WO2022017208A1 - SALT FORM AND CRYSTAL FORM OF PYRIDYLOXY PYRAZOLE COMPOUND AS TGF-βR1 INHIBITOR, AND PHARMACEUTICAL COMPOSITION THEREOF - Google Patents

SALT FORM AND CRYSTAL FORM OF PYRIDYLOXY PYRAZOLE COMPOUND AS TGF-βR1 INHIBITOR, AND PHARMACEUTICAL COMPOSITION THEREOF Download PDF

Info

Publication number
WO2022017208A1
WO2022017208A1 PCT/CN2021/105662 CN2021105662W WO2022017208A1 WO 2022017208 A1 WO2022017208 A1 WO 2022017208A1 CN 2021105662 W CN2021105662 W CN 2021105662W WO 2022017208 A1 WO2022017208 A1 WO 2022017208A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
crystal form
pharmaceutical composition
present
Prior art date
Application number
PCT/CN2021/105662
Other languages
French (fr)
Chinese (zh)
Inventor
付翔宇
李小庭
胡利红
房效娟
周晨晨
姚婷
吴松亮
丁照中
陈曙辉
Original Assignee
江苏奥赛康药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏奥赛康药业有限公司 filed Critical 江苏奥赛康药业有限公司
Priority to CN202180007608.5A priority Critical patent/CN114867723B/en
Publication of WO2022017208A1 publication Critical patent/WO2022017208A1/en

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to a salt form, a crystal form, a preparation method and a pharmaceutical composition of a 5-(4-pyridyloxy)pyrazole compound as a TGF- ⁇ R1 inhibitor and a preparation method thereof.
  • TGF- ⁇ Transforming growth factor- ⁇
  • TGF- ⁇ is a multifunctional growth factor superfamily with a wide range of biological activities, involved in early embryonic development, cartilage and bone formation, synthesis of extracellular matrix, inflammation, Interstitial fibrosis, regulation of immune and endocrine functions, tumor formation and progression.
  • TGF- ⁇ superfamily consists of a class of structurally and functionally related polypeptide growth factors, and TGF- ⁇ is one of the important members of this family.
  • TGF- ⁇ mainly exists in three forms: TGF- ⁇ 1, TGF- ⁇ 2 and TGF- ⁇ 3, which are located on different chromosomes, of which TGF- ⁇ 1 accounts for the highest proportion (>90%) in somatic cells, It is the most active, the most functional, and the most widely distributed.
  • TGF- ⁇ signaling molecules carry out signal transduction through transmembrane receptor complexes.
  • TGF- ⁇ receptors are transmembrane proteins that exist on the cell surface, and are divided into type I receptors (TGF- ⁇ R1), type II receptors (TGF- ⁇ R2) and type III receptors (TGF- ⁇ R3).
  • ⁇ R1 is also known as activin-like receptor 5 (activin receptor-like kinase 5, ALK5).
  • TGF- ⁇ R3 lacks intrinsic activity and is mainly related to the storage of TGF- ⁇ .
  • TGF- ⁇ R1 and TGF- ⁇ R2 belong to the serine/threonine kinase family
  • type II receptors can bind to TGF- ⁇ ligands with high affinity, and form heterologous receptor complexes with type I receptors, which bind I receptors.
  • a region rich in glycine and serine residues (GS domain) near the membrane of the receptor is phosphorylated to initiate intracellular signaling cascades.
  • TGF- ⁇ /Smads are important TGF- ⁇ signal transduction and regulation molecules in cells, which can directly transduce TGF- ⁇ signals from the cell membrane, such as in the nucleus.
  • the TGF- ⁇ /Smads signaling pathway plays an important role in the occurrence and development of tumors. .
  • activated TGF- ⁇ first binds to TGF- ⁇ R2 on the cell membrane surface to form a heterodimeric complex, which is recognized and bound by TGF- ⁇ R1.
  • TGF- ⁇ R2 phosphorylates serine/threonine in the GS domain of the cytoplasmic domain of TGF- ⁇ R1, thereby activating TGF- ⁇ R1; the activated TGF- ⁇ R1 further phosphorylates R-Smads (Smad2/Smad3) protein, which in turn interacts with Co-Smad (Smad4) binds to form a heterotrimeric complex, which enters the nucleus and cooperates with other co-activators and co-inhibitors to regulate the transcription of target genes . Changes in any link in the TGF- ⁇ /Smads signaling pathway will lead to abnormalities in the signal transduction pathway.
  • TGF- ⁇ can directly affect tumor growth (extrinsic effects of TGF- ⁇ signaling), or by inducing epithelial-mesenchymal transition, blocking anti-tumor immune responses, and increasing tumor-associated fibrosis and enhanced angiogenesis indirectly affects tumor growth (intrinsic effect of TGF- ⁇ ).
  • TGF- ⁇ has a strong fibrosis-inducing effect, and it is an activator of tumor-associated fibroblasts. These fibroblasts are a major source of collagen type I and other fibrotic factors. Induced products of fibroblasts and other fibrotic factors may go on to foster a microenvironment that reduces immune responses, increases drug resistance, and enhances tumor angiogenesis.
  • TGF- ⁇ affects blood vessels during ontogeny and tumor growth. regeneration.
  • TGF- ⁇ R1-deficient mouse embryos display severe defects in vascular development, demonstrating that the TGF- ⁇ signaling pathway is a key regulator in vascular endothelial and smooth muscle cell development.
  • TGF- ⁇ is significantly related to immune escape, and has a greater impact on CD8+ T cell-mediated anti-tumor immune responses.
  • patients with high expression of TGF- ⁇ gene had a low response to PD-L1 monoclonal antibody and a low simulated survival rate.
  • the basic research of TGF- ⁇ monoclonal antibody has also proved that when it is used synergistically with PD-L1 monoclonal antibody, more CD8+ T cells infiltrate and play a role, revealing the activation effect of blocking TGF- ⁇ on immunity and its mechanism. Due to the immunomodulatory effect of TGF- ⁇ , small molecule TGF- ⁇ R1 inhibitors alone or in combination with PD-(L)1 monoclonal antibody have great application prospects in the treatment of various solid tumors.
  • the present invention provides crystal form A of the compound of formula (I), the X-ray powder diffraction pattern of CuK ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 15.96 ⁇ 0.20°, 18.65 ⁇ 0.20°, 20.94 ⁇ 0.20° and 23.57 ⁇ 0.20 °,
  • the X-ray powder diffraction pattern of CuK ⁇ radiation of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.97 ⁇ 0.20°, 13.21 ⁇ 0.20°, 14.17 ⁇ 0.20°, 15.96 ⁇ 0.20°, 18.65 ⁇ 0.20°, 20.94 ⁇ 0.20°, 21.52 ⁇ 0.20° and 23.57 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of CuK ⁇ radiation of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.97 ⁇ 0.20°, 12.20 ⁇ 0.20°, 12.78 ⁇ 0.20°, 13.21 ⁇ 0.20°, 14.17 ⁇ 0.20°, 15.96 ⁇ 0.20°, 18.65 ⁇ 0.20°, 20.94 ⁇ 0.20°, 21.52 ⁇ 0.20°, 22.05 ⁇ 0.20°, 23.57 ⁇ 0.20° and 25.01 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the CuK ⁇ radiation of the crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.84°, 7.97°, 9.30°, 11.69°, 12.20°, 12.78°, 13.21° , 14.17°, 14.86°, 15.52°, 15.96°, 16.60°, 16.91°, 17.58°, 18.25°, 18.65°, 19.21°, 19.50°, 20.11°, 20.94°, 21.52°, 22.05°, 22.80°, 23.05 °, 23.57°, 24.06°, 25.01°, 25.33°, 26.49°, 26.93°, 27.36°, 28.09°, 28.54° and 29.96°.
  • the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1 .
  • the XRPD pattern diffraction peak data of the above-mentioned crystal form A is shown in Table 1.
  • the differential scanning calorimetry curve (DSC) of the above-mentioned Form A has an endothermic peak at 192.6°C.
  • the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2 .
  • thermogravimetric analysis (TGA) curve of the above-mentioned crystal form A is at 180.0° C. ⁇ 3° C.
  • the weight loss is 1.40%.
  • the TGA spectrum of the above-mentioned crystal form A is shown in FIG. 3 .
  • the DVS spectrum of the above-mentioned crystal form A is shown in FIG. 4 .
  • the present invention also provides pharmaceutically acceptable salts of the compounds of formula (I).
  • the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of hydrobromide, mesylate, oxalate or phosphate.
  • the present invention also provides the hydrate of the compound hydrobromide of the formula (I), the structure of which is shown in the formula (I-1),
  • x is 0.9 to 1.1
  • y is 0.9 to 1.1
  • the present invention also provides the crystalline form B of the compound of formula (II), the X-ray powder diffraction pattern of CuK ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 10.98 ⁇ 0.20°, 19.53 ⁇ 0.20°, 24.37 ⁇ 0.20° and 25.32 ⁇ 0.20°,
  • the X-ray powder diffraction pattern of the CuK ⁇ radiation of the crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.27 ⁇ 0.20°, 10.98 ⁇ 0.20°, 13.99 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.01 ⁇ 0.20°, 24.37 ⁇ 0.20°, 25.32 ⁇ 0.20° and 26.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the CuK ⁇ radiation of the crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.27 ⁇ 0.20°, 10.98 ⁇ 0.20°, 13.99 ⁇ 0.20°, 14.83 ⁇ 0.20°, 17.50 ⁇ 0.20°, 19.53 ⁇ 0.20°, 20.37 ⁇ 0.20°, 22.01 ⁇ 0.20°, 24.37 ⁇ 0.20°, 24.78 ⁇ 0.20°, 25.32 ⁇ 0.20° and 26.90 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the CuK ⁇ radiation of the crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41°, 9.27°, 10.98°, 11.64°, 13.99°, 14.44°, 14.83° , 17.50°, 18.55°, 19.53°, 19.78°, 20.37°, 21.08°, 21.48°, 22.01°, 22.76°, 23.41°, 23.84°, 24.37°, 24.78°, 25.32°, 26.90°, 27.34°, 28.15 °, 29.29°, 29.96°, 30.36°, 31.23°, 32.70°, 33.25°, 34.17°, 35.50° and 38.32°.
  • the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 5 .
  • the XRPD pattern diffraction peak data of the above-mentioned crystal form B are shown in Table 2.
  • the differential scanning calorimetry (DSC) curve of the above-mentioned Form B has endothermic peaks at 130.7°C and 181.8°C.
  • the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 6 .
  • thermogravimetric analysis (TGA) curve of the above-mentioned crystal form B is at 160.0° C. ⁇ 3° C.
  • the weight loss is 4.22%.
  • the TGA spectrum of the above-mentioned crystal form B is shown in FIG. 7 .
  • the DVS spectrum of the above-mentioned crystal form B is shown in FIG. 8 .
  • the present invention also provides a preparation method of the above-mentioned crystal form B, which comprises the following steps:
  • reaction solution was cooled to room temperature, filtered, and the filter cake was vacuum-dried;
  • the solvent is isopropanol.
  • the present invention also provides the hydrobromide salt of the compound of formula (I), the structure of which is shown in formula (III),
  • the present invention also provides the crystalline form C of the compound of formula (III), whose X-ray powder diffraction pattern of Cu K ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 11.21 ⁇ 0.20°, 18.69 ⁇ 0.20°, 22.47 ⁇ 0.20° and 25.60 ⁇ 0.20°,
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 7.38 ⁇ 0.20°, 11.21 ⁇ 0.20°, 16.64 ⁇ 0.20°, 18.69 ⁇ 0.20° , 21.25 ⁇ 0.20°, 22.47 ⁇ 0.20°, 25.60 ⁇ 0.20° and 29.98 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of CuK ⁇ radiation of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 7.38 ⁇ 0.20°, 11.21 ⁇ 0.20°, 16.64 ⁇ 0.20°, 18.69 ⁇ 0.20°, 20.57 ⁇ 0.20°, 21.25 ⁇ 0.20°, 21.80 ⁇ 0.20°, 22.47 ⁇ 0.20°, 25.60 ⁇ 0.20°, 26.27 ⁇ 0.20°, 28.50 ⁇ 0.20° and 29.98 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of CuK ⁇ radiation of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 7.38°, 10.33°, 11.21°, 14.75°, 16.64°, 17.84°, 18.69° a °.
  • the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 9 .
  • the XRPD pattern diffraction peak data of the above-mentioned crystal form C is shown in Table 3.
  • the differential scanning calorimetry curve (DSC) of the above-mentioned crystal form C has an endothermic peak at 232.4°C.
  • the DSC spectrum of the above-mentioned crystal form C is shown in FIG. 10 .
  • thermogravimetric analysis (TGA) curve of the above-mentioned crystal form C is at 200.0° C. ⁇ 3° C.
  • the weight loss is 1.18%.
  • the TGA spectrum of the above-mentioned crystal form C is shown in FIG. 11 .
  • the present invention also provides the mesylate of the compound of formula (I), the structure of which is shown in formula (IV),
  • the present invention also provides the crystal form D of the compound of formula (IV), the X-ray powder diffraction pattern of the Cu K ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 5.74 ⁇ 0.20°, 8.84 ⁇ 0.20°, 11.91 ⁇ 0.20°, 16.70 ⁇ 0.20°, 17.61 ⁇ 0.20°, 18.45 ⁇ 0.20°, 19.09 ⁇ 0.20°, 20.46 ⁇ 0.20°, 22.98 ⁇ 0.20°, 25.35 ⁇ 0.20°, 25.81 ⁇ 0.20° and 27.22 ⁇ 0.20°,
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 5.74°, 8.84°, 11.91°, 13.28°, 13.88°, 15.00°, 16.70° degrees 33.24°, 33.80°, 35.94° and 39.19°.
  • the XRPD pattern of the above-mentioned crystal form D is shown in FIG. 12 .
  • the XRPD pattern diffraction peak data of the above-mentioned crystal form D are shown in Table 4.
  • the differential scanning calorimetry curve (DSC) of the above-mentioned crystal form D has an endothermic peak at 204.4°C.
  • the DSC spectrum of the above-mentioned crystal form D is shown in FIG. 13 .
  • thermogravimetric analysis (TGA) curve of the above-mentioned crystal form D is at 180.0°C ⁇ 3°C
  • the weight loss is 0.58%.
  • the TGA spectrum of the above-mentioned crystal form D is shown in FIG. 14 .
  • the DVS spectrum of the above-mentioned crystal form D is shown in FIG. 15 .
  • the present invention also provides the oxalate of the compound of formula (I), the structure of which is shown in formula (V),
  • the present invention also provides the crystalline form E of the compound of formula (V), whose CuK ⁇ radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.83 ⁇ 0.20°, 7.25 ⁇ 0.20°, 10.56 ⁇ 0.20°, 13.18 ⁇ 0.20°, 18.10 ⁇ 0.20°, 19.00 ⁇ 0.20°, 19.77 ⁇ 0.20°, 20.20 ⁇ 0.20°, 22.16 ⁇ 0.20°, 23.90 ⁇ 0.20°, 24.37 ⁇ 0.20° and 25.58 ⁇ 0.20°,
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 5.12°, 6.39°, 6.83°, 7.25°, 9.96°, 10.56°, 12.75° degrees 23.90°, 24.37°, 25.00°, 25.58°, 26.01°, 26.93°, 27.66°, 28.36°, 29.27°, 32.17°, 32.68° and 36.51°.
  • the XRPD pattern of the above-mentioned crystal form E is shown in FIG. 16 .
  • the XRPD pattern diffraction peak data of the above-mentioned crystal form E are shown in Table 5.
  • the differential scanning calorimetry curve (DSC) of the above-mentioned Form E has endothermic peaks at 82.1°C, 129.3°C, 145.6°C and 168.3°C.
  • the DSC spectrum of the above-mentioned crystal form E is shown in FIG. 17 .
  • thermogravimetric analysis (TGA) curve of the above crystal form E shows a weight loss of 1.16% at 110.0°C ⁇ 3°C, and a weight loss of 2.30% again at 150.0°C ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form E is shown in FIG. 18 .
  • the present invention also provides the crystal form F of the compound of formula (V), the X-ray powder diffraction pattern of the CuK ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 5.15 ⁇ 0.20°, 7.93 ⁇ 0.20°, 10.56 ⁇ 0.20°, 15.40 ⁇ 0.20°, 16.79 ⁇ 0.20°, 17.98 ⁇ 0.20°, 19.33 ⁇ 0.20°, 20.20 ⁇ 0.20°, 21.11 ⁇ 0.20°, 22.49 ⁇ 0.20°, 23.84 ⁇ 0.20° and 26.63 ⁇ 0.20°,
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 5.15°, 6.44°, 7.93°, 10.56°, 11.69°, 12.82°, 13.45° degrees 34.57° and 36.44°.
  • the XRPD pattern of the above-mentioned crystal form F is shown in FIG. 19 .
  • the XRPD pattern diffraction peak data of the above-mentioned crystal form F are shown in Table 6.
  • the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form F has endothermic peaks at 97.6°C, 145.3°C and 211.5°C.
  • the DSC spectrum of the above-mentioned crystal form F is shown in FIG. 20 .
  • thermogravimetric analysis (TGA) curve of the above-mentioned crystal form F is at 120.0° C. ⁇ 3° C.
  • the weight loss is 4.19%.
  • the TGA spectrum of the above-mentioned crystal form F is shown in FIG. 21 .
  • the present invention also provides the phosphate of the compound of formula (I), the structure of which is shown in formula (VI),
  • the present invention also provides the crystal form G of the compound of formula (VI), the X-ray powder diffraction pattern of the Cu K ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 4.94° ⁇ 0.20°, 9.84° ⁇ 0.20°, 10.60° ⁇ 0.20°, 14.75° ⁇ 0.20°, 15.72° ⁇ 0.20°, 16.85° ⁇ 0.20°, 18.04° ⁇ 0.20°, 18.99° ⁇ 0.20°, 20.37° ⁇ 0.20°, 21.20° ⁇ 0.20°, 21.75° ⁇ 0.20° , 22.32° ⁇ 0.20°, 23.51° ⁇ 0.20°, 24.70° ⁇ 0.20°, 26.73° ⁇ 0.20° and 29.12° ⁇ 0.20°,
  • the XRPD pattern of the above-mentioned crystal form G is shown in FIG. 22 .
  • the XRPD pattern diffraction peak data of the above-mentioned crystal form G are shown in Table 7.
  • the differential scanning calorimetry curve (DSC) of the above-mentioned Form G has endothermic peaks at 62.4°C, 98.4°C, 110.7°C and 158.0°C.
  • the DSC spectrum of the above-mentioned crystal form G is shown in FIG. 23 .
  • thermogravimetric analysis (TGA) curve of the above-mentioned crystal form G is at 120.0° C. ⁇ 3° C.
  • the weight loss is 3.79%.
  • the TGA spectrum of the above-mentioned crystal form G is shown in FIG. 24 .
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient, a filler, a binder, a disintegrant and a lubricant, and the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of the compound of formula (I) in the above pharmaceutical composition is selected from the group consisting of hydrobromide, mesylate, oxalate and phosphate.
  • the active ingredients in the above-mentioned pharmaceutical composition are selected from: the crystal form A of the compound of formula (I), the crystal form B of the hydrate of the compound of formula (II) hydrobromide, the hydrogen of the compound of formula (III) Form C of bromate salt, Form D of methanesulfonate of compound of formula (IV), Form E and Form F of oxalate of compound of formula (V), Form G of phosphate of compound of formula (VI) .
  • the dosage form of the above-mentioned pharmaceutical composition is a tablet.
  • each tablet is composed of the following ingredients in mass fractions: 10% to 15% of active ingredients, 75% to 82% of filler, 1% to 3% of binder, disintegrating Solution 4% to 10% and lubricant 1% to 3%.
  • each tablet is composed of the following ingredients by mass fraction: 12.06% of active ingredients, 78.94% of fillers, 1.5% of binders, 6.0% of disintegrants and 1.5% of lubricants .
  • the filler in the above-mentioned pharmaceutical composition is selected from one or more of microcrystalline cellulose, mannitol, lactose, starch, sucrose or pregelatinized starch.
  • the binder in the above-mentioned pharmaceutical composition is selected from hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or sodium carboxymethyl cellulose one or more of them.
  • the disintegrant in the above-mentioned pharmaceutical composition is selected from one of croscarmellose sodium, sodium starch glycolate, hydroxypropyl starch, low-substituted hydroxypropyl cellulose or crospovidone. one or more.
  • the lubricant in the above-mentioned pharmaceutical composition is selected from one or more of colloidal silicon dioxide, magnesium stearate, stearic acid, talc or sodium stearyl fumarate.
  • each tablet is composed of the following ingredients in mass fractions: 12.06% of the compound of formula (I) hydrobromide, 58.94% of microcrystalline cellulose, 20% of mannitol, colloidal Silica 0.5%, Hypromellose 1.5%, Croscarmellose Sodium 6.0% and Magnesium Stearate 1.0%.
  • the hydrobromide salt of the compound of formula (I) is the crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III).
  • each tablet is composed of the following ingredients in mass fractions: 12.06% of the compound of formula (I) hydrobromide, 58.94% of microcrystalline cellulose, 20% of lactose, colloidal two Silica 0.5%, Hypromellose 1.5%, Croscarmellose Sodium 6.0% and Magnesium Stearate 1.0%.
  • the hydrobromide salt of the compound of formula (I) is the crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III).
  • each tablet is composed of the following ingredients in mass fractions: 12.06% of the compound of formula (I) hydrobromide, 20% of microcrystalline cellulose, 58.94% of lactose, colloidal two Silica 0.5%, Hypromellose 1.5%, Croscarmellose Sodium 6.0% and Magnesium Stearate 1.0%.
  • the hydrobromide salt of the compound of formula (I) is the crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III).
  • each tablet is composed of the following ingredients in mass fractions: 12.06% of the compound of formula (I) hydrobromide, 58.94% of microcrystalline cellulose, 20% of lactose, colloidal two Silica 0.5%, hypromellose 1.5%, sodium starch glycolate 6.0% and magnesium stearate 1.0%.
  • the hydrobromide salt of the compound of formula (I) is the crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III).
  • the present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps: accurately weighing the active ingredient, filler, lubricant and disintegrant in the recipe quantity, after mixing, adding a binder solution to prepare Granules, wet granules are granulated with a sieve (preferably a 20-mesh sieve), then dried (preferably below 60°C), the dry granules are sieved and granulated (preferably a 20-mesh sieve), and a disintegrant is added to mix. Evenly, then add lubricant and mix well and press into tablets.
  • a binder solution to prepare Granules
  • wet granules are granulated with a sieve (preferably a 20-mesh sieve)
  • dried preferably below 60°C
  • the dry granules are sieved and granulated (preferably a 20-mesh sieve)
  • a disintegrant is added to mix. Evenly,
  • the salt form and crystal form of the present invention are simple in preparation process, and the salt form and crystal form are stable, less affected by heat, humidity and light, and are convenient for preparation.
  • the crystal form of the present application has good pharmacokinetic properties and is suitable for use as a medicine.
  • the preparation of the invention has simple composition, stable preparation performance and simple preparation process, and is suitable for large-scale production and research and development.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • pharmaceutically acceptable salt refers to a salt of a compound of formula (I) prepared from a compound of formula (I) with a relatively nontoxic acid or base; based on the properties of the compound of formula (I), preferably a compound of formula (I) with a relatively nontoxic acid preparation.
  • Acid addition salts can be obtained by contacting a compound of formula (I) with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, oxalic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, caprylic acid acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and similar acids; also includes amino acids (eg, arginine, etc.) , and salts of organic acids such as glucuronic acid.
  • Compounds of formula (I) and pharmaceutically acceptable salts of compounds of formula (I) in the present invention can be in crystalline form or in Amorphous; when in crystalline form, it may be solvated or unsolvated.
  • a hydrate is a case of a solvate.
  • the solvent used in the present invention is commercially available.
  • the present invention adopts the following abbreviations:
  • N2 nitrogen gas
  • RH relative humidity
  • mL milliliter
  • L liter
  • min minute
  • s seconds
  • nm nanometers
  • MPa megapascals
  • lux lux
  • ⁇ w/cm 2 microwatts per square centimeter
  • h hours
  • Kg kilograms
  • nM nanomoles
  • RRT relative retention time
  • rpm rotational speed .
  • the compounds of the present invention are named according to the conventional nomenclature in the art, and the commercially available compounds use the names of the suppliers' catalogues.
  • Test Method Approximately 10 mg of sample was used for XRPD detection.
  • Test method Take a sample of 1-5 mg and place it in an aluminum crucible with a lid. The sample is raised from room temperature to 350 °C at a heating rate of 10 °C/min under the protection of 50 mL/min of dry N2, and recorded by the TA software. The thermal change of the sample during the heating process.
  • Test Methods 2-5 mg of sample was placed in a platinum crucible, by way of high-resolution detection of the segment, a heating rate of 10 °C / min at 50mL / min was dried under N 2 protection of the sample from room temperature to 350 °C, while the TA software records the weight change of the sample during the heating process.
  • RH gradient 10% (90%RH-0%RH-90%RH), 5% (95%RH-90%RH and 90%RH-95%RH)
  • Test procedure according to the potentiometric titration method, titrate the test solution and blank solution with silver nitrate titration solution (0.1moL/L), each 1mL silver nitrate titration solution (0.1moL/L) is equivalent to 7.990mg of bromine (Br)
  • each 1 mL of silver nitrate titration solution (0.1 mol/L) is equivalent to 7.990 mg of bromine (Br);
  • V SPL the volume (mL) of the silver nitrate titration solution (0.1mol/L) consumed by the test solution
  • V 0 the volume (mL) of the silver nitrate titration solution (0.1 mol/L) consumed by the blank solution
  • Test method Quickly add the accurately weighed sample (the water content in the sample is about 5-25mg), the stirring time is 10s, the Karl Fischer reagent is titrated to the end point, and the moisture content of the sample is obtained.
  • Mobile phase A 0.05% trifluoroacetic acid in water
  • Injection volume 5 ⁇ L
  • Test plan for testing the content of related substances in tablets :
  • Mobile phase A 0.05% trifluoroacetic acid in water
  • Injection volume 5 ⁇ L
  • the gradient program is shown in Table 13 below:
  • 1% reference solution can be stable for 205.0h at room temperature.
  • HPLC detector (Agilent 1260 with DAD detector or equivalent)
  • Mobile phase A 0.05% trifluoroacetic acid in water
  • Injection volume 5 ⁇ L
  • the gradient program is shown in Table 15 below:
  • 10mg specification reference solution can be stable for 109.0h at room temperature
  • 10mg specification sample solution is stable at room temperature for 108.0h
  • 50mg specification reference solution can be stable at room temperature for 108.0h
  • 50mg specification sample solution is stable at room temperature It can be stable for 108.0h.
  • Fig. 1 is the XRPD spectrum of the compound of formula (I) form A.
  • Figure 2 is the DSC spectrum of the crystal form A of the compound of formula (I).
  • Figure 3 is a TGA spectrum of the compound of formula (I) in Form A.
  • Fig. 4 is the DVS spectrum of the crystal form A of the compound of formula (I).
  • Fig. 5 is the XRPD spectrum of the compound of formula (II) form B.
  • Figure 6 is the DSC spectrum of the compound of formula (II) form B.
  • Figure 7 is a TGA spectrum of the compound of formula (II) in Form B.
  • Figure 8 is the DVS spectrum of the compound of formula (II) in Form B.
  • Fig. 9 is the XRPD spectrum of the compound of formula (III) form C.
  • Fig. 10 is the DSC spectrum of the crystal form C of the compound of formula (III).
  • Figure 11 is a TGA spectrum of the compound of formula (III) in Form C.
  • Figure 12 is the XRPD spectrum of the compound of formula (IV), Form D.
  • Figure 13 is a DSC spectrum of Form D of the compound of formula (IV).
  • Figure 14 is the TGA spectrum of the compound of formula (IV) in Form D.
  • Figure 15 is the DVS spectrum of the compound of formula (IV), Form D.
  • Figure 16 is the XRPD spectrum of the compound of formula (V), Form E.
  • Figure 17 is a DSC spectrum of Form E of the compound of formula (V).
  • Figure 18 is a TGA spectrum of the compound of formula (V) in Form E.
  • Figure 19 is the XRPD spectrum of the compound of formula (V), Form F.
  • Figure 20 is a DSC spectrum of Form F of the compound of formula (V).
  • Figure 21 is the TGA spectrum of the compound of formula (V), Form F.
  • Figure 22 is the XRPD spectrum of the compound of formula (VI), Form G.
  • Figure 23 is a DSC spectrum of Form G of the compound of formula (VI).
  • Figure 24 is a TGA spectrum of the compound of formula (VI), Form G.
  • Figure 25 is a comparative diagram of the crystal form stability study of the compound of formula (II) form B under high pressure.
  • Figure 26 is a comparative diagram of the crystal form stability study of the compound of formula (II) form B in different solvents.
  • Step A Compound 1-1 (10 g, 99.88 mmol, 1 equiv) was dissolved in methanol (150 mL), tert-butylcarbazate (13.20 g, 99.88 mmol, 1 equiv) was added, and the reaction was carried out at 25 degrees Celsius 10 hours. Concentration gave compound 1-2.
  • Step B Compound 1-2 (8 g, 37.34 mmol, 1 equiv) was dissolved in a mixed solvent of acetic acid (50 mL) and water (50 mL), stirred at 25°C for 1 hour, and added cyanoborohydride in batches Sodium (2.58 g, 41.07 mmol, 1.1 equiv) was reacted at 20 degrees Celsius for 2 hours. Adjust pH to 7 with 1 mol/L aqueous sodium hydroxide solution, extract with dichloromethane (100 mL ⁇ 3), wash with saturated aqueous sodium bicarbonate solution (100 mL ⁇ 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound 1 -3.
  • Step C Compound 1-3 (7.2 g, 33.29 mmol, 1 equiv) was dissolved in methanol (10 mL), methanol hydrochloric acid (4 mol/L, 40 mL) was added, and the reaction was carried out at 20 degrees Celsius for 4 hours. Concentration gave compound 1-4.
  • Step D Compound 1-4 (4.1 g, 35.30 mmol, 1 equiv, 2 HCl) and ethyl acetoacetate (9.19 g, 70.59 mmol, 2 equiv) were dissolved in acetic acid (40 mL) under nitrogen The reaction was carried out at 90 degrees Celsius for 10 hours in an atmosphere. Cool, concentrate, and purify by preparative high performance liquid chromatography (trifluoroacetic acid condition) to obtain compound 1-5. MS (ESI) m/z: 183.1 [M+H + ].
  • Step E Compound 1-5 (1.1 g, 6.04 mmol, 1 equiv) and compound 1-6 (873.44 mg, 6.64 mmol, 1.1 equiv) were dissolved in N,N-dimethylformamide (20 mL) In the solution, potassium carbonate (2.5 g, 18.11 mmol, 3 equiv.) was added, and the reaction was carried out at 90 degrees Celsius for 12 hours. Add water (50 mL) to dilute, and extract with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column separation to obtain compound 1-7. MS (ESI) m/z: 294.1 [M+H+].
  • Step F Compound 1-7 (300 mg, 1.02 mmol, 1 equiv), 1-8 (144.78 mg, 1.23 mmol, 1.2 equiv), 4,5-bis(diphenylphosphine)-9,9 - Dimethylxanthene (118.19 mg, 204.26 ⁇ mol, 0.2 equiv), cesium carbonate (998.26 mg, 3.06 mmol, 3 equiv) and tris(dibenzylideneacetone)dipalladium (187.04 mg, 204.26 ⁇ mol , 0.2 equiv.) was dissolved in dioxane (10 mL) and reacted at 100 degrees Celsius for 12 hours under nitrogen atmosphere.
  • Step G Compound 1-9 (270 mg, 718.19 ⁇ mol, 1 equiv), sodium hydroxide (719.19 ⁇ l, 2 mol per L, 2 equiv) and dimethyl sulfoxide (112.39 mg, 1.44 mmol, 2 equiv) was dissolved in ethanol (5 mL). Hydrogen peroxide (163.09 mg, 1.44 mmol, 138.21 ⁇ l, purity 30%, 2 equivalents) was slowly added to the reaction solution at room temperature, and the reaction was carried out at 25 degrees Celsius for 2 hours. Add water (10 mL) to dilute, and extract with ethyl acetate (10 mL ⁇ 3).
  • the compound crystal form B of formula (II), microcrystalline cellulose, mannitol, colloidal silicon dioxide and croscarmellose sodium are respectively weighed according to the recipe amount, mixed evenly, and set aside.
  • the wet granules are dried at 60°C and the moisture content is controlled below 3%.
  • the tablet weight was within the qualified range, the hardness was 5-9 Kp, and the tablet was completely disintegrated within 10 minutes.
  • the compound crystal form B of the formula (II), microcrystalline cellulose, lactose, colloidal silicon dioxide and croscarmellose sodium are respectively weighed according to the recipe amount, mixed evenly, and set aside.
  • Step (1) premixing, step (2) hypromellose solution configuration, step (3) granulation, step (4) drying, step (5) dry granulation and total mixing, step (6) tableting, Similar to Example 10.
  • Step (1) premixing, step (2) hypromellose solution configuration, step (3) granulation, step (4) drying, step (5) dry granulation and total mixing, step (6) tabletting, Similar to Example 10. Replace croscarmellose sodium with sodium starch glycolate.
  • the compound crystal form B of formula (II), microcrystalline cellulose, lactose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate are respectively weighed according to the recipe amount, mixed uniformly, and set aside.
  • the tablet weight is within the qualified range, the hardness is 5-9 Kp, and the tablet is completely disintegrated within 10 minutes.
  • the concentration of the hypromellose solution was changed from 6% to 4.5%, and it was compressed into a tablet using a tablet press with a die of 11 mm.
  • the raw material drug, lactose, microcrystalline cellulose, colloidal silicon dioxide, and croscarmellose sodium were weighed and added to the wet mixing granulator according to the recipe amount, and were stirred and mixed. Mix for 10 min with stirring speed of 370 rpm and shear speed of 1500 rpm.
  • Drying was carried out using a fluid granulation coater.
  • the inlet air temperature is set to 60°C, the moisture at the drying end is controlled at ⁇ 3.0%, and the drying time is determined according to the moisture measurement results.
  • the fixed hopper of the universal mixer is used for mixing, and the dry granules and the croscarmellose sodium (additional) are placed in the mixing hopper and mixed.
  • the mixing speed was 20 rpm, and the mixing time was 20 min; then magnesium stearate was added for total mixing, the mixing speed was 20 rpm, and the total mixing time was 3 min.
  • the quality of the intermediate is controlled after mixing is complete.
  • the standard tablet weight is converted, and a single punch tablet machine is used for tableting.
  • Die 6mm shallow arc circular punch, tablet weight: 100mg, tablet weight difference: ⁇ 7.5%, controlled tablet hardness: 6-9Kp (1Kp ⁇ 10N), tablet completely disintegrated within 10min.
  • Configuration of coating liquid configure the coating liquid according to the proportion of solid content of 12%
  • the coating powder is weighed according to the film coating premix with a weight gain of 3.0% to 6.0% of the weight of the plain tablet, stirred and dissolved in water to prepare a 12% film coating liquid, and the film coating is carried out by a high-efficiency coating machine.
  • the main machine speed of the coating pot is controlled at 8-10rpm, the main machine speed is 1200rpm, the inlet air temperature is set at 68°C, and the outlet air temperature is controlled between 40 and 50°C.
  • the atomization pressure is 0.17Mpa, and the fan pressure is 0.15Mpa.
  • Tablets and solid pharmaceutical high-density polyethylene non-woven fabric (Tyvec) bag desiccant were put into oral solid pharmaceutical high-density polyethylene plastic bottles (40 mL) together, and sealed with a hand-held induction sealing machine.
  • Power size 1000W; sealing time: 1.6s; packaging specification: 30 pieces/bottle.
  • Step (1) premix, step (2) hypromellose solution configuration, similar to Example 15.
  • Step (4) drying, step (5) granulation, step (6) blending, intermediate detection, are similar to Example 15.
  • the standard tablet weight is converted, and a single punch tablet machine is used for tableting.
  • the pre-stability study of the crystal form D of the compound of formula (IV) shows that the crystal form has no change in impurity content for 10 days under the conditions of 40°C/75% RH and light, which proves that it has good stability.
  • Solubility experiment of compound crystal form B of formula (II) in different pH buffers and biological media Weigh 2mg of the compound, weigh it into a 2mL glass bottle, add 1mL of medium, and add a magnet at 37°C and 700rpm. Stir on a magnetic stirrer.
  • the buffers were pH1.0, pH2.0, SGF and water, and the target concentration was 10 mg/mL. If it is in a clear state, continue to add the compound and continue to stir until the solution no longer becomes clear, until the sample is measured after stirring for 24 hours.
  • SGF simulates the gastric juice of empty stomach in human starvation state.
  • the thickness of the test sample is generally about 1 mm, and the total weight is accurately weighed in m2.
  • the weighing bottle is opened and placed in the above stability test box together with the bottle cap. Place in the stability test chamber for 24 hours. Close the lid of the weighing bottle, and accurately weigh the total weight m 3 .
  • weight gain percentage 100% ⁇ (m 3 -m 2 )/(m 2 -m 1 )
  • HEK293 cells 100 microliters of growth medium without gene protein
  • 35,000 HEK293 cells 100 microliters of growth medium without gene protein
  • the medium was removed the next day, 0.5% fetal bovine serum without genetic protein, 90 microliters of compound solutions (different concentration gradients) were added, and the cells were incubated for 4-5 hours at 37 degrees Celsius in a 5% carbon dioxide atmosphere.
  • Add 10 microliters of TGF ⁇ 1 (the final concentration of TGF ⁇ 1 is 20 ng/mL), add 10 microliters of culture medium to the control wells, and treat overnight. After cleavage, fluorescence was detected using a one-step luciferase assay.
  • the crystal form B of the compound of formula (II) has excellent pSmad inhibitory activity. It is proved that the crystalline form B of the compound of formula (II) can inhibit the TGF- ⁇ /SMAD signaling pathway.
  • Example 21 In vivo antitumor efficacy of mouse colon cancer CT-26 cells BALB/c mouse subcutaneous allograft model
  • the main purpose of this study is to study the antitumor efficacy of the tested compounds in the CT26 mouse allograft tumor model.
  • cell culture mouse colon cancer CT-26 cells were cultured in vitro in monolayer, culture conditions were RPMI-1640 medium plus 10% fetal bovine serum, 37 degrees Celsius and 5% carbon dioxide incubator. Conventional digestion treatments were passaged with trypsin-ethylenediaminetetraacetic acid (EDTA) twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded.
  • EDTA trypsin-ethylenediaminetetraacetic acid
  • Tumor inoculation 0.1 ml of DPBS cell suspension containing 3 ⁇ 10 5 CT26 cells was subcutaneously inoculated into the right groin of each mouse, and the administration started on the day of inoculation.
  • the compound of formula (I) has obvious antitumor efficacy in vivo in the mouse colon cancer CT-26 cell BALB/c mouse subcutaneous allograft tumor model.
  • the purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
  • mice 24 (12/sex) male and female beagle dogs were divided into 4 groups.
  • Group 1 animals were dosed with a single intravenous injection of 1 mg/kg of the test article.
  • Groups 2 and 4 animals were given a single oral dose of 5 and 50 mg/kg of the test article, respectively.
  • the animals in the third group were orally administered once a day for 7 consecutive days, and each dose of the test substance was administered at a dose of 15 mg/kg.
  • Animals in groups 1, 2 and 4 were treated at 0.0833 (5 minutes), 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 8, Plasma samples were collected at 12 and 24 hours.
  • T 1/2 half-life
  • Vd ss volume of distribution
  • Cl clearance
  • AUC 0-last area under the curve
  • C 0 initial concentration
  • C max maximum concentration
  • T max time to peak concentration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are a salt form and crystal form of a 5-(4-pyridyloxy) pyrazole compound as a TGF-βR1 inhibitor drug, a preparation method therefor, a pharmaceutical composition thereof and a method for preparing the pharmaceutical composition. In particular, disclosed are a crystal form and salt form of a compound of formula (I), and a crystal form of the salt form. In particular, also disclosed is a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Description

