WO2022247885A1 - Cristal et sel de composé trihétérocyclique et leur utilisation - Google Patents

Cristal et sel de composé trihétérocyclique et leur utilisation Download PDF

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WO2022247885A1
WO2022247885A1 PCT/CN2022/095126 CN2022095126W WO2022247885A1 WO 2022247885 A1 WO2022247885 A1 WO 2022247885A1 CN 2022095126 W CN2022095126 W CN 2022095126W WO 2022247885 A1 WO2022247885 A1 WO 2022247885A1
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compound
formula
angles
following
alternatively
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PCT/CN2022/095126
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WO2022247885A9 (fr
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毛魏魏
樊莉莉
钱文远
韦昌青
陈曙辉
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正大天晴药业集团股份有限公司
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Priority to CN202280033492.7A priority Critical patent/CN117295739A/zh
Publication of WO2022247885A1 publication Critical patent/WO2022247885A1/fr
Publication of WO2022247885A9 publication Critical patent/WO2022247885A9/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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This application relates to the crystal of the compound of formula (I), its salt and the crystal of the salt, and its application in the preparation of medicines for treating diseases related to JAKs.
  • Janus kinases are cytoplasmic tyrosine kinases that transmit cytokine signals, from membrane receptors to STAT transcription factors.
  • the JAK family consists of four members: JAK1, JAK2, JAK3 and TYK2.
  • the JAK-STAT pathway transduces extracellular signals from a variety of cytokines, growth factors and hormones to the nucleus and is responsible for the expression of thousands of protein-coding genes.
  • JAK-STAT intracellular signal transduction serves interferons, most interleukins, and various cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker W. et al .(2008).
  • JAK-1, JAK-2 and TYK-2 are expressed in various tissue cells of the human body, and JAK-3 is mainly expressed in various hematopoietic tissue cells, mainly in bone marrow cells, thymocytes, NK cells and activated B lymphocytes , T lymphocytes.
  • JAK1 has emerged as a novel target in disease areas such as immunity, inflammation and cancer.
  • a base mutation JAK2V617F on the JAK2 gene in humans is associated with polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), chronic It is closely related to the occurrence of myeloid leukemia (CML).
  • JAK3 Mutations in either JAK3 or ⁇ c can cause severe combined immunodeficiency.
  • the abnormal activity of JAK3 is manifested by a large reduction of T cells and NK cells and loss of B cell function, which seriously affects the normal biological functions of the immune system.
  • JAK3 Based on its functional characteristics and special tissue distribution, JAK3 has become an attractive drug target for immune system-related diseases.
  • the loss of TYK2 function will cause defects in the signaling pathways of various cytokine receptors, which will lead to viral infection, decreased antibacterial immune function, and increased the possibility of lung infection (John J.O'Shea, 2004 , Nature Reviews Drug Discovery 3, 555-564).
  • JAK inhibitors selectively bind to different cytokine receptors, endow signal transduction specificity, and thus play different physiological roles.
  • This selective mode of action makes JAK inhibitors relatively specific for diseases treat.
  • IL-2 or IL-4 receptors bind JAK1 and JAK3 along with a common gamma chain, whereas type I receptors with the same beta chain bind JAK2.
  • Type I receptors using gp130 (glycoprotein 130) and activated by heterodimeric cytokines preferentially bind JAK1/2 and TYK2.
  • Type I receptors activated by hormone-like cytokines bind and activate the JAK2 kinase.
  • Type II receptors for interferons bind JAK1 and TYK2, whereas receptors of the IL-10 cytokine family bind JAK1/2 and TYK2.
  • Various specific combinations of the cytokines and their receptors with JAK family members trigger different physiological effects and provide the possibility for the treatment of different diseases. Heterodimerization of JAK1 with other JAKs to transduce cytokine-driven pro-inflammatory signaling. Therefore, inhibition of JAK1 and/or other JAKs is expected to be of therapeutic benefit for a range of inflammatory disorders and other diseases driven by JAK-mediated signaling (Daniella M. Schwartz, 2017, Nature Reviews Drug Discovery 16, 843-862. )
  • the application provides a compound of formula (I) or a salt thereof
  • the salt of the compound of formula (I) is selected from phosphate or oxalate.
  • the present application provides crystals of the compound of formula (I) or a salt thereof.
  • the application provides crystals of the phosphate salt of the compound of formula (I) or crystals of the oxalate salt of the compound of formula (I).
  • the application provides the type A crystal of the compound of formula (I), which has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu K ⁇ radiation: 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20° and 12.28 ⁇ 0.2 °;
  • the X-ray powder diffraction pattern of the type A crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 9.25 ⁇ 0.20°, 12.28 ⁇ 0.20° and 14.46 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the type A crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 9.25 ⁇ 0.20°, 12.28 ⁇ 0.2°, 14.46 ⁇ 0.2°, 14.89 ⁇ 0.2°, and 21.06 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the type A crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 9.25 ⁇ 0.20°, 12.28 ⁇ 0.20°, 14.46 ⁇ 0.20°, 14.89 ⁇ 0.20°, 15.75 ⁇ 0.20°, 16.82 ⁇ 0.20°, 19.37 ⁇ 0.20°, and 21.06 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type A crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 8.80 ⁇ 0.20°, 9.25 ⁇ 0.20°, 12.28 ⁇ 0.20°, 14.23 ⁇ 0.20°, 14.46 ⁇ 0.20°, 14.89 ⁇ 0.20°, 15.75 ⁇ 0.20°, 16.82 ⁇ 0.20°, 17.32 ⁇ 0.20°, 17.84 ⁇ 0.20°, 19.37 ⁇ 0.20°, 21.06 ⁇ 0.20°, 22.76 ⁇ 0.20°, 24.11 ⁇ 0.20°, 26.16 ⁇ 0.20°, 26.76 ⁇ 0.20°, and 27.16 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type A crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 9.25 ⁇ 0.20°, 9.64 ⁇ 0.20°, 10.50 ⁇ 0.20°, 12.28 ⁇ 0.20°, and 14.46 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the type A crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 9.25 ⁇ 0.20°, 9.64 ⁇ 0.20°, 10.50 ⁇ 0.20°, 12.28 ⁇ 0.2°, 14.46 ⁇ 0.2°, 14.89 ⁇ 0.2°, and 21.06 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the type A crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, and 21.06 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type A crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 8.80 ⁇ 0.20°, 9.25 ⁇ 0.20°, 9.64 ⁇ 0.20°, 10.50 ⁇ 0.20°, 12.28 ⁇ 0.20°, 14.23 ⁇ 0.20°, 14.46 ⁇ 0.20°, 14.89 ⁇ 0.20°, 15.75 ⁇ 0.20°, 16.82 ⁇ 0.20°, 17.32 ⁇ 0.20°, 17.84 ⁇ 0.20°, 19.37 ⁇ 0.20°, 21.06 ⁇ 0.20°, 22.76 ⁇ 0.20°, 24.11 ⁇ 0.20°, 26.16 ⁇ 0.20°, 26.76 ⁇ 0.20°, and 27.16 ⁇ 0.20°.
