 结构式I所示化合物的磷酸盐晶型1的制备方法
将结构式I所示化合物(700.38g，1.23mol)、异丙醇(11L)和纯化水(1.58L)加入反应釜中，搅拌升温。内温77℃时，缓缓滴加85％磷酸水溶液(423.87g，3.68mol)，45min滴毕，继续保温反应，80℃时体系完全澄清，放料，趁热过滤，滤液重新加入反应釜中。加热至80℃，撤去油浴，自然降温。降温至65℃时加入3.5g磷酸盐晶型1做晶种。降温至大约45℃时，固体逐渐析出。12小时后，滴加正庚烷(11L)，2小时滴毕，搅拌6小时，抽滤，滤饼于60℃真空干燥得766.21g结构式I所示化合物的磷酸盐晶型1，XRPD图谱如图10所示。
1H NMR(500MHz,DMSO)：δ8.15(s,1H),8.12(s,1H),8.00(d,J＝7.8Hz,1H),7.79(s,1H),6.96(s,1H),6.59(d,J＝8.0Hz,1H),6.20(s,1H),6.03(d,J＝15.0Hz,1H),5.49(s,1H),4.74(q,J＝14.1Hz,2H),4.45(s,1H),4.27–4.19(m,1H),3.96(s,6H),3.87–3.81(m,2H),3.64–3.62(m,1H),3.54–3.51(m,1H),2.17(s,3H),1.99–1.92(m,1H),1.65–1.63(m,1H)。
结构式I所示化合物磷酸盐晶型1的X射线粉末衍射图主要数据如表9所示。
表9
Figure PCTCN2021083204-appb-000014
用离子色谱法对磷酸根含量进行检测(同一样品检测两次)，1.5个磷酸含量 理论值：20.46％，±10％范围：18.41％-22.50％，检测结果见表10。
表10
Figure PCTCN2021083204-appb-000015
磷酸盐晶型1的晶胞参数如下所示：
晶体属单斜晶系，空间群为P2 1，
a＝8.4064(17)，
b＝35.714(7)，
Figure PCTCN2021083204-appb-000016
α＝γ＝90.00°，
β＝91.14(3)°；
晶胞体积
Figure PCTCN2021083204-appb-000017
晶胞内不对称单位数Z＝2。
实施例7 结构式I所示化合物的马来酸盐晶型1的制备方法
取500mg结构式I所示化合物加入10mL丙酮中，40℃水浴搅拌溶解，取112mg马来酸溶于0.5mL丙酮中，室温下滴加到上述体系中，升温至50℃搅拌20min，固体析出，反应液自然降至室温并继续搅拌14小时。过滤，滤饼用5mL丙酮淋洗，滤饼室温真空干燥，得400mg结构式I所示化合物的马来酸盐晶型1。
1H NMR(500MHz,DMSO)δ8.15(s,1H),8.12(s,1H),7.98(d,J＝7.8Hz,1H),7.79(s,1H),6.96(s,1H),6.65(s,1H),6.25(s,2H),6.18(s,1H),6.03(d,J＝15.0Hz,1H),5.48(s,1H),4.74(q,J＝14.1Hz,2H),4.45(s,1H),4.27-4.19(m,1H),3.95(s,6H),3.90-3.74(m,2H),3.68-3.57(m,1H),3.56-3.48(m,1H),2.17(s,3H),2.00-1.88(m,1H),1.68-1.58(m,1H)。
结构式I所示化合物马来酸盐晶型1的X射线粉末衍射图主要数据如表11所示。
表11
序号 2θ±0.2(°) 相对强度(％)
1 3.7 57.9
2 9.7 60.7
3 9.9 71.5
4 11.0 93.5
5 11.7 44.9
6 13.4 53.6
7 14.4 11.5
8 16.2 100.0
9 17.2 47.6
10 18.7 42.7
11 19.2 26.6
12 19.4 56.0
13 19.9 12.1
14 20.6 68.9
15 20.9 25.6
16 21.8 33.1
17 22.6 56.9
18 23.5 15.3
19 24.4 57.2
20 26.4 26.1
实施例8 结构式I所示化合物的马来酸盐晶型2的制备方法
取600mg结构式I所示化合物加入20mL丙酮中，50℃水浴搅拌溶清，过滤，降至室温。取134.2mg马来酸溶于1mL丙酮中溶解，室温下搅拌滴加至上述体系中，室温搅拌40min后，向反应液中加入54mL甲基叔丁基醚，4℃搅拌过夜，析出固体，减压抽滤，室温真空干燥，得到486mg结构式I所示化合物的马来酸盐晶型2。
实施例9 结构式I所示化合物的L-酒石酸盐晶型1的制备方法