作为TGF-βR1抑制剂的吡啶氧基连吡唑类化合物的盐型、晶型以及其药物组合物Salt forms, crystal forms and pharmaceutical compositions of pyridyloxydipyrazole compounds as TGF-βR1 inhibitors
本申请要求申请日为2020/7/23的中国专利申请202010717761.4的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 202010717761.4 with an application date of 2020/7/23. This application cites the full text of the above Chinese patent application.
技术领域technical field
本发明涉及一类作为TGF-βR1抑制剂的5-(4-吡啶氧基)吡唑类化合物的盐型、晶型、其制备方法以及药物组合物及其制备方法。The invention relates to a salt form, a crystal form, a preparation method and a pharmaceutical composition of a 5-(4-pyridyloxy)pyrazole compound as a TGF-βR1 inhibitor and a preparation method thereof.
背景技术Background technique
转化生长因子β(Transforming growth factor-β，TGF-β)是一个多功能生长因子超家族，具有广泛的生物学活性，参与早期胚胎发育，软骨和骨的形成，包外基质的合成，炎症，间质纤维化，免疫和内分泌功能的调节，肿瘤的形成和发展。Transforming growth factor-β (TGF-β) is a multifunctional growth factor superfamily with a wide range of biological activities, involved in early embryonic development, cartilage and bone formation, synthesis of extracellular matrix, inflammation, Interstitial fibrosis, regulation of immune and endocrine functions, tumor formation and progression.
TGF-β超家族由一类结构和功能相关的多肽生长因子组成，TGF-β是该家族的重要成员之一。在哺乳动物中TGF-β主要以TGF-β1、TGF-β2和TGF-β3三种形式存在，它们位于不同的染色体上，其中TGF-β1在体细胞中所占比例最高(＞90％)，它活性最强、功能最多，分布也最广泛。The TGF-β superfamily consists of a class of structurally and functionally related polypeptide growth factors, and TGF-β is one of the important members of this family. In mammals, TGF-β mainly exists in three forms: TGF-β1, TGF-β2 and TGF-β3, which are located on different chromosomes, of which TGF-β1 accounts for the highest proportion (>90%) in somatic cells, It is the most active, the most functional, and the most widely distributed.
TGF-β信号分子通过跨膜的受体复合物进行信号转导。TGF-β受体是存在于细胞表面的跨膜蛋白，分为I型受体(TGF-βR1)、II型受体(TGF-βR2)和III型受体(TGF-βR3)，其中TGF-βR1又被称作活化素样受体5(activin receptor-like kinase 5，ALK5)。TGF-βR3缺乏内在活性，主要与TGF-β的储存有关。TGF-βR1和TGF-βR2属于丝氨酸/苏氨酸激酶家族，II型受体能以较高的亲和力与TGF-β配体结合，并与I型受体形成异源受体复合物，将I型受体近膜的一段富含甘氨酸、丝氨酸残基的区域(GS结构域)磷酸化，启动细胞内信号联级反应。TGF-β signaling molecules carry out signal transduction through transmembrane receptor complexes. TGF-β receptors are transmembrane proteins that exist on the cell surface, and are divided into type I receptors (TGF-βR1), type II receptors (TGF-βR2) and type III receptors (TGF-βR3). βR1 is also known as activin-like receptor 5 (activin receptor-like kinase 5, ALK5). TGF-βR3 lacks intrinsic activity and is mainly related to the storage of TGF-β. TGF-βR1 and TGF-βR2 belong to the serine/threonine kinase family, type II receptors can bind to TGF-β ligands with high affinity, and form heterologous receptor complexes with type I receptors, which bind I receptors. A region rich in glycine and serine residues (GS domain) near the membrane of the receptor is phosphorylated to initiate intracellular signaling cascades.
Smads是细胞内重要的TGF-β信号转导和调节分子，可以将TGF-β信号直接由细胞膜转导如细胞核内，TGF-β/Smads信号通路在肿瘤的发生和发展中起到重要的作用。在TGF-β/Smads信号转导中，活化的TGF-β首先与细胞膜表面的TGF-βR2结合，形成异源二聚体复合物，TGF-βR1识别并结合该二元复合物。Smads are important TGF-β signal transduction and regulation molecules in cells, which can directly transduce TGF-β signals from the cell membrane, such as in the nucleus. The TGF-β/Smads signaling pathway plays an important role in the occurrence and development of tumors. . In TGF-β/Smads signal transduction, activated TGF-β first binds to TGF-βR2 on the cell membrane surface to form a heterodimeric complex, which is recognized and bound by TGF-βR1.
TGF-βR2将TGF-βR1胞浆区GS结构域的丝氨酸/苏氨酸磷酸化，从而激活TGF-βR1；活化的TGF-βR1进一步磷酸化R-Smads(Smad2/Smad3)蛋白，后者再与Co-Smad(Smad4)结合成为异三聚体复合物，这一复合物进入细胞核内，与其他辅助活化因子(co-activator)和辅助抑制因子(co-inhibitor)协同作用，调节靶基因的转录。在TGF-β/Smads信号通路中任何一个环节发生改变，都会导致信号转导通路的异常。TGF-βR2 phosphorylates serine/threonine in the GS domain of the cytoplasmic domain of TGF-βR1, thereby activating TGF-βR1; the activated TGF-βR1 further phosphorylates R-Smads (Smad2/Smad3) protein, which in turn interacts with Co-Smad (Smad4) binds to form a heterotrimeric complex, which enters the nucleus and cooperates with other co-activators and co-inhibitors to regulate the transcription of target genes . Changes in any link in the TGF-β/Smads signaling pathway will lead to abnormalities in the signal transduction pathway.
目前的研究表明，在肿瘤细胞中，TGF-β能直接影响肿瘤的生长(TGF-β信号的非固有影响)，或者通过诱导上皮间质转化、阻断抗肿瘤免疫应答、增加肿瘤相关纤维化和强化血管再生间接地影响肿瘤生长(TGF-β的固有影响)。同时，TGF-β具有很强的纤维化诱导作用，它是与肿瘤相关的成纤维细胞的激活剂。这些成纤维细胞是胶原I型和其他纤维化因子的主要来源。成纤维细胞和其他纤维化因子的诱导产物可能继续培育出一个微环境，这个环境会减少免疫应答，增加抗药性和强化肿瘤血管生成另外，在个体发育和肿瘤生长过程中，TGF-β影响血管生再生。例如，TGF-βR1型缺陷的小鼠胚胎显示出了严重的血管发育缺陷，证明TGF-β信号通道是血管内皮及平滑肌细胞发育中的关键调节器。Current studies have shown that in tumor cells, TGF-β can directly affect tumor growth (extrinsic effects of TGF-β signaling), or by inducing epithelial-mesenchymal transition, blocking anti-tumor immune responses, and increasing tumor-associated fibrosis and enhanced angiogenesis indirectly affects tumor growth (intrinsic effect of TGF-β). Meanwhile, TGF-β has a strong fibrosis-inducing effect, and it is an activator of tumor-associated fibroblasts. These fibroblasts are a major source of collagen type I and other fibrotic factors. Induced products of fibroblasts and other fibrotic factors may go on to foster a microenvironment that reduces immune responses, increases drug resistance, and enhances tumor angiogenesis. Additionally, TGF-β affects blood vessels during ontogeny and tumor growth. regeneration. For example, TGF-βR1-deficient mouse embryos display severe defects in vascular development, demonstrating that the TGF-β signaling pathway is a key regulator in vascular endothelial and smooth muscle cell development.
近期的研究报道同时指出，TGF-β明显与免疫逃逸相关，对CD8+T细胞介导的抗肿瘤免疫反应影响较大。在针对转移型泌尿上皮癌的临床试验中，TGF-β基因高表达的患者对PD-L1单抗响应及模拟生存率低。TGF-β单抗的基础研究也证明，当其与PD-L1单抗协同使用时，更多CD8+T细胞浸润并发挥作用，揭示了阻断TGF-β对免疫的激活作用及其机理。由于TGF-β的免疫调节作用，小分子TGF-βR1抑制剂单药或与PD-(L)1单抗联用在多种实体瘤治疗上具有极大的应用前景。Recent research reports also pointed out that TGF-β is significantly related to immune escape, and has a greater impact on CD8+ T cell-mediated anti-tumor immune responses. In clinical trials for metastatic urothelial carcinoma, patients with high expression of TGF-β gene had a low response to PD-L1 monoclonal antibody and a low simulated survival rate. The basic research of TGF-β monoclonal antibody has also proved that when it is used synergistically with PD-L1 monoclonal antibody, more CD8+ T cells infiltrate and play a role, revealing the activation effect of blocking TGF-β on immunity and its mechanism. Due to the immunomodulatory effect of TGF-β, small molecule TGF-βR1 inhibitors alone or in combination with PD-(L)1 monoclonal antibody have great application prospects in the treatment of various solid tumors.
发明内容SUMMARY OF THE INVENTION
本发明提供式(I)化合物的晶型A，其CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.96±0.20°、18.65±0.20°、20.94±0.20°和23.57±0.20°，The present invention provides crystal form A of the compound of formula (I), the X-ray powder diffraction pattern of CuKα radiation has characteristic diffraction peaks at the following 2θ angles: 15.96±0.20°, 18.65±0.20°, 20.94±0.20° and 23.57±0.20 °,
Figure PCTCN2021105662-appb-000001
Figure PCTCN2021105662-appb-000001
本发明的一些方案中，上述晶型A的CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.97±0.20°、13.21±0.20°、14.17±0.20°、15.96±0.20°、18.65±0.20°、20.94±0.20°、21.52±0.20°和23.57±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of CuKα radiation of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 7.97±0.20°, 13.21±0.20°, 14.17±0.20°, 15.96±0.20°, 18.65±0.20°, 20.94±0.20°, 21.52±0.20° and 23.57±0.20°.
本发明的一些方案中，上述晶型A的CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.97±0.20°、12.20±0.20°、12.78±0.20°、13.21±0.20°、14.17±0.20°、15.96±0.20°、18.65±0.20°、20.94±0.20°、21.52±0.20°、22.05±0.20°、23.57±0.20°和25.01±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of CuKα radiation of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 7.97±0.20°, 12.20±0.20°, 12.78±0.20°, 13.21±0.20°, 14.17±0.20°, 15.96±0.20°, 18.65±0.20°, 20.94±0.20°, 21.52±0.20°, 22.05±0.20°, 23.57±0.20° and 25.01±0.20°.
本发明的一些方案中，上述晶型A的CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.84°、7.97°、9.30°、11.69°、12.20°、12.78°、13.21°、14.17°、14.86°、15.52°、15.96°、16.60°、16.91°、17.58°、18.25°、18.65°、19.21°、19.50°、20.11°、20.94°、21.52°、22.05°、22.80°、23.05°、 23.57°、24.06°、25.01°、25.33°、26.49°、26.93°、27.36°、28.09°、28.54°和29.96°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the CuKα radiation of the crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.84°, 7.97°, 9.30°, 11.69°, 12.20°, 12.78°, 13.21° , 14.17°, 14.86°, 15.52°, 15.96°, 16.60°, 16.91°, 17.58°, 18.25°, 18.65°, 19.21°, 19.50°, 20.11°, 20.94°, 21.52°, 22.05°, 22.80°, 23.05 °, 23.57°, 24.06°, 25.01°, 25.33°, 26.49°, 26.93°, 27.36°, 28.09°, 28.54° and 29.96°.
本发明的一些方案中，上述晶型A的XRPD图谱如图1所示。In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1 .
本发明的一些方案中，上述晶型A的XRPD图谱衍射峰数据如表1所示。In some embodiments of the present invention, the XRPD pattern diffraction peak data of the above-mentioned crystal form A is shown in Table 1.
表1 式(I)化合物晶型A的XRPD衍射峰数据Table 1 XRPD diffraction peak data of compound crystal form A of formula (I)
Figure PCTCN2021105662-appb-000002
Figure PCTCN2021105662-appb-000002
本发明的一些方案中，上述晶型A的差示扫描量热曲线(DSC)在192.6℃处有吸热峰。In some embodiments of the present invention, the differential scanning calorimetry curve (DSC) of the above-mentioned Form A has an endothermic peak at 192.6°C.
本发明的一些方案中，上述晶型A的DSC图谱如图2所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2 .
本发明的一些方案中，上述晶型A的热重分析(TGA)曲线在180.0℃±3℃时，失重为1.40％。In some embodiments of the present invention, when the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form A is at 180.0° C.±3° C., the weight loss is 1.40%.
本发明的一些方案中，上述晶型A的TGA图谱如图3所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form A is shown in FIG. 3 .
本发明的一些方案中，上述晶型A的DVS图谱如图4所示。In some embodiments of the present invention, the DVS spectrum of the above-mentioned crystal form A is shown in FIG. 4 .
本发明还提供了式(I)化合物药学上可接受的盐。The present invention also provides pharmaceutically acceptable salts of the compounds of formula (I).
本发明的一些方案中，式(I)化合物药学上可接受的盐选自氢溴酸盐、甲磺酸盐、草酸盐或磷酸盐。In some embodiments of the invention, the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of hydrobromide, mesylate, oxalate or phosphate.
本发明还提供了式(I)化合物氢溴酸盐的水合物，其结构如式(I-1)所示，The present invention also provides the hydrate of the compound hydrobromide of the formula (I), the structure of which is shown in the formula (I-1),
Figure PCTCN2021105662-appb-000003
Figure PCTCN2021105662-appb-000003
其中，x为0.9～1.1，y为0.9～1.1。Here, x is 0.9 to 1.1, and y is 0.9 to 1.1.
本发明的一些方案中，上述式(I)化合物氢溴酸盐的水合物的结构如式(II)所示，In some embodiments of the present invention, the structure of the hydrate of the hydrobromide salt of the compound of the above formula (I) is shown in the formula (II),
Figure PCTCN2021105662-appb-000004
Figure PCTCN2021105662-appb-000004
本发明还提供了式(II)化合物的晶型B，其CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.98±0.20°、19.53±0.20°、24.37±0.20°和25.32±0.20°，The present invention also provides the crystalline form B of the compound of formula (II), the X-ray powder diffraction pattern of CuKα radiation has characteristic diffraction peaks at the following 2θ angles: 10.98±0.20°, 19.53±0.20°, 24.37±0.20° and 25.32 ±0.20°,
Figure PCTCN2021105662-appb-000005
Figure PCTCN2021105662-appb-000005
本发明的一些方案中，上述晶型B的CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.27±0.20°、10.98±0.20°、13.99±0.20°、19.53±0.20°、22.01±0.20°、24.37±0.20°、25.32±0.20°和26.90±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the CuKα radiation of the crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.27±0.20°, 10.98±0.20°, 13.99±0.20°, 19.53±0.20°, 22.01±0.20°, 24.37±0.20°, 25.32±0.20° and 26.90±0.20°.
本发明的一些方案中，上述晶型B的CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.27±0.20°、10.98±0.20°、13.99±0.20°、14.83±0.20°、17.50±0.20°、19.53±0.20°、20.37±0.20°、22.01±0.20°、24.37±0.20°、24.78±0.20°、25.32±0.20°和26.90±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the CuKα radiation of the crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.27±0.20°, 10.98±0.20°, 13.99±0.20°, 14.83±0.20°, 17.50±0.20°, 19.53±0.20°, 20.37±0.20°, 22.01±0.20°, 24.37±0.20°, 24.78±0.20°, 25.32±0.20° and 26.90±0.20°.
本发明的一些方案中，上述晶型B的CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.41°、9.27°、10.98°、11.64°、13.99°、14.44°、14.83°、17.50°、18.55°、19.53°、19.78°、20.37°、21.08°、21.48°、22.01°、22.76°、23.41°、23.84°、24.37°、24.78°、25.32°、26.90°、27.34°、28.15°、 29.29°、29.96°、30.36°、31.23°、32.70°、33.25°、34.17°、35.50°和38.32°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the CuKα radiation of the crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.41°, 9.27°, 10.98°, 11.64°, 13.99°, 14.44°, 14.83° , 17.50°, 18.55°, 19.53°, 19.78°, 20.37°, 21.08°, 21.48°, 22.01°, 22.76°, 23.41°, 23.84°, 24.37°, 24.78°, 25.32°, 26.90°, 27.34°, 28.15 °, 29.29°, 29.96°, 30.36°, 31.23°, 32.70°, 33.25°, 34.17°, 35.50° and 38.32°.
本发明的一些方案中，上述晶型B的XRPD图谱如图5所示。In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 5 .
本发明的一些方案中，上述晶型B的XRPD图谱衍射峰数据如表2所示。In some solutions of the present invention, the XRPD pattern diffraction peak data of the above-mentioned crystal form B are shown in Table 2.
表2 式(II)化合物晶型B的XRPD衍射峰数据Table 2 XRPD diffraction peak data of compound crystal form B of formula (II)
Figure PCTCN2021105662-appb-000006
Figure PCTCN2021105662-appb-000006
本发明的一些方案中，上述晶型B的差示扫描量热曲线(DSC)在130.7℃和181.8℃处有吸热峰。In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned Form B has endothermic peaks at 130.7°C and 181.8°C.
本发明的一些方案中，上述晶型B的DSC图谱如图6所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 6 .
本发明的一些方案中，上述晶型B的热重分析(TGA)曲线在160.0℃±3℃时，失重为4.22％。In some embodiments of the present invention, when the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form B is at 160.0° C.±3° C., the weight loss is 4.22%.
本发明的一些方案中，上述晶型B的TGA图谱如图7所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form B is shown in FIG. 7 .
本发明的一些方案中，上述晶型B的DVS图谱如图8所示。In some embodiments of the present invention, the DVS spectrum of the above-mentioned crystal form B is shown in FIG. 8 .
本发明还提供了上述晶型B的制备方法，其包括如下步骤：The present invention also provides a preparation method of the above-mentioned crystal form B, which comprises the following steps:
1)将式(I)化合物加入溶剂中溶解，再加入氢溴酸水溶液在一定温度下搅拌；1) adding the compound of formula (I) to the solvent and dissolving, then adding the aqueous hydrobromic acid solution and stirring at a certain temperature;
2)反应液降至室温，过滤，滤饼真空干燥；2) the reaction solution was cooled to room temperature, filtered, and the filter cake was vacuum-dried;
其中所述溶剂为异丙醇。Wherein the solvent is isopropanol.
本发明还提供了式(I)化合物的氢溴酸盐，其结构如式(III)所示，The present invention also provides the hydrobromide salt of the compound of formula (I), the structure of which is shown in formula (III),
Figure PCTCN2021105662-appb-000007
Figure PCTCN2021105662-appb-000007
本发明还提供了式(III)化合物的晶型C，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.21±0.20°、18.69±0.20°、22.47±0.20°和25.60±0.20°，The present invention also provides the crystalline form C of the compound of formula (III), whose X-ray powder diffraction pattern of Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.21±0.20°, 18.69±0.20°, 22.47±0.20° and 25.60±0.20°,
Figure PCTCN2021105662-appb-000008
Figure PCTCN2021105662-appb-000008
本发明的一些方案中，上述晶型C的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.38±0.20°、11.21±0.20°、16.64±0.20°、18.69±0.20°、21.25±0.20°、22.47±0.20°、25.60±0.20°和29.98±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the Cu Kα radiation of the crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.38±0.20°, 11.21±0.20°, 16.64±0.20°, 18.69±0.20° , 21.25±0.20°, 22.47±0.20°, 25.60±0.20° and 29.98±0.20°.
本发明的一些方案中，上述晶型C的CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.38±0.20°、11.21±0.20°、16.64±0.20°、18.69±0.20°、20.57±0.20°、21.25±0.20°、21.80±0.20°、22.47±0.20°、25.60±0.20°、26.27±0.20°、28.50±0.20°和29.98±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of CuKα radiation of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.38±0.20°, 11.21±0.20°, 16.64±0.20°, 18.69±0.20°, 20.57±0.20°, 21.25±0.20°, 21.80±0.20°, 22.47±0.20°, 25.60±0.20°, 26.27±0.20°, 28.50±0.20° and 29.98±0.20°.
本发明的一些方案中，上述晶型C的CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.38°、10.33°、11.21°、14.75°、16.64°、17.84°、18.69°、19.41°、20.57°、21.25°、21.80°、22.47°、22.81°、23.12°、25.24°、25.60°、26.27°、27.61°、28.50°、28.76°、29.64°、29.98°、31.65°和32.94°。In some embodiments of the present invention, the X-ray powder diffraction pattern of CuKα radiation of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.38°, 10.33°, 11.21°, 14.75°, 16.64°, 17.84°, 18.69° a °.
本发明的一些方案中，上述晶型C的XRPD图谱如图9所示。In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 9 .
本发明的一些方案中，上述晶型C的XRPD图谱衍射峰数据如表3所示。In some embodiments of the present invention, the XRPD pattern diffraction peak data of the above-mentioned crystal form C is shown in Table 3.
表3 式(III)化合物晶型C的XRPD衍射峰数据Table 3 XRPD diffraction peak data of compound crystal form C of formula (III)
Figure PCTCN2021105662-appb-000009
Figure PCTCN2021105662-appb-000009
Figure PCTCN2021105662-appb-000010
Figure PCTCN2021105662-appb-000010
本发明的一些方案中，上述晶型C的差示扫描量热曲线(DSC)在232.4℃处有吸热峰。In some embodiments of the present invention, the differential scanning calorimetry curve (DSC) of the above-mentioned crystal form C has an endothermic peak at 232.4°C.
本发明的一些方案中，上述晶型C的DSC图谱如图10所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form C is shown in FIG. 10 .
本发明的一些方案中，上述晶型C的热重分析(TGA)曲线在200.0℃±3℃时，失重为1.18％。In some embodiments of the present invention, when the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form C is at 200.0° C.±3° C., the weight loss is 1.18%.
本发明的一些方案中，上述晶型C的TGA图谱如图11所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form C is shown in FIG. 11 .
本发明还提供了式(I)化合物的甲磺酸盐，其结构如式(IV)所示，The present invention also provides the mesylate of the compound of formula (I), the structure of which is shown in formula (IV),
Figure PCTCN2021105662-appb-000011
Figure PCTCN2021105662-appb-000011
本发明还提供了式(IV)化合物的晶型D，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.74±0.20°、8.84±0.20°、11.91±0.20°、16.70±0.20°、17.61±0.20°、18.45±0.20°、19.09±0.20°、20.46±0.20°、22.98±0.20°、25.35±0.20°、25.81±0.20°和27.22±0.20°，The present invention also provides the crystal form D of the compound of formula (IV), the X-ray powder diffraction pattern of the Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.74±0.20°, 8.84±0.20°, 11.91±0.20°, 16.70±0.20°, 17.61±0.20°, 18.45±0.20°, 19.09±0.20°, 20.46±0.20°, 22.98±0.20°, 25.35±0.20°, 25.81±0.20° and 27.22±0.20°,
Figure PCTCN2021105662-appb-000012
Figure PCTCN2021105662-appb-000012
本发明的一些方案中，上述晶型D的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.74°、8.84°、11.91°、13.28°、13.88°、15.00°、16.70°、17.61°、18.21°、18.45°、19.09°、20.46°、21.76°、22.98°、23.94°、25.35°、25.81°、26.64°、27.22°、27.82°、29.04°、30.64°、31.11°、33.24°、33.80°、35.94°和39.19°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2θ angles: 5.74°, 8.84°, 11.91°, 13.28°, 13.88°, 15.00°, 16.70° degrees 33.24°, 33.80°, 35.94° and 39.19°.
本发明的一些方案中，上述晶型D的XRPD图谱如图12所示。In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form D is shown in FIG. 12 .
本发明的一些方案中，上述晶型D的XRPD图谱衍射峰数据如表4所示。In some embodiments of the present invention, the XRPD pattern diffraction peak data of the above-mentioned crystal form D are shown in Table 4.
表4 式(IV)化合物晶型D的XRPD衍射峰数据Table 4 XRPD diffraction peak data of compound crystal form D of formula (IV)
Figure PCTCN2021105662-appb-000013
Figure PCTCN2021105662-appb-000013
本发明的一些方案中，上述晶型D的差示扫描量热曲线(DSC)在204.4℃处有吸热峰。In some embodiments of the present invention, the differential scanning calorimetry curve (DSC) of the above-mentioned crystal form D has an endothermic peak at 204.4°C.
本发明的一些方案中，上述晶型D的DSC图谱如图13所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form D is shown in FIG. 13 .
本发明的一些方案中，上述晶型D的热重分析(TGA)曲线在180.0℃±3℃时，失重为0.58％。In some embodiments of the present invention, when the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form D is at 180.0°C±3°C, the weight loss is 0.58%.
本发明的一些方案中，上述晶型D的TGA图谱如图14所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form D is shown in FIG. 14 .
本发明的一些方案中，上述晶型D的DVS图谱如图15所示。In some embodiments of the present invention, the DVS spectrum of the above-mentioned crystal form D is shown in FIG. 15 .