  • the application provides the type A crystal of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, including 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 9.25 ⁇ 0.20°, 12.28 ⁇ 0.20°, 14.46 ⁇ 0.20°, 14.89 ⁇ 0.20°, 15.75 ⁇ 0.20° , 16.82 ⁇ 0.20°, 19.37 ⁇ 0.20° and 21.06 ⁇ 0.20°.
  • the application provides the type A crystal of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5, 6, 7 or Eight diffraction peaks: 5.26 ⁇ 0.20°, 5.74 ⁇ 0.20°, 7.23 ⁇ 0.20°, 9.25 ⁇ 0.20°, 12.28 ⁇ 0.2°, 14.46 ⁇ 0.2°, 14.89 ⁇ 0.2° and 21.06 ⁇ 0.2°.
  • the XRPD pattern of type A crystal of the compound of formula (I) is shown in FIG. 1 .
  • the differential scanning calorimetry (DSC) spectrum of Form A crystal of the compound of formula (I) has an onset point of an exothermic peak at 188.8 ⁇ 3°C.
  • the DSC spectrum of type A crystal of the compound of formula (I) is shown in FIG. 2 .
  • thermogravimetric analysis (TGA) pattern of the Form A crystal of the compound of formula (I) has a weight loss of 3.13% at 200 ⁇ 3°C.
  • the TGA spectrum of type A crystal of the compound of formula (I) is shown in FIG. 3 .
  • the present application provides a method for preparing type A crystals of the compound of formula (I), the method comprising the following steps: dissolving the compound of formula (I) in ethanol to precipitate a solid.
  • the compound of formula (I) is mixed with ethanol, and the solution of the compound of formula (I) is clarified by heating and stirring.
  • the resulting solution is cooled to precipitate a solid.
  • the above method further comprises the step of isolating the solid and then drying the solid; optionally, drying under vacuum.
  • the application also provides type B crystals of the compound of formula (I), which has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu K ⁇ radiation: 5.08 ⁇ 0.20°, 9.78 ⁇ 0.20° and 13.76 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type B crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.08 ⁇ 0.20°, 9.78 ⁇ 0.20°, 13.76 ⁇ 0.20°, 18.96 ⁇ 0.20°, and 24.34 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type B crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.08 ⁇ 0.20°, 9.78 ⁇ 0.20°, 13.76 ⁇ 0.20°, 15.80 ⁇ 0.20°, 18.96 ⁇ 0.20°, 19.61 ⁇ 0.20°, and 24.34 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type B crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.08 ⁇ 0.20°, 6.31 ⁇ 0.20°, 9.78 ⁇ 0.20°, 13.76 ⁇ 0.20°, 15.80 ⁇ 0.20°, 18.96 ⁇ 0.20°, 19.61 ⁇ 0.20°, and 24.34 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type B crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 5.08 ⁇ 0.20°, 6.31 ⁇ 0.20°, 9.78 ⁇ 0.20°, 11.75 ⁇ 0.20°, 13.76 ⁇ 0.20°, 14.17 ⁇ 0.20°, 15.80 ⁇ 0.20°, 18.96 ⁇ 0.20°, 19.61 ⁇ 0.20°, 23.87 ⁇ 0.20°, and 24.34 ⁇ 0.20°.
  • the application provides the type B crystal of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks: 5.08 ⁇ 0.20°, 6.31 ⁇ 0.20°, 9.78 ⁇ 0.20°, 11.75 ⁇ 0.20°, 13.76 ⁇ 0.20°, 14.17 ⁇ 0.20°, 15.80 ⁇ 0.20°, 18.96 ⁇ 0.20° , 19.61 ⁇ 0.20°, 23.87 ⁇ 0.20° and 24.34 ⁇ 0.20°.
  • the application provides the type B crystal of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5, 6, 7 or Eight diffraction peaks: 5.08 ⁇ 0.20°, 6.31 ⁇ 0.20°, 9.78 ⁇ 0.20°, 13.76 ⁇ 0.20°, 15.80 ⁇ 0.20°, 18.96 ⁇ 0.20°, 19.61 ⁇ 0.20° and 24.34 ⁇ 0.20°.
  • the XRPD spectrum of the type B crystal of the compound of formula (I) is shown in FIG. 4 .
  • the differential scanning calorimetry (DSC) spectrum of the Form B crystal of the compound of formula (I) has an onset point of an endothermic peak at 172.9 ⁇ 3°C.
  • the DSC spectrum of the type B crystal of the compound of formula (I) is shown in FIG. 5 .
  • thermogravimetric analysis (TGA) spectrum of the crystal type B of the compound of formula (I) has a weight loss of 5.18% at 150 ⁇ 3°C.
  • the TGA spectrum of the type B crystal of the compound of formula (I) is shown in FIG. 6 .
  • the present application provides a method for preparing type B crystals of the compound of formula (I), the method comprising the following steps: the compound of formula (I) is mixed with DMF and MEK, precipitated and separated to obtain a solid.
  • the above precipitation process is carried out at -20° C. to room temperature.
  • the above method further comprises the step of drying the isolated solid; optionally, drying at room temperature.
  • the application also provides type C crystals of the compound of formula (I), which has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu K ⁇ radiation: 6.21 ⁇ 0.20°, 9.04 ⁇ 0.20° and 12.38 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type C crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 6.21 ⁇ 0.20°, 9.04 ⁇ 0.20°, 11.54 ⁇ 0.20°, 12.38 ⁇ 0.20°, and 23.29 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the type C crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 6.21 ⁇ 0.20°, 9.04 ⁇ 0.20°, 11.54 ⁇ 0.20°, 12.38 ⁇ 0.20°, 16.27 ⁇ 0.20°, 23.29 ⁇ 0.20°, and 25.62 ⁇ 0.20°.