取120mg结构式I所示化合物，加入4mL丙酮50℃搅拌，过滤，降至室温。取34.7mg L-酒石酸溶于1mL丙酮中，滴加到上述澄清体系中，搅拌30min后滴加16mL甲基叔丁基醚，转至4℃搅拌过夜，析出固体，减压抽滤，室温真空干燥，得到106mg结构式I所示化合物的L-酒石酸盐晶型1。
L-酒石酸盐晶型1的X射线粉末衍射图主要数据如表12所示。
表12
Figure PCTCN2021083204-appb-000018
Figure PCTCN2021083204-appb-000019
实施例10 结构式I所示化合物的己二酸盐晶型1的制备方法
取206mg结构式I所示化合物和63.3mg己二酸加入5毫升玻璃瓶中，再加入2.5mL乙酸乙酯，室温搅拌约2.5天后离心分离，40℃鼓风干燥，得到结构式I所示化合物的己二酸盐晶型1。
己二酸盐晶型1的X射线粉末衍射图主要数据如表13所示。
表13
Figure PCTCN2021083204-appb-000020
实施例11 结构式I所示化合物的晶型吸湿性测定
使用动态水分吸附仪(DVS)对样品(所述样品为表14所示的多种晶型)进行吸湿性测定，对样品进行0％RH(相对湿度)至80％RH范围内吸湿增重变化检测，检测结果见图19-23，检测结果见表14。
表14样品0％RH至80％RH范围内重量变化
晶型 吸湿增重
结构式I所示化合物无定形 6.53％
晶型A 0.03％
马来酸盐晶型2 6.64％
L-酒石酸盐晶型1 0.07％
磷酸盐晶型1 0.19％
由所述检测结果可知，结构式I所示化合物的晶型A、L-酒石酸盐晶型1和磷酸盐晶型1在在测试条件下是非吸湿性的，具有突出的优势。
实施例12：结构式I所示化合物的晶型稳定性测定
样品及实验准备：取适量的结构式I所示化合物无定形、结构式I所示化合物晶型A、马来酸盐晶型1、马来酸盐晶型2、磷酸盐晶型1和己二酸晶型1进行稳定性试验，分别在不同时间进行取样，进行HPLC检测，实验条件和检测结果见表15，其中包装均为：聚酯/铝/聚酰胺/聚乙烯药用复合膜、袋。
HPLC检测结果显示本发明所提供的结构式I所示化合物晶型A、马来酸盐晶型1、磷酸盐晶型1和己二酸晶型1具有较优的稳定性。
表15
Figure PCTCN2021083204-appb-000021
结构式I所示化合物的磷酸盐和马来酸盐相较于其他盐而言，具有意想不到的显著优势，例如高的物理稳定性和化学稳定性等。在盐型筛选过程中，在以下 酸存在下未观察到结构式I所示化合物的结晶盐的形成：苯磺酸、硫酸、对甲苯磺酸、天冬氨酸、柠檬酸、L-苹果酸、富马酸和草酸。进一步地，结构式I所示化合物的稳定晶型A，马来酸盐晶型1和磷酸盐晶型1具有令人惊讶的优点。例如FB晶型A，马来酸盐晶型1和磷酸盐晶型1具有低吸湿性，且不易因环境温度和湿度变化而改变结晶形态。相比之下，马来酸盐晶型2和结构式I所示化合物无定型在相对湿度条件下是吸湿的，稳定性也是较差的，易导致重量改变和/或相改变。
实施例13：结构式I所示化合物的晶型的药代动力学试验
药物配制：分别称取马来酸盐晶型1、磷酸盐晶型1和己二酸盐晶型1，均在0.5％CMC-Na溶液中配制成混悬待测溶液，各化合物终浓度为5mg/mL。
试验动物：SD大鼠被随机分为三组，每组包括3只雄鼠，分别命名为马来酸盐组、磷酸盐组和己二酸盐组。
给药和样品收集：对每组的SD大鼠进行口服给药，剂量为50mg/kg。采血时间为：给药前(0h)、0.25h、0.5h、1h、2hrs、4hrs、7hrs和24hrs，将血液样品采集于EDTA-K的预抗凝管中。4℃下，经每分钟4000转的转速离心10min分离出样品中的血浆。收集血浆样品并保存在-80℃条件下以备分析使用。通过AB4000 API LC/MS结合HPLC分析血浆样品中测试化合物的浓度，并分析每个动物的血浆浓度-时间数据，得到测试化合物的药代动力学参数，数据如表16所示。
表16
Figure PCTCN2021083204-appb-000022
实施例14：结构式I所示化合物的药理试验
实施例A：激酶试验
使用体外激酶检测实验评估本发明的结构式I所示化合物对酪氨酸激酶FGFR4活性的影响。试验中所用的方法是Mobility shift assay法，用于实验的底 物是带有荧光标记的多肽，在反应体系中酶的作用下，底物转变为产物，其所带的电荷也发生了相应的变化，该法可利用底物和产物所带电荷的不同，将二者进行分离，并分别进行检测。
试验步骤：
1)化合物配制：
300μM的化合物DMSO溶液在384孔板中稀释成100倍终浓度的DMSO溶液，3倍梯度稀释，使用分液器Echo 550向目的板OptiPlate-384F转移250nL的100倍终浓度的化合物。化合物终浓度为3000nM、1000nM、333.3nM、111.1nM、37.04nM、12.35nM、4.115nM、1.372nM、0.4572nM、0.1524nM，化合物和酶预孵育时间60mins；