本发明还提供了式(I)化合物的草酸盐，其结构如式(V)所示，The present invention also provides the oxalate of the compound of formula (I), the structure of which is shown in formula (V),
Figure PCTCN2021105662-appb-000014
Figure PCTCN2021105662-appb-000014
本发明还提供了式(V)化合物的晶型E，其CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.83±0.20°、7.25±0.20°、10.56±0.20°、13.18±0.20°、18.10±0.20°、19.00±0.20°、19.77±0.20°、20.20±0.20°、22.16±0.20°、23.90±0.20°、24.37±0.20°和25.58±0.20°，The present invention also provides the crystalline form E of the compound of formula (V), whose CuKα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.83±0.20°, 7.25±0.20°, 10.56±0.20°, 13.18 ±0.20°, 18.10±0.20°, 19.00±0.20°, 19.77±0.20°, 20.20±0.20°, 22.16±0.20°, 23.90±0.20°, 24.37±0.20° and 25.58±0.20°,
Figure PCTCN2021105662-appb-000015
Figure PCTCN2021105662-appb-000015
本发明的一些方案中，上述晶型E的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.12°、6.39°、6.83°、7.25°、9.96°、10.56°、12.75°、13.18°、13.60°、14.56°、14.95°、15.66°、16.76°、17.17°、18.10°、19.00°、19.36°、19.77°、20.20°、20.80°、21.80°、22.16°、22.53°、23.90°、24.37°、25.00°、25.58°、26.01°、26.93°、27.66°、28.36°、29.27°、32.17°、32.68°和36.51°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2θ angles: 5.12°, 6.39°, 6.83°, 7.25°, 9.96°, 10.56°, 12.75° degrees 23.90°, 24.37°, 25.00°, 25.58°, 26.01°, 26.93°, 27.66°, 28.36°, 29.27°, 32.17°, 32.68° and 36.51°.
本发明的一些方案中，上述晶型E的XRPD图谱如图16所示。In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form E is shown in FIG. 16 .
本发明的一些方案中，上述晶型E的XRPD图谱衍射峰数据如表5所示。In some embodiments of the present invention, the XRPD pattern diffraction peak data of the above-mentioned crystal form E are shown in Table 5.
表5 式(V)化合物晶型E的XRPD衍射峰数据Table 5 XRPD diffraction peak data of compound crystal form E of formula (V)
Figure PCTCN2021105662-appb-000016
Figure PCTCN2021105662-appb-000016
Figure PCTCN2021105662-appb-000017
Figure PCTCN2021105662-appb-000017
本发明的一些方案中，上述晶型E的差示扫描量热曲线(DSC)在82.1℃、129.3℃、145.6℃和168.3℃处有吸热峰。In some embodiments of the present invention, the differential scanning calorimetry curve (DSC) of the above-mentioned Form E has endothermic peaks at 82.1°C, 129.3°C, 145.6°C and 168.3°C.
本发明的一些方案中，上述晶型E的DSC图谱如图17所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form E is shown in FIG. 17 .
本发明的一些方案中，上述晶型E的热重分析(TGA)曲线在110.0℃±3℃时，失重为1.16％，在150.0℃±3℃时，再次失重2.30％。In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of the above crystal form E shows a weight loss of 1.16% at 110.0°C±3°C, and a weight loss of 2.30% again at 150.0°C±3°C.
本发明的一些方案中，上述晶型E的TGA图谱如图18所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form E is shown in FIG. 18 .
本发明还提供了式(V)化合物的晶型F，其CuKα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.15±0.20°、7.93±0.20°、10.56±0.20°、15.40±0.20°、16.79±0.20°、17.98±0.20°、19.33±0.20°、20.20±0.20°、21.11±0.20°、22.49±0.20°、23.84±0.20°和26.63±0.20°，The present invention also provides the crystal form F of the compound of formula (V), the X-ray powder diffraction pattern of the CuKα radiation has characteristic diffraction peaks at the following 2θ angles: 5.15±0.20°, 7.93±0.20°, 10.56±0.20°, 15.40 ±0.20°, 16.79±0.20°, 17.98±0.20°, 19.33±0.20°, 20.20±0.20°, 21.11±0.20°, 22.49±0.20°, 23.84±0.20° and 26.63±0.20°,
Figure PCTCN2021105662-appb-000018
Figure PCTCN2021105662-appb-000018
本发明的一些方案中，上述晶型F的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.15°、6.44°、7.93°、10.56°、11.69°、12.82°、13.45°、15.40°、16.26°、16.79°、17.98°、19.33°、20.20°、21.11°、22.04°、22.49°、23.49°、23.84°、24.32°、25.80°、26.63°、27.39°、28.47°、34.57°和36.44°。In some embodiments of the present invention, the X-ray powder diffraction pattern of Cu Kα radiation of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2θ angles: 5.15°, 6.44°, 7.93°, 10.56°, 11.69°, 12.82°, 13.45° degrees 34.57° and 36.44°.
本发明的一些方案中，上述晶型F的XRPD图谱如图19所示。In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form F is shown in FIG. 19 .
本发明的一些方案中，上述晶型F的XRPD图谱衍射峰数据如表6所示。In some embodiments of the present invention, the XRPD pattern diffraction peak data of the above-mentioned crystal form F are shown in Table 6.
表6 式(V)化合物晶型F的XRPD衍射峰数据Table 6 XRPD diffraction peak data of compound crystal form F of formula (V)
Figure PCTCN2021105662-appb-000019
Figure PCTCN2021105662-appb-000019
本发明的一些方案中，上述晶型F的差示扫描量热曲线(DSC)在97.6℃、145.3℃和211.5℃处有吸热峰。In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form F has endothermic peaks at 97.6°C, 145.3°C and 211.5°C.
本发明的一些方案中，上述晶型F的DSC图谱如图20所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form F is shown in FIG. 20 .
本发明的一些方案中，上述晶型F的热重分析(TGA)曲线在120.0℃±3℃时，失重为4.19％。In some embodiments of the present invention, when the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form F is at 120.0° C.±3° C., the weight loss is 4.19%.
本发明的一些方案中，上述晶型F的TGA图谱如图21所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form F is shown in FIG. 21 .
本发明还提供了式(I)化合物的磷酸盐，其结构如式(VI)所示，The present invention also provides the phosphate of the compound of formula (I), the structure of which is shown in formula (VI),
Figure PCTCN2021105662-appb-000020
Figure PCTCN2021105662-appb-000020
本发明还提供了式(VI)化合物的晶型G，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.94°±0.20°、9.84°±0.20°、10.60°±0.20°、14.75°±0.20°、15.72°±0.20°、16.85°±0.20°、18.04°±0.20°、18.99°±0.20°、20.37°±0.20°、21.20°±0.20°、21.75°±0.20°、22.32°±0.20°、23.51°±0.20°、24.70°±0.20°、26.73°±0.20°和29.12°±0.20°，The present invention also provides the crystal form G of the compound of formula (VI), the X-ray powder diffraction pattern of the Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.94°±0.20°, 9.84°±0.20°, 10.60°± 0.20°, 14.75°±0.20°, 15.72°±0.20°, 16.85°±0.20°, 18.04°±0.20°, 18.99°±0.20°, 20.37°±0.20°, 21.20°±0.20°, 21.75°±0.20° , 22.32°±0.20°, 23.51°±0.20°, 24.70°±0.20°, 26.73°±0.20° and 29.12°±0.20°,
Figure PCTCN2021105662-appb-000021
Figure PCTCN2021105662-appb-000021
本发明的一些方案中，上述晶型G的XRPD图谱如图22所示。In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form G is shown in FIG. 22 .
本发明的一些方案中，上述晶型G的XRPD图谱衍射峰数据如表7所示。In some embodiments of the present invention, the XRPD pattern diffraction peak data of the above-mentioned crystal form G are shown in Table 7.
表7 式(VI)化合物晶型G的XRPD衍射峰数据Table 7 XRPD diffraction peak data of compound crystal form G of formula (VI)
Figure PCTCN2021105662-appb-000022
Figure PCTCN2021105662-appb-000022
本发明的一些方案中，上述晶型G的差示扫描量热曲线(DSC)在62.4℃、98.4℃、110.7℃和158.0℃处有吸热峰。In some embodiments of the present invention, the differential scanning calorimetry curve (DSC) of the above-mentioned Form G has endothermic peaks at 62.4°C, 98.4°C, 110.7°C and 158.0°C.
本发明的一些方案中，上述晶型G的DSC图谱如图23所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form G is shown in FIG. 23 .
本发明的一些方案中，上述晶型G的热重分析(TGA)曲线在120.0℃±3℃时，失重为3.79％。In some embodiments of the present invention, when the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form G is at 120.0° C.±3° C., the weight loss is 3.79%.
本发明的一些方案中，上述晶型G的TGA图谱如图24所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form G is shown in FIG. 24 .
本发明还提供了一种药物组合物，其包含活性成分、填充剂、粘合剂、崩解剂和润滑剂，所述活性成分为式(I)化合物或其药学上可接受盐。The present invention also provides a pharmaceutical composition comprising an active ingredient, a filler, a binder, a disintegrant and a lubricant, and the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof.
本发明的一些方案中，上述药物组合物中式(I)化合物药学上可接受的盐选自氢溴酸盐、甲磺酸盐、草酸盐和磷酸盐。In some aspects of the present invention, the pharmaceutically acceptable salt of the compound of formula (I) in the above pharmaceutical composition is selected from the group consisting of hydrobromide, mesylate, oxalate and phosphate.
本发明的一些方案中，上述药物组合物中活性成分选自：式(I)化合物的晶型A，式(II)化合物氢溴酸盐的水合物的晶型B，式(III)化合物氢溴酸盐的晶型C，式(IV)化合物甲磺酸盐的晶型D，式(V)化合物草酸盐的晶型E和晶型F，式(VI)化合物磷酸盐的晶型G。In some aspects of the present invention, the active ingredients in the above-mentioned pharmaceutical composition are selected from: the crystal form A of the compound of formula (I), the crystal form B of the hydrate of the compound of formula (II) hydrobromide, the hydrogen of the compound of formula (III) Form C of bromate salt, Form D of methanesulfonate of compound of formula (IV), Form E and Form F of oxalate of compound of formula (V), Form G of phosphate of compound of formula (VI) .
本发明的一些方案中，上述药物组合物的剂型为片剂。In some aspects of the present invention, the dosage form of the above-mentioned pharmaceutical composition is a tablet.
本发明的一些方案中，上述片剂的特征在于，每片由以下质量分数的成分组成：活性成分 10％～15％、填充剂75％～82％、粘合剂1％～3％、崩解剂4％～10％和润滑剂1％～3％。In some solutions of the present invention, the above-mentioned tablets are characterized in that each tablet is composed of the following ingredients in mass fractions: 10% to 15% of active ingredients, 75% to 82% of filler, 1% to 3% of binder, disintegrating Solution 4% to 10% and lubricant 1% to 3%.
本发明的一些方案中，上述片剂的特征在于，每片由以下质量分数的成分组成：活性成分12.06％、填充剂78.94％、粘合剂1.5％、崩解剂6.0％和润滑剂1.5％。In some aspects of the present invention, the above-mentioned tablets are characterized in that each tablet is composed of the following ingredients by mass fraction: 12.06% of active ingredients, 78.94% of fillers, 1.5% of binders, 6.0% of disintegrants and 1.5% of lubricants .
本发明的一些方案中，上述药物组合物中的填充剂选自微晶纤维素、甘露醇、乳糖、淀粉、蔗糖或预胶化淀粉中一种或多种。In some aspects of the present invention, the filler in the above-mentioned pharmaceutical composition is selected from one or more of microcrystalline cellulose, mannitol, lactose, starch, sucrose or pregelatinized starch.
本发明的一些方案中，上述药物组合物中的粘合剂选自羟丙甲纤维素、聚维酮、羟丙基纤维素、甲基纤维素、乙基纤维素或羧甲基纤维素钠中一种或多种。In some aspects of the present invention, the binder in the above-mentioned pharmaceutical composition is selected from hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or sodium carboxymethyl cellulose one or more of them.
本发明的一些方案中，上述药物组合物中的崩解剂选自交联羧甲纤维素钠、羧甲淀粉钠、羟丙基淀粉、低取代羟丙纤维素或交联聚维酮中一种或多种。In some aspects of the present invention, the disintegrant in the above-mentioned pharmaceutical composition is selected from one of croscarmellose sodium, sodium starch glycolate, hydroxypropyl starch, low-substituted hydroxypropyl cellulose or crospovidone. one or more.
本发明的一些方案中，上述药物组合物中的润滑剂选自胶态二氧化硅、硬脂酸镁、硬脂酸、滑石粉或硬脂富马酸钠中一种或多种。In some embodiments of the present invention, the lubricant in the above-mentioned pharmaceutical composition is selected from one or more of colloidal silicon dioxide, magnesium stearate, stearic acid, talc or sodium stearyl fumarate.
本发明的一些方案中，上述片剂的特征在于，每片由以下质量分数的成分组成：式(I)化合物氢溴酸盐12.06％、微晶纤维素58.94％、甘露醇20％、胶态二氧化硅0.5％、羟丙甲纤维素1.5％、交联羧甲纤维素钠6.0％和硬脂酸镁1.0％。优选地，式(I)化合物的氢溴酸盐为式(II)化合物的晶型B或式(III)化合物的晶型C。In some solutions of the present invention, the above-mentioned tablets are characterized in that each tablet is composed of the following ingredients in mass fractions: 12.06% of the compound of formula (I) hydrobromide, 58.94% of microcrystalline cellulose, 20% of mannitol, colloidal Silica 0.5%, Hypromellose 1.5%, Croscarmellose Sodium 6.0% and Magnesium Stearate 1.0%. Preferably, the hydrobromide salt of the compound of formula (I) is the crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III).
本发明的一些方案中，上述片剂的特征在于，每片由以下质量分数的成分组成：式(I)化合物氢溴酸盐12.06％、微晶纤维素58.94％、乳糖20％、胶态二氧化硅0.5％、羟丙甲纤维素1.5％、交联羧甲纤维素钠6.0％和硬脂酸镁1.0％。优选地，式(I)化合物氢溴酸盐为式(II)化合物的晶型B或式(III)化合物的晶型C。In some solutions of the present invention, the above-mentioned tablets are characterized in that each tablet is composed of the following ingredients in mass fractions: 12.06% of the compound of formula (I) hydrobromide, 58.94% of microcrystalline cellulose, 20% of lactose, colloidal two Silica 0.5%, Hypromellose 1.5%, Croscarmellose Sodium 6.0% and Magnesium Stearate 1.0%. Preferably, the hydrobromide salt of the compound of formula (I) is the crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III).
本发明的一些方案中，上述片剂的特征在于，每片由以下质量分数的成分组成：式(I)化合物氢溴酸盐12.06％、微晶纤维素20％、乳糖58.94％、胶态二氧化硅0.5％、羟丙甲纤维素1.5％、交联羧甲纤维素钠6.0％和硬脂酸镁1.0％。优选地，式(I)化合物氢溴酸盐为式(II)化合物的晶型B或式(III)化合物的晶型C。In some solutions of the present invention, the above-mentioned tablets are characterized in that each tablet is composed of the following ingredients in mass fractions: 12.06% of the compound of formula (I) hydrobromide, 20% of microcrystalline cellulose, 58.94% of lactose, colloidal two Silica 0.5%, Hypromellose 1.5%, Croscarmellose Sodium 6.0% and Magnesium Stearate 1.0%. Preferably, the hydrobromide salt of the compound of formula (I) is the crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III).
本发明的一些方案中，上述片剂的特征在于，每片由以下质量分数的成分组成：式(I)化合物氢溴酸盐12.06％、微晶纤维素58.94％、乳糖20％、胶态二氧化硅0.5％、羟丙甲纤维素1.5％、羧甲淀粉钠6.0％和硬脂酸镁1.0％。优选地，式(I)化合物氢溴酸盐为式(II)化合物的晶型B或式(III)化合物的晶型C。In some solutions of the present invention, the above-mentioned tablets are characterized in that each tablet is composed of the following ingredients in mass fractions: 12.06% of the compound of formula (I) hydrobromide, 58.94% of microcrystalline cellulose, 20% of lactose, colloidal two Silica 0.5%, hypromellose 1.5%, sodium starch glycolate 6.0% and magnesium stearate 1.0%. Preferably, the hydrobromide salt of the compound of formula (I) is the crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III).
本发明还提供了一种制备上述药物组合物的方法，其包括以下步骤：准确称取处方量的活性成分、填充剂、润滑剂和崩解剂，混匀后，加入粘合剂溶液，制粒，湿颗粒用筛网湿整粒(优选为20目筛网)，然后干燥(优选为60℃以下)，干颗粒过筛网整粒(优选为20目筛网)，加入崩解剂混匀，再加入润滑剂混匀后压片，即得。The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps: accurately weighing the active ingredient, filler, lubricant and disintegrant in the recipe quantity, after mixing, adding a binder solution to prepare Granules, wet granules are granulated with a sieve (preferably a 20-mesh sieve), then dried (preferably below 60°C), the dry granules are sieved and granulated (preferably a 20-mesh sieve), and a disintegrant is added to mix. Evenly, then add lubricant and mix well and press into tablets.
技术效果technical effect
本发明的盐型、晶型制备工艺简单，并且所述盐型及晶型稳定、受热、湿度、和光照影响小，便于制剂。本申请的晶型具有良好的药代动力学性质，适合作为药物使用。The salt form and crystal form of the present invention are simple in preparation process, and the salt form and crystal form are stable, less affected by heat, humidity and light, and are convenient for preparation. The crystal form of the present application has good pharmacokinetic properties and is suitable for use as a medicine.
本发明的制剂组成简单，制剂性能稳定，制备工艺简单，适合大规模生产研发。The preparation of the invention has simple composition, stable preparation performance and simple preparation process, and is suitable for large-scale production and research and development.
定义和说明Definition and Explanation
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered indeterminate or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art. Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
术语“药学上可接受的盐”是指式(I)化合物的盐，由式(I)化合物与相对无毒的酸或碱制备；基于式(I)化合物的性质，优选为与相对无毒的酸制备。可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与式(I)化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如草酸、乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的一些方案中，示例性提供了氢溴酸盐、甲磺酸盐、草酸盐、磷酸盐等式(I)化合物药学上可接受的盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of formula (I) prepared from a compound of formula (I) with a relatively nontoxic acid or base; based on the properties of the compound of formula (I), preferably a compound of formula (I) with a relatively nontoxic acid preparation. Acid addition salts can be obtained by contacting a compound of formula (I) with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, oxalic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, caprylic acid acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and similar acids; also includes amino acids (eg, arginine, etc.) , and salts of organic acids such as glucuronic acid. In some aspects of the present invention, pharmaceutically acceptable salts of compounds of formula (I) such as hydrobromide, mesylate, oxalate, phosphate, etc. are exemplified.
本发明中式(I)化合物、式(I)化合物药学上可接受的盐(包括但不限于氢溴酸盐、甲磺酸盐、草酸盐、磷酸盐)，可以为晶体形式、也可以为无定形；当为晶体形式时，可以为溶剂合物、也可以为非溶剂合物。本发明中水合物是溶剂合物的一种情形。Compounds of formula (I) and pharmaceutically acceptable salts of compounds of formula (I) in the present invention (including but not limited to hydrobromide, mesylate, oxalate, phosphate) can be in crystalline form or in Amorphous; when in crystalline form, it may be solvated or unsolvated. In the present invention, a hydrate is a case of a solvate.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of specific embodiments of the present invention are carried out in suitable solvents suitable for the chemical changes of the present invention and their required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes on the basis of the existing embodiments.
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。The present invention will be specifically described below through examples, which do not imply any limitation to the present invention.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and used without further purification.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：The present invention adopts the following abbreviations:
N2：氮气；RH：相对湿度；mL：毫升；L：升；min：分钟；℃：摄氏度；μm：微米；mm：毫 米；μL：微升；moL/L：摩尔每升；mg：毫克；s：秒；nm：纳米；MPa：兆帕；lux：勒克斯；μw/cm 2：微瓦每平方厘米；h：小时；Kg：千克；nM：纳摩尔，RRT：相对保留时间；rpm：转速。 N2: nitrogen gas; RH: relative humidity; mL: milliliter; L: liter; min: minute; s: seconds; nm: nanometers; MPa: megapascals; lux: lux; μw/cm 2 : microwatts per square centimeter; h: hours; Kg: kilograms; nM: nanomoles, RRT: relative retention time; rpm: rotational speed .
本发明化合物依据本领域常规命名原则命名，市售化合物采用供应商目录名称。The compounds of the present invention are named according to the conventional nomenclature in the art, and the commercially available compounds use the names of the suppliers' catalogues.
仪器及分析方法Instruments and Analytical Methods
1.本发明X-射线粉末衍射(X-ray powder diffractometer，XRPD)方法1. X-ray powder diffraction (X-ray powder diffractometer, XRPD) method of the present invention
仪器型号：PANalytical X′Pert 3型X-射线衍射仪 Instrument model: PANalytical X'Pert 3 X-ray diffractometer
测试方法：大约10mg样品用于XRPD检测。Test Method: Approximately 10 mg of sample was used for XRPD detection.
详细的XRPD参数如下：The detailed XRPD parameters are as follows:
X射线类型：Cu，KαX-ray type: Cu, Kα
Figure PCTCN2021105662-appb-000023
1.540598；
Figure PCTCN2021105662-appb-000024
1.544426
Figure PCTCN2021105662-appb-000023
1.540598;
Figure PCTCN2021105662-appb-000024
1.544426
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45仟伏特(kV)Voltage: 45 thousand volts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
发散狭缝：1/16度Divergence slit: 1/16 degree
扫描模式：连续Scan Mode: Continuous
扫描范围：自3.0至40.0度Scanning range: from 3.0 to 40.0 degrees
每步扫描时间：46.665秒Scan time per step: 46.665 seconds
步长：0.0263度Step size: 0.0263 degrees
2.本发明差热分析(Differential Scanning Calorimeter，DSC)方法2. Differential Thermal Analysis (Differential Scanning Calorimeter, DSC) method of the present invention
仪器型号：TA Instruments Discovery DSC 2500及Q200型差示扫描量热仪Instrument model: TA Instruments Discovery DSC 2500 and Q200 Differential Scanning Calorimeter
测试方法：取1～5毫克的样品放置于加盖的铝坩埚内，以10℃/min的升温速度在50mL/min干燥N2的保护下将样品从室温升至350℃，同时TA软件记录样品在升温过程中的热量变化。Test method: Take a sample of 1-5 mg and place it in an aluminum crucible with a lid. The sample is raised from room temperature to 350 °C at a heating rate of 10 °C/min under the protection of 50 mL/min of dry N2, and recorded by the TA software. The thermal change of the sample during the heating process.
3.本发明热重分析(Thermal Gravimetric Analyzer，TGA)方法3. Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
仪器型号：TA Instruments Q5000型及Discovery TGA 5500型热重分析仪Instrument model: TA Instruments Q5000 and Discovery TGA 5500 thermogravimetric analyzer
测试方法：取2～5毫克的样品放置于铂金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在50mL/min干燥N 2的保护下将样品从室温升至350℃，同时TA软件记录样品在升温过程中的重量变化。 Test Methods: 2-5 mg of sample was placed in a platinum crucible, by way of high-resolution detection of the segment, a heating rate of 10 ℃ / min at 50mL / min was dried under N 2 protection of the sample from room temperature to 350 °C, while the TA software records the weight change of the sample during the heating process.
4.本发明动态蒸汽吸附分析(Dynamic Vapor Sorption，DVS)方法4. Dynamic Vapor Sorption (DVS) method of the present invention
仪器型号：SMS(Surface Measurement Systems)公司的DVS Intrinsic仪器Instrument model: DVS Intrinsic instrument of SMS (Surface Measurement Systems) company
DVS测试参数：DVS test parameters:
温度：25℃Temperature: 25℃
样品量：10-30毫克Sample volume: 10-30 mg