  • the application provides the type C crystal of the compound of formula (I), which contains 3, 4, 5, 6 or 7 crystals selected from the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu K ⁇ radiation. Diffraction peaks: 6.21 ⁇ 0.20°, 9.04 ⁇ 0.20°, 11.54 ⁇ 0.20°, 12.38 ⁇ 0.20°, 16.27 ⁇ 0.20°, 23.29 ⁇ 0.20° and 25.62 ⁇ 0.20°.
  • the XRPD pattern of the type C crystal of the compound of formula (I) is shown in FIG. 7 .
  • the differential scanning calorimetry (DSC) spectrum of the type C crystal of the compound of formula (I) has an onset point of an endothermic peak at 140.2 ⁇ 3°C.
  • the DSC spectrum of the type C crystal of the compound of formula (I) is shown in FIG. 8 .
  • thermogravimetric analysis (TGA) spectrum of the type C crystal of the compound of formula (I) has a weight loss of 3.10% at 130 ⁇ 3°C.
  • the TGA spectrum of the type C crystal of the compound of formula (I) is shown in FIG. 9 .
  • the present application provides a method for preparing type C crystals of the compound of formula (I), the method comprising the following steps: dissolving the compound of formula (I) in ACN, and cooling down to precipitate a solid.
  • a filtration operation is also included; optionally, the filtration is performed using a 0.45 micron PTFE filter head.
  • the above-mentioned cooling refers to cooling from 50° C. to 5° C. at a rate of 0.1° C./minute.
  • the above method further includes the step of isolating the obtained solid and then drying the solid; optionally, drying at room temperature.
  • the application also provides the D-type crystal of the compound of formula (I), which has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu K ⁇ radiation: 7.13 ⁇ 0.20°, 18.22 ⁇ 0.20° and 21.45 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the D-type crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 7.13 ⁇ 0.20°, 10.04 ⁇ 0.20°, 11.24 ⁇ 0.20°, 15.97 ⁇ 0.20°, 18.22 ⁇ 0.20°, and 21.45 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the D-type crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 7.13 ⁇ 0.20°, 10.04 ⁇ 0.20°, 11.24 ⁇ 0.20°, 15.97 ⁇ 0.20°, 16.94 ⁇ 0.20°, 18.22 ⁇ 0.20°, 21.45 ⁇ 0.20°, and 22.71 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the D-type crystal of the compound of formula (I) using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 7.13 ⁇ 0.20°, 10.04 ⁇ 0.20°, 11.24 ⁇ 0.20°, 15.97 ⁇ 0.20°, 16.94 ⁇ 0.20°, 18.22 ⁇ 0.20°, 20.28 ⁇ 0.20°, 21.45 ⁇ 0.20°, 22.71 ⁇ 0.20°, and 26.21 ⁇ 0.20°.
  • the application provides the type D crystal of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, including 3, 4, 5, 6, 7, 8, 9 or 10 diffraction peaks: 7.13 ⁇ 0.20°, 10.04 ⁇ 0.20°, 11.24 ⁇ 0.20°, 15.97 ⁇ 0.20°, 16.94 ⁇ 0.20°, 18.22 ⁇ 0.20°, 20.28 ⁇ 0.20°, 21.45 ⁇ 0.20°, 22.71 ⁇ 0.20° and 26.21 ⁇ 0.20°.
  • the application provides the D-type crystal of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5, 6, 7 or Eight diffraction peaks: 7.13 ⁇ 0.20°, 10.04 ⁇ 0.20°, 11.24 ⁇ 0.20°, 15.97 ⁇ 0.20°, 16.94 ⁇ 0.20°, 18.22 ⁇ 0.20°, 21.45 ⁇ 0.20° and 22.71 ⁇ 0.20°.
  • the XRPD spectrum of the type D crystal of the compound of formula (I) is shown in FIG. 10 .
  • the peak position and relative intensity of the diffraction peaks of the X-ray powder diffraction pattern using Cu K ⁇ radiation are shown in Table 4:
  • thermogravimetric analysis (TGA) spectrum of the type D crystal of the compound of formula (I) has a weight loss of 1.83% at 140 ⁇ 3°C.
  • the TGA spectrum of the D-type crystal of the compound of formula (I) is shown in FIG. 11 .
  • the present application provides a method for preparing type D crystals of the compound of formula (I), the method comprising the following steps: mixing the compound of formula (I) with maleic acid and acetone, and separating the solid.
  • the above method further includes a step of drying the separated solid; optionally, drying at room temperature under vacuum conditions.
  • the present application also provides the phosphate salt of the compound of formula (I).
  • the present application also provides crystals of the phosphate salt of the compound of formula (I).
  • the ratio of the number of molecules of the compound of formula (I) to phosphoric acid is 1: (1-1.5); in some embodiments, the formula ( 1) The ratio of the number of molecules of the compound to phosphoric acid is 1:1.
  • the phosphate salt of the compound of formula (I) is a compound of formula (II),
  • the phosphate of the compound of formula (I) is a crystal of the phosphate of the compound of formula (I).
  • the application also provides crystallization of the phosphate salt of the compound of formula (I), which has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu K ⁇ radiation: 7.87 ⁇ 0.20°, 16.64 ⁇ 0.20° and 20.04 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the phosphate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 6.69 ⁇ 0.20 °, 7.87 ⁇ 0.20 ° , 14.15 ⁇ 0.20°, 16.64 ⁇ 0.20° and 20.04 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the phosphate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 6.69 ⁇ 0.20 °, 7.87 ⁇ 0.20 ° , 14.15 ⁇ 0.20°, 16.64 ⁇ 0.20°, 20.04 ⁇ 0.20°, 21.73 ⁇ 0.20°, 26.17 ⁇ 0.20° and 28.11 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the phosphate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 6.69 ⁇ 0.20 °, 7.87 ⁇ 0.20 ° , 14.15 ⁇ 0.20°, 15.21 ⁇ 0.20°, 16.64 ⁇ 0.20°, 20.04 ⁇ 0.20°, 21.73 ⁇ 0.20°, 22.21 ⁇ 0.20°, 25.07 ⁇ 0.20°, 26.17 ⁇ 0.20°, 26.81 ⁇ 0.20° and 28.11 ⁇ 0.20° .
