WO2022017208A1 - FORME DE SEL ET FORME CRISTALLINE D'UN COMPOSÉ DE PYRIDYLOXY PYRAZOLE UTILISÉ EN TANT QU'INHIBITEUR DE TGF-βR1 ET COMPOSITION PHARMACEUTIQUE ASSOCIÉE - Google Patents

FORME DE SEL ET FORME CRISTALLINE D'UN COMPOSÉ DE PYRIDYLOXY PYRAZOLE UTILISÉ EN TANT QU'INHIBITEUR DE TGF-βR1 ET COMPOSITION PHARMACEUTIQUE ASSOCIÉE Download PDF

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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
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formula
compound
crystal form
pharmaceutical composition
present
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PCT/CN2021/105662
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Chinese (zh)
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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
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江苏奥赛康药业有限公司
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Priority to CN202180007608.5A priority Critical patent/CN114867723B/zh
Publication of WO2022017208A1 publication Critical patent/WO2022017208A1/fr

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    • 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.

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Abstract

L'invention concerne une forme de sel et une forme cristalline d'un composé de 5-(4-pyridyloxy) pyrazole utilisé en tant que médicament inhibiteur de TGF-βR1, un procédé de préparation correspondant, une composition pharmaceutique associée et un procédé de préparation de la composition pharmaceutique. En particulier, l'invention concerne une forme cristalline et une forme de sel d'un composé de formule (I), et une forme cristalline de la forme de sel. En particulier, l'invention concerne également une composition pharmaceutique comprenant le composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2021/105662 2020-07-23 2021-07-12 FORME DE SEL ET FORME CRISTALLINE D'UN COMPOSÉ DE PYRIDYLOXY PYRAZOLE UTILISÉ EN TANT QU'INHIBITEUR DE TGF-βR1 ET COMPOSITION PHARMACEUTIQUE ASSOCIÉE WO2022017208A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1951939A (zh) * 2001-05-24 2007-04-25 伊莱利利公司 作为药物的新的吡唑衍生物
TW201329067A (zh) * 2011-12-08 2013-07-16 Amgen Inc 作為ｇｋａ活化劑之脲化合物
CN106795139A (zh) * 2014-10-07 2017-05-31 伊莱利利公司 氨基吡啶基氧基吡唑化合物
WO2020151749A1 (fr) * 2019-01-24 2020-07-30 南京明德新药研发有限公司 COMPOSÉS 5-(4-PYRIDYLOXY)PYRAZOLE FAISANT OFFICE D'INHIBITEUR DE LA KINASE TGF-βR1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1951939A (zh) * 2001-05-24 2007-04-25 伊莱利利公司 作为药物的新的吡唑衍生物
TW201329067A (zh) * 2011-12-08 2013-07-16 Amgen Inc 作為ｇｋａ活化劑之脲化合物
CN106795139A (zh) * 2014-10-07 2017-05-31 伊莱利利公司 氨基吡啶基氧基吡唑化合物
WO2020151749A1 (fr) * 2019-01-24 2020-07-30 南京明德新药研发有限公司 COMPOSÉS 5-(4-PYRIDYLOXY)PYRAZOLE FAISANT OFFICE D'INHIBITEUR DE LA KINASE TGF-βR1

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