保护气体及流量：N 2，200mL/min Shielding gas and flow rate: N 2 , 200mL/min
dm/dt：0.002％/mindm/dt: 0.002%/min
最小dm/dt平衡时间：10minMinimum dm/dt equilibration time: 10min
最大平衡时间：180minMaximum balance time: 180min
RH范围：0％RH-95％RH-0％RHRH range: 0%RH-95%RH-0%RH
RH梯度：10％(90％RH-0％RH-90％RH)，5％(95％RH-90％RH和90％RH-95％RH)RH gradient: 10% (90%RH-0%RH-90%RH), 5% (95%RH-90%RH and 90%RH-95%RH)
5.本发明溴离子检测分析方法5. Bromide ion detection and analysis method of the present invention
测试程序：按照电位滴定法，用硝酸银滴定液(0.1moL/L)滴定供试品溶液和空白溶液，每1mL硝酸银滴定液(0.1moL/L)相当于7.990mg的溴(Br)Test procedure: according to the potentiometric titration method, titrate the test solution and blank solution with silver nitrate titration solution (0.1moL/L), each 1mL silver nitrate titration solution (0.1moL/L) is equivalent to 7.990mg of bromine (Br)
计算方法：Calculation method:
Figure PCTCN2021105662-appb-000025
Figure PCTCN2021105662-appb-000025
其中式中：where in the formula:
F：滴定度，每1mL硝酸银滴定液(0.1mol/L)相当于7.990mg的溴(Br)；F: titer, each 1 mL of silver nitrate titration solution (0.1 mol/L) is equivalent to 7.990 mg of bromine (Br);
W SPL：供试品溶液的称样量(g)； W SPL : the weighing sample amount of the test solution (g);
V SPL：供试品溶液消耗硝酸银滴定液(0.1mol/L)的体积(mL) V SPL : the volume (mL) of the silver nitrate titration solution (0.1mol/L) consumed by the test solution
V 0：空白溶液消耗硝酸银滴定液(0.1mol/L)的体积(mL) V 0 : the volume (mL) of the silver nitrate titration solution (0.1 mol/L) consumed by the blank solution
6.本发明水分含量检测分析方法6. Moisture content detection and analysis method of the present invention
仪器型号：METTLER TOLEDO V30水分测试仪Instrument model: METTLER TOLEDO V30 moisture tester
测试方法：迅速加入已经精确称量的样品(样品中含水量约为5-25mg)，搅拌时间为10s，卡尔费休试剂滴定至终点，得到样品的水分含量Test method: Quickly add the accurately weighed sample (the water content in the sample is about 5-25mg), the stirring time is 10s, the Karl Fischer reagent is titrated to the end point, and the moisture content of the sample is obtained.
7.本发明稳定性实验有关物质及含量分析方法7. Stability test related substances and content analysis method of the present invention
表8Table 8
Figure PCTCN2021105662-appb-000026
Figure PCTCN2021105662-appb-000026
Figure PCTCN2021105662-appb-000027
Figure PCTCN2021105662-appb-000027
8.本发明制剂过程所用主要仪器8. Main instruments used in the preparation process of the present invention
主要仪器如表9所示：The main instruments are shown in Table 9:
表9Table 9
设备名称device name 仪器型号Instrument model
湿法制粒混合机Wet granulation mixer G10G10
流化制粒包衣机Fluidized granulation coating machine Mini-XYTMini-XYT
万向混合机Universal mixer MD30MD30
单冲压片机Single punch tablet machine DP30ADP30A
高效包衣机Efficient coater Labcoating IIILabcoating III
9.片剂含量、含量均匀的测试：9. Test for tablet content and content uniformity:
9.1设备型号：9.1 Device model:
高效液相检测仪(岛津LC-20A配置PDA/UV检测器或等同)High performance liquid detector (Shimadzu LC-20A equipped with PDA/UV detector or equivalent)
色谱柱：Agilent Eclipse Plus C18(150*4.6mm，3.5μm)P.N.：959963-902或等同Chromatographic column: Agilent Eclipse Plus C18 (150*4.6mm, 3.5μm) P.N.: 959963-902 or equivalent
9.2色谱条件9.2 Chromatographic conditions
流动相A：0.05％的三氟乙酸的水溶液；Mobile phase A: 0.05% trifluoroacetic acid in water;
流动相B：100％的乙腈；Mobile phase B: 100% acetonitrile;
柱温：40℃；Column temperature: 40℃;
流速：1.0mL/min；Flow rate: 1.0mL/min;
检测波长：220nm；Detection wavelength: 220nm;
样品溶液浓度：0.1mg/mL，Sample solution concentration: 0.1mg/mL,
进样体积：5μL；Injection volume: 5 μL;
梯度程序如下表10所示：The gradient procedure is shown in Table 10 below:
表10Table 10
时间(min)time (min) 流动相A(％)Mobile phase A (%) 流动相B(％)Mobile phase B (%)
0.000.00 9595 55
2.002.00 9595 55
22.0022.00 55 9595
27.0027.00 55 9595
28.0028.00 9595 55
40.0040.00 9595 55
10.供试品溶液的制备10. Preparation of the test solution
10.1含量供试品溶液的制备：10.1 Content Preparation of the test solution:
按下表随机选取片子，准确称取所选片子的重量和，使用玛瑙研钵将片子研磨至细粉，按下表称取细粉于相应的棕色容量瓶中，加约量瓶体积的80％稀释剂，超声30min，放至室温，加稀释剂定容，取适量以8000rpm离心10min，取上清液。平行制备2份。Randomly select the tablets according to the following table, accurately weigh the weight and sum of the selected tablets, use an agate mortar to grind the tablets to fine powder, weigh the fine powder into the corresponding brown volumetric flask according to the table below, and add about 80% of the volume of the measuring bottle. % diluent, ultrasonicated for 30min, put it to room temperature, add diluent to volume, take an appropriate amount and centrifuge at 8000rpm for 10min, and take the supernatant. Prepare 2 copies in parallel.
表11Table 11
Figure PCTCN2021105662-appb-000028
Figure PCTCN2021105662-appb-000028
注：样品溶液在室温条件下可稳定78.0hNote: The sample solution is stable for 78.0h at room temperature
10.2含量均匀度供试品溶液的制备：10.2 Preparation of test solution for content uniformity:
取本品1片药品(规格：10mg)于100mL棕色量瓶中，加适量稀释剂崩解后，加约80％棕色量瓶体积的稀释剂，超声30min，放至室温，加稀释剂定容，取适量以8000rpm离心10分钟，取上清液。平行制备10份。Take 1 tablet of this product (specification: 10mg) in a 100mL brown volumetric bottle, add an appropriate amount of diluent to disintegrate, add about 80% of the volume of the brown volumetric bottle, ultrasonically for 30 minutes, put it to room temperature, add diluent to volume , take an appropriate amount and centrifuge at 8000rpm for 10 minutes, and take the supernatant. 10 copies were prepared in parallel.
取本品1片药品(规格：50mg)于500mL棕色量瓶中，加适量稀释剂崩解后，加约80％棕色量瓶体积的稀释剂，超声30min，放至室温，加稀释剂定容，取适量以8000rpm离心10分钟，取上清液。平行制备10份。Take 1 tablet of this product (specification: 50mg) in a 500mL brown volumetric flask, add an appropriate amount of diluent to disintegrate, add about 80% of the volume of the brown volumetric flask, ultrasonically for 30min, put it to room temperature, add diluent to make up the volume , take an appropriate amount and centrifuge at 8000rpm for 10 minutes, take the supernatant. 10 copies were prepared in parallel.
表12Table 12
Figure PCTCN2021105662-appb-000029
Figure PCTCN2021105662-appb-000029
注：样品溶液在室温条件下可稳定78.0h。Note: The sample solution is stable for 78.0h at room temperature.
10.3对照品溶液的制备10.3 Preparation of reference solution
称取24mg式(II)化合物晶型B的对照品于200mL棕色量瓶中，加稀释剂适量，超声5min左右，溶解后冷至室温，定容，摇匀。平行配制2份，标记为STD#1、STD#2。Weigh 24 mg of the reference substance of the compound crystal form B of the formula (II) into a 200 mL brown volumetric flask, add an appropriate amount of diluent, ultrasonicate for about 5 minutes, dissolve and cool to room temperature, dilute to volume, and shake well. Two copies were prepared in parallel, labeled STD#1, STD#2.
注：样品溶液在室温条件下可稳定98.0h。Note: The sample solution is stable for 98.0h at room temperature.
11.片剂有关物质含量的检测试验方案：11. Test plan for testing the content of related substances in tablets:
11.1设备型号：11.1 Device model:
高效液相检测仪(岛津LC-20A配置PDA/UV检测器或等同)High performance liquid detector (Shimadzu LC-20A equipped with PDA/UV detector or equivalent)
色谱柱：Agilent Eclipse Plus C18(150*4.6mm，3.5μm)P.N.：959963-902或等同Chromatographic column: Agilent Eclipse Plus C18 (150*4.6mm, 3.5μm) P.N.: 959963-902 or equivalent
11.2色谱条件11.2 Chromatographic conditions
流动相A：0.05％的三氟乙酸的水溶液；Mobile phase A: 0.05% trifluoroacetic acid in water;
流动相B：100％的乙腈；Mobile phase B: 100% acetonitrile;
柱温：40℃；Column temperature: 40℃;
流速：1.0mL/min；Flow rate: 1.0mL/min;
检测波长：220nm；Detection wavelength: 220nm;
样品溶液浓度：0.3mg/mL，Sample solution concentration: 0.3mg/mL,
进样体积：5μL；Injection volume: 5 μL;
梯度程序如下表13所示：The gradient program is shown in Table 13 below:
表13Table 13
时间(min)time (min) 流动相A(％)Mobile phase A (%) 流动相B(％)Mobile phase B (%)
0.000.00 9595 55
2.002.00 9595 55
22.0022.00 55 9595
27.0027.00 55 9595
28.0028.00 9595 55
40.0040.00 9595 55
11.3供试品溶液的制备11.3 Preparation of the test solution
11.3.1含量供试品溶液的制备：11.3.1 Contents Preparation of test solution:
按下表随机选取片子，准确称取所选片子的重量和，使用玛瑙研钵将片子研磨至细粉，按下表称取细粉于相应的棕色容量瓶中，加约量瓶体积的80％稀释剂，超声30min，放至室温，加稀释剂定容，取适量以8000rpm离心10分钟，取上清液。平行制备2份。Randomly select the tablets according to the following table, accurately weigh the weight and sum of the selected tablets, use an agate mortar to grind the tablets to fine powder, weigh the fine powder into the corresponding brown volumetric flask according to the table below, and add about 80% of the volume of the measuring bottle. % diluent, ultrasonicated for 30min, put it to room temperature, add diluent to volume, take an appropriate amount and centrifuge at 8000rpm for 10 minutes, and take the supernatant. Prepare 2 copies in parallel.
表14Table 14
Figure PCTCN2021105662-appb-000030
Figure PCTCN2021105662-appb-000030
注：样品溶液在室温条件下可稳定205.0h。Note: The sample solution is stable for 205.0h at room temperature.
11.4对照品溶液的制备11.4 Preparation of reference solution
11.4.1对照品储备液制备：11.4.1 Preparation of reference stock solution:
称取36mg式(II)化合物晶型B的对照品于100mL棕色量瓶中，加稀释剂适量，超声5min左右溶解后，放置至室温，定容，摇匀。Weigh 36 mg of the reference substance of the compound crystal form B of the formula (II) into a 100 mL brown volumetric flask, add an appropriate amount of diluent, dissolve it by ultrasonic for about 5 minutes, place it at room temperature, make up to volume, and shake well.
11.4.21％对照品溶液制备：11.4. Preparation of 21% reference solution:
用移液管移取1mL对照品储备溶液于100mL棕色量瓶中，加稀释剂至刻度，摇匀。Pipette 1 mL of the reference substance stock solution into a 100 mL brown volumetric flask, add diluent to the mark, and shake well.
注：1％对照品溶液在室温下可稳定205.0h。Note: 1% reference solution can be stable for 205.0h at room temperature.
12.片剂溶出含量的检测试验方案：12. Test plan for the detection of tablet dissolution content:
12.1设备型号：12.1 Device model:
高效液相检测仪(Agilent 1260配置DAD检测器或等同)HPLC detector (Agilent 1260 with DAD detector or equivalent)
色谱柱：Agilent Poroshell 120EC-C18(3.0*50mm，2.7μm)P.N.：699975-302或等同Chromatographic column: Agilent Poroshell 120EC-C18 (3.0*50mm, 2.7μm) P.N.: 699975-302 or equivalent
12.2色谱条件12.2 Chromatographic conditions
流动相A：0.05％的三氟乙酸的水溶液；Mobile phase A: 0.05% trifluoroacetic acid in water;
流动相B：100％的乙腈；Mobile phase B: 100% acetonitrile;
柱温：40℃；Column temperature: 40℃;
流速：0.8mL/min；Flow rate: 0.8mL/min;
检测波长：220nm；Detection wavelength: 220nm;
样品溶液浓度：0.3mg/mL，Sample solution concentration: 0.3mg/mL,
进样体积：5μL；Injection volume: 5 μL;
梯度程序如下表15所示：The gradient program is shown in Table 15 below:
表15Table 15
时间(min)time (min) 流动相A(％)Mobile phase A (%) 流动相B(％)Mobile phase B (%)
0.000.00 9090 1010
4.04.0 3030 7070
4.14.1 9090 1010
7.07.0 9090 1010
12.3对照品溶液的制备12.3 Preparation of reference solution
称取约24mg的式(II)化合物晶型B的对照品于200mL棕色量瓶中，精密称定，加适量稀释剂，超声5分钟左右溶解后，放至室温，定容，摇匀。平行配制2份。分别移取5mL上述溶液分别于25mL棕色量瓶中，加溶媒定容。Weigh about 24 mg of the reference substance of the compound crystal form B of the formula (II) into a 200 mL brown volumetric flask, accurately weigh, add an appropriate amount of diluent, dissolve by ultrasonic for about 5 minutes, put it at room temperature, make up to volume, and shake well. Prepare 2 copies in parallel. Pipette 5mL of the above solutions into 25mL brown volumetric flasks, add solvent to volume.
注：10mg规格对照品溶液在室温条件下可稳定109.0h，10mg规格样品溶液在室温条件下可稳定108.0h；50mg规格对照品溶液在室温条件下可稳定108.0h，50mg规格样品溶液在室温条件下可稳定108.0h。Note: 10mg specification reference solution can be stable for 109.0h at room temperature, 10mg specification sample solution is stable at room temperature for 108.0h; 50mg specification reference solution can be stable at room temperature for 108.0h, 50mg specification sample solution is stable at room temperature It can be stable for 108.0h.
12.4溶出程序12.4 Dissolution Procedure
(1)按中国药典所述的开始。(1) Begin as described in the Chinese Pharmacopoeia.
(2)溶媒温度平衡在37±0.5℃。(2) The temperature of the solvent is equilibrated at 37±0.5°C.
(3)随机取各批次片剂6片，称取每片片重，分别投放到6个溶出杯内(制剂中控实验每批次取3片)。(3) Randomly take 6 tablets from each batch, weigh the weight of each tablet, and put them into 6 dissolution cups respectively (3 tablets from each batch in the preparation control experiment).
(4)在每个取样时间点，抽取5mL溶液。(4) At each sampling time point, 5 mL of solution was withdrawn.
(5)立即通过合格的过滤器过滤一部分样品溶液，弃去4mL初滤液，转移最后的滤液到棕HPLC进样小瓶中。盖紧进样小瓶盖并放置到HPLC系统中以备进样。(5) Immediately filter a portion of the sample solution through a qualified filter, discard 4 mL of the initial filtrate, and transfer the final filtrate to a brown HPLC injection vial. Cap the injection vial tightly and place in the HPLC system ready for injection.
附图说明Description of drawings
图1为式(I)化合物晶型A的XRPD谱图。Fig. 1 is the XRPD spectrum of the compound of formula (I) form A.
图2为式(I)化合物晶型A的DSC谱图。Figure 2 is the DSC spectrum of the crystal form A of the compound of formula (I).
图3为式(I)化合物晶型A的TGA谱图。Figure 3 is a TGA spectrum of the compound of formula (I) in Form A.
图4为式(I)化合物晶型A的DVS谱图。Fig. 4 is the DVS spectrum of the crystal form A of the compound of formula (I).
图5为式(II)化合物晶型B的XRPD谱图。Fig. 5 is the XRPD spectrum of the compound of formula (II) form B.
图6为式(II)化合物晶型B的DSC谱图。Figure 6 is the DSC spectrum of the compound of formula (II) form B.
图7为式(II)化合物晶型B的TGA谱图。Figure 7 is a TGA spectrum of the compound of formula (II) in Form B.
图8为式(II)化合物晶型B的DVS谱图。Figure 8 is the DVS spectrum of the compound of formula (II) in Form B.
图9为式(III)化合物晶型C的XRPD谱图。Fig. 9 is the XRPD spectrum of the compound of formula (III) form C.
图10为式(III)化合物晶型C的DSC谱图。Fig. 10 is the DSC spectrum of the crystal form C of the compound of formula (III).
图11为式(III)化合物晶型C的TGA谱图。Figure 11 is a TGA spectrum of the compound of formula (III) in Form C.
图12为式(IV)化合物晶型D的XRPD谱图。Figure 12 is the XRPD spectrum of the compound of formula (IV), Form D.
图13为式(IV)化合物的晶型D的DSC谱图。Figure 13 is a DSC spectrum of Form D of the compound of formula (IV).
图14为式(IV)化合物晶型D的TGA谱图。Figure 14 is the TGA spectrum of the compound of formula (IV) in Form D.
图15为式(IV)化合物晶型D的DVS谱图。Figure 15 is the DVS spectrum of the compound of formula (IV), Form D.
图16为式(V)化合物晶型E的XRPD谱图。Figure 16 is the XRPD spectrum of the compound of formula (V), Form E.
图17为式(V)化合物的晶型E的DSC谱图。Figure 17 is a DSC spectrum of Form E of the compound of formula (V).
图18为式(V)化合物晶型E的TGA谱图。Figure 18 is a TGA spectrum of the compound of formula (V) in Form E.
图19为式(V)化合物晶型F的XRPD谱图。Figure 19 is the XRPD spectrum of the compound of formula (V), Form F.
图20为式(V)化合物的晶型F的DSC谱图。Figure 20 is a DSC spectrum of Form F of the compound of formula (V).
图21为式(V)化合物晶型F的TGA谱图。Figure 21 is the TGA spectrum of the compound of formula (V), Form F.
图22为式(VI)化合物晶型G的XRPD谱图。Figure 22 is the XRPD spectrum of the compound of formula (VI), Form G.
图23为式(VI)化合物的晶型G的DSC谱图。Figure 23 is a DSC spectrum of Form G of the compound of formula (VI).
图24为式(VI)化合物晶型G的TGA谱图。Figure 24 is a TGA spectrum of the compound of formula (VI), Form G.
图25式(II)化合物晶型B在高压下的晶型稳定性研究对比图。Figure 25 is a comparative diagram of the crystal form stability study of the compound of formula (II) form B under high pressure.
图26式(II)化合物晶型B在不同溶剂中的晶型稳定性研究对比图。Figure 26 is a comparative diagram of the crystal form stability study of the compound of formula (II) form B in different solvents.
具体实施方式detailed description
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。In order to better understand the content of the present invention, further description will be given below in conjunction with specific embodiments, but the specific embodiments do not limit the content of the present invention.
实施例1：式(I)化合物的制备Example 1: Preparation of compounds of formula (I)
Figure PCTCN2021105662-appb-000031
Figure PCTCN2021105662-appb-000031
Figure PCTCN2021105662-appb-000032
Figure PCTCN2021105662-appb-000032
步骤A：将化合物1-1(10克，99.88毫摩尔，1当量)溶于甲醇(150毫升)中，加入肼基甲酸叔丁酯(13.20克，99.88毫摩尔，1当量)，25摄氏度反应10小时。浓缩得到化合物1-2。Step A: Compound 1-1 (10 g, 99.88 mmol, 1 equiv) was dissolved in methanol (150 mL), tert-butylcarbazate (13.20 g, 99.88 mmol, 1 equiv) was added, and the reaction was carried out at 25 degrees Celsius 10 hours. Concentration gave compound 1-2.
步骤B：将化合物1-2(8克，37.34毫摩尔，1当量)溶于醋酸(50毫升)和水(50毫升)的混合溶剂中，25摄氏度搅拌1小时，分批加入氰基硼氢化钠(2.58克，41.07毫摩尔，1.1当量)，20摄氏度反应2小时。用1摩尔每升氢氧化钠水溶液调pH至7，二氯甲烷(100毫升×3)萃取，饱和碳酸氢钠水溶液(100毫升×2)洗，无水硫酸钠干燥，过滤，浓缩得到化合物1-3。Step B: Compound 1-2 (8 g, 37.34 mmol, 1 equiv) was dissolved in a mixed solvent of acetic acid (50 mL) and water (50 mL), stirred at 25°C for 1 hour, and added cyanoborohydride in batches Sodium (2.58 g, 41.07 mmol, 1.1 equiv) was reacted at 20 degrees Celsius for 2 hours. Adjust pH to 7 with 1 mol/L aqueous sodium hydroxide solution, extract with dichloromethane (100 mL×3), wash with saturated aqueous sodium bicarbonate solution (100 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound 1 -3.
步骤C：将化合物1-3(7.2克，33.29毫摩尔，1当量)溶于甲醇(10毫升)，加入盐酸甲醇(4摩尔每升，40毫升)，20摄氏度反应4小时。浓缩得到化合物1-4。Step C: Compound 1-3 (7.2 g, 33.29 mmol, 1 equiv) was dissolved in methanol (10 mL), methanol hydrochloric acid (4 mol/L, 40 mL) was added, and the reaction was carried out at 20 degrees Celsius for 4 hours. Concentration gave compound 1-4.
步骤D：将化合物1-4(4.1克，35.30毫摩尔，1当量，2盐酸盐)和乙酰乙酸乙酯(9.19克，70.59毫摩尔，2当量)溶于醋酸(40毫升)中，氮气气氛下90摄氏度反应10小时。冷却，浓缩，制备级高效液相色谱(三氟乙酸条件)提纯得到化合物1-5。MS(ESI)m/z：183.1[M+H +]。 Step D: Compound 1-4 (4.1 g, 35.30 mmol, 1 equiv, 2 HCl) and ethyl acetoacetate (9.19 g, 70.59 mmol, 2 equiv) were dissolved in acetic acid (40 mL) under nitrogen The reaction was carried out at 90 degrees Celsius for 10 hours in an atmosphere. Cool, concentrate, and purify by preparative high performance liquid chromatography (trifluoroacetic acid condition) to obtain compound 1-5. MS (ESI) m/z: 183.1 [M+H + ].
步骤E：将化合物1-5(1.1克，6.04毫摩尔，1当量)和化合物1-6(873.44毫克，6.64毫摩尔，1.1当量)溶解于N，N-二甲基甲酰胺(20毫升)中，加入碳酸钾(2.5克，18.11毫摩尔，3当量)，90摄氏度反应12小时。加水(50毫升)稀释，乙酸乙酯(100毫升×3)萃取。合并有机相，饱和食盐水(100毫升×3)洗，无水硫酸钠干燥，过滤，浓缩，柱分离纯化得到化合物1-7。MS(ESI)m/z：294.1[M+H+]。Step E: Compound 1-5 (1.1 g, 6.04 mmol, 1 equiv) and compound 1-6 (873.44 mg, 6.64 mmol, 1.1 equiv) were dissolved in N,N-dimethylformamide (20 mL) In the solution, potassium carbonate (2.5 g, 18.11 mmol, 3 equiv.) was added, and the reaction was carried out at 90 degrees Celsius for 12 hours. Add water (50 mL) to dilute, and extract with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column separation to obtain compound 1-7. MS (ESI) m/z: 294.1 [M+H+].
步骤F：将化合物1-7(300毫克，1.02毫摩尔，1当量)，1-8(144.78毫克，1.23毫摩尔，1.2当量)，4，5-双(二苯基膦)-9，9-二甲基氧杂蒽(118.19毫克，204.26微摩尔，0.2当量)，碳酸铯(998.26毫克，3.06毫摩尔，3当量)和三(二亚苄基丙酮)二钯(187.04毫克，204.26微摩，0.2当量)溶于二氧六环(10毫升)中，氮气气氛下100摄氏度反应12小时。加水(20毫升)稀释，乙酸乙酯(20毫升×3)萃取。合并有机相，饱和食盐水(20毫升×3)洗，无水硫酸钠干燥，过滤，浓缩，柱分离纯化得到化合物1-9。MS(ESI)m/z：376.1[M+H +]。 Step F: Compound 1-7 (300 mg, 1.02 mmol, 1 equiv), 1-8 (144.78 mg, 1.23 mmol, 1.2 equiv), 4,5-bis(diphenylphosphine)-9,9 - Dimethylxanthene (118.19 mg, 204.26 μmol, 0.2 equiv), cesium carbonate (998.26 mg, 3.06 mmol, 3 equiv) and tris(dibenzylideneacetone)dipalladium (187.04 mg, 204.26 μmol , 0.2 equiv.) was dissolved in dioxane (10 mL) and reacted at 100 degrees Celsius for 12 hours under nitrogen atmosphere. Add water (20 mL) to dilute, and extract with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column separation to obtain compound 1-9. MS (ESI) m/z: 376.1 [M+H + ].
步骤G：将化合物1-9(270毫克，718.19微摩尔，1当量)，氢氧化钠(719.19微升，2摩尔每升，2当量)和二甲基亚砜(112.39毫克，1.44毫摩尔，2当量)溶于乙醇(5毫升)。室温下将双氧水(163.09毫克，1.44毫摩尔，138.21微升，纯度30％，2当量)缓慢加入反应液，25摄氏度反应2小时。加水(10毫升)稀释，乙酸乙酯(10毫升×3)萃取。合并有机相，饱和食盐水(10毫升×3)洗，无水硫酸钠干 燥，过滤，浓缩，制备级高效液相色谱(甲酸条件)提纯得到式(I)化合物。MS(ESI)m/z：394.2[M+H +]。 Step G: Compound 1-9 (270 mg, 718.19 μmol, 1 equiv), sodium hydroxide (719.19 μl, 2 mol per L, 2 equiv) and dimethyl sulfoxide (112.39 mg, 1.44 mmol, 2 equiv) was dissolved in ethanol (5 mL). Hydrogen peroxide (163.09 mg, 1.44 mmol, 138.21 μl, purity 30%, 2 equivalents) was slowly added to the reaction solution at room temperature, and the reaction was carried out at 25 degrees Celsius for 2 hours. Add water (10 mL) to dilute, and extract with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative high performance liquid chromatography (formic acid condition) to obtain the compound of formula (I). MS (ESI) m/z: 394.2 [M+H + ].
1H NMR(400MHz，DMSO-d 6)δ＝9.26(s，1H)，8.13(d，J＝6.0Hz，1H)，8.04(t，J＝2.0Hz，1H)，7.89-7.79(m，2H)，7.39-7.35(m，1H)，7.33-7.24(m，2H)，6.57(dd，J＝2.4，6.0Hz，1H)，6.42(d，J＝2.4Hz，1H)，5.84(s，1H)，4.20(tt，J＝4.0，11.6Hz，1H)，3.90(br dd，J＝4.0，11.6Hz，2H)，3.35(br s，2H)，2.17(s，3H)，1.99(dq，J＝4.4，12.3Hz，2H)，1.76-1.67(m，2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ=9.26 (s, 1H), 8.13 (d, J=6.0 Hz, 1H), 8.04 (t, J=2.0 Hz, 1H), 7.89-7.79 (m, 2H), 7.39-7.35 (m, 1H), 7.33-7.24 (m, 2H), 6.57 (dd, J=2.4, 6.0Hz, 1H), 6.42 (d, J=2.4Hz, 1H), 5.84 (s , 1H), 4.20(tt, J=4.0, 11.6Hz, 1H), 3.90(br dd, J=4.0, 11.6Hz, 2H), 3.35(br s, 2H), 2.17(s, 3H), 1.99( dq, J=4.4, 12.3 Hz, 2H), 1.76-1.67 (m, 2H).
实施例2：式(I)化合物晶型A的制备Example 2: Preparation of compound crystal form A of formula (I)