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the phosphate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 6.69 ⁇ 0.20 °, 7.87 ⁇ 0.20 ° , 14.15 ⁇ 0.20°, 15.21 ⁇ 0.20°, 16.64 ⁇ 0.20°, 20.04 ⁇ 0.20°, 21.73 ⁇ 0.20°, 22.21 ⁇ 0.20°, 23.66 ⁇ 0.20°, 25.07 ⁇ 0.20°, 26.17 ⁇ 0.20°, 26.81 ⁇ 0.20° , 27.50 ⁇ 0.20° and 28.11 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the phosphate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 6.69 ⁇ 0.20 °, 7.87 ⁇ 0.20 ° , 14.15 ⁇ 0.20°, 15.21 ⁇ 0.20°, 16.64 ⁇ 0.20°, 20.04 ⁇ 0.20°, 21.73 ⁇ 0.20°, 22.21 ⁇ 0.20°, 23.66 ⁇ 0.20°, 25.07 ⁇ 0.20°, 25.94 ⁇ 0.20°, 26.17 ⁇ 0.20° , 26.81 ⁇ 0.20°, 27.50 ⁇ 0.20°, 28.11 ⁇ 0.20°, 29.06 ⁇ 0.20° and 29.85 ⁇ 0.20°.
  • the application provides the crystallization of the phosphate salt of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5, 6, 7 selected from the following 2 ⁇ angles. , 8, 9, 10, 11, 12, 13 or 14 diffraction peaks: 6.69 ⁇ 0.20°, 7.87 ⁇ 0.20°, 14.15 ⁇ 0.20°, 15.21 ⁇ 0.20°, 16.64 ⁇ 0.20°, 20.04 ⁇ 0.20°, 21.73 ⁇ 0.20°, 22.21 ⁇ 0.20°, 23.66 ⁇ 0.20°, 25.07 ⁇ 0.20°, 26.17 ⁇ 0.20°, 26.81 ⁇ 0.20°, 27.50 ⁇ 0.20°, and 28.11 ⁇ 0.20°.
  • the application provides the crystallization of the phosphate salt of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5, 6, 7 selected from the following 2 ⁇ angles. Or 8 diffraction peaks: 6.69 ⁇ 0.20°, 7.87 ⁇ 0.20°, 14.15 ⁇ 0.20°, 16.64 ⁇ 0.20°, 20.04 ⁇ 0.20°, 21.73 ⁇ 0.20°, 26.17 ⁇ 0.20° and 28.11 ⁇ 0.20°.
  • the XRPD pattern of the crystallization of the phosphate salt of the compound of formula (I) is shown in FIG. 12 .
  • the peak positions and relative strengths of the diffraction peaks of the X-ray powder diffraction spectrum using Cu K ⁇ radiation are as shown in Table 5 Show:
  • the differential scanning calorimetry (DSC) spectrum of the phosphate salt of the compound of formula (I) has an onset point of an exothermic peak at 141.9 ⁇ 3.0°C.
  • the DSC spectrum of the crystallization of the phosphate salt of the compound of formula (I) is shown in FIG. 13 .
  • the crystalline thermogravimetric analysis (TGA) spectrum of the phosphate salt of the compound of formula (I) has a weight loss of 5.50% at 130 ⁇ 3°C.
  • the TGA spectrum of the crystallization of the phosphate salt of the compound of formula (I) is shown in FIG. 14 .
  • the present application provides a method for preparing phosphate crystals of the compound of formula (I), said method comprising the following steps: mixing the compound of formula (I) with phosphoric acid, EtOH and H 2 O, and separating to obtain a solid.
  • the above preparation method includes stirring under heating after the mixing; optionally, stirring under heating to 40-80°C; optionally, heating to Stirring was carried out at 50°C.
  • the above method further includes a step of drying the isolated solid; optionally drying at room temperature under vacuum.
  • the present application also provides the oxalate salt of the compound of formula (I).
  • the ratio of the number of molecules of the compound of formula (I) to oxalic acid is 1:(1-1.5); in some embodiments, the The ratio of the number of molecules of the compound of formula (I) to oxalic acid is 1:1.1.
  • the oxalate salt of the compound of formula (I) is a compound of formula (III),
  • the oxalate of the compound of formula (I) is a crystal of the oxalate of the compound of formula (I), such as type I crystal of the oxalate of the compound of formula (I) or the formula ( I) Form II crystal of the oxalate salt of the compound.
  • the application also provides type I crystals of the oxalate salt of the compound of formula (I), which has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu K ⁇ radiation: 5.06 ⁇ 0.20°, 12.69 ⁇ 0.20° and 15.21 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the type I crystal of the oxalate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 5.06 ⁇ 0.20°, 12.69 ⁇ 0.20°, 15.21 ⁇ 0.20°, 17.92 ⁇ 0.20°, 20.77 ⁇ 0.20°, and 27.32 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the type I crystal of the oxalate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 5.06 ⁇ 0.20°, 11.28 ⁇ 0.20°, 12.69 ⁇ 0.20°, 15.21 ⁇ 0.20°, 16.48 ⁇ 0.20°, 17.92 ⁇ 0.20°, 19.52 ⁇ 0.20°, 20.77 ⁇ 0.20°, 22.90 ⁇ 0.20°, and 27.32 ⁇ 0.20°.
  • the application provides the type I crystal of the oxalate salt of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5 or Six diffraction peaks: 5.06 ⁇ 0.20°, 12.69 ⁇ 0.20°, 15.21 ⁇ 0.20°, 17.92 ⁇ 0.20°, 20.77 ⁇ 0.20° and 27.32 ⁇ 0.20°.
  • the XRPD pattern of type I crystal of the oxalate salt of the compound of formula (I) is shown in FIG. 15 .
  • the peak positions and relative intensities of the diffraction peaks of the X-ray powder diffraction spectrum using Cu K ⁇ radiation are as follows: Table 6 shows:
  • the DSC spectrum of the type I crystal of the oxalate salt of the compound of formula (I) is shown in FIG. 16 .
  • thermogravimetric analysis (TGA) pattern of the type I crystal of the oxalate salt of the compound of formula (I) has a weight loss of 11.44% at 150 ⁇ 3°C.
  • the TGA spectrum of type I crystal of the oxalate salt of the compound of formula (I) is shown in FIG. 17 .
  • the present application provides a method for preparing type I crystals of the oxalate salt of the compound of formula (I), the method comprising the following steps: mixing the compound of formula (I) with oxalic acid and acetone, and separating the solid.
  • the above preparation method includes stirring under heating after the mixing; optionally, the heating temperature is 40-80°C; optionally, the heating temperature is 50°C.