2)激酶反应：
配制1×激酶缓冲液(Kinase buffer)，用1×激酶缓冲液配制2.5倍终浓度的激酶溶液，在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液，在阴性对照孔中加10μL的1×激酶缓冲液，离心后反应板振荡混匀室温孵育60mins，用1×激酶缓冲液配制25/15倍终浓度的腺嘌呤核苷三磷酸(Adenosine Triphosphate，ATP)和激酶底物(Kinase substrate)22的混合溶液，加入15μL的25/15倍终浓度的ATP和底物的混合溶液，起始反应，将384孔板离心振荡混匀后室温孵育30mins，加入30μL终止检测液停止激酶反应，离心振荡混匀后用Caliper EZ Reader读取转化率；
3)数据分析：
计算公式：
Figure PCTCN2021083204-appb-000023
其中：Conversion％_sample是样品的转化率读数；Conversion％_min是阴性对照孔均值，代表没有酶活孔的转化率读数；Conversion％_max是阳性对照孔比值均值，代表没有化合物抑制孔的转化率读数。
以浓度的log值作为X轴，百分比抑制率作为Y轴，采用分析软件GraphPad Prism的log(inhibitor)vs.response-Variable slope(four parameters)拟合量效曲线，从而得到各个化合物对酶活性的IC50值。公式如下：Y＝Bottom+(Top-Bottom)/(1+10∧((LogIC50-X)*HillSlope))
所得的IC50数据如表17所示。
表17
Figure PCTCN2021083204-appb-000024
注:①BLU554为蓝图药物公司(Blueprint Medicines Corporation)在WO2015061572中公开的第40号化合物。
本发明的化合物对FGFR4激酶具有抑制作用，并且化合物对FGFR4的抑制作用远强于对FGFR1的抑制作用，具有非常好的选择性。
实施例B：细胞增殖试验
使用体外细胞试验评估本发明的化合物对人肝癌细胞Hep3B细胞增殖的影响。试验中所用的检测方法是CELL TITER-GLO(CTG)发光法，该法可通过对ATP进行定量测定来检测活细胞数目。因为ATP参与生物体内多种酶促反应，是活细胞新陈代谢的一个指标，其含量直接反应了细胞的数量及细胞状态，实验过程中向细胞培养基加入CellTiter-Glo TM试剂，测量发光值，发光值与ATP量成正比，而ATP又和活细胞数正相关，因此可通过检测ATP含量考察细胞活力。
试验步骤：
(1)细胞铺板：
取一瓶对数生长期的Hep3B细胞，消化重悬细胞后计数，调整细胞密度后接种到96孔板中，每孔接种180μL(1500个细胞/孔)，孔板置于37℃、5％CO 2的培养箱中培养24hrs；
(2)细胞给药：
溶解在DMSO中的600μM的供试品用DMSO以1:3比例梯度稀释成200倍终浓度的溶液，随后细胞培养液稀释20倍(10×)，取20μL化合物溶液加入到含细胞的96孔板中，化合物终浓度从高至低依次为3000nM、1000nM、333.3nM、111.1nM、37.04nM、12.35nM、4.115nM、1.372nM、0.4572nM，孔板放入37℃,5％CO2培养箱培养96hrs；
(3)CTG检测：
孵育96hrs后每孔加入60μL的
Figure PCTCN2021083204-appb-000025
Luminescent Cell Viability Assay溶液，轻轻震荡2mins，室温继续孵育10mins，在多功能酶标仪上读取各孔的发光值。
(4)数据分析：
根据发光值读数计算抑制率，
抑制率％＝(空白组值-给药组值)/(空白组值-调零组值)*100
以浓度的log值作为X轴，百分比抑制率作为Y轴，GraphPad Prism的log(inhibitor)vs.response-Variable slope(four parameters)拟合量效曲线，并计算化合物抑制细胞增殖的IC50。
实验数据如表18所示。
表18
Figure PCTCN2021083204-appb-000026
本发明的结构式I所示化合物对Hep3B细胞的增殖具有良好的抑制作用。
实施例C：异种移植肿瘤模型