称取式(I)化合物(500.65毫克)置于40毫升透明玻璃瓶中，加入7毫升乙醇，加热回流使完全溶解，关闭加热自然降温到25摄氏度后继续在25摄氏度下搅拌24小时，过滤，滤饼减压干燥(45摄氏度，≤-0.1MPa)得到式(I)化合物的晶型A，其XRPD、DSC、TGA和DVS谱图如图1-4所示。Weigh the compound of formula (I) (500.65 mg) and place it in 40 milliliters of transparent glass bottles, add 7 milliliters of ethanol, heat under reflux to dissolve completely, turn off the heating and naturally cool down to 25 degrees Celsius and continue to stir at 25 degrees Celsius for 24 hours, filter, The filter cake is dried under reduced pressure (45 degrees Celsius, ≤-0.1MPa) to obtain the crystal form A of the compound of formula (I), whose XRPD, DSC, TGA and DVS spectra are shown in Figures 1-4.
实施例3：式(II)化合物晶型B的制备Example 3: Preparation of compound crystal form B of formula (II)
依次将异丙醇(1154毫升)和式(I)化合物(57.7克)加入到3升的三口瓶中，开启加热至內温为80摄氏度，加入异丙醇(230.8毫升)，体系变为澄清，再加入氢溴酸水溶液(29.67克)，在回流状态下搅拌30分钟，关闭加热使体系自然降温到25摄氏度后继续在25摄氏度下搅拌16小时，过滤，滤饼用异丙醇淋洗两次(115.4毫升×2)，滤饼真空干燥(45摄氏度，≤-0.1MPa)得到式(II)化合物的晶型B，其溴离子含量检测值是16.1％，水分含量检测值是3.77％，其XRPD、DSC、TGA和DVS谱图如图5-8所示。 1H NMR(400MHz，DMSO-d 6)δppm 10.34(brs，1H)，8.09(d，J＝6.8Hz，1H)，8.01(brs，1H)，7.91(t，J＝1.6Hz，1H)，7.73(d，J＝7.6Hz，1H)，7.58(dd，J＝8.0Hz，J＝1.20Hz，1H)，7.51(t，J＝8.0Hz，1H)，7.46(brs，1H)，6.85(dd，J＝6.8Hz，J＝2.4Hz，1H)，6.64(d，J＝2.4Hz，1H)，5.96(s，1H)，4.28-4.20(m，1H)，3.91(dd，J＝11.2Hz，J＝3.6Hz，2H)，3.42-3.36(m，2H)，2.17(s，3H)，2.03-1.92(m，2H)，1.72(dd，J＝12.4，J＝2.4Hz，2H)。 Isopropanol (1154 milliliters) and formula (I) compound (57.7 grams) were added successively in the there-necked flask of 3 liters, the opening was heated to 80 degrees Celsius, and Isopropanol (230.8 milliliters) was added, and the system became clear , then add the aqueous solution of hydrobromic acid (29.67 g), stir for 30 minutes under reflux, turn off the heating and let the system naturally cool down to 25 degrees Celsius and continue to stir at 25 degrees Celsius for 16 hours, filter, and the filter cake is rinsed with isopropanol for two (115.4 ml × 2), the filter cake was vacuum-dried (45 degrees Celsius, ≤-0.1MPa) to obtain the crystal form B of the compound of formula (II), the detected value of its bromide ion content was 16.1%, and the detected value of moisture content was 3.77%, Its XRPD, DSC, TGA and DVS spectra are shown in Figure 5-8. 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.34 (brs, 1H), 8.09 (d, J=6.8Hz, 1H), 8.01 (brs, 1H), 7.91 (t, J=1.6Hz, 1H), 7.73(d, J=7.6Hz, 1H), 7.58(dd, J=8.0Hz, J=1.20Hz, 1H), 7.51(t, J=8.0Hz, 1H), 7.46(brs, 1H), 6.85( dd, J=6.8Hz, J=2.4Hz, 1H), 6.64 (d, J=2.4Hz, 1H), 5.96 (s, 1H), 4.28-4.20 (m, 1H), 3.91 (dd, J=11.2 Hz, J=3.6Hz, 2H), 3.42-3.36 (m, 2H), 2.17 (s, 3H), 2.03-1.92 (m, 2H), 1.72 (dd, J=12.4, J=2.4Hz, 2H) .
实施例4：式(III)化合物晶型C的制备Example 4: Preparation of compound crystal form C of formula (III)
称取式(II)化合物晶型B样品(50.18毫克)加入4毫升透明玻璃瓶中，再加入甲苯(0.5毫升)，加热到105摄氏度搅拌16小时，自然降温到25摄氏度后过滤，滤饼减压旋干(45摄氏度，≤-0.1MPa)得到式(III)化合物的晶型C，其XRPD、DSC和TGA谱图如图9-11所示。 1H NMR(400MHz，DMSO-d 6)δppm 10.08(brs，1H)，8.08(d，J＝6.4Hz，1H)，7.97(brs，1H)，7.93(s，1H)，7.64(t，J＝8.4Hz，2H)，7.47(t，J＝8.0Hz，1H)，7.43(brs，1H)，6.80(dd，J＝6.4Hz，J＝1.6Hz，1H)，6.57(d，J＝2.0Hz，1H)，5.94(s，1H)，4.27-4.19(m，1H)，3.91(dd，J＝11.2Hz，J＝3.6Hz，2H)，3.39(t，J＝12.0Hz，2H)，2.17(s，3H)，2.03-1.93(m，2H)，1.72(dd，J＝12.4，J＝2.0Hz，2H)。 Weigh a sample of the compound crystal form B of formula (II) (50.18 mg) into a 4 ml transparent glass bottle, then add toluene (0.5 ml), heat to 105 degrees Celsius and stir for 16 hours, naturally cool to 25 degrees Celsius, filter, filter cake Press and spin dry (45 degrees Celsius, ≤-0.1MPa) to obtain the crystal form C of the compound of formula (III), whose XRPD, DSC and TGA spectra are shown in Figures 9-11. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 10.08 (brs, 1H), 8.08 (d, J=6.4 Hz, 1H), 7.97 (brs, 1H), 7.93 (s, 1H), 7.64 (t, J =8.4Hz, 2H), 7.47(t, J=8.0Hz, 1H), 7.43(brs, 1H), 6.80(dd, J=6.4Hz, J=1.6Hz, 1H), 6.57(d, J=2.0 Hz, 1H), 5.94(s, 1H), 4.27-4.19(m, 1H), 3.91(dd, J=11.2Hz, J=3.6Hz, 2H), 3.39(t, J=12.0Hz, 2H), 2.17 (s, 3H), 2.03-1.93 (m, 2H), 1.72 (dd, J=12.4, J=2.0 Hz, 2H).
实施例5：式(IV)化合物晶型D的制备Example 5: Preparation of compound crystal form D of formula (IV)
称取式(I)化合物(约100.00毫克)加入8毫升玻璃瓶中，再加入丙酮(4.5毫升)，加热到60摄氏度使溶解，再加入甲磺酸(1.05当量，19.0微升)，60摄氏度搅拌1小时后关闭加热自然降温到室温，继 续在室温下搅拌12小时，过滤，滤饼减压干燥(50摄氏度)得到式(IV)化合物的晶型D，其XRPD、DSC、TGA和DVS谱图如图12-15所示。 1H NMR(400MHz，DMSO-d 6)δppm 9.99(brs，1H)，8.08(d，J＝6.4Hz，1H)，7.96(brs，1H)，7.94(s，1H)，7.64(t，J＝10.0Hz，2H)，7.45(t，J＝7.6Hz，1H)，7.42(brs，1H)，6.77(dd，J＝6.4Hz，J＝2.0Hz，1H)，6.54(d，J＝2.4Hz，1H)，5.93(s，1H)，4.27-4.19(m，1H)，3.91(dd，J＝11.6Hz，J＝4.0Hz，2H)，3.39(t，J＝12.0Hz，2H)，2.35(s，3H)，2.18(s，3H)，2.03-1.93(m，2H)，1.72(dd，J＝12.4，J＝2.4Hz，2H)。 Weigh the compound of formula (I) (about 100.00 mg) into an 8 ml glass bottle, then add acetone (4.5 ml), heat to 60 degrees Celsius to dissolve, then add methanesulfonic acid (1.05 equivalents, 19.0 μl), 60 degrees Celsius After stirring for 1 hour, turn off the heating and naturally cool to room temperature, continue to stir at room temperature for 12 hours, filter, and dry the filter cake under reduced pressure (50 degrees Celsius) to obtain the crystal form D of the compound of formula (IV), its XRPD, DSC, TGA and DVS spectra Figures are shown in Figure 12-15. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 9.99 (brs, 1H), 8.08 (d, J=6.4 Hz, 1H), 7.96 (brs, 1H), 7.94 (s, 1H), 7.64 (t, J =10.0Hz, 2H), 7.45(t, J=7.6Hz, 1H), 7.42(brs, 1H), 6.77(dd, J=6.4Hz, J=2.0Hz, 1H), 6.54(d, J=2.4 Hz, 1H), 5.93(s, 1H), 4.27-4.19(m, 1H), 3.91(dd, J=11.6Hz, J=4.0Hz, 2H), 3.39(t, J=12.0Hz, 2H), 2.35 (s, 3H), 2.18 (s, 3H), 2.03-1.93 (m, 2H), 1.72 (dd, J=12.4, J=2.4 Hz, 2H).
实施例6：式(V)化合物晶型E的制备Example 6: Preparation of Compound Form E of Formula (V)
称取式(I)化合物(约100.00毫克)加入8毫升玻璃瓶中，再加入异丙醇(2毫升)，加热到80摄氏度使溶解，再加入草酸(1.05当量，25.0毫克)，80摄氏度搅拌1小时后关闭加热自然降温到室温，继续在室温下搅拌12小时，过滤，滤饼减压干燥(50摄氏度)得到式(V)化合物的晶型E，其XRPD、DSC和TGA谱图如图16-18所示。1H NMR(400MHz，DMSO-d 6)δppm 9.29(s，1H)，8.13(d，J＝6.0Hz，1H)，8.04(t，J＝1.6Hz，1H)，7.85-7.82(m，2H)，7.37(d，J＝8.0Hz，1H)，7.30(t，J＝8.0Hz，1H)，7.28(brs，1H)，6.58(dd，J＝6.0Hz，J＝2.4Hz，1H)，6.41(d，J＝2.4Hz，1H)，5.85(s，1H)，4.23-4.17(m，1H)，3.90(dd，J＝11.6Hz，J＝4.0Hz，2H)，3.38(t，J＝12.0Hz，2H)，2.17(s，3H)，2.05-1.94(m，2H)，1.72(dd，J＝12.4，J＝2.0Hz，2H)。 Weigh the compound of formula (I) (about 100.00 mg) into an 8 ml glass bottle, then add isopropanol (2 ml), heat to 80 degrees Celsius to dissolve, then add oxalic acid (1.05 equivalents, 25.0 mg), and stir at 80 degrees Celsius After 1 hour, turn off the heating and naturally cool down to room temperature, continue to stir at room temperature for 12 hours, filter, and dry the filter cake under reduced pressure (50 degrees Celsius) to obtain the crystal form E of the compound of formula (V). Its XRPD, DSC and TGA spectra are shown in the figure 16-18. 1H NMR (400MHz, DMSO-d 6 ) δppm 9.29 (s, 1H), 8.13 (d, J=6.0Hz, 1H), 8.04 (t, J=1.6Hz, 1H), 7.85-7.82 (m, 2H) , 7.37(d, J=8.0Hz, 1H), 7.30(t, J=8.0Hz, 1H), 7.28(brs, 1H), 6.58(dd, J=6.0Hz, J=2.4Hz, 1H), 6.41 (d, J=2.4Hz, 1H), 5.85 (s, 1H), 4.23-4.17 (m, 1H), 3.90 (dd, J=11.6Hz, J=4.0Hz, 2H), 3.38 (t, J= 12.0 Hz, 2H), 2.17 (s, 3H), 2.05-1.94 (m, 2H), 1.72 (dd, J=12.4, J=2.0 Hz, 2H).
实施例7：式(V)化合物晶型F的制备Example 7: Preparation of Compound Form F of Formula (V)
称取式(I)化合物(约100.00毫克)加入8毫升玻璃瓶中，再加入乙腈(4毫升)，加热到80摄氏度使溶解，再加入草酸(1.05当量，25.0毫克)，80摄氏度搅拌1小时后关闭加热自然降温到室温，继续在室温下搅拌12小时，过滤，滤饼减压干燥(50摄氏度)得到式(V)化合物的晶型F，其XRPD、DSC和TGA谱图如图19-21所示。1H NMR(400MHz，DMSO-d 6)δppm 9.28(s，1H)，8.13(d，J＝5.6Hz，1H)，8.04(t，J＝2.0Hz，1H)，7.86-7.82(m，2H)，7.37(d，J＝7.6Hz，1H)，7.31(t，J＝7.6Hz，1H)，7.28(brs，1H)，6.58(dd，J＝6.0Hz，J＝2.4Hz，1H)，6.42(d，J＝2.4Hz，1H)，5.85(s，1H)，4.24-4.16(m，1H)，3.90(dd，J＝11.6Hz，J＝3.6Hz，2H)，3.38(t，J＝12.0Hz，2H)，2.17(s，3H)，2.05-1.94(m，2H)，1.72(dd，J＝12.0，J＝2.0Hz，2H)。 Weigh the compound of formula (I) (about 100.00 mg) into an 8 ml glass bottle, then add acetonitrile (4 ml), heat to 80 degrees Celsius to dissolve, then add oxalic acid (1.05 equivalents, 25.0 mg), and stir at 80 degrees Celsius for 1 hour Then turn off the heating and naturally cool down to room temperature, continue to stir at room temperature for 12 hours, filter, and dry the filter cake under reduced pressure (50 degrees Celsius) to obtain the crystal form F of the compound of formula (V). Its XRPD, DSC and TGA spectra are shown in Figure 19- 21 shown. 1H NMR (400MHz, DMSO-d 6 ) δppm 9.28 (s, 1H), 8.13 (d, J=5.6Hz, 1H), 8.04 (t, J=2.0Hz, 1H), 7.86-7.82 (m, 2H) , 7.37(d, J=7.6Hz, 1H), 7.31(t, J=7.6Hz, 1H), 7.28(brs, 1H), 6.58(dd, J=6.0Hz, J=2.4Hz, 1H), 6.42 (d, J=2.4Hz, 1H), 5.85 (s, 1H), 4.24-4.16 (m, 1H), 3.90 (dd, J=11.6Hz, J=3.6Hz, 2H), 3.38 (t, J= 12.0 Hz, 2H), 2.17 (s, 3H), 2.05-1.94 (m, 2H), 1.72 (dd, J=12.0, J=2.0 Hz, 2H).
实施例8：式(VI)化合物晶型G的制备Example 8: Preparation of compound crystal form G of formula (VI)
称取式(I)化合物(约100.00毫克)加入8毫升玻璃瓶中，再加入丙酮(4.5毫升)，加热到60摄氏度使溶解，再加入磷酸(1.05当量，16.0微升)，60摄氏度搅拌1小时后关闭加热自然降温到室温，继续在室温下搅拌12小时，过滤，滤饼减压干燥(50摄氏度)得到式(VI)化合物的晶型G，其XRPD、DSC和TGA谱图如图22-24所示。1H NMR(400MHz，DMSO-d 6)δppm 9.28(s，1H)，8.13(d，J＝5.6Hz，1H)，8.04(t，J＝1.6Hz，1H)，7.85-7.83(m，2H)，7.37(d，J＝8.0Hz，1H)，7.30(t，J＝8.0Hz，1H)，7.28(brs，1H)，6.58(dd，J＝5.6Hz，J＝2.0Hz，1H)，6.41(d，J＝2.4Hz，1H)，5.85(s，1H)，4.24-4.16(m，1H)，3.90(dd，J＝11.6Hz， J＝3.6Hz，2H)，3.38(t，J＝12.0Hz，2H)，2.17(s，3H)，2.05-1.94(m，2H)，1.72(dd，J＝12.8，J＝2.4Hz，2H)。 Weigh the compound of formula (I) (about 100.00 mg) into an 8 ml glass bottle, then add acetone (4.5 ml), heat to 60 degrees Celsius to dissolve, then add phosphoric acid (1.05 equivalents, 16.0 μl), and stir at 60 degrees Celsius for 1 After 1 hour, turn off the heating and naturally cool down to room temperature, continue to stir at room temperature for 12 hours, filter, and dry the filter cake under reduced pressure (50 degrees Celsius) to obtain the crystal form G of the compound of formula (VI). Its XRPD, DSC and TGA spectra are shown in Figure 22 -24 shown. 1H NMR (400MHz, DMSO-d 6 ) δppm 9.28 (s, 1H), 8.13 (d, J=5.6Hz, 1H), 8.04 (t, J=1.6Hz, 1H), 7.85-7.83 (m, 2H) , 7.37(d, J=8.0Hz, 1H), 7.30(t, J=8.0Hz, 1H), 7.28(brs, 1H), 6.58(dd, J=5.6Hz, J=2.0Hz, 1H), 6.41 (d, J=2.4Hz, 1H), 5.85 (s, 1H), 4.24-4.16 (m, 1H), 3.90 (dd, J=11.6Hz, J=3.6Hz, 2H), 3.38 (t, J= 12.0 Hz, 2H), 2.17 (s, 3H), 2.05-1.94 (m, 2H), 1.72 (dd, J=12.8, J=2.4 Hz, 2H).
实施例9Example 9
表16 10mg规格片剂的配方Table 16 Formulation of 10mg strength tablets
材料Material 量(％)quantity(%) 量(g)Amount (g)
式(II)化合物晶型BForm B of the compound of formula (II) 12.0612.06 2.4122.412
微晶纤维素microcrystalline cellulose 58.9458.94 11.78811.788
甘露醇Mannitol 20.020.0 4.04.0
胶态二氧化硅Colloidal silica 0.50.5 0.10.1
羟丙甲纤维素Hypromellose 1.51.5 0.30.3
交联羧甲纤维素钠(内加)Croscarmellose sodium (added) 3.03.0 0.60.6
交联羧甲纤维素钠(外加)Croscarmellose sodium (extra) 3.03.0 0.60.6
硬脂酸镁Magnesium stearate 1.01.0 0.20.2
总量total 100.0100.0 20.020.0
共制成(片)Co-produced (tablets) ---- 200200
工艺步骤：Process steps:
(1)预混(1) Premix
将式(II)化合物晶型B、微晶纤维素、甘露醇、胶态二氧化硅和交联羧甲纤维素钠分别按处方量称取，混合均匀，备用。The compound crystal form B of formula (II), microcrystalline cellulose, mannitol, colloidal silicon dioxide and croscarmellose sodium are respectively weighed according to the recipe amount, mixed evenly, and set aside.
(2)羟丙甲纤维素溶液配置(2) Hypromellose solution configuration
称取羟丙甲纤维素适量，用水溶液配置成含6％的羟丙甲纤维素溶液，备用。An appropriate amount of hypromellose was weighed, and an aqueous solution was used to prepare a 6% hypromellose solution for later use.
(3)制粒(3) Granulation
将预混料按处方量加入6％的羟丙甲纤维素溶液约5mL制粒，根据制粒情况适当调整水的用量。制粒完成后将湿颗粒用20目筛网湿整粒。Add about 5 mL of 6% hypromellose solution to the premix according to the recipe for granulation, and adjust the amount of water appropriately according to the granulation situation. After the granulation is completed, the wet granules are wet granulated with a 20 mesh screen.
(4)干燥(4) Drying
湿颗粒在60℃干燥，控制水分在3％以下。The wet granules are dried at 60°C and the moisture content is controlled below 3%.
(5)干整粒、总混(5) Dry granulation and total mixing
用20目筛网干整粒，颗粒加入处方量的交联羧甲纤维素钠混合均匀后，再加入处方量的硬脂酸镁混合均匀，备用。Use a 20-mesh sieve to dry and granulate, add the croscarmellose sodium in the recipe to the granules and mix them evenly, and then add the magnesium stearate in the recipe and mix them evenly for later use.
(6)压片(6) Tablet
采用冲模为6mm的压片机压制成片，压片中控制片重在合格范围内，硬度在5-9Kp，片子在10min内完全崩解。Using a tablet press with a die of 6 mm, the tablet weight was within the qualified range, the hardness was 5-9 Kp, and the tablet was completely disintegrated within 10 minutes.
实施例10Example 10
表17 10mg规格片剂的配方Table 17 Formulation of 10 mg strength tablets
材料Material 量(％)quantity(%) 量(g)Amount (g)
式(II)化合物晶型BForm B of the compound of formula (II) 12.0612.06 2.4122.412
微晶纤维素microcrystalline cellulose 58.9458.94 11.78811.788
乳糖 lactose 2020 4.04.0
胶态二氧化硅Colloidal silica 0.50.5 0.10.1
羟丙甲纤维素Hypromellose 1.51.5 0.30.3
交联羧甲纤维素钠(内加)Croscarmellose sodium (added) 3.03.0 0.60.6
交联羧甲纤维素钠(外加)Croscarmellose sodium (extra) 3.03.0 0.60.6
硬脂酸镁Magnesium stearate 1.01.0 0.20.2
总量total 100.0100.0 20.020.0
共制成(片)Co-produced (tablets) ---- 200200
工艺步骤：Process steps:
(1)预混(1) Premix
将式(II)化合物晶型B、微晶纤维素、乳糖、胶态二氧化硅和交联羧甲纤维素钠分别按处方量称取，混合均匀，备用。The compound crystal form B of the formula (II), microcrystalline cellulose, lactose, colloidal silicon dioxide and croscarmellose sodium are respectively weighed according to the recipe amount, mixed evenly, and set aside.
步骤(2)羟丙甲纤维素溶液配置，步骤(3)制粒，步骤(4)干燥，步骤(5)干整粒、总混，步骤(6)压片，与实施例9相似。Step (2) configuration of hypromellose solution, step (3) granulation, step (4) drying, step (5) dry granulation, total mixing, and step (6) tabletting, similar to Example 9.
实施例11Example 11
表18 10mg规格片剂的配方Table 18 Formulation of 10 mg strength tablets
材料Material 量(％)quantity(%) 量(g)Amount (g)
式(II)化合物晶型Crystal form of compound of formula (II) 12.0612.06 2.4122.412
微晶纤维素 microcrystalline cellulose 2020 4.04.0
乳糖lactose 58.9458.94 11.78811.788
胶态二氧化硅Colloidal silica 0.50.5 0.10.1
羟丙甲纤维素Hypromellose 1.51.5 0.30.3
交联羧甲纤维素钠(内加)Croscarmellose sodium (added) 3.03.0 0.60.6
交联羧甲纤维素钠(外加)Croscarmellose sodium (extra) 3.03.0 0.60.6
硬脂酸镁Magnesium stearate 1.01.0 0.20.2
总量total 100.0100.0 20.020.0
材料Material 量(％)quantity(%) 量(g)Amount (g)
共制成(片)Co-produced (tablets) ---- 200200
工艺步骤：Process steps:
步骤(1)预混，步骤(2)羟丙甲纤维素溶液配置，步骤(3)制粒，步骤(4)干燥，步骤(5)干整粒、总混，步骤(6)压片，与实施例10相似。Step (1) premixing, step (2) hypromellose solution configuration, step (3) granulation, step (4) drying, step (5) dry granulation and total mixing, step (6) tableting, Similar to Example 10.
实施例12Example 12
表19 10mg规格片剂的配方Table 19 Formulation of 10mg strength tablet
材料Material 量(％)quantity(%) 量(g)Amount (g)
式(II)化合物晶型BForm B of the compound of formula (II) 12.0612.06 2.4122.412
微晶纤维素microcrystalline cellulose 58.9458.94 11.78811.788
乳糖 lactose 2020 4.04.0
胶态二氧化硅Colloidal silica 0.50.5 0.10.1
羟丙甲纤维素Hypromellose 1.51.5 0.30.3
羧甲淀粉钠(内加)Sodium starch glycolate (added) 3.03.0 0.60.6
羧甲淀粉钠(外加)Sodium starch glycolate (extra) 3.03.0 0.60.6
硬脂酸镁Magnesium stearate 1.01.0 0.20.2
总量total 100.0100.0 20.020.0
共制成(片)Co-produced (tablets) ---- 200200
工艺步骤：Process steps:
步骤(1)预混，步骤(2)羟丙甲纤维素溶液配置，步骤(3)制粒，步骤(4)干燥，步骤(5)干整粒、总混，步骤(6)压片，与实施例10相似。将交联羧甲纤维素钠替换为羧甲淀粉钠。Step (1) premixing, step (2) hypromellose solution configuration, step (3) granulation, step (4) drying, step (5) dry granulation and total mixing, step (6) tabletting, Similar to Example 10. Replace croscarmellose sodium with sodium starch glycolate.
实施例13Example 13
表20 10mg规格片剂的配方Table 20 Formulation of 10mg strength tablets
材料Material 量(％)quantity(%) 量(g)Amount (g)
式(II)化合物晶型BForm B of the compound of formula (II) 12.0612.06 2.4122.412
微晶纤维素microcrystalline cellulose 58.9458.94 11.78811.788
乳糖 lactose 2020 4.04.0
胶态二氧化硅Colloidal silica 0.50.5 0.10.1
羟丙甲纤维素Hypromellose 1.51.5 0.30.3
交联羧甲纤维素钠Croscarmellose sodium 6.06.0 1.21.2
硬脂酸镁Magnesium stearate 1.01.0 0.20.2
总量total 100.0100.0 20.020.0
共制成(片)Co-produced (tablets) ---- 200200
工艺步骤：Process steps:
(1)混合(1) Mixed
将式(II)化合物晶型B、微晶纤维素、乳糖、胶态二氧化硅、交联羧甲纤维素钠和硬脂酸镁分别按处方量称取，混合均匀，备用。The compound crystal form B of formula (II), microcrystalline cellulose, lactose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate are respectively weighed according to the recipe amount, mixed uniformly, and set aside.
(2)压片(2) Tablet
采用冲模为6mm的压片机压制成片，压片中控制片重在合格范围内，硬度在5-9Kp，片子在10min内完全崩解。Using a tablet press with a die of 6 mm, the tablet weight is within the qualified range, the hardness is 5-9 Kp, and the tablet is completely disintegrated within 10 minutes.
实施例14Example 14
表21 50mg规格片剂的配方Table 21 Formulations of 50 mg tablets
材料Material 量(％)quantity(%) 量(g)Amount (g)
式(II)化合物晶型BForm B of the compound of formula (II) 12.0612.06 12.0612.06
微晶纤维素 microcrystalline cellulose 2020 2020
乳糖lactose 58.9458.94 58.9458.94
胶态二氧化硅Colloidal silica 0.50.5 0.50.5
羟丙甲纤维素Hypromellose 1.51.5 1.51.5
交联羧甲纤维素钠(内加)Croscarmellose sodium (added) 3.03.0 3.03.0
交联羧甲纤维素钠(外加)Croscarmellose sodium (extra) 3.03.0 3.03.0
硬脂酸镁Magnesium stearate 1.01.0 1.01.0
总量total 100.0100.0 100.0100.0
共制成(片)Co-produced (tablets) ---- 200200
工艺步骤：Process steps:
步骤(1)预混，步骤(2)羟丙甲纤维素溶液配置，步骤(3)制粒，步骤(4)干燥，步骤(5)干整粒、总混，步骤(6)压片，与实施例11相似。羟丙甲纤维素溶液浓度由6％变更为4.5％，采用冲模为11mm的压片机压制成片。Step (1) premixing, step (2) hypromellose solution configuration, step (3) granulation, step (4) drying, step (5) dry granulation and total mixing, step (6) tabletting, Similar to Example 11. The concentration of the hypromellose solution was changed from 6% to 4.5%, and it was compressed into a tablet using a tablet press with a die of 11 mm.
实施例15Example 15
表22 10mg规格片剂的配方Table 22 Formulations of 10 mg tablets
Figure PCTCN2021105662-appb-000033
Figure PCTCN2021105662-appb-000033
Figure PCTCN2021105662-appb-000034
Figure PCTCN2021105662-appb-000034
工艺步骤：Process steps:
(1)预混(1) Premix
将原料药、乳糖、微晶纤维素、胶态二氧化硅、交联羧甲纤维素钠分别按处方量称取加入到湿法混合制粒机中进行搅拌混合。以370rpm的搅拌速度和1500rpm的剪切速度混合10min。The raw material drug, lactose, microcrystalline cellulose, colloidal silicon dioxide, and croscarmellose sodium were weighed and added to the wet mixing granulator according to the recipe amount, and were stirred and mixed. Mix for 10 min with stirring speed of 370 rpm and shear speed of 1500 rpm.
(2)羟丙甲纤维素溶液配置(2) Hypromellose solution configuration
称取羟丙甲纤维素适量，用水溶液配置成含3.9％的羟丙甲纤维素溶液，备用。An appropriate amount of hypromellose was weighed, and an aqueous solution was used to prepare a 3.9% hypromellose solution for later use.
(3)制粒(3) Granulation
将预混料按处方量加入3.9％的羟丙甲纤维素溶液约230.77mL，以150rpm的搅拌速度，1200rpm的剪切速度继续搅拌，总制粒时间控制在4min内。制粒完成后将湿颗粒转出湿法混合制粒机，选用20目筛网湿整粒。About 230.77 mL of 3.9% hypromellose solution was added to the premix according to the recipe, and the stirring was continued at a stirring speed of 150 rpm and a shearing speed of 1200 rpm, and the total granulation time was controlled within 4 minutes. After the granulation is completed, the wet granules are transferred out of the wet mixing granulator, and a 20-mesh screen is used for wet granulation.
(4)干燥(4) Drying
采用流化制粒包衣机进行干燥。进风温度设定为60℃，干燥终点水分控制在≤3.0％，干燥时间根据水分测定结果确定。Drying was carried out using a fluid granulation coater. The inlet air temperature is set to 60°C, the moisture at the drying end is controlled at ≤3.0%, and the drying time is determined according to the moisture measurement results.
(5)整粒(5) Whole grain
干燥后选用20目筛网进行手工整粒。After drying, use a 20-mesh screen for manual granulation.
(6)总混，中间体检测(6) Mixing, intermediate detection
采用万向混合机固定料斗进行混合，先将干颗粒和交联羧甲纤维素钠(外加)置于混合料斗中混合。混合速度为20rpm，混合时间为20min；再加入硬脂酸镁进行总混，混合速度为20rpm，总混时间为3min。混合完成后控制中间体的质量。The fixed hopper of the universal mixer is used for mixing, and the dry granules and the croscarmellose sodium (additional) are placed in the mixing hopper and mixed. The mixing speed was 20 rpm, and the mixing time was 20 min; then magnesium stearate was added for total mixing, the mixing speed was 20 rpm, and the total mixing time was 3 min. The quality of the intermediate is controlled after mixing is complete.
(7)压片(7) Tablet
根据中间体含量，折算标准片重，采用单冲压片机压片。According to the content of the intermediate, the standard tablet weight is converted, and a single punch tablet machine is used for tableting.
冲模：6mm浅弧形圆冲，片重：100mg，片重差异：±7.5％，控制片子硬度为：6～9Kp(1Kp≈10N)，片子在10min内完全崩解。Die: 6mm shallow arc circular punch, tablet weight: 100mg, tablet weight difference: ±7.5%, controlled tablet hardness: 6-9Kp (1Kp≈10N), tablet completely disintegrated within 10min.
(8)包衣(8) Coating
包衣液的配置：按固含量12％的比例配置包衣液Configuration of coating liquid: configure the coating liquid according to the proportion of solid content of 12%