  • the above method further includes a step of drying the separated solid; optionally, drying at room temperature under vacuum conditions.
  • the application also provides type II crystals of the oxalate salt of the compound of formula (I), which has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern using Cu K ⁇ radiation: 5.44 ⁇ 0.20°, 11.75 ⁇ 0.20° and 13.77 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the type II crystal of the oxalate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 5.44 ⁇ 0.20°, 10.85 ⁇ 0.20°, 11.75 ⁇ 0.20°, 13.77 ⁇ 0.20°, 16.27 ⁇ 0.20°, and 27.42 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the type II crystal of the oxalate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 5.44 ⁇ 0.20°, 10.85 ⁇ 0.20°, 11.75 ⁇ 0.20°, 13.77 ⁇ 0.20°, 16.01 ⁇ 0.20°, 16.27 ⁇ 0.20°, 23.39 ⁇ 0.20°, and 27.42 ⁇ 0.20°.
  • the X-ray powder diffraction pattern using Cu K ⁇ radiation of the type II crystal of the oxalate salt of the compound of formula (I) has diffraction peaks at the following 2 ⁇ angles: 5.44 ⁇ 0.20°, 10.85 ⁇ 0.20°, 11.75 ⁇ 0.20°, 13.77 ⁇ 0.20°, 16.01 ⁇ 0.20°, 16.27 ⁇ 0.20°, 17.85 ⁇ 0.20°, 18.39 ⁇ 0.20°, 20.83 ⁇ 0.20°, 21.75 ⁇ 0.20°, 23.39 ⁇ 0.20°, 25.13 ⁇ 0.20° and 27.42 ⁇ 0.20°.
  • the application provides the type II crystal of the oxalate salt of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 diffraction peaks: 5.44 ⁇ 0.20°, 10.85 ⁇ 0.20°, 11.75 ⁇ 0.20°, 13.77 ⁇ 0.20°, 16.01 ⁇ 0.20°, 16.27 ⁇ 0.20°, 17.85 ⁇ 0.20°, 18.39 ⁇ 0.20°, 20.83 ⁇ 0.20°, 21.75 ⁇ 0.20°, 23.39 ⁇ 0.20°, 25.13 ⁇ 0.20°, and 27.42 ⁇ 0.20°.
  • the application provides the type II crystal of the oxalate salt of the compound of formula (I), which uses Cu K ⁇ radiation in the X-ray powder diffraction pattern, comprising 3, 4, 5, 6, 7 or 8 diffraction peaks: 5.44 ⁇ 0.20°, 10.85 ⁇ 0.20°, 11.75 ⁇ 0.20°, 13.77 ⁇ 0.20°, 16.01 ⁇ 0.20°, 16.27 ⁇ 0.20°, 23.39 ⁇ 0.20° and 27.42 ⁇ 0.20°.
  • the XRPD spectrum of the type II crystal of the oxalate salt of the compound of formula (I) is shown in FIG. 18 .
  • the peak positions and relative intensities of the diffraction peaks of the X-ray powder diffraction spectrum using Cu K ⁇ radiation are as follows: Table 7 shows:
  • Table 7 XRPD data of Form II crystals of the oxalate salt of the compound of formula (I)
  • the DSC spectrum of the type II crystal of the oxalate salt of the compound of formula (I) is shown in FIG. 19 .
  • thermogravimetric analysis (TGA) pattern of the type II crystal of the oxalate salt of the compound of formula (I) has a weight loss of 7.78% at 150 ⁇ 3°C.
  • the TGA spectrum of the type II crystal of the oxalate salt of the compound of formula (I) is shown in FIG. 20 .
  • the present application provides a method for preparing type II crystals of the oxalate salt of the compound of formula (I), the method comprising the following steps: mixing the compound of formula (I) with oxalic acid, EtOH and H 2 O, separating A solid was obtained.
  • the above preparation method includes stirring under heating after the mixing; optionally, stirring at 40-80°C; optionally, stirring at 50°C .
  • the above preparation method further includes a drying step; optionally, drying is performed at room temperature under vacuum conditions.
  • the present application provides a crystal form composition comprising the crystals described in the present application, wherein the crystals account for more than 50% of the weight of the crystal form composition, preferably more than 80%, more preferably more than 90%, Preferably more than 95%.
  • the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the crystal of the compound of formula (I), the salt of the compound of formula (I) or its crystal, or its crystal form combination.
  • the pharmaceutical composition of the present application may or may not contain pharmaceutically acceptable auxiliary materials.
  • the pharmaceutical composition of the present application may further include one or more other therapeutic agents.
  • the present application provides a solid pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of the crystals of the compound of formula (I) described herein, the salt of the compound of formula (I) or its crystals, or its crystalline composition.
  • the present application also provides the crystals of the compound of formula (I), the salt of the compound of formula (I) or its crystals, its crystal form composition, or its pharmaceutical composition in the preparation for treatment or Use in drugs for the prevention of JAK1 and/or JAK2 related diseases.
  • the application also provides the crystals of the compound of formula (I), the salt of the compound of formula (I) or its crystals, its crystal form composition, or its pharmaceutical composition in the treatment or prevention of JAK1 and /or applications in JAK2-associated diseases.
  • the present application also provides the crystals of the compound of formula (I) described in the present application, the salt of the compound of formula (I) or its crystals, and its combination of crystal forms for the treatment or prevention of JAK1 and/or JAK2-related diseases substance, or its pharmaceutical composition.
  • the present application also provides a method for treating or preventing JAK1 and/or JAK2-related diseases, comprising administering a therapeutically effective amount of the compound of formula (I) described in the present application to a mammal (preferably a human) in need of the treatment Crystals, salts of compounds of formula (I) or crystals thereof, crystal composition thereof, or pharmaceutical compositions thereof.
  • the JAK1 and/or JAK2-related diseases are selected from inflammatory disorders (such as arthritis) and the like.
  • the compounds of the present application, their crystals, their salts and the crystals of their salts exhibited good selective inhibition of JAK1 and/or JAK2 in the in vitro activity test of the four Janus kinase subtypes JAK1, JAK2, JAk3 and TYK2;
  • the animal to be tested may have good oral bioavailability, high exposure, good pharmacokinetic properties, and good drug efficacy in vivo.
  • the crystals of the compound of formula (I) of the present application, its salts and the crystals of their salts can exhibit advantages such as stable physical and chemical properties, little influence by light, heat and humidity, good solubility, and less likely to undergo crystal transformation, which is beneficial to drug production.