BALB/c nu/nu雌性小鼠右前肩胛处皮下接种5×10 6个人肝癌细胞Hep3B，细胞悬浮液与基质胶体积比为1:1(0.2/mL/只)。待肿瘤平均体积为158mm 3时，根据肿瘤大小随机分组，治疗组给予用适当的溶剂制备的待测化合物溶液，溶剂对照组给予空白溶剂。治疗过程中，每周测量两次肿瘤体积、末次给药后测定肿瘤重量以确定化合物活性。通过比较治疗组和溶剂对照组的肿瘤体积和重量，计算肿瘤增长抑制率(％，TGI)。体重测量作为毒性的常规测定，与肿瘤体积测量频率相同。在该模型中，本发明结构式I所示化合物显示出很好的抗肿瘤活性。例如，当剂量为50mg/kg、100mg/kg和200mg/kg(BID×14)时，结构式I所示化合物对Hep3B肿瘤体积增长抑制率分别为73.02％、86.26％和90.26％，对HepB肿瘤重量增长抑制率分别为84.76％、92.27％和98.15％，显示结构式I所示化合物在抑制肿瘤体积和重量方面均表现出剂量依赖效应。此外，整个实验过程中，给予结构式I所示化合物的动物均未出现明显的体重降低，提示两种化合物在受试剂量条件下耐受良好。

Claims (30)

  1. 一种结构式I所示化合物的盐型或其晶型：
    Figure PCTCN2021083204-appb-100001
  2. 一种结构式I所示化合物的盐型，其特征在于，所述盐型选自马来酸盐、磷酸盐、L-酒石酸盐或己二酸盐。
  3. 如权利要求2所述的盐型，其特征在于，所述盐型为磷酸盐，所述磷酸盐结构如式II所示：
    Figure PCTCN2021083204-appb-100002
  4. 如权利要求3所述的盐型，其特征在于，所述磷酸盐为磷酸盐晶型1，所述磷酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.9°±0.2°、10.7°±0.2°、16.8°±0.2°、21.3°±0.2°的特征峰。
  5. 如权利要求4所述的盐型，其特征在于，所述磷酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.9°±0.2°、8.3°±0.2°、10.7°±0.2°、11.6°±0.2°、12.8±0.2°、16.8°±0.2°、21.3°±0.2°的特征峰。
  6. 如权利要求4或5的盐型，其特征在于，所述磷酸盐晶型1的X射线粉末衍射图具有衍射角2θ为4.9°±0.2°、8.3°±0.2°、10.7°±0.2°、11.6°±0.2°、12.8±0.2°、16.8°±0.2°、20.1°±0.2°、21.3°±0.2°、28.5°±0.2°的特征峰。
  7. 如权利要求4-6任一所述的盐型，其特征在于，所述磷酸盐晶型1具有基本如图9或图10所示的X射线粉末衍射图。
  8. 如权利要求2所述的盐型，其特征在于，所述盐型为马来酸盐。
  9. 如权利要求8所述的盐型，其特征在于，所述马来酸盐为马来酸盐晶型1，其X射线粉末衍射图具有衍射角2θ为3.7°±0.2°、9.9°±0.2°、16.2°±0.2°、11.0°±0.2°的特征峰。
  10. 如权利要求9所述的盐型，其特征在于，所述马来酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.7°±0.2°、9.9°±0.2°、11.0°±0.2°、13.4°±0.2°、16.2°±0.2°、17.2°±0.2°、20.6°±0.2°的特征峰。
  11. 权利要求8或9所述的盐型，其特征在于，所述马来酸盐晶型1的X射线粉末衍射图具有衍射角2θ为3.7°±0.2°、9.9°±0.2°、11.0°±0.2°、13.4°±0.2°、16.2°±0.2°、17.2°±0.2°、18.7°±0.2°、19.4°±0.2°、20.6°±0.2°、22.6°±0.2°、24.4°±0.2°的特征峰。
  12. 权利要求9-11任一所述的盐型，其特征在于，所述马来酸盐晶型1的X射线粉末衍射图基本上如图4所示。
  13. 如权利要求1所述的盐型或其晶型，其特征在于，所述晶型为结构式I所示化合物的晶型A，其X射线粉末衍射图具有衍射角2θ为7.5°±0.2°、10.7°±0.2°、11.3°±0.2°、15.1°±0.2°的特征峰。
  14. 如权利要求13所述的盐型或其晶型，其特征在于，所述晶型A的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°、10.7°±0.2°、11.3°±0.2°、13.1°±0.2°、15.1°±0.2°、20.9°±0.2°、25.2°±0.2°的特征峰。