按素片重量增重3.0％～6.0％的薄膜包衣预混剂称取包衣粉，搅拌溶于水中配制成12％的薄膜包衣液，采用高效包衣机进行薄膜包衣。包衣锅主机转速控制在8-10rpm，主机转速1200rpm，进风温度设定为68℃，出风温度控制在40～50℃之间。雾化压力为0.17Mpa，扇面压力为0.15Mpa。The coating powder is weighed according to the film coating premix with a weight gain of 3.0% to 6.0% of the weight of the plain tablet, stirred and dissolved in water to prepare a 12% film coating liquid, and the film coating is carried out by a high-efficiency coating machine. The main machine speed of the coating pot is controlled at 8-10rpm, the main machine speed is 1200rpm, the inlet air temperature is set at 68°C, and the outlet air temperature is controlled between 40 and 50°C. The atomization pressure is 0.17Mpa, and the fan pressure is 0.15Mpa.
在片剂达到要求的增重后，关闭加热系统，继续烘约15min左右后取出包衣片剂。After the tablet reaches the required weight gain, turn off the heating system, continue to bake for about 15 minutes, and then take out the coated tablet.
(9)包装(9) Packaging
将药片和固体药用高密度聚乙烯非织造布(泰维克)袋装干燥剂一起装入口服固体药用高度密聚乙烯塑料瓶(40mL)中，使用手持式感应封口机封口。Tablets and solid pharmaceutical high-density polyethylene non-woven fabric (Tyvec) bag desiccant were put into oral solid pharmaceutical high-density polyethylene plastic bottles (40 mL) together, and sealed with a hand-held induction sealing machine.
功率大小：1000W；封口时间：1.6s；包装规格：30片/瓶。Power size: 1000W; sealing time: 1.6s; packaging specification: 30 pieces/bottle.
(10)成品检测(10) Finished product inspection
(11)入库(11) Storage
实施例16Example 16
表23 50mg规格药片的配方Table 23 Formulations of 50 mg tablets
Figure PCTCN2021105662-appb-000035
Figure PCTCN2021105662-appb-000035
工艺步骤：Process steps:
步骤(1)预混，步骤(2)羟丙甲纤维素溶液配置，与实施例15相似。Step (1) premix, step (2) hypromellose solution configuration, similar to Example 15.
(3)制粒(3) Granulation
将预混料按处方量加入3.9％的羟丙甲纤维素溶液约769.23mL，以200rpm的搅拌速度，1800rpm的剪切速度继续搅拌，总制粒时间控制在4min内。制粒完成后将湿颗粒转出湿法混合制粒机，选用20目筛网湿整粒。About 769.23 mL of 3.9% hypromellose solution was added to the premix according to the recipe, and the stirring was continued at a stirring speed of 200 rpm and a shearing speed of 1800 rpm, and the total granulation time was controlled within 4 minutes. After the granulation is completed, the wet granules are transferred out of the wet mixing granulator, and a 20-mesh screen is used for wet granulation.
步骤(4)干燥，步骤(5)整粒，步骤(6)总混、中间体检测，与实施例15相似。Step (4) drying, step (5) granulation, step (6) blending, intermediate detection, are similar to Example 15.
(7)压片(7) Tablet
根据中间体含量，折算标准片重，采用单冲压片机压片。According to the content of the intermediate, the standard tablet weight is converted, and a single punch tablet machine is used for tableting.
冲模：11mm浅弧形圆冲，片重：500mg，片重差异：±5％，控制片子硬度为：10～14Kp(1Kp≈10N)，片子在10min内完全崩解。Die: 11mm shallow arc circular punch, tablet weight: 500mg, tablet weight difference: ±5%, controlled tablet hardness: 10-14Kp (1Kp≈10N), tablet completely disintegrated within 10min.
步骤(8)包衣，步骤(9)包装，步骤(10)成品检测，步骤(11)入库，与实施例15相似。Step (8) coating, step (9) packaging, step (10) finished product detection, step (11) storage, similar to Example 15.
实施例17 式(IV)化合物晶型D、式(II)化合物晶型B及其制剂的稳定性研究Example 17 Stability study of compound crystal form D of formula (IV), crystal form B of formula (II) and preparations thereof
式(IV)化合物晶型D的预稳定性研究表明，该晶型在40℃/75％RH及光照条件下，10天未见杂质含量的变化，证明其具有较好的稳定性。The pre-stability study of the crystal form D of the compound of formula (IV) shows that the crystal form has no change in impurity content for 10 days under the conditions of 40°C/75% RH and light, which proves that it has good stability.
式(II)化合物晶型B在高压下的晶型稳定性研究：将式(II)化合物晶型B的粉末加入圆形模具(直径6mm)中，加压直至压力达到350MPa左右，再取压片后的样品直接平铺在XRPD盘上测试，检测结果见图25结果显示式(II)化合物晶型B未变化，说明式(II)化合物晶型B对高压稳定。Study on crystal stability of compound crystal form B of formula (II) under high pressure: add the powder of compound crystal form B of formula (II) into a circular mold (diameter 6mm), pressurize until the pressure reaches about 350MPa, and then take the pressure The sample after the tablet was directly tested on the XRPD disk. The test results are shown in Figure 25. The results showed that the compound crystal form B of formula (II) did not change, indicating that the compound crystal form B of formula (II) was stable to high pressure.
式(II)化合物晶型B在溶剂中的晶型稳定性研究：将4份式(II)化合物晶型B(50.98毫克，51.25毫克，52.11毫克，49.23毫克)分别加入到4个透明玻璃瓶中，然后分别加入乙醇、乙腈、丙酮和乙酸乙酯，在25摄氏度搅拌16小时后过滤，滤饼减压旋干(45摄氏度，≤-0.1MPa)得到的固体检测XRPD，检测结果见图26。实验结果如下表24：式(II)化合物晶型B未变化，说明式(II)化合物晶型B对常见溶剂中是稳定。Study on the stability of the crystal form of the compound of formula (II) form B in solvent: 4 parts of the crystal form B of the compound of formula (II) (50.98 mg, 51.25 mg, 52.11 mg, 49.23 mg) were added to 4 transparent glass bottles. Then add ethanol, acetonitrile, acetone and ethyl acetate respectively, filter after stirring at 25 degrees Celsius for 16 hours, filter cake under reduced pressure and spin dry (45 degrees Celsius, ≤-0.1MPa) to obtain solid detection XRPD, the detection results are shown in Figure 26 . The experimental results are as follows in Table 24: the crystal form B of the compound of formula (II) is unchanged, indicating that the crystal form B of the compound of formula (II) is stable in common solvents.
表24Table 24
编号Numbering 溶剂solvent 晶型Crystal form 对应XRPD谱图编号Corresponding XRPD spectrum number
11 乙醇Ethanol BB P12310-059-P1DP12310-059-P1D
22 乙腈Acetonitrile BB P12310-059-P2DP12310-059-P2D
33 丙酮acetone BB P12310-059-P3DP12310-059-P3D
44 乙酸乙酯Ethyl acetate BB P12310-059-P4DP12310-059-P4D
式(II)化合物晶型B在影响因素实验中的稳定性研究：每份样品称取1.5g，25℃/92.5％RH条件样品放入敞口的扁形称量瓶(70*35mm)，60℃条件下的样品放入敞口的表面皿中，然后分别放入不同的保干器和鼓风干燥箱中考察；光照样品放入干净的表面皿中，铺成薄层，盖上石英玻璃盖，放入5000±500lux(可见光)与90μw/cm 2(紫外)条件下照射。实验结果如下表： Stability study of compound crystal form B of formula (II) in influence factor experiment: weigh 1.5g of each sample, put the sample into an open flat weighing bottle (70*35mm) under the condition of 25℃/92.5%RH, 60 The samples under the condition of ℃ were placed in an open watch glass, and then placed in different desiccators and blast drying ovens for investigation; the illuminated samples were placed in a clean watch glass, spread into a thin layer, and covered with quartz glass. Cover, put into 5000±500lux (visible light) and 90μw/cm 2 (ultraviolet) under the condition of irradiation. The experimental results are as follows:
表25Table 25
Figure PCTCN2021105662-appb-000036
Figure PCTCN2021105662-appb-000036
结果表明：式(II)化合物晶型B在高温、高湿及光照条件下稳定。The results show that the crystal form B of the compound of formula (II) is stable under high temperature, high humidity and light conditions.
式(II)化合物晶型B在稳定性加速实验中的研究：稳定性加速实验：每份样品称取1.5g分别装入双层低密度聚乙烯(LDPE)袋，每层低密度聚乙烯袋分别扎扣密封，再将低密度聚乙烯袋子放入铝箔袋中并热封，分别放入40℃/75％RH条件下考察，实验结果如下表：Research on the Compound Form B of Formula (II) in Accelerated Stability Experiment: Accelerated Stability Experiment: Weigh 1.5 g of each sample into double-layer low-density polyethylene (LDPE) bags, and each layer of LDPE bags Snap and seal them respectively, then put the low-density polyethylene bags into aluminum foil bags and heat-seal them, respectively, and put them into 40°C/75%RH conditions for investigation. The experimental results are as follows:
表26Table 26
Figure PCTCN2021105662-appb-000037
Figure PCTCN2021105662-appb-000037
结果表明：式(II)化合物晶型B在长期放置条件下是稳定的。The results show that the crystal form B of the compound of formula (II) is stable under long-term storage conditions.
包含式(II)化合物晶型B的片剂产品的稳定性：Stability of Tablet Products Containing Form B of Compound of Formula (II):
加速实验：将下列各样品在40℃，75％RH条件下分别放置1、2、3、6个月取样，检测各样品中化合物的含量、有关物质和溶出情况。Accelerated experiment: The following samples were placed at 40°C and 75% RH for 1, 2, 3, and 6 months, respectively, for sampling, and the content of compounds, related substances and dissolution conditions in each sample were detected.
表27 加速实验各样品的含量、有关物质和溶出Table 27 Contents, related substances and dissolution of each sample in the accelerated experiment
Figure PCTCN2021105662-appb-000038
Figure PCTCN2021105662-appb-000038
Figure PCTCN2021105662-appb-000039
Figure PCTCN2021105662-appb-000039
*溶出检测时间T＝30min，n＝6*Dissolution testing time T=30min, n=6
从实验中可以观察到，本发明提供的片剂中的杂质在2个月的调查期间范围内保持相对稳定。片型的性能也在2个月的调查时间期限内保持。这些结果表明，本发明提供的制剂对于临床和其它用途投足够的稳定性。It can be observed from the experiments that the impurities in the tablets provided by the present invention remain relatively stable within the scope of the 2-month investigation period. The performance of the tablet form was also maintained over the 2-month investigation time period. These results demonstrate that the formulations provided by the present invention are sufficiently stable for clinical and other uses.
实施例18 式(II)化合物晶型B的溶解度实验Example 18 Solubility test of compound crystal form B of formula (II)
式(II)化合物晶型B在不同pH缓冲液和生物媒介中的溶解度实验：称取2mg化合物，称量到2mL的玻璃瓶中，加入1mL的媒介，加上磁子于37℃、700rpm条件下在磁力搅拌器上搅拌。其中，缓冲液为pH1.0、pH2.0、SGF和水，目标浓度为10mg/mL。如遇澄清状态，则持续加化合物，继续搅拌，直至溶液不再有变澄清状况，直至搅拌24小时后取样测定。Solubility experiment of compound crystal form B of formula (II) in different pH buffers and biological media: Weigh 2mg of the compound, weigh it into a 2mL glass bottle, add 1mL of medium, and add a magnet at 37°C and 700rpm. Stir on a magnetic stirrer. The buffers were pH1.0, pH2.0, SGF and water, and the target concentration was 10 mg/mL. If it is in a clear state, continue to add the compound and continue to stir until the solution no longer becomes clear, until the sample is measured after stirring for 24 hours.
表28Table 28
Figure PCTCN2021105662-appb-000040
Figure PCTCN2021105662-appb-000040
注：SGF：模拟人类饥饿状态下空胃时的胃液。Note: SGF: simulates the gastric juice of empty stomach in human starvation state.
结果表明：式(II)化合物晶型B在纯水、酸性溶液及胃模拟液中溶解度佳。The results show that the crystal form B of the compound of formula (II) has good solubility in pure water, acidic solution and gastric simulated solution.
实施例19 式(II)化合物晶型B的引湿性实验Example 19 Hygroscopicity test of compound crystal form B of formula (II)
取两个干燥的具塞玻璃称量瓶(50×30mm)放置25/80％RH稳定性试验箱中平衡，精密称取平衡后称量瓶的重量m1，取供试品适量，分别平铺于上述两个称量瓶中，供试品厚度一般约为1mm，精密称量总重m2，将称量瓶敞口，并与瓶盖同置于上述稳定性试验箱中，于25℃药品稳定性试验箱中放置24小时。盖好称量瓶盖子，精密称定总重m 3。 Take two dry stoppered glass weighing bottles (50 × 30 mm) and place them in a 25/80% RH stability test chamber for balance, accurately weigh the weight m1 of the weighing bottles after the balance, take an appropriate amount of the test sample, and spread them out respectively. In the above two weighing bottles, the thickness of the test sample is generally about 1 mm, and the total weight is accurately weighed in m2. The weighing bottle is opened and placed in the above stability test box together with the bottle cap. Place in the stability test chamber for 24 hours. Close the lid of the weighing bottle, and accurately weigh the total weight m 3 .
引湿性增重计算公式如下：增重百分率＝100％×(m 3-m 2)/(m 2-m 1) The calculation formula of hygroscopic weight gain is as follows: weight gain percentage=100%×(m 3 -m 2 )/(m 2 -m 1 )
表29 式(II)化合物晶型B的引湿情况表Table 29 Moisture introduction table of compound crystal form B of formula (II)
Figure PCTCN2021105662-appb-000041
Figure PCTCN2021105662-appb-000041
吸湿性评价标准见下表30：The evaluation criteria for hygroscopicity are shown in Table 30 below:
吸湿性分类Hygroscopic classification 吸湿增重＊(ΔW％)Moisture absorption weight gain*(ΔW%)
潮解deliquescence 吸收足量水分形成液体Absorbs enough water to form a liquid
极具吸湿性Very hygroscopic ΔW％≥15％ΔW%≥15%
有吸湿性hygroscopic 15％＞ΔW％≥2％15%>ΔW%≥2%
略有吸湿性slightly hygroscopic 2％＞ΔW％≥0.2％2%>ΔW%≥0.2%
无或几乎无吸湿性No or almost no hygroscopicity ΔW％＜0.2％ΔW%＜0.2%
注：*在25±1℃和80±2％RH下的吸湿增重Note: * Hygroscopic weight gain at 25±1°C and 80±2% RH
实施例20 Smad磷酸化抑制活性实验Example 20 Smad phosphorylation inhibitory activity experiment
实验方法：在白色透明底96孔微板中每孔加入35000个HEK293细胞(100微升不含基因蛋白的生长培养基)。5％二氧化碳气氛中37摄氏度孵化过夜。第二天除去培养基，加入不含基因蛋白的0.5％胚胎牛血清，90微升化合物溶液(不同浓度梯度)，5％二氧化碳气氛中37摄氏度孵化4-5小时。加入10微升TGFβ1(TGFβ1最终浓度为20ng/mL)，对照孔中加入10微升培养液，处理过夜。之后裂解，采用一步荧光素酶检测法检测荧光。Experimental method: 35,000 HEK293 cells (100 microliters of growth medium without gene protein) were added to each well of a white transparent bottom 96-well microplate. Incubate overnight at 37°C in a 5% carbon dioxide atmosphere. The medium was removed the next day, 0.5% fetal bovine serum without genetic protein, 90 microliters of compound solutions (different concentration gradients) were added, and the cells were incubated for 4-5 hours at 37 degrees Celsius in a 5% carbon dioxide atmosphere. Add 10 microliters of TGFβ1 (the final concentration of TGFβ1 is 20 ng/mL), add 10 microliters of culture medium to the control wells, and treat overnight. After cleavage, fluorescence was detected using a one-step luciferase assay.
数据分析：原始数据换算成抑制率，曲线拟合得出IC 50值。表31提供了本发明化合物对Smad磷酸化的抑制活性。 Data analysis: The raw data were converted into inhibition rates, and IC 50 values were obtained by curve fitting. Table 31 provides the inhibitory activity of compounds of the invention on Smad phosphorylation.
实验结果：见表31：Experimental results: see Table 31:
表31Table 31
化合物compound pSmad抑制IC 50(纳摩尔每升) pSmad inhibition IC 50 (nanomoles per liter)
式(II)化合物晶型BForm B of the compound of formula (II) 63.263.2
结论：式(II)化合物晶型B具有优异的pSmad抑制活性。证明式(II)化合物晶型B能够起到抑制TGF-β/SMAD信号通路的作用。Conclusion: The crystal form B of the compound of formula (II) has excellent pSmad inhibitory activity. It is proved that the crystalline form B of the compound of formula (II) can inhibit the TGF-β/SMAD signaling pathway.
实施例21 小鼠结肠癌CT-26细胞BALB/c小鼠皮下同种移植瘤模型的体内抗肿瘤药效研究Example 21 In vivo antitumor efficacy of mouse colon cancer CT-26 cells BALB/c mouse subcutaneous allograft model
实验目的：本研究主要的目的是在CT26小鼠同种移植瘤模型上研究受测化合物的抗肿瘤药效。Experimental purpose: The main purpose of this study is to study the antitumor efficacy of the tested compounds in the CT26 mouse allograft tumor model.
实验操作：细胞培养：小鼠结肠癌CT-26细胞体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，37摄氏度5％二氧化碳孵箱培养。一周两次用胰酶-乙二胺四乙酸(EDTA)进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。Experimental operation: cell culture: mouse colon cancer CT-26 cells were cultured in vitro in monolayer, culture conditions were RPMI-1640 medium plus 10% fetal bovine serum, 37 degrees Celsius and 5% carbon dioxide incubator. Conventional digestion treatments were passaged with trypsin-ethylenediaminetetraacetic acid (EDTA) twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded.
动物：BALB/c小鼠，雌性，6～8周龄。Animals: BALB/c mice, female, 6-8 weeks old.
肿瘤接种：将0.1毫升含3×10 5个CT26细胞的DPBS细胞悬液皮下接种于每只小鼠的右侧腹股沟处，接种当天开始给药。 Tumor inoculation: 0.1 ml of DPBS cell suspension containing 3×10 5 CT26 cells was subcutaneously inoculated into the right groin of each mouse, and the administration started on the day of inoculation.
实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5L×W 2，L和W分别表示肿瘤的长径和短径。 Experimental index: The experimental index is to examine whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V=0.5L×W 2 , L and W represent the long and short diameters of the tumor, respectively.
实验结果：化合物肿瘤抑制效果见表32。Experimental results: The tumor inhibitory effects of the compounds are shown in Table 32.
实验结论：式(I)化合物在小鼠结肠癌CT-26细胞BALB/c小鼠皮下同种移植瘤模型中具有明显的体内抗肿瘤药效。Experimental conclusion: The compound of formula (I) has obvious antitumor efficacy in vivo in the mouse colon cancer CT-26 cell BALB/c mouse subcutaneous allograft tumor model.
表32 CT26同种异位移植实验结果Table 32 Results of CT26 allotransplantation experiments
Figure PCTCN2021105662-appb-000042
Figure PCTCN2021105662-appb-000042
实施例22 体内药代动力学研究Example 22 In vivo pharmacokinetic study
式(II)化合物晶型B的体内药代动力学研究In Vivo Pharmacokinetic Study of Compound Form B of Formula (II)
实验目的：本实验目的是评价化合物单次静脉注射和灌胃给药后的药代动力学行为，考察灌胃给药后的生物利用度。Experiment purpose: The purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
实验操作：24只(12/性别)雌雄比格犬被分成4组。第1组动物单次静脉注射给药1mg/kg的测试物。第2组和第4组动物分别单次口服给予5和50mg/kg的测试物。第3组动物每天1次，连续7天口服给药，每次给药15mg/kg剂量的测试物。第1、2组和第4组的动物于给药前(0)和给药后0.0833(5分钟)、0.25(15分钟)、0.5(30分钟)、1、2、4、6、8、12和24小时采集血浆样品。第3组动物于第1天和第7天的给药前(0)和给药后0.0833(5分钟)、0.25(15分钟)、0.5(30分钟)、1、2、4、6、8、12和24小时，和第3、4、5和第6天的给药前(0)采集血浆样品。应用LC-MS/MS方法测定血浆样本中测试物的浓度。实验结果：PK性质评价结果见表33。Experimental operation: 24 (12/sex) male and female beagle dogs were divided into 4 groups. Group 1 animals were dosed with a single intravenous injection of 1 mg/kg of the test article. Groups 2 and 4 animals were given a single oral dose of 5 and 50 mg/kg of the test article, respectively. The animals in the third group were orally administered once a day for 7 consecutive days, and each dose of the test substance was administered at a dose of 15 mg/kg. Animals in groups 1, 2 and 4 were treated at 0.0833 (5 minutes), 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 8, Plasma samples were collected at 12 and 24 hours. Animals in group 3 were pre-dose (0) and post-dose 0.0833 (5 minutes), 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 8 on day 1 and day 7 , 12 and 24 hours, and pre-dose (0) on days 3, 4, 5 and 6. Concentrations of test substances in plasma samples were determined using an LC-MS/MS method. Experimental results: Table 33 shows the evaluation results of PK properties.
实验结论：式(II)化合物晶型B在犬体内有极佳的PK性质，口服生物利用度高。Experimental conclusion: The crystal form B of the compound of formula (II) has excellent PK properties in dogs and high oral bioavailability.
表33 式(II)化合物晶型B的体内PK性质评价结果Table 33 Evaluation results of in vivo PK properties of compound crystal form B of formula (II)
组别group 11 22 3(第1天)3 (Day 1) 3(第7天)3 (Day 7) 44
给药途径Route of administration 静脉注射intravenous injection 口服oral 口服oral 口服oral 口服oral
剂量(mg/kg)Dosage (mg/kg) 11 55 1515 1515 5050
药动学参数Pharmacokinetic parameters 均值mean 均值mean 均值mean 均值mean 均值mean
C 0(nM) C 0 (nM) 15101510 ---- ---- ---- ----
组别group 11 22 3(第1天)3 (Day 1) 3(第7天)3 (Day 7) 44
给药途径Route of administration 静脉注射intravenous injection 口服oral 口服oral 口服oral 口服oral
剂量(mg/kg)Dosage (mg/kg) 11 55 1515 1515 5050
药动学参数Pharmacokinetic parameters 均值mean 均值mean 均值mean 均值mean 均值mean
C max(nM) Cmax (nM) ---- 31503150 94109410 1090010900 5790057900
T max(h) Tmax (h) ---- 11 0.5830.583 0.750.75 0.5420.542
T 1/2(h) T 1/2 (h) 1.031.03 2.232.23 2.452.45 2.812.81 2.732.73
Vd ss(L/kg) Vd ss (L/kg) 1.591.59 ---- ---- ---- ----
CL(mL/min/kg)CL(mL/min/kg) 17.117.1 ---- ---- ---- ----
AUC 0-last(nM·h) AUC 0-last (nM h) 24902490 86308630 2620026200 2570025700 160000160000
生物利用度(％)bioavailability(%) ---- 69.869.8 69.869.8 ---- 127127
T 1/2：半衰期；Vd ss：分布容积；Cl：清除率；AUC 0-last：曲线下面积；C 0：起始浓度；C max：最大浓度；T max：浓度达峰时间。 T 1/2 : half-life; Vd ss : volume of distribution; Cl: clearance; AUC 0-last : area under the curve; C 0 : initial concentration; C max : maximum concentration; T max : time to peak concentration.
实施例23 包含式(II)化合物晶型B的片剂产品的体内药4代动力学研究Example 23 In vivo pharmacokinetic study of tablet product containing compound of formula (II) Form B
口服给药组3只比格犬(雄性)，通过口服给予实施例14所得包含式(II)化合物晶型B的片剂产品。口服给药片剂产品组动物于给药前(0)和给药后0.25、0.50、1.0、2.0、4.0、8.0和24.0小时采集血浆样品。经乙腈沉淀蛋白后，取上清进样，采用LC-MS/MS法测定血药浓度，使用WinNonlin Version 6.3(Pharsight，Mountain View，CA)药动学软件，以非房室模型线性对数梯形法计算包含式(II)化合物晶型B的片剂产品的相关药代动力学参数。In the oral administration group, 3 beagle dogs (male) were orally administered the tablet product comprising the crystal form B of the compound of formula (II) obtained in Example 14. Plasma samples were collected from animals in the oral tablet product group at pre-dose (0) and at 0.25, 0.50, 1.0, 2.0, 4.0, 8.0, and 24.0 hours post-dose. After protein precipitation with acetonitrile, the supernatant was injected, and the plasma concentration was determined by LC-MS/MS. The relevant pharmacokinetic parameters of the tablet product comprising the compound of formula (II) Form B were calculated by the method.
药代动力学研究结果显示，与静脉注射相比(见表33所示静脉注射数据)，口服给药后的片剂产品(表34)在犬体内具有极佳的PK性质，口服生物利用度高。The results of the pharmacokinetic study showed that the tablet product (Table 34) after oral administration had excellent PK properties in dogs compared to intravenous administration (see Table 33 for intravenous data), and oral bioavailability high.
表34 实施例14所得片剂产品在比格犬体内的药代动力学评价结果Table 34 Pharmacokinetic evaluation results of the tablet product obtained in Example 14 in Beagle dogs
给药方式way of administration 口服给药Oral administration
给药量Dosage 150mg/动物150mg/animal
C max(nM) Cmax (nM) 1896718967
T max(h) Tmax (h) 0.5000.500
T 1/2(h) T 1/2 (h) 2.532.53
AμC 0-last(nM·h) AμC 0-last (nM h) 4375143751
AμC 0-inf(nM·h) AμC 0-inf (nM h) 4448544485
F％F% 83.6783.67