  • the position of the peak or the relative intensity of the peak may vary due to factors such as measuring instruments, measuring methods/conditions, and the like.
  • the measurement error of the 2 ⁇ value may be ⁇ 0.2°. Therefore, when determining each crystal form, this error should be taken into consideration, and values within the error range also belong to the scope of the present application.
  • the position of the endothermic peak in DSC may vary due to factors such as measuring instruments, measuring methods/conditions, and the like.
  • the error may be ⁇ 5°C, or ⁇ 3°C. Therefore, when determining each crystal form, this error should be taken into consideration, and values within the error range also belong to the scope of the present application.
  • “Pharmaceutically acceptable excipients” refer to the inert substances that are administered together with the active ingredients and are beneficial to the administration of the active ingredients, including but not limited to acceptable drugs for humans or animals approved by the State Food and Drug Administration (such as livestock) any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, Isotonic agent, solvent or emulsifier.
  • Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the crystals described herein or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous Internal administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Therapeutic dosages of the compounds of the present application may depend, for example, on the particular use for the treatment, the mode of administration of the compound, the health and state of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compounds of the present application in the pharmaceutical composition may vary, depending on various factors, including dosage, chemical properties (eg, hydrophobicity) and route of administration.
  • treating means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing a disease or disease state from occurring in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • the term "therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • a therapeutically effective amount of the crystals described herein is from about 0.0001 to 20 mg/Kg body weight/day, such as from 0.001 to 10 mg/Kg body weight/day.
  • the dosage frequency of the crystals described herein is determined by the needs of the individual patient, for example, once or twice a day, or more times a day. Dosing can be intermittent, eg, wherein the patient receives a daily dose of crystals for a period of several days, followed by a period of several or more days in which the patient receives no daily dose of crystals.
  • parameter values should be understood as being modified by the term "about”.
  • the term “about” indicates an error value exists, for example, it means a variation within ⁇ 5%, such as ⁇ 1% or ⁇ 0.1%, of a certain value.
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • TsOH stands for p-toluenesulfonic acid
  • ATP Represents adenosine triphosphate
  • MEK represents methyl ethyl ketone
  • ACN represents acetonitrile
  • Boc represents tert-butoxycarbonyl
  • TBS represents tert-butyldimethylsilyl
  • Et represents ethyl
  • Ts represents p-toluenesulfonyl
  • PE represents petroleum ether
  • EA or EtOAc represents ethyl acetate
  • ADDP represents azodicarbonyl dipiperidine
  • TBAF represents tetrabutylammonium fluoride
  • DCM dichloromethane
  • THF represents tetrahydrofuran
  • Test method About 10-20 mg of sample is used for XRPD detection.
  • Phototube voltage 40kV
  • phototube current 40mA
  • Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N 2 , heat the sample from 25°C to 300°C at a heating rate of 10°C/min.
  • Test method Take a sample (2-5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/min N 2 , heat the sample from room temperature to a weight loss of 20% at a heating rate of 10°C/min.
  • Fig. 1 is the Cu-K ⁇ radiation XRPD spectrum of type A crystal of the compound of formula (I).
  • Fig. 2 is the DSC spectrum of type A crystal of the compound of formula (I).
  • Fig. 3 is the TGA spectrum of type A crystal of the compound of formula (I).
  • Fig. 4 is the Cu-K ⁇ radiation XRPD spectrum of type B crystal of the compound of formula (I).
  • Fig. 5 is a DSC spectrum of type B crystal of the compound of formula (I).
  • Fig. 6 is the TGA spectrum of type B crystal of the compound of formula (I).
  • Fig. 7 is the Cu-K ⁇ radiation XRPD spectrum of type C crystal of the compound of formula (I).
  • Fig. 8 is a DSC spectrum of type C crystal of the compound of formula (I).
  • Fig. 9 is a TGA spectrum of type C crystal of the compound of formula (I).
  • Fig. 10 is the Cu-K ⁇ radiation XRPD spectrum of the type D crystal of the compound of formula (I).
  • Fig. 11 is the TGA spectrum of the D-type crystal of the compound of formula (I).
  • Fig. 12 is the Cu-K ⁇ radiation XRPD spectrum of the crystallization of the phosphate salt of the compound of formula (I).
  • Fig. 13 is a DSC spectrum of the crystallization of the phosphate salt of the compound of formula (I).
  • Fig. 14 is a TGA spectrum of the crystallization of the phosphate salt of the compound of formula (I).
  • Fig. 15 is the Cu-K ⁇ radiation XRPD spectrum of type I crystals of the oxalate salt of the compound of formula (I).
  • Fig. 16 is a DSC spectrum of the type I crystal of the oxalate salt of the compound of formula (I).
  • Fig. 17 is a TGA spectrum of the type I crystal of the oxalate salt of the compound of formula (I).
  • Fig. 18 is the Cu-K ⁇ radiation XRPD spectrum of the oxalate salt type II crystal of the compound of formula (I).
  • Fig. 19 is a DSC spectrum of the type II crystal of the oxalate salt of the compound of formula (I).
  • Fig. 20 is a TGA spectrum of the type II crystal of the oxalate salt of the compound of formula (I).
  • Embodiment 1 the preparation of formula (I) compound
  • Step 1 Under nitrogen protection at -78°C, add n-butyllithium in n-hexyl dropwise to a solution of tert-butyldimethyl(2-propynyloxy)silane (200g, 1174.24mmol) in tetrahydrofuran (2L) alkane solution (2.5M, 427.54mL), and the reaction solution was stirred at -78°C for 30 minutes. Then, a solution of compound 1-1 (250 g, 971.7 mmol) in tetrahydrofuran (2 L) was added dropwise to the reaction solution at -78°C. The reaction solution was reacted at -78°C for 3 hours.
  • Step 2 Add hydrazine hydrate (34.71 g, 1.03 mol, 98%) to a solution of compound 1-2 (400 g, 935.44 mmol) in DMF (3 L) under ice bath. The reaction was carried out at 25°C for 2 hours. LC-MS showed that the reaction was complete, the reaction solution was diluted with water (10L), extracted with EA (2L*2), the combined reaction solution was washed with saturated brine (2L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Compounds 1-3. MS (ESI) 442 [M+H] + .