  15. 如权利要求13或14所述的盐型或其晶型，其特征在于，所述晶型A的X射线粉末衍射图具有衍射角2θ为7.5°±0.2°、10.7°±0.2°、11.3°±0.2°、13.1°±0.2°、15.1°±0.2°、20.9°±0.2°、21.6°±0.2°、22.8±0.2°、23.5°±0.2°、25.2°±0.2°、30.2±0.2°的特征峰。
  16. 如权利要求13-15任一所述的盐型或其晶型，其特征在于，所述晶型A的X射线粉末衍射图基本上如图1所示。
  17. 如权利要求2所述的盐型，其特征在于，所述盐型为L-酒石酸盐，所述L-酒石酸盐为L-酒石酸盐晶型1，其X射线粉末衍射图具有衍射角2θ为5.4°±0.2°、17.6°±0.2°、19.7°±0.2°、20.7°±0.2°的特征峰。
  18. 如权利要求17所述的盐型，其特征在于，所述L-酒石酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.4°±0.2°、12.9°±0.2°、16.5°±0.2°、17.6°±0.2°、 19.7°±0.2°、20.7°±0.2°的特征峰。
  19. 如权利要求17或18所述的盐型，其特征在于，所述L-酒石酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.4°±0.2°、12.9°±0.2°、16.5°±0.2°、17.6°±0.2°、19.7°±0.2°、20.7°±0.2°、22.2°±0.2°、26.4°±0.2°的特征峰。
  20. 如权利要求17-19任一所述的盐型，其特征在于，所述L-酒石酸盐晶型1的X射线粉末衍射图基本上如图13所示。
  21. 如权利要求2所述的盐型，其特征在于，所述盐型为己二酸盐，所述己二酸盐为己二酸盐晶型1，其X射线粉末衍射图具有衍射角2θ为5.8°±0.2°、8.4°±0.2°、12.3°±0.2°、22.9°±0.2°的特征峰。
  22. 如权利要求21所述的盐型，其特征在于，所述己二酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.8°±0.2°、8.4°±0.2°、10.0°±0.2°、10.4°±0.2°、12.3°±0.2°、17.5°±0.2°、22.9°±0.2°的特征峰。
  23. 如权利要求21或22所述的盐型，其特征在于，所述己二酸盐晶型1的X射线粉末衍射图具有衍射角2θ为5.8°±0.2°、8.4°±0.2°、10.0°±0.2°、10.4°±0.2°、12.3°±0.2°、17.5°±0.2°、22.9°±0.2°、25.4°±0.2°、25.9°±0.2°的特征峰。
  24. 权利要求21-23任一所述的盐型，其特征在于，所述己二酸盐晶型1的X射线粉末衍射图基本上如图16所示。
  25. 一种药物组合物，其特征在于：含有治疗有效量的权利要求1-24任一项所述的盐型或晶型，和药学上可接受的辅料，辅助剂和/或载体。
  26. 权利要求1-24任一项所述的盐型或晶型或权利要求25所述的组合物在制备药物中的应用，其特征在于，所述药物用于治疗、预防、延迟或阻止癌症或癌症转移的发生或进展。
  27. 权利要求1-24任一项所述的盐型或晶型或权利要求25所述的组合物在制备药物中的应用，其特征在于，所述药物用于治疗由FGFR4介导的疾病。
  28. 如权利要求27所述的应用，其特征在于，所述FGFR4介导的疾病为癌症。
  29. 如权利要求26或28所述的应用，其特征在于，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细 胞癌、头颈部肿瘤、颅内肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
  30. 一种治疗癌症的方法，包括向治疗对象施用治疗有效量的1-24任一项所述的盐型或晶型或权利要求25所述的组合物，其特征在于，所述癌症是乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞癌、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、许旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
PCT/CN2021/083204 2020-03-27 2021-03-26 Fgfr4抑制剂的盐型、晶型及其用途 WO2021190623A1 (zh)

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