Claims (21)

  1. 式(I)化合物的晶型A，其Cu Kα辐射的X射线粉末衍射图谱在下列任意一组2θ角处具有特征衍射峰：The crystal form A of the compound of formula (I), the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at any of the following sets of 2θ angles:
    (1)15.96±0.20°、18.65±0.20°、20.94±0.20°和23.57±0.20°；(1) 15.96±0.20°, 18.65±0.20°, 20.94±0.20° and 23.57±0.20°;
    (2)7.97±0.20°、13.21±0.20°、14.17±0.20°、15.96±0.20°、18.65±0.20°、20.94±0.20°、21.52±0.20°和23.57±0.20°；(2) 7.97±0.20°, 13.21±0.20°, 14.17±0.20°, 15.96±0.20°, 18.65±0.20°, 20.94±0.20°, 21.52±0.20° and 23.57±0.20°;
    (3)7.97±0.20°、12.20±0.20°、12.78±0.20°、13.21±0.20°、14.17±0.20°、15.96±0.20°、18.65±0.20°、20.94±0.20°、21.52±0.20°、22.05±0.20°、23.57±0.20°和25.01±0.20°；(3) 7.97±0.20°, 12.20±0.20°, 12.78±0.20°, 13.21±0.20°, 14.17±0.20°, 15.96±0.20°, 18.65±0.20°, 20.94±0.20°, 21.52±0.20°, 22.05± 0.20°, 23.57±0.20° and 25.01±0.20°;
    (4)5.84°、7.97°、9.30°、11.69°、12.20°、12.78°、13.21°、14.17°、14.86°、15.52°、15.96°、16.60°、16.91°、17.58°、18.25°、18.65°、19.21°、19.50°、20.11°、20.94°、21.52°、22.05°、22.80°、23.05°、23.57°、24.06°、25.01°、25.33°、26.49°、26.93°、27.36°、28.09°、28.54°和29.96°；(4) 5.84°, 7.97°, 9.30°, 11.69°, 12.20°, 12.78°, 13.21°, 14.17°, 14.86°, 15.52°, 15.96°, 16.60°, 16.91°, 17.58°, 18.25°, 18.65° , 19.21°, 19.50°, 20.11°, 20.94°, 21.52°, 22.05°, 22.80°, 23.05°, 23.57°, 24.06°, 25.01°, 25.33°, 26.49°, 26.93°, 27.36°, 28.09°, 28.54 ° and 29.96°;
    Figure PCTCN2021105662-appb-100001
    Figure PCTCN2021105662-appb-100001
  2. 根据权利要求1所述的晶型A，其特征在于，具备下列任意一项特征：The crystal form A according to claim 1, characterized in that it has any one of the following characteristics:
    (1)其XRPD图谱如图1所示；(1) Its XRPD pattern is shown in Figure 1;
    (2)其差示扫描量热曲线在192.6℃处有吸热峰；(2) Its differential scanning calorimetry curve has an endothermic peak at 192.6 °C;
    (3)其DSC图谱如图2所示。(3) Its DSC spectrum is shown in Figure 2.
  3. 式(I)化合物药学上可接受的盐，其特征在于，所述药学上可接受的盐为氢溴酸盐、甲磺酸盐、草酸盐或磷酸盐，A pharmaceutically acceptable salt of the compound of formula (I), wherein the pharmaceutically acceptable salt is hydrobromide, mesylate, oxalate or phosphate,
    Figure PCTCN2021105662-appb-100002
    Figure PCTCN2021105662-appb-100002
  4. 根据权利要求3所述的药学上可接受的盐，其特征在于，所述药学上可接受的盐为如式(I-1)所示的水合物、如式(II)所示的水合物、如式(III)所示的化合物、如式(IV)所示的化合物、如式(V)所示的化合物或如式(VI)所示的化合物，The pharmaceutically acceptable salt according to claim 3, wherein the pharmaceutically acceptable salt is a hydrate represented by formula (I-1), a hydrate represented by formula (II) , a compound represented by formula (III), a compound represented by formula (IV), a compound represented by formula (V) or a compound represented by formula (VI),
    Figure PCTCN2021105662-appb-100003
    Figure PCTCN2021105662-appb-100003
    其中，x为0.9～1.1，y为0.9～1.1。Here, x is 0.9 to 1.1, and y is 0.9 to 1.1.
  5. 如权利要求4中所述式(II)化合物的晶型B，其Cu Kα辐射的X射线粉末衍射图谱在下列任意一组2θ角处具有特征衍射峰：The crystalline form B of the compound of formula (II) as claimed in claim 4, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at any of the following sets of 2θ angles:
    Figure PCTCN2021105662-appb-100004
    Figure PCTCN2021105662-appb-100004
    (1)10.98±0.20°、19.53±0.20°、24.37±0.20°和25.32±0.20°；(1) 10.98±0.20°, 19.53±0.20°, 24.37±0.20° and 25.32±0.20°;
    (2)9.27±0.20°、10.98±0.20°、13.99±0.20°、19.53±0.20°、22.01±0.20°、24.37±0.20°、25.32±0.20°和26.90±0.20°；(2) 9.27±0.20°, 10.98±0.20°, 13.99±0.20°, 19.53±0.20°, 22.01±0.20°, 24.37±0.20°, 25.32±0.20° and 26.90±0.20°;
    (3)9.27±0.20°、10.98±0.20°、13.99±0.20°、14.83±0.20°、17.50±0.20°、19.53±0.20°、20.37±0.20°、22.01±0.20°、24.37±0.20°、24.78±0.20°、25.32±0.20°和26.90±0.20°；(3) 9.27±0.20°, 10.98±0.20°, 13.99±0.20°, 14.83±0.20°, 17.50±0.20°, 19.53±0.20°, 20.37±0.20°, 22.01±0.20°, 24.37±0.20°, 24.78± 0.20°, 25.32±0.20° and 26.90±0.20°;
    (4)8.41°、9.27°、10.98°、11.64°、13.99°、14.44°、14.83°、17.50°、18.55°、19.53°、19.78°、 20.37°、21.08°、21.48°、22.01°、22.76°、23.41°、23.84°、24.37°、24.78°、25.32°、26.90°、27.34°、28.15°、29.29°、29.96°、30.36°、31.23°、32.70°、33.25°、34.17°、35.50°和38.32°。(4) 8.41°, 9.27°, 10.98°, 11.64°, 13.99°, 14.44°, 14.83°, 17.50°, 18.55°, 19.53°, 19.78°, 20.37°, 21.08°, 21.48°, 22.01°, 22.76° , 23.41°, 23.84°, 24.37°, 24.78°, 25.32°, 26.90°, 27.34°, 28.15°, 29.29°, 29.96°, 30.36°, 31.23°, 32.70°, 33.25°, 34.17°, 35.50° and 38.32 °.
  6. 根据权利要求5所述的晶型B，其特征在于，具备下列任意一项特征：The crystal form B according to claim 5, characterized in that it has any one of the following characteristics:
    (1)其XRPD图谱如图5所示；(1) Its XRPD pattern is shown in Figure 5;
    (2)其差示扫描量热曲线在130.7℃和181.8℃处有吸热峰；(2) Its differential scanning calorimetry curve has endothermic peaks at 130.7°C and 181.8°C;
    (3)其DSC图谱如图6所示。(3) Its DSC spectrum is shown in FIG. 6 .
  7. 如权利要求4中所述式(III)化合物的晶型C，其Cu Kα辐射的X射线粉末衍射图谱在下列任意一组2θ角处具有特征衍射峰：The crystalline form C of the compound of formula (III) as claimed in claim 4, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at any of the following sets of 2θ angles:
    Figure PCTCN2021105662-appb-100005
    Figure PCTCN2021105662-appb-100005
    (1)11.21±0.20°、18.69±0.20°、22.47±0.20°和25.60±0.20°；(1) 11.21±0.20°, 18.69±0.20°, 22.47±0.20° and 25.60±0.20°;
    (2)7.38±0.20°、11.21±0.20°、16.64±0.20°、18.69±0.20°、21.25±0.20°、22.47±0.20°、25.60±0.20°和29.98±0.20°；(2) 7.38±0.20°, 11.21±0.20°, 16.64±0.20°, 18.69±0.20°, 21.25±0.20°, 22.47±0.20°, 25.60±0.20° and 29.98±0.20°;
    (3)7.38±0.20°、11.21±0.20°、16.64±0.20°、18.69±0.20°、20.57±0.20°、21.25±0.20°、21.80±0.20°、22.47±0.20°、25.60±0.20°、26.27±0.20°、28.50±0.20°和29.98±0.20°；(3) 7.38±0.20°, 11.21±0.20°, 16.64±0.20°, 18.69±0.20°, 20.57±0.20°, 21.25±0.20°, 21.80±0.20°, 22.47±0.20°, 25.60±0.20°, 26.27± 0.20°, 28.50±0.20° and 29.98±0.20°;
    (4)7.38°、10.33°、11.21°、14.75°、16.64°、17.84°、18.69°、19.41°、20.57°、21.25°、21.80°、22.47°、22.81°、23.12°、25.24°、25.60°、26.27°、27.61°、28.50°、28.76°、29.64°、29.98°、31.65°和32.94°。(4) 7.38°, 10.33°, 11.21°, 14.75°, 16.64°, 17.84°, 18.69°, 19.41°, 20.57°, 21.25°, 21.80°, 22.47°, 22.81°, 23.12°, 25.24°, 25.60° , 26.27°, 27.61°, 28.50°, 28.76°, 29.64°, 29.98°, 31.65° and 32.94°.
  8. 根据权利要求7所述的晶型C，其特征在于，具备下列任意一项特征：Crystal form C according to claim 7, is characterized in that, possesses any one of the following characteristics:
    (1)其XRPD图谱如图9所示；(1) Its XRPD pattern is shown in Figure 9;
    (2)其差示扫描量热曲线在232.4℃处有吸热峰；(2) Its differential scanning calorimetry curve has an endothermic peak at 232.4 °C;
    (3)其DSC图谱如图10所示。(3) Its DSC spectrum is shown in Figure 10.
  9. 如权利要求4中所述式(IV)化合物的晶型D，其Cu Kα辐射的X射线粉末衍射图谱在下列任意一组2θ角处具有特征衍射峰：The crystalline form D of the compound of formula (IV) as claimed in claim 4, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at any of the following sets of 2θ angles:
    Figure PCTCN2021105662-appb-100006
    Figure PCTCN2021105662-appb-100006
    (1)5.74±0.20°、8.84±0.20°、11.91±0.20°、16.70±0.20°、17.61±0.20°、18.45±0.20°、19.09±0.20°、20.46±0.20°、22.98±0.20°、25.35±0.20°、25.81±0.20°和27.22±0.20°；(1) 5.74±0.20°, 8.84±0.20°, 11.91±0.20°, 16.70±0.20°, 17.61±0.20°, 18.45±0.20°, 19.09±0.20°, 20.46±0.20°, 22.98±0.20°, 25.35± 0.20°, 25.81±0.20° and 27.22±0.20°;
    (2)5.74°、8.84°、11.91°、13.28°、13.88°、15.00°、16.70°、17.61°、18.21°、18.45°、19.09°、20.46°、21.76°、22.98°、23.94°、25.35°、25.81°、26.64°、27.22°、27.82°、29.04°、30.64°、31.11°、33.24°、33.80°、35.94°和39.19°。(2) 5.74°, 8.84°, 11.91°, 13.28°, 13.88°, 15.00°, 16.70°, 17.61°, 18.21°, 18.45°, 19.09°, 20.46°, 21.76°, 22.98°, 23.94°, 25.35° , 25.81°, 26.64°, 27.22°, 27.82°, 29.04°, 30.64°, 31.11°, 33.24°, 33.80°, 35.94° and 39.19°.
  10. 根据权利要求9所述的晶型D，其特征在于，具备下列任意一项特征：Crystal form D according to claim 9, is characterized in that, possesses any one of the following characteristics:
    (1)其XRPD图谱如图12所示；(1) Its XRPD pattern is shown in Figure 12;
    (2)其差示扫描量热曲线在204.4℃处有吸热峰；(2) Its differential scanning calorimetry curve has an endothermic peak at 204.4 °C;
    (3)其DSC图谱如图13所示。(3) Its DSC spectrum is shown in FIG. 13 .
  11. 如权利要求4中式(V)化合物的晶型E或晶型F，其中，Form E or Form F of the compound of formula (V) in claim 4, wherein,
    所述晶型E在Cu Kα辐射的X射线粉末衍射图谱在下列任意一组2θ角处具有特征衍射峰：The X-ray powder diffraction pattern of the crystal form E in Cu Kα radiation has characteristic diffraction peaks at any of the following 2θ angles:
    Figure PCTCN2021105662-appb-100007
    Figure PCTCN2021105662-appb-100007
    (1)6.83±0.20°、7.25±0.20°、10.56±0.20°、13.18±0.20°、18.10±0.20°、19.00±0.20°、19.77±0.20°、20.20±0.20°、22.16±0.20°、23.90±0.20°、24.37±0.20°和25.58±0.20°；(1) 6.83±0.20°, 7.25±0.20°, 10.56±0.20°, 13.18±0.20°, 18.10±0.20°, 19.00±0.20°, 19.77±0.20°, 20.20±0.20°, 22.16±0.20°, 23.90± 0.20°, 24.37±0.20° and 25.58±0.20°;
    (2)5.12°、6.39°、6.83°、7.25°、9.96°、10.56°、12.75°、13.18°、13.60°、14.56°、14.95°、15.66°、16.76°、17.17°、18.10°、19.00°、19.36°、19.77°、20.20°、20.80°、21.80°、22.16°、22.53°、23.90°、24.37°、25.00°、25.58°、26.01°、26.93°、27.66°、28.36°、29.27°、32.17°、32.68°和36.51°；(2) 5.12°, 6.39°, 6.83°, 7.25°, 9.96°, 10.56°, 12.75°, 13.18°, 13.60°, 14.56°, 14.95°, 15.66°, 16.76°, 17.17°, 18.10°, 19.00° , 19.36°, 19.77°, 20.20°, 20.80°, 21.80°, 22.16°, 22.53°, 23.90°, 24.37°, 25.00°, 25.58°, 26.01°, 26.93°, 27.66°, 28.36°, 29.27°, 32.17 °, 32.68° and 36.51°;
    所述晶型F在Cu Kα辐射的X射线粉末衍射图谱在下列任意一组2θ角处具有特征衍射峰：The X-ray powder diffraction pattern of the crystal form F in Cu Kα radiation has characteristic diffraction peaks at any of the following sets of 2θ angles:
    (1)5.15±0.20°、7.93±0.20°、10.56±0.20°、15.40±0.20°、16.79±0.20°、17.98±0.20°、19.33±0.20°、20.20±0.20°、21.11±0.20°、22.49±0.20°、23.84±0.20°和26.63±0.20°；(1) 5.15±0.20°, 7.93±0.20°, 10.56±0.20°, 15.40±0.20°, 16.79±0.20°, 17.98±0.20°, 19.33±0.20°, 20.20±0.20°, 21.11±0.20°, 22.49± 0.20°, 23.84±0.20° and 26.63±0.20°;
    (2)5.15°、6.44°、7.93°、10.56°、11.69°、12.82°、13.45°、15.40°、16.26°、16.79°、17.98°、19.33°、20.20°、21.11°、22.04°、22.49°、23.49°、23.84°、24.32°、25.80°、26.63°、27.39°、28.47°、34.57°和 36.44°。(2) 5.15°, 6.44°, 7.93°, 10.56°, 11.69°, 12.82°, 13.45°, 15.40°, 16.26°, 16.79°, 17.98°, 19.33°, 20.20°, 21.11°, 22.04°, 22.49° , 23.49°, 23.84°, 24.32°, 25.80°, 26.63°, 27.39°, 28.47°, 34.57° and 36.44°.
  12. 根据权利要求11所述的晶型E或晶型F，其特征在于，The crystal form E or crystal form F according to claim 11, wherein,
    所述晶型E具备下列任意一项特征：The crystal form E has any one of the following characteristics:
    (1)其XRPD图谱如图16所示；(1) Its XRPD pattern is shown in Figure 16;
    (2)其差示扫描量热曲线在82.1℃、129.3℃、145.6℃、168.3℃处有吸热峰；(2) Its differential scanning calorimetry curve has endothermic peaks at 82.1°C, 129.3°C, 145.6°C and 168.3°C;
    (3)其DSC图谱如图17所示；(3) its DSC spectrum is shown in Figure 17;
    所述晶型F具备下列任意一项特征：The crystal form F has any one of the following characteristics:
    (1)其XRPD图谱如图19所示；(1) Its XRPD pattern is shown in Figure 19;
    (2)其差示扫描量热曲线在97.6℃、145.3℃、211.5℃处有吸热峰；(2) Its differential scanning calorimetry curve has endothermic peaks at 97.6°C, 145.3°C and 211.5°C;
    (3)其DSC图谱如图20所示。(3) Its DSC spectrum is shown in Figure 20.
  13. 如权利要求4中所述式(VI)化合物的晶型G，其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：The crystal form G of the compound of formula (VI) as claimed in claim 4, the X-ray powder diffraction pattern of its Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles:
    Figure PCTCN2021105662-appb-100008
    Figure PCTCN2021105662-appb-100008
    4.94°±0.20°、9.84°±0.20°、10.60°±0.20°、14.75°±0.20°、15.72°±0.20°、16.85°±0.20°、18.04°±0.20°、18.99°±0.20°、20.37°±0.20°、21.20°±0.20°、21.75°±0.20°、22.32°±0.20°、23.51°±0.20°、24.70°±0.20°、26.73°±0.20°和29.12°±0.20°。4.94°±0.20°, 9.84°±0.20°, 10.60°±0.20°, 14.75°±0.20°, 15.72°±0.20°, 16.85°±0.20°, 18.04°±0.20°, 18.99°±0.20°, 20.37° ±0.20°, 21.20°±0.20°, 21.75°±0.20°, 22.32°±0.20°, 23.51°±0.20°, 24.70°±0.20°, 26.73°±0.20° and 29.12°±0.20°.
  14. 根据权利要求13所述的晶型G，其特征在于，具备下列任意一项特征：The crystal form G according to claim 13, characterized in that it has any one of the following characteristics:
    (1)其XRPD图谱如图22所示；(1) Its XRPD pattern is shown in Figure 22;
    (2)其差示扫描量热曲线在62.4℃、98.4℃、110.7℃、158.0℃处有吸热峰；(2) Its differential scanning calorimetry curve has endothermic peaks at 62.4°C, 98.4°C, 110.7°C and 158.0°C;
    (3)其DSC图谱如图23所示。(3) Its DSC spectrum is shown in FIG. 23 .
  15. 一种药物组合物，其包含活性成分、填充剂、粘合剂、崩解剂和润滑剂，A pharmaceutical composition comprising an active ingredient, a filler, a binder, a disintegrant and a lubricant,
    Figure PCTCN2021105662-appb-100009
    Figure PCTCN2021105662-appb-100009
    所述活性成分为式(I)化合物或其药学上可接受盐。The active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  16. 根据权利要求15所述的药物组合物，其特征在于，所述药物组合物的剂型为片剂。The pharmaceutical composition according to claim 15, wherein the dosage form of the pharmaceutical composition is a tablet.
  17. 根据权利要求16所述的药物组合物，其特征在于，所述片剂每片由以下质量分数的成分组成：活性成分10％～15％、填充剂75％～82％、粘合剂1％～3％、崩解剂4％～10％和润滑剂1％～3％。The pharmaceutical composition according to claim 16, wherein each tablet is composed of the following components by mass fraction: 10%-15% of active ingredients, 75%-82% of filler, and 1% of binder ~3%, disintegrant 4%~10% and lubricant 1%~3%.
  18. 根据权利要求17所述的药物组合物，其特征在于，所述片剂每片由以下质量分数的成分组成：活性成分12.06％、填充剂78.94％、粘合剂1.5％、崩解剂6.0％和润滑剂1.5％。The pharmaceutical composition according to claim 17, wherein each tablet is composed of the following ingredients in mass fraction: active ingredient 12.06%, filler 78.94%, binder 1.5%, disintegrant 6.0% and lubricant 1.5%.
  19. 根据权利要求15-18任一项所述的药物组合物，其特征在于，所述填充剂选自微晶纤维素、甘露醇、乳糖、淀粉、蔗糖或预胶化淀粉中一种或多种；The pharmaceutical composition according to any one of claims 15-18, wherein the filler is selected from one or more of microcrystalline cellulose, mannitol, lactose, starch, sucrose or pregelatinized starch ;
    所述粘合剂选自羟丙甲纤维素、聚维酮、羟丙基纤维素、甲基纤维素、乙基纤维素或羧甲基纤维素钠中一种或多种；The binder is selected from one or more of hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or sodium carboxymethyl cellulose;
    所述崩解剂选自交联羧甲纤维素钠、羧甲淀粉钠、羟丙基淀粉、低取代羟丙纤维素或交联聚维酮中一种或多种；The disintegrating agent is selected from one or more of croscarmellose sodium, sodium starch glycolate, hydroxypropyl starch, low-substituted hydroxypropyl cellulose or crospovidone;
    所述润滑剂选自胶态二氧化硅、硬脂酸镁、硬脂酸、滑石粉或硬脂富马酸钠中一种或多种。The lubricant is selected from one or more of colloidal silicon dioxide, magnesium stearate, stearic acid, talc or sodium stearyl fumarate.
  20. 根据权利要求16所述的药物组合物，其特征在于，所述片剂每片由选自以下任意一组质量分数的成分组成：The pharmaceutical composition according to claim 16, wherein each of the tablets is composed of ingredients selected from any of the following mass fractions:
    (1)活性成分12.06％、微晶纤维素58.94％、甘露醇20％、胶态二氧化硅0.5％、羟丙甲纤维素1.5％、交联羧甲纤维素钠6.0％和硬脂酸镁1.0％；(1) Active ingredients 12.06%, microcrystalline cellulose 58.94%, mannitol 20%, colloidal silica 0.5%, hypromellose 1.5%, croscarmellose sodium 6.0% and magnesium stearate 1.0%;
    (2)活性成分12.06％、微晶纤维素58.94％、乳糖20％、胶态二氧化硅0.5％、羟丙甲纤维素1.5％、交联羧甲纤维素钠6.0％和硬脂酸镁1.0％；(2) Active ingredient 12.06%, microcrystalline cellulose 58.94%, lactose 20%, colloidal silicon dioxide 0.5%, hypromellose 1.5%, croscarmellose sodium 6.0% and magnesium stearate 1.0 %;
    (3)活性成分12.06％、微晶纤维素20％、乳糖58.94％、胶态二氧化硅0.5％、羟丙甲纤维素1.5％、交联羧甲纤维素钠6.0％和硬脂酸镁1.0％；(3) Active ingredients 12.06%, microcrystalline cellulose 20%, lactose 58.94%, colloidal silicon dioxide 0.5%, hypromellose 1.5%, croscarmellose sodium 6.0% and magnesium stearate 1.0 %;
    (4)活性成分12.06％、微晶纤维素58.94％、乳糖20％、胶态二氧化硅0.5％、羟丙甲纤维素1.5％、羧甲淀粉钠6.0％和硬脂酸镁1.0％；(4) Active ingredients 12.06%, microcrystalline cellulose 58.94%, lactose 20%, colloidal silicon dioxide 0.5%, hypromellose 1.5%, sodium starch glycolate 6.0% and magnesium stearate 1.0%;
    所述活性成分为权利要求3所述的如式(I-1)所示的水合物、如式(II)所示的水合物、如式(III)所示的化合物、权利要求5或6所述的式(II)化合物的晶型B或权利要求7或8所述的式(III)化合物的晶型C。The active ingredient is the hydrate represented by the formula (I-1) of claim 3, the hydrate represented by the formula (II), the compound represented by the formula (III), claim 5 or 6 The crystalline form B of the compound of formula (II) or the crystalline form C of the compound of formula (III) according to claim 7 or 8.
  21. 根据权利要求15-18或20任一项所述的药物组合物，其特征在于，所述活性成分为式(II)化合物的晶型B。The pharmaceutical composition according to any one of claims 15-18 or 20, wherein the active ingredient is the crystal form B of the compound of formula (II).
PCT/CN2021/105662 2020-07-23 2021-07-12 SALT FORM AND CRYSTAL FORM OF PYRIDYLOXY PYRAZOLE COMPOUND AS TGF-βR1 INHIBITOR, AND PHARMACEUTICAL COMPOSITION THEREOF WO2022017208A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180007608.5A CN114867723B (en) 2020-07-23 2021-07-12 Salt forms, crystal forms and pharmaceutical compositions of pyridyloxy-pyrazoles as TGF-beta R1 inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010717761 2020-07-23
CN202010717761.4 2020-07-23