  • Step 3 NaBH 4 (77.71 g, 2.05 mol) was added in portions to a solution of compound 1-3 (432 g, 978.18 mmol) in THF (3 L) under ice-bath conditions. Afterwards, methanol (0.6 L) was slowly added dropwise, and the reaction solution was stirred at 25° C. for 12 hours. LC-MS showed that the reaction was complete.
  • Step 4 To a solution of compound 1-4 (336 g, 840.84 mmol) in tetrahydrofuran (4 L) was added tributylphosphine (340.24 g, 1.68 mol) under ice-bath conditions. The reaction solution was stirred for 30 minutes under ice-bath conditions, and ADDP (424.31 g, 1.68 mol) was added to the reaction solution. The reaction solution was stirred and reacted at 20° C. for 12 hours. LC-MS showed the reaction was complete.
  • Step 5 To a solution of compound 1-5 (390 g, 1.02 mol) in THF (1 L) was added TBAF (1 M, 1.02 L, 1.02 mol) at room temperature, and the reaction was carried out at 20° C. for 1.5 hours. LC-MS showed the reaction was complete.
  • MS (ESI) 268 [M+H] + MS (ESI) 268 [M+H] + .
  • Step 6 Add manganese dioxide (37.40 g, 430.19 mmol) to a solution of compound 1-6 (11.5 g, 43.02 mmol) in DCM (150 mL) and MeOH (15 mL), replace with nitrogen for 3 times, and then Stir at °C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was filtered and concentrated to obtain compound 1-7. MS (ESI) 266 [M+H] + .
  • Step 8 To a solution of compound 1-8 (11 g, 41.94 mmol) in DCM (150 mL) was added TMSI (10.91 g, 54.52 mmol, 7.42 mL) at 0°C. The reaction solution was stirred at 0°C for 1 hour. TLC showed disappearance of starting material and formation of new spots. The reaction solution was concentrated under reduced pressure to obtain the hydroiodide salt of compound 1-9. MS (ESI) 163 [M+H] + .
  • Step 9 To a solution of compound 1-10 (20g, 131.08mmol, 1eq) in DCM (50mL) was added p-toluenesulfonyl chloride (27.49g, 144.19mmol, 1.1eq), DMAP (1.6g, 13.11 mmol, 0.1eq) and triethylamine (19.9g, 196, 62mmol, 27.37mL), the resulting solution was stirred at 25°C for 16 hours, the reaction was complete, the solvent was removed under reduced pressure, and saturated NaHCO 3 solution (50mL) was added, filtered, The filter cake was washed with water and dried to obtain product 1-11. MS (ESI) 307 [M+H] + .
  • Step 10 To a solution of compound 1-11 (10 g, 32.60 mmol, 1 eq) in DCM (50 mL) was added dropwise tetrabutylammonium nitrate (29.78 g, 97.79 mmol, 3 eq) in dichloromethane ( 50mL) solution, and then slowly dropwise added trifluoroacetic anhydride (20.54g, 97.79mmol, 13.60mL, 3eq).
  • Step 11 Add DIEA (26.73g, 206.82mmol) to a solution of compound 1-9 (12g, 41.36mmol, hydroiodide) and compound 1-12 (11.64g, 33.09mmol) in isopropanol (200mL) ,36.0mL). The reaction liquid was replaced with nitrogen three times, and stirred at 90° C. for 12 hours. LC-MS showed the reaction was complete. The reaction solution was cooled, added H 2 O (200 mL), filtered and dried to obtain compound 1-13. MS (ESI) 478 [M+H] + .
  • Step 12 Add Fe (9.36 g, 167.54 mmol) and NH 4 Cl (12.55 g, 234.56 mmol) to a solution of compound 1-13 (16 g, 33.51 mmol) in THF (200 mL) and H 2 O (50 mL) , replaced with nitrogen three times, and stirred at 100° C. for 1 hour. LCMS showed the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with H 2 O (100 mL), and then extracted with ethyl acetate (150 mL*2). The filter cake was washed with DCM:MeOH (20:1, 100 mL*3). The extract and the washing solution of the filter cake were combined, dried over sodium sulfate, filtered, and concentrated to obtain compound 1-14. MS (ESI) 448 [M+H] + .
  • Step 13 To a solution of compound 1-14 (150 mg, 335.19 ⁇ mol) and TsOH (5.8 mg, 33.52 ⁇ mol) in AcOH (5 mL) was added tetramethylorthocarbonate (456.4 mg, 3.35 mmol). The reaction liquid was replaced with nitrogen three times, and stirred at 50° C. for 2 hours. LCMS showed the reaction was complete. The reaction solution was concentrated to remove the solvent, and H 2 O (5 mL) was added to the obtained concentrate to dilute, and extracted with dichloromethane (5 mL*3). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered and concentrated to obtain compound 1-15. MS (ESI) 488 [M+H] + .
  • Step 14 Compound 1-15 (180 mg, 369.21 ⁇ mol) was dissolved in THF (10 mL), then TBAF (1M, 738.4 ⁇ L) was added. The reaction liquid was replaced with nitrogen three times, and stirred at 70° C. for 12 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated, and the resulting concentrate was diluted with aqueous NaHCO 3 (15 mL), extracted with DCM (15 mL*3), and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain a crude product.
  • JAK2, JAK3 and TYK2 were diluted in a solution prepared as follows: 20 mM 3-(N-morpholine) propanesulfonic acid (MOPS), 1 mM EDTA, 0.01% Brij-35.5% glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/ mL BSA.
  • JAK1 was diluted in a solution prepared as follows: 20 mM TRIS, 0.2 mM EDTA, 0.1% ⁇ -mercaptoethanol, 0.01% Brij-35.5% glycerol.
  • the compound of formula (I) in Example 1 was prepared as a solution in 100% DMSO at a concentration 50 times that of the subsequent assay.
  • the tested compound of formula (I) was serially diluted 3 times to obtain a total of 9 concentrations ranging from 10 ⁇ M to 0.001 ⁇ M, and the content of DMSO in the detection reaction system was 2%.
  • a working stock solution of this compound was added as the first component of the reaction to the corresponding assay well, followed by the addition of the remaining components following the assay protocol detailed below.
  • JAK1(h) was incubated with 20 mM Tris/HCl pH 7.5, 0.2 mM EDTA, 500 ⁇ M MGEEPLYWSFPAKKK (SEQ ID NO: 1), 10 mM magnesium acetate and [ ⁇ - 33P ]-ATP (activity and concentration as required).
  • the reaction was started by adding Mg/ATP mixture and after 40 min incubation at room temperature, the reaction was stopped by adding phosphoric acid at a concentration of 0.5%. Then 10 ⁇ L of the reactant was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried and counted by scintillation.
  • JAK2(h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 ⁇ M KTFCGTPEYLAPEVRREPRILSEEEQEM FRDFDYIADWC (SEQ ID NO: 2), 10 mM magnesium acetate and [ ⁇ - 33P ]-ATP (activity and concentration as required).
  • the reaction was started by adding Mg/ATP mixture and after 40 min incubation at room temperature, the reaction was stopped by adding phosphoric acid at a concentration of 0.5%. Then 10 ⁇ L of the reactant was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried and counted by scintillation.
  • JAK3(h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 ⁇ M GGEEEEYFELVKKKK (SEQ ID NO: 3), 10 mM magnesium acetate and [ ⁇ - 33P ]-ATP (activity and concentration as required).
  • the reaction was started by adding Mg/ATP mixture and after 40 min incubation at room temperature, the reaction was stopped by adding phosphoric acid at a concentration of 0.5%. Then 10 ⁇ L of the reactant was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried and counted by scintillation.
  • TYK2(h) were incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 ⁇ M GGMEDIYFEFMGGKKK (SEQ ID NO: 4), 10 mM magnesium acetate and [ ⁇ - 33P ]-ATP (activity and concentration as required).
  • the reaction was started by adding Mg/ATP mixture and after 40 min incubation at room temperature, the reaction was stopped by adding phosphoric acid at a concentration of 0.5%. Then 10 ⁇ L of the reactant was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried and counted by scintillation.
  • IC 50 results were analyzed using XLFIT5 (formula 205) from IDBS, see Table 8 for details.
  • Example 1 After the compound of formula (I) of Example 1 was dissolved in 5% DMSO and 95% (v:v) of SBE- ⁇ -CD with a mass percent concentration of 12%, the resulting clear solution was injected through the tail vein respectively And intragastrically administered to male SD rats (fasted overnight before administration, 7-8 weeks old). After giving the test compound, at 0.117, 0.333, 1, 2, 4, 7 and 24 hours for intravenous injection group (1mg/kg) rats, for intragastric administration (5mg/kg) rats at 0.25, 0.5, 1 , 2, 4, 8 and 24 hours, blood was collected from the mandibular vein of each rat and centrifuged to obtain plasma.
  • the blood drug concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software.
  • the test results are as follows:
  • AUC 0-inf Area under the plasma concentration-time curve from time 0 to time extrapolated to infinity.
  • the rat collagen-induced arthritis model was used to verify the effect of the compound of formula (I) on treating arthritis.
  • Lewis rats were immunized, and the day of the first immunization was recorded as day 0, and the subsequent days were marked sequentially.
  • 50 microliters of the prepared collagen emulsion (containing 200 micrograms of CII) was subcutaneously injected into the tail (2-3 centimeters from the base of the tail).
  • the same volume of collagen emulsion was subcutaneously injected into the tail by the same method.
  • Lewis rats in the normal group do not need to be immunized.
  • Example 1 On the 27th day of modeling, the animals after modeling were divided into groups, and the corresponding compound of formula (I) in Example 1 was given, and the rats were given different doses (see Table 11 for specific doses) of 0.5% dissolved in water.
  • the body weight of the rats in the treatment group also recovered in a dose-dependent manner, and when the administration ended on the 14th day, the body weight of the rats in the 3mg/kg BID group returned to the normal group. rat level.
  • Mobile phase A 10mmol/L ammonium formate solution (adjust the pH value to 3.5 with formic acid)
  • each sample was set out for complete exposure, and in addition, two (1.2g each) tape Pack the samples, put each sample into a double-layer medicinal low-density polyethylene bag, each layer of medicinal low-density polyethylene bag is buckled and sealed separately, and then put the medicinal low-density polyethylene bag into a package of dry Put it in an aluminum foil bag of the agent and heat seal it.
  • control samples Under the condition of light (total illuminance 1.2 ⁇ 10 6 Lux ⁇ hr/near ultraviolet 200w ⁇ hr/m 2 ), add 2 copies of control samples.
  • the packaging method of the control samples is the same as that of the light samples, but the surface glass is covered with aluminum film.
  • the above samples were sampled and analyzed at 5 days, 10 days and 30 days respectively.
  • the samples placed under the conditions of light (visible light 1200000Lux, ultraviolet 200W) are fully exposed at room temperature.
  • Each of the crystals described in this application can exhibit the following favorable properties under the conditions of light, high temperature, high humidity, and accelerated test: stable physical and chemical properties, stable content of each single impurity and total impurities, basically unchanged moisture content, and no crystallization. Type transformation, and the hygroscopicity of the crystal form is small.

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Abstract

L'invention concerne un cristal d'un composé de formule (I), un sel de celui-ci et un cristal du sel de celui-ci, et l'utilisation de celui-ci dans la préparation d'un médicament pour le traitement ou la prévention de maladies associées à des JAKs.
PCT/CN2022/095126 2021-05-26 2022-05-26 Cristal et sel de composé trihétérocyclique et leur utilisation WO2022247885A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102712640A (zh) * 2010-01-12 2012-10-03 弗·哈夫曼-拉罗切有限公司 三环杂环化合物、其组合物和应用方法
WO2013007765A1 (fr) * 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Composés tricycliques fusionnés utilisés en tant qu'inhibiteurs des janus kinases
WO2020244614A1 (fr) * 2019-06-05 2020-12-10 南京明德新药研发有限公司 Composé de pyrrolopyrimidine et son utilisation
WO2021104488A1 (fr) * 2019-11-27 2021-06-03 正大天晴药业集团股份有限公司 Composé tri-hétérocyclique en tant qu'inhibiteur de jak et son utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102712640A (zh) * 2010-01-12 2012-10-03 弗·哈夫曼-拉罗切有限公司 三环杂环化合物、其组合物和应用方法
WO2013007765A1 (fr) * 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Composés tricycliques fusionnés utilisés en tant qu'inhibiteurs des janus kinases
WO2020244614A1 (fr) * 2019-06-05 2020-12-10 南京明德新药研发有限公司 Composé de pyrrolopyrimidine et son utilisation
WO2021104488A1 (fr) * 2019-11-27 2021-06-03 正大天晴药业集团股份有限公司 Composé tri-hétérocyclique en tant qu'inhibiteur de jak et son utilisation

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