Publications (1)

Publication Number Publication Date
WO2022017208A1 true WO2022017208A1 (en) 2022-01-27

Family

ID=79728505

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/105662 WO2022017208A1 (en) 2020-07-23 2021-07-12 SALT FORM AND CRYSTAL FORM OF PYRIDYLOXY PYRAZOLE COMPOUND AS TGF-βR1 INHIBITOR, AND PHARMACEUTICAL COMPOSITION THEREOF

Country Status (2)

Country Link
CN (1) CN114867723B (en)
WO (1) WO2022017208A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1951939A (en) * 2001-05-24 2007-04-25 伊莱利利公司 Novel pyrrole derivatives as pharmaceutical agents
TW201329067A (en) * 2011-12-08 2013-07-16 Amgen Inc Urea compounds as GKA activators
CN106795139A (en) * 2014-10-07 2017-05-31 伊莱利利公司 Aminopyridine base epoxide pyrazole compound
WO2020151749A1 (en) * 2019-01-24 2020-07-30 南京明德新药研发有限公司 5-(4-PYRIDYLOXY)PYRAZOLE COMPOUNDS SERVING AS TGF-βR1 KINASE INHIBITOR

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1951939A (en) * 2001-05-24 2007-04-25 伊莱利利公司 Novel pyrrole derivatives as pharmaceutical agents
TW201329067A (en) * 2011-12-08 2013-07-16 Amgen Inc Urea compounds as GKA activators
CN106795139A (en) * 2014-10-07 2017-05-31 伊莱利利公司 Aminopyridine base epoxide pyrazole compound
WO2020151749A1 (en) * 2019-01-24 2020-07-30 南京明德新药研发有限公司 5-(4-PYRIDYLOXY)PYRAZOLE COMPOUNDS SERVING AS TGF-βR1 KINASE INHIBITOR

Also Published As

Publication number Publication date
CN114867723B (en) 2023-05-30
CN114867723A (en) 2022-08-05

Similar Documents

Publication Publication Date Title
US11753406B2 (en) Salts of a PD-1/PD-L1 inhibitor
EP3390389B1 (en) Polycyclic tlr7/8 antagonists and use thereof in the treatment of immune disorders
TW202126652A (en) Pyrido[3,2-d]pyrimidine compounds as immunomodulators
EP1557415B1 (en) Heterocyclic compounds and antitumor drugs containing the same as the active ingredient
TR201807311T4 (en) Dispiropyrrolidine derivative.
TW201536779A (en) Chemical compounds
WO2018018986A1 (en) Diphenylaminopyrimidine and triazine compound, and pharmaceutical composition and use thereof
KR20070032810A (en) 2,4,6-trisubstituted pyrimidines as phosphatidyl inositol (PI) 3-kinase inhibitors and their use in the treatment of cancer
WO2018228446A1 (en) Aminopyrimidine compound, preparation method therefor and use thereof
TW202208375A (en) Salt and crystal forms of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1h-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7h)-one
TW200800194A (en) Kinase inhibitors
EP3725786B1 (en) Crystal form and salt form of tgf-bri inhibitor and preparation method therefor
WO2022028367A1 (en) Solid form of compound
WO2022017208A1 (en) SALT FORM AND CRYSTAL FORM OF PYRIDYLOXY PYRAZOLE COMPOUND AS TGF-βR1 INHIBITOR, AND PHARMACEUTICAL COMPOSITION THEREOF
CN102971296A (en) Pharmaceutical compositions comprising n-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-l-(4-fluorophenyl)-2-oxo- 1,2-dihydropyridine-3 -carboxamide
WO2023151559A1 (en) Heterocyclic compound, pharmaceutical composition containing same, and anti-tumor use thereof
WO2021197339A1 (en) Crystal form of quinopyrrolidine-2-one compound serving as atm inhibitor and use thereof
CA3098336A1 (en) Crystal form of c-met inhibitor and salt form thereof and preparation method therefor
WO2022016420A1 (en) Quinazolinone compound crystal form, preparation method therefor, and use thereof
TW201941774A (en) Dihydrochromene derivative
WO2023025164A1 (en) Crystal forms, preparation method and application of aryl phosphine oxide compound
WO2023104107A1 (en) Salt of 3,4-dihydroisoquinoline compound and use thereof
WO2022017446A1 (en) Unit dosage composition of akt inhibitor
WO2020043078A1 (en) Salt form and crystal form of novel azatricyclic compound and use thereof
US20230115605A1 (en) Crystal form of aromatic vinyl derivatives, and preparation method therefor and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21847111

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21847111

Country of ref document: EP

Kind code of ref document: A1